4 Aliphatic and Alicyclic Chemistry By PETER QUAYLE Department of Chemistry University of Manchester M 13 9PL UK Introduction As stated in the last report the interplay between scientific disciplines becomes ever more apparent and again features heavily this year. In some quarters this interplay is regarded with suspicion as it is believed that it represents an erosion of the standing of the synthetic organic chemist within the scientific community at large. However this reviewer believes that such collaborations will provide fertile areas of research in which the traditional skills of the synthetic chemist can be used in tandem with other disciplines to provide a rational basis for the design and manipulation of complex systems. Such collaborations will hopefully generate new methodology which can then be applied to the more traditional areas of interest.A number of key papers have appeared this year which nicely illustrate this point. Bio-organic Chemistry The use of enzyme systems as reagents for organic synthesis is by no means a novel concept. Traditionally their utilization in organic synthesis has been primarily concerned with stereoselective transformations and is now relatively widespread.’-3 More significant however is the approach adopted by a number of interdisciplinary research groups who have by recombinant genetic engineering techniques begun to manipulate the enzyme systems themselves i.e. to prepare ‘tailor-made’ systems in order to divert natural biosynthetic pathways. The application of molecular biology to enzyme manipulation presents a number of exciting possibilities especially for the synthesis of ‘designed’ natural products which may have useful biological properties and therefore has far ranging implications in the pharmaceutical industry.This approach to ‘natural product’ synthesis is exemplified in the isolation of the novel tetracenomycin (1) by diversion of the normal polyketide assembly path~ay.~ The application of modern analytical techniques new developments in combinatorial synthesis’ and traditional synthetic methodology have enabled a number of groups to gain further insights into protein structure and protein-ligand ligand recognition by E-selecting and DNA binding of oligosaccharides. loAn understanding of such interactions is of prime importance for the development of new therapeutic agents.l1 Olefin Metathesis Olefin metathesis reactions have been extensively investigated by polymer chemists as a means of preparing polymeric systems from simple olefins.It is not until recently 73 Peter Quayle however that well characterized and highly efficient metathesis catalysts such as (2) have been described and in-depth investigations of their metathesis chemistry been undertaken.12 The potential utility of olefin metathesis in natural product synthesis as opposed to polymer synthesis is enormous but impossible to realize until the development of metathesis catalysts tolerant to polar functionality and which are also readily prepared using relatively unsophisticated anaerobic experimental procedures.Pioneering work from Grubbs' groupI3 has established that the stable but metatheti- cally active complexes such as (2) are readily prepared from simple intermediates with the result that a number of groups have begun to investigate their synthetic chemistry.14.15 A most striking feature of catalysts such as (2) is their degree of functional group tolerance in ring closing metathesis reactions (RCM). This type of reaction has been successfully applied to the synthesis of five-16 six-17 seven-18 and even in certain circumstances eight-membered rings,lg Scheme 1. Heteroatoms (e.g.N and 0,P) and polar functionality e.g. N-H bonds are also accommodated.20 Nugent and co-workers have demonstrated that the closely related catalyst system (3)enables metathesis of the diene (4)to the cyclopentene (5) on a multi-gram scale and with complete retention of optical activity Scheme l.17 Two further examples the preparation of a 'peptide cylinder' (6) by Clark and Ghadiri2' and the application of RCM to the synthesis of the macrocyclic lactam (7) by Hoveyda and co-workers22 clearly demonstrate the potential of this new technology to complex synthetic undertakings Scheme 2.The application of metathesis-type reactions in an inter-molecular sense is at present less well developed although initial investigations by both Grubbs and co-~orkers~~ indicate that such processes and Snapper and co-~orkers~~ provide a viable alternative to existing olefin syntheses. C-H Activation Catalytic C-H activation is the Holy Grail of organometallic chemistry and has many potential applications in organic ~ynthesis.~'-~' Recent results26 from Murai's group have convincingly demonstrated that C-H insertion of aryl ketones can be achieved under mild conditions using catalytic [Ru(H),(Ph,P),(CO)] (8).Furthermore reaction of the derived organometallics (9)with a variety of olefins and acetylenes to AIiphatic and Alicyclic Chemistry 0 BubKN (2) (Ref. 16) TH PhH,room temp: 92% 'OH -'"0 [cat.] (Ref. 17) 90"C 64% (99% ee) [cat.] = PhH 25 "C 99% [ Ref. 19(a)] RJ H OBn ,OBn / Qp-Qo 77% [Ref. 19(b) J yv I COCF3 COCF3 H I ( Ref. 20) I H ( Ref. 17) (4) (5) Scheme 1 Peter Quayle Covalent capture (Ref.21) Scheme 2 the formation of a variety of functionalized aryl ketones Scheme 3. Of note is the observation that the insertion-coupling sequence is catalytic in the complex (8). Although extensive investigations have yet to be reported these results nevertheless suggest that catalytic C-H insertion-coupling sequences may be relatively general as clearly demonstrated in an application of this methodology to C-H insertion of functionalized olefinic substrates as recently reported by Tr~st,~' Scheme 4.In a related series of experiment^,^^ Murahashi and co-workers have also shown that the complex (8)catalyses aldol and Michael reactions of nitriles with aldehydes and x,b-unsaturated Aliphatic and Alicyclic Chemistry (9) (Ref.28) [Rul + Y Si(OEt)3 H3 i cat. (8) t +cH3 (Ref. 29) NMe2 NMe2 + 85% @Si(OEt)3 ii (8) -(Ref. 30) + Si(OEt)3 @Si(OEt)3 -quantitative ____t iii (8) Et& + (Ref.31) '& \ 73% 27% + \ (9) Scheme 3 Reagents and conditions i PhCH, 135 "C 8 h; ii PhCH, 175 "C 1 h; iii PhCH, 135"C 4 h Peter Quayle C\02C2H5 i (8),ii 0 (Ref. 32) X-qo c ko pSi(0Et)s Scheme 4 Reagents and conditions i PhCH, 135"C (70%);ii H202 KHCO (63%) CN C02Et Ro2c+co2Et + 54%-(8) CH3 Scheme 5 carbonyl functionality respectively Scheme 5. Further investigations primarily with respect to 'fine-tuning' of the catalyst systems currently employed will hopefully expand the general utility of these transformations.General The development of new methodology for asymmetric synthesis continues to grow exponentially3L43 as do various applications of organ~metallics~~~' and heterogen- eous catalysis72 in organic synthesis. Carbohydrate chemistry poses many challenges to the synthetic organic chemist,73 although in recent years significant advancements in oligo- and poly-saccharide synthesis have been reported.74 Emerging technology in this area e.g. polymer-supported solution synthesis73 will doubtless be avidly scrutinized by workers in the field. Ho~t-guest,~~ molecular supra-molecular chemistry," including novel polymers' 'and multidisciplinary approaches aimed at understanding the role and synthesis of enzyme analogues again featured heavily.'* In related areas the synthesis of 'receptors' capable of enantioselective discriminationg3 or recognition of specific sugarss4 has been realized.Fullerene chemistry continues to grasp the imagination of chemists across the whole spectrum of the disciplines5 and has for example led to the synthesis of azafulleroids.86 Likewise the chemistry of enediynes continuesg7 to attract much attention from synthetic and mechanistic chemists. A timely overviews8 of combinatorial approaches to synthesis presents a rational view of one of the more frenzied areas of contemporary synthesis whereas articles on 'two-directional' ~ynthesis'~ and the use of tandem or cascade reactions in synthesisg0 discuss advances in more traditional aspects of the subject.The chemistry of oxyster~ls,~' acetogeninsg2 and oligotetrahydrof~rans,~~ antisense nu~leotides,'~P-la~tams,'~ fungal metabolite^,^^ duocarmycins,97 oxetan-2-0nes,'~ Aliphatic and Alicyclic Chemistry 0 A Hi' OH I Me.. Figure 1 80 Peter Quayle 2 \ \ C6H13 0 I 0x C6H13 93% liv (Ref. 112) Scheme 6 Reagents and conditions i AD-mix /3 (91%); ii SOIm, THF; iii RuCl, NaIO (82%); (iv) CH,CN-H,O 80 "C inositol~,~~ and organofluorine compounds"' have been reviewed in detail. The art of organic synthesis is embodied in the achievements of Gilbert Stork who for fifty years has been a master of his craft."' A splendid compilation'02 of reports on natural product synthesis has also appeared.Contrary to popular belief the development of new synthetic methodology should remain a paramount consideration as present day methodology is still lacking in terms of chemoselectivity as illustrated by the requirement to develop sophisticated protection-deprotection strategies in complex synthetic undertakings. '03 The total synthesis of complex natural products is now a relatively common event and this year has been no exception. Representative examples (Figure 1)include the synthesis of brevetoxin (10),'04 dynemycin (1 l),'" Taxol(12) milbemycins G 1069107 (13)''* and B, (14),'" sLeX tetrasaccharide glycals (15)"' and a full report"' on the total synthesis of rapamycin (16). The current drive to develop cascade processes in order to simplify the total synthesis of complex natural products is nicely demonstrated by Rychnovsky's polyepoxide-type cyclizations (utilizing Sharpless's asymmetric dihydroxylation methodology),' ' Scheme 6 and Eyrisch and Fessner's synthesis of dissacharide mimics which incorporates tandem enzyme-mediated aldol reactions,' '' Scheme 7.3 Aliphatic Chemistry Oxidations Sharpless-type dihydroxylation reactions continue to gain favour for the enantioselec- tive functionalization of alkenes.' 'u2'Care should be taken when invoking the Aliphatic and Alicyclic Chemistry HO -___ti "OhoH w " O W O H (Ref. 113) OHC CHO ii HE*: HO ii CHO ] OH OH OH R = PO:-iii( R = H Scheme 7 Reagents and conditions i 0,-MeOH -78 "C Me,S room temp.; ii 1.0 equiv.FBP FruA (500U) triosephosphate isomerase (500U) pH 7.2 7 days 40% conversion; iv acid phosphatase (50U) pH 5.8 16h i w R2 R3 >%yo (Ref. 123) RlxsiMe2R4 n ii -(Ref. 124) g C02Me 84% MOMOC02Me 85% Scheme 8 Reagents and conditions i DMDO acetone 20°C; ii DMDO CH2C1,-acetone; iii BF,-OEt,; iv DMDO acetone 0 "C empirical paradigm used to predict the stereochemical outcome of such reactions as to be expected in certain cases anomalous results have been reported.'22 Dimethyl- dioxirane (DMDO) and its derivatives continue to find applications for the chemoselective o~idationl~~-~~' of sensitive substrates Scheme 8. The in situ gener- Peter Quayle cF3 OMe H -~ i (Ref.128) \ CH3 0 80% (20% se) via Scheme 9 Reagents and conditions i KHSO, pH 7.5 CT".. 'CH3 98% Scheme 10 ation of the chiral non-racemic derivative (17)has been reported thus far epoxidations of prochiral alkenes with this reagent proceed with only modest levels of asymmetric induction (12-20% ee) Scheme 9.'" It is anticipated that these findings will serve as a catalyst for the development of more efficient and more discriminating enantioselective oxygen-transfer agents. Recent mechanistic investigations point to the intermediacy of free radical species during related oxidations using these reagent^.'^' The search for 'cleaner' (i.e. environmentally friendly) reagentsI3' has resulted in renewed interest in the development of hydrogen peroxide as a chemical reoxidant for a variety of catalytic oxidation rea~ti0ns.l~' Most notable are the reports concerning the use of an MTO-H,O system which appears to have much potential as a selective oxidizing agent for organic synthesis Scheme The use of a relatively innocent silicon A1ipha t ic and Alicyclic Chemistry &SiMe2Ph t c Oyo'n.0-/SiMe2Ph lii 71% OH 60%1v vi (Ref.135) Ph Scheme 11 Reagents and conditions i BF *OEt, CH,Cl, -78 "C; ii AcOOH Hg(OAc), AcOH; iii PhSeC1 Et,O -60°C; iv Bu,SnH AIBN PhH; v F- vi H,O ,-K F moiety as a masked OH group has been exploited to good effect this year. This methodology should gain further acceptance with the development of more versatile unmasking procedures Scheme 11.' 33-136 Corey and Palani have developed a simple method',' for the direct conversion of diols into lactols a transformation which until now required a multi-step sequence.Pflatz and co-workers have dem~nstrated',~ that cyclic alkenes can be converted directly into allylic benzoates with respectable levels of asymmetric induction (up to 82% ee) when reacted with PhC0,Bu' in the presence of chiral copper(1) complexes Scheme 12. Reich selenoxide elimination is recognized as one of the most valuable alkene- generating reactions. Note however should be made of subtle steric and/or electronic effects which may be operative in certain cases which can lead to either unexpected products'39 or enhanced levels of regiocontrol'08 in the synthesis of unsymmetrical alkenes Scheme 13.Peter Quayle 64% (77% ee) (Ref. 138) Scheme 12 Reagents and conditions i PhCO,Bu' Cu'OTf (5mol%) L* (6-8 mol%) ace tone C02Et qO2Et -(Ref. 108) HO CH3 HO OH OH OH 40 60 C02Et q02Et q02Et ____) BU'O~H 92% jQ jQ HOQCH3 SePh HO HO OCO,CCI3 RO OR 7 1 Scheme 13 Reagents and conditions i KOH-H,O,-MeOH Reductions Asymmetric catalytic hydrogenation reactions continue to be developed for the synthesis of a variety of useful synthetic intermediates. 140-144 Buchwald and co- workers have developed a catalytic method for the reduction of lactones to lactols Scheme 14,145whilst a versatile reducing reagent [LiH-Bu'OH-Ni(OAc),] prepared by activation of commercial lithium hydride has been reported by Fort.'46 Chirally modified boranes again have been used to good effect for the enantioselective reduction of prochiral or ('quasi' prochiral) carbonyl compounds Scheme 15.'47-'50 Finally catalytic hydrogenation of aromatic substrates provides access to polyalkylated cyclohexanes which are themselves of some synthetic utility Scheme 16.15' Aliphatic and Alicyclic Chemistry -BnoBOH Oxo CH3 \ CH3 CH3 CH3 \ CH3 CH3 94% 89% 94% ?oc ?OC 92% 'Ti complex' = [Ti+OoC1)2 Cpp] Scheme14 Reagents and conditions i 'Ti complex' (2 mol%) TBAF-Al,O (1mol%) PMHS PhCH, 20°C Ph Ph d C H 3 &OH i ,,h%r(0.1equiv.) H-B:OO0 (1.1 equiv.) 1 th ,-i+ ii H30+ (Ref.147) 82% ee 100% yield NHZ NHZ (SO% 2 95%de) Scheme 15 Peter Quayle Scheme 16 Reagents and conditions i Raney-Ni H + PhSnC13 -+ Pd" (Ref.153) Pd" + PhSnC13 -phwco2H Brwco2H (Ref. 154) I I H H 79% B(W2 \ 6 ox1' Pd" + R Scheme 17 Coupling Reactions R (Ref. 155) The direct synthesis of ketones from acyl bromides and Grignard reagents can be achieved' 52 in the presence of [Ni(dppe)CI,] [dppe = ethylenebis(dipheny1phos-phine)]. Palladium-mediated coupling reactions continue to dominate catalytic processes for C-C bond formation. The use of hydroxystannanes in aqueous Stille-type reactions palladacycles as modified catalysts high pressure techniques water soluble palladium catalysts vinylsilanes solid phase synthesis and immobilized palladium Aliphatic and Alicyclic Chemistry X X (trace) + X ii 'Uo OH PhP (Ref.161) Scheme 18 Reagents and conditions i [Pd(Ph,P),] (Pr'),NH CuI-THF; ii Ph,P (3 equiv.) [(Ph,P),Pd] (Pr'),NH CuI (0.01equiv.) THF 120"C catalysts are all apparently advantageous under certain conditions. l5'-l6' Note should be made however of potential problems which can be encountered when using such reactions as depicted above where preferential migration of a phenyl group from the ligand system to substrate occurs. 16' Nevertheless palladium-mediated cross coup- lings are exceedingly useful as exemplified above,' s ,-' 5,'62 Schemes 17-20.A seminal contribution from Falck et a!. underscores the potential of Stille-type coupling reactions at sp3 hybridized C-Sn bonds Scheme 20.'62d Aldol and related methodology is of major importance to organic synthesis; given this pre-eminence it is a little surprising that our understanding of 'simple' salt effects in such processes are still somewhat empiri~al.'~~-'~' Gallagher Lichtenhaler and co-workers have prepared well behaved sugar-derived enolates and found them to undergo a number of useful akylation reactions Scheme 21.'66 4 Alicyclic Chemistry Cyclopropanes A pleasing aspect in recent years has been the revitalized interest in the preparation of novel structures with a view to probing bonding theories and the design of new materials.For example Volhardt and co-workers have rep~rted'~' the preparation of the first [2.1.2.1.2.l]hexaannulene (19)from the cyclohexatriene (18).The hexaannu- Peter Quayle [Ref.162(a)] &J n = 6 24% n = 8 16% 0 0 [Ref. 162(b)] 71% 70% e-;" / Bu Bu 43% Scheme 19 Reagents and conditions i CO (1 atm); [C12Pd(PPh,),] (5mol%) Et,N Pr'OH 75°C lene (19) exhibits remarkable thermal (stable > 200 "C) and chemical stability. Diederich and co-workers have reported168 the synthesis of a number of radialenes (20) which possess interesting redox properties and Gleiter et al. have reported the preparation of the C5.5)biscyclopropanyliumphane (21) a new class of cyclophanes containing 2n-Hiickel aromatic^.'^' Most intriguing is the report by bio-organic chemists at MIT who have conclusively dem~nstrated"~ that the inactivation of thiamine hydroxylase by 5-ethynyluracil results in the formation of an unusually stable norcaradiene (22).The first synthesis of a marine sterol containing a cyclopropene Aliphatic and Alicyclic Chemistry [Ref. 162(d)] Scheme 20 Reagents and conditions i CuCN (8mol%) THF 80 “C -0 OBz (Ref. 166) OH -100% yield (8:l mixture of diastereoisomers) Scheme 21 Reagents and conditions i Zn-Cu THF -35 “C moiety has been reported by Wicha and co-workers Scheme 22.’” The isolation of FR-900848 has stimulated much interest in the development of reliable methodology for the enantioselective synthesis of cyclopropanes. Most work in this area has centred upon developing enantioselective/diastereoselectivevariations of the Simmons-Smith reaction as demonstrated by the work of Barrett and co-~orkers,”~ Armstrong and Ma~rer,”~ Scheme 23.In a characteristically detailed andTheberge and Zer~her,’~~ investigation Denmark et al. have studied17’ the effect of a variety of C,-symmetric ligand systems upon the enantioselectivity observed in the catalytic Simmons-Smith Peter Quayle (Ref. 170) C02H 0 &x { -CH2 H 0 (22) reaction (Scheme 24) whilst Charette and C6te have demonstrated the synthetic utility of their auxiliary-based Simmons-Smith methodology in the enantiodivergent syn- thesis of all four isomers of coronamic acid Scheme 25.58,176 Contamporaneous reports by Hoberg and B02ell'~~ and Nagarajan and co-i-iii (Ref. 171) A OMe Scheme 22 Reagents and conditions i CHBr,-NaOH; ii MeLi-Et,O -78 "C;iii MeI -78 "C Aliphatic and Alicyclic Chemistry /94% \ 100% Me2 N C,OdCO N M e2 Me2NCh,CONMe2 cat .1 = cat.2 = O\/ o\B/o I I Bu Bu Scheme 23 Reagents and conditions i Zn (CH21)2 CH2C12 0-25"C7 cat. 1; ii Zn(CH,I), CH2C1, 0-25"C7 cat. 2 + EtsZn + CH212 -i (Ref. 175) ph* OH phqOH 80% ee NHS02R cat. = 'NHSO~R Scheme 24 Reagents and conditions i CH,Cl, -25 "C cat. workers178 describe the preparation of 172-cyclopropanated sugars which themselves prove to be useful synthetic intermediates Scheme 26. Doyle Martin and co-workers have continued to probe the intricacies of intramolecular asymmetric cyclopropana- tion reactions using chirally modified rhodium catalysts.' 79 An elegant extrapolation of this chemistry has resulted in the development of a novel macrocyliz- Peter Quayle BnO OH (Ref.176) Scheme 25 RO' OR (Ref. 177) ca. 80% OAc Scheme 26 Reagents and conditions i Et,Zn CH212 Et,O or toluene; ii 40% TMSOTf TMSCN CH,CN; iii CHCl, 50% aq. NaOH BnEt,NCI; iv LiAlH, THF ation-cyclopropanation strategy as outlined in Scheme 27.180 Finally White and Jensen have validated the Corey-Brash cascade hypothesis for marine prostanoid biosynthesis in their total synthesislS1 of constanolactones A and B Scheme 28. Cyclobutanes Substituent effects in electrocylization reactions leading to cyclobutenes continue to generate interest. For example electrocyclization of the silicon-substituted allene (23) generates (24) in high yields (990/)under relatively mild conditions (toluene 145"C 2 h) whereas electrocylization of the unsubstituted compound (25) results in the Aliphatic and Alicyclic Chemistry cHTH3 (Ref.180) Scheme 27 SnC14 MeN02 C02H 1.5 h 0 "c HO\/e-.-47% /+ (Ref. 181) J % J Takai coupling HO Scheme 28 isolation of a mixture of (25)and (26) (as a 19:8 1 mixture) only after prolonged reaction times and under much more forcing conditions (360"C; 19 h) Scheme 29.lS2Vollhardt and co-workers have succeeded in preparing the C,-symmetric [7]phenylene (27) the largest member of its class yet prepared.18 Of note is that the central six-membered ring of (27)is completely bond localized (1.326 and 1.509A).Photochemical methods of cyclobutane formation are already widely utilized and two new this year will doubtless expand this methodology.Toda et al. have reported'84 that photoirradiation of a suspension of the inclusion compound (28) in water affords the [2 + 21 adducts (29) Peter Quayie pPh SiMe3 i 99% -SPh SiMe3 (Ref. 182) iii --(25) (26) 19 81 Scheme29 Reagents and conditions i PhMe 145 "C 2 h 99%; ii Bu,NF THF-H,O 70 "C; iii 360 "C 19 h in acceptable chemical yield (32-90%0) and more importantly in optical purities approaching 100%ee Scheme 30. Hoffman and Pete have described a formal "2 + 21' cycloaddition reaction of salicylate ethers which in one step generates the tricyclic system (30) in moderate to good isolated yield (35-80%) Scheme 31.185 Padwa et al.have demonstrated that the readily available dienes (31a,b) undergo a variety of [2 + 21 cycloaddition reactions affording a general route to a number of polycyclic cyclobutane-containing systems Scheme 32. lS6 Finally Olah and co-workers have provided the first experimental evidence for the generation of cubylcarboxonium ions such as (32). lS7 Aliphatic and Alicyclic Chemistry 95 90% (Ref. 184) PhbOH Ph (28) (29) 'Ph 100% ee Scheme 30 R (Ref. 185) Scheme 31 (Ref. 186) Cyclopen tanes The synthesis of cyclopentanes via the 5-exo-trig cyclization of carbon-centred radicals is now a well established method and numerous examples of this type of cyclization have again been reported this year.'88 A nice exemplification of Nugent's under- utilized reductive epoxide opening-olefin capture sequence is presented in Clive and Peter Quayle 0 I H H ii iii (Ref.189) I OH " \ Scheme 33 Reagents and conditions i MCPBA CH,Cl, 0°C; ii Cp,TiCl THF 20 "C; iii H30+ Magnuson's synthesis of ( f)-ceratopicanol Scheme 33.' 89 The first report of a radical cyclization onto a chromium bound aromatic substrate has also been describedlgO this year Scheme 34. The reductive cyclization of enones catalysed by titanocene complexes adds further credence to the potential of such processes in organic synthe~is.'~'*'~~ Recent practical improvements associated with the Pauson-Khand reaction indicate that it will no longer remain a curiosity but will increasingly be adopted as a viable method for the synthesis of functionalized cyclopentenones as (Scheme 35);'93-'95 in certain cases the adoption of [Mo(CO),] rather than [Co,(CO),] as the source of the 'CO' moiety may be ~referab1e.l~~ In a related sequence bis-acetylenes have been 97 Aliphatic and Alicyclic Chemistry OH (Ref.190) CH3-z:,0cH3 H H3 OCH3 Scheme 34 Reagents and conditions i SmI, THF; HMPT Bu‘OH -73 “C transformed into cyclopentenones using catalytic quantities of [Rh,(CO),,] in the presence of R,SiH under CO Scheme 35.”’ Synthetic applications of Fisher carbene complexes,’9’~’99 rhodium carbenoid,200 and alkylidene carbenes201*202 continue to show promise for the construction of cyclopentanes.The Ramberg-Backlund reac-tion,’ has been used in a synthesis of trans-carbovir and a pyranone-cyclopentenone rearrangement provides rapid access to functionalized cyclopentenones for use in the construction of neocarzinostain analogue^."^ Carbohydrates continue to be used as readily available as chiral non-racemic starting materials. It is a little surprising therefore that the first example205 of an intramolecular aldol reaction on a sugar template leading to formation of a cyclopentenone appeared only this year; these 00-20 5 are summarized in Scheme 36. Cyclohexanes The preoccupation of the synthetic community with Taxol has necessarily meant that the synthesis of densely functionalized cyclohexanes has been an area of intense activity Scheme 37.206-209 The Diels-Alder reaction still remains one of the most important methods for the construction of six-membered rings (Scheme 38).Discussions into the concerted nature”’ and stereochemical aspe~ts~~j-~~~ of these reactions continue to arouse interest. Again this year a variety of catalysts have been reported which enable such reactions to proceed with high levels of asymmetric indu~tion.~~~-~~~ Lithium perchlorate has been shown2j1 to have a profound effect upon the rate of certain Diels-Alder reactions whilst the addition of cyclodextrins to Diels-Alder reactions conducted in aqueous media may have substantial effects in terms of the regioselectivity of these reactions.232 Given the wealth of literature concerning Diels-Alder reactions in the laboratory it is surprising that the identifica- tion of biological equivalents is still at an embryonic state.However it was disclosed this year that the crude enzyme system extracted from Alternaria solani catalyses the intramolecular Diels-Alder reaction of (33) to the exo-adduct (34) with good levels of optical purity (92 f8% ee) Scheme 39.233Other cycloaddition reactions have also been used to good effect for the synthesis of polycyclic substrates e.g. Scheme 40.234 Organ~metallic-~~~~~~~ approaches continue to be used and radi~al-based’~’~~~’ extensively as have enzymatic strategies’,’ for the preparation of chiral non-racemic substrates Scheme 41. Medium and Large Ring Systems Boland et al. have shown239 that cycloheptadienes such (35),once thought to be the sex Peter Quayle OR .-0 ii-+ i ('+I I H&' '0-H (Ref.193) ca. 80% 40-92% -+o (Ref. 196) 47% \ SiMe3 TBDMS TBDMS 54% 14% Scheme 35 Reagents and conditions i [co2(co)8] CH2Cl, room temp.; ii CH,Cl, 10min; iii NMO (6 equiv.) CH2C1, 0 "c; iv [co,(c0)8] CH,Cl,; v [Mo(CO),] DMSO lOO"C PhMe; vi Bu'Me,SiH CO [Rh,(CO),,] PhH 95°C pheromones of marine brown algae are in fact degradation products of the divinylcyc- lopropanes (36) which are now believed to be the active pheromones Scheme 42. The halflife of cyclopropanes such as (36) is approximately 1 h at 8 "C which evidently is much longer than the sexual encounter in brown algae! Boger and Takahashi have described a highly convergent route to grandirubine (37) via an initial [4 + 21 cycloaddition reaction between the acetal(38) and the pyrone (39) Scheme 43.,,' Novel ring expan~ion,~~'.~~~ [3 + 4)-cycloaddi-organ~metallic,~~~ Aliphatic and Alicyclic Chemistry 0KO OX? (Ref.200) ___) 89% Me02CLx i Me02Cd ii 84% -iii 69% (Ref.201) I 'I' Ts SnBu3 TrO TrO iv (Ref. 202) -60% LQuOTBDMS ox0 ox0 v vi (Ref. 203) Ror= a" so2 BrHBoc HO 0-vii (Ref. 204) 71-76% &fH OR OR (Ref. 205) ix ___) CH3 CH3 Scheme 36 Reagents and conditions i [Rh,(octanoate),] (cat.) CH,Cl,; ii PhIC- NOTf; iii Bu'OK THF; iv TMSC(Li)N, THF 0°C; v Bu'OK(2.2 equiv.) THF -78 "C 77%; vi HCl MeOH 100%;vii Et,N DMF 80°C; viii PdCl, CuCl, 0, DMF 0.5 h 80%; ix Bu'OK 0.5 h 90% 100 Peter Quayle YOPMB-ii iii iv -POPMB -.CN (Ref.207) 0 TMSO -0 2 MeO-(Ref. 208) OMe OMe OMe Scheme 37 Reagents and conditions i BF -OEt, CHCI,; ii 140"C 72 h 38%; iii Na,S EtOH -78 "C 21%; iv TMSCN 90%; v piperidine HOAc PhH 70 "C 65% (Ref. 213) H Aliphatic and Alicyclic Chemistry (Ref. 216) (Ref. 217) r 1 OCH3 -@fly (Ref. 219) 0 L -I + (Ref. 221) Scheme 38 tion244 and rearrangement245*246 reactions have appeared this year for the synthesis of cycloheptanes. The asymmetri~ation~~’,~~~ of cycloheptadienes promises to be a valuable synthetic for the synthesis of chiral non-racemic building blocks.The ‘higher order’ cycloadditions of cycloheptatriene(tricarbony1)chromium complexes developed 102 Peter Quayle CHO Scheme 39 5:l (Ref. 235) Scheme 40 Reagents and conditions i i BuLi THF -78 "C; ii H,O 1 OMOM OMOM ___) (Ref. 237) 0 \ aoAc \ OH + aOAC OAc (Ref. 238) Scheme 41 Aliphatic and Alicyclic Chemistry (Ref. 239) Scheme 42 ?Me ?Me Me0 Me0 MeO%o t MO> 0 1 (39) OMe (Ref. 240) OH (37) Scheme 43 by Rigby et al.249and the related intramolecular Diels-Alder reactions pioneered by Shea and co-w~rkers~~~ provide ready access to functionalized cycloheptanes Scheme 44. The chemistry of eight-membered rings has once again been dominated by Taxol. Interestingly the isolation of the bicycloC9.3.llpentadecatriene canadensene (40) a putative biogenetic taxane precursor was reported this year.251 Whilst biological conversion of (40) into the taxane skeleton still remains a matter for conjecture a number of wholly synthetic routes to the ring B system of Taxol have appeared some of the more noteworthy examples are collated in Scheme 45.252-254 Paquette et af. have utilized a Claisen rearrangement to good effect in their synthesis of (+)-acetoxy~reunulide.~~~ There is continued interest in the synthesis of medium rings containing ene-diyne moieties as illustrated below Scheme 46. Of note is that the Nozaki-Kishi reaction was 104 Peter Quayle (Ref. 246) OH (Ref. 249) R (Ref. 250) OTBS OTBS Scheme 44 adopted as the optimal method for ring closure for all of these sensitive substra- te~.~~~-~~~ The same coupling procedure has also been adopted by Proctor and co-workers in their approach to the bicyclo[8.4.0] tetradecane skeleton of solenolide F S~heme47.~'~ The aromatic character of [lOlannulene isomers has once more been the subject of further scrutiny.Schleyer and co-workers have now provided arguments which suggest that a mono-trans-conformer of [lolannulene (41) should indeed be stable and exhibit aromatic properties.260 Clearly this debate will continue until a thorough re-evaluation of this system is undertaken. Finally Oppolzer et al. have developed a new macrocyclization strategy which has been utilized in a synthesis of (+)-aspicilin Scheme 48.261 References 1 C.Wong R. L. Halcomb Y. Ichikawa and T. Kajimoto Angew. Chem. Int. Ed. Engl. 1995 35 412. 2 C. 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