摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) Dr J. R. Hanson Dr R. B. Herbert Professor J. Mann Professor D. J. Robins Dr C. J. Schofield Dr D. A. Whiting Editorial Staff Dr Sheila R. Buxton Ma nag in g Editor Miss Nicole Brooks Deputy Editor Miss Nicola P. Coward Production Editor Dr Anthony P. Breen Mr Michael J. Francis Technical Editors Miss Daphne E. Houston Miss Karen L. White Editorial Secretaries University of Bristol University of Sussex University of Leeds University of Reading University of Glasgow U n iversity of Oxford University of Nottingham Editorial Office The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF Telephone +44 (0)1223 420066 Facsimile +44 (0) 1223 420247 E-mail rscl@rsc.org RSC Server http://c hem ist ry.rsc.org/rsc/ Natural Product Reports is a bimonthly journal of critical reviews.It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis biological activity and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. This is augmented by frequent reviews of the wider context of bioorganic chemistry including developments in enzymology nucleic acids genetics chemical ecology primary and secondary metabolism and isolation and analytical techniques which will be of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. 1996 Annual Subscription Price EEA €325.00 USA $615.00 Rest of World f333.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. UK SG6 IHN. Air Freight and mailing in the USA by Publications Expediting Service Inc.200 Meacham Avenue Elmont NY 11003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Periodicals postage paid at Jamaica NY 11431-9998.All other despatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the UK. Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. ~ ~~ 0 The Royal Society of Chemistry 1996 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1996 EEA f325.00 USA $615.00 Rest of World f333.00

ISSN:0265-0568    

DOI:10.1039/NP99613FX013

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99613BX015

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Dietary Antioxidants in Disease Prevention Michael H. Gordon Department of Food Science & Technology The University of Reading Whiteknights PO Box 226 Reading RG6 6AP UK 1 Introduction 2 Mechanism of Lipid Oxidation 2.1 Oxyl Radicals 3 Antioxidant Defences 4 Mechanism of Atherogenesis 5 Antioxidants in the Prevention of Coronary Heart Disease 5.1 Vitamin E 5.2 Ubiquinol- 10 5.3 Carotenoids 5.4 Other Aspects of Fat-soluble Antioxidants 5.5 Vitamin C 5.6 Flavonoids 6 Epidemiological Evidence for the Effects of Dietary Antioxidants in the Prevention of Specific Cancers 7 Mechanistic Aspects of the Effects of Antioxidants on Cancer Development 8 Flavonoids as Anticancer Agents 9 References 1 Introduction Autoxidation which is an autocatalytic free radical reaction leading to the ageing of rubber and the development of off-flavours in edible oils and fats has been studied by Chemists and Food Scientists for many years.However in recent years the role of free radicals and reactive oxygen species in human disease processes including cancer atherosclerosis rheumatoid arthritis inflammatory bowel disease immune system decline brain dysfunction cataracts and malaria has become apparent.l This has led to considerable research on the possible con- tribution of dietary antioxidants to disease prevention since antioxidants are able to remove or prevent the formation of free radicals and reactive oxygen species and prevent oxidative deterioration in vitro.Although the generation of reactive oxygen species is an essential defence mechanism in some instances in excessive concentrations or in the wrong location it can cause tissue degeneration and other harmful effects. Examples of beneficial effects of active oxygen species include the production of 02*-as well as hydrogen peroxide and hypochlorous acid by activated phagocytic cells (including monocytes neutrophils eosinophils and most types of macrophages) in order to kill some of the bacterial strains that they engulf. The production of small amounts of 02*-by the vascular endothelium may allow the regulation of vascular tone by reaction with nitric oxide which acts as an endothelium derived relaxing factor. 2 Mechanism of Lipid Oxidation Lipids in biological systems comprise triacylglycerols phospho- lipids diacylglycerols sterols steryl esters cholesterol toco- pherols and other lipids.In storage tissues triacylglycerols are the major lipid species but in membranes phospholipids are the main components. During the oxidation of lipids an induction period or lag phase is observed during which oxidation of the lipids is slow and antioxidants are consumed. The induction period is sensitive to the presence of antioxidants such as tocopherols prooxidants such as transition metal ions and the Initiation X' + RIH -+ XH + R'' R'OOH -+ R'O' + HO' 2 R'OOH + RIO+ H,O + R'00' Propagation R" + 0 -,R'00' R'OO' + R2H-+ R'OOH + R2. Termination R'OO' + R200' + R'OOR' + 0 R'O' + R2' + R10R2 Figure 1 Mechanism of lipid oxidation (X' is an initiating radical; RIH and R2Hare lipid molecules).In the presence of metal ions e.g. Fe2+ and Cu2+,radical formation also proceeds by other reactions (see Equations 1 2 6 and 7) structure of the fatty acyl components of the lipids with polyunsaturated fatty acyl groups being oxidised much faster than monounsaturated fatty acyl moieties. Hydroperoxides (ROOH) accumulate during the induction period and hydro- peroxide decomposition products including aldehydes ketones and hydrocarbons are produced rapidly after the end of the induction period. The characteristics of this reaction have been extensively studied and the mechanism for lipid deterioration is established to be that shown in Figure 1.2.1 Oxyl Radicals The oxyl radicals produced by hydroperoxide decomposition and physiological processes include the hydroxyl radical (HO') alkoxyl radical (RO') superoxide anion (02*-) and peroxyl radicals (ROO'). The hydroxyl radical is the most reactive radical in biological tissues and is believed to have significance as an initiator for peroxidation of lipids. The high reactivity of the radical has the consequence that it is unselective in its reactions which occur within a short range of the site of generation. Rate constants for reaction of hydroxyl radicals with fatty acids a-tocopherol and ascorbate are in the range of 109-1010 M-l s-~.~ Alkoxyl radicals are 2 to 3 orders of magnitude less reactive than hydroxyl radicals and consequently are more selective.However they decay relatively rapidly by /3-scission with a rate constant of 106-10' s-l and this limits their potential for damage to membranes and biological tissues. Peroxyl radicals are much less reactive and hence act more selectively over a larger distance. Rate constants of 0.1-1 ca. 60 ca. 120 and ca. 180 M-l s-l have been quoted for reaction of peroxyl radicals with oleic acid 1 linoleic acid 2 linolenic acid 3 and arachidonic acid 4 respectively and this compares with rate constants of 5.7 x lo6 and 2.2 x lo6 M-l s-l for reaction with a-tocopherol 5 and ascorbate 6 re~pectively.~ i,C -OOH 1 oleic acid kC -OOH 2 linoleic acid 265 j - C - O- O H 3 a-linolenic acid c C- - O - O- H 4 arachidonic acid 5 a-tocopherol (vitamin E) 0 OH 6 ascorbic acid (vitamin C) Superoxide radicals are unreactive towards fatty acids but can be quenched by a-tocopherol and ascorbate with rate constants of ca.lo4 and 5.0 x lo4 M-l s-l . However super- oxide radicals do become more reactive if they are protonated to form HOO' (pK = 4.75). The charge on the superoxide radical also reduces its ability to pass into biological mem- branes. The decomposition of hydroperoxides is sensitive to traces of metal ions such as iron or copper and this represents a low- energy initiation reaction (Equation 1) Fe2++ROOH eFe3++RO' +OH-(1) Fe3++ROOH S Fe2++ROO' +H+ (2) The oxidised metal can be reduced back to the initial valence state by enzymes or the hydroperoxide may be involved (Equation 2) but the latter reaction is very slow compared to Equation 1.5 Allylic alkyl radicals which are produced during the propagation stage are reducing agents and can also reduce the metal back to its lower valence state (Equation 3).Chelating agents such as citric acid have a dramatic effect on increasing the induction period because they chelate prooxidant metal ions. In vivo there are four likely sources of oxidants and oxyl radicals in ce1ls.l These are mitochondria which produce the superoxide radical and hydrogen peroxide during normal respiration by the leakage of electrons from electron carriers phagocytes which produce nitric oxide and hypochlorite as well as superoxide and hydrogen peroxide during the 'respiratory burst ' peroxisomes (microbodies) which degrade fatty acids and other substances to give hydrogen peroxide cytochrome P-450 enzymes which are responsible for many oxidation reactions of endogenous substrates (e.g.nitric oxide and production of steroid hormones) and exogenous foreign substrates (detoxification) Although 0,'-is relatively unreactive it is a precursor of more active oxygen species. Superoxide dismutase (SOD EC 1.15.1.1) removes 02*-by converting it into hydrogen peroxide and oxygen (Equation 4).6 20,'-+2H+-+H,O,+O (4) The H,O formed is not able to react directly with an NATURAL PRODUCT REPORTS 1996 unsaturated lipid but since it is not charged it can move around in the biological surroundings.In the presence of Fe2+ which can be generated from Fe3+ by 02*-(Equation 5) hydrogen peroxide can be reduced to the highly active hydroxyl radical (OH') by the Fenton reaction (Equation 6). 0,'-+Fe3+-+ 0,+Fe2+ (5) H,O +Fe2+-+ HO' +Fe3++OH-(6) Haemoglobin and myoglobin are normally contained within erythrocytes and myocytes where they are involved in the transport and storage of oxygen respectively. However rupture of these cells can allow the exposure of these proteins to oxidants which cause destabilisation and release of ir~n.~-~ Abstraction of H' from the porphyrin ring of haem proteins such as haemoglobin or myoglobin by peroxides induces their activation to iron-oxo species such as ferry1 (FeIV) radicals (Equation 7) or perferryl (Fe'*) radicals which are more selective than the hydroxyl radical but are capable of inducing oxidative damage to cell and membrane comp~nents.~-l~ (HX-Fe" represents the haem protein).HX-Fe" +H,O -+ 'X-[Fe"'=O] +H,O (7) Excess peroxide can also cause fragmentation of the tetrapyrrole rings allowing the release of chelatable iron.'' l3 3 Antioxidant Defences Cells have a wide array of defences against oxidative damage. These can prevent damage due to free radical reactions by several mechanisms including (a) prevention of radical formation (b) removal of radicals before damage to key lipids proteins nucleic acids etc. can occur (c) repair of oxidative damage (d) elimination of damaged molecules (e) prevention of mutations due to damaged molecules Within cells superoxide dismutases actively promote the dismutation of superoxide into hydrogen peroxide and oxygen (Equation 4).The hydrogen peroxide formed is removed by the enzymes catalase (EC 1 .11-1.6) and glutathione peroxidase (EC 1 .1 1 .1 .9) as shown in Equations 8 and 9. A small pool of available iron is present in the cell for the synthesis of both DNA and iron-containing proteins and consequently efficient removal of hydrogen peroxide is essential to avoid generation of hydroxyl radicals by the Fenton reaction (Equation 6). catalase 2 H,O,-0,+2 H,O H,O +2 GSH glutathione peroxidase * GSSG +2 H,O (9) In extracellular fluids the binding of copper and iron by proteins is the major strategy for protection against radical generation.Transferrin is the iron transport protein and is very effective at binding ferric ions. It is normally only one third loaded with iron and is an effective antioxidant for iron catalysed reactions since it will not participate in radical reactions.14.l5 Lactoferrin like transferrin binds two moles of iron per mole of protein and is similarly effective as an anti0~idant.l~ Since haemoglobin and haem are prooxidants haptoglobins which bind haemoglobin and haemopexin which binds haem also contribute to the antioxidant defences. Caeruloplasmin is the major copper transport protein and binds copper ions to make them unavailable as prooxidants. Caeruloplasmin also removes reactive oxygen species including 0 and H,0,.16- l7 Extracellular superoxide dismutase activity is low and the low levels of glutathione present in plasma limit glutathione peroxidase activity.Small molecule radical scavengers including NATURAL PRODUCT REPORTS 1996M. H. GORDON HOOC COOH 7 bilirubin OH I 8 uric acid bilirubin 7 urate 8 glucose and ascorbic acid 6 also play a role in stabilising plasma. Fat-soluble antioxidants including vit- amin E carotenoids retinyl stearate and coenzyme Q play a major role as antioxidants in membranes and lipoproteins as discussed below. 4 Mechanism of Atherogenesis Coronary heart disease (CHD) is the principal cause of premature death in the Western world. Dietary saturated fat is an important risk factor due to its cholesterol-raising effect but this effect together with that of other classical risk factors is insufficient to explain fully the risk of CHD in individuals.l8 There has been much interest in recent years in the possible effect of antioxidants in retarding oxidative modification of low density lipoproteins (LDL) which is believed to lead to atherosclerosis (the narrowing of arteries by lipid deposition on the inner arterial walls).19 2o LDL is formed from very low density lipoprotein (VLDL) which is synthesized in the liver and contains large quantities of triacylglycerols from the diet cholesterol from the diet or from synthesis in the liver and genetically determined proteins mainly apoproteins B100 C and E.Once in the systemic circulation the triacylglycerol content of VLDL is reduced by lipolysis which liberates fatty acids as an energy source especially for muscle and as a precursor for adipose tissue triacylglycerol stores. The bulk of the triacylglycerols are removed from VLDL and these particles disintegrate leaving LDL. LDL are lipid rich particles with an average relative molecular mass of about 2.5 million. They contain a central core of about 1600 cholesteryl ester molecules and 200 molecules of triacyl- glycerols. The core is surrounded by a monolayer shell of 700 phospholipids and 600 free cholesterol molecules. The outer monolayer carries the protein which is mainly apo BlOO (25 % by weight). The cellular uptake of LDL is largely mediated by a high affinity cell surface receptor a process first recognised by Brown and Goldstein.21 This LDL receptor present on many cells recognises apo BlOO and apo E in the LDL and cellular uptake of LDL occurs followed by digestion by lysosomes (vesicles containing hydrolytic enzymes).Cholesterol and triacylglycerols are thus made available to cells.22 The lipids in the LDL include esterified polyunsaturated fatty acids mainly linoleic acid 2 (18 :2 n-6),* arachidonic acid (20 :4 n-6) 4 and docosahexaenoic acid (22 :6 n-3) which are sensitive to oxidation. Oxidised LDL has been isolated from plasma and has increased mobility during electrophoresis compared to normal LDL.23 When LDL becomes oxidised the * Fatty acid structures are indicated as (number of C atoms number of C =C double bonds n-x) where x is the number of C atoms from the methyl end of the molecule to the first double bond.structure of apolipoprotein B becomes modified and no longer binds to the LDL receptor but instead it binds to the receptor present on the surface of macrophages which act as scavengers. Oxidised LDL is taken up in an uncontrolled manner and this leads to the formation of foam cells which contain droplets of cholesterol and cholesteryl esters and possibly lipid oxidation products. Foam cells are characteristic of early atherosclerotic lesions. As the disease progresses most of the foam cells die and deposit their lipid material extracellularly. Cytotoxic and atherogenic effects have been demonstrated for several cholesterol oxidation products which may be formed under mildly oxidative conditions including cholest-5-ene- 3P,7P-diol 9 3P-hydroxycholest-4-en-6-one10 3P-hydroxy-cholest-5-en-7-one 11 5a-cholestan-3~,5a,6~-triol 12 5,6-epoxy-5a-cholestan- 3p-01 13 and 5,6-epoxy- 5p-choles tan-3P-01 14.2426The accumulation of cytotoxic products from oxidised LDL on the arterial wall leads to damage of the endothelial layer and provokes harmful effects including platelet aggre- gation release of growth factors disturbance of eicosanoid homeostasis and immigration of inflammatory cells.Oxidised 9 cholest-5-ene-3P,7P-diol *-..A HOW 0 10 3~-hydroxycholest-4-en-6-one HO-‘0 11 3P-hydroxycholest-5-en-7-one HO OH 12 Sa-cholestan-3~,Sa,G~-triol -..A HOW 0 13 5,6-epoxy-5a-cholestan-3~-ol 14 5,6-epoxy-5P-cholestan-3P-ol LDL inhibits the relaxation of smooth muscle cells by nitric oxide which acts as an endothelial derived relaxing factor and promotes formation of autoantibodies.Human LDL is defined as those lipoproteins that can be isolated from plasma by ultracentrifugation within a density range of 1.019-1.063 g ml-l. Within this group subgroups varying in size relative molecular mass density and com-position have been identified. Small dense LDL has been shown to be significantly more susceptible to oxidation and is associated with increased risk of myocardial infarction (death of heart muscle cells due to lack of oxygen) and coronary artery disease.279 28 5 Antioxidants in the Prevention of Coronary Heart Disease Vitamin E (a-tocopherol 5) is the main antioxidant present in LDL but several other antioxidants within LDL (e.g.caro-tenoids Table l) or in the aqueous phase (e.g. ascorbic acid vitamin C 6)also contribute to LDL stability. The effectiveness of antioxidants in inhibiting oxidation of LDL depends on several factors including (a) the rate constant for reaction with a radical (b) the rate constant for propagation of the chain reaction by the antioxidant-derived radical (c) the site of generation of the initiating radical (d) the site of the antioxidant (e) the concentration of the antioxidant (f) interactions with other antioxidants 5.1 Vitamin E Epidemiological studies dietary supplementation and in vitro studies have been used to investigate the effects of dietary antioxidants on coronary heart disease.Epidemiological studies either involve large surveys in which information is obtained by questionnaires or small studies in which plasma or tissue antioxidant levels as well as measures of other risk factors are analysed. 5 a-tocopherol (vitamin E) Several studies have shown the beneficial effect of dietary or high serum vitamin E 5 on CHD.29-33 On the other hand three other studies have failed to show a clear association between serum vitamin E and CHD m~rtality.~~-~~ A recent study has shown that the mortality rate due to CHD was 17 YOlower in the northernmost area of Finland than in the south of Finland.37 Despite the higher levels of plasma cholesterol and LDL cholesterol higher serum levels of vitamin E due to con-sumption of reindeer meat and selenium due to fish con-sumption were considered significant contributors to the lower mortality rate from CHD.Selenium is significant because it is an integral part of glutathione peroxidase. In vitro LDL oxidation can be divided into a lag phase during which there is minimal formation of oxidised lipids a propagation phase during which the content of hydroperoxides increases rapidly and a decomposition phase during which the level of hydroperoxides declines due to decomposition or further reaction of the hydroperoxides. The length of the lag phase is dependent on the level of antioxidants present.The antioxidants present in a typical LDL particle are shown in Table 1. a-Tocopherol is the major antioxidant present and the level of this component varies widely between individuals with values in the range 2.9-15.7 mol tocopherol per rnol LDL being NATURAL PRODUCT REPORTS 1996 Table 1 Antioxidants in native LDL59 nmol per mg Antioxidant LDL protein mol per mol LDL a-tocopherol 5 y-tocopherol 16 p-carotene 17 lycopene 23 y-carotene 11.58 0.93 0.53 0.29 0.22 6.37 0.51 0.29 0.12 0.16 crypt oxanthin 0.25 0.14 canthaxanthin 20 0.04 0.02 lutein +zeaxanthin 22 0.07 0.04 phytofluene 24 ubiquinol- 10 15 0.09 0.18 0.05 0.10 Total antioxidants 14.2 7.8 Enrichment of plasma from a single donor with a-tocopherol followed by isolation of the LDL leads to an increase in the lag phase of LDL oxidation in linear proportion to the tocopherol concentrati~n.~~ Oral supplementation with a-tocopherol leads to an increase in plasma and LDL tocopherol and the oxidation resistance of the LDL from a single donor increases with a-tocopherol content or with the total LDL antioxidants.Supplementation with 100 IU* of vitamin E per day was found to reduce coronary artery lesion progression in men with previous coronary bypass graft surgery.4o Other studies have found that higher levels of vitamin E intake were required to increase the oxidative stability of LDL from healthy adult~.~l-~~ These intake levels are much higher than the current recom- mended dietary allowance values of vitamin E which are 10 and 8 IU per day for men and women respectively in the USA.There is a wide variation between individuals in the magnitude of the increase in oxidative stability with tocopherol content. When the increase in lag time with tocopherol content in an in vitro study was expressed as a linear equation the coefficient varied from 0.7 to 17 and the independent variable from 68.6 to 108.6.38 This strong variation between individuals has been confirmed by in vivo studies involving vitamin E supplementation.44 Vitamin E may also reduce the risk of coronary heart disease by other mechanisms. The vitamin may prevent progression of a fatty streak and cell proliferation to an advanced lesion by modulation of platelet adherence and aggregati~n.~~ Vitamin E regulates platelet aggregation by inhibiting platelet cyclooxy- genase (EC 1 .14.99.1) activity and this decreases thromboxane prod~ction.~~ 5.2 Ubiquinol-10 Ubiquinol-10 15 is the reduced form of coenzyme Q which is a lipid-soluble electron-carrying coenzyme that participates in the transport of electrons from organic substrates to oxygen in the respiratory chain of mitochondria.It is depleted before a-tocopherol during the in vitro oxidation of LDL initiated by a water-soluble radical generator 2,2’-azobis(2-amidinopropane) a lipid-soluble radical generator 2,2’-azobis(2,4-dimethylvalero-nitrile)47 and copper Me Me0 15 ubiquinol-10 The lag time for oxidation of LDL correlated with ubiquinol- 10 and a-tocopherol content which together accounted for 80% of the total variation in lag times for oxidation initiated * 1 International Unit (IU) of vitamin E is provided by 1 mg of a-tocopherol or a larger mass of other tocopherol homologues.NATURAL PRODUCT REPORTS 1996-M. H. GORDON I 16 y-tocopherol by copper Other studies on Cu2+ catalysed oxidation of LDL found that a-tocopherol was consumed before y- tocopherol 16 and carotenoids and that rapid LDL oxidation only occurred after consumption of all these antioxidant^.^^ 50 5.3 Carotenoids Epidemiological studies have produced evidence that dietary carotenoids are inversely related to heart disease and stroke5’ 52 and that concentrations of plasma ,&carotene 17 are inversely related to the risk of angina.53 17 p-carotene The Lipid Research Clinics Coronary Primary Prevention Trial found that in men with type 11-a hyperlipidaemia subjects with serum carotenoid levels in the highest quartile had a 36 YO lower adjusted relative risk than subjects in the lowest quartile.For men who never smoked the adjusted relative risk of coronary heart disease was 72% lower for subjects in the highest quartile of serum carotenoid levels than for those in the lowest quartile. Daily supplementation with 20 mg ,&carotene was found to reduce the output of pentane in the breath of smokers but no significant reduction in the breath pentane output was observed for non-~mokers.~~ Pentane is one of the products from oxidation of fatty acids in the n-6 series and consequently is a measure of lipid oxidation in vivo.p-Carotene acts as an antioxidant in vitro at low oxygen concentrations by forming a stabilized radical after addition of a peroxyl The formation of 5,6-epoxy-P,/?-carotene 18 and 15,15’-epoxy-/3,/?-carotene19 from the reaction of p-carotene with peroxyl radicals supports this mechanism.56* 57 Other carotenoids that occur in LDL would also appear to be able to act by this mechanism. Canthaxanthin 20 and astaxanthin 21 which possess 0x0 groups retarded hydro- peroxide formation more efficiently than ,&carotene and zeaxanthin 22 in an in vitro study.58 18 5,6-epoxy-P,P-carotene 19 15,15’-epoxy-P,~carotene 0 20 canthaxanthin HO 0 21 astaxanthin HO 22 zeaxanthin Whereas ,&carotene and other hydrocarbons are located in the core of the LDL carotenoids containing polar groups may be closer to the membrane.In LDL antioxidants are consumed in the order a-tocopherol 5 y-tocopherol 16 lycopene 23 phytofluene 24 and p-carotene 17.59 23 lycopene 24 phytofluene 5.4 Other Aspects of Fat-soluble Antioxidants Although y-tocopherol16 is an important antioxidant in edible oils.6o occurring in a wide range of raw materials including soybean oil and corn oil a discrimination mechanism in the liver favours secretion of a-tocopherol into the plasma and this causes the level of y-tocopherol in LDL to be low.61 y- Tocopherol in the plasma is reduced by oral supplementation with a-tocopherol.44 a-Tocopherol occurs in the membrane of LDL and its location close to the polyunsaturated fatty acyl chains of the LDL phospholipids is crucial for its antioxidant activity.In vitro studies show that the a-tocopherol molecules of LDL undergo a relatively rapid intermolecular exchange as well as exchange with other lipoproteins (VLDL HDL) and blood cells. The estimated half lives for the spontaneous a-tocopherol transfer between LDL molecules are in the range 20-70 minutes which is about 2-3 times slower than cholesterol transfer. On the other hand the spontaneous exchange (in vitro) of /?-carotene which occurs in the core of the LDL is very slow and no equilibration occurs within 18 h.62 5.5. Vitamin C Seven epidemiological studies performed in the USA Japan and Finland have been reviewed by Trout.63 These studies showed a significant negative correlation between vitamin C 0 OH 6 ascorbic acid (vitamin C) intake or plasma vitamin C levels and both diastolic and systolic blood pressure.Possible explanations for this effect may be a role for vitamin C in enhancing prostaglandin production or decreasing norepinephrine production or serum However it has not been shown conclusively that this effect is due to the vitamin C since foods rich in vitamin C are also rich in potassium which has been reported as causing reductions in blood pressure.,j Other epidemiological studies have investigated the effect of vitamin C on CHD mortality.Some studies have shown that vitamin C intake is inversely related to the standardised mortality ratio6j but other studies have found no effect of vitamin C intakes from diet or supplements on cardiovascular risk.” 67 Dietary supplementation with vitamin C has been shown to inhibit in vitro oxidation of lipoproteins.6s Ascorbate appears to be the most important non-protein antioxidant in plasma. The sequence of antioxidant depletion in human blood plasma exposed to aqueous peroxyl radicals was shown to be ascorbate = protein thiols > bilirubin > urate > a-toc~pherol.~~ Lipid hydroperoxides could only be detected after the ascorbate was consumed. Although protein thiols were consumed at a similar rate to ascorbate they were inefficient radical scavengers and were consumed by autoxidation.In vitro studies have indicated that ascorbate may also function synergistically with a-tocopherol by regenerating the latter from tocopheroxyl radical~.~O-’~ Regeneration of toc- opherol may also involve enzymatic red~ction.~ The recycling of vitamin E in this way allows it to act efficiently despite being present at low levels in membranes and LDL. 5.6 Flavonoids During the 1960s and 1970s Robbins found that citrus flavonoids may reduce aggregation of blood platelets and hence may have an effect on coronary thrornbosi~.~~ Epidemiological studies indicate that there is a low incidence of CHD in some French cities despite a high intake of dairy fat which has been termed the ‘French paradox’.This has been explained by the consumption of wine in the French diet.78 79 This may be due to the antioxidant effect of flavonoids in the wine.8o The Zutphen Elderly Study was another epidemiological study that indicated that the dietary intake of flavonoids by elderly men correlated with reduced CHD mortality.a1 Relative risks of mortality from CHD and incidence of a first fatal or nonfatal myocardial infarction were about 50% lower in the highest tertile of flavonoid intake (> 29.9 mg d-l) than in the lowest tertile (< 19 mg d-l). The consumption of the flavonols quercetin 25 myricetin 26 kaempferol 27 and the flavones luteolin 28 and apigenin 29 was implicated in the reduction of CHD. The main foods supplying these components were tea onions and apples.The relationship persisted despite adjust- ments for dietary variables and non-dietary risk factors. OH ?H 25 quercetin 26 myricetin OH 27 kaempferol 28 luteolin NATURAL PRODUCT REPORTS 1996 OH 0 29 apigenin Flavonoids present in wine have been shown to inhibit the oxidation of LDL in vitro.80Resveratrol30 another phenolic in wine,H2 has also been shown to inhibit the oxidation of LDL.s3 However there is no evidence for the occurrence of flavonoids or resveratrol in LDL and a more likely mechanism for their effects on CHD would be the inhibition of eicosanoid synthesis a key step in platelet aggregation by their action on cyclooxygenase or lipoxygena~e.~~-~~ Ho\ HO 30 resveratrol 6 Epidemiological Evidence for the Effects of Dietary Antioxidants in the Prevention of Specific Cancers The protective effects of fruits and vegetables against stomach cancer are well established.@ However evidence linking specific nutrients to a protective effect against specific cancers is less well established.Newberne and Locniskara9 identified the following micronutrients as being associated with cancer risk methionine cys teine tryptophan arginine riboflavin folic acid vitamin B, vitamins A C D and E choline /I-carotene calcium zinc copper iron and selenium. Other dietary variables that affect the risk of cancer include added fibre; fat; a variety of carotenoids ;flavonoids ; food contaminants like pesticides aflatoxins and nitrates ;and substances that affect cytochrome P-450 enzymes.so This complexity makes the confident in- terpretation of epidemiological data extremely difficult.Byers and Perry have published a useful review of the epidemiological evidence for the effects of dietary carotenes vitamin C and vitamin E as protective antioxidants in human cancers.9o Epidemiological findings suggest that higher intakes of vitamin E and other dietary antioxidants may decrease the risk for certain cancers.91 The most consistent associations have been reported for cancers of the lung oesophagus and colorectum. Dietary /I-carotene is associated with decreased risk for several types of cancer including lung cancer particularly squamous cell cancer and cervical cancer.92 About 16 studies have shown that a low dietary intake of ,&carotene is associated with an increased risk of lung In the case of vitamin C evidence indicating that this vitamin may help to protect against cancer of the oesophagus and stomach cancer is more convincing than that suggesting protection against pancreatic cancer colon and rectal cancer breast cancer and prostate ovarian uterine bladder and lung cancer.However there have been few intervention studies with human subjects and further research is required before conclusions can be drawn.65 7 Mechanistic Aspects of the Effects of Antioxidants on Cancer Development Carcinogenesis progresses by a number of steps that eventually lead to the uncontrolled growth of a normally quiescent cell (Figure 2).1293 13* At least three stages corresponding to NATURAL PRODUCT REPORTS 1996-M.H. GORDON 27 1 (electrophile) DNA chemopreventative mechanisms intercept carcinogen 3(covalent RNA or protein adducts) DNA-carcinogen adducts I t--l:::::I I stimulate DNA repair I I initiated cell slow down promotion (antioxidant or antiinflammatory effect or blocking of promoters) I pre-neoplastic cell I I neoplastic (cancer) cell Figure 2 Mechanism of carcinogenesis (based on references 129 130) a malignant lymphoma was rapidly killed by ascorbic acid. lo' However cases where vitamin C enhances growth of cancer cells have also been reported.108-109 Studies of this type have been re~iewed.~~'~~ Vitamin E inhibits mutagenesis and cell transformation mainly through its antioxidant function eliminating oxygen free radicals and decreasing DNA damage.Experiments with mice have shown that supplementation with vitamin E suppresses the promotion by ethanol of chemically-induced oesophageal cancer."O It is believed that vitamin E has an effect due to the quenching of radicals generated from ethanol during oxidation in microsomes. Besides prevention of the formation of carcinogens antioxi- dants may also scavenge carcinogenic electrophiles or induce phase I1 enzymes that speed carcinogen removal. Epigallo- catechin gallate 31 which is one of the antioxidants in green tea has been shown to accelerate the disappearance of benzo[a]pyrene diol2-epoxide which is mutagenic and carcino- genic.l" ?H HO-@yo OH OH OH 0 'OH 31 epigallocatechin gallate Antioxidants may also act at later stages in carcinogenesis by their effect on enzymes that relate to cellular DNA repair or cell proliferation.ll* They may also enhance the activity of individual immune systems such as natural killer cells and reduce reactive oxygen species produced by inflammatory cells.' l3 Carotenoids may act directly as antioxidants but they may also function by being metabolised to retinoids or apocaro- tenoids which may either enhance or inhibit the effects of retinoic acid 32.Retinoic acid blocks promotion and pro- initiation promotion and progression can be disting~ished.~~ liferation and induces differentiation and cellular adhesion.It An initial insult to the genetic material may be caused by a chemical mutagen or may be inherited or viral in origin. Activation of the pre-carcinogen occurs to produce a physio- logical state that signals reading of the altered DNA. Where the altered message leads to a repetitive cycle of cellular division the cell is cancerous. Dietary antioxidants may act at several stages during carcinogenesis. Initially they may inhibit the formation of carcinogens from precursor substances. Thus vitamins C and E may react with nitrite to reduce the nitrosation of secondary amines to nitrosamines in Also phenolics from green tea have been shown to prevent the formation of nitrosamines both in vitro and in vi~o.~~~-'~' Green tea also inhibits nitrosamine-induced formation of lesions and papillomas in the oesophageal mucosa of the rat.lo2 Liehr found that vitamin C reduced the incidence of estradiol- or diethylstilbestrol-induced kidney tumours in male African hamsters by 50 %.lo3 It was suggested that the carcinogenicity of estrogens was due to their oxidation to quinones and the protective effect was ascribed to the reduction of quinones to unreactive hydroquinones.Other studies have also shown that vitamin C has an antiestrogenic effect in animals.lo4 Vitamin C has also been shown to suppress quinone formation from benzo[a]pyrene by free radicals.los A number of other animal studies have shown that vitamin C suppresses tumour formation induced by carcinogens in animals but other studies indicate that vitamin C may have a neutral effect or may even enhance tumour production.Cell culture studies also provide evidence that vitamin C is effective in inhibiting cancer cell growth or mitosis. Ascorbic acid provided protection against mutagen- induced damage to chromosomes in human lymphoblastoid cells and lymphocytes.'o6 A malignant T-cell line isolated from also interacts with cell membranes binds to intracellular cytoplasmic proteins and nuclear receptors affects enzyme action and represses expression of oncogenes.114 COOH M 32 retinoic acid 8 Flavonoids as Anticancer Agents Some flavonoids have been found to have anticarcinogenic and antitumour activity but other studies have implicated some members of this group as being genotoxic and carcinogenic.Since O-glycosides can be hydrolysed by human gut flora most studies have concentrated on the properties of the aglycones. 14-1 16. The polymethoxyflavones tangeretin 33 and nobiletin 34 that occur in citrus fruit were found to enhance carcinogen removal by inducing benzo[a]pyrene hydroxylase activity in the liver and lung of the Quercetin 25 also inhibits initiation and promotion of chemically-induced tumours.120 OMe OMe 0 OMe 0 33 tangeretin 34 nobiletin 272 Research relevant to the anticarcinogenic effects of flavonoids has been reviewed by Fujiki.lP1 Quercetin 25 and myricetin 26 usually inhibit cytochrome P-450 monooxygenase activity whereas tangeretin and nobiletin are inducers and activators of phase I enzyme monooxygenase activity.122 Despite interest in the antioxidant properties of quercetin and other flavonoids early reports of bacterial mutagenicity of flavonoid~l~~l~~ led to further studies on their genetic toxicity and carcinogenicity.Quercetin is well established as a geno- toxicant but its carcinogenicity is still a matter of debate.125-126 At alkaline pH values quercetin spontaneously auto-oxidises producing the superoxide anion12' and this may give rise to oxygen species of higher reactivity. 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ISSN:0265-0568    

DOI:10.1039/NP9961300265

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Recent Advances in Annonaceous Acetogenins Lu Zeng Qing Ye Nicholas H. Oberlies Guoen Shi Zhe-Ming Gu Kan He and Jerry L. McLaughlin Department of Medicinal Chemistry and Pharmacognos y School of Pharmacy and Pharmacal Sciences Purdue University West Lafa yette lndiana 47907 USA Reviewing the literature published up to January 1996 (Continuing the coverage of literature by J. L. McLaughlin et al. in Recent Advances in Phytochemistry ed. J. T. Arnason R. Mata and J. T. Romeo Plenum Press New York 1995 VOI. 29 pp. 249-310) 1 Introduction 2 Biosynthesis and Classification 3 Extraction Isolation and Purification 4 Structural Elucidation Strategies 4.1 Structural Elucidation of the THF or THP Ring(s) and Flanking Hydroxyls 4.2 Absolute Configuration of Stereogenic Centres bearing Hydroxyl Groups Distant from the THF Rings 5 Biological Activities 5.1 Studies of Mitochondria1 Complex I 5.2 Inhibition of Tumour Cell Growth 5.3 Potential as Pesticides 5.4 SARs and Tumour Selectivities 6 Annonaceous Acetogenins containing a Mono-THF Ring 6.1 Annonacin Type 6.2 cis-Annonacin Type 6.3 Annonacin A Type 6.4 Gigantetrocin A Type 6.5 Muricatetrocin A Type 6.6 Muricatalin Type 7 Annonaceous Acetogenins containing Adjacent Bis- THF Rings 7.1 Asimicin Type 7.2 Bullatacin Type 7.3 Squamocin-I Type 7.4 Trilobacin Type 7.5 Squamocin-N Type 7.6 Rolliniastatin 1 Type 7.7 Bulladecin Type 7.8 Rollidecin A Type 8 Non-adjacent Bis-THF Annonaceous Acetogenins 8.I Gigantecin Type 8.2 12,15-cis-Bullatanocin Type 8.3 Bullatalicin Type 8.4 12,15-cis-Bullatalicin Type 8.5 Sylvaticin Type 8.6 cis-Sylvaticin Type 8.7 Aromin Type 9 Annonaceous Acetogenins containing Non-adjacent THF and THP Rings 9.1 Mucocin Type 10 Annonaceous Acetogenins containing Adjacent Tris- THF Rings 10.1 Goniocin Type 11 Annonaceous Acetogenins containing no THF or THP Rings 12 Semi- and Totally-synthesized Annonaceous Acetogenins 13 Uncertain Structures of Acetogenins 14 References 15 Appendix New Structures of Annonaceous Acetogenins (July 1994-January 1996) I Introduction Annonaceous acetogenins are waxy substances consisting of C, or C, long chain fatty acids which have been combined with a propan-2-01 unit at C-2 to form a y-lactone.They are only found in several genera of the plant family Annonaceae. Their diverse bioactivities as antitumour immunosuppressive pesticidal antiprotozoal antifeedant anthelmintic and anti- microbial agents have attracted more and more interest worldwide. Recently we reported that the Annonaceous acetogenins can selectively inhibit the growth of cancerous cells and also inhibit the growth of adriamycin resistant tumour ce1ls.l As more acetogenins have been isolated and additional cytotoxicity assays have been conducted we have noticed that although most acetogenins have high potencies among several solid human tumour cells lines some of the derivatives within the different structural types and some positional isomers show remarkable selectivities among certain cell lines e.g.against prostate cancer (PC-3). We now understand the primary modes of action for the acetogenins. They are potent inhibitors of NADH :ubiquinone oxidoreductase which is an essential enzyme in complex I of the electron transport system (ETS) which eventually leads to oxidative phosphorylation in mit~chondria.~-~ A recent report showed that they act directly at the ubiquinone catalytic site(s) within complex I and in microbial glucose dehydrogenase.‘ They also inhibit the ubiquinone-linked NADH oxidase that is peculiar to the plasma membranes of cancerous cells and functions to permit cytosolic phosphorylation (substrate level phosphorylation) by restoration of NAD’ levels.Thus the end result of both of these mechanisms is ATP deprivation.7 Using advanced Mosher ester methodology,* more and more acetogenins are being reported with defined stereochemistries. Recently the stereostructures of gigantecin an acetogenin con- taining non-adjacent bis-tetrahydrofuran (THF) rings was proven by X-ray analysis and Mosher ester determinati~n.~ Several other acetogenins such as those with adjacent bis-THF l3 rings -e.g. asimicin,l0,l1 parviflorin,I2 bullatacinlO~ll and rolliniastatin-114 and those with mono-THF rings -e.g. sola- rnin,l5-l7 retic~latacin,~~.~~ corossolone,18 corossolinls and gigantetrocin A (13,14-threo-densicorna~in)~~ -have now been synthesized.As additional information regarding the stereo- chemistries of acetogenins has accumulated we consider that it is now most logical to classify the Annonaceous acetogenins according to their stereostructures across their THF rings. Since publishing our last three reviews which summarized research on Annonaceous acetogenins up to June 1994,20 six new species of Annonaceae have been reported to contain acetogenins they are Annona aternoya,”-23 A. co~iacea,~,A. A. glauca,26 Asimina l~ngifolia~~-~~ cra~si$ora,~~ and Uvaria tonkine~is.~~ A new structural type of acetogenin mucocin 207,,l is the first acetogenin containing both a THF ring and a tetra-hydropyran (THP) ring.Rollidecins A 176 and B 17732are the first acetogenins bearing adjacent bis-THF rings and one tbreo fbreo cis I trans 176 rollidecin A R' = OH; R2 = H 1TT rollidecin B R' = H; R2= OH tbreo trans fbreo g (35) 32 CH3(CH2)n201 W(cH2)4-19 0*'16 15 OH OH 0 205 aromin n= 11 206 arornicin n=13 flanking hydroxyl with relative stereoconfigurations of trans- threo-cis-threo (we always designate relative stereochemistries from lower to higher positions down the hydrocarbon chain). Aromin 205 and aromicin 20633are the first acetogenins having two non-adjacent THF rings at C-4 and C-15. Three mono-acetyl acetogenins 4-acetyl gigantetrocin A 79,34 4-acetyl annonacin 20,28and 4-acetyl xylomaticin 38,28have recently been isolated; no naturally acetylated acetogenins have been reported since the first acetogenin ~varicin,~~ with a mono-acetyl group at C-24 was published.Three six hydroxyl mono-THF acetogenins annohexocin 6426and murihexocins A 82 and B 83,37have been reported. Annohexocin has a 1,3,5- trio1 moiety between the THF and y-lactone rings and murihexocins A and B have two threo-1,2-diols in their molecules. The isolation of coriadienin 223,24the first aceto- genin bearing two double bonds has provided further evidence for the hypothesized biogenetic pathway. In our first review in 1990 we described 28 Annonaceous acetogenins isolated from 11 species;38 in our second review in 1993 we summarized 61 acetogenins isolated from 16 species;39 in our third review in 1995 another 80 acetogenins from 20 species of Annonaceae were added to this class of compounds.20 Some recent reviews of more limited scope have been published by other gro~ps.~O-~~ At the time of preparation (January 1996) of this our fourth review over 220 Annonaceous acetogenins have been reported from 26 species.2 Biosynthesis and Classification In our previous review^,^^.^^. 39 the Annonaceous acetogenins were classified as mono-THF adjacent bis-THF non-adjacent bis-THF and non-THF ring compounds followed by sub- classification of the y-lactone substituted y-lactone or ketolactone variations. As more Annonaceous acetogenins have been found and especially as the absolute stereochemistries of the acetogenins have been proven either by total synthesis or by the Mosher ester method we have realized that the type of stereostructures across the THF rings offer a more convenient method for classifying these compounds.Previously we have proposed biogenetic pathways likely to NATURAL PRODUCT REPORTS 1996 thnso trans 3:. OH OH 79 4-acetyl gigantetrocin A (35) fbreo tra,ns tho 20 4-acetyl annonacin n = 11 38 4-acetyl xylomaticin n = 13 0 64 annohexocin tbreo trans fbreo 32 OH OH 0 82 murihexocin A R1 = R3 = OH; R2 = R4= H 83 rnurihexocin B R' = R3 = H; R2 = R4= OH 223 coriadienin lead to the acetogenins.20 Most of the acetogenins including those with mono-THF rings with one flanking hydroxyl mono- THF rings with two flanking hydroxyls adjacent bis-THF rings with one flanking hydroxyl adjacent bis-THF rings with two flanking hydroxyls and non-adjacent bis-THF rings can be hypothetically related in a similar way (see Schemes 1-4).Three types of acetogenins bearing a mono-THF ring with two flanking hydroxyls (the annonacin cis-annonacin and annona- cin A types) are considered to be formed from cis-cis or trans-cis dienes through epoxidation followed by cyclization starting from the left hand side of the molecule. Three types of acetogenins bearing a mono-THF ring with one flanking hydroxyl (gigantetrocin A muricatetrocin A and muricatalin types) can be formed from a keto cis-alkene or keto trans- alkene through reduction of the keto group followed by cyclization starting from the right side (see Scheme 1).Six types of adjacent bis-THF ring acetogenins having two flanking hydroxyls (asimicin bullatacin rolliniastatin 1 trilo- bacin squamocin-I and squamocin-N types) can be classified in a similar way. After epoxidation these six types all start from the left side to pursue further cyclizations (Scheme 2). NATURAL PRODUCT REPORTS 1996-J. L. McLAUGHLIN ET AL. # k-)TI &-)Ti 0 x) 19 16 15 1.2 1 I I 1 'hi % / \ J 1 Ho\ 1 1 1 threo trans threo threo cis threo erythro trans threo threo trans threo cis ervthro trans annonacin type cisannonacin type annonacin A type gigantetrocin A type muricatetrocinA type muricatalin type Scheme 1 t + t threo three threo threo trans I trans threo ervthro trans I trans threo elvthro cis I cis threo 24 23 0 20 19'0' 16 15 OH OH OH OH OH asimicin type bullatacin type rolliniastatin 1 type 24 20 19 15 24 I 1 I etythro threo threo threo cis I trans threo threo trans I trans erythro threo cis I cis threo OH OH OH OH trilobacin type squamocin-I type squamocin-N type Scheme 2 278 NATURAL PRODUCT REPORTS 1996 1 I 1 U t thmo thmo thteo threo erythro threo trans I trans threo threo cis I trans HO OH OH bH bulladecin type rollindecin A type goniocin type Scheme 3 HO I LJ I t threo trans thmo threo A OH OH OH gigantecin type ( A = trans) 12,15-cisbullatanocin type (A = cis) W I I t t t erythm trans threo threo A erythm cis thmo threo OH OH OH OH t)H OH OH OH bullatalicin type ( A = trans) sykaticin type ( A = trans) mucocin type 12,15-ci~bullatalicin type (A = cis) cis-sylvaticin type (A = cis) Scheme 4 Two other types of acetogenins bearing adjacent bis-THF cis-threo tris-THF ring moiety) derived from goniodenin rings with one flanking hydroxyl (bulladecin and rollindecin A are other examples of adjacent tri-THF ring compound^.^^ types) can be formed from hydroxylated cis-cis-trans or Goniocin and cyclogoniodenin T have the same relative stereo- hydroxylated cis-cis-cis trienes through epoxidation and chemistries around the adjacent tri-THF ring moiety i.e.cyclization starting from the right side (Scheme 3). trans-threo-trans-threo-trans-threo but the absolute configu- The formation of acetogenins bearing adjacent tri-THF rings rations are different.Goniocin has C-24R and cyclogoniodenin (goniocin type) which was found recently in Goniothalamus T has C-24s. gigante~s,*~ can also be explained in the same way; this is a new Six types of acetogenins having non-adjacent bis-THF rings type of Annonaceous acetogenin of which only one example (gigantecin 12 15-cis-bullatanocin bullatalicin 12,15-cis-has been found so far. Two semisynthetic products cyclo- bullatalicin sylvaticin and cis-sylvaticin types) have been goniodenins T (with a trans-threo-trans-threo-trans-threo tri-found. These compounds consist of one mono-THF ring THF ring moiety) and C (with a trans-threo-trans-threo-bearing one flanking hydroxyl and one mono-THF ring bearing NATURAL PRODUCT REPORTS 1996-J.L. McLAUGHLIN ET AL. Table 1 Separations of certain Annonaceous acetogenins (pairs of epimers or isomers) by HPLC Retention UV detector Compounds time (min) Column" Solvents (nm) Asimicin 105 51 Si gel 8p 9% MeOH/THF 230 Bullatacin 126 56 in hexane Bullatalicin 191 60 C-18 8p 70% CH,CN 230 12,15-cis-Bullatacin 199 62 in water Rollinecin A 72 150 C-18 8,~ 70% CH,CN 230 Rollinecin B 73 155 in water Squamotacin 123 95 Si gel 8p 7% MeOH/THF 230 Bullatacin 126 99 in hexane Murihexocin A 82 89 Si gel 8,u gradient not Murihexocin B 83 91 G3Y0 MeOH used in CH,C1 2,4-cis-Asimicinone 114 19 C-18 8,~ gradient 20 5 2.4-trans-Asimicinone 115 22 7&8Ooh CH,CN in water (I Column size 21.4 x 250 mm flow rate 10 ml min-' usually 20-50 mg samples can be separated two flanking hydroxyls separated by two methylenes.The C-14s. Squamotacin 123 and bullatacin 126 are different only formation of these acetogenins can be considered to result from in the placement of their adjacent bis-THF ring systems and the cyclization starting from both sides (Scheme 4). The new type flanking hydroxyls. The adjacent bis-THF ring starts at C-14 in of acetogenin mucocin 207 which has non-adjacent THF and squamotacin while it starts at C-16 in bullatacin. 2,4-cis- tetrahydropyran (THP) rings,31 likely has quite a similar Asimicinone 114 and 2,4-trans-asimicinone 115 are epimers at biogenetic pathway; the cyclization would start from the left C-2 of the ketolactone ring; the former has C-2R and the later side the same as with other non-adjacent bis-THF acetogenins has C-2s.but it would start at C-23 instead of C-24; the stereochemistries of mucocin are consistent with this hypothesis (Scheme 4). threo Aromin 205 and aromicin 206 from Xylopia arornatica trans I trans threo belong to another new type of non-adjacent bis-THF aceto- 34 genin., Two THF rings are located beginning at C-4 and C-16. CHdCHdQ 24 23 0.'20 19 o..16 I 15 The THF ring at C-16 is likely formed as with all the other mono-THF ring compounds and the THF ring at C-4 may be R' R2 OH 0 formed by the loss of one molecule of water (dehydration) 105 asirnicin R' = OH; R2 = H between hydroxyls at C-4 and C-7. Two acetogenins bearing 126 bullatacin R' = H; R2= OH 4,7-hydroxyl groups murihexocins A 82 and B37 83 recently isolated from A.muricata provide evidence for such a eryfhro trans threo threo A 3:. mechanism of formation of the aromin type compounds. 3 Extraction Isolation and Purification Ethanol extraction of plant biomass to yield the acetogenins is I91 bullatalicin A = trans used in our laboratory as a general method. Although most of 199 12,lS-cis-bullatalicin A = cis the acetogenins are easily soluble in chloroform or dichloro- 3?' methane recently we found that some six hydroxyl acetogenins etythro trans threo such as annohexocin 64 and murihexocins A 82 and B 83 are 34 not as soluble as other acetogenins in these chlorinated solvents and might be lost if ethanol were not used. Several partitioning operations starting from the residue of the ethanol extract can OH OH 0 concentrate the acetogenins.The concentration can be easily 72 rollinecin A R' = OH; R2= H demonstrated by using the brine shrimp lethality test (BST) to 73 rollinecin B R' = H; R2 = OH guide their activity directed fractionation.**% *L46 Separation of acetogenins by repeated open column chroma- threo tography and HPLC can be achieved depending on their eMhm trans I trans threo polarities. Polarities are controlled by THF rings and other functional groups such as hydroxyls ketones epoxides and double bonds and sometimes depend on the positions of the THF rings and functional groups along the hydrocarbon chain. 123 squamotacin Some successful separations of epimers using HPLC in different systems are given in Table I.Asimicin 105 and threo bullatacin 126 adjacent bis-THF acetogenins are epimers and threo trans I trans threo are different only at C-24. Asimicin has C-24R and bullatacin CH3(CH2)~)xhichc (CH~Q~..?? has C-24s. Bullatalicin 191 and 12,15-cis-bullatalicin 199 non-34 adjacent bis-THF acetogenins are epimeric at C- 12. Bullatalicin 24 23 o"20 19 0°'16 15 has C- 12R and 12,15-cis-bullatalicin has C-12s. Rollinecins A 0 0 OH 72 and B 73 are epimeric mono-THF acetogenins which are OH 114 2,4-cis-asimicinone 0 different at C-14. Rollinecin A has C-14R and rollinecin B has 115 2,4-trans-asirnicinone Separation of murihexocins A 82 and B 83 two six-hydroxyl mono-THF acetogenins which differ at their C- 19 20 vicinal diols (the former has C-19S 20s and the latter has C-l9R 20R),was conducted using chloroform and methanol.Since the UV detector cannot be used as a monitor in this system careful control of the blind collection of small fractions and monitoring their retention times separated the pure compounds. Using program control systems HPLC separations of these isomeric acetogenins are usually reproducible. 4 Structural Elucidation Strategies Several strategies for the structural elucidation of Annonaceous acetogenins have been summarized in our previous re-views.20,38* 39 From the first acetogenin uvaricin found in 1982 until 1992 most acetogenins were reported as planar struc- ture~.~~,~~ During this time several adjacent bis-THF aceto- genins have been reported with their relative stereochemical relationships among the stereogenic centres around the THF rings based on the 'H NMR data from synthetic adjacent bis- THF ring model compounds (twelve acetylated isomers of adjacent bis-THF ring systems bearing two flanking hydroxyls have been rep~rted).~~.~~ Synthetic efforts on the relative stereochemistries of single THF rings provide data for determinations of the relative stereochemistries of mono-THF ring acetogenins with one flanking hydroxyl (four isomers of this type of compound have been ~ynthesized)~~ and mono- THF ring acetogenins with two flanking hydroxyls (four isomers of this type of compound have been synthe~ized).~~ Using these models the relative stereochemistries of non- adjacent bis-THF acetogenins can also be solved by 'H NMR.However no model compounds of adjacent bis-THF rings bearing one flanking hydroxyl and adjacent tris-THF rings bearing one flanking hydroxyl have been synthesized. Thus systematic studies synthesizing models for these types of compounds such as a bulladecin rollindecin A and goniocin types of acetogenins are still needed. Diols are common structural features found in the aceto- genins and include 1,2- 1,3- 1,4- or 1,5-diols. 'H NMR analyses of acetonide or formaldehyde acetal derivatives can usually solve the relative stereochemistries of these diol~.~~ 51 Advanced Mosher ester methodology was introduced to determine the absolute configurations of stereogenic carbinol centres in Annonaceous acetogenins in late 1992.Since then most of the acetogenins reported by our group20 and by Fujimoto's group52 have been defined with absolute stereo- chemistries. Basically the Mosher ester method can be directly used to determine the absolute stereochemistries of carbinol centres (the flanking hydroxyls of THF ring moieties) in the NATURAL PRODUCT REPORTS 1996 acetogenins which have mono-THF rings bearing one flanking hydroxyl mono-THF rings bearing two flanking hydroxyls adjacent bis-THF rings bearing one flanking hydroxyl and adjacent bis-THF rings bearing two flanking hydroxyls. Combined with the formation of formaldehyde acetals of the 1,4-diols between the two THF rings the absolute stereo- chemistries of the non-adjacent bis-THF ring acetogenins (except for the aromicin type) can also be The stereochemistries of isolated mono-hydroxyl groups near the terminal methyl group (including C-28 29 30 31 or 32-hydroxyl and mono-hydroxyl groups near the y-lactone ring (including C-4 5 or 6-hydroxyls) can be also directly solved by the Mosher ester method.The positions of the THF ring and other functional groups along the hydrocarbon chain are important for controlling their bioactivities and thus the placements of such groups are essential in the structural determination of acetogenins. Usually a combination of chemical methods 'H and 13C NMR analysis and mass spectrometry with high resolution mass analyses of certain fragments can give satisfactory results.The placements of hydroxyls can be achieved by EI-MS of the trimethylsilyl (TMS) or perdeutero-TMS derivatives most of the time; the cleavages between hydroxylated carbons and adjacent carbons provide relatively prominent peaks. Amine derivatives (N,N-dimethylethylenediamine) of precursor-ion scanning FAB- MS/MS52 and lithium cationization B/E linked scan FAB- MS54 are also useful for this purpose. 4.1 Structural Elucidation of THF or THP Ring(s) and Flanking Hydroxyls IH and 13C NMR are useful in recognizing the different structural types of acetogenins. By identifying the lH NMR signals which appear around S 3.W.0 one can usually distinguish the specific THF or THP types. Table 2 summarizes 'H NMR data of different acetogenins.Sometimes the signals of 1,2- or 1,3-diols in the molecule may interfere with these characterizations. The signals of 1,2-threo-diols appear at about 63.4 and both 1,3-threo- or erythro-diols appear at about 6 3.8-3.95.55956 The structural elucidations of adjacent bis-THF ring aceto- genins with two flanking hydroxyls sometimes pose a question as to which side is which. These situations happen in the cases of asymmetric structures such as with the bullatacin squamocin I trilobacin and rolliniastatin 1 types. Indeed we initially placed the erythro arrangement of bullatacin on the wrong ~ide,~.~~ and we initially picked the wrong model for the relative stereochemistries of triloba~in.~~~~~ In the structural elucidation of trilobacin which has a Table 2 The characteristic 'H NMR patterns (in CDC1,) for identification of THF (or THP) Annonaceous acetogenins Annonacin Type cis-Annonacin Type Annonacin A Type Gigantetrocin A Type cis-Gigantetrocin Type Muricatalin Type 6 3.35-3.47 2H 2H s 3.7 - - s 3.75-3.95 2H 2H 6 3.35-3.47 Asimicin Type 2H Bullatacin Type 1H s 3.75-3.95 4H 5H -6 3.95-4.05 Gigantacin Type Bullatalicin Type 1H 1H --3H 2H Rolliniastatin 1 Type Trilobacin Type 1H -1H 1H 3H Squamocin-I Type Squamocin-N Type 1H 2H 5H 5H 12,15-~is-cis-Sylvaticin Type Bullatalicin Type 2H 2H 1H 1H 4H 411 Aromicin Type -2H 1H 3H 1H 5H -Sylvaticin Type 2H -5H Goniocin Type -1H -6H 2H 2H 2H 12,154s-Bullatanocin Type 3H 1H 3H Mucocin Type 3H 2H -2H 6 3.35-3.47 3H -63.7 6 3.75-3.95 4H Bulladecin Type -6 3.0-3.3 6 3.35-3.47 1H -6 3.6 63.75-3.95 4H 2H -5H Rollindecin A Type -1H -4H NATURAL PRODUCT REPORTS 1996-5.L.McLAUGHLIN ET ,415. 28 1 relative stereochemical relationship across the adjacent THF A new approach for using the Mosher ester method to rings and flanking hydroxyls of threo-trans-erythro-cis-threo determine the absolute stereochemistries of epimers or enan- with the two flanking hydroxyls both R,the questions that tiomers has been recently explored.68 The AS values of 'H needed to be answered were which side is cis and which side is NMR signals of the same S(or R)-MTPA esters in two epimers trans.By selective acetylation of one hydroxyl adjacent to the (instead of using the two different S-and R-MTPA esters of THF-ring system followed by lH NMR and MS analyses the one epimer as is performed in the conventional methods) can correct stereostructure of trilobacin was finally deter~ined.~~ predict the absolute configuration of the two epimers. Two Similarly bullatacin has a relative stereochemical relationship for the adjacent THF rings and two flanking hydroxyls of threo-trans-threo-trans-erythro and is R,S for the two flanking hydroxyls. By formation of the mono-MTPA ester followed by MS analysis of the TMS derivative the S-configuration was assigned at C-25 placing the erythro on this side of the ring system.6o For mono-THF ring acetogenins bearing two flanlung hydroxyls such as in the annonacin A type of compound with a relative stereochemical relationship of threo-trans-erythro and in the cis-annonacin type of compound which are threo-cis-threo it is necessary to decide on which side the threo configuration is located in the annonacin A type of compound or which flanking hydroxyl is R or S in the cis-annonacin type of compound.The different 'H NMR patterns for mono-THF ring acetogenins bearing two flanking hydroxyls (the annonacin type) are quite distinguishable when another hydroxyl is located two four or six carbons away. These were called the goniothalamicin annonacin and annomontacin patterns.20 In the goniothalamicin pattern the signals of the methine protons of two flanking hydroxyls become two separated peaks; one appears at 6 3.43.61 Characteristic chemical shift values are found among several other types of acetogenins e.g.the hydroxymethine protons adjacent to the THF ring with a threo relationship appear at ca. 6 3.36-3.41. When there is another hydroxyl located two carbons away the above protons will shift downfield to 63.43-3.46.36 In this way the threo configurations are unambiguously assigned to several anno- nacin A type of acetogenins (muricatocins B56 and C,55 l~ngicin,~' and rollinecins A and B62). For annohe~ocin~~ structural determination of cis-annonacin the C- 15 and C-20 mono-MTPA esters were prepared and the absolute con-figurations were assigned as C-15R and C-20S7 respectively ; also the successful formation of the formaldehyde acetal across the two ring flanking hydroxyls served to prove the cis-THF 4.2 Absolute Configuration of Stereogenic Centres bearing Hydroxyl Groups Distant from the THF Rings The absolute configurations of a chiral alcohol which is located close to the y-lactone ring or the terminal methyl group can be easily determined by analysis of 'H NMR spectra of per- MTPA esters because the signals of the y-lactone ring and terminal methyl are easily differentiated from signals of other protons.It is more difficult to recognize the nearby proton signals when a hydroxyl is close to the THF ring system or in the case of 1,2- or 1,3-diols. By controlling the experimental esterification conditions the mono-MTPA esters have been made to prove the configurations of C-1OR in ~is-annonacin~~ and of C-18s in gigantetrocin B (another hydroxyl is at C-17).64,65 By the obsevation of the differences in the 'H NMR signals at H-4 between per R-and S-MTPA esters the C-10 hydroxyl in trilobin was determined to be of the R-config~ration.~~.~~ By transformation of longicin to its ketolactone derivative and then observing the differences of the signals at H-4 between the S-and R-per-MTPA esters the C-10 hydroxyl in longicin was also proven to be of the R-c~nfiguration.~' By formation of formaldehyde acetal deriva- tives between the C- 10 and C- 13 hydroxyls in goni~thalamicin~l and longifolicin,6' and between the C-14 and C-17 hydroxyls in gigantetrocin A,51 and then tracing their relative stereo-chemistries the absolute configurations of these compounds have been assigned to be C-10 R in the first two and C-18R in the last.models given in Figure 1 demonstrate how the new approach works. When there are multichiral centres in the same molecule the method still can assign the epimeric centres but each of the epimers must be separated and in hand. Several such examples of epimeric pairs of acetogenins bullatacin 126 and asimicin 105 bullatalicin 191 and bullatanocin 182 rollinecins A 72 and B 73 and rollidecins A 176 and B 177 shown in Figure 2 have illustrated the application of the method.68 Ph PMe i I H O I \ I I11 plane L2&'+CF3 Ph pMe 1I i L3 L2v0$CF3 ph H O H O I1 IV I OMTPA(S) OMTPA(R) H H Model A Model B I Figure 1 New Mosher ester approach for determination of the absolute stereochemistries of epimers or enantiomers -0.03 +O.M +0.10 +0.32 +0.03 t(S)-MTPA M126105:{4.12 -0.07 -0.27 -0.09 I -0.01 / t(R)-MTPA l&qqJJ$o 0..8 0" 9 OH OH 0 126 bullatacin (C-14s) and 105 asimicin (C-24R) -0.01 -0.02 -0.07-0.08t(S)-MTPA As72-73:{ +0.01 +0.05 +0.03 t(R)-MTPA 10 OH OH 0 72 rollinecin A (C-14R) and 73 rollinecin B (C-14s) +0.07-0.03 +0.01+0.04 t(S)-MTPA A'191-182:{ 2:: -0.06 -0.24+0.10 1 I t(R)-MTPA 0 191 bullatalicin(C-24s) and 182 bullatanocin (C-24R) OH 0 176 rollidecinA (C-24R) and 177 rollidecin B (C-24s) Figure 2 Epimeric pairs of acetogenins assigned using the method shown in Figure 1 NATURAL PRODUCT REPORTS 1996 The 1,2,5-triol group is a fairly common structural feature annonacin (annonin VI).In this work they found that with among the Annonaceous acetogenins ; thirteen examples are respect to ubiquinone 2 annonacin inhibits mammalian found among mono-THF ring compounds with one flanking NADH :ubiquinone oxidoreductase in a partially competitive hydroxyl group. Twelve of these 1,2,5-triol groups have a threo manner while inhibiting the bacterial equivalent ubiquinone- configuration for their vicinal 1,2-diol and the absolute linked glucose dehydrogenase in a competitive manner. Other stereochemistries may either be R,Ror S,S. By formation of the molecules such as piericidin A fenpyroximate phenalamid formaldehyde acetal to connect the two hydroxyl groups of the A2 thiangazole and the aurachins responded similarly and the 2,5-diols and subsequent Mosher esterification of the 1-alcohol authors collectively grouped these as ‘class I inhibitors ’.the stereochemistries of the 1,2-diol at C- 17,18 of gigantetrocin Alternatively compounds such as rotenone phenoxan aureo- A were determined as R,R51 By using mono-Mosher esteri- thin and benzimidazole which inhibit complex I in a non- fications at C-18 in both gigantetrocins A and B the competitive manner with respect to ubiquinone 2 and have no stereochemistries of their 1,2-diols were proven to be R,R and effect on the bacterial glucose dehydrogenase were termed S,S respe~tively.~~,~~ The IH NMR spectra of the acetonides of ‘class 11 inhibitors’.Thus the acetogenins may act at a the hydroxy methine protons in the 1,2,5-triol moiety gave a different site than rotenone as proposed by Espositi et ~1.~~ different pattern i.e. a doublet of double doublets for an R,R Complex I is a complicated protein system in the mito- 1,2-diol; and a quartet for an S,S 1,2-diol. Analyses of the tri- chondria; its biochemistry will undoubtedly be deciphered Mosher ester data of the 1,2,5-triol moieties in all of these more thoroughly in the future and the acetogenins will become acetogenins provide characteristic chemical shift values of the instrumental in those future experiments. esterified methine proton signals e.g. at ca. 64.914.94 and 65.01-5.03 (6 4.91-4.94 and 6 5.05 in cases where another 5.2 Inhibition of Tumour Cell Growth double bond is located two carbons away) for the S-Mosher An in vitro disk diffusion assay,’ which measures zones of esters in the R,R 1,2-diols and at ca.6 5.10-5.15 and inhibition of cell growth around a filter paper disk was used to 65.16-5.19 (65.16 and 85.18-5.20 in cases where another test the anticancer potential of ten different Annonaceous double bond is located two carbons away) for the R-Mosher acetogenins. All the compounds were extremely potent to both esters in R,R 1,2-diols. In contrast these signals are located at ‘normal’ cancer cells as well as to adriamycin (multidrug) ca. 6 5.03-5.06 and 6 5.10-5.16 for the S-Mosher esters in the resistant cancer cells while the effects on the growth of non-S,S 1,2-diols and at ca.6 5.03-5.04 and 6 5.17 for the R-Mosher cancerous rat GI epithelial cells (118) were minimal. This study esters in the S,S 1,2-diols. also showed how important careful dosing is when dealing with this class of compounds. For example in Figure 3 note how bullatacin (126) at a concentration of 2.5 pgldisk is cytotoxic 5 Biological Activities to all of the cell lines. At a one-tenth dilution to 0.25 pgldisk 5.1 Studies of Mitochondria1 Complex I bullatacin remained still more effective than adriamycin (at a In our last review,2o we predicted that the Annonaceous dose of 2.5pgldisk) in all cell lines including the multidrug acetogenins would become valuable tools for the examination resistant mouse mammary cell line M17/Adr. Furthermore have of complex I in the mitochondria.Indeed Friedrich et ~1.~ the acetogenins are only equipotent or less potent than now studied the binding sites of complex I inhibitors including adriamycin to the non-cancerous I1 8 cells. bullatacin (126) 2.50 pg/disk hl bullatacin (126) 0.25 pg/Uisk 88 asimicin (105) 2.50 pg/disk el bullatacinones (148,149) 12.50 pg/disk g( bullatacinonea (148,149) 2.50 pg/disk 1000 pd bullatacinones (148,149) 1.00 pg/disk El bullatacinones (148,149) 0.25 pg/disk 900 8 adriamycin 2.50 pg/disk 800 700 600 500 400 300 200 100 0 . P38810 . PO3 *M17/AdrmH8/H125’I18 ’ cell line Figure 3 Inhibition of cell growth in an in vitro disk diffusion assay.’ A clear zone indicating no tumour cell growth up to a definite point is given a number representing distance from the disk (200 units = 6.5 mm) and is illustrated by the height of the bars in the graph; beyond such a distance ‘normal’ tumour cell growth exists.Further if there is cell growth beyond the clear zone which is sporadic and fewer in number an ‘error’ bar is drawn to illustrate how far such a region exists before ‘normal’ tumour cell growth commences. Note; not all determinations displayed sporadic growth and therefore they do not all receive error bars. Murine tumour cells P388 -B cell lymphoma; PO3 -pancreatic ductile adenocarcinoma; M17/Adr -adriamycin resistant mammary carcinoma. Human cells; HS/H125 -either human colon carcinoma 8 or human lung carcinoma 125; results with either are considered comparable.’ ‘Normal’ cells I18-immortalized rat GI epithelial cells NATURAL PRODUCT REPORTS.199G-J. L. McLAUGHLIN ET AL. It cannot be overemphasized how essential it is to examine carefully a wide range of concentrations when studying this class of compounds. The selectivity for cancerous cells vs non-cancerous cells is reminiscent of the inhibition of the ubiquinone linked NADH oxidase which is peculiar to the plasma membranes of cancerous cells as proposed by Morre et al.’ An in vivo study7 with a murine teratoma model failed to test bullatacin 126 at its proven effective dose i.e. 50 pg kg-1;4 this teratoma study also failed to include a positive control to demonstrate that any drug is effective against this highly differentiated tumour.5.3 Potential as Pesticides Ratnayake et al. 71 tested several different plant parts of Asirnina triloba the North American pawpaw to determine which parts yielded both the greatest quantity of F005 (a partitioned 90 % aqueous methanol extract containing a complex mixture of acetogenins) and which parts had the most potent bioactivity in the brine shrimp lethality test BST.45*46 It was found that although the unripe fruit and seeds produced the highest yield their harvest is not always reliable. Therefore it was concluded that the harvesting of small twigs and stems may be the optimum source of biomass to supply a pesticidal mixture of the Annonaceous acetogenins. Johnson et al. 72 have now improved the extraction screen for the pesticidal preparation by reducing it to one step and have studied the variation in bioactivity of twigs from single trees grown in New York state over the course of one year.A single extraction with dichloromethane yielded an extract of equal potency to the partitioned F005 in the Ratnayake et al. The potency of this extract decreased significantly in the plant material collected in the late fall and winter months. Their conclusion was that the prime collection time is from May to July which likely coincides with the time when the plant tissue is in the greatest need of protection against insects. Thus biomasses consisting of twigs and small branches of pawpaw and the seeds of guanabana (Annorta rnuricata) could well serve as sustainable sources of acetogenin mixtures.The guanabana juice industry produces tons of guanabana seeds as a by-prod~ct,~~ and these are currently quite likely the most abundant readily available source of natural acetogenins. Unfortunately these seeds only contain the less potent mono- THF ring corn pound^,^^ yet their extracts are still quite effective against several insect pest species. The use of the Annonaceous acetogenins in pest control is protected by our US patent^.'^,^ In the late 18OOs Eli Lilly and Company offered a fluid extract of the seeds of pawpaw (Asimina triloba) for sale to physicians and pharmacists to be used as an emetic.76 In unpublished results at Asta Laboratories bullatacin was emetic to pigs at 185 pg kg-’. Such emetic effects are encouraging and serve as a safeguard against poisoning from accidental ingestion of the pesticidal acetogenin mixture.5.4 SARs and Tumour Selectivities The structure-activity relationships (SARs) of twenty diverse Annonaceous acetogenins in the inhibition of oxygen uptake in the rat liver mitochondrial assay77 were explained in our last review.2o This SAR work has now been extended to include thirteen additional The latter study examined new structurally diverse compounds that have been recently isolated. A positive control of bullatacin 126 was examined during every separate determination so that the data could be both normalized to this value and compared in a ‘bullatacin index’ (Table 3) thereby limiting day to day rat to rat and other variabilities that are inherent in an assay of this nature.The results (Table 3) show that two compounds trilobin 164 and asiminacin 109 are both more active than bullatacin 126. Also the new structural type having a hydroxylated tetra- hydropyrane ring (THP) mucocin 207 was nearly as active as bullatacin 126. With non-adjacent bis-THF ring compounds Table 3 Mitochondrial data compared as a Bullatacin Index. Mitochondrial data have been normalized by the daily determination of bullatacin such that a value < 1.00 signifies an activity more potent than that of bullatacin 126.78 Compound Normalized value Bullatacin 126 1.oo Trilobin 164 0.85 Trilobacin 163 3.72 Asiminacin 109 0.58 Motrilin 132 I .70 Aromin 205 28.7 Mucocin 207 1.94 Asiminenin A 56 33.0 Asiminenin B 40 8.01 Longicoricin 41 17.9 Longifolicin 1 3.22 Gigantetroneninones 90 and 91 4.89 Annomuricin A 60 41.2 Annomuricin C 14 45.9 such as aromin 205 separation by more than 4 carbons between the rings caused a decrease in potency to that of a mono-THF ring acetogenin.With two virtually identical mono- THF ring acetogenins asiminenin A 56 vs asiminenin B 40 the latter with a trans THF ring was approximately four times more potent than the former with a cis THF ring. The mitochondrial assay measures activity at the sub-cellular level which of course does not address absorption protein binding metabolism excretion and transport across cellular membranes. In several recent papers some acetogenins appear to be selectively cytotoxic for certain cancer types ;altered biologkp1 transport or slight variations in receptor geometry in the membranes of such cell lines might explain these selectivities and we hope to be able to have these compounds tested in the larger panel of human tumour cell lines at the National Cancer Institute.Longicin 57 a mono-THF ring compound shows a potent ED, value of 1.25 x lo-’ ppm in PaCa-2 cells (human pancreatic carcinoma) ;27 longicoricin another mono-THF ring acetogenin showed a selective ED, of < 1 x ppm in PC-3 cells (human prostate adenocarcinoma).67 Usually the mono- THF ring acetogenins show much reduced levels of cyto- toxicities in cell cultures. Trilobacin 163 while not being very active against A-549 or MCF-7 cells (human lung and human breast carcinomas respectively) had an ED, of < 1 x in HT-29 cells (human colon carcinoma) ; trilobin a trilobacin analogue with the 4-OH shifted to the 10 position was more generally cytotoxic but extremely potent in all cell lines.59 cis-Annonacin 54 also showed a surprising selectivity (ED, of 1.O x ppm) against HT-29 cells (colon ~arcinoma).~~ Squamotacin 123,with the hydroxylated bis-THF ring system of bullatacin 126 shifted from C-15 to C-13 and its 35 carbon counterpart molvizarin 117 both exhibited significant selective cytotoxicities against PC-3 (prostate) cells (on the order of ED, 1 x ppm) with only moderate toxicity to the five other cell lines.2 Similarly longimicin D 103 with the bis-THF ring system of asimin 107 shifted from C- 15 to C- 13 showed an ED,, value of 1.69 x ppm against PaCa-2 (pancreatic) cells.29 The new structural type mucocin 207 with its hydroxylated THP ring had significant cytotoxicity to both the PaCa-2 and A-549 cell lines (pancreatic and lung carcinomas respectively) while its formaldehyde acetal derivative was only toxic to the A-549 cells.31 In all of the above studies which are from our laboratories adriamycin a standard anticancer agent was always run as a positive control and consistently showed nonselective cytotoxicities at ED, values ranging from 10-1 to 10-3ppm with variation between runs of not greater than two orders of magnitude (10 to 100 times).284 NATURAL PRODUCT REPORTS 1996 A notable point in these comparisons is that slight variations ring and flanking hydroxyls is threo-trans-threo; thus the 2,5- in structure may lead to significant variability in bio-positions of the substituted THF ring also have an absolute 2o Additional in vivo studies4 are sorely needed to configuration of R,R.There are fifty-one compounds now verify such in vitro selectivities.These observations serve to included in this type 1-51; thirty-three are C-35 compounds demonstrate the necessity and merit of a search for new struc- and eighteen are (2-37 compounds. Nearly half (twenty-four) of tural themes in this rapidly growing class of compound. Less this compound class have been published with defined than thirty Annonaceous species have yielded more than 220 stereostructures.Four compounds solamin 5 reticulatacin 47 acetogenins; there are undoubtedly many more diverse com- corossolin 7 and corossolone 8 have been synthesized. Besides pounds to be found among the > 2000 various species in this the THF ring this type of compound usually has two to five family.79 Some of these compounds will be optimum in structure hydroxyls with 1,2-threo-or erythro-diols ketones and acetoxy for specific tumour types and various other uses. groups sometimes present. cis-Double bonds have only been found so far among the C-37 compounds. The THF ring is usually positioned at C-14 16 18 or 20. 6 Annonaceous acetogenins containing a In the following tabulations under the core structure the Mono-THF Ring compound name is followed by the functional groups and their Mono-THF compounds are the largest group of Annonaceous positions in the carbon chain; the plant resource is given in the acetogenins.A total of ninety-four of these compounds has parentheses. R2 represents the terminal hydrocarbon chain; R1 been reported. They can be further divided into six types represents the hydrocarbon chain ending with the y-lactone or according to the stereochemistries of the THF ring and flanking ketolactone. An asterisk (*) indicates those compounds which hydroxyl(s). These are the annonacin cis-annonacin annonacin are new in this review and are not included in our previous A gigantetrocin A muricatetrocin A and muricatalin types of reviews. Full structures spectroscopic data biological activities acetogenins (see Scheme 1 before).The first three are mono- and sources for these (*) new compounds are given in the THF ring acetogenins with two flanking hydroxyls and the Appendix (Section 15). The plant names in alphabetical order latter three are mono-THF acetogenins with one flanking are as follows (a) Annona atemoya; (b) An. bullata; (c) An. hydroxyl. Usually the potencies of mono-THF acetogenins to cherimolia; (d) An. coriacea; (e) An. crass$ora; (f) An. the different human solid tumour cell lines are around lo-' to densicoma; (g) An. glauca; (h) An. montana; (i) An. muricata; pug ml-l; they are usually not so active when compared to (j)An. purpurea; (k) An. reticulata; (1) An. senegalensis; (m) An. the adjacent bis-THF acetogenins. Recently a mono-THF squamosa; (n) Asimina parviflora; (0)As.longifolia; (p) As acetogenin longicin isolated from Asimina longifolia showed triloba; (9) Goniothalamus giganteus; (r) Rollinia membranacea; surprisingly potent selectivity to the human pancreatic car- (s) R. mucosa; (t) R.papilionella; (u) R. sylvatica;(v) R. ulei; (w) cinoma (PaCa-2) cell line at ED, lop9 pg ml-1.27 Uvaria acuminata; (x) U.narum; (y) U. tonkinesis and (z) Xylopia aromatica. 6.1 Annonacin Type The annonacin type of acetogenin contains a mono-THF ring 6.2. cis-Annonacin Type bearing two flanking hydroxyls. The flanking hydroxyls have The cis-annonacin type of acetogenins has a mono-THF ring R,R-stereochemistry and the relative relationship of the THF bearing two flanking hydroxyls. The flanking hydroxyls have fhmo trans fhreo C-35 compounds 29 (2,4-frans)-sq~amone~~~~~ 16-THF 15,20-OH 9-0x0 ketolactone 1 *~ongifo~icin~~ 14-THF 1 OR,13R 18R-OH (0) (2,4-trans)(k m) 2 goniott~a~amicin~~~~" 14-THF 4R,lOR,13R,18R-OH (i n q) 30 (2,4-~is)-isoannonacin~ 1 &THF 1OR15R,20R-OH ketolactone 3 *ariana~in~~ 16-THF 4R,12S,15R,20R-OH (i) (2A-W (i P) 4 *ja~oricin~~ 1 6-THF 4R 1 2R 15 R,20 R-OH (i) 31 (2,4-tmns)-isoannonacinM 16-THF 1 OR,1 5R,20R-OH ketolactone 5 solamin" 16-THF 15,20-OH (k) (2,4-trans) (f P) 6 muriiolin81 lS-THF 4,15,20-OH (i) 32 (2,4-cis -Isoannonacin- 16-THF 15R,20R-OH 10-0x0 7 corossoiine2 16-THF 10,15,20-OH (i) 1O-oneLS ketolactone (2,4-cis) (f i) 8 corossolone8* 16-THF 15,20-OH 10-0x0 (i) 33 (2,4-fmns isoannonacin- 16-THF 15R,20R-OH 10-0x0 ketolactone (2,4-frans) (1 i) 9 annoreticuin-9-onee0 l&THF 4,15,20-0H 9-0x0 (k) 1 O-oneee- 1o *reticutacinoneB3 l&THF 4,15,20-OH 1l-0x0 (k) 11 xy~opianin~~ 16-THF 4,8,15,20-OH (z) C-37 compounds 14-THF 13,18-OH (b,X) 12 annoreticuine5 16-THF 4,9,15,20-OH (k) 34 wariamicin IV~~,~~ 13 *muriatwin As 1 6-THF 4R 10,12(fh),1~R,~oR-OH 35 giganenin34ss IdTHF 10R,13R,18ROH 21-ene (9) (i) 14 *annomurkin c~~ l&THF 4R,10,11 (fh),15R,20R-OH (i) 36 gonionenin'OO 14-THF 4,10,13,18-OH 21-ene (q) 15 annona~in~~,~-~-~~ ~~ 16-THF 4R,lOR,15R,20R-OH (f h i,m n q z) 37 wariamicin I~~,16-THF 15,20-OH (b,X) l&THF 4R,15R,20R-OH 10-0x0 (f h i) 38 *4-acety1x Iomaticin28 16-THF ~ROAC 10R,15R,20R-OH (0) 16 annor1acin-10-one~~~~~ 17 8-hydr~xyannonacin~ 16-THF 4,8,10,15,20-OH (f) 39 bullateninsil 16-THF 15,20-OH 23-ene (b) (p) 18 annomoni~in~~~~~ 16-THF 4,8,13,15,20-OH (h k) 40 *asiminenin 8''' 16-THF 4R,15R,20R-OH 23-e~ 19 'muticatatin cgZ 16-THF 4,15,20,25-OH 10-0x0 (i) 41 'l~ngicoricin~~ 16-THF 10R,15R,20R-OH (0) 20 *dacetyl annonacin28 lSTHF ~R-OAC 1 OR,15R,20R-OH (0) 42 xylopiacine4 lBTHF 4,8,15,20-OH (z) 21 *annotemoyin-lg3 18-THF 17,22-0H 43 xyIopien1O2 16-THF 4R,8,15R,20R-OH 23-ene (z) 22 *(2,4-cis)-gonio-14-THF 1 OR,13R 18R-OH ketolactone 44 xy~omaticin'~ 16-THF 4,10,15,20-OH (Z) thalami~inone~~ (2,4-cis) (0) 45 xylomatenin"* 1&THF 4R 10,l 5R,20R-OHI 23-ene (z) 23 *(2,4-frans)-gonio-14-THF 10,13,18-OH ketolactone (annogalenelm (0) 46 squamosten-Aib4 1 6-THF 4R,12 l5R,20R-OHI thalami~inone~~ (2,4-?mn~) 24 (2,4-cis)-isoannoreticuina5 16-THF 9,15,20-OH ketolactone (2,4-cis) (k) 23-ene (m) 25 (2,4-tran~)-isoannoreticuin~~ ISTHF 9,15,20-OH ketolactone (2,6rrans) (k) 47 reticu~atacin~~'~~ 18-THF 17,22-OH @ k X) 26 *(2,4-~r;s)-murisoIinone~ 1&THF 15R,20R-OH ketolactone (2,4-cr;S) (p) (uvariamicin 27 '(2,4- frans)-murisolinoneQ4 16-THF 15R,20R-OH ketolactone 48 ronkinecinm lS-THF 5S,17R,22R-OH (y) (2,4-tmn~)@) 49 annomontacine4 18-THF 4,10,17,22-OH (h q Z) 28 (2,4-~is)-squamone~~~~~ 16-THF 15,20-OH 9-0x0 ketolactone SO wariamicin III~~-~20-THF 19,24-OH (b,X) (2,4-cis) (k m) 51 montanacing' 20-THFI 4,8,lOI19,24-OH (h) NATURAL PRODUCT REPORTS 1996J.L. McLAUGHLIN ET AL. R,S-stereochemistry and the relative stereochemical relation- the flanking hydroxylated carbon on the hydrocarbon chain ship of the THF ring and flanking hydroxyls is threecis-threo ; side.The hexahydroxylated compound annohexocin thus the 2,5-positions of the substituted THF ring also have an which has a 1,3,5-triol group at the C-8 10 and 12 positions absolute configuration of R,S. Five acetogenins 52-56 have and the 33-OH compound jetein 65,1°7 which has a saturated been reported so far with the cis-annonacin type of structure. y-lactone ring are unique structural features for the annonacin There are four C-35 compounds and one C-37 compound in A type of acetogenins. this type. The stereostructure of cis-annonacin 54 has been directly assigned by the mono-MTPA ester meth~d,~~,~~ which proves the R and S configurations at C-15 and C-20; thus the 6.4 Gigantetrocin A Type R and S configurations were assigned for C-16 and C-19.The The gigantetrocin A type of acetogenin has a mono-THF ring absolute stereochemistries of cis-goniothalamicin can be in- bearing one flanking hydroxyl. There are eighteen compounds directly solved by observation of the chemical shift of one included in this type 7491; twelve are C-35 compounds and oxymethine proton (H- 13) which appears downfield at 6 3.47 six are C-37 compounds. All compounds of this type have the because there is another hydroxyl at the C-10 position. To ring flanking hydroxyl on the hydrocarbon chain side of the distinguish between the cis-annonacin and annonacin types of THF ring; all have a 1,2-diol two carbons away from the acetogenin,lH NMR signals around 6 1.5-2.0 are examined flanking hydroxyl of the ring with either the threo or erythro with the cis-THF ring two groups of signals (the protons on configurations.The flanking hydroxyls have S-stereochemistry the THF ring) appear at ca. 6 1.74 and 1.93; in contrast with and the relative relationship of the THF ring and flanking the trans-THF ring these are at ca. 6 1.66 and 1.98 respectively. hydroxyls is trans-threo; thus the 2,5-positions of the substituted THF ring also have an absolute configuration of R,R.Two hexahydroxylated compounds of this type muri- threo cis threo hexocins A 82 and B 83,37have been reported to bear two 1,2- threo-diols. Two pentahydroxylated acetogenins of this type R muricatatins A 77 and B 7892have been isolated.Muricatatin OH OH B has a 1,2,3-triol at C-17 18 and 19 with a relative C-35compounds stereochemical relationship as threeerythro. A mono-acetyl 52 ‘cis-goniothalarnicin” 14-THF 4R,1 OR,13R,18SOH (i) derivative 4-acetyl gigantetrocin A 79,34has recently been 53 ‘16,19-ci~murisolin’06 IBTHF 4R,15R,20SOH (p) found and its absolute structure has been determined by 54 *~is-annonacin~~ 16-THF 4R,10 R,15 R,20 SOH (i) correlation to gigantetrocin A 75 whose absolute stereo-55 *cis-ann~nacin-lO-one~~ 16-THF 4R,15R,20SOH 10-0x0 (i) chemistry is known. C-37 compound Generally the Mosher ester method can be used directly to 56 *asirnineninA’’’ 16-THF 4R,15R,20SOH 23-ene (p) determine the absolute configurations of the flanking hydroxyl. The absolute configurations of the 1,2-diol in the 1,2,5-triol moiety with R,Ror S,S-stereochemistry among the gigante- 6.3 Annonacin A Type trocin A type of acetogenin can be solved either by use of per- There are seventeen acetogenins reported so far with the Mosher esters or by acetonide derivatives.An effort to solve the annonacin A type of structure 57-73; twelve of them are C-35 absolute configurations of the 1,Zerythro-diols of muricate- and five are C-37. These types of acetogenin are mono-THF trocin C 81 using the per-Mosher ester method has been ring compounds bearing two flanking hydroxyls with a made,32 but careful assignments of the ‘H NMR signals are threo-trans-erythro relative relationship. The flanking hy- necessary since it is difficult to distinguish the signals of 1,2- droxyls have R,S-stereochemistry and thus the 2,5-positions of diols in the per-Mosher esters.the substituted THF ring also have an absolute configuration of R,R.The stereochemistries of several compounds of this type threo trans (muricatocins B 6256and C 63,55longicin 5727and rollinecins A 72 and B 7362)have been proven to have the R-configuration R2ykR’ OH for the flanking hydroxylated carbon on the y-lactone or ketolactone side of the THF ring and the S-configuration for C-35 compounds 74 gigantriicin34-1’0 10-THF 14S,17R,18R-OH (9) ewthru trans threo 75 gigantetrocin 10-THF 4R,14S,17R,18R-OH (f i,q z) (10- 1 3- trans-1 3,14- fhree densicomacin’ ’ ’ ) 76 gigantetrocinBW4.& 10-THF 4R,14S,17S,18S-OH (f i) (10-1 3- trans-13~4-eryfhm ciensicornacin’ ”) C-35 compounds 77 ‘muricatatin A’* 1 O-THF 4,14,17,18(th),23-OH (i) 57 *~ongicin*~ 14-THF 4R,lOR,13R,18SOH (0) 78 “muricatatinBW 1 O-THF 4,14,17,18 (th) ,19(ery)-OH (i) 58 ‘murisolin A’06 16-THF 4R,15R,20S-OH (p) 79 ‘4-acetyl gigantetrocin A34 1 O-THF 4R-OAc 14S,17R,18R-OH (4) 59 annonacin A~ 16-THF 4,10,15,20-OH (rn) 80 rnuricatetrocin B64365 12-THF 4R,16S,19R,20R-OH (i) 60 annornuricinA’’ 1 6-THFI 4R 1 0,l1(th) 15R,20S-OH (i) 81 ‘muricatetrocin C3* 1 2-THFI 4R 1 6 S,19R,20S(ery)-OH (s) 61 annomuricin Be’ 1 6-THF 4R 1 0,ll (ery) ,1 5R,20S-OH (i) 82 ’murihexocin A34*37 12-THF 4R,7S,8S,16S,19R,20R-OH (i) 62 ‘rnuricatocin 8% 1 6-THF 4R,10,12( ery) ,15R,20SOH (i) 83 ‘rnurihexocin B34*37 12-THF 4R,7S,BS,16S,19S,20S-OH (i) 63 *rnuricatocinc~~ 16-THF 4R,10,12(th) 15R,20S-OH (i) 84 (2,4-ci -gigantetrocin- 1 0-THF 14S,17R,18R-OH ketolactone 64 ‘annohe~ocin~~ 16-THF 4,8,10,12,15,20-OH (i) A-OW’9 (2 94- cis) (PI 65 jetein97a’07 16-THF 10,15,20,33-OH 2,33-saturated (c) 85 (2,4-frans)-gigantetrocin-1 O-THF 14S,17/?),18R-OH ketolactone 66 *ann0temoyin-2’~ 18-THF 17,22-OH (a) A-one’ Oe (2,4-trans) (p) 67 (2,4-cis -annonacin- 16-THF 10R,15R,20SOH ketolactone A-One’ d (2A-W (P) C-37 compounds 68 (2,4- trans)-annonacin- 16-THF 10R,15R,20SOH ketolactone 86 gigantri~nenin~~*”~ 10-THF 14S,17R,18R-OH 21-ene (4) A-one’OB (2,4-trans)(p) 87 gigantetronenin’ l2 10-THF 4,14,17,18(th)-OH (senega~ene”~) 21-ene (I,q z) C-37 compounds 88 *~oriacin”~ 10-THF 4,14,21,22-OH 17-ene (d) 69 ’anno~enegalin’~ 16-THF 4,10,15,20-OH (c I) 89 ‘4-deoxy~oriacin”~ 10-THF 14,21,22-OH 17-ene (d) 70 *reticulatain-1109 18-THF 17,22-OH (k) 90 *(2,4-cis)-10-THF 14S,17/?,18R(th)-OH 21,22-ene 71 ‘reticulatain-2‘@ 20-THF 19,24-OH (k) gigantetronenin~ne~~ ketolactone (2,4-cis) (0) 72 *rollinecinA@ 18-THF 4,14R,17R,22SOH (s) 91 *(2,4-tfans)-1 O-THF 14S 1 7R 1 8R(th)-OH 21 -ene 73 *roIlinecinB@ 1&THF 4,14S,17R,22SOH (s) gigantetrone ninone’ ketolactone (2,4-trans) (0) 6.5 Muricatetrocin A Type Two examples 92 and 93 of the muricatetrocin A type of acetogenins have been published and both are C-35.This type of acetogenin has a mono-THF ring and one flanking hydroxyl. The relative stereochemistries are cis-threo. The flanking hydroxyl is on the terminal hydrocarbon chain side of the THF ring and is proven to have an S-configuration; thus the 2,5- positions of the substituted THF ring have an absolute stereochemistry of S,S.threo cis R2WRI OH C-35 compounds 92 *~is-gigantrionenin~~ 10-THF 14S,17R,18R-OH (9) 93 muricatetrocinA64865 12-THF 4R,16S,19R,20R-OH (i) 6.6 Muricatalin Type One acetogenin muricatalin 94,115was recently reported from Annona muricata to have a mono-THF ring and one flanking hydroxyl with a relative stereochemical relationship of trans-erythro. From the hypothetical biogenetic pathway for the formation of mono-THF acetogenins this type of compound can be assumed to have an R,S,R-configuration; however further experiments are still needed to prove its absolute NATURAL PRODUCT REPORTS 1996 methyl group and the nearest flanking hydroxyl carbon).Recently we found that longimicins A 102 and C 95 exhibit their terminal methyl signals at 60.880 under the same conditions (these have 13 carbons between the terminal methyl group and the flanking hydroxyl carbon) which is the same value as those of most mono-THF ring acetogenins (usually these also have 13 carbons between the terminal methyl group and the flanking hydroxyl carbon).29 threo threo trans I trans threo OH C-35ComDounds 95 *longimicin ~29 10,14-bis-THF 4R,QR,18R-OH (0) 96 *longimicin 12,16-bis-THF 4R,11 R,POR-OH (p) 97 squamocin-K1I6 14,l 8-bis-THF 13R,22R-OH (a m) (atemoyinn 98 14,l &bis-THF 4R,13R,22R-OH (a b m n) (squarnocin-E’ atemoyacin ~$1) 99 bullacin’ ” 14,l 8-bis-THF 6S,13R,22R-OH (b) 100 ci~isomolvizarin-2” 14,l 8-bis-THF 13,22-OH ketolactone (2,4-cis) (k) 101 trans-isomohrizarin-223 14,18-bis-THF 13,22-OH ketolactone (2,4-trans) (k) C-37 compounds 102 ‘longi*micinA2’ 12,16-bis-THF 4R,11 R,2OR-OH ( 0) stereochemistry.was initially reported to be of the muricatalin type; however comparisons of published data have led us to conclude that it is identical to gigantetrocin B.64,65 ervthro trans OH C-35 compound 94 ’muricatalin’ l5 1 O-THF 4,14,15( ery),l7,18(th)-OH (i) 7 Annonaceous Acetogenins containing Adjacent Bis-THF Rings Adjacent bis-THF ring compounds are the second largest group among the Annonaceous acetogenins. Eighty adjacent bis-THF acetogenins have been reported.They can be divided into eight types considering the stereochemistries of the THF rings and flanking hydroxyl(s). They are the most potent group biologically among all the acetogenins; some of them e.g. bullatacin 126 asimicin 105 trilobacin 163 and trilobin 164 are active at ED, values of < pg ml-’ to certain human tumour cell lines. 7.1 Asimicin Type The asimicin type of acetogenin has adjacent bis-THF rings bearing two flanking hydroxyls with relative stereochemistries of threetrans-threo-trans-threo. Twenty-one compounds of this type 95-115 have been reported. The THF ring is usually placed at C-10 C-12 or C-14 in the C-35 compounds and at C-12 C-14 or C-16 in the C-37 compounds. The system of the bis-THF rings and the two flanking hydroxyls is pseudo- symmetrical and the two flanking hydroxyls have R,R-stereochemistry ;thus the 2,5-positions of the substituted THF rings all have an absolute stereochemistry of R.Usually the terminal methyl group of adjacent bis-THF ring acetogenins shows a characteristic lH NMR signal at 6 0.878 as a triplet (in 500 MHz CDCl,) (there are nine carbons between the terminal 10,13-trans-13,14-erythro-Den~icomacin~~~103 ‘longimicin DB 14,18-bis-THF 1 OR,13R,22R-OH (0) 104 isodesacet ylwaricin’ 16,20-bis-THF 15,24-OH @ m x) (4-deoxyasimicin?8 squamocin-M”6) 105 asirnicinl 20-1 22.8 4R,15R,24R-OH (c I,m,p) (squarnocin-H’ ’6 106 narumicin P9 16,20-bis-THF 5,15,24-0H (x) 107 asiminl23 16,20-bis-THF 1 OR,15R,24R-OH (p) 108 squamocin- F’ l6 16,20-bis-THF 12,15R,24R-OH (m) 109 asiminacin’ 23 16,20-b~-THF,15R,24R,28S-OH (m p) (squamocin-D” 6,124) 110 asirninecin’ 23 15R,24R,29S-OH (p) 111 ‘asiminocin’ 25 15R,24R,3OS-OH(p) 112 ‘~ompound-2~~ 4R lOI15R,20 R-OH (m) 113 *cornp~und-l~~ 12,15R,20R,28SOH (k) 114 (2,4-~is)-asimicinone‘~ 15R,24R-OH ketolactone (2,4-cis) (p) 115 (2,4- trans)- 16,2O-bis-THF 1 5R,24R-OH ketolactone asimicinone’26 (2,4-trans) (p) 7.2 Bullatacin Type The bullatacin type acetogenins are epimers of the asimicin type of compound.Bullatacin and asimicin differ only at C-24; the former has C-24s and the latter has C-24R. Thus the bullatacin type acetogenins have a threo-trans-threo-trans-erythro relative relationship across their bis-THF rings and two flanking hydroxyls.Forty-six compounds of the bullatacin type 116-161 have so far been reported; seven of them are C-35 and thirty-nine are C-37 compounds. The THF ring system is usually placed at C-14 or C-16 and they have two to four hydroxyl groups ;a 172-erythro-diol has been found in annonin XIV 144.12’To place the R or S configurations on the proper side of the bis-THF ring system the mono-MTPA ester method was applied to bullatacin 126 which proved its (2-25s configuration,60 and the formaldehyde acetyl method combined with the MTPA ester method was applied to squamocin 129 which proved its C-15R configuration.,’ 7.3 Squamocin-I Type The squamocin-I type of acetogenin has exactly the same relative and absolute stereochemistries of the bis-THF ring and flanking hydroxyls as the bullatacin type; however the R and S flanking hydroxyl carbons are on the opposite side making them erythro-trans-threo-trans-threo (from right to left).The NATURAL PRODUCT REPORTS 1996-J. L. McLAUGHLIN ET AL. threo ervfhro trans I trans threo OH OH 16,20-bk-THF 4R,15R,24S,30R-OH (b) C-35 compounds 140 '(3OR)-hydroxybullata~in'~~ 116 neoannonin116 14,18-bis-THF 13R,22S-OH (m) 1 41 +31 -hydroxyb~llatacin'~~ 16,20-bk-THF 4R,15R,24S,31 R-OH (b) (squarnocin-Jl2' 142 *32-hydrox b~llatacin'~~ 16,20-bis-THF 4R,15R,24S,32R-OH (b) 117 molvizarin120s90~1 14,18-bis-THF 4,13,20-OH (c I,n) 143 panatkin' 4x 16,20-bis-THF 5,15,24,28-OH (x) 118 sq~amocin-B"~~'~~ 14,18-bis-THF 26S,13R,22SOH (m) 144 annonin XIV1" 16,2OO-bis-THF,11,12(ery),15-24-OH(m) I19 itrabingO*' 14,l a-bis-THF 13,22,23-OH 145 laherradurins0u121 16,20-bis-THF 15,24,35-OH 'O 2,33-sat urat ed (c) 2,35-saturated (c) 120 'atemoyacin B~~ 14,18-bis-THF 13,22,27-OH 146 (2,4-cis)-bullatacin-16,20-bis-THF 15,24-OH ketolactone 121 cisisomoivizarin- 1 23 14,18-bis-THF 13,22-OH ketolactone 0ne8.57,95,23.58 (2,4-cis) (b k m p) (2,4-cis) (k) 147 (2,4-trans)-bullatacin-1 6,20 -b is-T H F 1 5,24-0 HI ke tolactone 122 trans-isomo~vizarin-~~~14,18-bis-THF 13,22-OH ketolactone 0ne8,57,95,23,58 (2,4-trans) @ k rn P) (2,4-fmn~)(k) 148 (2,4-cis)-lO-h dro Y-16,20-bis-THFI 10,15,24-OH ket olactone bullatacinoneY43s14 (2,4-cis) (b) C-37 compounds 149 (2,4-frans)-lO-h droxy- 16,200-bis-THF 10,l 5,24-OHI ketolactone 42 123 *squamotacin2 14,18-bis-THF 4,13,22-OH (9 rn) bullata~inone'~~~ (2,4-tmns) @) (g~aucanisin' 150 (2,4-cis)-12-h dro 16,2O-bis-THF 12,15,24-0H ketolactone ' 16,20-bis-THF 15R-OH 24S-OAc (j w) bullatacinoneY43,Y-(2,4-cis) (b) 124 ~varicin~~~~'~~ 16,20-bis-THF 15R,24S-OH (b m w) 151 (2,4-trans)-12h droxy-16,20-bis-THF 12,15,24-0H ketolactone 125 desa~etvlwaricin'~~~'~~ 42 (squam&in-L116) bullatacin~ne'~~~ (2,4- trans) @) 126 bullatacin57~8~58~95.'05 16,20-bis-THF 4R,15R,24S-OH 152 *(2,4-cis)-28-hydroxy-16,20-bis-THF 1 5R,24S,28S-OHV (squamocin-G,"' (b c I,k m n P s) bullata~inone'~~ ketolactone (2,4-cis) (b) 14-hydroxy-25-153 '(2,4-trans)-28-hydroxy-16,20-bis-THF 15R,24S,28R-OH desoxyrollinicin,'34*'35 b~llatacinone'~~ ketolactone (2,4-trans) (b) rolliniastatin 2.135,90 154 (2,4-cis)-29-h dro Y-16,2O-bis-THF 15R,24S,29S-OH Y annonin VI'~~ bullatacinone 43*1 ketolactone (2,4-cis) (b) 127 narumicin 11" 1 16,20-bis-THF 5,15,24-OH (x) 1 55 (2.4-trans)-29-hydroxy-1 6,20-bis-THF 1 5 R,24 S,29 R-OH ,142 ket olactone (2.4- frans) (b) 128 bullat in' 36 16,200-bis-THF 10S,15R,24SOH (r) b~llatacinone'~ 129 squamocin90,Q8,1 13.124.16,2O-bis-THF 15R,24S,28SOH 156 (2,4-cis)-30-hg!roxy-16,20-bis-THF 15R,24S,30-OH 1122) 128.137.138,51(annonin (b c rn I r k) bullatacinone 9142 ketolactone (2,4-cis) @) 130 r~llinicin'~~ 16,20-bis-THFl 15,24,28-OH (1) 157 (2,4-trans)-30-hydroxy-1 6,20-bis-THF 15 R,24S,30-OH ' 42 131 squamocin-28-0ne'~~ 16,20-bis-THF 15,24-0H 28-0x0 (x) b~llatacinone~~' ketolactone(2,4-trans)(b) 132 motrilin squamocin-C) 16,20-bis-THF 15R,24S,29SOH (c m) 158 (2,4-cis)-31 -h droxy- 16,20-bis-THF 15R,24S,31-OH 133 b~llaninj~~ 16,20-bis-THF 15,24,30-OH (p) b~llatacinone'~~~~ ketolactone (2,4-cis) (b) 134 '(30S)-b~llanin'~' 16,20-bis-THF 15R,24S,30SOH (p) 159 (2,4-frans)-31-hydroxy-16,2O-bis-THF 15R,24S,31-OH 42 135 *(30R)-bullanin141 16,20-bis-THF 15R,24S,30R-OH (p) b~llatacinone~*' ketolactone (2,4-trans) (b) 136 purp~reacinl~~ 16,20-bis-THF 4,12,15,24-OH (j) 160 (2,4-~k)-32-hgt~~-16,20-bis-THF 15R,24S,32-OH 137 +annoglaucin26 16,20-bis-THF 4,10,15,24-OH (9) bullatacinone ketolactone (2,4-cis) (b) 138 ri~clarin~~~ 16,2O-bis-THF 4,15,24,28-OH (r) 161 (2,4-trans)-32-hydroxy-16,2O-bis-THF 15R,24S,32-OH 139 *(30S)- hy droxy bullatacinl 42 16 ,20-bis-THFl 4R,lSR,24S,30S-OH (b) b~llatacinone~~'~~ ketolactone (2,4-trans) (b) assignments of the stereochemistries of this compound were etythro made by direct comparison of squamocin-J (neoannonin) and threo cis I trans threo squamocin-I ;l16 the two compounds have different retention times on reversed phase HPLC and also there are tiny differences of some signals in the 13C NMR spectra.Since squamocin-I 162 represents a new type of structure further OH 6H evidence would be helpful to confirm its absolute stereo- C-37 compounds chemistry. 163 triloba~in~~~~~ 16,20-bis-THF 4R,15R,24R-OH (p) 164 trilobin5' 16,20-bis-THF 10R,15R,24R-OH (p) threo 165 'asitribing4 16,2O-bis-THF 15R,24R,28S-OH @) threo trans I trans eryfhro OH OH 7.5.Squamocin-N Type The squamocin-N type of acetogenin has a threo-cis-three C-35 compound cis-threo relative stereochemical relationship and R,R con-162 squamocin-1116 14,18-bis-THF 13S,22R-OH (m) figurations for the adjacent bis-THF rings and their flanking hydroxyls. This type of structure is pseudo-symmetrical and using the MTPA ester method can give definite results. Only 7.4 Trilobacin Type one C-37 compound of this type 166 has been reported.l16 The trilobacin type of acetogenin has a threo-trans-erythr+ cis-threo relative stereochemistry and R,R-configurations for their adjacent bis-THF rings and two flanking hydroxyls. Three threo C-37 compounds of this type 163-165 have been isolated so far threo cis 1 cis threo from Asimina triluba.They are probably the most potent acetogenins discovered so far; in several solid human tumour cell lines they are active at ED, values of < 10-l' pg m1-1.58.59 Since they have the erythro configuration between the two THF rings these erythro protons show characteristic signals in their C-37 compound lH NMR spectra at S 3.95-4.05 as two separated multiplets. 166 squamocin-N116 16,20-bis-THF 15R,24R-OH (m) 7.6 Rolliniastatin 1 Type Five acetogenins 167-171 have been published so far having the rolliniastatin 1 type of adjacent bis-THF structure with two flanking hydroxyls. They have a threo-cis-threo-cis-erythro relative stereochemical relationship and R,S configurations around the adjacent bis-THF rings and flanking hydroxyls. The absolute stereochemistry of rolliniastatin 1 168 was proven by Mosher ester analysis8 and has now been confirmed by total ~ynthesis.'~ threo ervthro cis I cis threo C-37 compounds 167 rnembranacini3* 16,20-bis-THF 15,240H (r) 168 rolliniastatin 114438p'38~132 16,2O-bis-THF 4R,15R,24R-OH (i r s) 169 4-hydroxy-25- 16,20-bis-THF 4,15,24-OH (1) deoxyneoro~~inicin' 45 170 (2,4-cis)-r0llinone'~,'~~16,20-bis-THF 15,24-OH ketolactone (2,4-cis) (s) 171 (2,4-tran~)-rollinone'~~~'~ 16,20-bis-THF 15,24-OH ketoladone (2,4-tmn~)(s) 7.7 Bulladecin Type The bulladecin type acetogenins have adjacent bis-THF rings and one flanking hydroxyl.The MTPA ester method was applied to asimilobin 172 and goniodenin 173; in this way the absolute stereochemistry of the flanking hydroxyl carbon was determined to be S.By tracing the trans-threo-trans-threo relative relationship the 2,5-substituted THF rings have an absolute stereochemistry of R,S,S,S respectively. This unique structural feature prompts us to speculate that their biogenesis starts with cyclization from the left hand side of the molecule (see Scheme 3). threo threo trans I trans C-35 compound 172 *asimilobin94.bq 10,i rbbis-THF C-37 compounds 173 'g~niodenin~~ 10,14-bis-THF 4R,18SOH 21,22-ene (9) 174 (2,4-cis)- 1 2,l 6-bis-THFt 20,23,24(ery)-OH bulladecinone' 42*50 ketolactone (2,4-cis) (b) 175 (2,rbrrans)- 12,16-bis-THF 20,23,24(ery)-OH bullade~inone'~~~~~ ketolactone (2,4-trans) (b) 7.8 Rollidecin A Type Two rollidecin A types of C-37 acetogenin 176 and 177 have been isolated recently from Rollina mucosa.The flanking hydroxyl carbon was determined to have an absolute con- figuration of R by the Mosher ester method and the two THF rings were deduced to be trans and cis respectively. Since no model compounds are available for comparison further evidence is needed to confirm the absolute stereochemistry of this type of acetogenin. thmo threo cis I trans OH C-37 compounds 176 *rollidecin A32 12,le-bis-THF. 4R,20R,23R,24R-OH (s) 177 'rollidecin B32 12,16-bis-THF 4R,20R,23R,24SOH (s) NATURAL PRODUCT REPORTS 1996 8 Annonaceous Acetogenins containing Non- adjacent Bis-THF Rings Twenty-eight non-adjacent bis-THF acetogenins have been reported so far and they can be divided into seven types.They are the gigantecin 12 15-cis-bullatanocin bullatalicin 12,15- cis-bullatalicin sylvaticin cis-sylvaticin and aromin types. The first six types consist of two separated mono-THF rings one bearing one flanking hydroxyl and the other bearing two flanking hydroxyls and the two THF rings are separated by four carbons. The last type the aromin type has two THF rings at C-4 and C-14. Because the spectral features are quite similar to some of the adjacent bis-THF ring acetogenins some incorrect structures and/or assignments of relative stereochemistries exist in the 1iterat~re.l~~'~~~ The formaldehyde acetal method was introduced to determine the absolute stereochemistries of the non-adjacent bis-THF ring acetogenins and provided unambiguous solutions of the absolute structures for bulla- tanocin 182 bullatalicin 191 cis-and trans-bullatanocinones and cis- and trans-bullatali~inones.~~ Later the same method was used with sylvaticin 203 and cis-sylvaticin 204.148Using per-Mosher ester derivatives compared with model compounds the absolute stereostructures of squamostatins-C 184 and -E 181 and squamostatins-A194 -B 192 and -D 190 have been determined.149 Recently the absolute structure of gigantecin 180 has also been determined by X-ray crystallography and the Mosher ester meth~d.~ 8.1 Gigantecin Type The gigantecin type acetogenins have two non-adjacent THF rings separated by four carbons.One THF ring has one flanking hydroxyl and the other has two flanking hydroxyls.By comparisons with model compounds of mono-THF rings bearing one or two flanking hydroxyls it is not difficult to determine their relative configurations. They are trans-tho threo-trans-threo (from right to left). Several compounds of this type have had their absolute stereostructures defined by using the formaldehyde acetal and Mosher ester methods.51 The stereochemistry of the mono-THF ring with one flanking hydroxyl is the same as that of the gigantetrocin A type of mono-THF acetogenin and the stereochemistry of the other mono-THF ring with two flanking hydroxyls is the same as that of the annonacin type of acetogenin. Nine compounds 178-186 belong to the gigantecin type one is C-35 and eight are C-37.tho trans threo threo trans C-35 compound 178 parvifl~racin"~ 10,18-bis-THF 4,14,17,22-OH (n) C-37 compounds 179 4-deoxygigante~in~ 10,18-bis-THF 14,17,22-OH(9) 180 gigantecin' 50v9 10,l 8-bis-THF 4,14,17,22-OH (d 4) 181 squam~statin-E'~~ 12,20-bis-THF 16S,19R,24R-OH (m) 182 buIlatanocin5' ,15'3'52 12,2O-bis-THF 4R 16S 1 9 R,24 R-OH (annonin IV,'~~ (b e m) crassif~orin~~) 183 cherim0lin-2~~ 12,20-bis-THF 4,16,19,24-OH (C) 12,2O-bis-THF 4R,16S,19R,24R-OH (rn) 184 sq~m~statin-C'~~ *'52 12,20-bis-THF 16S,19R,24R-OH, 185 (2,4-cis)- bullatan~cinone~' ketolactone (2,4-cis) (b) *'52 12,20-bis-THF 1 6S,l9R,24R-OH 186 (2,4-trans)- b~llatanocinone~' ketolactone (2,4-trans) (b) 8.2. 12,15-cis-Bullatanocin Type The 12,15-cis-bullatanocin type of acetogenin is different from the gigantecin type at only one chiral centre; it has an S-configuration at the first THF ring on the non-flanking hydroxyl side whereas the gigantecin type has an R-configuration at this NATURAL PRODUCT REPORTS 1996-5.L.McLAUGHLIN ET AL. chiral centre. These acetogenins have cis-threo threo-trans-threo relative stereochemical relationships with their respective THF rings and flanking hydroxyls. Three C-37 acetogenins of found and all have C-12s threo threo cis 8.5 Sylvaticin Type The sylvaticin type of acetogenin so far has only one example. This type of compound has a trans-threo threo-cis-erythro relationship for the THF rings and flanking hydroxyls. Sylvaticin 203 was the third example reported of the non- adjacent bis-THF ring acetogenins ;incorrect assignments were made for the erythro configuration at C-19/20 and both THF rings were assigned as trans.15sThe revision of the structure was first made in our third review based on the reanalysis of published spectral data;20 later the formaldehyde acetal and Mosher ester methods provided experimental evidence of the absolute In sylvaticin 203 the second THF ring and flanking hydroxyls have a threo-cis-erythro relationship.No other natural mono-THF ring acetogenins so far have been found to have this relationship. ewthro cis threo threo trans C-37 compound 203 syIvati~in~~*~’~~~’~ 12,20-bis-THF 4R,16S,19R,24SOH (j u s v) (uleicin 8.6 cis-Sylvaticin Type The cis-sylvaticin type of acetogenin also has only one example.cis-Sylvaticin 204 and sylvaticin 203 are epimeric. They are different at C-12 as cis-sylvaticin is C-12s and sylvaticin is C- 12R. The absolute stereostructure of cis-sylvaticin 204 has been recently determined also by the formaldehyde acetal and Mosher ester methods. It has S,S,S-stereochemistry for the first THF ring and its one flanking hydroxyl and S,S,R,S,-stereochemistry for the second THF and its two flanking hydroxyls. etythro cis threo threo cis C-37 compound 204 *cksybat kin1 48 1 2,20- bis-THF 4R 1 6S,19 S,24 SOH (s) 8.7 Aromin Type Aromin 205 and aromicin 206 represent a new type of acetogenin recently isolated from Xylopia arornatica. This type of compound has two-non-adjacent THF rings at C-4 and C-15 the first THF ring without any flanking hydroxyls and the second THF ring bearing two flanking hydroxyls.They differ in that aromin 205 is C-35 and aromicin 206 is C-37 with two additional methylenes on the hydrocarbon end of the chain. threo trans threo trans C-35 compound 205 *ar~min~~ 4,16-bis-THF 15R,20R-OH 9-0x0 (z) C-37 compound 206 *a~ornicin~~ 4,16-bis-THF 15R,20R-OH 9-0x0 (z) this type 187-189 have been configurations. threo trans OH C-37 compounds 187 12,15-cis-12,20-bis-THF 4R,16S,19R,24R-OH (b) bullatanocin’53 188 (2,4-cis)-12,15- cis- 12,24-bis-THF 16S 19 R,24R-OHI bullatanocinone‘53 ketolactone (2,4-cis) (b) OH OH 189 (2,4- trans)- 12.1 5- cis-12,24-bis-THF 16S l9R,24R-OHt bullatanocinone’53 ketolactone (2,4-trans) @) 8.3 Bullatalicin Type The bullatalicin type of acetogenin is also epimeric with the gigantecin type of compounds.The difference between the bullatalicin type and the gigantecin type is at the flanking hydroxyl carbon of the second THF ring on the side of the terminal hydrocarbon chain. The bullatalicin type have trans-threo threetrans-erythro relative stereochemical rela- tionships at the two THF rings and flanking hydroxyls. Nine C- 37 compounds 190-198 belong to this type of acetogenin and all are C-24s. 190 191 192 193 194 195 196 197 198 8.4 ervthro trans threo threo trans 16S,19R,24S-OH (m x) 4R,16S,19R,24R-OH (b m) 51 (annonin VIII’27) squam~statin-B’~~~~~~ 4R,16S 19R,24R-OH (m) cbrimolifil 155,90.132 4,16,17,24-0H (c j) squamost at in-A 24s 16S,19R,24R,28S-OH (m) 149.156 (annoninXVI,’~~ squamostatin-B‘ 57) a~munequin~**~~’ 12,20-bis-THF 16S,19R,24R,28S-OH (c k) ” otivaringO 12,2O-bis-THF 16,19,24,35-OH (dihydrocherimolin)55 2,35-saturated (c) (2,4-cis)-12,20-bis-THF 16S,19R,24R-OH bullatalicinone (cis-iso- ketolactone (2,4-cis) (b,k) c~~m~in23.51,147.1511 (2,4- trans)- 16S,19R,24R-OH ketolactone (2,4-trans) (b k) The 12,15-cis-bullatalicin type acetogenins are epimeric to the bullatalicin type just as the 12,15-cis-bullatanocin type is epimeric with the gigantecin (bullatanocin) type.They are different at the first THF ring on the non-flanking hydroxyl side. They have cis-threo threo-trans-erythro relative relation- ships at the THF rings and flanking hydroxyls.Four C-37 acetogenins 199-202 belong to this type and all are C-12s and c-24s’ ervthro trans threo threo cis C-37 compounds 199 12,154s-12,20-bis-THF 4R,16S,19R,24S-OH (b) bullatalicin‘ 53 200 12,15-~iS 12,20-bis-THF 16S,19R,24S,28SOH (m) squamostatin-A’569149 201 (2,4-cis)-12,15-cis-12,24-bis-THF 16S,19R,24SOH bullatalicinone’53 ketolactone (2,4-cis) (b) 202 (2,4-trans)- 12,15- cis 12,24-bisTHF 16S,1 9R,24SOHt bullatalicinone’53 ketolactone (2,4-lrans) @) 9 Annonaceous Acetogenins containing Non- adjacent THF and THP Rings 9.1 Mucocin Type A unique acetogenin containing a tetrahydropyran (THP) ring mucocin 207,has been recently isolated from Rollinarn~cosa.~~ 223 *c~riadenin”~ NATURAL PRODUCT REPORTS 1996 C-37 compounds 217 *tonkinelin’6a 17,18( fh)-OH (y) 218 dieporeticanin-1165 17,21-epoxy (k) 219 dieporeticanin-2165 19,23-epoxy(k) 220 dieporeticer~in’~~ 15,19-epoxy 23-ene (k) 221 tripoxyro~~in~~~ 1 5,19,23-epoxy (r) 222 triep~reticanin’~~ 15,19,23-epoxy (k) 4,10,21,22(th)-OH 13,17-diene (d) Mucocin has a mono-THF ring bearing one flanking hydroxyl and a 2,6-substituted 5-hydroxy pyran ring.The hypothetical biogenetic pathway for mucocin (Scheme 4) is quite similar to those of several other non-adjacent bis-THF ring acetogenins such as sylvaticin 203,and bullatalicin 191;it seems that the cyclization simply started from C-23 instead of from C-24. Mucocin 207 showed very good potencies against several human solid tumour cell lines (lung carcinoma ED 1.O x lop6 pg ml-l; pancreas carcinoma ED, 4.7 x lop7 pg m1-I) and was active in inhibiting oxygen uptake by rat liver mito- chondria ; the latter observation demonstrated that some new cytotoxic mechanism was not created by the THP ring.31 threo threo trans R2 OHS OH R l C-37 compound 207 *rnucocin3’ 12-THF 20-THP 4R,16S,19S,23R-OH (s) 10 Annonaceous Acetogenins containing Adjacent Tris-THF Rings 10.1 Goniocin Type The goniocin type of acetogenin has only one example 208.The relative stereochemical relationship seems to be trans- threo-trans-threo-trans-threo based on the analysis of ‘H NMR data. Using the Mosher ester method the flanking hydroxyl carbon was determined to have the R-configuration.The other chiral centres thus were deduced from the relative stereochemistries. threo threo threo trans I trans I trans i)H C-37 compound 10,14,18-tri-THF 4R,22R-OH(9) 208 g~niocin~~ 11 Annonaceous Acetogenins containing no THF or THP Rings These refer to the growing list of Annonaceous compounds with (2-35 or C-37 long hydrocarbon chains and a methylated cc,P-unsaturated y-lactone at one end but no THF or THP rings. They often bear hydroxyls ketones epoxides and/or double bonds. Due to the locations of their dienes expoxides or hydroxyls they are considered to be precursors in the formation of the THF or THP acetogenins. So far fifteen non-ring acetogenins 209-223 have been isolated.C-35 compounds 209 ret iculat arnol’ 6o 15-OH (k) 21o *reticu~atarnone~~~ 15-OX0 (k) 21 1 giganinI6’ 4,10,17,18( ih)-OH 13-ene (4) 212 epornuricenin-B’62 13-epoxy 17-ene (i) epornurienin-A’62 15-epoxy 19-ene (i) (epoxyrnurin-A’ 63) 21 3 epoxyrnurin-B’63 19-epoxy 15-ene (i) 15,lg-epoxy (i k) 214 dieporn~ricanin‘~~’~~ 21 5 corepoxytone’66 15,19-epoxy 10-0x0 (i) 216 *~enezenin’~~ 4,17,18(ih)-oH 21-ene 10-0x0 (z) I2 Semi- and Totally-synthesized Annonaceous Acetogenins The potent and diverse bioactivities of Annonaceous aceto- genins are attracting the attention of many synthetic chemists who are striving to achieve their total syntheses. Earlier results have been summarized in our previous three More recent successes include the total syntheses of bullatacin asimicin 105,10.11 126,10.11.13 ( +)-15,24-bisepi-bullatacin227,13 corossolone 8 and corossolin 7,1° gigantetrocin A 75 [13,14-threo-densic~rnacin],~~ and parviflorin 98.12It is interesting to observe that the unnatural ( + )-I 5’24-bisepi-bullatacin 227 has decreased in vitro antitumour activity against P388 compared with bullatacin 126,its natural stere~isomer.~~ To date most synthesized acetogenins belong to the mono- THF ring and adjacent bis-THF ring compounds.It is generally difficult to synthesize acetogenins of the latter type due to the increased complexities of their stereochemical structures although their superior bioactivities are attractive. Almost without exception convergent strategies based on the coupling of a bis-THF ring core and a terminal y-lactone synthon are employed.Although the tactical details are very individualistic with each synthetic team it seems that for most cases the construction of the bis-THF ring moiety involves the opening of epoxide(s) by neighbouring hydroxyl(s) which are often masked in the earlier stages of the synthesis. This idea which was termed as directional ‘epoxide cascading’ by Hoye et a!. 170 is very reminiscent of the hypothesized biogenesis of the acetogenins (Schemes 14).20.38339 To achieve the specific stereochemistry either chiral starting materials or some efficient asymmetric reactions such as Sharpless asymmetric epoxi- dation and Sharpless asymmetric dihydroxylation are employed.The enantiomeric excesses of the intermediates are usually monitored by applying Mosher’s method. It is amazing that several teams have already achieved two-digit total yield returns after executing fifteen or more synthetic steps. No successful syntheses of the other major type acetogenins i.e. those having adjacent bis-THF rings bearing one flanking hydroxyl non-adjacent bis-THF rings non-adjacent THF and THP rings and adjacent tris-THF rings have been reported to date. This could be related to the challenge of modifying the existing protocols for synthesizing other types of acetogenin. For more details about the syntheses interested readers are asked to refer to the original papers as listed above and some reviews which are devoted to this specific area.42*171-172 During the structural determinations and total syntheses of acetogenins some unnatural acetogenins have been produced.Because these compounds are unnatural they could not be conveniently classified in the same way as the natural acetogenins. These are the mono-THF ring acetogenin 10,15R 16S719S,20S,34R- corossolin 224173 the adjacent bis-THF acetogenins ( +)-15,16,19,20,23,24-hexepi-uvaricin 225,1’4(-)-bullatacin 226,175(+)-15,24-bisepi-bullatacin 22713and cyclogonionenins C 228 and T 229’’’ the non-adjacent bis-THF acetogenin C- 18,2 1-cis-gigan-tecin 2301°0 the adjacent tris-THF acetogenins cyclogoniodenins C 231 and T 23244 NATURAL PRODUCT REPORTS 1996-J. L. McLAUGHLIN ET AL. 29 1 32 OH OH 0 224 105,15 R,16S,19S,2OS,34 R-corossolin thmo -7 OH 0 225 (+)-15,16,19,20,23,24-hexepCuvaricin 13 Uncertain Structures of Acetogenins In our previous reviews we revised several incorrect structures of acetogenins.However there are still some published structures of acetogenins which remain uncertain. These structures will be presented here. Isorollinicin was reported as a non-ring acetogenin with one hydroxyl but the placement of the hydroxyl was Uleicins-B D and E have been described as adjacent bis-THF ring acetogenins bearing two flanking hydroxyls a 4-hydroxyl and one more hydroxyl which could not be defined; uleicin-C was a non-adjacent bis- THF a~et0genin.l~~ The authors mentioned in a more recent publication that their published structures were in~0rrect.j~ Purpureacin-1 was published as a non-adjacent bis-THF acetogenin without the assignment of relative stereochemistries.From the published data it seems to be a mixture of C-12/15 cis and -trans isomers.132 Annonastatin and epoxyrollins A and B were reported to be C-38 or C-36 No high resolution MS data supported the proposed molecular formulae; these structures could be highly unusual and it is unlikely that they will be confirmed. 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Longifolicin 1,27C,,H,,O, MW 580 threo trans 3% CHdCH2h07(C 32 17 o"14H 13 2 10 )540 OH OH 0 Carbon No. 10 13 14 17 18 'H(6) 3.63 m 3.45 m 3.83 m 3.82 m 3.41 m "C(4 71.61 74.32 82.71 82.59 74.03 White waxy solid; MP 83 "c; [MID + 13.0" (C 0.001 CH,Cl,); UV (A,,, MeOH nm) 228 (log F = 2.43); IR (v,,, film cm-') 3400,2900,2820 1750 1440 1300 1073,667; MS CI-MS (isobutane m/z) 581 563 545 527; NMR 'H NMR (500 MHz CDCl,) 13C NMR (1 25 MHz CDCl,) ;Derivatives tri-acetate (lH NMR); formal acetal ('H NMR); TMS (EI- MS); per-Mosher ester (lH NMR); Biological activities BST LC, = 3.52 ,ug ml-l A-549 ED, = 1.13 x lo- pg ml-l MCF- 7 ED, = 1.23 x lo-' ,ug ml-l HT-29 ED, = 1.23pg ml-l A-498 ED, = 4.55 x 10-' pg ml-' PA-3 ED, < lo-' pg ml-l PaCa-2 ED, = 4.22 x lo- pg ml-l; Source:Asimina longifolia leaves and twigs.2. Arianacin 3,' C3,HS40, MW 596 Carbon No. 12 15 16 19 20 'H(6) 3.60 m 3.46ddd 3.80 m 3.80 m 3.41dt 13C(6) 71.8 74.4 82.6 82.7 74.1 White amorphous powder; MP 64°C; [a] +12.5" (c 0.14 CHCl,); UV +(A,,, MeOH nm) 215 (F = 12500); IR (vmax film cm-l) 3629 2925 2847 1734 1469; MS CI-MS (isobutane m/z)597,561,543,526;EI-MS (m/z)327,309,291 269 199; NMR 'H NMR (500MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives formal acetal ('H NMR) TMS (EI-MS); Biological activities BST LC, = 7.1 pg ml-' PD % inhibition = 26 % A-549 ED, = 4.7 x lop3pg ml-l MCF-7 ED, = 0.4 pg ml-l HT-29 ED, = 4.4 pg ml-l Source Annona muricata seeds.3. Javoricin 4,73C35H6407, MW 596 Carbon No. 12 15 16 19 20 'H(6) I3C(6) 3.63 m 71.6 3.46ddd 74.3 3.77-3.85 m 82.5 3.77-3.85 m 82.7 3.41dt 74.1 NATURAL PRODUCT REPORTS 1996 White amorphous powder; MP 70°C; [a] f13.6" (c 0.1 CHC1,); UV (A,,, MeOH nm) 217 (e = 11800); IR (v,,, film cm-') 3450 2924 2853 1750 1457; MS CI-MS (isobutane m/z) 597 561 543 526; EI-MS (m/z) 327 309 291 ;NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-acetate (lH NMR) TMS (EI-MS); Biological activities BST LC, = 4.9 pg ml-l PD YOinhibition = 47 YO A-549 ED, = 1.7 x lo-' pg ml-' MCF-7 ED, = 0.23 pg ml-' HT-29 ED, = 1.8 pg ml-l Source Annona muricata seeds.4. Reticulacinone C35H6207, MW 594 Carbon No. 11 15 16 19 20 'H(6) -3.4 m 3.8-3.95 m 3.8-3.95 m 3.40 m 13C(6) 211.5 74.1 82.6 82.6 73.9 Waxy solid MS EI-MS (m/z) 583 581 571 557 555 529 489 487 471 459 431 429 401 375 361 359 357 331 301 259; NMR lH NMR (400 MHz CDCl,) 13C NMR (50 MHz CDC1,) ; Source Annona reticulata stem bark.5. Muricatocin A 13,, C,,H,,O, MW 612 pseudo-^r thm trans threo erythro 33 32 CHdCH2h1 19 o.-16 OH OH 0 Carbon No. 10 12 15 16 19 20 'H(6) 3.94m 3.86m 3.45 m 3.85 m 3.87m 3.46 m l3C(6) 72.82 72.60 74.39 82.69 82.45 74.03 White powder; [a],+21.8" (c 0.001 EtOH); UV (A,,, MeOH nm) 216 (c = 8500); IR (v,,, film cm-l) 3433 2920 2851 1747 1466 1321 1076; MS CI-MS (BuOH m/z) 613 595 577 559 541 523 413 395 377 359 353 343 325 285 271 269 241 223 205 199 141; EI-MS (m/.~) 325 307 269 241 223 213 199 141 ; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives acetonide ('H NMR) per-acetate ('H NMR) per-MTPA esters ('H NMR) TMS (EI-MS); Biological activities BST LC, = 6.99 x lO-',ug ml-l A-549 ED, = 7.55 x pg ml-' MCF-7 ED, = 1.23 x lo-' pg ml-l HT-29 ED, = 1.56 pg ml-*; Source Annona muricata leaves.6. Annomuricin C 14,j5C,,H,,O, MW 612 threo trans thrm threo 32 OH OH OH 0 Carbon No. 10 11 15 16 19 20 ~~ 'H(6)I3C(6) 3.43 m 74.14 3.43 m 74.16 3.41 m 74.39 3.83 m 82.72 3.85 m 82.56 3.40 m 74.39 NATURAL PRODUCT REPORTS. 1996-J. L. McLAUGHLIN ET AL. APPENDIX White powder; [a] +57.7" (c. 0.0005 EtOH); UV (A,,, MeOH nm) 220 (c = 3800); IR (vmax film cm-l) 341 1 2920 2851 1743 1467 1321 1073; MS CI-MS (BuOH m/~) 613 595 577 559 541 395 377 353 325 271 269 253 241 223 205 199 141; EI-MS (m/~) 341 325 307 269 241 223 213 205 199 141 ; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCI,); Derivatives acetonide ('H NMR) per- acetate ('H NMR) per-MTPA esters ('H NMR) (EI-MS); Biological activities BST LC, = 6.13 x lo-' pg ml-' A-549 ED, = 3.08 x lo-' pg ml-l MCF-7 ED, = 2.28 x lo-' pg ml-l HT-29 ED, = 1.54 pg ml-l; Source Annona muricata leaves.7. Muricatatin C 19,92C,,H,,O, MW 614 OH OH OH 0 Carbon No. 10 15 16 19 20 25 'H(S) -3.37 m 3.80 m 3.80m 3.37 m 3.80m I3C(S) 211.04 73.77 82.58 82.72 74.06 74.34 Amorphous solid; MP 61 "C; [a],+ 15.40" (c 0.49 MeOH); IR (vmax film cm-I) 3400 1740; MS EI-MS (m/z)51 1 481 463 445 427 425 407 389 395 377 359 325 307 289 239 21 1 141; NMR 'H NMR (400 MHz CDCl,) 13C NMR (100 MHz CDCI,) ;Source Annona muricata seeds and stem bark. 8. 4-Acetyl annonacin 20,28 C,,H,,O, MW 638 threo trans fhreo ?* OH OH 0 Carbon No.4 10 15 16 19 20 'H(S) 5.10m 3.59m 3.41 m 3.80dt 3.80dt 3.41 m I3C(S) 71.9 71.7 74.0 82.6 82.6 74.0 Colourless wax; MP 67-68 "C [a] + 13" (c 0.10 MeOH); NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,) ;Derivatives per acetate (lH NMR) per-MTPA esters ('H NMR) TMS (EI-MS); Biological activities BST LC, = 21.86 pg ml-l A-549 ED, = 3.38 x lo- pg ml-l MCD-7 ED, = 2.65 x lo-' pg mP1 HT-29 ED, = 1.85 x lo- pg ml-l A-498 ED, = 3.59 x pg ml-l PA-3 ED, = 3.56 x 10-' pg ml-l PaCa-2 ED, = 1.46 x lo- pg ml-l; Source Asimina longifolia leaves and twigs. 9. Annotemoyin-1 2l,' C,,H,,O, MW 564 fhreo trans thmo H2) ,4 32 cH3(CH2)Q~(C White waxy solid; [a],+21" (cO.13 MeOH); UV (A,,, EtOH nm) 216.9 (log B = 3.63); IR (v,,, film cm-I) 3448 2927 2857 1756 1652 1452 1376 1321 1116 1064 1028,952,872 754 724; MS CI-MS (methane) 565 547 529 511 393 375 323 305 295 267 241 223 171 167 153 139 125 111 97; EI-MS 528 375 357 347 323 295 267 241 223 205 153 139,135,125,111,97;NMR 'H NMR (200 MHz CDCl,) 13C NMR (50 MHz CDCl,); Source Annona atemoya seeds.Goniothalamicinone 22/23,27 C,5H6407 MW 596 (reported as a cis and trans mixture) fhreo trans fhreo 10. (2,4-~is)-GoNothalamicinone22 (A = cis) Carbon No. 10 13 14 17 18 'H(S) 3.65 m 3.45 m 3.83 m 3.83 m 3.41 m l3C(S) 71.6 74.4 82.6 82.6 74.0 11. (2,4-trans)-Goniothalamicinone 23 (A = trans) Carbon No. 10 13 14 17 18 'H(S) 3.65 m 3.45 m 3.83 m 3.83 m 3.41 m 13C(S) 71.6 74.4 82.6 82.6 74.0 Whitish wax; MP 98 "C; [a] +22.9" (c 1.0 CH,Cl,); UV (A,,,, MeOH nm) 210 (c = 10000); IR (v,,, film cm-l) 3450,2900,2820 1782 1726 1457 1388 1218 1072; MS CI-MS (isobutane m/z)597,561,543,525,351,333,309,297,281 263 245 241 141; NMR lH NMR (500MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives tri-acetate (lH NMR) per-MTPA esters (lH NMR) tri-TMS (EI-MS); Biological activities BST LC, = 0.14 pug mP1 A-549 ED, = 2.06 x lo-') pg ml-l MCF-7 ED, = 9.67 x 10-1 pg rnl-l HT-29 ED, = 4.05 x pg ml-l A-498 ED, = 2.91 x 10-1 pg ml-l PA-3 ED, = 1.37 x 10-1pg ml-l PaCa-2 ED, = 1.33 x lop3pg ml-l ; Source Asimina longifolia leaves and twigs.12. (2,4-cis)-Murisolinone 26,94 C,,H,,O, MW 580 Carbon No. 15 16 19 20 'H@) 3.40 m 3.80 m 3.80 m 3.40 m 13C(S) 74.04 82.61 82.61 74.03 Amorphous powder; MP 92-93 "C; [alD +13.3" (c 0.1 CH,Cl,); UV (A,,, MeOH nm); 220 (log B = 3.8); IR (v,,, film cm-l) 3494 2916 2848 1764 1723 1587 1531 1467 1188 1069; NMR 'H NMR (500 MHz CDCl,) 13C NMR OH OH 0 Carbon No.17 18 21 22 'WS) 13C(S) 3.40 m 74.17 3.80 m 82.71 3.80 m 82.71 3.40 m 74.17 (125 MHz CDCl,); Derivatives tri-acetate (lH NMR) per- MTPA esters ('H NMR) TMS (EI-MS); Biological activities BST LC, = 12.3pug ml-' A-549 ED, = 1.48 x 10-1 pg ml-' MCF-7 ED, = 7.93 x lo- pg ml-l HT-29 ED, 7.54 x lo-' pg mF1 A-498 ED, = 3.44 pg ml-l PC-3 ED, = 1.48 pg ml-' PaCa-2 ED, = 1.07 x lo-' pg ml-l; Source Asimina triloba seeds. NATURAL PRODUCT REPORTS 1996 13. (2,4-tvans)-Murisolinone 27,94C,5H6406 MW 580 Carbon No.15 16 19 20 WS) 3.40 m 3.80 m 3.80 m 3.40 m 13C(S) 74.04 82.61 82.61 74.03 Amorphous powder; MP 101-102 "C; [a] +20.0" (c 0.1 CH,Cl,); UV (A,,, EtOH nm) 218 (log e =3.43); IR (v,,, film cm-l) 3490 2916 2848 1744 1713 1589 1183 1070; NMR lH NMR (500MHz CDCl,) 13C NMR (125MHz CDCl,) ;Derivatives per-acetate (lH NMR) per-MTPA esters (lH NMR) TMSi (EI-MS) Biological activities BST LC, = 18.2 pg ml-l A-549 ED, =2.76 xpg ml-l MCF-7 ED, =2.96 xlo- pg ml-l HT-29 ED, =1.16 pg ml-l A-498 ED, =1.23pg mi-' PC-3 ED, =2.14 x10-1 pg ml-l PaCa-2 ED, =5.90 xlo- pg m1-l' Source Asimina triloba seeds. 14. 4-Acetyl xylomaticin 38,28C,,H,,O, MW 666 threo trans thr-37 OH OH 0 Carbon No. 4 10 15 16 19 20 'H(6) 5.10m 3.59m 3.41 m 3.80dt 3.80dt 3.41 m I3C(S) 71.9 71.7 74.0 82.6 82.6 74.0 Colourless wax; MP 67-68 "C; [a] +13" (c 0.10 MeOH); NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-acetate (lH NMR) per-MTPA esters (lH NMR) TMS (EI-MS); Biological activities BST LC, = 34.12 pg ml-' A-549 ED, =1.25 xlo- pg ml-l MCF-7 ED, =3.04 xlo-' pg ml-l HT-29 ED, =1.12 xlo- pg ml-l A- 498 ED, =2.66 xpg ml-l PA-3 ED, =3.51 x10-1 pg ml-' PaCa-2 ED, =6.22 xlop4 pg ml-l; Source Asimina longifolia leaves and twigs.15. Asiminenin B 4O,lo1 C,,Hs60, MW 606 Carbon No. 15 16 19 20 23 24 'H(6) 3.42m 3.81 m 3.81 m 3.42 m 5.36m 5.39 '3C(S) 74.03 82.55 82.65 73.50 128.92 130.83 Amorphous powder; MP 54-55 "C; [a] +17.0" (c 0.1 CH,Cl,); UV (A,,, MeOH nm) 230 (log E =2.93); IR (v,,, film cm-l) 3458 2918 2850 1764 1731 1590 1316 1081 669; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,) ;Derivatives:per-acetate (lH NMR) per-MTPA esters (lH NMR) TMS (EI-MS); Biological activities BST LC, = 5.82 xlO-'pg rnl-l A-549 ED, =3.22 xlo- pg ml-l MCF-7 ED, =3.61 xlo- pg mF1 HT-29 ED, =6.94 xlo- pg ml-' A-498 ED, =5.72 xlop3 pg ml-l PC-3 ED, =3.66 x pg ml-l PaCa-2 ED, =6.34 xlo-' pg ml-'; Source Asimina triloba seeds.16. Longicoricin 14,, C,,H,,O, MW 608 threo trans threo 37 Carbon No. 10 15 16 19 20 'H(6) 3.59m 3.41 m 3.80dt 3.80 dt 3.41 m I3C(S) 71.85 74.03 82.65 82.59 73.97 Whitish wax; MP 7675°C; [a] +12.0" (c 0.001 CH,Cl,); UV (A,,, MeOH nm) 222 (log t =2.93); IR (v,,, film cm-l) 3422 2923 2855 1734 1650 1456 1076; MS CI-MS (isobutane) 609 591 573 555; EI-MS 381 363 345 311 293 275,225 207; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) per MTPA esters (IH NMR) TMS (EI-MS); Biological activities BST LC, =1.56 pg ml-l A-549 ED, =1.04 pg ml-l MCF-7 ED, =2.31 pg mi-' HT-29 ED, =1.36xloT3 pg ml-' A-498 ED, =1.71pg ml-' PC-3 ED, =3.04 xlo- pg ml-' PaCa-2 ED, =1.36 pg ml-l ; Source:Asimina longifolia leaves and twigs.17. Tonkinecin 48,,O C,,H,,O, MW 608 threo trans thmo 37 Carbon No. 3 4 5 17 18 21 22 'H(6) 2.40m 1.65m 3.58 m 3.39m 3.79m 3.79m 3.39m "C(6) 21.49 35.34 70.87 74.13 82.66 82.66 74.13 White crystals; MP 70-72 "C; [a],+26.54" (c 0.09 CHC1,); IR (Y,,, film cm-l) :3441,2920,285 1 1743 1709 1469 1074 ; MS CI-MS (isobutane) 591 573 555 537; EI-MS 483 465 447 409 391 373 339 321 303 271 269; 155; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-MTPA esters (lH NMR) TMS (EI-MS); Biological activities HCT-8 IC, =3.8 x10-1pm Be17402 IC, =1.5 pM BGC IC, =5.1 pM HL-60 IC, =5.2 x 10-1 pM; Source Uvaria tonkinesis roots.18. cis-Goniothalamicin 52,' C,,H,,O, MW 596 Carbon No. 10 13 14 17 18 ___~~~~~ ~~~ ~~ ~~ ~~ 'H(S) 3.65 m 3.47 m 3.83 m 3.83 m 3.41dt 13C(S) 71.5 74.3 82.6 82.7 74.4 White amorphous powder; MP 80 "C [a] +7.2" (c 0.03 CHC1,); UV (A,,, MeOH nm) 213 (e =10500); IR (v,,, film cm-l) 3628 2923 1750 1469; MS CI-MS (isobutane) 597 579 561 543 525; EI-MS 281 263 241 223; NMR 'H NMR (500 MHz CDCl,) I3C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) per-MTPA esters ('H NMR) TMS (EI-MS); Biological activities BST LC, = NATURAL PRODUCT REPORTS 1996-5.L.McLAUGHLIN ET AL. APPENDIX 5.2 pg ml-l PD YO inhibition = 47 Yo A-549 ED, = 1.3 x IO-lpg ml-l MCF-7 ED, = 1.05 pg ml-' HT-29 ED, = 5.3 x lop3 pg ml-'; Source Annona muricata seeds. 19. 16,19-cis-Murisolin53,'06 C,,H,,O, MW 580 Carbon No. 15 16 19 20 'H(4 3.42 m 3.82 m 3.82 m 3.42 m 13C(S) 74.36 82.65 82.65 74.36 White amorphous powder ;MP :67-68 "C ;[a],+11.O" (c 0.1 CH,Cl,); UV (A,,, MeOH nm) 213 (log e = 3.57); IR (v,,, film cm-l) 3433 1740; MS CI-MS (isobutane) 581 563 545 527 311 293 275 269 251 381 363 345; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate ('H NMR) per-MTPA esters (lH NMR) TMS (EI-MS) Biological activities BST LC, = 3.46 x lo-' ,ug ml-l A-549 ED, = 3.41 x pg ml-l MCF-7 ED, = 1.58 x lo- pg ml-l HT-29 ED, = 1.27 pg ml-l A-498 ED, = 4.16 pg ml-' PC-3 ED, = 1.42 pg ml-' PaCa-2 ED, = 1.53 x lo- pg ml-' ;Source Asimina triloba seeds.20. cis-Annonacin 54,, C,,H,,O, MW 596 35, threo cis threo EH3(CH2h1m ( C OH OH 0 Carbon No. 10 15 16 19 20 'H(6) 3.59 m 3.42 m 3.82 m 3.82 m 3.42 m 13C(S) 71.6 74.3 82.7 82.7 74.3 White amorphous powder; MP 77 "C; [a] +lo" (c 0.17 CHCl,); UV (A,,, MeOH nm) 215 (e = 9700); IR (vmax film cm-') 3395 2920 2851 1734 1469; MS CI-MS (isobutane) 597 579 561 543 525; EI-MS 327 309 291 273; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-acetate ('H NMR) per-MTPA esters (lH NMR) mono-MTPA esters at each individual OH position (lH NMR) TMS (EI-MS); Biological activities BST LC, = 2.3 pg ml-l PD % inhibition = 28 YO,A-549 ED, = 2.3 x lo-' pg ml-l MCF-7 ED, = 1.18 pg ml-l HT-29 ED, = 1.0 x lo-* pg ml-'; Source Annona muricata seeds.21. cis-Annonacin-10-one 55,73C,,H,,O, MW 594 35, threo cis threo cm-l) 3444 2918 2850 1750 1705 1467; MS CI-MS (isobutane) 595 577 559 541 325 307; NMR lH NMR (500 MHz CDCl,) NMR (125 MHz CDCl,); Derivatives per-acetate ('H NMR) per-MTPA esters (lH NMR) TMS (EI-MS); Biological activities BST LC, = 1.8 pg ml-l PD YO inhibition = 32 YO,A-549 ED, = 3.5 x lo-' pg rnl-l MCF-7 ED, = 2.9 x lo-' pg ml-l HT-29 ED, = 9.0 x lop4pg ml-l; Source Annona muricata seeds.22. Asiminenin A 56,1°1 C,,H,,O, MW 606 Carbon No. 15 16 19 20 23 24 'H(S) 3.43 m 3.83 m 3.83 m 3.43 m 5.36m 5.39 13C(S) 74.31 82.61 82.68 73.82 128.96 130.77 Amorphous powder; MP 58-59°C; [a& +10.0" (c 0.1 CH,Cl,); UV (A,,, MeOH nm) 228 (log e = 3.55); IR (vmax film cm-l) 341 1,2921,2852,1756 1588 1078,669; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCI,); Derivatives per-acetate ('H NMR) per-MTPA esters (lH NMR) TMS (EI-MS); Biological activities BST LC, = 4.73 x lo-' pg ml-l A-549 ED, = 2.85 x pg ml-l MCF-7 ED, = 2.39 x lo- pg ml-l HT-29 ED, = 8.12 x lo- pg ml-' A-498 ED, = 6.26 x lo- pg ml-l PC-3 ED, = 1.66 pg ml-' PaCa-2 ED, = 8.58 x lo- pg ml-l; Source Asimina triloba seeds.23. Longicin 57,, C,,H,,O, MW 596 erythro trans thmo 35 32 OH OH 0 Carbon No. 10 13 14 17 18 'H(S) 3.64m 3.45 m 3.84m 3.81 m 3.88 m 13C(S) 71.5 74.6 83.1 82.2 71.6 Whitish wax; MP 83 "C [aJD+13.0" (c 1.0 CH,Cl,); UV (A,,, MeOH nm) 228 (log e = 3.70); IR (vma, film cm-l) 3400 2900 2820 1750 1440 1300 1073; MS CI-MS (isobutane m/z) 597 579 561 543 525 351 333,281 ;NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives:peracetate ('H NMR) ;TMS (EI-MS) ;per-Mosher ester ('H NMR) longicinone ('H NMR) ;Biological activities BST LC, = 0.1 1 pg ml-' A-549 ED, = 1.77x pg ml-l MCF-7 ED, > 1 pg ml-' HT-29 = 2.4 x lo- pg ml-l A-498 ED, = 1.99 x lo-' pg ml-l PA-3 ED, = 4.26 x lo- pg ml-l PaCa-2 ED, = 1.25x 1O-' pg ml-l ; Source :Asimina longifolia leaves and twigs.0 24. Murisolin A 58,1°6 C,,H,,O, MW 580 EH3(CH2h w(CH2)3A(C H2)5wo OH OH Carbon No. 10 15 16 19 20 -~ ~ ~~ 'H(S) -3.42m 3.82m 3.82 m 3.42m Carbon I3C(S) 211.3 74.3 82.7 82.7 74.3 No. 15 16 19 20 White amorphous powder; MP 70 "c; [a] +6.2" (c 0.07 CHCl,); UV (A,,, MeOH nm) 209 (e = 8400); IR (vmax film 'H(4'3C(S) 3.40 m 74.33 3.82 m 83.21 3.88 m 82.12 3.82 m 71.51 298 Colourlesspowder; MP 83-84 "C; [aID+ 17.0" (cO.1 CH,Cl,); UV (A,,, MeOH nm) 226 (log B = 3.02); IR (v,,, film cm-l) 3433 1740; MS CI-MS (isobutane) 581 563 545 527 311 293,275,269 251 381 363 345; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives:per-acetate (lH NMR) per-MTPA esters ('H NMR) TMS (EI-MS); Biological activities BST LC, = -1.83x lo-' pg ml-l A-549 ED, = 3.16 x lo- pg ml-l MCF-7 ED, = 5.40 pug ml-l HT- 29 ED, = 1.06 x pg ml-' A-498 ED, = 6.67 x lo- pg ml-l PC-3 ED, = 8.41 pg ml-l PaCa-2 ED, = 5.18 x ,ug ml-I ; Source Asimina triloba seeds.25. Muricatocin B 62,, C,,H,,O, MW 612 pseudo-erythro trans threo erythro Carbon No. 10 12 15 16 19 20 'H(&) 3.94m 3.86 3.45 m 3.85 m 3.80m 3.89 m 13C(S) 72.87 72.63 74.61 82.96 82.21 71.52 White powder; [@ID +62.5" (c 0.001 EtOH); UV (A,,, MeOH nm) 214 (c = 9500); IR (v,,, film cm-l) 3416 2920 2850 1744 1467 1322 1075; MS CI-MS (BuOH m/z) 613 595 577 559 541 523 413 395 377 359 343 325 285 271 269 267 253 241 223 205 199; EI-MS (m/z)413 377 359 343 325 307 285 269 253 241 223 213 199 141; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives:acetonide (lH NMR) per-acetate ('H NMR) per- MTPA esters (lH NMR) penta-TMS (EI-MS); Biological activities BST LC, = 5.57 x lo-' pg ml-l A-549 ED, = 3.34 x ,ug ml-' MCF-7 ED, = 1.03 x lo-' pg ml-' HT-29 ED, = 1.66pg ml-l ; Source Annona muricata leaves.26. Muricatocin C 63,j5C,,H,,O, MW 612 pseudo-__ erythro trans threo thm 35 32 CH3(CH2h 1w(c~~)~ OH OH 0 Carbon No. 10 12 15 16 19 20 'H(6) 3.94 m 3.86m 3.45 m 3.85 m 3.80m 3.89 m 13C(&) 69.62 69.23 74.28 83.04 82.22 71.48 White powder; [a],+32.5" (c 0.001 EtOH); UV (A,,, MeOH nm) 225 (e = 9100); IR (v,,, film cm-l) 3410 2920 2850 1745 1466 1322 1074; MS CI-MS (BuOH m/z) 613 595 577 559 541 523 413 395 377 359 343 325 285 271 269 267 253 241 223 205 199; EI-MS (m/z)413 377 359 343 325 307 285 269 253 241 223 213 199 141; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives:acetonide ('H NMR) per-acetate (lH NMR) per- MTPA esters (lH NMR) TMS (EI-MS); Biological activities BST LC, = 6.04 x lo-' pg ml-l A-549 ED, = 9.09 x lo-,pg ml-' MCF-7 ED, = 6.45 x pg ml-l HT-29 ED, = 1.48pg ml-I ; Source Annona muricata leaves.NATURAL PRODUCT REPORTS 1996 27. Annohexocin C,,H,,O, MW 628 OH OH 0 Carbon No. 8 10 12 15 16 19 20 'H(S) 3.95m 4.13dt 3.89m 3.45dt 3.88m 3.86m 3.81 m I3C(6) 72.3 73.7 72.3 74.6 86.2 82.8 71.5 White powder; [a]D+ 18.5" (c 0.33 CHCl,); UV (A,,, MeOH nm) 208 (log e = 3.24); IR (v,,, film cm-') 3410,2920,2850 1745 1466 1322 1074; MS FAB-MS 629; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) TMS (EI-MS) ; Biological activities BST LC, = 34.4 pg ml-' A-549 ED, = 0.34 pg ml-l MCF-7 ED, = 2.26 pg ml-l HT-29 ED, = 0.78 pg rnl-l A-498 ED, = 2.36 pg ml-l PC-3 ED, = 0.0195 pg ml-l PaCa-2 ED, = 0.77 pug ml; Source Annona muricata leaves.28. Annotemoyin-2 66,, C,,H,,O, MW 564 Carbon No. 17 18 21 22 'H(6) 3.39 m 3.81 m 3.87 m 3.81 m 13C(S) 74.30 83.30 82.05 71.63 White waxy solid; [a],+20" (c 0.1 1 MeOH); UV (A,,, EtOH nm) 217.1 (log t'= 3.66); IR (vmax film cm-l) 3448 2927 2858 1756 1661 1459 1376 1319 1200 1066 1028,954,875 756 723 ;MS CI-MS (methane) 565 547 529 51 1 393 375 323,295,267,241,223,171,111,97; EI-MS 528,393,375,357 323 295 267 241 235 223 209 195 181 167 153 139 125 111 97; NMR 'H NMR (200 MHz CDCl,) 13C NMR (50 MHz CDC1,) ;Source Annona atemoya seeds.q' 29. Annosenegalin 69,1°3 C3,H6,0, MW 624 eryfhru trans threo EH3(CH2h3* '9 O"16 15 (CH2)a '0 (CH2)s OH OH 0 Carbon No. 10 15 16 19 20 'H(6) 3.57 m 3.40 m 3.82 m 3.82m 3.82m 13C(S) 71.70 74.31 83.24 82.26 71.70 Amorphous form IalD+ 15" (c 0.27 CHC1,); UV (A,,, EtOH nm) 207; IR (v,,, film cm-l) 3400 2910 2845 1745; MS FAB-MS (NBa+LiCl) 631 625 613 595 577 559; EI-MS 397 379 361 343 327 309 297 291 273 241 227 223 141 11 1 ;NMR 'H NMR (200 MHz CdCl,) 13CNMR (50 MHz CDCl,) ;Source Annona senegalensis seeds.NATURAL PRODUCT REPORTS. 1996-5. L. McLAUGHLIN ET AL. APPENDIX 30. Reticulatain-17O,lo9 C,,H,,O, MW 592 33. Rollinecin B 73,62C,,H,,0T MW 624 OH OH 0 Carbon No. 17 18 21 22 'H(6) 3.40 m 3.84 m 3.84 m 3.84 m I3C(6) 71.45 82.08 83.16 74.24 Whitish amorphous solid; [a],+22" (c 1 CHC1,); UV (A,,, EtOH nm) 207; IR (v,,, film cm-l) 3500 3930,2850 1750; MS CI-MS (isobutane) 593; EI-MS 592 574 556 403 375 351 323 295 241; NMR lH NMR (200 MHz CDCI,) 13C NMR (50 MHz CDC1,); Source Annona reticulata seeds. 31. Reticulatain-2 71,1°9 C,,H,,O, MW 592 erythro trans threo 37 Carbon No. 19 20 23 24 'H(6) 3.40 m 3.84 m 3.84 m 3.84 m 13C(6) 71.74 82.25 83.25 74.32 Whitish amorphous solid; [a],$28" (c 1 CHC1,); UV (A,,, EtOH nm) 207; IR (v,,, film cm-l) 3500,2930,2850 1750; MS CI-MS (isobutane) 593; EI-MS 592 574 556,403 385 351,323,241;NMR 'H NMR (200 MHZ CDCl,) 13C NMR (50 MHz CDCl,) ;Source Annona reticulata seeds.32. Rollinecin A 72,62C,,H,,O, MW 624 erythtv trans threo 35 Carbon No. 14 17 18 21 22 'H(6) 3.63 m 3.44m 3.85 m 3.86-3.90m 3.86-3.90m l3C(S) 71.72 74.59 83.10 82.18 71.55 Whitish waxy solid; MP 61-62 "C [&ID + 10.0" (CH,Cl,); UV (A,,, MeOH nm) 227 (log e = 3.80); IR (v,,, film cm-') 3400,2910,2800,1745,1665,1075; MS EI-MS (m/z)407,389 371 337 319 301 297,279 141; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,) ;Derivatives:per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 3.1 x lo-' pg rnl-l A-549 ED, = 1.14x pg ml-l MCF-7 ED, = 1.44 ,ug ml-l HT-29 ED, = 1.60pg ml-' A-498 ED, = 7.25 x pug ml-' PC-3 ED, = 2.62 x pg ml-l PaCa-2 ED, = 3.47 x lo- pg ml-I Source Rollinia mucosa leaves.Carbon No. 14 17 18 21 'H(6) 3.62 m 3.44 m 3.85 m 3.86-3.90 m 3.86-3.90 m 13C(6) 71.90 74.67 83.11 82.19 71.54 Whitish waxy solid; MP 61-62°C; [a],+12.7" (CH,Cl,); UV (A,,, MeOH nm) 227 (log c = 3.80); IR (v,,, film cm-l) 3400 2910 2800 1745 1665 1075; MS EI-MS (m/z) 407 389 371 337 319 301 297 279 141; NMR lH NMR (500 MHz CDCl,) I3C NMR (125 MHz CDC1,); Derivatives per-MTPA ester (lH NMR) TMS (EI-MS); Biological ac- tivities BST LC, = 1.3 x 10-1 pg mF1 A-549 ED, = 4.23 x ,ug ml-' MCF-7 ED, = 2.72 pg ml-l HT-29 ED, = 1.44pg ml-' A-498 ED, = 2.29 x lop4pg ml-l PC-3 ED, = 3.62 x lop4pug ml-' PaCa-2 ED, = 2.53 x lo-* pg ml-l Source Rollinia mucosa leaves.34. Muricatatin A 77,' C,,H,,O, MW 612 OH OH Carbon No. 10 13 14 17 18 23 'H(6) 3.83 m 3.78 m 3.37 m 3.37 m 3.37 m 3.78 m '3C(6) 79.30 81.81 74.70 74.36 74.26 74.51 Amorphous solid; MP 83 "C; [a] f7.10" (c 0.63 MeOH); UV (A,,, MeOH nm) 227 (log c = 3.80); IR (v,,, film cm-l) 3400,1740; MS EI-MS (m/z)485,467,449,431,399,381,363 369 351 333 315 281 263 239 221 141; NMR 'H NMR (400 MHz CDCl,) 13C NMR (100 MHz CDC1,); Source Annona muricata seeds and stem bark. 35. Muricatatin B 78,92C3,H6,08 MW 612 Carbon No. 10 13 14 17 18 19 'H(6) 3.82 m 3.78 m 3.37m 3.37m 3.78m 3.78 m I3C(6) 80.36 80.57 74.56 74.67 70.38 71.36 Amorphous solid; MP 128 "C [a],-11.43" (c 0.18 MeOH); UV (A,,, MeOH nm) 227 (log c = 3.80); IR (vmax,film cm-l) 3400,1740; MS EI-MS (m/z)429,401,383,355,369,351,333 315 297,281,263 239,221 141; NMR 'H NMR (400 MHz CDCl,) 13C NMR (100 MHz CDC1,); Source Annona muricata seed and stem bark.36. 4-Acetyl Gigantetrocin A 79,34C,,H,,O, MW 638 Carbon No. 4 10 13 14 17 18 ~~~ ~~~~ 'H(S) 5.10ddt 3.88 m 3.81q 3.42m 3.44m 3.44m 13C(S) 71.9 79.2 81.8 74.6 74.3 74.4 Colourless oil; [a]D + 13.5" (c 0.11 MeOH); UV (A,,, EtOH nm) 208 (log e = 3.2); IR (vmax film cm-l) 3445 2930 2867 1750 1745 1430 1347; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); CD negative Cotton effect at 243 nm; Derivatives per-acetate ('H NMR) acetonide (lH NMR) per-MTPA ester (lH NMR) TMS (EI-MS) ;Biological activities BST LC, = 6.78 ,ug ml-l A-549 ED, < 10-2,ug ml-l MCF-7 ED, = 8.50 x 10-l ,ug ml-* HT-29 ED, < ,ug mkl A-498 ED, = 1.55 x 10-1,ug ml-l PC-3 ED, = 1.02 ,ug ml-l PaCa-2 ED, < ,ug ml-I; Source Annona muricata leaves.37. Muricatetrocin C 81,32C35H6407, MW 596 Carbon No. 12 15 16 19 20 'H(S) 3.89m 3.82m 3.45m 3.62m 3.62m '3C(S) 79.3 81.7 74.3 74.4 7.47 White amorphous powder; MP 65-66 "C; [a] +6.3" (CH,Cl,); UV (A;,,, MeOH nm) 224 (log E = 3.80); IR (vmax film cm-l) 3400 2910 2800 1745 1665 1075; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-MTPA ester ('H NMR) tetra-TMS (EI-MS) Biological activities BST LC, = 7.6 x lo-' ,ug ml-l A-549 ED, = 5.55 x lo- ,ug ml-l MCF-7 ED, = 3.19 ,ug ml-l HT- 29 ED, = 1.98 pg ml-l A-498 ED, = 3.39 x ,ug ml-l PC-3 ED, = 1.35x ,ug ml-' PaCa-2 ED, = 5.69 x ,ug ml-l ; Source Rollinia mucosa leaves.38. Murihexocin A 82,34,37 MW 628 C35H6409 Ihmo threo trans threo Carbon No. 7 8 12 15 16 19 20 'H(S) 3.43m 3.43 m 3.90m 3.84q 3.45m 3.43m 3.43m 'jC(6) 74.4 74.5 79.4 81.7 74.1 74.3 74.5 White wax; NMR 'H NMR (500MHz CDCl,) 13C NMR (125 MHz CDCl,) Derivatives per-acetate ('H NMR) ace- tonide ('H NMR) per-MTPA ester (IH NMR) TMS (EI-MS); Biological activities BST LC, = 28.6 ,ug ml-l A-549 ED, = 1.32 pg ml-' MCF-7 ED, = 12.54 ,ug ml-l HT-29 ED, = 3.0 ,ug ml-' A-498 ED, = 2.51 pg ml-l PC-3 ED, = 1.71 x lod2 ,ug ml-' PaCa-2 ED, = 9.73 x ,ug ml-I; Source Annona muricata leaves.NATURAL PRODUCT REPORTS. 1996 39. Murihexocin B S3,34,37 MW 628 C35H6409 threo threo trans threo 33 32 OH OH 0 Carbon No. 7 8 12 15 16 19 20 'H(6) 3.43 m 3.43 m 3.90m 3.84q 3.45 m 3.43 m 3.43m 13C(6) 74.4 74.5 79.4 81.9 74.7 74.4 74.5 White wax; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-acetate (lH NMR) aceto- nide ('H NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 33.7 pug ml-l A-549 ED, = 1.08 ,ug ml-l MCF-7 ED, = 6.95 pug ml-l HT-29 ED, = 2.30 pg ml-' A-498 ED, = 4.92 ,ug rnl-' PC-3 ED, = 1.26x 10-1 pg ml-l PaCa-2 ED, = 4.13 x lo-' ,ug ml-l; Source Annona muricata leaves. 40. Coriacin 88,114 C37H6607 MW 622 Carbon No.10 13 14 17 18 21 22 'H(6) 3.90m 3.80dt 3.37m 5.37m 5.37m 3.38m 3.39m 13C(S) 79.4 81.6 74.3 129.8 129.9 73.0 72.7 Amorphous waxy solid; MP 49-50 "C [a] + 14.0" (c 1.0 EtOH); UV (Amax. EtOH nm) 204 (log c = 3.98); IR (vmax film cm-l) 3473 2931 2858 1762 1542 1075; NMR 'H NMR (400 MHz CDCI,) 13C NMR (50 MHz CDC1,); MS EI-MS CID-B/E-MS Derivatives per-acetate ('H NMR) acetonide (lH NMR); oxidized and cyclized to gigantecin (lH NMR); Source Annona coreacea roots. 41. 4Deoxycoriacin 89,114 C,,H6,0, MW 606 thmo threo trans Carbon No. 10 13 14 17 18 21 22 'H(6) 3.88 m 3.78 m 3.38 m 5.29111 5.39m 3.38m 3.38m I3C(S) 79.5 74.3 74.3 129.9 130.1 72.9 72.7 White waxy solid; [a]D + 10.0"(c 1.O EtOH); UV (A,,, EtOH nm) :207 (log E = 3.93); IR (v,,, film cm-l) 359 1 3007,2934 2858 1752 1459 1076; NMR 'H NMR (400 MHz CDCI,) 13C NMR (50 MHz CDCl,); MS EI-MS CID-B/E-MS Derivatives per-acetate (lH NMR) acetonide ('H NMR) ; oxidized and cyclized to 4-deoxygigantecin (lH NMR) ; Source Annona coreacea roots.Gigantetroneninone 90/91,67 C37H6607 MW 622 (reported as a cis and trans mixture) threo threo trans 1 NATURAL PRODUCT REPORTS 1996-J. L. McLAUGHLIN ET AL. APPENDIX 30 1 42. (2,4-~is)-Gigantetroneninone90 (A = cis) Carbon No. 10 13 14 17 18 21 22 ~ ~~ 'H(S) 3.88rn 3.81ddd 3.44111 3.44m 3.44m 5.37 dt 5.39dt I3C(S) 79.20 81.73 74.40 74.16 74.21 128.96 130.77 43. (2,4-tvans)-Gigantetroneninone 91 (A = trans) Carbon No.10 13 14 17 18 21 22 'H(S) 3.88m 3.81ddd 3.44111 3.44m 3.44rn 5.37 dt 5.39dt I3C(S) 79.20 81.73 74.40 74.16 74.21 128.96 130.77 Whitish wax; MP 98 "C; [a],+22.9" (c 0.01 CH,Cl,); UV (A,,, MeOH nm) 210 (B = 10000); IR (v,,, film cm-') 3450,2900,2853 1782 1726 1457 1388 1218 1072; MS CI-MS (isobutane m/z) 623 605 587 569; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives tri-acetate (lH NMR) acetonide (lH NMR) per-MTPA esters (lH NMR) tri-TMS (E-MS); Biological activities BST LC, = 0.11 pg ml-I A-549 ED, = 1.O x lo- pg rnl-l MCF-7 ED, = 1.98pg ml-l HT-29 ED, = 4.81 x lo- pg ml-l A-498 ED, = 1.12 x lo-' pg ml-l PC-3 ED, = 8.35 x lo- pg ml-l PaCa- 2 ED, = 1.79x lo- pg ml-l ; Source:Asimina longifolia leaves and twigs. 44.cis-Gigantrionenin 92,34 C,,H,,O, MW 606 37, threo fhreo cis Carbon No. 10 13 14 17 18 21 22 'H(6) 3.87 m 3.73q 3.41 m 3.45 m 3.45 rn 5.40dt 5.36dt I3C(S) 80.0 82.0 74.9 74.2 74.2 129.0 130.8 Colourless oil; [a],f8.5" (c 0.18 MeOH); UV (A,,, EtOH nm) 207 (log 6 = 3.1); IR (v,,, film cm-') 3440 2928 2860 1750 1455 1325; NMR lH NMR (500MHz CDCl,) 13C NMR (125 MHz CDC1,); CD 243 nm; Derivatives acetonide (lH NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 2.52 pg mF1 A-549 ED, = 5.99 x lo- pg ml-l MCF-7 ED, = 2.68 x 10-1 pg ml-l HT-29 ED, = 6.94 x lo- pg ml-l A-498 ED, = 1.39 x lo- ,ug ml-l PC-3 ED, = 1.11 x 10-1 pg ml-l PaCa-2 ED, = 1.15 x lo-' pg ml-I ; Source Annona muricata leaves. 45. Muricatalin 94,11j C,,H,,O, MW 612 ervthro trans 35/ OH OH 0 Carbon No.10 13 14 17 18 21 22 'H(S) 3.88 m 3.78 rn 3.38 m 5.39 rn 5.39m 3.38 rn 3.38 rn 13C(S) 79.5 74.3 74.3 129.9 130.1 72.9 72.7 White waxy solid; MP 143-144 "C; [alD +8.8" (c 0.06 MeOH); UV (A,,, EtOH nm) 220 (log B = 3.75); IR (vmax film cm-l) 3410 1740; NMR lH NMR (400 MHz CDCl,) 13C NMR (50MH2 CDC1,); MS EI-MS CID-B/E-MS Derivatives TMS (EI-MS) Source Annona rnuricata seeds. 46. Longimicin C 95,29C,,H6,0, MW 622 threo Carbon No. 9 10 13 14 17 18 'H(6) 13C(S) 3.39 m 73.82 3.83 m 83.16 3.83 m 81.76 3.83 m 81.76 3.83 m 83.00 3.39 m 74.09 Colourless wax; [a],+ 14" (c 1 EtOH); uv (A,,, EtOH nm) 208 (log B = 3.2); IR (v,,, film cm-l) 3400 2925 2855 1750 1457 1318 1200 1069 954 870; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives :per-acetate ('H NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 9.42 pg ml-l YFM LC, = 75.7 pg ml-l A-549 ED, = 4.55 x 10-1 pg ml-l MCF-7 ED, = 8.80 x pg ml-' HT-29 ED, = 1.00pg ml-l A- 498 ED, = 1.27x 10-1 pg ml-l PC-3 ED, = 2.96 pg ml-l PaCa-2 ED, = 1.09 pg ml-' ;Source Asimina longifolia leaves and twigs.47. Longimicin B 96,29 C,,H,,O MW 594 threo I threo trans trans threo 32 W(C O'f2 H&,qZ CH3(CH2h120 19 O"16 15 OH OH 0 Carbon No. 11 12 15 16 19 20 ~ ~ ~ ~ ~ ~~~ ~~~~~ 'H(6) 3.39m 3.83 m 3.83 m 3.83m 3.83m 3.39 m 13C(S) 74.00 83.14 81.74 81.74 83.14 74.09 Colourless wax; [a],+ 14" (c 1 EtOH); uv (A,,, EtOH nm) 208 (log E = 3.2); IR (v,,, film cm-l) 3400 2925 2855 1750 1457 1318 1200 1069,954,870; NMR IH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 7.34 pg rnl-l YFM LC, = 30.4 ,ug ml-l A-549 ED, = 1.43x lo-' pg ml-l MCF-7 ED, = 1.54 x lo- ,ug ml-l HT-29 ED, = 3.32 x lo- pg ml-l A- 498 ED, = 6.40 x lo- pg rnl-l PC-3 ED, = 2.20 pg ml-l PaCa-2 ED, = 7.92 x pg ml-l; Source:Asirnina longifolia leaves and twigs.48. Longimicin A C,,H,,O MW 622 threo Carbon No. 11 12 15 16 19 20 'H(6) 3.39m 3.83 m 3.83 m 3.83 m 3.83m 3.39 m 13C(S) 74.09 83.23 81.82 81.82 83.15 74.17 Colourless wax; [a] + 14" (c 1 EtOH); UV (A,,, EtOH nm) 208 (log E = 3.2); IR (v,,, film cm-l) 3400 2925 2855 1750 1457 1318 1200 1069,954 870; NMR lH NMR (500 MHz CDCl,) 13C NMR (1 25 MHz CDCl,) ;Derivatives :per-acetate 302 (lH NMR) per-MTPA ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 18.7 pg ml-l YFM LC, = 141 pg ml-l A-549 ED, = 2.95 x lo-' pg ml-' MCF-7 ED, = 8.89 x lo-' pg ml-' HT-29 ED, = 5.25 x 10-1 pg ml-l A-498 ED, = 5.54 x lo-' pg ml-' PC-3 ED, = 7.01 x lo2 pg ml-' PaCa-2 ED, = 1.73x pg ml-'; Source Asimina longifolia leaves and twigs.49. Longimicin D 103,29 C,,H,,O, MW 622 threo Carbon No. 11 12 15 16 19 20 'H(6)13C(S) 3.39m 74.09 3.83 m 83.23 3.83 m 81.82 3.83 m 81.82 3.83 m 83.15 3.39m 74.17 Colourless wax; [a] + 14" (c 1 EtOH); UV (A,,, EtOH nm) 208 (log 6 = 3.2); IR (v,,, film cm-') 3400 2925 2855 1750 1457 1318 1200 1069 954 870; NMR 'H NMR (500 MHz CDCl,) I3C NMR (125 MHz CDC1,); Derivatives:per-acetate (lH NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 4.58 pg ml-l YFM LC, = 8.29 pg ml-' A-549 ED, = 4.93 x lop4 pg ml-l MCF-7 ED, = 2.15 x lo-' pg ml-l HT-29 ED, = 1.16 x pg rnl-l A- 498 ED, = 3.53 x lop2 pg ml-' PC-3 ED, = 2.42 x lop4 pg ml-' PaCa-2 ED, = 1.69 x lo-' pg ml-' ; Source Asimina longifolia leaves and twigs.50. Asiminocin 111,12 C,,H,,O, MW 622 threo three trans I trans three Carbon No. 15 16 19 20 23 24 30 'H(S) 3.40m 3.86m 3.86m 3.86m 3.86m 3.40m 3.59m 'jC(8) 74.07 83.15 81.80 81.78 83.07 73.99 71.92 Colourless wax ;[alD+26" (c 1 CHC1,) ;UV (A,,, EtOH nm) 215 (log e = 3.1); CD 237 nm; IR (v,,, film cm-l) 3445 2927 2854 1753 1457 1414 1266 1180 1021 926 729; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) per-MTPA ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 4.9 x lo- pg ml-' A-549 ED, = 3.1 x pg rnl-' MCF-7 ED, = 2.9 x ,ug ml-l HT-29 ED, < pug ml-l; Source Annona triloba stem bark.51. Compound-2 1 12,52 fhreo thrm trans trans threo =7 24 OH (CH2)3 ff(c~~),qo EHdcH2b& OH 0'" l9 0"l6 15 0 NATURAL PRODUCT REPORTS 1996 52. Compound-1 113,52 34 OH OH OH 53. Atemoyacin B 120,22 C35H6207, MW 594 threo Carbon No. 13 14 17 18 21 22 27 'H(S) 3.41 m 3.88m 3.94m 3.94m 3.88 m 3.88 m 3.61 m 'jC(8) 74.17 83.33 82.55 82.66 82.27 71.48 71.63 Colourless wax; [a],+ 12.9" (c 0.021 MeOH); UV (A,,, MeOH nm) 210 (t = 7147); IR (vmax film cm-l) 3445 3079 2927 2855 1756 1652 1461 1374 1319 1198 1117 1069 1027,953 875,722; MS EI-MS; NMR 'H NMR (600 MHz CDCl,) 13C NMR (125 MHz CDCl,); Source Annona atemoya seeds.54. Squamotacin 123,2 C37H6607, MW 622 threo Carbon No. 13 14 17 18 21 22 'H(6) 3.39m 3.85 m 3.93 m 3.85 m 3.93 m 3.85 m 13C(S) 74.08 83.20 82.52 82.28 82.81 71.36 MS CI-MS 623 EI-MS 283,335; NMR 'H NMR (500 MHz CDCl,) 13CNMR (125 MHz CDC1,); Derivatives:TMS (EI- MS); Biological activities BST LC, = 6.80 x lop3 pg rnl-l A- 549 D, = 2.77 x pg ml-' MCF-7 ED, > 1 pug ml-' HT-29 ED, = 1.00 x lo- pg ml-' A-498 ED, > 1 pg ml-l; PC-3 ED, = 1.72 x lop9 pg ml-l; PaCa-2 ED, = 1.33x Source Annona squamosa bark.Bullanin 134/135,14' C,,H,,O, MW 622 (isolated as 30S/R mixture) threo 55. (30S)-Bullanin 134,14' Carbon No. 15 16 19 20 23 24 30 'H(S) 3.40m 3.85m 3.83m 3.93m 3.93m 3.88m 3.58m I3C(S) 74.1 83.3 82.5 82.3 82.7 71.3 71.87 NATURAL PRODUCT REPORTS 1996-5.L. McLAUGHLIN ET AL.:APPENDIX 56. (30R)-Bullanin 135,14' Carbon No. 15 16 19 20 23 24 30 'H(Sj 3.40m 3.85 m 3.83 m 3.93 m 3.93 m 3.88 m 3.58m '%J6) 74.1 83.3 82.5 82.3 82.7 71.3 71.93 Colourless wax; [&ID +28" (c 0.5 EtOH); UV (A,,, EtOH nm) 220 (log t =2.42); IR (vmax film cm-') 3442,2927 2852 1747 1459 1320 1193 1070; MS EI-MS 565 511 417 295 277 291,239 221 187 169 151; NMR 'H NMR (500 MHz CDCl,) ''TNMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) per-MTPA ester (lH NMR) TMS (EI-MS),tris- Si (CD,) (EI-MS); Biological activities BST LC, =6.0 x lo- pg mi-' A-549 ED, < pg ml-l MCF-7 ED, < lo-" pg ml-' HT-29 ED, =4.8 x10-l2pg m1-l; Source Asimina triloha.stem bark. 57. Annoglaucin 137,26 C,,H,,O, MW 638 threo erythro trans trans threo 34cH3(cH2)g~(CI OH OH 0 Carbon No. 10 15 16 19 20 23 24 'H(6) 3.59 m 3.39m 3.8Om 3.90m 3.90m 3.80111 3.85 m '-'C(S) 71.6 74.0 83.1 82.4 82.1 82.6 71.3 Waxy solid; [a],+15.4"(c 0.6 CHCI,); UV (A,,, EtOH nm) 210 (e =10000); IR (v,,, film cm-l) 3430 2930 2855 1740 1460 1320 1070; MS CI-MS (CH,) 639 621 603 585; EI- MS 590 570 520,471,467 379 361 341,323 309 305 297 291 279 261 241 223 205 141 123; NMR 'H NMR (200 MHz CDCl,) 13C NMR (50 MHz CDC1,); Source Annona glauca roots.30-Hydroxybullatacin 139/140,142 C,,H,,O, MW 638 (reported as 30S/R mixture) threo 58. (30S)-Hydroxybullatacin 139 Carbon No. 15 16 19 20 23 24 30 'H(Sj 3.40m 3.85 m 3.93 m 3.85 m '-'C(S) 74.1 83.3 82.3 82.5 3.93 m 82.8 3.87111 71.3 3.58m 71.77 59. (30R)-Hydroxybullatacin 140 Carbon No. 15 16 19 20 23 24 30 'H(S) 3.40m 3.85m 3.93 m 3.85 m 13C(S) 74.1 83 2 82.3 82.5 3.93m 82.8 3.87m 71.3 3.58 m 71.84 White powder; [a] +14" (c 0.5 CHC1,); IR (vmax,film cm-I) 3629 2928 1753; NMR 'H NMR (500MHz CDCl,) 13C NMR (125 MHz CDCI,); Derivatives per-MTPA ester ('H NMR) tri-TMS (EI-MS); Biological activities BST LC, = 6.55 x pg ml-' A-549 ED, <lo-' pg ml-' MCF-7 ED, <lo-* pg ml-l HT-29 ED, =1.17 Fg ml-l A-498 ED, < lo-' pg ml-' PC-3 ED, =4.33 xlo- ,ugml-' PaCa-2 ED, < 1O-* pg ml-l ; Source:Annona bullata bark.60. 31-Hydroxybullatacin 141,142 C,,H,,O, MW 638 threo ervthro trans Itrans threo 37 Carbon No. 15 16 19 20 23 24 31 ~~~ 'H(S) 3.40m 3.85 m 3.93 m 3.85m 3.93 m 3.87 m 3.60m I3C(S) 74.1 83.2 82.3 82.5 82.8 71.3 71.7 White powder; [alD+19" (c 0.08 CHCI,); IR (vmax film cm-I) 3630 2926 2854 1752; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-MTPA ester (lH NMR) tri-TMS (EI-MS); Biological activities; BST LC, =5.72 xlop2pg ml-l A-549 ED, <lo- pg ml-I MCF-7 ED, <lo-' ,ug mP1 HT-29 ED, =1.21pg ml-l A-498 ED, <lo- pg ml-l PC-3 ED, =3.16 xlo-' pg ml-l PaCa-2 ED, <1O-* pg ml-l ;Source:Annona bullata bark.61. 32-Hydroxybullatacin 142,142 C3,Hs608 MW 638 threo etvihro trans Itrans threo 37 Carbon No. 15 16 19 20 23 24 32 'H(S) 3.40m 3.85 m 3.93 m 3.85 m 3.93 m 3.87 m 3.52111 13C(8) 74.1 83.2 82.3 82.5 82.8 71.3 73.3 White powder; [a] +19" (c 0.08 CHC1,); IR (vmax film cm-l) 3630 2926 2854 1752; NMR 'H NMR (500 MHz CDCl,) I3CNMR (125 MHz CDCI,); Derivatives per-MTPA ester ('H NMR) tri-TMS (EI-MS); Biological activities BST LC, =8.00 x pg ml-l A-549 ED, <lo-* pg ml-l MCF- 7 ED, < pg ml-l HT-29 ED, =1.48 pg m1-l. A-498 ED, <lo-@pg ml-l PC-3 ED, =1.62 x pg ml-' PaCa-2 ED, <lo-* pg ml-' ;Source :Annona bullata bark. 28-Hydroxybullatacinone 152/ 153,14' C,H,,O, M W 638 (reported as a cis and trans mixture) threo ervthro trans Itrans threo 62.(2,4-cis)-28-Hydroxybullatacinone 152 (A =cis) Carbon No. 15 16 19 20 23 24 28 'H(6j 3.40m 3.86m 3.93 m 3.86111 3.93 m 3.87 m 3.62111 'jC(S) 74.1 83.3 82.3 82.5 82.8 71.8 71.4 Whitish wax; [ajD+19" (c 0.08 CHCI,); IR (vmax film cm-I) 3621 1760 1716; NMR lH NMR (500 MHz CDCI,) 13C 304 NMR (125 MHz CDCl,); Derivatives per-MTPA ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 7.98 x lo-' pg ml-' A-549 ED, = 4.38 x pg ml-l MCF-7 ED, = 4.46 x lop4 pg ml-' HT-29 ED, = 6.9 x pg ml-' A-498 ED, = 4.35 pg ml-l PC-3 ED, = 2.33 pg ml-l PaCa- 2 ED, = 1.02 x pg ml-l ; Source Annona bullata bark. 63. (2,4-tvans)-28-Hydroxybullatacinone 153 (A = trans) threo Carbon No.15 16 19 20 23 24 28 'H(6j 3.40m 3.86m 3.93m 3.86m 3.93 m 3.87m 3.62m 13C(6j 74.1 83.3 82.2 82.5 82.8 71.8 71.4 Whitish wax; [a],19" (c 0.08 CHC1,); IR (v,,, film cm-l) 3621 1760 1716; NMR lH NMR (500MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-MTPA ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 7.98 x lo- pg ml-l A-549 ED, = 3.18 x pg ml-l MCF-7 ED, = 1.71 pg ml-l HT-29 ED, = 1.45 pg ml-l A-498 ED, = 1.OO x lo- pg ml-l PC-3 ED, = 9.04 pg ml-l PaCa-2 ED, = 1.19 x lo- pg ml-l ; Source Annona bullata bark. 64. Asitribin 165,94 C3,H6,0, MW 622 etythro threo cis I trans three Carbon No. 15 16 19 20 23 24 28 'H(6) 3.36m 3.85m 3.97m 4.08m 3.84m 3.42m 3.59m 13C(6) 74.58 83.01 81.69 80.97 82.48 73.56 71.77 Colourless powder; [a],+ 19" (c.0.08 CHC1,); IR (vmax film cm-l) 3448 2925 2827 1757 1589 1073; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives tri-acetate (lH NMR EIMS) per-MTPA ester (lH NMR) tri- TMS (EI-MS); Biological activities BST LC, = 2.35 x lo- pg ml-l A-549 ED, = 2.25 x 10-lo pg rnl-l MCF-7 ED, = 1.24x pg ml-' HT-29 ED, = 7.04 x lo- pg ml-l A- 498 ED, = 1.69pg ml-' PC-3 ED, = 1.30pg ml-l PaCa-2 ED, = 1.25x lop4pg ml-l; Source Asimina triloba seeds. 65. Asimilobin 172,44,94 C,,H,,O, MW 578 threo threo trans trans 35 32 CH3(CH2)13& (CH2)3*0 OH 0 Carbon No. 10 13 14 17 18 'H(6) 3.85 m 3.94m 3.85 m 3.85 m 3.38 m 13C(6) 79.88 81.25 82.03 83.09 74.13 NATURAL PRODUCT REPORTS 1996 White needles; MP 56-57 "C; [a],+6.0" (c 0.05 CHC1,); UV (A,,, EtOH nm) 228 (log E = 2.98); IR (vmax film cm-l) 3440,2924,2853 1755 1597 1448 1319 1065,845; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives per-acetate ('H NMR) per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 1.06pg ml-' A-549 ED, = 3.01 x lo-' pg ml-l MCF-7 ED, = 2.14 pg ml-l HT-29 ED, = 6.30 x lo-' pg ml-' A-498 ED, = 2.26 x lo- pg ml-' PC-3 ED, = 1.47 pg ml-l PaCa-2 ED, = 1.04x 10-' pg ml-l ; Source Asimina triloba seeds.66. Goniodenin 173,44C,,H,,O, MW 604 threo threo trans I trans 37 Carbon No. 10 13 14 17 18 21 22 'H(6) 3.93 m 3.92-3.92-3.83 m 3.41 m 5.36m 5.39m 3.83 m 3.83 m '3C(6) 79.90 81.24 82.09 83.02 73.57 129.09 130.62 Colourless oil; MP 56-57 "C; [a],+5.0" (c 1.10 CH,Cl,); UV (A,,, EtOH nm) 209 (e = 1000); IR (v,,, film cm-l) 3435 2926 2856 1755 1454 1320; MS CI-MS 621; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives per-acetate (lH NMR) cyclogoniodenins T and C ('H NMR) MTPA ester of cyclogoniodenins T and C ('H NMR) TMS (EI-MS); Biological activities BST LC, = 0.85 pg ml-l A-549 ED, = 1.86 x lo-' pg ml-' MCF-7 ED, = 8.40 pg mF1 HT-29 ED, = 4.45 x lo- pg ml-l A-498 ED, = 8.98 x lo-' pg ml-' PC-3 ED, = 1.21 pg ml-' PaCa-2 ED, = 1.88 x 10-1 pg ml-l; Source Goniothalamus giganteus bark.67. Rollidecin A 176,,' C,,H,,O, MW 638 thm Carbon No. 12 15 16 19 20 23 24 'H(6) 3.92-3.92-3.92-3.92-3.41 m 3.54m 3.60m 3.98 m 3.98 m 3.98 m 3.98 m I3C(6) 80.3 80.7 81.4 82.6 74.6 74.8 75.4 Colourless waxy solid; MP 60-61 "C; [a] + 13.0" (CH,CI,); UV (A,,, EtOH nm) 222 (e = 3300); IR (vmax film cm-l) 3441,2930,2855,1739,1671,1072; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives:per-MTPA ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 0.42 pg mF1 A-549 ED, = 1.04 x lo-' pg ml-l MCF- 7 ED, = 1.78pg ml-l HT-29 ED, = 1.42 pg ml-l A-498 ED, = 5.4 x lo-' pg ml-l PC-3 ED, = 1.65x ,ug rnl-l PaCa-2 ED, = 1.41 x lo- pug ml-' ; Source Rollinia mucosa leaves.NATURAL PRODUCT REPORTS 1996-5. L. McLAUGHLIN ET AL. APPENDIX 305 68. Rollidecin B 177,32C,,H,,O, MW 638 31.86 pg ml-l A-549 ED, = 2.89 x 10-l pg ml-' MCF-7 ED, = 1.22 pug ml-' HT-29 ED, = 1.18pug ml-l A-498 ED, = 7.50 x lo-' pg rnl-' PC-3 ED, = 5.98 x 10-1 ,ug rnl-', threo PaCa-2 ED, = 8.99 x 10-1pg ml-' ;Source :Xylopia aromatica stem bark.71. Aromicin 206,, C3,H640, MW 620 Carbon No. 12 15 16 19 20 23 24 threo trans threo ~~~~~ IH(S) 3.92-3.98 m 3.92-3.98 m 3.92-3.98 m 3.92-3.98m 3.41 m 3.39-3.42m 3.39-3.42 m 34 13C(S) 80.2 80.8 81.4 82.7 74.6 74.9 75.6 OH 0 Colourless waxy solid MP 57-58°C [a],+8.8" (CH,Cl,); UV Carbon No. 4 7 9 15 16 19 20 (A,,, EtOH nm) 224 (E = 2800); IR (vmax film cm-l) 3445 2935 2854 1739 1670 1074; NMR 'H NMR (500MHz 'H(6) 3.59m 3.85m -3.40m 3.79m 3.79m 3.40m CDCl,) 13C NMR (125 MHz CDC1,) ;Derivatives:per-MTPA I3C(S) 75.6 74.0 209.3 73.7 82.7 82.5 73.7 ester ('H NMR) TMS (EI-MS); Biological activities BST LC, = 0.28 pug ml-' A-549 ED, = 3.73 x 10-5pg ml-l MCF- 7 ED, = 1.32,ug ml-l HT-29 ED, = 1.69pg ml-l A-498 White waxy solid; MP 61-63 "C; [a],+9.9" (c 0.43 CHCl,); ED, = 2.28 x ,ug ml-' PC-3 ED, = 1.73x lo- ,ug mF1 UV (A,,, EtOH nm) 230 (E.= 965); NMR 'H NMR PaCa-2 ED, = 3.44 x lop6pug ml-l Source Rollinia mucosa (500 MHz CDCl,) 13C NMR (1 25 MHz CDCl,) ;Derivatives leaves.per-acetate ('H NMR) per-MTPA ester ('H NMR) 9-hydroxyl aromicin ('H NMR) TMS (EI-MS); Biological activities BST LC, = 10.28pg mk1 A-549 ED, = 2.17 x lo-' pg rnl-', 69. cis-Sylvaticin 204,14,C,,H,,O, MW 638 MCF-7 ED, = 4.24 x lo-' pug ml-' HT-29 ED, = 1.09pug mF1 A-498 ED, = 2.61 x 10-l pg ml-l PC-3 ED, = 3.01 x lo-' pug ml-l PaCa-2 ED, = 2.25 x 10-1pg ml-' Source Xylopia aromatica stem bark.72. Mucocin 207,,' C3,H6,08 MW 638 Carbon No. 12 15 16 19 20 23 24 threo threo trans 37 'H(6) 3.88 m 3.71 q 3.41 m 3.51 m 3.86m 3.93 m 3.86m 13C(S) 80.05 82.08 74.89 74.23 82.45 82.99 72.51 0 Colourless waxy solid MP 63-64 "C [a],+5.2" (CH,Cl,); UV (A,,, EtOH nm) 224; IR (vmax film cm-') 1752; NMR Carbon 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCI,); No. 12 15 16 19 20 23 24 Derivatives formal acetal ('H NMR) per-MTPA ester ('H 'H(S) 3.88 3.80 3.43 3.48 3.15 3.28 3.05 NMR) TMS (EI-MS); Biological activities BST LC, = '3C(S) 79.3 81.9 73.8 73.5 80.1 70.5 82.0 1.1 ,ug ml-' A-549 ED, < ,ug ml-' MCF-7 ED, = 1.50 x lo-' pg rnl-' HT-29 ED, = 5.23 x 10-1 5.23 x lo-' ,ug ml-' A-498 ED, = 1.41pg ml-' PC-3 ED, = Colourless waxy solid; MP 57-58 "C; [a],-10.8" (CH,CI,); 1.80,ug ml-' PaCa-2 ED, < lo-' ,ug ml-l; Source Rollinia UV (A,,, EtOH nm) 207 (log E = 3.84); IR (vmax film cm-l) rnucosa leaves.3419 2925 2853 1748 1716 1456 1066; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCI,); Derivatives formal acetal ('H NMR) per-MTPA ester (lH NMR) tri-TMS 70. Aromin 205,, C3,H6,0, MW 592 (EI-MS); Biological activities BST LC, = 1.3 pg ml-' A-549 ED, = 1.O x lop6pug ml-l MCF-7 ED, = 1.8pg ml-' HT-29 ED, = 9.4 x lo-' pug ml-' A-498 ED, = 2.6 pug ml-' PC-3 threo trans threo ED, = 1.6 x lo-' pug ml-l PaCa-2 ED, = 4.7 x lo-' ,ug ml-'; 32 Source Rollinia mucosa leaves. OH OH 0 73. Venezenin 216,16' C3,HS606 MW 606 Carbon No. 4 7 9 15 16 19 20 threo 37 'H(6) 3.59m 3.84m -3.40m 3.79m 3.79m 3.40m I%(&) 75.6 74.1 209.3 74.1 82.7 82.5 73.7 White waxy solid; MP 48-49 "C; [a) + 10.3" (c 0.25 CHC1,); UV (A,,, EtOH nm) 230 (c = 965); CD (MeOH) [O],,,, Carbon 1514.57,[O],,,,,-810.15; NMR 'H NMR (500 MHz CDCl,) No.10 17 18 21 22 13C NMR (125 MHz CDC1,); Derivatives per-acetate ('H NMR) per-MTPA ester (lH NMR) 9-hydroxyl aromin (lH 'H(6) -3.42 m 3.42 m 5.36 dd 5.40 dd NMR) TMS (EI-MS); Biological activities BST LC, = I3C(S) 211.5 74.4 74.2 128.8 131.0 Whitewaxyso1id;MP 72-73 "C; [a],+ 16.8"(c0.001 MeOH); UV (A,,, EtOH nm) 225 (log B = 3.28); IR (vmax film cm-l) 3375 2924 2854 1732 1700 1642 1490 1282 1074 669; MS FAB-MS (606,588,570,552; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives:per-MTPA ester (lH NMR) TMS (EI-MS); Biological activities BST LC, = 9.33 pg ml-' A-549 ED, = 1.08 x pg ml-' HT-29 ED; = 1.58pg ml-l ;Source Xylopia aromaticu bark.74. Coriadienin 223 114 C,,H,,O, MW 606 Carbon No. 10 13 14 17 18 21 22 'H(S) 3.58 m 5.43-5.43-5.43-5.43-3.41 m 3.39m 5.35 5.35 5.35 5.35 IT(&) 71.5 129.7 129.9 129.8 129.6 74.0 74.5 White waxy solid; MP 58-60 "C [a],+6.2" (c 0.30 EtOH); UV (A,,, EtOH nm) 203 (log B = 4.08); IR (vmax solution in CCI, cm-l) 3468 3009 2934 2857 1732 1750 1600 1457; MS FABMS 606 588 570 552; NMR 'H NMR (500 MHz CDCl,) 13C NMR (125 MHz CDC1,); Derivatives acetonide (lH NMR) 13 14 17 18-bisepoxycoriadienin ('H NMR); Biological activities 9KB ED, = 1.9 x lo- pg rnl-' VERO ED, = 1.5 x 10-1 pg ml-l; Source Annona coriacea roots.NATURAL PRODUCT REPORTS 1996 75. Reticulatamone 210,'09 C,,H, 0, MW 638 Carbon No. 15 'H(6) -I3C(S) 21 1.51 White solid; MP 83-85 "C; [a],+ 12" (c 1.0 CHC1,); IR (vmax film cm-I) 2914 2848 1750 1710 1470; MS CI-MS (isobutane) 533,505; NMR lH NMR (200 MHz CDCl,) I3C NMR (50 MHz CDCI,) ;Source Annona reticulata seeds. 76. Tonkinelin 217,168 C,,H,,O, MW 578 Carbon No. 17 18 'H(6) 3.42 3.42 13C(8) 74.53 74.53 White amorphous powder; MP 6466°C; [a],+14.49" (c 0.07 CHC1,); UV (A,, EtOH nm) 203 (log B = 4.08); IR (vmax solution in CCI, cm-l) 3341 29 15,2848 1742 ;MS CI- MS (isobutane); EI-MS; NMR lH NMR (500 MHz CDCl,) 13C NMR (125 MHz CDCl,); Derivatives acetonide (lH NMR) Biological activities HL-60 IC, = 1 p~, HCT-8 IC, KB IC, > 10p~,A 2780 IC, > 10~~; = 6.7 p~ Source Uvaria tonkinesis bark roots.

ISSN:0265-0568    

DOI:10.1039/NP9961300275

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Natural Sesquiterpenoids Braulio M. Fraga lnstituto de Products Naturales y Agrobiologl‘a CSlC La Laguna 38206 Tenerife Canary Islands Spain ~~~~~ ~~ ~~ Reviewing the literature published in 1994 (Continuing the coverage of literature in Natural Product Reports 1995 Vol. 12 p. 303). 1 Farnesane 2 Monocyclofarnesane and Bicyclofarnesane 3 Bisabolane and Chenopodane 4 Sesquipinane Sesquibornane and Sesquicamphane 5 Chamigrane 6 Trichothecane Cuparane Herbertane Laurane and Gymnomitrane 7 Carotane Cedrane Acorane Prezizaane and Zizaane 8 Cadinane Copaane Sativane and Helminthosporane 9 Himachalane Longipinane and Longifolane 10 Caryophyllane Caryolane Clovane Isocomane and Botrydiane 11 Humulane Illudalane Marasmane Lactarane Isolactarane Merulane Pentalenane Africanane Lippifoliane Capnellane and Cycloprecapnellane 12 Germacrane 13 Elemane 14 Eudesmane Valerane and Lindelane 15 Eremophilane and Bakkane 16 Guaiane and Pseudoguaiane 17 Aromadendrane Bicyclogennacrane Maaliane Zierane and Brasilane 18 Pinguisane and Trifarane 19 Miscellaneous Sesquiterpenoids 20 References This report describes both the isolation and structures of new naturally occurring sesquiterpenoids and in a concise form partial and total synthesis in the area.In previous years only selected examples of synthesis mainly enantiospecific have been included. A review with many references on the synthesis of sesquiterpenoids has appeared.l The capacity of fifteen sesquiterpenoids containing an unsaturated dialdehyde functionality to damage cellular membranes has been investigated.Abbreviations The following structural abbreviations are used in this article \q; Epang = \q0 Ang = ; Meacr = \ \OH \OAc 0 Cinn = \,-I. Farnesane Two new acyclic sesquiterpenes farnes-5,15-olide and 9,12-dihydroxy-farnes-7( 14)-ene have been isolated from the stem bark of Mangifera indi~a.~ The farnesyl acetophenone 1 has been obtained from Ferula communis.3 The aerial parts of Boroniu racemosa contain further novel compounds of this type 3-farnesyl-2,4,6-trihydroxyacetophenone,4-farnesyl-2,-6-dihydroxyacetophenone,and the sesquiterpene flavanone 6-farnesy1-3’,4’,5’,7’-tetrahydroxyfla~anone.~ The norsesqui-terpene 2 and the sesquiterpene 3 related to davanone have been isolated from Artemisia herba-albd and Artemisiu reptuns,7 respectively.Two unusual homofarnesane lactones 4 and 5 and the new farnesane lactone 6 have been found in the aerial parts of Gochnatia glutinosa. This is the first time that homofarnesanes have been isolated from plants although several compounds of this type have been obtained from insects.8 2 3 OH 4 5 I OH 6 Incubation of farnesol with fractions from homogenized cells of Botryococcus braunii gave farnesyl oleate and three other 307 308 farnesyl fatty acid esters.’ The new sesquiterpene 7 has been obtained from the Australian marine brown alga Perithalia caudata.l* Another two compounds of this type 8 and 9 have been found in the Southern Australian marine sponge Thorecta choanoides.” Y COsH 7 Me0 0 8 OH 9 The Hawaiian sponge Spongia Oceania contains pokepola ester 10 a diester of phosphoric acid where the alcohols are 5-methylhexan- 1-01 and homoserine.The amine of homoserine forms an amide with a trinorfuranosesquiterpenic acid.12 The isolation and structure determination of two furanosesquiterpenes 11 and 12 from the soft coral Sinularia lochmodes have been described.13 Another Sinularia sp. also contains the furanosesquiterpene ll.14 Pleuplotin 13 is a supposed biogenetic precursor of the euplotins and has been isolated from strains of the marine ciliated protist Euplotes crassus. HO 10 13 The crystal structure of avian recombinant farnesyl diphosphate synthase the first three-dimensional structure for any prenyltransferase has been determined.16 Seven geranyl diphosphate analogues having oxygen atoms in their alkyl chains were synthesized and examined for their reactivity as substrates with pig liver farnesyl diphosphate synthase.” The cyclizations and rearrangements of farnesol and nerolidol in superacids have been studied.’$ An efficient synthesis of enantiomerically pure juvenile hormone I1 has been deve10ped.l~ NATURAL PRODUCT REPORTS 1996 2 Mono- and Bicyclofarnesane 4,5-Dihydroblumenol A has been obtained from Perrottetia multiflora (Celastraceae).2o p-Ionil sesquiterpene glycosides have been isolated from the leaves of Vits vinifera2l and Malus domestica.22 The structure and absolute stereochemistry of kamahine A kamahine B and kamahine C have been determined as 14-16 respectively.These three norsesqui-terpenes have been obtained from New Zealand 24 A new sesquiterpene 17 has been found in the sponge Dysidea herbacea collected from the Andaman and Nicobar Islands (India).25 The red alga Laurencia obtusa contains the novel sesquiterpene ether dactyloxene D 18,26whilst the brominated sesquiterpene palisadin B 19 has been found in another species of this genus Laurencia karlae.27 14 R1= a-OH; R2= a-Me 17 15 R1= a-OH; R2 = PMe 16 R1 = H; R2= a-Me Br 18 19 The sponge Reniera mucosa contains eight new sesquiterpene hydroquinones 20-27.2s The structure of 3,4-epoxypalisadin A has been confirmed by X-ray crystallographic analy~is.~’ OH I )$I R2 \ R’ovH 20 R’ = H;R* = CHO 21 R1=R2=Me OH OH 22 R=Me 24 R=H 23 R = CH20H 25 R=Me OH OH 26 27 NATURAL PRODUCT REPORTS 1996-B.M. FRAGA The fungitoxic modified sesquiterpene (-t-)-chokol A has An efficient chemical conversion of (*)-f been synthe~ized.~~ C02H OMe NH chokol G to (i-)-chokols A B C F and K chokolic acid B and 8@OHo chokolal A has been carried A stereoselective synthesis of (E,E) and (E,Z)-P-ionylideneacetaldehydes has been achieved,32 O* 38 39 Gametophytes of the liverwort Marchantiu polymorpha contain abscisic acid and 2-trans-abscisic acid. This is the first chemical demonstration that ABA and its 2-trans-isomer occur in the Hepat~phyta.~~ 2,3-Dihydroabscisic alcohol has been identified as a component of starfruit A verrhoa ~arambola.~~ Unnatural phaseic acid has been identified as a minor component of the metabolites derived from exogenously added (-)-abscisic acid in a maize cell suspension A facile preparation of chiral abscisic acid has been achieved.36 A one pot synthesis and optical resolution of a synthetic mimic of ABA which affects plant physiology have been de~cribed.~’ The structure of drimendiol has been determined as 28.This new drimane sesquiterpene has been found in an extract of the aerial parts of Drymis ~interii.~~ Another three compounds of this type albicanic acid 29 albicanal 30 and isoalbicanal 31 have been isolated from the liverwort Diplophyllum serrulatum.“9 Two new fatty acid esters of uvidin A and drimenol have been obtained from Lactarius uvidus.40 28 29 R =C02H 31 30 R =CHO The new nordrimane panudial 32 has been isolated from the fermentation of a Panus species.This compound is a potent inhibitor of human platelet aggregation.*l MER-NF5003-B 33 MER-NFSOO3-E 34 and MER-NFSOO3-F 35 are three novel biologically active drimane sesquiterpenes which have been found in the culture broth of a fungal strain Stachybotrys sp. MER-NF5003.4z WCHO R2$ HO An alga of the genus Peyssonneliu and the sponge Hyatella intestinalis contain three novel sesquiterpene hydroquinones peyssonol A 36 peyssonol B 37 and hyatellaquinone 38.43 Nakijiquinone A 39 and nakijiquinone B 40 are two antifungal sesquiterpene quinones with an amino acid residue which have been found in an Okinawan marine sponge of the family 40 Three new furanosesquiterpenoids em-pallescensin A 41 and two acetoxy derivatives 42 and 43 have been obtained from the skin of the porostome nudibranch Doriopsilla are~lata.~~ A dictyoceratid sponge of the genus Fusciospongiu collected in the Philippines contains a glycine derivative of ilimaquinone which has been named glycinylilimaquinone 44.46Two protein kinase C inhibitors corallidictyal A 45 and corallidictyal B 46 have been identified as components of a mixture obtained from the marine sponge Aka coralliphagum (Siphonodictyon corulliphagum).47 41 R’=R~=H 42 R’ =OAC; R~= H 43 R’ =R~ =OAC 44 HO $yo 45 46 S~ongiidae.~~ HoncHo OH Br@ 36 C02Me 8 37 The mniopetals 47 are new inhibitors of reverse transcriptases which have been isolated from a fungus of the Mniopetalum genus.These compounds have also shown antimicrobial and cytotoxic properties.48. 49 Axinellin A 48 and axinellin B 49 are two new sesquiterpenes which have been isolated from an Indian sponge of the genus Axinellaso The absolute configuration of a tetracyclic drimane sesquiterpene has been determined by Mosher's method indicating that the highly functionalized drimanes isolated from basidiomycetes have the ( -)-drimenol stere~chemistry.~~ The structure of avarol has been confirmed by X-ray analysis.52 47 R' ,R~various 48 49 = Two reviews of recent developments in the synthesis of drimane sesquiterpenes have been published.s3* s4 The acid- catalysed rearrangements of ilimaquinone 5-epi-ilimaquinone avarol and arenarol have been The labdane diterpene zamoranic acid has been used as starting material in the synthesis of the drimane sesquiterpenes poligodial and ~arburganal.~~' 57 Another diterpene ( -)-sclareol has been employed in the preparation of drimenyl acetate and albicanyl acetate.58A new synthesis of (-)-8-epi-ambreinolide starting from ( -)-drimenol has been described.59 Total syntheses of ( +)-confertifolin,60 ( & )-mamanuthaquinone,61 ( rt )-iso-acanthodoraP2 and ( )-e~ryfuran~~ have been reported.Sesquiterpene coumarin ethers have been isolated from Eriostemon myoporoides,64 Heptaptera unisopterd' and Ferulu laserpitium.66A spectroscopy study of farnesiferol B has been reported.67 3.Bisabolane and Chenopodane ( + )-(2)-Lanceol acetate 50 has been obtained from the essential oil of the fruit of Torilis arvensis.68 The dried rhizomes of ginger Zingiber oficinale contain an antirhinoviral NATURAL PRODUCT REPORTS 1996 Six new sesquiterpenes cheimonophyllons A-E 54-58 and cheimonophyllal 59 have been obtained from the culture fluid of the basidiomycete Cheimonophyllum cundidissimum. These compounds exhibit nematicidal antifungal antibacterial and cytotoxic activities. 73. 74 0 54 55 R' = H; R2 = 0 56 R1 = OH; R2 = P-OH,H 57 R' =OH;R2=0 58 59 A homosesquiterpenoid 60 has been identified as a major component of the scent emitted by calling males of Eurygaster integriceps a major pest of wheat in southeast The trans-and cis-(2)-a-bisabolene epoxides are the main components of the male sex pheromone in the green stink bug (Nezara viridula).The role of the cis isomer and the importance of the proportion of cis and trans for the activity and specificity of the pheromone have now been studied.S6 On the other hand a stereocontrolled synthesis of the main pheromone of this insect has been achieved." 60 The total synthesis of yingzhaosu B and its three 7-epi-Zingiberene 51 is a novel bisabolane sesquiterpene which has been found in leaves from the wild tomato Lycopersicon hirsut~rn.'~ Another two compounds of this type 52 and its 5-monoacetate have been isolated from the rhizomes and roots of Valerianafauriei." The investigation of the leaf fragrance of Rosa rugosa led to the isolation of the new norsesquiterpene 7-nor-a-bisabonol 53.72 50 51 diastereoisomers has been carried out.iS A total synthesis of sesquiterpene which was identified as P-sesq~iphellandrene.~~(+)-paniculide A has been reported.7g (+)-Zingiberin the enantiomer of the natural sesquiterpene has been prepared in nine steps from l-menthol.so The first synthesis of (+)-curcudiol ( & )-curcuhydroquinone and ( & )-curcuquinone has been described.81 Two bisabolane norsesquiterpenes isolated from Senecio digitalifolius have been synthesized in racemic form.82 New synthetic routes to (+)-andiralactone have been devised.83 A new class of bioactive sesquiterpenes heliannuol A (Nat.Prod. Rep. 1995 12 316; structure 349) and heliannuols B-D 6143 found in Helianthus annuus may be involved in the 61 62 Ha\ 52 53 63 NATURAL PRODUCT REPORTS 1996-B. M. FRAGA cultivar sunflower defence against invasion by other dicotyledon species.a4 A total synthesis of (+)-heliannuol A has been reported .85 Parvifoline,a6 a bicyclic sesquiterpene derived from a bisabolane derivative by cyclization has been synthesized in racemic form. The liverwort Marchuntiu chenopodu collected in Venezuela contains a new sesquiterpene chenopodene 64 which possesses a novel carbon 64 4 Sesquipinane Sesquibornane and Sesquicamphane The syntheses of (E)-endo-bergamoten- 12-oic acids (a-form p-form) have been carried out.These moth oviposition stimulants have been isolated from wild tomato leaves.88 A sesquiterpenoid ant repellent 65 has been obtained from the fruits of Dysoxylum spect~bile.~~ A short and simple approach to both enantiomers of epi-p-santalene and (2)-epi-6-santalol has been devised.’O The total synthesis of two further compounds of this type (-)-2-and (-)-E-/?-santalol and ent-p-santalene has been reported .91 65 5 Chamigrane A facile synthesis of the sesquiterpenes a-chamigrene and a-chamigren-3-one has been described. a-Chamigrene had been isolated from Shizandru ~hinensis.’~ 6 Trichothecane Cuparane Herbertane Laurane and Gymnomitrane A new trichothecene sesquiterpene harzianum A 66 has been 31 1 The structure of isolaurenisol has been determined as 68.This laurane sesquiterpene has been obtained from a red alga of the genus Laurenciu collected from New Zealand waters.’O1 Enantiocontrolled total syntheses of (-)-debromoaplysin (-)-aplysinlo2 and (-)-filiforminlo3 have been described. A novel gymnomitrane sesquiterpene 69 has been found in an extract of the liverwort Marsupella aquatica.Io4 68 69 7 Carotane Cedrane Acorane Prezizaane and Zizaane The carotane class of sesquiterpenes has been reviewed.lo5 The aerial parts of Cleome droserifbliu contain the carotane derivative 7O.Io6Another three compounds with this skeleton 71-73 have been found in the leaf fragrance of Rosa r~gosa.~~ The antinociceptive antiinflammatory and antipyretic effects of the carotane sesquiterpene lapidin have been studied.lo7 A simple and efficient synthesis of a norcarotadiene a potentially useful precursor of carotane and tormensane derivatives has been described.los P OHO H HO-’ 70 71 72 73 The crystal structure and the absolute configuration of (+)-isocedranol have been determined.log The hydroboration of (-)-a-cedrene and the configuration of the products formed have been studied.’1° The first total synthesis of (-t)-allocedrol (khusiol) has been described.ll’ Bakerol 74 is an unusual noracorane hemiketal which has been isolated from the foliage of Cupressus bakeri.l12 A new A sensitive gas chromatographic method for the quantitative analysis of thirteen trichothecene mycotoxins in corn has been developed.95 An enantioselective synthesis of an ent-trichothecene 67 has been de~cribed.’~ Several regioselective reactions of derivatives of the trichothecene mycotoxins nivalenol and vomitoxin have been carried Incubation studies of (7S)-6,7-dihydrofarnesyl diphosphate with tricho- diene synthase have given further support for the proposed step of isomerization of farnesyl diphosphate to (3R)-nerolidyl diphosphate in the enzymatic formation of tri~hodiene.’~ isolated from the soil-borne fungus Trichodermu hur~ianum.~~ antibiotic with a zizaene skeleton 75 has been obtained from a The inhibition of trichothecane biosynthesis in Fusurium morphologically novel highly odorous species of the The structure of jinkoholic tricinctum by sodium hydrogen carbonate has been ~tudied.’~ Streptomyces ulbidojiuvus acid has been determined as 76.This prezizaene sesquiterpene has been found in an extract of the wood of Neocullitropsis pancheri.ll4 The roots of Rudbeckia luciniuta contain the new sesquiterpene prelacinan-7-01 77,115 whilst the ketone 78 has been found in the roots of Acorus caZumus.116.117 The total synthesis of the tricyclic ketone 79 and the alcohol 80 have been 74 75 76 66 A synthetic approach to cuparane and sesquiterpenoids from a common intermediate developed.” A total synthesis of (-t)-herbertine described.loo 67 herbertane has been has been described.lls These compounds had previously been obtained from Eremophila georgei.llg> 120 A racemic total synthesis of prezizaene prezizanol and jinkohol I1 has been reported.8 Cadinane Copaane Sativane and Helminthosporane Three new cadinane sesquiterpenes (+)-4-muurolen-6a-o1 81 scapanol 82 and ent-T-muuronol 83 have been found in an extract of the liverwort Scapania undulata.122 Another two compounds of this type 84 and 85 have been isolated from the Taiwanese liverwort Lepidozia ~itrea.l~~ Acremonium strain 6 18 has been shown to produce a cytotoxic metabolite which was identified as heptilidic acid chlorohydrin 86.124 A 81 82 83 84 R=H 86 85 R=OOH Two novel cadinane sesquiterpenes 87 and 88 have been obtained from an extract of the leaves and twigs of the Ecuadorian medicinal plant Siparuna mar~rotepala,'~~ whilst epoxycadinenal 89 has been isolated from the aerial parts of Boltonia asteroides.126 Raimondalone 90 is a new quinone which has been found in a specific hybrid of the cotton ~1ant.I~' The foliage of Cupressus bakeri contains four novel sesquiterpenes cis-muurol-3,5-diene 91 cis-muurol-4( 14),5- diene 92 cis-muurol-5-en-4a-01 93 and cis-muuro1-5-en-4/?-01 94 and two new norsesquiterpenes 95 and 96.128 87 88 M e 0 O qCHO H II OHC OH 14 89 90 93 R=wOH 95 96 94 R=P-OH NATURAL PRODUCT REPORTS 1996 Investigation of a Mexican medicinal plant locally known as arnica (Heterotheca inuloides) afforded 7-hydroxy-3,4-dihydrocadalin 97 and 7-hydroxycadalin 98 which exhibited potent antibacterial activity.129 Three known cadinane derivatives found in a chloroform extract of the aerial parts of Eupatorium adenophorum were shown to have seed germination inhibitory activity.130 97 98 Five new sesquiterpenes 99-103 have been isolated from the aerial parts of Fabiana imbri~ata.'~~ This plant also contains 3 I 1-amorphadiene 104,132 the secoamorphane fabianane 105133 and fourteen muurolane and amorphane derivatives 106-1 19.134 The structure of millecrol B has been determined as 120.This compound has been isolated from the South African nudibranch Leminda mille~ra.'~~ Two new cadinanolides baccharocephol 121 and its methyl ether 122 have been obtained from Baccharis ~phaerocepha1a.l~~ The lactones 123 and 124 have been obtained from Vernonia menthaef01ia.l~' R'q oq R2 /t\ /t\ A OH OH OH 99 R1=O; R2=Me 102 103 100 R' = H,; R2 = CHO 101 R' = H2; R2 = C02H I OR i\ HA lo4 105 106 R = (CO)CH2CO,H 107 R = Cinn (trans) 108 R = Cinn (cis) 109 R = (C0)CHZPh p3 R "yo 'I- 0 A 110 111 R=Me 112 R= CHO 113 R=C02H -.-# Rq 0 OH 11s 116 R=Me 117 R=CHO 118 R = C02H 11 9 R = O(CO)CH&@H NATURAL PRODUCT REPORTS 1996-B.M. FRAGA centred radical for the antimalarial activity of artemisinin derivatives has been A series of artemisinin derivatives have been assayed in vitro for anti-HIV a~tivity.'~' A synthesis of [15-14C]-labelled artemisinin has been described.158 A novel sesquiterpene 130 has been obtained from Artemisia ~ubdigitata.'~' Nine sesquiterpenes structurally related to ( +)-HA a-copaene the male lure for Mediterranean fruit fly (Ceratitis 120 121 R=H capitata) have been tested in field bioassays.16* A total synthesis 122 R=Me of (+)-sativene via a high pressure Diels-Alder route has been devised.16' Analogues of helminthosporic acid for example 131 have been found to induce the production of amylase in barley aleurone layers.162 HO-%oR bMeacr 0 123 R=Me 124 R=Et The biosynthesis of cadinane sesquiterpenes in cell cultures of the liverwort Heteroscyphus planus has been studied.'".139 A predicted 1,2-hydride shift has been observed in a study of the biosynthesis of ( +)-epicubenol by incubation of labelled FPP with epicubenol synthase isolated from species of The total syntheses of ( )-epicuben01'~~ Strept~myces.'~~ and cis-7,8-dihydroxy- 1 1,12-dehydro~alamenenel~~ have been de- scribed.The investigation of Artemisia annua and its antimalarial components has continued. Thus three new cadinanes 125-127,143 a secocadinane 128 and two diastereoisomers of the dihydroxycadinanolide 129 have been isolated from the aerial parts of this species.144 Current developments in the chemistry of artemisinin and related compounds have been re~iewed.'~~ The proton and carbon-13 NMR of several quinghaosu derivatives have been assigned.146 The effects of artemisinin and arteannuic acid on the physiology of Lemna minor have been e~aluated.'~' The cytotoxic activity of several terpenoids from Arternisia annua has been studied.'** The amount of artemisinin and other related lactones obtained from Artemisia annua growing in Vietnam have been \ OH 1 0 CH20H 130 131 9 Himachalane Longipinane and Longifolane A novel dimeric sesquiterpene chinensioll32 has been isolated from the roots of Juniperus ~hinensis.'~~ himachalane A sesquiterpene has been used as an example in the application of two-dimensional NMR spectroscopy in the structure elucida- tion of natural A new total synthesis of (+)-a-himachalene has been achieved.165 The aerial parts of Santolina viscosa contain five novel longipinene derivatives 133-137.'66 Another compound of this type 9-acetoxymarsupellol 138 has been obtained from the liverwort Marsupella emarginata.'''A conformational analysis of moreliene derivatives produced by acid catalysed rearrangement of naturally occurring longipinanes has been described.168 eoH & @Rl @H OH ~2 C02Me 132 133 R' = R2= Me 138 OH OHC 9qo 134 R' = Me; R2 = CH20H 125 1 26 127 135 R'=CH,OH; R2=Me OHC" C02H 0 128 129 A short and practical synthesis of artemisinin has been described.150 Arteannuin B has been transformed by de-epoxidation in 6a-hydroxyisoannulide another component of Artemisia annua. 15' The synthesis conformational analysis and antimalarial activity of several tricyclic analogues of artemisinin have been reported. lS2Silica gel catalysed rearrangement and subsequent Baeyer-Villiger reactions of artemisinin derivatives have been described.'j3 A novel rearrangement of the trioxane ring system of arteether upon treatment with acid has been 0b~erved.l~~ A synthesis of a novel ring contracted artemisinin derivative has been achieved.155 The importance of a carbon 136 R' =Me; R2 = CH2me 137 R' = CH20Me; R2 = Me Three isomeric alcohols have been prepared from isolongifolene to provide easy to make and cheap The aromatization reaction of longifolene with Lewis acids has been st~died."~ 10 Caryophyllane Caryolane Clovane lsocomane and Botrydiane The structure and absolute stereochemistry of 9-epi-p-caryophyllene has been determined as 139 by 2D NMR 139 techniques and chemical methods.This compound has been isolated from the foliage of the New Zealand rimu tree Dacrydium cupressinum."' A sesquiterpene from Juniperus oxycedrus to which a 15-hydroxy-9-epi-/3-caryophyllene struc-ture had been assigned has been shown to be the trans-fused isomer 1 5-hydroxy-/3-caryophyllene 140.Its absolute stereochemistry was determined by synthesis from (-)-/?-~aryophyllene."~ fOH H ;-'" 140 Ten new sesquiterpenes with caryophyllane 141-145 isocaryolane 146 caryolane 147-149 and clovane 150 skeleta have been isolated from the dried pods of Sindora surnatrana. The epoxidation of P-caryophyllene could form both the a-and p-epoxides. Whilst the former could lead to the caryolane derivatives the latter could lead to isocaryolane type NATURAL PRODUCT REPORTS 1996 11 Humulane Illudalane Marasmane Lactarane Isolactarane Merulane Pentalenane Africanane Lippifoliane Capnellane and Cycloprecapnellane A synthesis of humulendione and (-)-cubenol starting from natural ( + )-aromadendrane has been achieved.ls2 Three new chlorinated sesquiterpenes chloriolins A B and C 151-153 have been isolated from an unidentified fungus which was initially separated from a Jaspis marine sponge and then cultured on marine media.183 The antimicrobial hirsutane sesquiterpene 1-deoxyhypnophilin 154 has been obtained from Lentinus crinitus.ls4 The hirsutane sesquiterpene (+)-precoriolin obtained from (S)-(+)-carvone has been transformed into (+)-coriolin B.Is5 A total synthesis of (+)-illudin M has been described.ls6 A new bioactive illudalane sesquiterpene pholiotic acid 155 has been obtained from the fungus Pholiota de~truens.'~' compounds and then to those with a clovane ~ke1eton.l'"~~~ 151 HO OH H .*H ,@ 141 142 OH 152 R = (CO)(CH&Me 153 R = (CO)CH(OH)(CH&Me Aa-p H 143 a-epoxy 145 144 p-epoxy 1 54 155 A marasmane and a lactarane sesquiterpene 156 and 157 respectively have been found in Lactarius vellereous.ls8The conformational analysis by molecular mechanics of two lactarane sesquiterpenes furoscrobiculin D and blennin D has .."/ been studied.The results of the molecular modelling were related to the observed 'H NMR data allowing the structure of V O H 146 147 R=O 150 148 R = a-OH,H 149 R=P-OH,H The biotransformation of caryophyllene oxide by a cell HO 1 56 suspension culture of Eucaliptusperriniana has been rep~rted.'~~ New sesquiterpenoid compounds obtained by rearrangement of isocaryophyllene have been found to inhibit the growth of Botrytis cine~ea.~~~ The hydrolysis and rearrangement reactions of caryophyllene oxide have been 17* The thermal conversion of caryophyllene sesquiterpenes into farnesane derivatives has been reported.17' A stereocontrolled synthesis of isocomene has been de- scribed.Is0 The synthesis and antifungal activity of analogues of naturally occurring botrydial precursors have been rep0rted.l" 157 NATURAL PRODUCT REPORTS 1996B.M. FRAGA furoscrobiculin D to be corrected to 158 and confirming that of blennin D.lS9 3-Ethoxylactaranes have shown high antifeedant activity against the storage pests Sitophilus granarius and Tribolium confusum.lgo The synthesis of lactarane sesquiterpenes has been reviewed.53 A lactarane sesquiterpene with trans-fused rings 8-epi-9-epi-furandiol 159 has been synthesized starting from furandiol,lgl and its structure confirmed by X-ray ana1y~is.l~~ The first total synthesis of the lactarane sesquiterpene furoscrobiculin B has been carried out.lg3 Three new sesquiterpenes 163-165 possessing a lippifoliane skeleton have been isolated from Lippia integrifoli~.'~~ Viridianol 166 has been found in an extract of the red alga Laurencia viridis. This new sesquiterpene possesses a new carbon framework (cycloprecapnellane) which probably derives from the precapneliane carbon skeleton.2oo A formal synthesis of the marine metabolite (-)-A9'12)-capnellene has been achieved.201 158 159 The structure of hyphodontal has been determined as 160.This isolactarane sesquiterpene inhibits the growth of several yeasts and viruses and has been obtained from fermentation of a Canadian Hyphodontiu species.lg4 The aldehyde 161 and the lactone 162 have been isolated from the culture filtrate of the fungus Merulius tremellosus. The former is an isolactarane derivative and the latter meruliolactone 162 possesses a new carbon skeleton which has been named merulane."" yHo OH @( H 0 160 &HO A OH 161 "Yo\ 162 The cyclization of farnesyl diphosphate to the sesquiterpene hydrocarbon pentalenene which is catalysed by pentalenene synthase has been studied.This enzyme was isolated from a Streptomyces species.lg6 The total synthesis of the natural sesquiterpenes (-)-silphiperfol-6-ene and ( -)-methyl cantabradienate has been achieved.lg7 The full paper with the revision of the structure of caespitenone has appeared.lgs This africanane sesquiterpene had been obtained from Porella species of liverwort (see Nut. Prod. Rep. 1995 12 309; structure 141). 163 R = a-H 165 166 164 R=P-H 12 Germacrane A novel sesquiterpene 167 has been isolated from Cremanthodium ellisii.202 6~-Tigloyloxyglechomafuran168 is a new germacrane derivative which has been obtained from the aerial parts of Sulvia glutinos~.~~~ The biotransformation of germacrone by cell suspension cultures of Lonicera japonicu Bupleorum falcutum Polygonum tinctorium and Solidugo altissima has been investigated.204 Total syntheses of (+)-periplanone B205and ( -)-periplanone C206have been described.(-)-Guaiol has been used as starting material in the synthesis of the germacrane sesquiterpene (+)-hedycary~I.'~~ An enantiospecific synthesis of curcumanolide A a spirolactone probably derived from a germacrane derivative has beell achieved.208 Many new germacrane lactones have been isolated from natural sources during 1994 and are given in Table 1. Structures 169-197 represent the new germacranolides whilst structures 198-201 have been assigned to the heliangolides 202-207 to the melampolides and 208 to the cis,cis-germacranolides.Table 1 Sources of germacrane lactones Source Germacranolides Ref. Artemisia herba-alba 169-1 72 6 Blainvillea latifolia 173 209 Centaurea sphaerocephala 174 2 10 Cyathocline Iutea 175 21 1 hula salsoloides 176 177 212 Mikania dusenii 189-191 213 Montanoa tomentosa 187 188 214 Neotlisea aciculata 194-196 215 Peucephyllum schottii 186 216 Pyrethrum santolionoides 18&185 217 Stevia breviaristata 192 193 218 Tanacetum argenteum 178 179 219 Vernoniu menthaefolia 197 137 Heliangolides Centaurea paui 198 199 220 Liatris ohlingerae 200 201 22 1 Melampolides Montanoa Ieucantha 202-204 222 Stevia breviaristata 207 218 Vernonia syringifolia 205,206 223 cis&-Germacranolides Vicoa indica 208 224 316 NATURAL PRODUCT REPORTS 1996 R2 OR’ OAng 167 168 169 R’=H; R2=0 1 73 174 1 75 170 R’ = Ac; R2 = 0 171 R’ = H; R2 = P-OH,H 172 R’ = Ac; R2 = P-OOH,H 176 inulasalsolin R = H 178 179 180 181 182 177 inulasalsolide R = OH 183 1 84 185 186 187 R=H 188 R=OH HO AcO I(..- 0 AcO 189 190 R=H 192 R=H 194 neolicianolide A 191 R=OH 193 R=Ac 195 neolicianolide B 196 neolicianolide C 197 198 R=HorAc 199 R=Ac ,OAc 200 R=Sen montaleucantholideA B and C 0 208 201 R=Acserr 202 2a,3a-epoxy; R =Acserr 203 R’=(CO)Pr‘; R2=H 204 ~1 = Mebu; R* = H 206 R = \%HoH 205 R’ =Ang; R2 = OH 207 R = Eprneacr NATURAL PRODUCT REPORTS 1996B.M. FRAGA There are several points to note in relation to these sesquiterpene lactones.Known furanoheliangolides have been isolated from Viguiera m011is.~~~ Inhibitory effects of tagitinin A and tagitinin C on the germination of radish cucumber and onion seeds have been observed.226 The (E,E)-germacranolide hanphilline has been photochemically transformed into its (Z,Z)-i~omer.~~' The unusual lactone 209 has been isolated from Montanoa tomento~a.~~~ The montahibisciolides 210-213 represent a new skeletal type of sesquiterpene lactones. These compounds have been obtained from Montanoa leuchanta.222 The influence of cnicin on the ovipositional response and larval development of insect herbivores has been examined.228 209 210 R = (C0)Pr' 213 211 R=Mebu 212 R =Ang 13 Elemane The new sesquiterpene 214 has been obtained from Mikania dusenii.213The novel elemanolides 215 and 216 have been found in extracts of the aerial parts of Centaurea sphaerocephala210 and Centaurea paui,200 respectively.0 HO AcO 0 214 215 OHC *..OH b '0 216 14 Eudesmane Valerane and Lindelane A new sesquiterpene erigeside A 217 has been found in Erigeron brevi~aupus.~~~ Another two compounds of this type 218 and 219 have been isolated from Brocchia ~inerea~~O and Seseli vayredanum,231respectively. The flowers of Chrysanthemum indicum contain the new eudesmane sesquiterpene chrysantherol 220.232The structure of a new eudesmane-4,ll- 217 218 0 21 9 220 diol isolated from Pluchea arguta has been revised to 221.233 Another compound with this skeleton 222 has been obtained from the liverwort Lepidozia ~itrea.~~~ HO "d @.& cb 221 222 Various analogues of the norsesquiterpene chamaecynone 223 have been prepared from a-santonin and their termiticidal activity has been examined.234 The total synthesis of the marine furanosesquiterpenes tubipofuran and 15-acetoxytubipofuran has been achieved.235 The synthesis of (+)-1,2-dihydro-tubipofuran 224 starting from u-santonin has also been devised.236 223 224 The first total synthesis of 3u,4u-oxidoagarofuran and (-)-3P,4a-dihydroxy-P-dihydroagarofuran has been Novel P-agarofurans have been isolated from Euonymus f~rtunei,~~~ Euonymus nanu~,~~' Euonymus kiauts~hovicus,~~~ Maytenus b~aria,~~~.Euonymus sa~halinensis,~~~ 243 Ma ytenus Maytenus chuchuh~asca,~~~ canariensi~,~~~ Maytenus 247 Maytenus ilicifolia,248, emarginata,246.249 Maytenus magellani~a~~~ 251 and Tripterygium ~ilfordii.~~~. New eudesmanolides have been obtained from different species (see Table 2) and their structures shown to be 225-250. Three ent-spiroeudesmane sesquiterpenes named spiro-dilatanolides A B and C 251-253 have been isolated from the liverwort Frullania dilatata.256- 257 The microbiological trans- formation of 7a-hydroxyfrullanolide by a fungus of the Aspergillus genus has been investigated.258 A formal synthesis of (-)-a-santonin has been achieved using an optically active key intermediate prepared by asymmetric hydrolysis of its ra~emate.~~~ The partial synthesis of 6P-eudesmanolides and 6P-guaianolides from 6a-eudesmanolides has been reported.26o A synthesis of 11P-angeloyloxy-a-santoninhas been devised.In this work the X-ray structure of 1I@-hydroxy-a-santonin has been described.261 Santonin and other sesquiterpene lactones react with pyrrolidine at room temperature to afford y-hydroxyalkylamides.262 Conformational analysis studies of 6a- and 6P-eudesmanolides and 8a-and 8P-eudesmanolides have been carried Table 2 Sources of eudesmanolides Source Eudesmanolides Ref. Artemisiu hugueti 225-237 239 252 Artemisiu ifranensis 226 235 238 252 Artemisia herbu-alba 245 6 Frulluniu m uscicolu 241-244 253 Seseli vayredanum 246 247 23 1 Steviu breviuristata 240 218 Tunacetum densum 248 254 Wedelia paludosa 249 250 255 ;’H 318 NATURAL PRODUCT REPORTS 1996 225 R’ = Ac; R2 =a-H 230 R=H 233 R’ = 0-OH; R2= H 235 R’ = H; R2 = CC-OH 238 226 R’ = H; R2 = a-OH 231 R=OH 234 R’ = a-OAC; R2= OH 236 R’ = H; R2 = 0-OH 227 R’ = H; R2= 0-OH 232 R=OAc 237 R’ = Ac; R2 = 0-OH 228 R’ = Ac; R2 = a-OH 229 R’ = Ac; R2 = 0-OH OH I 239 240 241 R=CH;! 243 242 R=P-Me,H @% OSen 0 0 0 244 245 246 247 248 eginensolide 249 R’ = (co)pri; ~2 = A? 250 R’ = Ac; R2 = (C0)Pr’ 15 Eremophilane and Bakkane Ligularia ~agitta~~’ contains four novel eremophilane 1 derivatives 258-261 whilst Ligularia veit~hiana~~~-yields another four new compounds of this type 262-265.This latter 0 0 species is used in northwestern China for the treatment of 251 R=CHp 253 influenza cough ulcer and tuberculosis.Eremopetasidione 266 252 R = B-Me,H is a new norsesquiterpene which has been isolated from the rhizomes of Petasites japonic~s.~~’ An inhibitor of brassinolide named KM-01 has been obtained A lactone with a valerane skeleton 254 has been isolated from the fungus Drechslera auenae. Its structure and absolute from Seneciojacquemontzanus.264 The structures of chloranoside A and chloranoside B have been determined as 255 and 256 respectively. These two sesquiterpene glucosides with a lindelane skeleton have been obtained from Chloranthus SOAC glaber.265Another compound with this carbon framework leucerolide 257 has been found in Leuceria jloribundu.266 258 R = a-Me 260 259 R=P-Me HO” OGlC 254 255 261 R=Ac 263 262 R = H OH HOmo OH 264 R=C02H 266 256 257 265 R=OH NATURAL PRODUCT REPORTS 1996-B.M. FRAGA stereochemistry have been determined as 267.2i0 The structure of the eremophilane part was identical with bipolaroxin which had been found in Bipolaris cynodontis.271The naphthofuran 268 has been obtained from the roots of another species of this genus Ligulariu przewal~kii.~~~ The eremophilane derivatives petasin and isopetasin components of an extract of Petusites hybridus have been found to inhibit peptidoleukotriene biosynthesis in isolated peritoneal rnacrophage~."~ The novel eremophilanolide 269 has been found in the This liverwort Frulluniu mu~ciculu.~~~ lactone and its dihydroderivative 270 have been obtained from another species of this genus Frullunia dilututa.2"6 The synthesis of a furanosesquiterpene with a secoeremophilane skeleton which had been isolated from Ligulariu virgaureu (Nut.Prod. Rep. 1993 10 41 1 ; structure 375) has been rep~rted.~' Me0 267 268 pqR 0 0 269 R = CH2 270 R=B-Me,H The vinyl analogues of farnesyl diphosphate 12-methylidenefarnesyl diphosphate has been shown to be an effective mechanism based inactivator of aristolochene ~ynthase."~ The incorporation of 13C labelled 5-epi-aristolochene into the phytoalexin capsidiol in green pepper seedlings has been in~estigated.~'~ Capsidiol and debneyol have been obtained from hairy roots of Nicotiuna tubacum elicited with yeast or fungu~.~" The detoxification of another potato phytoalexin rishitin by the fungus Gibberella pulicuris has been studied.278 Stereoselective total syntheses of (f)-bakkenolide A (fukinan~lide)"~ and (-t)-homogynolide BZ8"have been described.16 Guaiane and Pseudoguaiane The new guaiane diol 271 has been obtained from Leuceriu floribundu,266whilst 10-0-methylalismoxide has been isolated from the fresh rhizomes of Alismu On the other hand the dried rhizome of this plant contains the new bioactive sesquiterpenes named sulfoorientalols A-D 272-275. These & H03SQ 4 OH H ; compounds were found to inhibit the carbachol induced contraction of bladder smooth muscle isolated from the guinea pig.282 The structures of alismol alismoxide and oriental01 A-C have been shown to be the enantiomers of those previously reported (Nut.Prod. Rep. 1994,11,546; structures 333-336).283 A chamazulene derivative 276 has been shown to be an inhibitor of leucotriene B formation.284 Achimillic acids A-C 277-279 are three novel antitumour sesquiterpenes which have been obtained from Achilleu rnillef~lium.~~~ An enantiospecific synthesis of the trinorguaiane sesquiterpene clavukerin A starting from (-)-carvone has been achieved.286 A total synthesis of racemic 10-isothiocyanatoguaia-6-enehas been devised.287 276 277 R = a-Me,P-OH 279 R = a-OH,B-Me 278 The sources of the new guaianolides that have been isolated during the period of coverage of this review are listed in Table 3 and the novel guaian-6a,l2-olides i.e.38&313 are listed in Table 4. The other new guanianolides are represented by structures 314-325. Table 3 Sources of guaianolides Source Guaianolides Ref. Achillea crithm ifolia 283 288 Achillea species Ajania Jruticulosa 280-282,315-317 284 289 290 Andryala integrfolia Artemisia reptans 297 299 300 285-288 29 1 7 Centaurea glastifolia 207-309 292 Centaurea hermunnii 310-312 293 Centaurea scoparia 313 314 294 295 HO \ H Cheirolophus mauritanicus 294 295 296 Cheirolophus ulginosus 296 271 272 273 274 275 Crepis crocea 297 297 Ferula oopoda 293 298 Ixrris chinensis 304 299 heris dentata Montanoa tomentosa 301 302 305 306 318 300 301 214 Pe ucephy llum schottii 319 216 Seseli vayredanum 320-325 23 1 Stevia breviaristata 289-292 218 Vernon ia leopoldi 303 223 Vernonia moaensis 298 137 NATURAL PRODUCT REPORTS 1996 Table 4 Novel guain-6a,l2-olides 14 \ 0 Name Structure Position of double bond(s) Substituents and configurations Ref.Artabsin derivative 280 1-2,4-5 ga-OAng I OP-OH 1 1 a 289 Artabsin derivative 281 1-2,45 8a-OTig lOP-OH 1 la 289 Artabsin derivative 282 1-2 4-5 8a-OAc lop-OH 1la 289 Hymenopappolide derivative 283 2-3 10-14 11-13 1a-OH 4P-OH 8a-OAng 288 Apressin derivative 284 2-3 11-13 1a-OH 4a-OH 9a-OAng 1Oa-OH 290 Leucodin derivative 285 3-4 2-0X0 10a lla 14-0xO 7 Leucodin derivative 286 3-4 2-OX0 lop Ila 14-OXO 7 Leucodin derivative 287 34,10-1 2-0x0 1 la 14-OH 7 Leudocin derivative 288 3-4,10-1 2-0x0 lip 14-OH 7 Breviarolide derivative 289 3-4 11-13 8P-OTig lop 14-OH 218 Breviarolide derivative 290 34 11-13 8P-OR1 lop 14-OAc 218 Breviarolide derivative 291 34 11-13 8P-OR2 lop 14-OH 218 10-epi-Breviarolide 292 3-4 11-13 8P-OR1 10a 14-OH 218 Dih ydroeremanthin 293 4-15 9-10 1 la 298 Dihydroaguerin B 294 4-15 10-14 3/?-OH 8a-OMeacr 11a 296 Dih ydrocynaropicrin 295 4-15 10-14 3/3-OH 8aOR3 Ila 296 Zaluzanin C derivative 296 4-15 10-14 3P-OH 8a-OH lla 296 Zaluzanin C derivative 297 4-15 10-14 3p-OH 8/3-OH lla 291 297 Annuolide D derivative 298 4-15 10-14 3/3-OH 9P-OH Ila 137 Integrifolin derivative 299 4-15 10-14 ~P-OG~C, 8P-OH lla 29 1 Integrifolin derivative 300 4-15 10-14 ~P-OGIC,8/3-OH 11a,13-OME 29 1 Dentatin B 301 4-15 10-14 ~P-OGIC,8/3-OH 1lP 300 Dentatin C 302 4-15 10-14 ~P-OGIC, 9P-OH 1I/3 300 Zaluzanin A isobutyrate 303 4-15 10-14 11-13 3,8-0( C0)Pr' 223 8-epi-Crepioside G 304 4-15 10-14 11-13 ~P-OGIC, 8/3-O(CO)CH2(C,H,)OH 299 Dentatin A 305 10-14 3P-OGlc 4p 8P-OH llp 300 Dentalactone 306 10-14 3/3-OH 4i3 8@-OH 1lp 30 1 epi-Cebellin J 307 10-14 11-13 3P-OH 4a-OH 8a-0R5 15-OH 292 Hermanoid 1 308 10-14 11-13 3/?-OH 4a-OH 8a-OR3 15-00H 293 Hermanoid 2 309 10-14 11-13 3P-OH 4a-OH 8a-OH 15-00H 293 Desoxypicrolide A derivative 310 10-14 11-13 3/3-OH 4a-OH &OR3 15-OH 293 Chloroscoparin 311 10-14 11-13 3P-OH 4a-OH &-OR4 15-C1 294 Dentatin A 312 10-14 3P-OGlc 4p 8P-OH Ilp 300 Den talactone 313 10-14 3/3-OH 4/? 8p-OH Ilp 30 1 The structure of the guaianolide rupin A now isolated from Achillea crithrnifolia has been revised from a la,2a 3a,4a- diepoxide to a 1/?,2/? 3/?,4/?-die~oxide.~~~ OTig The structures of three guaianolides and the corresponding 3-oxaguaianolides considered to be 10-epi-artabsin derivatives have been 0 revised to the artabsin derivatives 280-282 and 315-317 respectively.289A new chlorinated guaianolide with an unusual 0 0 structure dianin 314 has been obtained from Centaurea 318 319 scop~ria.~~~ A full paper on the isolation and structure HO -OVOH CI 0 ?tJ HO 0 -)-0 0 0 315 R =Ac 320 R=Aw 322 323 R=a-OSen 314 316 R = Ang 321 R=Sen 324 R=P-OAng 317 R = Tig 325 R=p-OSen NATURAL PRODUCT REPORTS 1996-B.M. FRAGA determination of several guaianolides found in species of the Centaurea genus has appeared.In this work the X-ray structure of linichlorin B has been described.302 Known guaianolides derived from zaluzanin C have been isolated from the roots of Crepis p~lchra,~~~ and from tissue cultures of Lactuca viro~a.~O~ The structure of cladantholide has been confirmed by X-ray analysis."05 Eleven naturally occurring guaianolides 1lp,13-dihydrokauniolide estafiatin isodehydrocostuslactone 2-oxodeoxyligustrin arborescin 1lp 13-dihydroludartin 8-deoxy-1lp,13-dihydrorupiculin B ludartin kauniolide dehydroleucodin and leucodin have been synthesized via a common cationic intermediate which was derived from an eudesman~lide.~~~ a-Santonin has been used as starting material in the synthesis of the lactone 326.Recently its enantiomer has been found in Ferula ~vrigonii.~'' d$ 0 0 326 The aerial parts of Artemisia douglasiana have been used in folk medicine as a treatment for peptic ulcer. Its active principle dihydroleucodine has been shown to be a cytoprotective agent that prevents the formation of gastric lesions.3us The anti-inflammatory activity of hydroxyachillin has been Several thapsigargin derivatives have been prepared to evaluate their properties as Ca2+ pump inhibit01-s.~~' The new xanthanolide 327 and the novel bisnorxanthanolide 328 have been obtained from a chloroform extract of the aerial parts of Xanthiurn ca~anillesii.~'~ Another species of this genus Xanthium strumarium contains the new lactone 329.312The cytotoxic activity of xanthatin and that of the crude extracts of Xanthium strumarium and Xanthium italicum have been 314 327 328 329 The structure of the pseudoguaianolide parthenin has been confirmed by X-ray analysis.315 The production of psilostachyinolide by a callus culture of Ambrosia tenuifolia has been examined."I6 The cytotoxicity of five pseudoguaianolides obtained from species of the genus Arnica has been 17 Aromadendrane Bicyclogermacrane Maaliane Zierane and Brasilane The liverwort Plagiochila porelloides contains three new sesquiterpene esters of the secoaromadendrane alcohol 330 with three different fatty acids.31s Plagiochiline N 331 321 acetoxyisoplagiochilide 332 and 4a,lop-dihydroxy-ent-aromadendrane 333 are three novel aromadendrane derivatives which have been isolated from a species of the same genus Plagiochila ov~lifolia.~~~ The sesquiterpene millecrone B 334 has been found in extracts of the nudibranch Leminda millecra.13' 331 332 333 334 The structure of two aromadendrane sesquiterpenes 335 and 336 derived from (+)-ledene and spathunol have been determined by X-ray analysis.32o The biotransformations of (-)-globulol and (+)-led01 by Glomerella cingulata have been inve~tigated,~'~ whilst another fungus Cephalosporium aphidicula has been used in the microbiological transformation of globulol and 7-epi-globul01.~~~ OH HO'**.1 H\ HOq 335 336 Plagiochiline A has been converted into plagiochilal B and furan~plagiochilal.~~~ A stereoselective synthesis of (+)-1,2-didehydroaromadendrane has been carried An easy route to isothiocyanoalloaromadendrane derivatives has been An efficient and concise multigram purification of the bicyclogermacrane sesquiterpene guayulin A has been de- The structure of prostanterol an antimicrobial sesquiterpene isolated from Prostanthera aff.melissifolia and Prostanthera rotundifolia has been determined as 337.32i The synthesis of (+)-maaliol starting from natural (+)-aroma- dendrane has been The liverwort Saccugyna viticulosa contains two novel zierane sesquiterpenes which have been named saccogynol 338 and deoxysaccogynol 339.329The structure of a brasilane sesquiterpene isolated from the red alga Laurencia implicata has been revised to 340.330 /t\OH 337 338 R=OH 340 339 R=H 18 Pinguisane and Trifarane Four novel pinguisane sesquiterpenes bryopterins A-D 341-344 have been isolated from the Panamanian liverwort Bryopteris fili~ina,~~' whilst dehydropinguisone 345 has been obtained from the New Zealand species Plagiochila retro~pectana.~'~ Another liverwort Cheilolejeunea trifaria which was collected in Malaysia contains two novel bicyclic sesquiterpenes trifarienol A 346 and trifarienol B 347.These compounds possess a new carbon skeleton which has been named trifa~ane.~,~ 341 342 R=H 344 343 R=OH 345 346 R=a-Me 347 R=P-Me 19 Miscellaneous Sesquiterpenoids Porosadienone 348 is a new sesquiterpene with a novel carbon framework which can be derived from an eudesmane skeleton.This compound has been found in Phoebe whilst cylindrene 349 is another novel sesquiterpene which possesses inhibitory activity on rabbit vascular smooth muscle and has been isolated from Imperata cylindric^."^ The structure of hispidospermidin has been elucidated as 350.This substance is a novel phospholipase C inhibitor produced by Chaetosphaeronema hispidulum. 335 348 349 I I drN-" 4 350 A new furodysidin derivative 351 has been obtained from the nudibranch Hypselodoris webbi collected on the Spanish Another three new furanosesquiterpenes of this type 352 353 and the enantiomer of 352 have been isolated from Dysidea herb~cea.~~' The new sesquiterpene raikovenal 354 which possesses a new carbon skeleton has been found in the marine ciliate Euplotes raikovi.This compound favours the adaptive radiation of this Eupolotes species by selectively killing the predacious ciliate Litonotus lamella.338 Another species of this genus Euplotes crassus contains euplotin C 355 which is derived biogenetically from preeuplotin 13.15 13a-Acetoxypukalide has been isolated from a species of the genus Sin~1aria.l~ NATURAL PRODUCT REPORTS 1996 H H U 351 352 353 OH 354 355 Tridensone has been synthesized in optically active forms. Spectral data of the natural compounds indicate that the structure should be 356,339 the enantiomer of that previously Two 'isodaucane ' sesquiterpenes millecrone A 357 and millecrol A 358 have been isolated from the nudibranch Leminda mi1le~ra.l~' Another compound of this type 359 containing a rare trans ring junction has been found in Sindora ~umatrana.'~~ Sorokinianin 360 is a new phytotoxin produced by the fungus Bipolaris sorokiana.A preliminary study indicated that this metabolite can be derived biogenetically from a sesquiterpene probably prehelminthosporal and an additional C 356 357 R=O 358 R = a-OH,H HO'8 359 360 A total synthesis of the sesquiterpene quinone. metachromin A has been The first total synthesis of the unusual sesquiterpene (_+ )-myltayl-4( 12)-ene has been a~hieved."~ A concise stereoselective synthesis of the axane family of sesquiterpenes has been The marine sesquiterpenes and ~pia1~~~ nanaim0a1~~~ have been synthesized in an enantioselective form.20 References 1 A. 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Jia and L.Yang Planta Med. 1994 60 91. 269 Y. Yaoita and M. Kikuchi Phytochemistry 1994 37 1765. 270 S. K. Kim K. Mizuno M. Hatori and S. Marumo. Tetrahedron Lett. 1994 35 1731 271 F. Sugawara and G. Strobel Proc. Natl. Acad. Sci. USA 1985,82 829 1. 272 Z. Jia and Y. Zhao J. Nut. Prod. 1994 57 146. 273 D. Bickel T. Roder H. J. Bestmann and K. Brune Planta Med. 1994 60,318. 274 H. Liu L. M. Gayo R. W. Sullivan A. Y. H. Choi and H. W. Moore J. Org. Chem. 1994 59 3284. 275 D. E. Cane and C. Bryant J. Am. Chem. Soc. 1994 116 12063. 276 Y. Yuko T. Yamaura S. Kawai T. Hoshino and J. Mizutani Biosci. Biotechnol. Biochem. 1994 58 305. 277 M. S. Wibberley J. Lenton and S. J. Neill Phytochemistry 1994 37 349. 278 H. W. Gardner A. E. Desjardins S.P. McCormick and D. Weisleder Phytochemistry 1994 37 1001. 279 A. Srikrishna T. J. Reddy S. Nagaraju and J. A. Sattiger Tetrahedron Lett. 1994 35 7841. 280 A. Srikrishna S. Nagaraju and S. Venkateswarlu Tetrahedron Lett. 1994 35 429. 281 Y. Nakajima Y. Satoh M. Katsumata K. Tsujiyama Y. Ida and J. Shoji Phytochemistry 1994 36 119. 282 M. Yoshikawa S. Yamaguchi H. Matsuda N. Tanaka J. Yamahara and N. Murakami Chem. Pharm. Bull. 1994 42 2430. 283 M. Yoshikawa S. Yamaguchi H. Matsuda Y. Kohda H. Ishikawa N. Tanaka J. Yamahara and N. Murakami Chem. Pharm. Bull. 1994 42 18 13. 284 H. Safayhi J. Sabieraj E. R. Sailer and H. P. T. Ammon Planta Med. 1994 60 410. 285 T. Tozyo Y. Yoshimura N. Uchida Y. Takeda H. Nakai and H.Ishii Chem. Pharm. Bull. 1994 42 1096. 286 T. Honda H. Ishige and H. Nagase J. Chem. Soc. Perkin Trans. I 1994 3305. 287 N. Iwasawa M. Funahashi and K. Narasaka Chem. Lett, 1994 1697. 288 S. Milosavijrvic S. Macura M. Stefanovic 1. Aljancic and D. Milinkovic J. Nat. Prod. 1994 57 64. 289 H. Schroder U. Kastner M. Budesinsky E. Halinger J. Jurenitsch and W. Kubelka Phytochemistry 1994 36 1449. 290 W. Z. Wang R. X. Tan Y. M. Yao Q. Wang and F. X. Jiang Phytochemistry 1994 37 1347. 291 J. A. Marco J. F. Sanz-Cervera A. Yuste and M. C. Oriola Phytochemistry 1994 36 725. 292 S. Oksiiz and G. Topqu Phytochemistry 1994 37 487. 293 S. Oksiiz S. Serin and G. Topq~ Phytochemistry 1994 35 435. 294 D. Youssef and A. W. Frahm Planta Med.1994 60 267 295 D. Youssef and A. W. Frahm Planta Med. 1994 60 572. 296 J. A. Marco J. F. Sanz-Cervera V. Garcia-Lliso A. Susanna and N. Garcia-Jacas Phytochemistry 1994 37 1101. 297 W. Kisiel J. Jakupovic and S. Huneck Phytochemistry 1994 35 269. 298 Atta-Ur-Rahman R. Zeidi M. 1. Choudhary S. Firdous and N. Hasan Fitoterapia 1994 65 62. 299 S. W. Lee Z. T. Chen and C. M. Chen Heterocycles 1994 38 1933. 300 H. S. Chung W. S. Woo and S. J. Lim Arch. Pharmacol. Res. 1994 17 323. 301 H. S. Chung W. S. Wo and S. J. Lim Phytochemistry 1994 35 1583. 302 M. Budesinsky G. Novak U. Rychlewska D. J. Hodgson D. Saman W. M. Daniewski B. Drozdz and M. Holub Collect. Czech. Chem. Commun. 1994 59 1 175. 303 W. Kisiel and D. Gromek Pol. J.Chem. 1994 68,535. 304 A. Stojakowska J. Malarz and W. Kisiel Planta Med. 1994 60 93. 305 J. W. Krajewski P. Gluzinski W. M. Daniewski M. Gumulka A. Kemme and A. Mishnev Pol. J. Chem. 1994 68,509. NATURAL PRODUCT REPORTS 1996 306 M. Ando K. Ibayashi N. Minami T. Nakamura K. Isogai and H. Yoshimura J. Nut. Prod. 1994 57 433. 307 P. Delair N. Kann and A. E. Greene J. Chem. SOC. Perkin Trans. 1 1994 1651. 308 T. Guardia J. A. Guzman M. J. Pestchanker E. Guerreiro and 0.S. Giordano J. Nut. Prod. 1994 57 507. 309 M. J. Abad P. Bermejo S. Valverde and A. Villar Planta Med. 1994 60 228. 310 A. Andersen C. Cornett A. Lauridsen C. E. Olsen and S. Broegger-Christensen Acta Chem. Scand. 1994 48 340. 31 1 E. C. De Riscala M. A. Fortuna C.A. N. Catalan J. G. Diaz and W. Herz Phytochemistry 1994 35 1588. 312 V. K. Saxena and S. K. Mondal Phytochemistry 1994,35 1080. 313 C. Roussakis I. Chinou C. Vayas C. Harvala and J. F. Verbist Planta Med. 1994 60,473. 314 E. T. Tsankova A. B. Trendafilova A. I. Kujumgiev A. S. Galavov and P. R. Robeva Z. Naturforsch. C Biosci. 1994 49 154. 315 V. K. Gupta K. N. Goswami and K. K. Bhutani Cryst. Res. Technol. 1994 29 373. 316 G. L. Silva and M. E. Goleniowski J. Nut. Prod. 1994 57 225. 317 H. J. Woerdenbag I. Merfort C. M. Pabreiter T. J. Schmidt G. Willuhn W. van Uden N. Pras H. H. Kampinga and A. W. T. Konings Planta Med. 1994 60 434. 318 M. Toyota I. Nakamura S. Huneck and Y. Asakawa Phjtochemistry 1994. 37 109 1. 319 F.Nagashima H. Tanaka M. Toyota T. Hasimoto Y. Kan S. Takaoka M. Tori and Y. Asakawa Phytochemistry 1994,36 1425. 320 E. L. Ghisalberti W. C. Patalinghug B. W. Skelton and A. H. White Aust. J. Chem. 1994 47 943. 321 M. Miyazawa T. Uemura and H. Kameoka Phytochemistry 1994 37 1027. 322 J. R. Hanson P. B. Hitchcock and R. Manickavasagar Phytochemistry 1994 37 1023. 323 T. Hashimoto H. Tanaka and Y. Asakawa Chem. Pharm. Bull. 1994 42 1542. 324 T. Tanaka Y. Funakoshi K. Uenaka K. Maeda H. Mikamiyama and C. Iwata Chem. Pharm. Bull. 1994 42 1243. 325 C. C. Da Silva V. Almagro J. Zukerman-Schpector E. E. Castellano and A. J. Marsaioli J. Org. Chem. 1994 59 2880. 326 J. H. Zoeller Jr J. P. Wagner and G. A. Sulikowski J. Agric. Food Chem. 1994,42 1647.327 J. E. Dellar M. D. Cole A. 1. Gray S. Gibbons and P. Waterman Phytochemistry 1994 36 957. 328 H. J. M. Gijsen J. B. P. A. Wijnberg C. van Ravenswaay and Ae. de Groot Tetrahedron 1994 50 4733. 329 J. D. Connolly L. J. Harrison and D. S. Rycroft J. Chem. Res. (9,1994 284. 330 M. Tori K. Nakashima M. Seike Y. Asakawa A. D. Wright G. M. Koenig and 0. Sticher Tetrahedron Lett. 1994 35 3105. 331 F. Hagashima H. Izumo S. Takaoka M. Tori and Y. Asakawa Phytochemistry 1994 37 433. 332 T. Hashimoto H. Koyama S. Takaoka M. Tori and Y. Asakawa Tetrahedron Lett. 1994 35 4787. 333 P. Weyerstahl H. Marschall and U. Splittgerber Liebigs Ann. Chem. 1994 523. 334 K. Matsunaga M. Shibuya and Y. Ohizumi J. Nut. Prod. 1994 57 1183.335 T. Ohtsuca Y. Itezono N. Nakayama A. Sakai N. Shimma K. Yokose and H. Seto J. Antibiot. 1994 47 6. 336 A. Fontana E. Trivellone E. Mollo G. Cimino C. Avila E. Martinez and J. Ortea J. Nut. Prod. 1994 57 510. 337 P. H. Searle N. M. Jamal G. M. Lee and T. F. Molinski Tetrahedron 1994 50 3879. 338 G. Guella F. Dini F. Erra and F. Pietra J. Chem. SOC. Chem. Commun. 1994 2585. 339 M. Tori K. Kosaka and Y. Asakawa J. Chem. SOC. Perkin Trans. I 1994 2039. 340 C. L. Wu and C. L. Chen Phytochemistry 1992 31 4213. 341 H. Nakajima K. Isomi T. Hamasaki and M. Ichinoe Tetrahedron Lett. 1994 35 9597. 342 W. P. Almeida and C. R. D. Correia Tetrahedron Lett. 1994,35 1367. 343 A. Srikrishna C. V. Yelamaggad K. Krishnan and M. Nethaji J.Chem. Soc. Chem. Commun. 1994 2259. 344 A. C. Guevel and D. J. Hart Synlett 1994 169. 345 T. Omodani and K. Shishido J. Chem. Soc. Chem. Commun. 1994 278 1. 346 H. Nagaoka K. Shibuya and Y. Yamada Tetrahedron 1994,50 661.

ISSN:0265-0568    

DOI:10.1039/NP9961300307

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Recent Progress in the Chemistry of the Monoterpenoid lndole Alkaloids J. Edwin Saxton School of Chemistry University of Leeds Leeds LS2 9JT UK Reviewing the literature published between July 1994 and December 1995 (Continuing the coverage of literature in Natural Product Reports 1995 Vol. 12 p. 385) ~ ~~~~~~~~~~ ~ ~ ~ 1 General reversing activity of H. welwitschii and most of the insecticidal The structure and absolute stereo- 2 Monoterpenoid Indole Alkaloids activity of W. intri~ata.~ 2.1 Alkaloids Containing an Unrearranged chemistry of 1 were established by X-ray crystallography. Monoterpenoid Unit Fourteen other metabolites were isolated from H. welwitschii; 2.2 Corynantheine Heteroyohimbine and Yohimbine these include a novel spirocyclic oxindole 2 and five oxindoles Group and Related Oxindoles 3-7 closely related to 1.Four others 8-11 were related to 2.3 Sarpagine Ajmaline and Gelsemine Group fischerindole and the remaining four 12-15 were hapalindoles. 2.4 The Strychnine Group The six isonitriles (2,7-9,12 and 13) appear to be responsible 2.5 Ellipticine Uleine and Apparicine Group for the fungicidal activity of H. welwitschii. Compounds 3 and 2.6 Aspidospermine and Vincamine Group 6 were also isolated from W. intricata. Of these fifteen 2.7 Catharanthine and Ibogamine Group metabolites only 12-epihapalindole E isonitrile 12 was pre- 3 Bisindole Alkaloids viously known having been isolated by Schwartz et al.4 from 4 Biogenetically Related Quinoline Alkaloids Fischerella sp.ATCC 553558. 4.1 Cinchona Group The first enantiospecific total synthesis of a tetracyclic blue- 4.2 Camptothecin green alga constituent hapalindole 0 16 has been rep~rted.~ 5 References The desired chirality was obtained by use as starting material of (R)-(-)-carvone 17 which was converted into the un-saturated ketone 18 as shown in Scheme 1. The now redundant 1 General In a new monograph progress in monoterpenoid indole alkaloid chemistry from mid-1981 to early 1993 has been surveyed.' Recent volumes in the series 'Studies in Natural Product Chemistry' include chapters on the synthesis of indolo-quinolizidine alkaloids2" and Gelsemium alkaloids.2b 17 18 19 I xoH 2 Monoterpenoid lndole Alkaloids 2.1 Alkaloids Containing an Unrearranged Monoterpenoid Unit N-Methylwelwitindolinone C isothiocyanate 1 the major alkaloid of the blue-green alga HapalosQhon welwitschii W.and G. S. West UH IC-52-3 and Westiella intricata Borzi UH HT-29-1 is responsible for some of the multiple drug resistance- + epimeric azide 21 xiiil ?Et R' H OkHMe 1 R' = Me; R2 = NCS 2 6 R' = H; R2 = NCS 7 R' = Me; R2 = NC I! ' xiv-xvi xvii __c Ts H 16 hapalindole0 Me Reagents and conditions i LiAlH,; ii Me,CCOCI py; iii. CrO, 3.5-dimethylpyrazole; iv NaOMe MeOH ; v CH,=CHMgBr H H -H CuBr.Me,S; vi HCI; vii LDA; viii Me,SiCI; ix 20 SnCI,; x BF;OEt,; xi NBS (PhCOO),; xii NaN,; xiii DIBAL; xiv. 8 R1= NC; R2 = CI 11 12 R' = NC; R2 = CI CH = CHOEt pyridinium toluene-p-sulfonate; xv LiAlH ; xvi, 9 R'=NC; R~=H 13 R' = NC; R2= H thiocarbonyldi-imidazole; xvii AcOH MeOH H,O.10 = NCS; R~ = H 14 R1 = NCS; R2 = CI 15 R' = NCS; R2= H Scheme 1 327 isopropylidene group was removed by a retroaldol reaction and the synthesis pursued along lines broadly similar to the same workers' earlier synthesis of hapalindoles J and M.6Thus the major bond-forming processes include the stannic chloride- catalysed attachment of the silyl ether 19 to the 4-substituted indole derivative 20 and the cyclization of the product 21 by means of boron trifluoride. Subsequent stages to hapalindole 0 16 were unexceptional (Scheme 1). H reflux i ' H L I H 23 Be R 25 R = indol-Syl The structure of (+)-hobartinol an alkaloid first isolated' from the aerial parts of Aristotelia australasica by Quirion in 1986 has been established following a reinterpretation of the NMR spectrum of its diacetate and its total synthesis via (+)-makomakine 22.In the original investigation' the ambiguities in the proposed structure 23 related to the configuration of the tertiary hydroxy group at C-17 and the fact that hobartinol readily gives a diacetate which was presumed to be an 0,O-i,ii ___) H Mps 22 (+)-rnakomakine 28 1 iii OH N c- Mps Mps 30 29 H Mps 26 X=AC 31 27 (+)-hobartinol X = H Mps = 4-methoxyphenylsulfonyl Reagents and conditions i NaH THF then p-MeOC,H,SO,Cl; ii HCI AcOH heat; iii OsO, THF 15 h at 25 "C then Na,SO, H,O; iv DMSO TFAA CH,Cl,; v LiBHEt, THF; vi 6% Na-Hg NaH,PO, MeOH.Scheme 2 NATURAL PRODUCT REPORTS 1996 diacetate 24 ; this was explained by postulating neighbouring group participation in the acetylation process by the basic piperidine nitrogen atom. In fact the NMR spectrum of the diacetyl derivative rather favours an N,O-diacetyl derivative i.e. 25 or 26 in which case the configuration at C-17 remains uncertah8 However a synthesis of (+)-hobartin01 from (+)-makomakine itself synthesised from (-)-P-pinene and 1H-indol-3-ylacetonitrile leaves no doubt that the correct structure 27 is the 17-epimer of that originally proposed. Na-Protection of (+)-makomakine 22 followed by double bond iso-merization gave the alkene 28 which on cis-hydroxylation afforded the em-diol 29 as sole isolable product.Oxidation of 29 gave a hydroxy ketone obtained as an equimolecular mixture of hydroxy ketone 30 and carbinolamine 31 which on reduction and deprotection gave the diol27 identified as (+)-hobartin01 (Scheme 2).8 The first total synthesis of (+)-aristolone 32 has been described by Dobler and Bor~chberg.~ The known intermediate 33 prepared by a modified version of the method of Stevens and Kenney,l* was hydroxylated by means of osmium tetroxide-N-methylmorpholineN-oxide and then oxidised to the nor-ketone 34.Reaction of 34 with methyllithium gave exclusively the tertiary alcohol 35 which on deprotection afforded (+)-17,2O-dihydro-17-(endo-hydroxy)-makornakine 36. Alternatively oxidation of 35 by osmium tetroxide-N- methylmorpholine N-oxide gave 37 which on deprotection of the indole nitrogen atom gave (+)-aristolone 32 (Scheme 3).HO 33 1 ii iii c- 35 \ 34 H 36 (+)-17,2O-dihydro- 17ado -hydroxy makomakine 32 (+)-atistolone X = H H H (+)-ll,l2-didehydro-lO-oxo-(-)-1 1,12-didehydro-l O-oxo- makomakine hobartine Reagents and conditions i OsO, N-methylmorpholine N-oxide dioxan H,O; ii NaIO, THF; iii MeLi Et,O -78 "C; iv Na-Hg NaH,PO, MeOH; v SOCl, py CH,Cl,. Scheme 3 NATURAL PRODUCT REPORTS 1996-J. E. SAXTON Since the configuration of 35 at C-17 had been established (NOE between the methyl group and the hydrogen at C-15) the configuration of (+)-aristolone 32 must be as shown (17R) i.e. epimeric at C-17 with that earlier postulated.Since the CD spectra of synthetic and natural aristolone are closely similar the hitherto unknown absolute configuration of (+)-arktolone must also be as shown in 32. Dehydration of synthetic (+)-aristolone 32 gave a separable mixture of (+)-1 1,12-didehydro- 10-oxomakomakine and (-)-1 1,12-didehydro- 10-oxohobar- tine alkaloids of Aristotelia chilensis (Scheme 3).9 The oxidation of (+)-arktoteline 38 has been further investigated," and has resulted in syntheses of (+)-makonine 39 (+)-arktotelinone 40 and (+)-11,12-didehydroaristoteline 41. Thus oxidation of 38 with iodine yields mainly (+)-11,12- didehydroaristoteline 41 a correlation which establishes the absolute configuration of this alkaloid. In the presence of triethylamine oxidation of 38 with iodine affords (+)-makonine 39 whereas in the presence of aqueous base the allylic alcohol 42 presumably the precursor of (+)-makonine is obtained.Reduction of 42 by means of sodium borohydride followed by oxidation of the product with manganese dioxide then gives (+)-aristotelinone 40 (Scheme 4). I 39 42 vii 1 %vi HN-- HN. I HO I 40 Reagents and conditions i I, THF 5min 25 "C; ii I, THF 1 mol dmP3 NaHC0,-H,O 25 "C; iii I, THF 25 "C then NEt,; iv I, THF 20 min 25 "C; v NaBH, dioxan H,O; vi MnO, CHCl, 25 "C vii Hg(OAc),. Scheme 4 Synthetically prepared optically pure samples of the rare Aristotelia alkaloids (+)-makomakine 22 (-)-hobartine 43 and (+)-axistoteline 38 have been exposed to several fungi which has resulted in the preparation of some known as well as hitherto unknown hydroxylated derivatives occasionally in acceptable yield.' For example (+)-makomakme 22 was hydroxylated at positions 7 and 19 (exo),to give the derivatives 44 and 45 by Cunninghamella echinulata NRRL 3655 and C.baineri ATCC 9244. (-)-Hobarthe 43 was similarly hydroxyl- ated by these organisms to give 46 and 47; while exposure of (-)-hobartine 43 to Mucor plumbens CBSl10-16 gave only a low yield of [(-)-471. The first three of these hydroxylated derivatives were thus encountered for the first time but 19- hydroxyhobartine 47 had earlier been prepared in racemic form. R' [(+)-221 R' = R2 = H [(+)-441 R' = OH; R2 = H [(+)A51 R' = H; R2 = OH [(-)-431 R' = R2 = H [(-)-461 R' = OH; R2= H [(-)-47I R' =H; R2=OH In contrast (+)-arktoteline 38 gave four products when exposed to Mucor plumbens; these were the knjown 10-hydroxyaristoteline 48 and (-)-tasmanine 49 and two pre- viously unknown bases which were identified as (+)-1 1,12- didehydrotasmanine 50 and (+)-14-hydroxyaristoteline 51.This last compound was also the major product when (+)-aristoteline 38 was incubated with Cunninghamella baineri and Actinomucor elegans MMP 3 122. The structure of (+)-50 was verified by its direct synthesis from tasmanine 49 (Scheme 5). Seven other micro-organisms tested did not metabolise these alkaloids.l2 [(+)-=I R' = R2 = H [(-)-491 tasmanine [(-)-MIR' = OH; R2 = H [(+)-511 R' = H; R2 =OH Reagents and conditions i Mucor plumbens CBS110-16; ii I, K,CO, THF 25 "C.Scheme 5 2.2 Corynantheine Heteroyohimbine and Yohimbine Group and Related Oxindoles Alangium lamarckii Thwaites a deciduous shrub common to India and S.E. Asia which is used extensively in folk medicine as an anthelmintic purgative emetic and febrifuge and in the treatment of leprosy and other skin conditions has been investigated on a number of previous occasions. The fruits of this plant have now been extracted and have yielded several glucosides most of which are tetrahydroisoquinoline deriva- tives; the one indolic one to be encountered was identified as I O-hydroxyvincoside lactam 52a.13 The barks of Sickingia tinctoria (HBK) Schum. and S. williamsii Standl.two Peruvian species used in folk medicine for the treatment of a variety of inflammatory diseases have yielded a new glycosidic alkaloid sickingine 52b together with four known alkaloids 5aH-carboxystrictosidine ophiorines A and B and lyalosidic acid.14 Lyalosidic acid has also been found together with palicoside in the leaves of Ophiorrhiza acuminata L grown in the Phi1i~pines.l~ 52a 1 O-hydroxyvincoside lactam 52b sickingine H HO 53 3aH 5aH-tetrahydrodeoxycordifoline 3aH,5aH-Tetrahydrodeoxycordifoline53 has been isolated from the bark of Nauclea diderrichiP” and from the roots of Guettarda ovalifolia Urb. a small tree found only in Puerto Rico and Hispaniola.16o Details have been published of the investigations of Achenbach and co-workers on the alkaloids of the Panamanian tree Psychotria correae (Dwyer and Hayden) C.M. Taylor.” The leaves and roots of this species contain isodolichantoside and the new alkaloid correantoside 54; in addition the leaves contain 10-hydroxycorreantoside 55 correantines A< 56-58 and 20-epicorreantine B 59 which are also new. All are regarded as genuine alkaloids with the possible exception of this last base which can readily be obtained by acid-catalysed epimerization of correantine B 57. 54 coneantoside R=H 56 correantine A 55 10-hydroxycorreantoside R = OH 57 correantine B R’ = H; R2= CHO 58 correantine C 59 20-epicorreantine B R’ = CHO; R2 = H NATURAL PRODUCT REPORTS 1996 1O-Methoxygeissoschizol is one of ten alkaloids isolated from the aerial parts of Peschiera van heurkii (Muell.Arg.) L. Allorge from the Peruvian Amazon region.18 A second South American Peschiera species P. buchtieni (H. Winkler) Mgf. (Tabernaemontana buchtieni Mgf.) collected in the Chapare rain forest of Bolivia where it is used locally for the treatment of leishmaniasis has yielded 34 alkaloids which include (l6R 19E)-isositsirikine as the sole representative of this particular group.lg This alkaloid is also the only alkaloid from this group to be found among the 22 alkaloids isolated from the bark of a related species T. markgrafiana Macbride from Ecuador.20 60 7a-hydroxy-7H-mitragynine 7a-Hydroxy-7H-mitragynine 60 has been isolated from the leaves of Mitragyna speciosa (Korth.) Havil.a constituent of the Thai drug ‘Kratom’ which is used both as a stimulant and a depressant.21 This base was readily prepared by oxidation of mitragynine by means of iodosobenzene diacetate ;whether it is a genuine alkaloid or an artefact of the isolation process remains to be established. Tubulosine desmethyltubulosine deoxydesmethyl-tubulosine O-methyltubulosine and deoxytubulosine have been extracted from the leaves of Alangium bussayanum Harms. ;22a deoxytubulosine also occurs in the flowers of Alangium lamarckii.22bP-Yohimbine P-yohimbine pseudoindoxyl and P-yohimbine oxindole have been found in the leaves and stem bark of Ervatamia corymbusa Roxb. ex Wall; yohimbine also occurs in the leaves.23 The occurrence of the yohimbine skeleton in the Ervatamia genus is unusual.Different parts of this plant which was collected at Keluang Johore (Malaysia) are used in traditional medicine for the treatment of syphilis and orchitis ulcerations; the bark and roots are also used in the preparation of arrow poisons. Yohimbine P-yohimbine 3-epi- P-yohimbine and 1I-methoxy-3-epi-P-yohimbinehave been reported to be present in the roots and stems of Cuban RauwolJia linearifolia B~-itt.~~ Vallesiachotamine is one of four alkaloids produced in very small amounts in somatic hybrid cell cultures of R. serpentina x Rhazya stricta.25 Pleiocarpamine and fluorocarpamine are among the 14 alkaloids mainly of the ajmaline-sarpagine type that have been isolated from the leaves of Hunteria zeylanica (Retz) Gardn.ex Thw.26 The structure of the Nauclea alkaloid nauclefidine originally formulated as 61 has now been revised to 62 following the synthesis of the lactam-aldehyde 61 and the demonstration of its non-identity with na~clefidine.~’ Subsequent syntheses of the isomeric lactam-aldehyde 62 by both chemical and biomimetic (from vincoside lactam aglycone 63) routes as outlined in Scheme 6 proved conclusively that nauclefidine has the structure 62. New light has been thrown on the vexed question of the structures of rhazimanine and bhimberine two alkaloids of Rhazya stricta which were initially suspected to be the two possible epimers of 3-epi-(E)-iso~itsirikine.~~ However it appears29 that these alkaloids are not identical with any of the eight (E)-isositsirikine stereoisomers but reexamination and reassignment of their NMR spectra reveal that they probably belong to the (E)-isositsirikine series rather than the 3-epi series.Since the NMR data closely resemble those of (l6R)-(E)- NATURAL PRODUCT REPORTS 1996J. E. SAXTON 33 1 In 1983 Robert et isolated two N-oxides from Aspidosperma marcgraviunurn Woodson which were formu- lated as (1 6R)-(E)-isositsirikine cis N,-oxide 65 and its (16s)-epimer 66. Following the synthesis of the related deoxy compounds 67 and 68 which should serve as appropriate 61 R' =H; R~=CHO models for these alkaloids and a comparison of their NMR 62 nauclefidine R' = CHO; R2 = H spectra Lounasmaa et al. have concluded that the original assignments of stereochemistry at C- 16 in the alkaloids obtained by Robert et al.should be Another alkaloid whose structure has come in for further scrutiny is ajmalicidine for which the structure 69 was originally However this time the result is inconclusive. The 13CNMR data are certainly not consistent with 69 and it is ~uggested,~ that ajmalicidine is either identical with ajmalicinine 70 or that the methoxycarbonyl group is differently situated in the molecule rather than on nitrogen. Two new syntheses of nau~lefine~~,~~ and one of angustine dihydroangustine and na~cletine,~ have been reported. Bosch's proceeds via the enamide 71 which is simply prepared from harmalan and 3-bromonicotinoyl chloride hydrochloride. Cyclization of 71 by means of acetyl chloride or Reagents and conditions i ButOC1 then NaOMe; ii MnO,; iii (preferably) thermally gave the common intermediate 72 DIBAL; iv MnO,; v 10% aqueous sulfuric acid dioxan heat; vi regiospecifically.Removal of the bromine atom in 72 by autoxidation. Helquist's method gave nauclefine 73 while a Stille coupling with the appropriate alkyltin derivative catalysed by palla- Scheme 6 dium(0) gave angustine 74 and 18,19-dihydroangustine 75 (Scheme 7). Finally naucletine 76 was obtained from 72 by palladium-catalysed carbonylative coupling with isositsirikine and the R values are extremely close it is tetramethyltin. concluded that rhazimanine and bhimberine consist essentially of (16R)-(E)-isositsirikine 64 but with different impurities; in particular it is suggested that bhimberine may have been contaminated with the acetate of / I 9 73 nauclefine \N Br 71 i or ii MeO2C H p iii 1 OH 64 rhazimine? 74 angustine 72 / Ivi 65 (-)-(16R)-(E)-isositsirikine cis Nb-OXide R =OH; 16R 66 (-)-(lGS)-(E)-isositsirikine cis Nb-OXide R = OH; 16s 67 R=H; 16s 68 R=H; 16R / I 9 0 \N Et 75 18,19-dihydmangustine 76 naucletine Reagents and conditions i MeCOC1 CH,Cl, heat; ii 180 "C 0.1 mmHg; iii NaOMe Pd(PPh,), DMF 100 "C;iv CH,=CH .Sn Bu, Pd(PPh,), PhMe DMF 100 "C; v Et,Sn Pd(PPh,), HMPA 100 "C; vi CO (80 psi) Me,Sn Pd(PPh,), HMPA LiCI 75 "C.Scheme 7 332 A new synthesis of flavopereirine 773sutilizes a new approach in which closure of ring C and its aromatization form the final stages.The most noteworthy stage in this synthesis involves the formation of the indole 78 from the anilide 79 by means of potassium-graphite laminate (C,K) and titanium chloride (Scheme 8). 0 i-iii Et 79 1" Et 78 viii ix vii I 77 flavopereirine perchlorate Reagents and conditions i HC-CCH,OMe PdCl, CuI PPh, NEt,; ii HgSO, MeOH H,O heat ; iii 5-ethylpyridine-2-carboxylic acid chloride py DMAP; iv TiCl, C,K THF heat; v BBr, CH,Cl, -78 "C to -15 "C; vi HCl CHCI,; vii NaClO, H,O; viii DDQ AcOH heat; ix NaOH CHCI,. Scheme 8 As an aid to the elucidation of structure and stereochemistry in this series Lounasmaa and co-workers have prepared all eight model deoxy-(2)-isositsirikine derivatives80 and the cor- responding cis Ni-o~Ides.~~~ In an extension of this work the same group have prepared the isomeric (2)-isositsirikine methyl ethers 81 and several (2)-geissoschizine derivatives,37b* using the synthetic route developed earlier,38 which involves as key step the Claisen orthoester rearrangement.80 R=HorMe 81 R=OMe (& )-(2)-Geissoschizine 82 itself which has recently been ~ynthesised,~ by this brief route has been used in a new synthesis of (_+ )-corynantheidine 83. Reaction of (2)-geissoschizine with methyl orthoformate and toluene-p-sulfonic acid gave the methyl ether which on hydrogenation gave as unique product (rtr )-corynantheidine 83 (Scheme 9).39 NATURAL PRODUCT REPORTS 1996 &-I 82 (2)-geissoschizine 83 cotynantheidine Reagents and conditions i HC(OMe), TsOH MeOH; ii H, PtO,.Scheme 9 The modified Polonovski reaction on the N-oxide of Na,O-di-Boc-(Z)-geissoschizine84 gives on work-up with potassium cyanide four compounds of which the two major ones are the 5P-cyano derivative 85a and the 2la-cyano compound 85b.,O Derivative 85a offers an entry into the sarpagine series of alkaloids while the latter Na-Boc-21a-cyanotetrahydro-alstonine is equivalent to N,-Boc-cathenamine and is identical with the product obtained together with N,-Boc-SP- cyanotetrahydroalstonine 86 and Na-Boc-3,14-didehydrotetra-hydroalstonine 87 by the modified Polonovski reaction on Na-Boc-tetrahydroalstonine(Scheme 1 O).,' Me02C9 Me02CT OBoc OBoc 85a 84 J i 07% Boc ,i' ,*H -i ii OT%N Bcc 6' -OH..MB w-*'Me H= \o Me0& \o Me02C Na-Boc-tetrahydroalstonine 85b i ii ..Me 86 87 Reagents and conditions i MCPBA; ii TFAA then KCN -17 "C.Scheme 10 In earlier investigations Takano et al. developed syntheses of some racemic secologanin-derived indole alkaloids eg. antirhine,42 starting from (&)-norcamphor. Optically active (+)-norcamphor 88 having now become available Ogasawara and his collaborator have returned to this problem and with some variations on the original approach have completed NATURAL PRODUCT REPORTS 1996J. E. SAXTON PhCH2O' 91 92 94a 1 1 ix xiii-xv OH OH 93 94b x xi mi mii I I OH 90 (+)-isocotynantheol OH 89 (-)-antirhine Reagents and conditions i MCPBA; ii PhCH,OCH,I LDA THF -78 "C ;iii DIBAL -78 "C; iv Ph,PMeBr BuLi THF -78 "C; v PCC NaOAc CH,Cl,; vi pyrrolidine C,H, heat then CH,(CH,STs), NEt, MeCN heat; vii BBr, CH,Cl, -78 "C;viii KOH ButOH heat then acid workup; ix tryptamine PhMe heat; x MeI MeCN H,O; xi LiAlH, THF heat; xii phthalimide PPh, DEAD THF r.t.; xiii MeNH, MeOH r.t.to reflux; xiv 3-indolyl- acetic acid DCC THF; xv KOH ButOH heat; xvi LiAIH, dioxan heat; xvii HC1-EtOH then MeI MeCN H,O heat. Scheme 11 C02Et CO2Et 97 96 98 R=O 1 99 R=H2 xi xii H \C02Et 95 (-)-ophiorrhizine 100 Reagents and conditions i MeCOC1 Na,CO,; ii RuO,; iii A1,0,; iv 190 "C 15 min; v p-MeOC,H,CH,OH DMAP DCC CH,Cl,; vi fractional crystallization; vii H, Pd-C EtOH; viii EtOH HCI; ix Et,OBF ;x 6-benzyloxy-3-chloroacetylindole, KBr DMF 60 "C ; xi POCI, PhMe 110 "C; xii Pt H, EtOH; xiii LiAlH, THF; xiv TsC1 py; xv DMF heat; xvi Amberlyst A-26(C1-) MeOH H,O; xvii Pd-C H, EtOH.Scheme 12 syntheses of (-)-antirhine 89 and (+)-isocorynantheol 90.43 The essential intermediate 91 for both syntheses was prepared from 88 as outlined in Scheme 11. Cleavage of 91 by means of potassium hydroxide then gave the lactone 92 which was condensed with tryptamine to give the amide 93; removal of the thioacetal protecting group followed by cyclization and reduction stages then gave (-)-antirhine 89. For the synthesis of (+)-isocorynantheol90 the intermediate 91 was converted into the phthalimide derivative 94a by the Mitsunobu reaction.Removal of the phthalimido group by methylamine and replacement by an indolylacetyl group gave the amide 94b; reduction followed by removal of the thioacetyl group and cyclization then gave (+)-isocorynantheol 90 (Scheme 11). The structure of (-)-ophiorrhizine 95 has been confirmed by synthesis from the lactim ether (+)-96 which is readily available from cincholoipon ethyl ester (+)-97.44Condensation of 96 with 6-benzyloxy-3-chloroacetylindolegave the lactam 98 which was reduced to the lactam 99 via the oxazolium salt 100. Bischler-Napieralski cyclization followed by several routine stages converted 99 into (-)-ophiorrhizine 95 (Scheme 12) whose absolute configuration is also confirmed by this synthesis.Danieli et al. have contributed the first enantioselective synthesis of (-)-akagerine 101 by a chemoenzymatic ap- proa~h.~~ The monoacetate 102 prepared from the corre-sponding diol by enzyme-catalysed acetylation was converted into the lactone 103 by methods used earlier3* in the enantiomeric series. Condensation of 103 with tryptamine followed by Bischler-Napieralski cyclization reduction Nb-protection and oxidation stages gave the dialdehyde 104 which on acid-catalysed cyclization gave the tetracyclic 17a- hydroxycarbinolamine 105 as single product in 84 YO yield. Several efficient conventional stages which included the introduction of the double bond by Grieco's method eventually gave (-)-akagerine 101 which was thus obtained in 17 steps from the monoacetate 102 in 19.3 YOoverall yield (Scheme 13).H H __c __c OH OAc H 102 103 I v-xi OHC oHc~OCOPh A 104 OHCAOCOPh +OCOPh A 105 1H xix-xxi HOYcHo H 101 (-)-akagerine Reagents and conditions i porcine pancreatic lipase EtOAc; ii CBr, PPh,; iii KCN DMSO; iv H,O,; v tryptamine BuOH heat; vi PhCOCl PrLNH CH,Cl,; vii POCl,; viii EtOH HC1; ix NaBH, EtOH; x NEt, CH,Cl, then add ClCO,Me CH,Cl, 0°C; xi chromatographic separation; xii OsO, NMMO ;xiii NaIO, THF H,O; xiv 0.02 mol dm- HC1 THF 25 "C; xv NaBH, MeOH; xvi HCl(g) MeOH; xvii PBu, o-O,NC,H,SeCN THF N,; xviii NaIO, H,O MeOH then PriNH; xix LiAlH,; xx SO, py DMSO NEt,; xxi 1 mol dmP3 HCI THF H,O r.t. Scheme 13 In the first total ~ynthesis~~ of melinonine-E 106 ring D was closed by cyclization of a radical generated during the reduction of the trichloroacetyl group in the amide 107 by means of tributyltin hydride.The product 108 was cyclized by the Bischler-Napieralski reaction followed by reduction to give an intermediate 109 with a 3P-H and a trans-quinolizidine ring junction. Epimerization of the nitrile group then gave the desired configuration at C-20 and the synthesis of melinonine- E 106 was completed by conventional conversion of the nitrile group into the primary hydroxy group and aromatization of ring C (Scheme 14).46 NATURAL PRODUCT REPORTS 1996 108 I ii iii 106 rnelinonine-E chloride 109 Reagents and conditions i (SiMe,),SiH PhH AIBN 16 h then Bu,SnH AIBN 7 h; ii POCl, PhH heat; iii NaBH, MeOH; iv LDA THF -78 "C then 0.5 mol dm-3 HC1 -78 "C; v DIBAL PhMe -20 "C then 5% H,SO,; vi NaBH, MeOH r.t.; vii Pd maleic acid H,O; then NaC10 *H,O; viii IRA-400.Scheme 14 Martin's synthetic approach6 to tetrahydroalstonine the major feature of which relates to the formation of rings D and E by a vinylogous Mannich cyclization has been refined and extended and has led to asymmetric syntheses of (-)-tetra- hydroalstonine (-)-ajmalicine and (+)-19-epiajmali~ine.~~" In essence the synthesis of (-)-tetrahydroalstonine 110 followed the course of the earlier synthesis except that a degree of stereoselectivity was introduced by starting with L-tryptophan rather than tryptamine.The redundant carboxyl group was then eliminated at the pentacyclic stage 111 by use of the Barton reaction. The product was the pentacyclic vinyl ether 112 which has previously47b been converted into (-)-tetrahydroalstonine (Scheme 15). CQMe H 81 CHO 1iii ii iv v-vii 112 111 1 ref. 4% 110 (-)-tetrahydroalstonine Reagents and conditions i 1-trimethylsilyloxybutadiene,crotonyl chloride; ii chromatographic separation of epimers;iii mesitylene 170 "C; iv Me,SiOK THF ; v CICO,But N-methylmorpholine THF; vi N-hydroxypyridinethione sodium salt NEt,; vii ButSH hv. Scheme 15 NATURAL PRODUCT REPORTS 1996J.E. SAXTON 335 H 114 OSiMe2Bu' i-iii 1 dOMe 115 ix x xi -_I_t 0 Me Me02C' 116 118 0 0 119 120 iv-viii I ref.48 117 113 (-)-ajmalicine 121 (+)-19-epiajmaIicine Reagents and conditions i 115 CH,Cl,; ii MeCOCH=CH, 60 "C; iii pyrrolidine MeCN 4A molecular sieves; v Pd(OH),-C H, EtOAc EtOH ;v ClCO,Bu' N-methylmorpholine; vi N-hydroxypyridinethione sodium salt NEt ; vii ButSH hv;viii NaBH,; ix NaBH, MeOH; x p-O,NC,H,CO,H PPh, DEAD THF; xi NaOH THF MeOH silicic acid. Scheme 16 For the synthesis of (-)-ajmalicine 113 the imine salt 114 reaction then reduction of the ketone function gave a lactone prepared from D-tryptophan was reacted with the silyl ketene 117 which has previously4* been converted into (-)-ajmalicine acetal 115 obtained from methyl crotonate. Addition of 113. methyl vinyl ketone followed by cyclization then gave the The reduction of the keto ester 116 fortuitously gave the tetracyclic keto ester 116 (Scheme 16).Removal of the trypto- related hydroxy ester 118 rather than the expected lactone. phan ester group by hydrogenolysis followed by the Barton Inversion of the C-19 hydroxy group by the Mitsunobu C02H ___c __c 122 Tf 1 25 123 H 126 ~ viiCx 1 13 (-)-ajmalicine xi-xiii( + -0 1 24 6Me 1 27 Reagents and conditions i (Z)-MeCH=CHMgBr CuI TMSCl THF -78 "C +r.t.; ii pig liver esterase pH 7.5; iii resolution with (R)-methylbenzylamine; acidic work-up; iv (COCl), CH,Cl,; v N,-triflyl-N,-2,4-dimethoxybenzyl-2,3-dihydrotryptamine, NEt, THF; vi LiOH H,O THF; vii (CH,O), TFA CHC1,; viii DDQ PhH 140 "C; ix ButOCH(NMe,),; x HCl MeOH 120 "C; xi K,CO, MeOH; xii POCl, PhH; xiii NaBH, MeOH.Scheme 17 reaction followed by hydrolysis and lactonization then gave 119 which was converted into the desired lactone 120 by hydrogenolysis and Barton decarboxylation (Scheme 16). The synthesis of (+)-19-epiajmalicine 121 was then completed according to the procedure of van Tamelen et~11.~~ Overman and his collaborators have recently turned their attention to the synthesis of the heteroyohimbine alkaloids and have developed an extremely ingenous synthesis of (-)-ajmalicine 113 which involves as critical stage a Mannich bi~cyclization.~~ The glutaric half ester 122 prepared as outlined in Scheme 17 was coupled with N,-trifyl-N,-dimethoxybenzyldihydrotryptamine to give the amide 123 which was treated with trifluoroacetic acid and formaldehyde ; this hydrolysed the ester group cleaved the dimethoxyphenyl protecting group and following condensation with formal- dehyde cyclized to give the tetracyclic lactam lactone 124 presumably via a transition state derived from the conformation 125.Regeneration of the indole ring followed by introduction of the vinylogous carbonate functionality in ring E by NATURAL PRODUCT REPORTS 1996 "%Me H' OH 130a li OMe I 130b Brederick's method gave a mixture of 126 and 127. Removal of I A the triflyl group cyclization and reduction then gave (-)-OMe ajmalicine 113 (Scheme 17). Points of particular interest in this synthesis are the use of a dihydrotryptamine derivative to avoid cyclization onto the 2-position of the indole ring the introduction of a dimethoxybenzyl group on to N to discourage the formation of a symmetrical glutarimide derivative with consequent loss of optical activity during the hydrolysis of the ester function in 131a 131b 123 and protection of N by a triflyl group which effectively iii iii reduces the nucleophilicity of position 5in the indoline ring 1 and thus removes the possibility of Friedel-Crafts reaction at that position with formaldehyde.OMe I F02Me H-* 132 'C02Me FMe 0 128 A broadly similar reaction sequence which also involves a Mannich biscyclization resulted in the formation of the carbamate lactone 128 which has obvious potential as a late intermediate in a new synthesis of (+)-lg-epiajmalicine 121.49 The first asymmetric synthesis of (-)-mitragynine 129 has been accomplished by Sakai and co-~orkers.~~ The chiral alcohol (+)-130a obtained from the racemate of the cor- responding acetate by preferential enzymic hydrolysis of the desired epimer was condensed with 3-(2-bromoethyl)-4-methoxyindole to give the pyridinium salt lMb which was reduced by means of sodium borohydride to give a mixture of epimeric allylic alcohols 131a and 131b.Reaction of the former with methyl orthoacetate followed by Claisen rearrangement of the resulting unsaturated acetal gave the desired tetracyclic ester 132 which could also be obtained by similar treatment of 131b followed by epimerization at C-3. The synthesis was then completed by formylation of 132 conversion into the 0-methyl ether and hydrogenation of the C-20 ethylidene group (Scheme 18).The oxidative rearrangement of ajmalicine 113 has been reinvestigated and the stereochemistry of the acetoxyindolenine intermediate 133 has been However contrary to an earlier the reaction of 133 with sodium methoxide in methanol yields not one but two pseudoindoxyl derivatives. The major isomer 134a was identified with the one previously obtained and its stereochemistry originally tentatively proposed rigorously established; the new minor isomer vi vii or vi viii ix J OMe OMe I I 129 (-)-mitragynine Reagents and conditions i 3-(2-bromoethyl)-4-methoxyindole,cat. NaI PhH heat; ii NaBH,; iii MeC(OMe), cat. PhCO,H o-xylene heat; iv ButOC1 then HCl EtOH; v NaBH,; vi LDA HCO,Me THF -78 "C; Vii CH,N,; viii HCl MeOH; ix ButOK DMF; x H, PtO, EtOH.Scheme 18 obtained in 13 % yield was shown to be the C-2 epimer 134b (Scheme 19). This represents the first pseudoindoxyl derivative of type B to be prepared in this series. It is assumed that pseudoindoxyl A 134a is the initial rearrangement product and that this is subsequently equilibrated with pseudoindoxyl B in the reaction medium ;this latter proposal was confirmed experimentally by the observation that either of the pure isomers 134a or 134b gave the same equilibrium mixture under the conditions of the rearrangement. NATURAL PRODUCT REPORTS 1996-5.E. SAXTON HH Me 1 13 ajrnalicine 133 Me -Me n -134a 134b Reagents and conditions i Pb(OAc), CH,Cl,; ii NaOMe MeOH heat Scheme 19 135 R' = H; R2 =C02Me 139 R' = CO&e; R2= H 141 1 iii iii iii ,/ !!LN +H AcOr \ 142 OAc -136 R' = H; R2=CO2M0 140 R' = Code; R2 = H A H H 137a 137b 138b Reagents and conditions i Hg(OAc), AcOH 60 "C;ii Zn HC1 0 "C; iii Pb(OAc), CH,Cl, 25 "C; ivy0.1 mol dm-3 NaOMe MeOH heat; v / 0.5 mol dm-3 NaOMe MeOH heat.Scheme 20 Yohimbine 135 shows very similar behaviour. The initially formed 7a-acetoxy-7H-yohimbine 136 also rearranged to a mixture of epimeric pseudoindoxyls ;the major isomer identical to that previously isolated,51b was shown unambiguously to be yohimbine pseudoindoxyl A 137a and the minor isomer to be the previously unknown pseudoindoxyl B 137b.In this case the equilibration of 137a and 137b gave rise to a third isomer 138a which has an axial ester group. This together with its pseudoindoxyl B isomer 138b should be the product of the oxidative rearrangement of corynanthine 139.Indeed when the 7a-acetoxy derivative 140 was rearranged in base under mild conditions both 138a and 138b were obtained; under stronger basic conditions all four isomers 137a,b and 138a b were produced (Scheme 20). NATURAL PRODUCT REPORTS 1996 OH I Me02C OMe m-#lMe ?H "1 \ 0 Me02C OMe Me02C Me0 N OMe H 143 1 44 145a 145b r *-OH Me02C 0 0 1 46 147 R' = H; R2 = OMe 148 R' = OMe; R2 = H 149 R' = R2 = OMe Similarly pseudoyohimbine 141 gave rise to the pseudo- expansion procedure for the construction of ring D.The same indoxyls 137a and 137b via the 7a-acetoxyindolenine 142 and group have now modified and improved this approach and methyl reserpate 143 and methyl isoreserpate 144 gave rise to have completed asymmetric total syntheses of (+)-the pseudoindoxyls 145a (major isomer) and 145b. alloyohimbane (-)-yohimbane (-)-yohimbone and (+)-The spectroscopic data for these pseudoindoxyl derivatives y~himbine.~~ For example the chiral ketone 150 obtained in allow the stereochemistry of several natural products to be very high ee from the Diels-Alder adduct of dimenthyl fumarate assigned or confirmed. Thus P-yohimbine pseudoindoxyl 146 and butadiene was converted into a mixture of diastereo- from Aspidosperma oblongum and Ervatamia hirta tetraphylline isomeric oxaziridines 151a b in which the constitution of the pseudoindoxyl 147 from Neisosperma glomerata aricine major isomer 151a was established by X-ray crystallographic pseudoindoxyll48 and isoreserpiline pseudoindoxyll49 from analysis.Rearrangement with ring enlargement of this mixture Rauwolfia vomitoria and several other plants are all confirmed afforded a mixture of lactams 152a,b in which the desired as A isomer 152a predominated. Hydrolysis of 152a followed by In an earlier investigation Aubi and co-worker~~~ described preferential esterification of the equatorial (C-17) hydroxy a novel enantioselective route to (-)-alloyohimbane via a ring- group gave 153a which was dehydrated by Martin's sulfurane 0 0 i ii iii iv H-* ___) __c V v5 ___c @bAc OAc 150 OAc 151a PO \ 152b 151b cdl + xii oT% H" -c--viii-xi H-* vi vii H" ___t xiii xiv OH 0 0 Me3CC02 OAc 154 15-152a /A-xviii xx __c 0 OH 132 (+)-yohimbine 155 yohimbinone 156 P-yohimbine Reagents and conditions i OsO,; ii Ac,O; iii tryptamine Et,O heat; iv MCPBA -78 "C; v hv; vi K,CO,; vii Me,CCOCI; viii [PhC(CF,),O], Ph,S ; ix Bischler-Napieralski cyclization and reduction; x NaOH ; xi Pr,NRuO,; xii H, Pd-C ; xiii LDA HMPA then PhSeC1; xiv 30% H,O,; xv LDA; xvi NCC0,Me; xvii H, Pd-C; xviii K,CO, MeOH; xix L-Selectride; xx NaBH, MeOH.Scheme 21 NATURAL PRODUCT REPORTS 1996J. E. SAXTON Conversion of 154 (also prepared as a relay from yohimbine as shown) into (+)-yohimbine was achieved by a new improved procedure in which the C-16 ester function was introduced by use of Mander's reagent; the indole nitrogen was simultaneously acylated.Hydrogenation of the' C( 18)=C( 19) bond followed by removal of the superfluous ind-N-acyl group and reduction of the carbonyl group by L-selectride finally gave (+)-yohimbine 132. Alternatively reduction of yohimbinone 155 by sodium borohydride was stated to yield exclusively /3-yohimbine 156.53* 54 A new synthesis of Woodward's aldehyde 157 starting from an unsaturated hexopyranose derivative (Ferrier's alkene) offers an alternative route to reserpine.55 s' Me02C OMe d3 157 158 N-methylpericyclivine R' =C02Me; R2 = H; R3 = Me 159 18-hydroxyaff inisine R' = H; R2 = R3 = CH2OH 2.3 Sarpagine Ajmaline and Gelsemine Group Several new extractions of alkaloids of this group have been recorded during the last 18 months.Normacusine B occurs in the stem bark of Ervatarnia corymbosa Roxb. ex Wall.,23 and (1 9E)-akuammidine in the bark of Tabernaemontana markgruJiana Macbride ;zO this work also includes the con-firmation of the structure of this latter alkaloid by means of X-ray crystallography. Two groups of workers have investigated the constituents of the aerial parts of South American Peschieva van heurkii (Muell.-Arg.) L. Allorge. In a specimen collected in the Peruvian Amazon region Tournon et al. found affinisine and vobasine,Is while Muiioz et al.working on a specimen collected in the tropical rain forest of Chapare Bolivia where it is used medicinally for its alleged leishmanicidal and bactericidal activity found 20 alkaloids including affinisine normacusine B N-methylpericyclivine 158 which is new perivine 16-epiaffinine vobasine and vobasin01.~~ The stem bark of a related species Peschiera buchtieni (H. Winkler) Mgf. contains ochropamine affinisine N-oxyaffinisine normacusine B voachalotine and the new alkaloid N-methylpericyclivine 158 together with another new alkaloid from this group namely 18-hydroxyaffinisine 159;I9 N,-chloromethylaffinisinium chloride an artefact of the isolation process was also obtained. Another new alkaloid 1 1 -hydroxy-N-methylmacusine A 160 has been isolated as its chloride from the stem bark of Panamanian Stemmadenia obovatu Benth.,57 and two new alkaloids from the leaves of Alstonia macrophylla Wall.10- hydroxystrictamine and alstomacrocine have the structures 161a and 161b.58"From the bark of a specimen of Alstonia macrophylla collected in Sabah Malaysia Wong et isolated two new oxindole alkaloids and three known ones. The new alkaloids are N,-demethylalstophyllal oxindole 162a and alstonal 162b and the known ones are N,-demethyl-alstophylline oxindole alstonisine and talcarpine. The thirteen alkaloids obtained from the leaves of Thai RauwolJia Jack. include from this group 1 1-methoxystrictamine 163 which is also new tetraphyllicine lanceomigine perakine peraksine and 10-hydroxys trictamine.59 Reinvestigation of the constituents of the leaves and twigs of Ghanaian Tubemaemontuna glundulosa Stapf has yielded60 1 1 alkaloids which include three new ones difforlemenitine 164 and its 19-epimer 165 and 10,12-dimethoxynareline 166. Five further alkaloids from this group difforlemenine 167 tabernulosine 5,10,12-trimethoxystrictamine168 vincadiffine and vobasine were also isolated. 5,10,12-Trimethoxy-9H20H ,C02Me 160 N,-methyl-1 1-hydroxyrnacusine A 161a 1 0-hydroxystrictamine R' =OH; R2= H 163 11-methoxystriictamine R' = H; R2 = OMe HH -. . 161b alstomacrocine 162a Nt,-dernethylalstophyllaloxindole R = OMe 162b alstonal R = H 166 10,12-dimet hoxynareline 168 5,10,12-trimethoxystrictarnine strictamine 168 has apparently been isolated on a previous occasionG1 from an unspecified source although details have not been published in the accessible literature.A re-examination of the NMR spectrum of difforlemenine resulted in a revision of its structure and it is now formulated as 167. Treatment of difforlemenine with acid opened the oxirane ring with formation as major product of the chlorhydrin 169; the minor product which appears to be the result of migration of Nb from C-21 to C-20 (Scheme 22) was identified as diffor-lemenitine 164.60 Me02C M e02C\ Me/ k 167 difforlemenine Ji Me02C Me02C\ Me 169 164 difforlemenitine RLOH; R~=H 165 1 9-epidifforiemenitine R' = H; R2=OH Reagents and conditions i MeCOMe 2 mol dm-3 HCI (CO,H), H,O 50 "C.Scheme 22 Martinez et a1.24 state that spectroscopic and chromato- graphic evidence has been obtained for the presence of ajmaline sandwicine and isosandwicine in the leaves and stems of Cuban RauwolJia linearifolia Britt. but there appears to be no record of the isolation of these alkaloids in the Experimental section of their memoir. Me0 Q+3&Me -R 170 10-methoxyperakine R =CHO 171 vincawajine R =CH20Ac NATURAL PRODUCT REPORTS 1996 OH C02Me cat. ByNHS04 H-RO HO 172 demethylcotyrnine R =H 173 dernethyldeforrnylcorymine 175 corymine R =Me R=H 176 deformylcorymine R =Me Scheme 23 contain silicine 177a and 16-episilicine 177b which is new ;64a these alkaloids were identified as Alkaloids K and J re-spectively which were isolated in 1975 from this same species.64b Finally two new echitamine derivatives 17-0-acetyl-N,- demethylechitamine 178 and echitaminic acid 179 together with three known alkaloids N,-demethylechitamine 180 its N,-oxide and echitamine 181 itself have been isolated from H H kt the stem bark of Thai Alstoniaglaucescens (K.Sch.) M~na.~~~,~~ 0 1 74 N~-rnethyl-3a-amino-secovoacarpine 177a silicine 1%-H 177b 16-epkiliCine 16a-H 178 179 echitarninic acid 180 181 Recent extractions of the aerial parts of Vinca major ssp. hirsuta grown in Turkey have yielded 10-methoxyvinorine and two new alkaloids 10-methoxyperakine 170 and vinca- wajine 171.62The first of these alkaloids has not previously been isolated from this species.[10-Methoxyperakine is illustrated in ref. 62 with a /I-formyl group at C-20. However the 13C NMR data indicate that in all probability this alkaloid has the same stereochemistry as perakine and it must therefore contain an a-formyl group as depicted in 170. Vincawajine 171 is presumedfi2 to have the same stereochemistry as 170 at C-20 but this point remains to be proved]. Four new alkaloids and 12 known ones have been shown to occur in the leaves of Hunteria zeylanica (Retz) Gardn. ex Thw. grown in jgb,63 The latex of this plant is used in folk medicine for the treatment of sores caused by yaws and recent studies have confirmed its antipyretic and anti-inflammatory activity. The three new ones that belong to this group are Na-demethylcorymine 172 N,-deme thyldeformyl- corymine 17326.63and N,,-methyl-3a-aminosecovoacarpine 174;26the known alkaloids include corymine 175 deformyl-corymine 17626.The deformyl derivatives 63 and lance~migine.~~ 173 and 176 may well be artefacts since concentrated aqueous ammonia was used in the extraction process; it was shown experimentally that the formyl groups are readily removed from corymine 175 and demethylcorymine 172 by alkali (Scheme 23).63 The stem bark root bark and leaves of Pandaca caducifolia Mgf. collected in the Diego Suarez region of N. E. Madagascar N,-Methylervitsine 182 has been synthesised in a four-stage sequence by Bosch and his collaborators.66 The 1,4-dihydropyridine derivative 183 prepared by the addition of the enolate derived from 2-acetyl-N-methylindole on to pyridine 3-acrylic ester methiodide was cyclized by reaction with phenylselenyl bromide presumably via the intermediate 184.The acrylic ester residue in the product 185 was converted into the desired (E)-ethylidene derivative 186 by hydrolysis and decarboxylation followed by reduction ;oxidation of the phenylselenyl group methylation and elimination then generated the exocyclic 16-methylene group with formation of Na-methylervitsine 182 (Scheme 24). GY C02Me C02Me A 183 184 Me 1 85 1 ii. iii Me iv-vi c- 0 182 N,-rnethylervitsine 186 Reagents and conditions i PhSeBr -30 to 0 "C; ii 4mol dm-3 HC1-H,O; iii NaBH, MeOH 0 "C; iv MCPBA CH,Cl, -70 "C; v LDA MeI THF -70 "C; vi Pr',NH THF heat.Scheme 24 NATURAL PRODUCT REPORTS 1996-5. E. SAXTON In an outstanding paper,67 Cook and co-workers have 68 recorded details of their of (-)-alstonerine and (+)-macroline and the partial synthesis of (+)-villalstonine as well as detailss9 of the preparati~n,~ of the intermediates 187 and 188 for the synthesis of alstonisine and chitosenine respectively. 0 34 1 gardnerine 190 was converted as before into the oxindole 191; this was methoxylated to 192 and the synthesis completed also as before to give 11-methoxy-( 19R)-gelselegine 189 (Scheme 25).'O In the first partial synthesis of gelsemicine 193 Sakai et oxidised the N,-trichloroethoxycarbonyl derivative of gardnerine 190 with osmium tetroxide as in previous work; however in this instance only one equivalent of oxidant was o?Me used with the result that the product was the (7s)-oxindole 194 the C(19)=C(20) bond remaining intact.In order to obtain the gelsemicine skeleton it was necessary to lose C-21 and attach Nbto C-20; this was achieved by a process in which 'Me 0 the oxindole 194 was first isomerized to the enamine 195 by Me means of trimethylsilyl chloride and sodium iodide. Oxidation 187 1 88 of 195 followed by reduction of the hydroxy aldehyde and hydroxycarbinolamine mixture thus produced gave the diol Sakai and co-workers have continued their work on the 196 which was converted into the aminoalcohol 198 via the partial synthesis of the Gelsemium alkaloids from gardnerine. amidoepoxide 197.C-21 was then removed by oxidation of 198 The synthesis70 of the relatively new alkaloid 1l-methoxy-by means of sodium periodate; stereoselective hydrogenation (19R)-hydroxygelselegine 189,'' follows the same route as that then gave the secondary amine 199 into which the N,-methoxy employed in the earlier synthesis68b of its N,-demethoxy group was introduced to give gelsemicine 193 by the method derivative except that a methoxylation stage was interposed developed by the same group in earlier partial syntheses in this after the rearrangement to an oxindole intermediate. Thus area (Scheme 26).72 192 190 I OMe 189 11-methoxy-(l9R)-19-hydroxygelselegine Reagents and conditions i ref. 68b; ii BH;SMe,; iii H,NCONH;H,O, Na,WO,; iv CH2N2 Et20.Scheme 25 HO1 I ii Me0n..JH -194 190 gardnerine 1 I 1 iii 197 196 195 (on R = Me) Me0 Me0 Me0 0-XN OR OMe 'R=H 193 gelsemicine nER=Me Reagents and conditions i ClCO,CH,CCl, MgO THF H20; ii OsO (1 equiv.) py THF; iii TMSCl NaI MeCN; iv OsO, py THF; v NaBH, MeOH; vi MsC1 py CH,Cl,; vii K,CO, MeOH; viii Zn AcOH; ix NaIO, MeOH; x H, PtO, EtOH; xi ClCO,CH,CCl, py CH,Cl ;xii BH * SMe, THF then Me,NO. H,O MeOH ;xiii H,NCONH,. H,O, Na,WO,. 2H,O MeOH; xiv Pb(OAc), CH,Cl, then K,CO, MeOH; xv CH,N, MeOH. Scheme 26 NATURAL PRODUCT REPORTS 1996 I 190 gardnerine R =OMe 204 iii-v ref. 68a K 203 koumidine R=H 1 -c-\ +X,V Q)--q@J-q-J-oT& 0 \ Y I Yo H C02CH2CC13 OMe OMe OMe 206 200 gelsedine 202 gelsenicine 201 gelselegine Reagents and conditions i ClCO,CH,CCl, MgO H,O THF; ii OsO, py THF -78 "C then NaHSO, H,O; iii CH(OMe), PPTS THF; iv Ac,O heat; v 5 % KOH-H,O MeOH; vi TMSC1 NaI MeCN; vii OsO, py THF; then NaHSO, H,O; viii NaBH, MeOH; ix BH,.SMe, THF heat then Me,NO MeOH heat; x H,NCONH .H,O, Na,WO, H,O MeOH; xi CH,N, Et,O; xii Me,NCON=NCONMe, PBu, DMF; xiii Zn AcOH; xiv 5 d at r.t.; xv NaIO, H,O MeOH; xvi H, PtO, EtOH.Scheme 27 Gelsedine 200 is 11-demethoxygelsemicine and in a parallel reintroduced by reaction of the orthoester derived from 205 investigation the same group of workers have synthesized with acetic anhydride. Manipulation of the product 206 was gelsedine together with gelselegine 201 and gelsenicine 202 then undertaken essentially by the route employed in the partial from gardnerine 190.' Gardnerine was first converted into its synthesis of gelsemicine; only the order of the various stages 1 1 -demethoxy analogue (19E)-koumidine 203 following the was changed (Scheme 27).En route to gelsemicine gelselegine sequence published earlier ;68a it was then transformed into 201 and gelsenicine 202 were also prepared. Since (19E)- gelsedine 200 by use of the same strategy as that employed in koumidine 203 has been synthesised by Magnus et aL6 this the partial synthesis of gelsemicine. In this instance oxidation work also constitutes formal total syntheses of these Gelsemium of the derivative 204 to the corresponding oxindole could not a1 kaloids. be achieved without simultaneous oxidation of the A new synthesis of (+)-2l-oxogelsemine 20774constitutes C(19)=C(20) bond; hence the double bond had to be the third total synthesis of gelsemine 208.In this new synthesis ,OCH2P h ,OCH2Ph i-X __t XiiXN 0q C(0Me)Php CH2CH20THP 21 2 210 C02Et IXV 214 215 R'=H; R2=OAc 213 216 R' = OAC; R2 = H xviii xix xvi xvii 21 7 207 21-oxogelsernine 208 gelsemine Reagents and conditions i N-methylmaleimide PhMe heat; ii 2,2-dimethyl-l,3-propanediol TsOH; iii o-O,NC,H,SeCN Bu,P; iv H,O ; v NaBH, MeOH; vi NaH EtI THF; vii LDA PhCH,OCH,Cl; viii 0,,MeOH Me,S; ix Ph,P=CHCO,Et CH,Cl,; x PhSH TsOH CH,Cl,; xi Bu,SnH AIBN PhH heat; xii PhMgBr THF; xiii NaH MeI DMF; xiv TsOH MeCOMe; xv NaH-KH o-BrC,H,NCO THF heat; xvi Ac,O NEt, DMAP DMF; xvii Bu,SnH hv PhH; xviii TsOH CH,Cl, then MeOH; xix 0, CH,Cl, MeOH Me,S; xx 6 mol dm- HCl-H,O DME 48 "C; xxi TFA Et,SiH CH,Cl,; xxii BBr, CH,Cl,; xxiii Dess-Martin oxidation; xxiv Cp,TiMe, THF heat.Scheme 28 NATURAL PRODUCT REPORTS 1996-5. E. SAXTON Hart and his collaborators selected as first critical goal the preparation of the tricyclic part-structure 209 which was obtained by Diels-Alder cycloaddition of the diene 210 with N-methylmaleimide; conventional stages then led to the perhydroisoindoline derivative 21 1 free radical cyclization of which gave the intermediate 209. Further manipulation of 209 gave the tricyclic ketone 212 onto which the oxindole residue was attached uiu the vinylogous carbamic acid 213. The product 214 of this reaction was accompanied by smaller amounts of the epimeric acetates 215 and 216 which could be converted into oxindoles having the desired stereochemistry by retroaldol-aldol isomerization of the related alcohols.The tetrahydropyran ring was then attached to the oxindole 214 via the aldehyde 217 and the final stages to 21-oxogelsemine 207 involved conversion of the benzyloxymethyl group attached to C-21 into a vinyl group (Scheme 28).74 2.4 The Strychnine Group Echitamidine echitamidine N,-oxide (which is new) and 20- epi- 196-echitamidine (presumably 20-epi- 19-epi-echitamidine see below) have been found among the constituents of the stem bark of Alstonia gZauces~ens,~~~~ 65 and compactinervine is one of the thirteen alkaloids of the leaves of RauwolJu sumatranu Jack.5g Aside from vomicine which has been shown to be produced in leaf callus cultures of Strychnos nux v~mica,~~ these are the only alkaloids of the strychnine group to be isolated in recent months; all other isolation reports concern alkaloids of the aspidospermatan group.Tubotaiwine occurs in the leaves of Hunteria zeylanicu (Retz) Gardn. ex Thw.26 and together with condylocarpine aspido- spermatine and 1I -methoxydichotine in the leaves and stems 219 220a 221 of Vallesia glabra (Cav.) Link grown in the Bolivian province of Misq~e.~~ 11-Hydroxytubotaiwine 218 is one of two novel metabolites isolated from cell suspension cultures of Aspidosperma quebrachoblunco ;77 the other is a relatively simple dioxopiperazine derivative.C0,Me 218 1 1 -hydroxytubotaiwine Teuber and Lahnstein have reported an interesting study in which a strychnine derivative has been rearranged to a substituted indoloquinolizidine.7s Oxidation of isostrychnic acid 219 by means of peracetic acid followed by reduction of N-oxides with sulfurous acid afforded a mixture of products including the indolenine derivative 220a which appears to be in equilibrium with the zwitterion 220b; accordingly reduction by means of lithium aluminium hydride gives the diol 221 and reduction by means of sodium borohydride gives the lactone 222. On treatment with hot dilute hydrochloric acid the indolenine 220 undergoes rearrangement ;C-3 migrates to C-2 and the C(2)-C(16) bond is broken and the product is the keto acid 223 (Scheme 29).Reduction then gives the epimeric lactones 224a and 224b of which the former was subjected to X-ray crystal structure analysis. 220b 222 223 224a 1k-H 224b 1%-H Reagents and conditions i MeC0,H; ii SO, H,O; iii 2 mol dm-3 HCl heat; iv NaBH, MeOH; v LiAlH, THF Et,O. Scheme 29 NATURAL PRODUCT REPORTS 1996 r IYH2Ph -I C02Me H C02Me L02Me 4 229 230 228 ii iii 232 Ph I 235 233 234 231 x-xii V 236 227 (+)-19-epi20-epCechitamidine 225 (+)-echilamidine 226 xvii xiv 237 (3enf-232) 238 239 Reagents and conditions i OHCCH,C(OCH,),Me PhMe heat; ii HCO,H 70 "C; iii LiAlH,; iv NaBH, CeCl, MeOH; v NaBH, AcOH 110 "C; vi DBU PhMe heat; vii H, Pd EtOAc; viii (ButOCO),O; ix Ac,O NEt,; x BdOCl TEA; xi DBU; xii TFA; xiii CH,=CHOAc NEt, heat; xiv MeOH K,CO, H,O; xv MeOH 150 "C; xvi OHCCH,SePh PhMe heat; xvii Bu,SnH PhMe heat xviii TFAA DMSO; xix NaOMe MeOH; xx NaBH, MeOH 0 "C.Scheme 30 C02Me C02Me C02Me 246 225 W-echitamidine 245 vi vii 1-/1. I Me viii - 240 (k)-alstogustine 247 243 1 xi I I vii t 242 (f)-akuammiune 241 (k)-epi.alstogustine 248 Reagents and conditions i 4 A molecular sieves BF;Et,O PhMe heat 3 d; ii 10% Pd-C HCO,NH, MeOH EtOAc heat; iii CH,O(g) MeOH 0 "C; iv HCl 0 "C to reflux; v HCI H,O; vi NaOMe MeOH; vii NaBH, MeOH; viii NaBH, CeCI; 5H,O MeOH 0 "C; ix Me4 MeOH; x PhCH,SH BF;Et,O AcOH; xi Raney Ni MeOH. Scheme 31 NATURAL PRODUCT REPORTS 1996J. E. SAXTON Details of Overman's synthesis38 of natural (-)-strychnine have been published," and the synthesis of ent-( +)-strychnine by essentially the same route has also been completed; only the preparation of the chiral starting material the enantiomeric cyclopentene derivative was necessarily changed.Kuehne and co-workers have reported two syntheses of ( f)-echitamidine 225. The first of these,8o which also encompasses the synthesis of ( f)-2O-epi-echitamidine 226 and ( f)-19-epi-20-epi-echitamidine 227 employs intramolecular Diels-Alder cycloadditions in two vital processes for the construction of the ring system (Scheme 30). In the early stages the tetracyclic intermediate 228 was prepared by the familiar Kuehne route from the indoloazepine ester 229 and an appropriate aldehyde via the transient intermediate 230.Release of the carbonyl group followed by reduction could then be arranged to give either equimolecular amounts of the epimeric alcohols 231 and 232 or predominantly (96 %) 232 according to conditions. Further reduction of 231 gave a mixture of epimeric indole esters 233 and 234 [the latter could be epimerized to generate more 2331 of which the former 233 was converted into the ester 235 by conventional means; reintroduction of the double bond and deprotection of the basic nitrogen then gave the substrate 236 for the final critical cyclization. Reaction of 236 with vinyl acetate at elevated temperature gave a transient N-vinyl intermediate which spontaneously cyclized to give (f)-19-epi-20-epi-echitamidine227 identical with the echitamidine stereo- isomer of unknown configuration at C- 19 isolated from Alstonia angustiloba in 1984 by Zeches et a1.*' and more recently from A.glaucescens (vide At high temperature 227 could be isomerized in low yield presumably via a reverse Diels-Alder mechanism into ( f)-echitamidine 225. In an improved procedure the tetracyclic ester 237 (= 232 since all compounds are racemic) was converted into the tricyclic ester 238 exactly as in the conversion of 231 into 236. Reaction of 238 with phenylselenylacetaldehyde then gave an N-vinyl intermediate which immediately cyclized to give a pentacyclic 14-phenylselenyl ester 239. Reductive removal of the phenylselenyl group and hydrolysis of the 19-acetoxy group then gave (f)-2O-epi-echitamidine 226 which was epimerized at C-20 via the corresponding 19-ketone to give (&)-echitamidine 225 (Scheme 30).*O In a subsequent investigation Kuehne et a1.82 used a relatively new condensation-sigmatropic rearrangement sequence for the synthesis of (k)-echitamidine 225 ( f)-alstogustine 240 (+)-19-epi-alstogustine 241 and ( f)-akuammicine 242 (Scheme 3 1).Here the pivotal pentacyclic intermediate 243 was prepared from the tryptamine derivative 244 and the protected un-saturated keto aldehyde 245. Prolonged heating of these two components eventually gave the tetracyclic compound 246 as outlined in Scheme 31. Debenzylation of 246 reaction with formaldehyde release of the ketone function and cyclization then gave 243.For the synthesis of ( f)-echitamidine 225 it was simply necessary to epimerize 243 at C-20 and reduce the C-19 carbonyl group. Alternatively direct reduction of 243 gave either alcohol 247 or a mixture of epimers 247 and 248 according to conditions; quaternization of these alcohols with methyl iodide then gave (+)-alstogustine 240 and (&)-19-epi-alstogustine 241. (f)-Akuammicine 242 was then simply obtained by Raney nickel desulfurization of the benzyl thioenol ether derived from 243.82 Continuing their outstanding synthetic work in this area Kuehne and co-workers have completed a new synthesis of 251 1 i-iii 0-p-rN7 N .-I C02Me 252 253 HI C02Me 249 lagunamine 254 19-epilagunarnine vi vi vi 1 x 1 vi vii -t- 250 condylocarpine 255 isocondylocarpine Reagents and conditions i TFA; ii r-COMe CH,Cl,; iii 110 "C; iv HCI THF; v NaBH, -20 "C; vi Ph,P CCl,; vii AcOH CHCI, r.t.or PhMe heat 4h. Scheme 32 to the more basic pentacyclic amino ketone 252 by treatment with acid. Reduction of 252 then gave lagunamine 249 and 19- epi-lagunamine 254 and dehydration of either epimer by means of triphenylphosphine and carbon tetrachloride gave condylocarpine 250 and isocondylocarpine 255 in a 2 :1 ratio. This equilibrium mixture of geometrical isomers was obtained from either pure isomer when allowed to stand for 24 h in chloroform containing some acetic acid or when heated in lagunamine 249 condylocarpine 250 and their stere~isomers.~~ toluene in the absence of acid.Interestingly an old sample of On this occasion the essential starting material was the indoloazonine derivative 251 prepared earlier'' in connection with the synthesis of tubotaiwine. Deprotection of N in 251 followed by alkylation by means of butynone and Diels-Alder cyclization gave the pentacyclic ketone 252 and the new enaminone 253 (Scheme 32). In this reaction the ketone 252 is the primary product; it can be converted into the enaminone 253 by heating in toluene but more importantly for the synthesis of the target alkaloids the enaminone can be cyclized condylocarpine was also found to contain both isomers and it seems possible although as yet not definitely proved that the natural alkaloid is a mixture of E/Z-isomers rather than the E-isomer hitherto universally accepted.In an earlier synthesis of tubifolidine and echitamidine Bosch and co-workers formed the C(15)-C(20) bond by in in-tramolecular Michael addition onto the P-position of an enone system.68b The same group have now developed an alternative method of formation of this crucial bond in a new synthesis of 258 257 1 ii 2 56 dehydrotubifoli ne Reagents and conditions i (2)-BrCH,CI=CHMe K,CO, MeCN; ii Ni(cod), NEt, LiCN 1 1.5 MeCN-DMF. Scheme 33 (f)-dehydrotubifoline 256.84Here the essential tricyclic in- termediate 257 prepared by alkylation of the known6sb arylhexahydroindol-4-one derivative 258 was cyclized by treatment with nickel di(cyc1o-octadiene) in the presence of triethylamine and lithium cyanide ; ( _+ )-dehydrotubifoline 256 was thus obtained directly in 40% yield (Scheme 33).The presence of lithium cyanide appears to be vital in this reductive cyclization procedure in which case the operative reagent may well be a cyanonickelate(0) species of as yet undetermined constitution. A new preparations5 of the tetracyclic amino ketone 259 constitutes a new formal synthesis of tubotaiwine and the synthesiss5of 260 affords new syntheses of tubifoline tubifoli- dine and 19,20-dihydroakuamrni~ine.~~ 261 NATURAL PRODUCT REPORTS 1996 Peschieru buchtieni; olivacine was also found in the 1ea~es.l~ Vallesamine 0-acetylvallesamine and an unidentified isomer of vallesamine have been found in the bark of Tubernuemontuna markgruJunu,20 and apparicine has been shown to occur both in the leaves and stems of Vullesiu gl~bru,'~ and in the leaves of the double flower variety of Malaysian Tubernuernontuna divuricata (L.) R.Br. ex Roem et S~hult.~~ Et R'=Et; R2=H H R'=H; R2=Et C02Me + + V C02Me 259 Reagents and conditions i Cl2Pd(PPh3), DIBAL heat; ii TsOH EtOH heat; iii separation of isomers; iv HC1 MeOH; v H, PtO,; vi Ba(OH), dioxan heat; vii PPA 85-90 "C. Scheme 34 The new synthesis of (-t)-nordasycarpidone 259 (Scheme 34) constitutes a formal synthesis of dasycarpidone uleine dasycarpidol and 17-hydroxy- 16,17-dihydrouleine which have all been obtained previously from this ketone.85 In an ingenious new approach to the construction of indole alkaloids Blechert and co-workers have completed a synthesis of ( )-2O-epidasycarpidone 265.90The indole derivative 266 prepared from phenylhydroxylamine cyanoallene and the urethane aldehyde 267 was deprotected and reacted with Me09 butyraldehyde in the presence of molecular sieves.The transient enamine so generated spontaneously cyclized to give the tetracyclic nitrile 268 together with an isomer 269 formed by 0-GH cyclization on to the indole nitrogen. Partial reduction of 268 i-l H O 262 263 Me I OH Me 264 3-hydroxytetrahydroolivacine 260 Some progress has been made towards the enantioselective synthesis of the Strychnos alkaloids by the preparation of the enantiopure intermediates 261 and 262,87while the synthesis of the racemic tetracyclic substructure 263 affords an independent approach to these alkaloids.88 2.5 Ellipticine Uleine and Apparicine Group 3-Hydroxytetrahydro-olivacine 264 which is a new alkaloid has been isolated together with olivacine 3,14-dihydro- olivacine janetine and vallesamine from the stem bark of followed by aerial oxidation then gave (-t)-20-epidasycarpidone 265 (Scheme 35).By appropriate modification of this approach the synthesis of simple derivatives of ellipticine olivacine and guatambuine was also achieved.g0 The approach of Rubiralta and co-workers to the asymmetric synthesisg1 of dasycarpidone-type alkaloids involved the initial preparation of the achiral piperideinone derivative 270 which when condensed with the dianion from the dithianylindole 271 gave a mixture of epimers 272a and 272b.Partial reduction of 272a followed by acid-promoted cyclization then gave the dasycarpidone derivative 273 (1 5R 2123 while similar treat- ment of 272b gave the 15S 21R-stereoisomer (Scheme 36). 2.6 Aspidospermine and Vincamine Group Vallesine (deacetylaspidospermine) aspidospermine vin-cadifformine haplocidine 18-oxohaplocidine and (-)-rhazinilam have been isolated from the leaves and stems of Bolivian Vullesiu gl~bru~~ and N-methylaspidospermidinefrom the leaves and stem bark of Malaysian Ervutumia pedunculuris King and Gamble.92 Voaphylline N,-methylvoaphylline voaharine and pachysiphine occur in the double flower variety of Tabernaemontuna divaricutu together with a new alkaloid NATURAL PRODUCT REPORTS 1996J.E. SAXTON 0 (-)-mehranine 274.89 Its enantiomer (+)-mehranine was earlierg3 isolated from Ervatamia coronaria but its stereo- Me chemistry was not defined. Apodine and hedrantherine are OHCNNk02CH2CH=CH2 -among the 20 alkaloids contained in the leaves and stem bark of Peschiera van heurkii (Muell.-Arg.) L. All~rge,~~ 267 while CN modestanine (deoxoapodine) and vandrikine occur in the I' 266 leaves and stem bark of Ervatamia corymbosa Roxb. ex Wall.23 Voaphylline and voaphylline hydroxyindolenine are among the iii N 31 alkaloids extracted from the stem bark of Peschiera buchtieni and apodine was isolated from the 1eaves.l' Me + 'N H?!TH fJ-po MeN Et CN 269 268 Me J v vi 274 (-)-rnehranine Me C&J$p 0 ..C02Me 275 15a-hydroxy-14.15-dihvdrovindolinine 16P-C02Me 265 (*)-epidasycarpidone 276 15a-hydroxy-l4,15-dihydro-16-epivindolinine1Ga-C02Me Reagents and conditions i PhNHOH MeOH -25 "C; ii CH,=C=CHCN 20 "C; iii Pd(PPh,), morpholine; iv Two new alkaloids 15a-hydroxy-14,15-dihydrovindolinine MeCH,CH,CHO MeCN molecular sieves; v DIBAL PhMe; vi 275 and its 16-epimer 276 have been found together with eight 02. known alkaloids in Melodinus morsei Tsiang grown in the Scheme 35 Guangzi province in China.94 The eight known alkaloids are vindolinine epivindolinine and their N,-oxides quebrachamine vincadifformine kopsinine and 15-hydroxykopsinine. Extracts of this plant are used in Chiidx folk medicine for the treatment of meningitis in children and H H rheumatic heart disease.Ph-rOH Ph-y'.. Yet more new alkaloids have been isolated from the roots of Rhazya stricta. The two newest ones are N-methylleuconolam 277 and saifine 27tLg5This latter can readily be imagined to ___c 0 arise from eburnamine 279 by fission of the C(2)-C(21) bond 270 271 followed by oxidation at C-7 and C-21 attachment of N to C- 2 and lactonisation (Scheme 37). N,v -(on272a) 15 12 Me U 277 N-methyl-leuconolam 278 saifine Ph' H \ 272a aR,4R + \ 272b aR,4S t 273 279 eburnamine Reagents and conditions i Bu'Li THF -78 "C then PhSeBr; ii MCPBA CH,Cl, 0 "C to r.t. ;iii BuLi THF -78 "C; iv chromato- Reagents and conditions i oxidation at C-7 oxidative fission of graphic separation of isomers; v Red-Al THF -78 "C to r.t.; vi C(2kC(21) and C(21)-Nb bonds; ii reduction of C-16; iii attachment AcOH H,O CH,Cl,.of Nb to C-2; lactonisation. Scheme 36 Scheme 37 NATURAL PRODUCT REPORTS 1996 9-Hydroxyepimeloscine 280 another new alkaloid from the leaves of Melodinus scandens is only the second phenolic quinolinone to be encountered in this group.96 Three new alkaloids lundurines A-C 281-283 which contain a novel ring system incorporating a cyclopropyl unit have been obtained from Kopsia tenuis Leenh and Steenis a previously uninvestigated species from North B~rneo.~' An obvious biosynthetic derivation of these alkaloids from a precursor related to the lapidilectines is emphasized by the presence in the same plant of 10-methoxy-3-oxolapidilectine B 284 which is also new.280 4hydroxyepimeloscine 281 lundurine A Me0xlJQD14 R' Qy@ R2 / 285 Nmethoxycarbonyl-1 1,12-methylenedioxy -A'6'17-kopsinine R' R2 = -0CH20-286 R' = H; R2 = OMe 287 R' = H; R~ = OH 288 R'=R2=H; R3=OH 289 R' = R2 = H; R3 = OMe 290 R' R2 = -O-CH,-O-; R3 = OH 291 R' R2 = -0-CH2-O-; R3 = OMe 282 lundurine B 283 lundurine C 284 10-methoxy-3-oxolapidilectine B Of the five kopsinine derivatives isolated from the leaves and stems of Kopsia profunda Mgf. from Terengganu (Malaysia) three are new.9s The known bases are N-methoxycarbonyl- 1 1,l 2-methylenedioxy-Al6> 17-kopsinine 285 and 12-methoxy-N-methoxycarbony1-Al6- I7-kopsinine 286 and the new ones are 12-hydroxy-N-methoxycarbonyl-A16~ 17-kopsinine287 and the N-oxides of 285 and 286.Another Malaysian plant K. singapurensis Ridley from Mersing has yielded four new alkaloids singapurensines A-D 288-291 together with the known 11,l2-methylenedioxykopsaporine.g9 Finally two bases obtainedloO from Kopsia teoi when ammonia was used in the extraction process are admitted to be artefacts; these are mersingine A 292 and mersingine B 293 and are presumably derived from kopsinitarines B and C,38 via ammonolysis of the isomeric a-ketols. Lewin and Poisson have reported a method for func-tionalizing C-6 in vincadifformine 294.1°1Polonovski-Potier reaction on 16-chlorovincadifformine N-oxide followed by addition of methanol gives 295 which on treatment with cyanogen bromide in dichloromethane gives the two epimers 296a and 296b presumably via the 5,6-enamine.Reaction of this mixture with sodium iodide removes the chlorine and regenerates the anilinoacrylate chromophore with formation 292 mersingine A R = 293 rnersingine B R = 1501-OH of 297 as sole stereoisomer; the C-5 epimer is not formed. Finally reduction of 297 by sodium borohydride gives (6S)-6- bromovincadifformine 298 (Scheme 38). Eight compounds in this series were tested for cytotoxicity in the L-1210 cell culture test system; of these compounds 295 and 299 were shown to have significant activity.lo2 The nitration of vincadifformine 294 gives a mixture of the 10-nitro derivative and 16-nitrovincadifformine indolenine 300a.lo3Reduction or hydrogenolysis of the latter regenerates vincadifformine while treatment with trifluoroacetic acid at room temperature causes isomerization to 10-nitro-vincadifformine.Reaction of 300a with aqueous sulfuric acid however results in hydration of the indolenine double bond followed by fission of the C(2)-C(16) bond with formation of the oxindole derivative 301a. An exactly similar sequence of reactions can be performed on 10-bromovincadifformine via I O-bromo- 16-ni trovincadifformine indolenine 300b. Reduction of 301b by means of sodium borohydride results in fission of the C(7)-C(21) bond with formation of the epimers 302 (Scheme 38).lo3 The structures of kopsidines A-C 303-305 and kopsinganol 306 have been confirmed by partial synthesis from kopsingine 307.The method adopted by Husson and c~-workers~~* involved the generation of the enaminium salt 308 by a Polonovski-Potier reaction on kopsingine N-oxide ;reaction of 308 with methanol or ethanol then gave kopsidine A 303 or kopsidine B 304 (Scheme 39). Tan et a1.1°5oxidized kopsingine NATURAL PRODUCT REPORTS. 1996J. E. SAXTON vi v (j300b) -Q-vEt v (4300a) \ vii 'N C02Me C02Me 294 (-)-vineadifformine 300a R=H R = H or Br 300b R=Br 295 C02Me 301a R=H 1 ii 301b R=Br I ix (on 301b) IV -296a R' = CN; R2= H 297 298 C02Me 296b R' = H; R2= CN 302 299 R'= R2=H Reagents and conditions i TFAA CH,Cl, then MeOH; ii BrCN CH,Cl,; iii NaI AcOH; iv NaBH, MeOH; v AcOH TFA HNO,; vi NBS TFA r.t.; vii.SnCI or hydrogenolysis; viii 0.9 mol dm-3 H,SO, THF heat 45 min; ix NaBH,. Scheme 38 307 electrochemically in the presence of lutidine as proton scavenger to generate 308; work-up with methanol ethanol or aqueous acetonitrile then gave kopsidine A 303 B 304 or C OH OH 305 respectively. Finally reduction of kopsidine C 305 by means of sodium borohydride gave kopsinganol 306 (Scheme 39). Crooksidine 309 has been synthesizedloG by a straightforward 307 kopsingine 308 route from 2-ethyltryptamine. Condensation with methyl 4-N (+303) formylhexanoate gave the dihydropyridone derivative 310 v (+304) which on reduction followed by oxidation gave crooksidine 309 vi (+305) (Scheme 40). OH 303 kopsidine A R = Me 304 kopsidine B R = Et H H 305 kopsidine C R = H 31 0 vii (on305) I I ii iii s- ayqN Me H 306 kopsinganol 309 crooksidine Reagents and conditions i oxidation; ii TFAA CH,Cl,; iii electrochemical oxidation; iv MeOH; v EtOH; vi H,O MeCN; vii Reagents and conditions i EtCH(CHO)CH,CH,CO,Me PhH heat; NaBH, MeOH.ii H, Pd-C EtOH; iii LiAlH,; iv DDQ THF H,O. Scheme 39 Scheme 40 ( +)-Demethoxycarbonyl-15,16,17,20-tetrahydrosecodine 311 has been obtained by an enantiocontrolled synthesis which unequivocally establishes its absolute config~ration.'~' The chiral bromocyclopentenol 312 prepared from the corre-sponding racemate by preferential transesterification of its enantiomer by means of vinyl acetate in the presence of porcine pancreatic lipase followed by separation was converted via a Claisen rearrangement of the acrylate ester 313 into the aldehyde 314 (Scheme 41).Conventional elaboration of 314 led via the cyclopentene derivative 315 to the dimesylate 316 which was the substrate for condensation with 2-ethyltryptamine. The product 317 was then hydrolysed and the hydroxy group removed by the Grieco method to give (+)-demethoxycarbonyl-15,16,17,20-tetrahydrosecodine 311 which exhibited a specific rotation of (+)-I 1.8O. This compound definitely has the R-configuration but it is not possible to identify it unequivocally with the alkaloid of this structure isolated earlier from Tabernaemontana cumminsii Aspido- sperma marcgravianum or Haplophyton crooksii since no optical rotation has been quoted nor with the alkaloid of Rhazya stricta for which a specific rotation of (+)-90° was reported.los -C02Me OH 9' S-(-)-312 31 3 314 1 NATURAL PRODUCT REPORTS 1996 i-iii H C02Me 318 321 0-G-vi vii H 319 S02Ph 322 viii 1 320 323 iii-v Reagents and conditions i BuLi ClCO,Me THF; ii NaBH, CeCl, TrOMs MeOH ;iii BF .Et,O ;iv PhSO,CH=CH, PhH ;v EtSLi HMPA THF; vi Ni Me,CHOH Ar; vii LiAlH, THF; viii KOBut ...CH20SiBu'Ph2 *~...dCH20SiButPhs HOCH,CH,OH 150 "C. 316 315 I viii Nip/*\osi8utph2 ix-xi o\ -aTip*-Et Scheme 42 H H 31 7 31 1 Reagents and conditions i HC-CCO,Me N-methylmorpholine Et,O; ii Lil DMF 140OC; iii NaBH,; iv ButPh,SiC1 PriNEt CH,Cl,; v BuLi THF; then 1 mol dm- (CO,H),-H,O; vi O, MeOH Me$ then NaBH,; vii MsC1 NEt, CH,Cl,; viii 2- ethyltryptamine MeCN LiI 12-crown-4; ix Bu,NF THF; x o-O,NC,H,SeCN PBu, THF; xi NiCl, NaBH, MeOH THF.Scheme 41 Wenkert and Liu have used the previously preparedloga pentacyclic lactam 318 in new syntheses of (f)-aspidofractinine 319 and (f)-aspidospermidine 320.1°gbConversion of 318 into the ring C diene 321 followed by Diels-Alder addition of phenyl vinyl sulfone and removal of the urethane methoxycarbonyl group as shown in Scheme 42 gave a hexacyclic intermediate 322 which on hydrogenolysis and reduction gave (& )-aspidofractinine 319. Alternatively base- catalysed elimination on 322 with fission of the C(2)-C( 18) bond gave a pentacyclic indolenine 323 which on reduction gave (f)-aspidospermidine 320 (25 %) together with 16,17-didehydroaspidospermidine (49 YO).Padwa and Price'lO have introduced a radical new approach to the synthesis of vindoline and vindorosine in which rings C and E are formed by an ingenious tandem cyclization-cycloaddition of a transient carbenoid intermediate 324 generated from the diazoimide 325 by treatment with rhodium acetate (Scheme 43). This carbenoid presumably cyclises to a Me 325 1 iii 2 326 'N 0 0 Me H ' 327 328 Reagents and conditions i N-methylindole 3-acetyl chloride 4 A molecular sieves; ii MsN, NEt,; iii Rh,(OAc) (cat.) PhH 50 "C; iv Lawesson's reagent heat; v Raney nickel; vi H, PtO, MeOH HC1. Scheme 43 NATURAL PRODUCT REPORTS 1996-J.E. SAXTON 295 I' Me02C' CI 1 'Et -331 329 1 iit q$ :Me qg ~ :Me WN N. Et '6' Et 332 333 Reagents and conditions i MCPBA CH,Cl,; ii 0.2 mol dm- NaOH in MeOH r.t.; iii TFA CH,Cl,. Scheme 44 dipole 326 which subsequently cycloadds across the indole x-bond to give the hexacyclic product 327. Removal of the amide carbonyl group via the thioamide followed by hydrogenolysis of the C-21 to oxygen bond in acid solution then gave desacetoxy- 17-0x0- 14,15-dihydrovindorosine 328 whose structure and stereochemistry were unequivocally established by X-ray crystal structure analysis. The potential of this new route for the total synthesis of vindorosine and vindoline is obvious; indeed the 11-methoxy derivative of 328 has already 351 Lewin and co-workers have initiated an investigation with the aim of converting vincadifformine 294 into goniomitine by a biomimetic process.112 The 16-chloro-5-methoxy derivative 295 prepared as described above (Scheme 38) was oxidized by means of rn-chloroperoxybenzoic acid which gave the tetrahydro-oxazine derivative 329 probably via the peroxy- benzoic ester 330 (Scheme 44).Methanolysis then gave the hemiacetal 331 which on acid-catalysed rearrangement gave a mixture of compounds 332 and 333 whose relationship to goniomitine 334 is apparent. Other synthetic work reported recently includes a new approach to the aspidospermine framework which has so far reached the tetracyclic compound 335,113and the synthesis of several desethyl derivatives including ( & )-2O-desethyl-tabersonine and its 3-0x0 derivative and (-k)-20-desethylapovincamine.114 GI-! H S02Me 334 goniomitine 335 In the first of two new syntheses of (&)-eburnamonine 336lI5 the critical stage involves the formation of ring C by an intramolecular Diels-Alder cyclization.The substrate 337 for this cyclization was constructed from bvalerolactam via the cyclopropyl ester 338a as outlined in Scheme 45.Interestingly the epimeric ester 338b also generated in the cyclopropanation stage could be epimerized to 338a by treatment with a Lewis acid; this presumably occurs via the corresponding ketene immonium salt. The p-nitrophenyl ester 339 was then coupled with indole 3-carboxaldehyde and the desired 3-vinylindole derivative 340 obtained by a simple Wittig reaction.Removal of the P-trimethylsilylethoxycarbonylprotecting group with concomitant opening of the cyclopropyl ring was achieved by means of benzyltrimethylammonium fluoride; Diels-Alder cyclization of the product 337 then gave the cycloadduct 341 in which the double bond appeared to be stable in the 6,7-position. (+)-Eburnamonine 336 was finally obtained by been converted into vindoline by Kutney and co-workers."' mineral acid-catalysed isomerization of 341 (Scheme 45). C02CH2CH2SiMe3 C02CH&H2SiMe3 C02CH2CH2 H I I '0-i-iii N -EtO2C+\ + EtOZC--43 SiMe3 Et Et 338a '338b ~~~~02CH&H2SiMe3 viii ix -P%NC6H402C OW Et 340 lx wJ+-&0-& ___) xi vi vii I CO&H2CH2 I 45 SiMe3 Et 339 ___c xii 0-7 0 0 0 Et Et Et 337 341 336 (f)-eburnamonine Reagents and conditions i BuLi 0 "C then Etl then Me,SiCH,CH,OCOOC,H,NO,-p; ii LiAlHBu; -50 "C; iii H,SO, Et,O; iv N,CHCO,Et Cu 135 "C; v BF .Et,O CH,CI, 0 O0C; vi saponification; vii O,NC,H,OH DCC; viii N-lithio-indole 3-carboxyaldehyde -20 "C;ix Ph,P=CH, THF; x PhCH,NMe,F 4A molecular sieves THF 45 "C; xi TFA PhH heat; xii EtOH H,SO, heat 12 h.Scheme 45 3 52 The second new synthesis116 makes use of an a-amino nitrile but on this occasion it is not generated by a modified Polonovski-Potier reaction but by a photolytic single electron transfer process. Hydrolysis of the benzyl ether 342 obtained by reduction of the corresponding pyridinium salt gave a ketone which was converted into a mixture of geometrical isomers 343 by a Wittig-Horner reaction (Scheme 46).Photolytic oxidation then gave an a-aminonitrile 344,which was cyclized in acid to a mixture of tetracyclic aminoesters 345a b. Finally conjugate addition of an ethyl group cis to the C-21 hydrogen atom by means of ethylmagnesium bromide gave a transient intermediate which spontaneously cyclized to ( )-eburnamonine 336. (-)-Vincinone 346 can be prepared from 11-bromovincamine 347 in a one-pot process by reaction with sodium methoxide and cuprous iodide at elevated temperature (Scheme 47). 342 C02Et 343 iii I k02Et C02Et 345a,b 344 I. 336 (&)-eburnamonine Reagents and conditions i 6 mol dmP3HCI MeOH 40 "C; ii (EtO),- POCH,CO,Et THF BuLi -78 "C; iii hv 0, 9,lO-dicyanoanthracene Me,SiCN MeCN; iv 0.5 mol dm-3 HCl Ar; v EtMgBr CuCl Et,O.Scheme 46 Br 347 346 (-)-v incino ne Reagents and conditions i NaOMe CuI DMF N, 110 "C. Scheme 47 As with other ring D enamines in this series (e.g. A3-lQ-vincamone) criocerine 348a and several close relatives 348k give dimeric bases 349a-e when treated with acid e.g. acetic acid."" Owing to the presence of an allylic ether linkage attached to C-15 in 348a-e the C-15 to oxygen bond is necessarily broken in the formation of these dimers (Scheme 48). The hydrogenation of ethyl apovincaminate under a variety of conditions gives predominantly the 16P-H dihydro de- NATURAL PRODUCT REPORTS 1996 b R1=NO2; R2=H; R3= Me c R'=Br; R2=H; R3=Me HO-LJWJ R302C i2Et d R'=H; R2=CI; R3=Me e R'=H; R2=CI; R3=Et 349-Reagents and conditions i AcOH r.t.24 h. Scheme 48 rivative predictable if it is assumed that hydrogen will be added preferentially at the less hindered face of the molecule. Preliminary experiments have been conducted to examine the effect of this dihydro ester on the enantioselective hydro- genation of isophorone and ethyl pyruvate with or without added dihydrocinchonidine.l18 2.7 Catharanthine and Ibogamine group Ibogamine coronaridine voacangine and voacangarine have been isolated from the aerial parts of Peruvian Peschiera van heurkii;18 other workers have found coronaridine and coronaridine 7-hydroxyindolenine among other alkaloids in a Bolivian specimen.56 These last two alkaloids together with eglandine eglandulosine heyneanine and heyneanine 7-hydroxyindolenine have been found in the leaves and stem bark of Malaysian Ervatamia pedunc~laris,~~ and coronaridine and voacangine have been isolated from the twigs and leaves of Tabernaemontana glandulusa from Ghana.60 Of the 34 alkaloids extracted from the stem bark and leaves of Bolivian Peschiera buchtieni (H.Winkler) Mgf. coronaridine coronaridine 7-hydroxyindolenine heyneanine eglandine eglandulosine 19- epi-heyneanine ibogamine and the new alkaloid (1 8 19R)- dihydroxycoronaridine 350 (from the stem bark) and voacristine and its 7-hydroxyindolenine derivative (from the leaves) belong to this group.lg Another source of voacristine has been reported in the leaves of Panamanian Stemmadenia obovata (Benth.) Woods.which also contain 11-hydroxyc~ronaridine.~~~ Tabernaemontana markgrafiana Macbride (syn. Bonafousia longituba Mgf.) is a South American tree whose latex is widely used in traditional medicine e.g.,as a febrifuge and disinfectant in Brazil as a contraceptive agent also as a fungicide and in the treatment of insect bites in Peru and in the alleviation of toothache in Peru and Ecuador. The first examination of the 350 (18,1QR)-dihydroxycoronandine R1 ia 351 R' = R' = H A''' 354 10,ll-didemethoxychppiine 352 R' = H; R2 = OMe (3R) 353 R' =OMe R2 =OMe (3R) NATURAL PRODUCT REPORTS 1996J.E. SAXTON MeOhOMe oh, u 356 I iv-vi u 357 h02Me 355 de-ethylibophyllidine Reagents and conditions i NaBH, MeOH; ii AcOH H,O; iii (CH,OH), CaCl, Amberlyst- 15 iv ClCO,CH,Ph H,O THF Na,CO, 50°C; v Ac,O DMAP; vi NaCN DMSO 95°C; vii HCl(g) MeOH 4 "C 16 h then H,O 90 min. Scheme 49 alkaloids of the bark of this species has yielded 22 mono- terpenoid indole alkaloids primarily of the iboga type. These include four new ones among the minor constituents; these were deduced to be 5,6-dehydrocoronaridine 351 (3R)-methoxycoronaridine 352 (3R)-methoxyvoacangine 353 and 10,ll -didemethoxychippiine 354.20Known alkaloids include coronaridine (19s)-heyneanine voacangine and ibogamine which were the major ones; minor constituents were identified 362 12b-H 1-H 3-H 363 a 14P-H; 1701-OH b 1@-H; 17P-OH i (on362d) c 14a-H; 17u-OH d 1&-H; 17D-OH 1 as (1 9s)-voacristine ibogaine 3-oxocoronaridine 3-oxovoacangine (3R/3S)-hydroxycoronaridine coronaridine 7-hydroxyindolenine voacangine 7-hydroxyindolenine and (1 9s)-heyneanine 7-hydroxyindolenine.De-ethylibophyllidine 355 has been synthesized in an extraordinarily simple and direct manner by Bosch and co- workers.120 The protected tetracyclic indoloquinolizidine alde- hyde 356 obtained as two C-14 epimers and prepared as outlined in Scheme 49 was subjected to cleavage of the C(3)-Nb bond by reaction with benzyl chloroformate in aqueous tetrahydrofuran. The resulting C-3 alcohol was converted into the corresponding nitrile 357 which was again obtained as a mixture of C-14 epimers regardless of whether the starting acetal 356 was either of the two pure epimers or the epimeric mixture.When the nitrile 357 was treated with hydrogen chloride in methanol no fewer than six chemical processes occurred and the product after formation of rings C D and E and hydrolysis of the nitrile function was de-ethylibophyllidine 355 (Scheme 49). Lounasmaa and co-workers have completed a new synthesis of (+)-tacamine 358.lZ1The amino ester 359 previously prepared,38 was treated with a saturated solution of hydrogen chloride in methanol to which a small amount of water had been added. The major product was tacamine 358 together with a small amount of (f)-apotacamine 360 and a trace of 16-epitacamine (Scheme 50).As reported earlier,38 reaction of 359 with trifluoroacetic acid gave apotacamine. A simple modification of this route resulted in an improved synthesis of (+)-apotacamine 360 and its 20-epimer 361.122a The most unsatisfactory stage in the tacamine synthesis involved the equilibration of the mixture of aldehydes 362 which gave the desired stereoisomer 362a only as a very minor component. It was subsequently shown that epimerization of the mixture of aldehydes 362a and 3621 with weak base gave a mixture in which the major isomer (77%) was 362d. Repetition of the earlier synthesis on 362d then gave ( f)-2O-epiapotacamine 361 from which (f)-apotacamine 360 could be obtained by a Polonovski-Potier reaction followed by reduction of the 20,21-enamine by means of sodium borohydride in acetic acid.The 3,14-enamine also obtained in the Polonovski-Potier reaction on 361 was not reduced by sodium borohydride (Scheme 50).122a iii ___t -Et H HO 359 358 (+)-tacamine IN 360 (*)-apotacarnine I Et H 361 (k)-ZO-epiapotacarnine Reagents and conditions i LDA Me,NCH,CO,Me; ii NaOAc Ac,O; iii MeOH HCl H,O 50 "C;iv TFA heat; v NaHCO, MeOH 60 "C; vi MCPBA; vii TFAA; viii NaOH; ix NaBH, AcOH MeOH; x HCN or Me,SiCN; xi MeOH H,O HCI. Scheme 50 354 Formation of the cyanhydrins from the aldehyde mixture 362a b followed by hydrolysis and cyclization gave a mixture of hydroxytacamonines 363a4 from which the major cis D/E isomer 363a was obtained pure.122b This proved to have an 17a-equatorial hydroxy group (NOE measurements) but was not identical with the natural hydroxytacamonine isolated from Tabernaemontana eglandulosa by van Beek et a/.and formu- lated as 363a.93In contrast the 17P-hydroxy epimer 363b isolated in trace amounts from this sequence of reactions exhibited NMR characteristics very similar to those reported for the natural hydroxytacamonine which thus contains an axial hydroxy group (Scheme 50). The same group of workers have also contributed a new synthesis of ( +)-tacamonine 364.123The tetracyclic ester 365a also prepared on a previous occasion,38 was epimerized to the ester 365b which was converted into 20-epitacamonine 366 by conventional reactions.Position 20 was then epimerized by a Polonovski-Potier reaction which gave the enamine 367 together with the isomeric 3,14-enamine. ( f)-Tacamonine 364 was finally obtained from 367 by reduction with sodium borohydride in acetic acid (Scheme 51). 365a 365b ii-vi I 367 366 IX t U-Et HH 364 (+)-tacamonine Reagents and conditions i TFA; ii LiAlH, 60 “C; iii TsC1 py; iv NaCN DMF 60 “C; v NaOH H,O; vi POCl,; vii MCPBA; viii TFAA; ix NaOH; x NaBH, AcOH MeOH. Scheme 51 Full details of the synthesis of (&)-tacamonine364 by Ihara et aL3*have been published,124 and an improved preparation of an important lactam intermediate in this synthesis has also been ~ep0rted.l~~ 3 Bisindole Alkaloids Cook and co-workers have published details of their synthesis3* of (+)-villalstonine from natural pleiocarpamine and synthetic (+)-macroline or its 0-silyl ether.67 This is the first synthesis of any Alstonia bis-indole alkaloid which involves the use of a synthetically prepared monomer unit.Guaianensine 368 a new yellow fluorescent zwitterionic alkaloid from the stem bark of Strychnos guaianensis (Aubl.) Mart. collected in the Manaus region of Brazil is composed of flavopereirine and Strychnos-type units. Its structure was elucidated mainly by NMR spectroscopy.126 Two new bisindole alkaloids rasutrine 369 and rasutranine 370 have been found in the leaves of Thai RauwolJia sumatrana NATURAL PRODUCT REPORTS 1996 I OMe 368 guaianensine ,C02Me 369 rasutrine 370 rasutranine Jack.59a Both alkaloids are based on oxidized vincorine and cabucraline components.Known alkaloids from this source include flexicorine and cabufiline; this last alkaloid is the N,O- dimethyldihydro derivative of rasutrine. Three new bisindole alkaloids together with (1 7R)-and (1 7s)-17,4’,5’,6’-tetrahydrousambarensine, have been isolated from the leaves of Hunteria zeylanica (Retz) Gardn. ex Thw. also from Thailand.26 127 Hunteriatryptamine 371 is composed of tryptamine and vobasine-type units and is only the second known example in which the tryptamine unit is attached via its aromatic ring; the first known example was ceridimine which has almost the same structure but lacks the hydroxymethyl group. However no correlation between these two alkaloids appears to have been attempted.26 The other two new alkaloids from this source are coryzeylamine 372 and deformyl-coryzeylamine 373 which are formed from vobasine- and echitamine-type components.26. 12’ Three new alkaloids each belonging to a different structural subgroup have been extracted from the stem bark of Bolivian Peschiera buchtieni. l9 Demethylaccedinisine 374 is composed of vobasine and sarpagine-type units demethylceridimine 375 from vobasine and tryptamine units and buchtienine 376 from geissoschizine and tryptamine units the union having resulted in the closure of the tetrahydro-P-carboline ring. The four known alkaloids found in this species are (3’R/S)-hydroxy- N-demethyltabernamine N-demethyltabernamine 4’,17P-di hydro tchi bangensine and ceridimine.N,-Demethylaccedinisine has also been found in the leaves and stem bark of a Bolivian sample of Peschiera van heurkii together with gabunine conodurine conoduramine and a~cedinisine.~~ Extracts of this plant are used locally for their reputed antileishmanial and antibacterial activity. Examination of these alkaloids showed that the last three exhibited the strongest leishmanicidal activity while conodurine and gabunine were also cytotoxic. Another sample of this plant from the Peruvian Amazon yielded voacamine 16’-demethoxycarbonylvoacamine and voacamidine from its aerial parts. NATURAL PRODUCT REPORTS 1996-J. E. SAXTON 371 hunteriatryptamine 372 coryzeylamine Me02C CH20H Me02C H oy2 OFT Me Y 373 deformylcoryzeyiamine 374 demethylaccedinisine 375 dernethylceridimine 376 buchtienine The pharmacology of conoduramine and voacamine has also been investigated.128 Apparently these alkaloids enhance the cytotoxic response mediated by vinblastine with multidrug- resistant KB cells.Divarine an alkaloid isolated from Strychnos divaricans Dicke has the structure 377 and is evidently formed from two molecules of the deoxy-Wieland-Gumlich aldehyde with further oxidation at C-16.129bDivarine has the same molecular formula as 16-methoxyisomatopensine,6 which has a similar structure to that of divarine except that the methoxy group and the C-16 ether link are transposed. The physical data for these two alkaloids are different but any suspicion that they might be identical could not be resolved since a specimen of 16-methoxyisomatopensine was not available for comparison.Conofoline a new alkaloid from the leaves of the double flowering variety of Malaysian Tabernaemontana divaricata (L.) R. Br. ex Roem. et Schult has the structure 378 and is composed of a mehranine unit attached via C-10 to a 10-hydroxy-11,12-dimethoxytabersonineP-epoxide moiety.89 The leaves also contain conophylline which has also been found to occur in the leaves and twigs of T. gfandufosa.60 Me0 OMe 377 divarine 378 conofoline 0 HO -0 OMe Me0 OMe 379 polyervinine 380 polyervine 381 pedunculine I OMe &02Me 382 peduncularidine The leaves of Ervatamia polyneura Scortechini ex King and Gamble from Selangor (Malaysia) have yielded two alkaloids one of which polyervinine 379 is a dark purple amorphous base with an interesting zwitterionic quinoneiminium salt Its companion alkaloid polyervine 380 is also formed from two oxidized vincadifformine units and is formulated as the methylation product of reduced polyervinine.This structure 380 has also been attributed to con~phylline,~~ whose structure and stereochemistry have been established by the X-ray method and it appears to be accepted that these two alkaloids are identical. Another Ervatamia species E. peduncufaris King and Gamble from the same region of Malaysia has a history of use in traditional medicine for the treatment of syphilis and ulcerations of the nose.The leaves and stem bark of this species contain seven alkaloids of the coronaridine group (vide supra) and two new bisindole alkaloids which perhaps surprisingly are not composed of iboga units but of a highly oxidized tabersonine unit and an aspidospermidine epoxide unit linked via C-3 of the former and C-10 of the latter.92 Pedunculine has the structure 381 and peduncularidine 382 is the related trans-diol. Finally the leaves of Stemmadenia obovata (Benth.) Woods. contain two bis-iboga alkaloids; bis( 11-hydroxycoronaridin-12-yl) 383 is already known and the new alkaloid obovatine is simply its monomethyl ether 384.118 In confirmation the methylation of 383 with diazomethane gives a mixture of obovatine and the dimethyl ether 385.NATURAL PRODUCT REPORTS 1996 vinblastine derivatives. The dimeric species 388 was first prepared by acid-catalysed condensation of (+)-eburnamine with 11-methoxytabersonine; oxidation at C-17 was then achieved by means of benzeneseleninic anhydride to give the p-alcohol 389 and the conversion to the vindoline substitution pattern as in 390 was completed as in the earlier synthesis of vindoline from 1 1 -methoxytabersonine (Scheme 53). 383 bis(l1-hydroxycoronaridin-12-yl) R' = R2 = H 384 obovatine R' = Me; R2 = H 385 bis(11-methoxycoronaridin-12-yl)R' = R2 = Me There is very little new work in the vinblastine subgroup to report. Atta-ur-Rahman et aZ. have discussed in some detail the synthetic work on vinblastine and vincristine up to 1992.13' The nitration of vincristine 386 gives a 7'-nitro derivative 387 together with the 9'-nitro and 11'-nitro derivatives.13 Interestingly reduction of the 7'-nitrovincristine 387 by means of sodium dithionite or sodium borohydride-palladium regenerated vincristine 386 (Scheme 52).Since 7'-nitro-vincristine has a very low toxicity in contrast to vincristine it is hoped that it will be possible to administer the 7'-nitro derivative and reduce it to vincristine at the site of the tumour to be attacked perhaps by a reductase enzyme; in this way serious side effects might be avoided. 6HO CO2Me 386 vincristine iili i CHO C02Me 387 Reagents and conditions i fuming HNO, AcOH CHCl, -20 "C; ii NaBH,-Pd MeOH; or Na,S,O,. Scheme 52 Further new analogues of vinblastine have been prepared; these include some noranhydrovinblastine derivatives1, and some 15'- and 2 1'-alkyl-20'-deoxyvinblastinederivatives.134 The structural elucidation and NMR chemical shift assignments of several navelbine (noranhydrovinblastine) derivatives have been rep0~ted.l~~ Danieli et aZ.'36 have investigated methods for the intro- duction of functional groups to C-17 in bisindole derivatives with the aim of developing new methods for the synthesis of (+)-eburnamine + i 11-methoxytabersonine C02Me 388 1 ii.iii iv v -Me0 Me0 390 389 Reagents and conditions i acid; ii benzene seleninic anhydride PhH 35 "C; iii 0, MeOH H,O Rose Bengal Na,S,O, NaOH; iv CH,O H,O NaBH,CN; v Ac,O py.Scheme 53 The bisignate circular dichroic curves of vinblastine and vincristine at ca. 210 and 220-230 nm have been shown to be due to exciton coupling between the indole and indoline moieties and a convenient means of estimating the preferred solution conformations of these alkaloids by a combination of X-ray crystal structure data with MM2 local energy minimization has been de~eloped.'~' 4 Biogenetically Related Quinoline Alkaloids 4.1 Cinchona Group In another demonstration of the synthetic value of (+)-norcamphor 88 the phthalimide derivative 94a prepared as illustrated above (Scheme ll) has been utilised in a new synthesis of (+)-N-benzoylmeroquinene aldehyde 391 (Scheme 54).43 Most of the new chemical work on the Cinchona alkaloids has been in connection with their use as resolving agents or co- catalysts in asymmetric reactions.2-Amino-2-deoxy-2-epicinchonine and 2-amino-2-deoxy-2- epiquinine* have been prepared from cinchonine and quinine respectively by Mitsunobu reaction with hydrazoic acid followed by reduction of the azides produced.13* The aim of this investigation was to prepare more effective co-catalysts in enantioselective reactions for use with low valent transition metals e.g. Rhl. The preferred conformations of dihydroquinidine in ether solutions have been determined following a combination of variable temperature NMR and CD spectroscopy and mol-* Biogenetic numbering. NATURAL PRODUCT REPORTS 1996J. E. SAXTON 94a ii 1 H 391 (+)-Nbenzoylmeroquinene aldehyde Reagents and conditions i KOH ButOH heat then acidify then CH,N ; ii NH,NH,.H,O CH,=CHCH,OH EtOH heat; iii LiAlH, THF; iv PhCOC1 K,CO,; v MeI Na,CO, MeCN H,O. Scheme 54 ecular mechanics calculations.139 However this seems to have little relevance to the alkaloid’s activity as a catalyst in asymmetric reactions since the energy barriers between the various conformations are very small. [Fluoro(hydroxyphenylphosphinyl)methyl]phosphonic acid 392 has been resolved by crystallisation of its (-)-quinine sa1t.l4O The laevorotatory diquinine salt 393 corresponding to (+)-392 was analysed by X-ray crystallography and found to contain the S-enantiomer of 392. This constitutes the first assignment of absolute configuration of an a-halomethylene pyrophosphate derivative.Other reports are concerned with the resolution of 1,l’-bis-2- naphth01l~l-l~~ and 9,9’-bis- 10-phenanthrol141 by means of N-alkylcinchonidinium halides. Polymers containing Cinchona alkaloids have been shown to catalyse the enantioselective cycloaddition of ketene and r OMe I JL 393 I 394 poly(quinidine-co-acrylonitrile) C-3 C-8 C-9 395a poly(acryloy1quinidine) R R S 395b poly(acryloy1quinine) R S R ~hlora1.l~~ Of the two polymers poly(Cinchona alkaloid-co- acrylonitrile) 394 and poly( Cinchona alkaloid-acrylate) 395 the latter was the more effective showing a similar catalytic activity and enantioselectivity to that observed with the monomeric alkaloids. The best enantioselectivity (94 YOee) in this reaction was exhibited by poly(acryloy1quinidine) 395a at a temperature of -30 “C.The reaction catalysed by 395a gave 396 with the R-configuration and when catalysed by 39513 gave 396 with the S-configuration. In all cases whether catalysed by 394 or 395 it appears that the configuration at C-8 in the Cinchona alkaloid determines the configuration of the product. The enantioselective hydrogenation of methyl pyruvate has been further Catalysis by iridium modified by cinchonidine or quinine yields the (R)-lactate in excess whereas catalysts modified by cinchonine or quinidine favour the formation of (S)-lactate. Wells’ ‘template model’ theory for the mechanism of this reaction has been critici~ed,~~~~ and Johnston and Wells have published a rejoinder refuting these criticisms.146b The enantioselective hydrogenation of (E)-a-phenylcinnamic acid over alumina- and titania-supported palladium catalysts modified with cinchonidine gives optical yields of 36.9 and 44.4 % respectively in favour of (S)-(+)-2,3-diphenyl-propionic The use of a solvent of higher dielectric constant results in higher enantioselectivity.Thus in dimethyl- formamide containing 10 YOof water and a 5 YOpalladium on titania catalyst an optical yield of 53% of (S)-2,3 diphenyl- propionic acid is C13C QO LL 396 397 398 399 The remaining papers devoted to the Cinchona alkaloids are concerned with enantioselective hydroxylation reaction^.'^^-'^^ Corey et have shown that the ligand 397 which contains one Cinchona alkaloid unit and an anthryl unit can catalyse the enantioselective osmium tetroxide hydroxylation of olefins as effectively as the ligand containing two Cinchona alkaloid units attached to the pyridazine ring owing to the very similar shape of the complexes.This supports Corey’s mechanism which postulates attachment of osmium tetroxide to N, of dihydro- quinidine with the alkene held in the binding pocket consisting of two parallel methoxyquinoline units or one methoxy-quinoline and one anthryl unit. Owing to the different rates of hydroxylation of enantiomers in the presence of these catalysts a kinetic resolution of alkenes can be achieved. Thus hydroxylation of (&)-3-buten-2-y1 4-methoxybenzoate 398 with osmium tetroxide and the 3a- diastereoisomer of 397 proceeds faster on the R(-)-enantiomer ; after incomplete reaction therefore the S( +)-enantiomer can be recovered.14’ Similarly after incomplete hydroxylation of ( -t)-1-phenyl-2-propen- 1 -yl 4-methoxybenzoate 399 the R(-)-enantiomer can be obtained. 400 401 Reagents and conditions :i K,OsO,. 2H,O DHQD-PYDZ-(S)-anthryl ligand (3a epimer of 397) 1 1 ButOH-H,O 0 "C. Scheme 55 The selective dihydroxylation of dienes with this reagent has also been accomplished. For example hydroxylation of 1,4-pentadien-3-yl 4-methoxybenzoate 400 gives the diol 401 in 70 YOisolated yield with 98 YOee (Scheme 55).149 The mechanistically designed bis-Cinchona ligand 402 has also been used successfully in conjunction with osmium tetroxide to hydroxylate the terminal isopropylidene unit in several terpenoid For example (2E 6E)-farnesyl acetate 403 gives the diol 404 in 80% yield (based on unrecovered material) with an ee of 96 YO.H -Ye-0 402 ,OAc fOAC 403 404 While Corey and co-workers have designed complex catalysts based on a central unit of pyridazine 397 or naphthopyridazine 402 other workers have followed Sharpless in using phthalazine attached to either dihydroquinine or dihydr~quinidine.'~~ Yet other b have concentrated on the development of polymeric catalysts for example poly(dihydroquinidine acry- late) poly(dihydr0quinidine 4-~inylbenzoate),l~~" or 3,6-(9-0- bisdihydroquinidy1)pyridazine immobilized on ethylene glycol dimethylacrylate polymer ba~kb0ne.l~~ 4.2 Camptothecin Camptothecin occurs in Camptotheca acuminata in up to 0.4% of the dry mass in young leaves,154 which is higher than that found in the seeds and bark the two current sources of the drug.As the leaves mature the yield of alkaloid decreases. It is suggested that the young leaves could provide an easily harvested non-destructive source of camptothecin. New extractions of the trunk bark of Nothapodytes foetida (Wight) Sleumer grown in the mountains of Tamil Nadu (India) have resulted in the isolation of camptothecin and 9-methoxycamptothecin together with five new alkaloids which were identified as mappicine 20-O-p-~-ghcopyranoside 405 mappicine 20-@/3-~-gentiobioside 406 17-hydroxymappicine NATURAL PRODUCT REPORTS 1996 20-O-p-~-glucopyranoside407 9-methoxymappicine 20-O-p- D-gentiobioside408 and the di-p-coumaroylspermidine ester of a camptothecin derivative now named foetidin 1 409.155The stems of a Taiwanese specimen of this plant have yielded camptothecin 9-methoxycamptothecin pumiloside and O-acetylcamptothecin which is ne~.~~~ R' FR2 %/ OAc 409 foetidin1 A technique involving high speed countercurrent chromato- graphy has been developed for the complete separation of camptothecin and 9-methoxycamptothecin contained in a dichloromethane extract of Nothapodytes foetida.15' A new two-stage method for the preparation of 10-methoxycamptothecin 410 from camptothecin required for conversion into the clinically useful derivative topotecan has been reported.15* Hydrogenation of camptothecin in the presence of a partly-poisoned platinum catalyst gives the tetrahydro derivative 411 which on oxidation by means of iodosobenzene diacetate in aqueous acetic acid gives 10-hydroxycamptothecin in very high yield (Scheme 56).If necessary this preparation can be carried out on a multi-kilogram scale. The conversion of 10-hydroxycamptothecin prepared independently from camptothecin into (20S)-9-aminocampto thecin 412 via 10-hydroxy-9-nitrocampto thecin 413 constitutes a more efficient partial synthesis of 9-aminocamptothecin than the method hitherto available (Scheme 56).159 Three new syntheses of camptothecin have been recorded recently. The most recent contribution from Comins et al.lS0 is a six-stage synthesis of (+)-camptothecin 414 in which 2- methoxypyridine is first converted into the important pyridone lactone 415 as shown in Scheme 57.The initially prepared lithium derivative 416 proved to be too basic to condense satisfactorily with enolizable a-ketoesters ; hence it was first converted into an organocerium derivative before condensation with a-ketobutyric ester. The product 417 was then reduced and hydrolysed with acid to give the lactone 415. Coupling of 4 15 with 2- bromo- 3-hydroxymethylquinoline itself prepared by an improved method was achieved by a Mitsunobu-type reaction to give 418 which was cyclized to (*)-camptothecin 414 by a Heck reaction. In a subsequent communication161 a new asymmetric NATURAL PRODUCT REPORTS 1996J.E. SAXTON synthesis of the enantiopure lactone 415was reported starting from 2-fluoropyridine7 and taking advantage of the whimsically- / I I ccly$ named 'halogen dance ' reaction. Of the two preparations reported the preferred one involved the conversion of 2-fluoro- fH0 0 __c /;lo 0 0 0 camptothecin 41 1 ii- 0 413 410 0 412 Reagents and conditions i H, Pt-C DMSO AcOH; ii PhI(OAc), AcOH H,O; iii HNO, H,SO,; iv RSO,Cl NEt, DMAP CH,Cl,; v Pd(OAc), DPPF HCOOH.NEt, 90 "C Ar dioxan. Scheme 56 QOMe 418 414 camptothecin Reagents and conditions i MeLi ii Me,NCH,CH,NMeCHO; iii BuLi; iv CeCI, THF -23 "C; v EtCOCO,Me -78 "C; vi Al(OPr'), Pr'OH; vii 1 mol dmP3 HC1 H,O; viii 2-bromo-3-hydroxymethylquinoline DEAD PPh, THF; ix Pd(OAc), KOAc MeCN.Scheme 57 3-iodopyridine into 2-fluoro-4-iodo-3-methylpyridine by the halogen dance reaction and condensation of the lithium derivative of the latter with the (-)-trans-2-(a-cumy1)cyclohexyl ester of a-ketobutyric acid which gave the chiral a-hydroxy ester 419 in 80% yield and 94% de. Functionalization of the methyl group was then achieved by free radical bromination the product 420was transformed into the corresponding acetate and the synthesis of enantiopure (+)-415was completed by saponification followed by treatment with acid (Scheme 58). 419 0 1. vii viii ~ c-zOAC vi z B r H 420 415 R = (-)-frans2-(a-cumyl)cyclohexyloxy Reagents and conditions i LDA; ii MeI; iii BuLi; iv EtCOC0,R; v NBS (PhCOO), CCI,; vi KOAc MeCOEt; vii NaOH; viii 3 mol dm- HCl.Scheme 58 The other two new syntheses of (20s)-camptothecin rely on the Sharpless asymmetric dihydroxylation procedure for the introduction of chirality. The route developed by Fang et aZ.162 involved the construction from 2-methoxypyridine of the pyrido-fused cyclic enol ether derivative 421a which was obtained together with its double bond isomer 421b,as outlined in Scheme 59. Fortunately the latter could be isomerized to 422 421a 421b 1 ix 0 0 H 423 415 Reagents and conditions i ButLi; ii MeN(CHO)CH,CH,NMe ;iii BuLi; iv I,; v HOCH,CH=CHMe Et,SiH TFA; vi Pd(OAc), K,CO, Bu,NCl DMF; vii (PPh,),RhCl; viii K,OsO,*.2H,O K,Fe(CN), dihydroquinidine-pyrimidine K,CO, MeSO,NH, 1:1 ButOH-H,O; ix I, CaCO,; x 1 mol dm- HCl H,O heat. Scheme 59 360 421a by means of Wilkinson's catalyst. Asymmetric dihydroxylation of 421a was achieved by use of potassium osmate and potassium ferricyanide in the presence of the dihydroquinidine-pyrimidine ligand methanesulfonamide water and tert-butyl alcoh01.l~~ The product 422 was oxidized in situ to give the lactone 423 with a de of 94%. Hydrolysis then gave the pyridone 415 which as noted above had previously been converted into (20s)-camptothecin by Comins et ai. The formal synthesis of (20s)-camptothecin owing to Jew et ai. takes the form of a new preparation of the tricyclic lactone 424,164and essentially constitutes a variant of the synthesis by Terasawa et ai.68aHere Terasawa's lactone 425 was reduced and dehydrated to the enol ether 426 which was then dihydroxylated by potassium osmate in the presence of the dihydroquinidine-phthalazine ligand165 to give the hydroxy lactol427 in 91 Oh yield.Direct oxidation of 427 to the desired hydroxyl actone could not be achieved in satisfactory yield ; hence the tertiary hydroxy group was protected as shown in Scheme 60. Oxidation by means of pyridine chlorochromate then gave the protected hydroxylactone 428 and acid hydrolysis then cleaved both the methoxymethyl ether and the acetal function to give the target tricyclic lactone 424. i ii __t __c Et--Et iii HO c% 427 OH 0 425 426 1iv-vi o%o Et--viii vii HO 0 0 OH 424 428 Reagents and conditions i DIBAL THF -78 "C; ii MsCl NEt, THF; iii dihydroquinidine-phthalazine K,Fe(CN), K,CO, K20sO;2H,0 MeSO,NH, 1:1 ButOH-H,O; iv Ac,O py; v MeOCH,Cl PfiNEt, CH,Cl,; vi K,$O, MeOH H,O; vii pyridinium chlorochromate NaOAc 4 A molecular sieves; viii HCI THF H,O 60 "C.Scheme 60 Numerous new derivatives of camptothecin have been prepared for pharmacological evaluation; in general the emphasis has been on procuring derivatives with increased water solubility. These include the trifluoroacetate salts of the piperazine derivatives 429 and 430 which exhibit potent inhibition of topoisomerase I as well as potent antitumour activity against a range of human tumour cell lines.166 All the novel hexacyclic derivatives 431 and 432 of camptothecin exhibited antitumour activity in vitro which was comparable or superior to that shown by 7-ethyl-10-hydroxy~amptothecin.~~' Other compounds which show prom- ising activity include the 7-aminoalkyl derivatives 433,16*the 7- acylhydrazonoformyl derivatives 434,169the oxazoio derivative 435,170several 7-ethylcamptothecin derivatives 43617' and two ring E-opened 7-ethylcamp to thecin derivatives 437.171 NATURAL PRODUCT REPORTS 1996 0 0 429 430 0 0 431a X=O 432 431b X=NH C-20 config.a R = OH; X = CH;! (RSand S) b R = Me; X = CH2 (S) c R=Me; X=O (RS) d R=Me; X=S (RS) e R=Me; X=NH (RS) f R=OH; X=O (RS) $H=NNHCOR 0 0 433 n= 1 or2 434 RCO = L-tyrosyl L-serinyl L-alanyl L-1 ~ptophyl / Et--HO 0 435 Et Et' 0 436 X Y a H F b OMe F c Me F d CI H e Br H f Me H gh H F CI F NATURAL PRODUCT REPORTS 1996-5.E. SAXTON ? Et--HO+O NHCH2CH2NMe2 437a X = Me; Y = H; R = C&CH2SMe 437b X=H; Y=F; R=Et Fortunak et al. have prepared several mappicine ketones by thermolysis of the parent camptothecin while other have preferred to prepare them by total synthesis. 5 References 1 The Monoterpenoid Indole Alkaloids ed. J. E. Saxton Wiley- Interscience Chichester New York 1994. 2 (a) M. Lounasmaa in Studies in Natural Product Chemistry vol. 14:Stereoselective Synthesis part 1 ed. Atta-ur-Rahman Elsevier Amsterdam 1994; (b) S.Sakai in Studies in Natural Product Chemistry vol. 15 ed. Atta-ur-Rahman Elsevier Amsterdam 1995. 3 K. Stratmann R. E. Moore R. Bonjouklian J. B. Deeter G. M. L. Patterson S. Shaffer C. D. 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ISSN:0265-0568    

DOI:10.1039/NP9961300327

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Hot off the Press Robert A. Hill' and Andrew R. Pitt2 Department of Chemistry Glasgo w University Glasgo w G 12 800,UK. E-mail bobh@chem.gla.ac.uk Department of Pure and Applied Chemistry Strathclyde University Thomas Graham Building 295 Cathedral Street Glasgo w G I IXL UK. E-mail a.r.pitt@strath.ac. uk Reviewing the recent literature on natural products and bioorganic chemistry The study of marine organisms continues to produce natural products with interesting structural features and biological properties. The unusual symmetrical dimeric diketopiperazine 1has been found in the starfish Pentantaceraster regulus (A. S. R. Anjaneyulu J. Chern. Res. (S). 1996 50). The authors suggest that the diketopiperazine 1 may been derived by dimerisation of two cleaved cyclo[alanyl-3-hydroxyprolyl] units.Faulkner's group have reported the isolation and characterisation of the first glucopeptidolipids from a marine source (J.Am. Chern. Soc. 1996 118 4314). The aciculitins such as 2 have been isolated from Aciculites orientalis. 0 0 1 CONH2 I ,OH HN I HN-N OH OwNH Leucascandrolide A 3 from a calcareous sponge (Leuca-scandra cavenlata) is a macrolide with an unusual side chain which shows powerful antifungal and cytotoxic properties (F. Pietra and co-workers Helv. Chim. Acta 1996,79,51). Focardin 4 and its 14,15-epoxide epoxyfocardin are representatives of a new diterpenoid skeletal class from the marine ciliate Euplotes focardii from the coastal waters of Antarctica (F. Pietra and co- workers Helv.Chim. Acta 1996 79 439). Suberosene 5 from Subergorgia suberosa is the first sesquiterpene with a quadrane skeleton to be isolated from a marine source (H. R. Bokesch et ... 111 al. Tetrahedron Lett. 1996 37 3259). Previously quadranes have only been isolated from the fungus Aspergillus terreus. 3 H& ... 0 H 4 5 Torreyanic acid 6 an unusual cytotoxic dimeric quinone has been isolated from the endophytic fungus Pestalotiopsis rnicrospora,the pathogen likely to be responsible for the decline of the Florida torreye (Torreya taxifolia) (J. C. Lee et al. J. Org. Chern. 1996 61 3232). The postulated biosynthesis is via a Diels-Alder dimerisation of two quinones (Scheme 1). Valinoctins A 7 and B 8 are farnesyl protein transferase inhibitors from Streptomyces strain MJ858-NF3 (R.Sekizawa et al. J. Nat. Prod. 1996 59 232). Their structures were confirmed by synthesis and X-ray analysis to be N-(3-amino-2- hydroxyoctanoy1)valine 7 and the corresponding 6-methyl analogue 8. Laccarin 9 is a metabolite of the mushroom Laccaria vinaceoavellanea that has a structural resemblance to tenuazonic acid (M. Matsuda et al. Heterocycles 1996 43 685). Laccarin 9 shows inhibitory activity towards cyclic-AMP phosphodies terase. 6 Scheme 1 7 R=H 9 8 R=Me The unusual bisfuranone phamiceroside 10 has been isolated from Juniperusphanicea together with psydrin 11 and phamicein 12 (A. J. Chulia and co-workers Tetrahedron Lett. 1996 37 2955). It is not clear whether pheniceroside 10 is produced biogenetically or is an artefact of the isolation procedure since phamiceroside 10 was isolated as a mixture of diastereoisomers and can be prepared from a mixture of psydrin 11 and phenicein 12 by treatment with diethylamine at room tem- perature.Soyasapogenol G 13 from Melilotus messanensis contains a cyclic carbonate (F. A. Macias et al. Phytochemistry 1996 41 1573). This is the first report of a naturally occurring cyclic carbonate. 11 12 10 A wide ranging review of enzyme mechanisms models and mimics has been published (A. J. Kirby Angew. Chem. Int. Ed. Engl. 1996 35,706). The incorporation of l80,into aflatoxin B 14 in Aspergillus parasiticus generated three labelled oxygen atoms (C. M. H. Watanabe and C.A. Townsend J. Org. Chem. 1996,61,1990). The labelling pattern is consistent with the previously proposed two Baeyer-Villiger type oxidations in the early part of the pathway and a mechanism is proposed for the final oxidative cleavage. M. Rohmer et al. have confirmed the presence of a non-mevalonate pathway to isoprenoids by studying the in- corporation of I3C labelled glycerol and pyruvate into Escherichia coli ubiquinone Q8 (J. Am. Chem. Soc. 1996 118 2564). Glycerol is incorporated as a C unit whereas pyruvate is the source of the remaining two carbons. O* R II 14 E. J. Corey’s group (Tetrahedron Lett. 1996 37 2709) has provided more evidence for a ring-C expansion step in sterol NATURAL PRODUCT REPORTS 1996 biosynthesis.The C, truncated 2,3-oxidosqualene analogue 15 forms a mixture of tricyclic products such as 16 which implies the involvement of the cation 17. Higher plants convert 1-aminocyclopropane-1-carboxylic acid into the growth regulator ethylene. It has been shown that lower plants such as liverworts and ferns do not use l-aminocyclopropane-l-carboxylicacid for the production of ethylene (D. J. Osborne et al. Phytochemistry 1996 42 51). The pathway for the production of ethylene in lower plants now awaits discovery. 17 15 / f 16 Saccharomyces cerevisiae has been successfully engineered to express the Acinetobacter sp. cyclohexanone monooxygenase (J. D. Stewart et al. J. Chem. SOC.,Perkin Trans. 1 1996 755). The useful easily-grown ‘designer yeast’ performs enantio- selective Baeyer-Villiger oxidations (Scheme 2) with ee’s in excess of 98 %.A Pseudomonas species has been shown to convert medium- and long-chain alkanoic acids into poly(3- hydroxyalkanoates) (Y. Doi and co-workers Bull. Chem. SOC. Jpn. 1996 69 515). Different polymer mixtures were formed depending whether the alkanoic acids had odd or even numbers of carbons. The results suggest that there are two types of poly(3-hydroxyalkanoate) synthase present in the Pseudo-monas species which have different substrate specificities. 0 ’designer yeast’ R R s (4 Scheme 2 Directed random mutagenesis of a farnesyl diphosphate synthase gene by S. Ohnuma et al. (J. Biol. Chem. 1996 271 10087) gave rise to a geranylgeranyl diphosphate synthase.Characterisation of the clones suggests that a tyrosine in the active site may be responsible for controlling chain length in farnesyl diphosphate synthase by blocking further elongation. Targeted random mutagenesis has been used by Hilvert’s group to examine the mechanism of chorismate mutase (J. Am. Chem. Soc. 1996 118 3069). The results agree with the proposal that Glu-78 is involved in generating an electrostatic gradient at the active site as a major factor in the catalysis. Moniliformin 18 (a fungal toxin from Fusarium moniliforme) has been shown to be a time dependent inhibitor of thiamine cofactor utilising enzymes (M. C. Pirrung et al. J. Org. Chem. 1996,61,2592). It has been postulated that it acts as a pyruvate mimic which then rearranges to forms a stable spirocyclic species (Scheme 3).An extensive examination of the X-ray structure of acetylcholinesterase with the inhibitor m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone 19 has NATURAL PRODUCT REPORTS 1996-HOT OFF THE PRESS allowed the estimation of the contribution of the individual parts to the overall binding energy (M. Hare1 et al. J. Am. Chem. SOC.,1996 118 2340). The geometrical convergence of the protein-ligand interactions in the binding site of the enzyme appears to be mainly responsible for the strong binding. thiamine diDhosDhate n 18 ‘OPP Scheme 3 0 19 A short efficient synthesis of (2S)-O-phosphohomoserine 20 an intermediate in threonine biosynthesis (Scheme 4) and its C-2 and C-3 deuterated analogues has been reported by F.Barclay E. Chrystal and D. Gani (J. Chem. SOC.,Perkin Trans. I 1996 683). The synthesis from dimethyl acetylenedi- carboxylate uses P-methyl aspartase to introduce the chiral centres. The kinetic isotope effect of the deuterated substrates with threonine synthase suggest that the removal of protons from both C-2 and C-3 are kinetically important. ternary complex between enolpyruvylshikimate-3-phosphate synthase shikimate-3-phosphate and the inhibitor N-(phosphonomethy1)glycine (glyphosate) (L. M. McDowell et al. Biochemistry 1996,35,5395). It appears that the glyphosate does not bind in the same fashion as phosphoenolpyruvate suggesting that it does not act as a transition state analogue as previously thought.A uracil dimer with a covalently attached flavin 21 has been synthesised which acts as a mimic of DNA photolyase and undergoes light induced cleavage of the cyclobutane ring (T. Carell et al. Angew. Chem. In?.Ed. Engl. 1996 35,620). 21 A. M. Westley and J. Westley have reported a mathematical investigation of the behaviour of reversible dead-end inhibitors in open systems a realistic biochemical model where there is constant input of substrates and removal of products which indicates that uncompetitive inhibitors may be far superior to substrate competitive inhibitors as enzyme inactivators (J. Biol. Chem. 1996 271 5347). This goes against the generally th reon ine accepted design criterion for pharmacologically active com- synthase ____t pounds. H2Nv-0p032- H02C HO& The directionality of sulfur hydrogen bonding has been 20 investigated by calculation and examination of the Cambridge Scheme 4 crystallographic database (J. A. Platts et al. J. Am. Chem. Soc. 1996 Z18 2726). Calculation agrees with the crystallographic REDOR and DRAMA solid state NMR techniques have data that the bonding is significantly different to oxygen with been used to probe the geometry of the ligands in the stable the sulfur preferring a more perpendicular bond.

ISSN:0265-0568    

DOI:10.1039/NP996130iiid

出版商:RSC    

年代:1996

数据来源: RSC