摘要:

Introduction 1 John A. Joule and John P. Richard Department of Chemistry The University of Manchester Manchester UK M13 9PL Department of Chemistry State University of New York at Bu.alo Bu.alo NY 14260—3000 USA The reporters for this year’s volume have done an excellent job of identifying and discussing the most important .ndings from an ever-increasing volume of literature. We have continued to increase the scope of coverage of important topics in physical organic chemistry by the addition of a new report on ‘Gas phase organic ion—molecule reaction chemistry’ by W. Y. Feng and S. Gronert. This chapter emphasizes the valuable information about reaction mechanisms that can be obtained from studies in the absence of solvent. The coverage of enzyme reaction mechanisms by N.G. J. Richards and the reactions of radical ions by D. E. Falvey that was introduced last year has been continued in this volume. Advances in NMR spectroscopy relevant to the organic chemist are reported once again by B. A. Salvatore and I. Alberts has written another engaging report on the progress in theoretical organic chemistry. Finally J. C. Fishbein has replaced I. W. Ashworth as the reporter on polar reaction mechanism. Professor Fishbein presents an admirable overview of the important work which has resulted in the continued re.nement in our understanding of the mechanism for heterolytic reactions in solution. Following the pattern which was established last year this year’s volume sees the .rst biennial report on ‘Natural Products’ which is to alternate with biennial reports on ‘Biosynthesis’ and the .rst biennial report on ‘Natural polymers’ which is to alternate with ‘Man made polymers’.We have continued coverage of synthetic chemistry using the inevitably occasionally overlapping topics of ‘Pericyclic Methods’ ‘Heteroatom Methods’ ‘Radical Methods’ ‘Enzyme Chemistry’ and ‘Protecting Groups’.The enormous and hugely important area of organometallic chemistry is subdivided into discussions of ‘Stoichiometric Applications’ and ‘Catalytic Methods’. The traditional ‘Aromatic Chemistry’ and ‘Heterocyclic Chemistry’ topics are covered separately. It is worth re-iterating that it is impossible to devise subdivisions which would ensure no overlap between reports especially given the short time available for editing given our continuing aim to produce Annual Reports as soon after the year being covered as possible. 1 Annu. Rep. Prog. Chem. Sect. B 1999 95 1 MMMM Annu. Rep. Prog. Chem. Sect. B 1999 95 0—00 2 3 Annu. Rep. Prog. Chem. Sect. B 1999 95 1

ISSN:0069-3030    

DOI:10.1039/OC095001

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

2 Synthetic methods Part (i) Free-radical reactions Clive S. Penkett and Iain D. Simpson School of Chemistry Physics and Environmental Science University of Sussex Falmer Brighton East Sussex UK BN1 9QJ 1 Introduction Sadly Sir Derek Barton one of the great names of radical chemistry passed away during 1998 and his contributions to the .eld will be missed by all. Professor Barton was one of the early pioneers of the use of free radicals in organic synthesis and it is a testament to his lasting in.uence that the .eld remains so strong today. New reagents and catalytic procedures have been developed which dramatically improve chemoand stereoselectivity of radical reactions. There were many examples of organometallic reagents (such as organosamarium -titanium -chromium -iron -manganese and -copper) being used to accomplish complex radical induced reactions suggesting a general move away from the use of toxic organotin reagents.A number of spectacular tandem cascade reactions have been reported which demonstrate the elegance and power of radical cyclisation reactions. In a number of cases acyclic precursors have been transformed very e.ciently into highly complex molecules which have subsequently been converted into natural products. 2 Initiators and reagents This year a number of novel reagents and improvements to existing reaction conditions have become available to allow radical reactions to proceed with improved e.ciency economy and selectivity. Gansa� uer has reported a system for the radical opening of epoxides using a catalytic amount of titanocene dichloride.This o.ers a considerable improvement on the standard conditions which require two equivalents of the titanium reagent. It was found that either manganese or zinc could be used as the co-reductant although manganese often caused fewer side reactions due to the manganese(..) chloride by-product being a weaker Lewis acid than zinc(..) chloride. The reaction conditions were found to tolerate a variety of functionality including ketones halides and silyl ethers and many of the standard reactions of Nugent’s reagent were successfully performed (Scheme 1). 3 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 O HO 5 % Cp2TiCl2 Mn 78 % Collidine.HCl EtO2C CO2 Et EtO2C CO2 Et OEt I O O Scheme 1 Because radical cyclisation reactions generally favour exo ring closure a cyclisation usually leaves a functional or alkyl group adjacent to the point of ring closure.If this group is not desired in the .nal product it must be removed thereby introducing more complexity into the synthesis. One solution to this problem has been developed by Kim, who carried out cyclisations onto aldehydes in the presence of triphenylphosphine. The oxy-radical initially formed is deoxygenated under these conditions to give a carbon radical which ultimately leads to a cycloalkane with no functionality at the position of ring closure (Scheme 2). PPh3 350 nm O Bu3SnH Ph O Ph O OH Bu3SnH Ph Br OEt + 78 % OH Scheme 2 The search for non-toxic hydrogen atom donors to replace tin hydrides remains an important area of research and two new reagents for the Barton—McCombie reduction of xanthates have been described.Jang reported the use of dibutylphosphine while Barton used phosphine—borane adducts to carry out the reaction. The latter combination is particularly interesting since alkyl bromides and chlorides did not react under the same conditions allowing potentially useful selectivity in radical reactions. The Surzer—Tanner rearrangement (1,2-acyloxy shift of -acyloxy radicals) has long been of interest to radical chemists since it has no equivalent in ionic chemistry. The reaction is generally too slow to be of practical use but Renaud has shown that it can be considerably accelerated by the presence of a Lewis acid.For the rates to be useful there must be a nearby hydroxy group to encourage chelation between the Lewis acid and the carbonyl group (Scheme 3). O OH O O O AIBN Additive A B Additive Ratio A B None 3 97 Sc(OTf)3 Lutidine 98 2 Scheme 3 4 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 Initiators which can be used at low temperatures represent another important area of study. The most commonly used methods are photolysis or the use of triethylborane in the presence of oxygen but these procedures are unsatisfactory where photolabile or oxygen-sensitive compounds are involved. Schiesser has reported that 9- borabicyclo[3.3.1]nonane can be used to initiate stannane mediated reductions of a variety of radical precursors at temperatures as low as 78 °C (Scheme 4).The reaction could be carried out under a nitrogen atmosphere allowing the use of air-sensitive compounds though the authors did not exclude the possibility that small traces of oxygen present in the system may be required for the reaction to proceed. Another low temperature initiation system which has recently been described is the use of diethylzinc in air. Bu3SnH + Br 9-BBN PhMe 68 % (0 °C) 32 % (-78 °C) 29 % (0 °C) 67 % (-78 °C) O Scheme 4 Kim has developed a novel method for the generation of alkoxy radicals based on the addition of tin or tris(trimethylsilyl)silane radicals to one of the carbonyl groups of N-alkoxyphthalimides. Cleavage of the nitrogen—oxygen bond follows leaving an oxygen radical which was shown to undergo many of the expected reactions including 1,5-hydrogen abstraction and cyclisation reactions (Scheme 5).The desired N-alkoxyphthalimides were easily prepared by reaction of N-hydroxyphthalimide with either alkyl halides or alcohols. Bu3SnH AIBN O Ph Ph N PhH reflux O 93 % O Scheme 5 Kim has also reported that methyloxalyl chloride can be used for the carboxylation of alkyl radicals. Treatment of a radical precursor with an initiator in the presence of this reagent gives initially a mixture of the corresponding acyl chloride and methyl ester which can be converted to the pure ester on work-up with methanol and triethylamine. This procedure can be combined with a radical cyclisation to give -cycloalkylcarboxylic acids (Scheme 6).3 Intermolecular reactions Intermolecular radical reactions remain relatively under-utilised in comparison with intramolecular cyclisations. However a striking demonstration of the synthetic power of such reactions has been reported by Takai and co-workers. In a single reaction an 5 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 E 2. MeOH Et3N CO2Me I 63 % O I Scheme 6 alkyl iodide a diene and an aldehyde can be coupled as shown in Scheme 7. The mechanism is believed to involve generation of an alkyl radical from the iodide which adds to the diene. The resulting allyl radical is then reduced to the organochromium species which adds to the aldehyde to give the .nal product. Regio- and stereoselectivities were generally good and yields of up to 76% of a single diastereomer could be achieved after puri.cation.CrCl2 DMF H + + 76 % OH CO2Me Scheme 7 Curran and Fuchs have reported the use of allylic tri.uoromethylsulfones (triflones) for selective activation of solvent CH bonds (Scheme 8). The addition of an alkyl radical to the electron-de.cient double bond yields a substituted ole.n after elimination of sulfur dioxide and a tri.uoromethyl radical. The highly electrophilic CF radical then abstracts a hydrogen atom from solvent thereby propagating the chain. AIBN CO2Me + SO2CF3 O 0.016 M O E E RH SO E EE 1. MeOC(O)COCl (Bu3Sn)2 h. 2 + + R R + CF3 R CO2CF3 Scheme 8 Curran has also developed a method for the halogen atom transfer of -bromocarbonyl compounds to enol ethers (Scheme 9).Under standard conditions (neutral benzene as solvent) this class of addition reactions is unsuccessful despite the fact that electronic factors should be in its favour. Reasoning that the failure may be due to the reversibility of the atom transfer step Curran introduced a nucleophile (typically a mixture of an alcohol and triethylamine) to trap the bromoether as its acetal thereby forcing the reaction to proceed in the desid direction. In this manner a variety of -carbonyl esters could be prepared usefully extending the scope of atom transfer addition reactions. The radical mediated addition of aldehydes to ole.ns is an important method of carbon—carbon bond formation but tends to only give good yields when electronde .cient ole.ns are used.Roberts has described the use of thiols as polarity reversal 6 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 O Sn2Me6 hí O O + O EtO Br EtO OBn BnOH Et3N PhH 91 % OBu E OBu E E OBu E ROH Et3N Br + + + OR E E Br OBu Scheme 10 O Scheme 9 catalysts improving the yields for electron-rich and neutral ole.ns and thus providing a valuable extension to the scope of the reaction (Scheme 10). Carbonylation of alkyl radicals is a useful method for chain extension and Ryu has used this method to form -lactones (Scheme 11). Treatment of an alcohol with lead tetraacetate yields initially an oxygen centered radical which rapidly undergoes 1,5-hydrogen atom abstraction.Carbonylation of the resulting alkyl radical followed by ring closure gives the cyclic ester products. CO (80 atm) OH O Pb(OAc)4 51 % O Scheme 11 N B Bu3SnH r N AIBN CO (80 atm) 81 % Scheme 12 Ryu has also reported the use of carbonylation reactions for the generation of acyl radicals for cyclisation onto imines (Scheme 12). Reaction of analogous alkyl radicals often gives poor selectivity between 5-exo and 6-endo cyclisation products but in the 7 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 case of acyl radicals good selectivity is observed due to the matching of opposite polarities between the carbon of the acyl group and the nitrogen of the imino group. Mikami has shown that a samarium() iodide mediated addition of ketones to acrylates can be carried out in an enantioselective manner by the use of the chiral ligand 2,2-bis(diphenylphosphino)-1,1-binaphthyl oxide (BINAPO) (Scheme 13).Though the yields and enantiomeric excesses were variable the procedure represents another addition to the small but growing list of radical reactions which can be manipulated to give nonracemic products. O O POPh O SmI 2 2 tBuOH OMe + Ph POPh2 BINAPO Ph O (R)- BINAPO 46 % yield 67 % ee O HO Scheme 13 SmI2 80 % H HO OH 4 Intramolecular reactions Molander has continued his work in the area of samarium() iodide induced ketyl radical formation. He has shown that the addition of a ketyl radical to a nitrile group can be enhanced by the use of visible light. He also found that the yields for 5- membered ring formation were much better than for 6-membered ring formation (Scheme 14).O CN O O Scheme 14 SmI2 HMPA 50 % THF Scheme 15 In another series of experiments by Molander samarium() iodide was employed in a sequential ketyl¡Xolen coupling/-elimination reaction (Scheme 15). This process causes the stereoselective incorporation of an alkenyl group via an intramolecular delivery system. The advantage of this is that it introduces an alkenyl group stereoselectively and avoids the basic reaction conditions typical of alkenylmagnesium halides and alkenyllithium reagents which are often used to perform similar 8 Annu. Rep. Prog. Chem. Sect. B 1999 95 3¡X17chemical transformations. The high degree of stereocontrol results from the SmI mediated cyclisation between the ketyl radical and the ole.n.Naito has used the unique properties of a samarium(..) iodide induced ketyl radical cyclisation onto an oxime ether to control the relative stereochemistry of the resulting product. Initially .ve-membered ring variants were investigated resulting in the preparation of cyclic trans-amino alcohols which were subsequently used for the formation of 4-purinylpyrrolidin-3-ol nucleoside analogues. In another paper the same technology was used to prepare the potent inhibitor of protein kinase C ()-balanol. In the key step samarium(..) iodide was used to form a seven-membered ring trans-amino alcohol which was subsequently converted to the target molecule (Scheme 16). O SmI2 HMPA NOR THF 53 % N Boc O Scheme 16 Kim investigated the use of samarium(..) iodide for the reductive cleavage of -halo epoxides. The use of hexamethylphosphoramide (HMPA) had a signi.cant bearing on the nature of the products so that cyclopropanols were prepared in the presence of HMPA and allyl alcohols were produced in its absence (Scheme 17).2.2 SmI2 6 HMPA Ph Br 2.2 SmI THF 75 % 2 O THF 70 % Ph PhS O Br N Bn Scheme 17 Zard has discovered that upon treatment with nickel powder in hot acetic acid N-alkenyl trichloroacetamides undergo reversible 4-exo radical closure. This radical can be trapped by elimination of a thio radical leading to the formation of a -lactam. In the absence of such a trap irreversible 5-endo closure occurs leading to a variety of 5—membered ring lactams.In a subsequent paper he showed how the chemistry could be used to prepare erythrina alkaloids (Scheme 18). Ni AcOH iPrOH CCl3 CCl3 Ni AcOH O N i O PrOH N Bn Scheme 18 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 OH OH NHOR NHOR + N Boc N Boc 1 6.6 OH Ph OH Ph Cl Cl BnN 50 % O Cl 42 % Bn 9 Roy reported the stereoselective formation of polysubstituted tetrahydrofuran derivatives by titanium() mediated radical cyclisation of epoxides (Scheme 19). The chemistry was subsequently used for the synthesis of the antitumor antibiotics ()- methylenolactocin and ()-protolichesterinic acid. O HO (i) Cp2TiCl THF (ii) H3O+ Ph Ph 71 % O O Scheme 19 In a very elegant piece of work Rawal showed how strained oxetanes could undergo radical anion induced fragmentation.Lithium di-tert-butylbiphenylide (LDBB) was used to initiate the tandem radical fragmentation/cyclisation reaction to produce the linear triquinane as shown (Scheme 20). HO HO H H H LDBB Et3Al + H THF 54 % O H H H H 10 1 O O OSiMe3 Fe(NO3)3 DMF + Scheme 20 Further to his work on the use of iron() induced radical fragmentation/cyclisation reactions of silyl-protected cyclopropanols Booker-Milburn has reported an example which initially undergoes a transannular cyclisation and then an intramolecular cyclisation to give an angular triquinane model (Scheme 21). H H rt to 60 ¢XC 39 % H CN Scheme 21 A number of research groups have carried out radical cascade reactions with a view to constructing the steroidal type nucleus.Zoretic used manganese() acetate¡Xcopper() acetate to initiate an oxidative radical cascade to give the polycyclic 5-pregnane skeleton (Scheme 22). In so doing seven stereogenic centres were set 1. Mn(OAc)3 Cu(OAc)2 CN 10 % H H 2. TFA O O H Cl 61 % CO2Me MeO2C Cl Scheme 22 10 Annu. Rep. Prog. Chem. Sect. B 1999 95 3¡X17although the cyano group was subsequently converted to an angular hydrogen in a later step. Snider has continued with his investigations into the use of manganese() acetate¡Xcopper() acetate to prepare tetracyclic diterpenes containing both bridged and fused rings. In one synthetic operation the tetracycle shown was prepared (along with various partially cyclised products) which was subsequently converted to both ()- isosteviol and ()-beyer-15-ene-3,19-diol (Scheme 23).Mn(OAc)3 H Cu(OAc)2 O O 35 % H EtO2C EtO2C Scheme 23 Pattenden used his tin hydride promoted acyl radical technology to perform a similar radical cascade to produce an azasteroid starting from the seleno ester shown (Scheme 24).Ac N Ac H N Bu3SnH NAc H H AIBN O 45 % H SePh O O SePh Bu3SnH O Scheme 24 Pattenden also investigated the use of ,-unsaturated selenoesters to form - ketenyl radicals and subsequently used them in a trans annulation/cyclisation sequence which resulted in a formal synthesis of ()-modhephene (Scheme 25). C O O AIBN 59 % Scheme 25 Malacria published a marvellous example of a tandem radical cyclisation to produce linear triquinanes from acyclic precursors. In the absence of an intermolecular radical trap the diquinane was produced in a highly respectable 66% yield.When acrylonitrile was also incorporated into the reaction medium an eleven elementary step process occurred resulting in the formation of a linear triquinane in an impressive 54% yield. A 1,6-H atom transfer step with a vinyl radical to generate an -silylstabilised radical and an unprecedented -elimination of a trimethylsilyl radical were 11 Annu. Rep. Prog. Chem. Sect. B 1999 95 3¡X17amongst the key elementary steps to form this highly complex molecule from an acyclic precursor (Scheme 26). Si Si O Si Si Bu3SnH O 28 % O Bu3SnH AIBN SiMe3 + Si AIBN Br CN CN 66 % SiMe3 Si Si O 54 % H H Scheme 26 Typically one would expect 5-exo- radical cyclisations to be much more likely than 8-endo-cyclisations but Lee has shown that under certain circumstances the opposite can be true (Scheme 27).This arises from the conformational bias of (alkoxycarbonyl) methyl radicals which prefer to sit in the Z- rather than the E-conformation hence disfavouring the 5-exo mode of cyclisation. Bu3SnH MOMO MOMO O AIBN O H H O Br 80 % O R R R Scheme 27 Further radical cascade studies performed by De Kimpe resulted in a one pot reaction for the formation of pyrrolizidines from -bromomethylaziridines. The - methylaziridyl radical fragmented to a nitrogen centred radical which underwent a tandem radical cyclisation to form the bicyclic heterocycle shown (Scheme 28). Bu3SnH N R N AIBN Br 49 - 63 % Scheme 28 Kim and Lee have recently reported the total synthesis of -cedrene via a tandem radical cyclisation.They utilised the unique nature of N-aziridinylimines which can 12 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 Ph O N Ph O SMe I S THPO O 3SnH PhS AIBN Bu N C5H11 C5H11 O O serve as both radical acceptors and donors sequentially and are ideal for setting up complex quaternary centres. In the .nal elementary step there was a mixture of .veand six-membered ring products formed (Scheme 29). Parsons has demonstrated the utility of radical additions to furans. If an all carbon tether is used in conjugation with a radical trap a complex addition/fragmentation sequence occurs which after an electrocyclic reaction and aerial oxidation of the .nal product results in the formation of an aromatic species (Scheme 30).If a heteroatom is used in the tether a Diels—Alder-like reaction occurs presumably via a halogen atom transfer pathway. Scheme 29 [3,3] shift O (Me3Si)3SiH O C5H11 AIBN 26 % Br O O (i) Bu3SnH AIBN + H H (ii) TsOH MeOH 15 % 45 % H O OTHP OTHP C5H11 51 % Br H O O O O + C [ O ] 5H11 C5H11 1 6 Scheme 30 13 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 Crimmins used the unique properties of radicals to cause the fragmentation of a strained ring followed by a ring expansion reaction to form a spirofused 6,5-ring system. The radical product was subsequently converted into ()-lubiminol (Scheme 31). OH O O CO2Me H Bu3SnH AIBN S OH CO2Me 92 % O N OH OH Me (±)-lubiminol O O Bu3SnO HO Bu3SnH then H2O O O Scheme 31 The incorporation of anionic charge is often used to accelerate [3,3]-sigmatropic shifts and Enholm reasoned that radical anion type species may also accelerate these reactions.He showed that tin radical addition to an appropriately functionalised enone led to the formation of a formal [3,3]-Claisen rearrangement product (Scheme 32). Bu3SnO [3,3] Bu3Sn O 74 % PhH + N N reflux CO2Me Scheme 32 Little extended his work on the use of trimethylenemethane-like diyls by coupling them with a vinylcyclopropane and a cyclopropylcarbinyl radical. Upon thermolysis the diazene shown evolved nitrogen and resulted in the formation of both the [6.3.0] and the [4.3.0] adducts.If an enol ether was used instead of an unsaturated monoester only the [4.3.0] adduct was isolated (Scheme 33). MeO2C 26 % 64 % CO2Me Scheme 33 Murphy continues to prove that radical reactions do not have to be initiated by toxic tin reagents by extending the use of the catalytic ‘radical-polar crossover’ 14 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 reaction. In the example shown below tetrathiafulvalene promoted radical cyclisation of a diazonium salt resulted in the formation of a cyclic ether in the .nal step (Scheme 34). NH2 O O 1. NOBF4 2. TTF (cat) O HO 57 % Scheme 34 Bu3SnH AIBN 5 Stereoselectivity Studer investigated a novel 1,5-aryl migration from sulfur and silicon to carbon. Both methods allow for stereoselective arene transfer from the oxygen substituent via a chair-like transition state (Scheme 35).2 S O Ph O OH Ph I 49 % d.r. = 7 1 Ph Ph OH O Si Me3Si (i) Bu3SnH AIBN Ph I (ii) MeLi 70 % d.r. = 10 1 Scheme 35 Continuing the ipso-substitution theme Malacria has reported the results of forming enantioenriched .ve-membered rings by performing a radical cyclisation onto an ole.n which is adjacent to a homochiral sulfoxide. He also found that the stereoselectivity could be reversed if the reaction was performed in the presence of a very bulky Lewis acid such as methylaluminium bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) (Scheme 36). Further to his work on the radical cyclisation of substituted hex-5-enyl radicals Beckwith has investigated the stereochemical in.uences of anomeric e.ects.Typically pseudoaxially substituted transition states are disfavoured but in the presence of an anomeric e.ect pseudoaxial substituents are stabilised and hence give rise to products with the reverse stereochemistry to that normally observed (Scheme 37). 15 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 E E E E PhSe E E Bu3SnH 0 °C + MeO MeO MeO O Et3B O2 S pTol 98 2 93 % No Lewis acid 0 94 52 % With MAD Typically... Br Scheme 36 Bu3SnH R R O O AIBN but... Br Bu3SnH EtO EtO O O (tBuON)2 61 % d.r. = 5.8 1 Scheme 37 References 1 A. Gansa� uer M. Pierobon and H. Bluhm Angew. Chem. Int. Ed. Engl. 1998 37 101; A. Gansa� uer H.Bluhm and M. Pierobon J. Am. Chem. Soc. 1998 120 12 849. 2 H. J. Gold Synlett 1999 159. 3 S. Kim and D. H. Oh Synlett 1998 525. 4 D.O. Jang D. H. Cho and D. H. R. Barton Synlett 1998 39. 5 D.H.R. Barton and M. Jacob Tetrahedron Lett. 1998 39 1331. 6 E. Laco� te and P. Renaud Angew. Chem. Int. Ed. Engl. 1998 37 2259. 7 V.T. Perchyonok and C. H. Schiesser Tetrahedron Lett. 1998 39 5437. 8 I. Ryu F. Araki S. Minakata and M. Komatsu Tetrahedron Lett. 1998 39 6355. 9 S. Kim T. A. Lee and Y. Song Synlett 1998 471. 10 S. Kim and S. Y. Jon Tetrahedron Lett. 1998 39 7317. 11 K. Takai N. Matsukawa A. Takahishi and T. Fujii Angew. Chem. Int. Ed. Engl. 1998 37 153. 12 J. Xiang J. Evarts A. Rivkin D. P. Curran and P. L. Fuchs Tetrahedron Lett. 1998 39 4163.13 D. P. Curran and S.-B. Ko Tetrahedron Lett. 1998 39 6629. 14 H.-S. Dang and B. P. Roberts J. Chem. Soc. Perkin Trans. 1 1998 67. 15 S. Tsunoi I. Ryu T. Okuda M. Tanaka M. Komatsu and N. Sonoda J. Am. Chem. Soc. 1998 120 8692. 16 I. Ryu K. Matsu S. Minakata and M. Komatsu J. Am. Chem. Soc. 1998 120 5838. 17 K. Mikami and M. Yamaoka Tetrahedron Lett. 1998 39 4501. 18 G. Molander and C. N. Wolfe J. Org. Chem. 1998 63 9031. 19 G. A. Molander and C. R. Harris J. Org. Chem. 1998 63 812; G. A. Molander and C. R. Harris J. Org. Chem. 1998 63 4374. 20 H. Miyabe S. Kanehira K. Kume H. Kandori and T. Naito Tetrahedron 1998 54 5883. 21 H. Miyabe M. Torieda K. Inoue K. Tajiri T. Kiguchi and T. Naito J. Org. Chem. 1998 63 4397. 22 H. S. Park S. H. Chung and Y.H. Kim Synlett 1998 1073. 23 J. Cassayre B. Quiclet-Sire J.-B. Saunier and S. Z. Zard Tetrahedron 1998 54 1029. 24 J. Cassayre B. Quiclet-Sire J.-B. Saunier and S. Z. Zard Tetrahedron Lett. 1998 39 8995. 25 P. K. Mandal G. Maiti and S. C. Roy J. Org. Chem. 1998 63 2829. 26 C. A. Dvorak C. Dufour S. Iwasa and V. H. Rawal J. Org. Chem. 1998 63 5302. 27 T. Cohen and M. Bhupathy Acc. Chem. Res. 1989 22 152. 28 K. I. Booker-Milburn and R. F. Dainty Tetrahedron Lett. 1998 39 5097. 16 Annu. Rep. Prog. Chem. Sect. B 1999 95 3—17 29 P. A. Zoretic and H. Fang J. Org. Chem. 1998 63 7213. 30 B. B. Snider J. Y. Kiselgof and B. M. Foxman J. Org. Chem. 1998 63 7945. 31 P. Double and G. Pattenden J. Chem. Soc. Perkin Trans. 1 1998 2005. 32 B. De Boeck N. Herbert and G.Pattenden Tetrahedron Lett. 1998 39 6971. 33 B. De Boeck and G. Pattenden Teron Lett. 1998 39 6975. 34 P. Devin L. Fensterbank and M. Malacria J. Org. Chem. 1998 63 6764. 35 E. Lee C. H. Yoon T. H. Lee S. Y. Kim T. J. Ha Y.-S. Sung S.-H. Park and S. Lee J. Am. Chem. Soc. 1998 120 7469. 36 D. De Smaele P. Bogaert and N. De Kimpe Tetrahedron Lett. 1998 39 9797. 37 H.-Y. Lee S. Lee D. Kim B. K. Kim J. S. Bahn and S. Kim Tetrahedron Lett. 1998 39 7713. 38 A. Demircan and P. J. Parsons Synlett 1998 1215. 39 M.T. Crimmins Z. Wang and L. A. McKerlie J. Am. Chem. Soc. 1998 120 1747. 40 E. J. Enholm K.M. Moran P. E. Whitely and M. A. Battiste J. Am. Chem. Soc. 1998 120 3807. 41 G. L. Carroll and R. D. Little Tetrahedron Lett. 1998 39 1893. 42 J. A. Murphy F. Rasheed S. J. Roome K. A. Scott and N. Lewis J. Chem. Soc. Perkin Trans. 1 1998 2331. 43 A. Studer and M. Bossart Chem. Commun. 1998 2127. 44 A. Studer M. Bossart and H. Steen Tetrahedron Lett. 1998 39 8829. 45 E. Laco� te B. Delouvrie� L. Fensterbank and M. Malacria Angew. Chem. Int. Ed. Engl. 1998 37 2117. 46 A. L. Beckwith and D. M. Page J. Org. Chem. 1998 63 5145. 17 Annu. Rep. Prog. Chem. Sect. B 1999 95 3&mdas

ISSN:0069-3030    

DOI:10.1039/a808602h

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

2 Synthetic methods Part (ii) Pericyclic methods Paul J. Stevenson School of Chemistry The Queen’s University of Belfast Belfast Northern Ireland BT9 5AG 1 Diels–Alder reaction Catalysis The .rst examples of the use of the salen ligand in transition metal catalysed formal Diels—Alder reactions have been independently reported by two groups this year. The metals employed were cobalt(..) and chromium(...) catalysts 1a and 1b respectively (Scheme 1). With 10 mol% of the cobalt catalyst 1a and the activated aldehyde ethyl glyoxalate 2 cycloaddition took place in toluene at 40 °C and gave predominantly the endo stereoisomers 3 and 4 in 90% overall yield. In all the ratio of endo to exo isomers was 93 7 and the Si Re face selectivity was 86 14. When the reaction was performed in the absence of the salen catalyst 1a with diene and aldehyde neat at 60 °C in an autoclave for 4 h then the isomers 3 and 4 only comprised 55% of the reaction mixture with the mass balance 45% comprising the exo isomers.This con.rmed that the chirality already present in the diene was having little in.uence on the stereochemical outcome of the Diels—Alder reaction. The chromium catalyst 1b could be used to promote reactions of aldehydes with the reactive Danishefsky diene. Hence benzaldehyde 5a reacted with Danishefsky’s diene in diethyl ether as solvent at 30 °C containing 2mol% of the chromium salen complex 1b for 24 h to give the cycloadduct 6a in 85% yield and 87% ee. The ee is crucially dependent on the nature of the counterion and tetra.uoroborate was found to be the most e.cient anion.Obviously from a synthetic viewpoint the use of aromatic aldehydes is restrictive. With aliphatic aldehyde 5b and using tert-butyl methyl ether as solvent and 10mol% catalyst 1b cycloaddition proceeded at 30 °C for 24 h to give cycloadduct 6b in high yield and 80% ee. Reduction of the ketone to a secondary alcohol gave a crystalline derivative which was recrystallised to 99% ee. The overall yield for the two steps was 55%. This intermediate was used in a synthesis of muconin. Cationic chiral C symmetric anhydrous copper complexes 7a–d (Scheme 2) and hydrated 7e are .nding further application in Diels—Alder chemistry. An improved procedure for preparing the tert-butyloxazolidine ligand has been published. Complex 7a 10mol% in methylene chloride at room temperature for 18 h catalyses 19 Annu.Rep. Prog. Chem. Sect. B 1999 95 19—38 1a M = Co(II) N N M O But O But But But TBSO CO2Et H TBSO CO2Et O i O O 2 O 3 O O 80% 1b M = Cr(III) counterion tetrafluoroborate CO2Et TBSO O O O 13% 7% exo isomers O H TMSO R ii O 4 O R OMe 6a,b 5a R = Ph 5b R = CH2OPMB Scheme 1 Reagents i toluene 40 °C 10mol% 1a; ii diethyl ether or tert-butyl methyl ether,30 °C 2mol% 1b. Diels—Alder reaction between activated aldehyde ethyl glyoxalate 2 and cyclohexadiene 8 giving cycloadduct 9 in 90% yield. The reaction was completely regioselective the stereoselectivity was very high with only the endo-isomer being detected by NMR spectroscopy and the ee for cycloadduct 9 was 97%.This intermediate was converted to R-actinidolide in four additional synthetic steps. Reaction of carbonyl-activated ketone 10 with Danishefsky’s diene in THF at 78 °C for 20 h in the presence of 0.05mol% catalyst 7b gave cycloadduct 11 in 90% yield and an incredible 98% ee for the newly generated tertiary chiral centre. The catalyst loading is tiny and is approaching enzyme e.ciency in terms of turnover. ,-Unsaturated carbonyl compounds with an additional electron-withdrawing group attached to the carbonyl group usually alkoxycarbonyl or phosphonate are very reactive heterodienes which react with electron-rich alkenes. Hence reaction of diene 12 with ethyl vinyl ether in THF at45 °C in the presence of 10mol% catalyst 7b gave the cycloadduct 13 in high yield and 99% ee. When the reaction was conducted at 78 °C the yield was 89% and the ee increased to 99.7% though the reaction time 50 h was rather long to keep the reaction cold.Copper complex 7e is a blue powder easily stored and is an attractive alternative to the hygroscopic anhydrous complex 7b. Using 2 mol% of catalyst 7e in THF at 0 °C for 0.25 h in the presence of 3Å molecular sieves gave cycloadduct 13 in 87% yield de(endo exo) greater than 24 1 and 97% ee for the endo isomer shown. The ee increases to 99% on dropping the 20 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 7a R = But Counterion SbF 6 – 2+ 7b R = But Counterion TfO– O O 7c R = But Counterion PF 6 – N N Cu R R X X 7d R = Ph Counterion SbF 6 – 7e R = But X = H2O Counterion TfO– 7f R = But X = H2O Counterion SbF6 – O H CO2Et 8 OMe CO2Me TMSO 2 O 10 iii O EtO2C or iv OEt 12 v O EtO2P OEt 14 PhS CO2Et 17 Scheme 2 Reagents i,CH Cl 7a 10 mol% 18 h 25 °C; ii THF,78 °C 0.05mol% 7b 20 h; iii THF 78 °C 10 mol% 7b 50 h; iv THF 0 °C 2mol% 7e 15 min; v CH Cl 78 °C 10mol% 7b 48 h; vi HCl MeOH; vii PPTS acetone—water 4 1; viii CH Cl 78 °C 10 mol% 7d 1 h; ix NaOH (PhO) PON .Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O i H CO2Et 9 ii O O CO2Me 11 OEt O EtO2C 13 vi vii CHO OEt O MeO O EtO2P 15 16 viii ix SPh O CO2Et 18 19 21 temperature to 78 °C.On decreasing the catalyst loading to 0.5mol% the de(endo exo) decreased to 19 1 and the ee to 96%. Heterodiene 14 reacts with ethyl vinyl ether in methylene chloride at78 °C for 48 h in the presence of 10mol% 7b to give cycloadduct 15 in 89% yield. The de for endo exo was 99 1 and the ee was 99%. The nature of the counterion in the catalyst is important in determining the reactivity and enantioselectivity. Hence with catalyst 7c the ee value was lower in reaction of 14 with ethyl vinyl ether. The heterocycle 15 reacted with hydrogen chloride in methanol followed by PPTSin acetone—water to give the ester-aldehyde 16 in 73% yield. Copper complex 7d 10mol% in methylene chloride at 78 °C for one hour catalyses the Diels—Alder reaction of -thioacrylate 17 with cyclopentadiene to give the cycloadduct 18 in 92% yield. The endo exo selectivity was 15 1 and the ee for the endo adduct was greater than 95%.The -thioacrylate 17 is a ketene equivalent and in order to get good ee values in this cycloaddition it seems to be necessary to have two point binding (carbonyl oxygen and sulfur) to the copper catalyst. Hydrolysis of the ester followed by reaction of the carboxylic acid with diphenylphosphoryl azide gave the required ketone 19 in 88% yield and 88% ee. The apparent drop in ee for ketone 19 is due to the presence of the racemic exo-Diels—Alder adduct in the mixture that was hydrolysed. Activated Diels–Alder reactions The activation of dienophiles with electron-withdrawing groups remains popular and this can be enhanced using Lewis acid catalysis.However even with this further activation some dienophiles are still not su.ciently reactive to give clean Diels—Alder reactions with electron-rich dienes so other methods of activation have been sought. One particularly attractive option is to generate a cationic dienophile. Dioxolenium ions have been generated from acetals of ,-unsaturated aldehydes by reaction with silyl tri.ates and these species readily participate in Diels—Alder reactions under very mild conditions (Scheme 3). Hence treatment of diene 20 with dienophile 21 and trimethylsilyl tri.ate in methylene chloride at 90 °C regioselectively gave the endo adduct 22 in 67% yield together with 5% of an unidenti.ed isomer.Of particular note is the use of one quaternary chiral centre in the starting material controlling the stereochemistry of a quaternary centre in the product. The use of cationic dienophiles in intramolecular Diels—Alder reactions has also been reported (Scheme 4). Hence treatment of triene 23 with tri.uoroacetic acid in 2M lithium perchlorate in diethyl ether gave the exo cycloadduct 25 in 66% yield. It is likely that the intermediate for this cycloaddition is the oxygen stabilised carbonium ion 24 and after cycloaddition the intermediate loses its positive charge by proton loss to regenerate the enol ether. Intermediate 25 was used in a synthesis of lycopodine. On the same theme dihydropyridinium ions 27 derived from cyclic amino cyanohydrins 26 readily undergo exo-selective Diels—Alder reaction with Danishefsky’s diene in re.uxing THF containing a catalytic quantity of zinc bromide to give the cycloadduct 28 plus the enone 29 in 66% yield as a 1 1 mixture (Scheme 5). Treatment of this mixture with potassium tert-butoxide in tert-butyl alcohol converted 28 to 29.The dihydropyridinium species 27 is believed to be formed which activates the 22 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 + TBDPSO TBDPSO Scheme 3 Reagents i CH Cl ,90 °C TMSOTf. 22 SPh i 20 HO OTBDPS O OTBS 23 Scheme 4 Reagents i 2MLiClO in Et O 10% CF CO H 1 h. isolated double bond to cycloaddition. In the absence of zinc bromide no reaction was observed.Styrene is unreactive as a diene in Diels—Alder chemistry mainly because cycloaddition involves loss of aromaticity. Very reactive dienophiles or harsh conditions are 25 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O O 21 i O O SPh + OTBDPS O 24 OTBS SPh OTBDPS O OTBS 23 OSiMe3 i + N N CN Bn Bn 27 26 O + OMe N CN N CN 29 28 Bn Bn Scheme 5 Reagents i catalytic ZnBr THF re.ux. 2+ OMe Os(NH3)5 30 i 2+ OMe O ii O Os(NH3)5 OMe O H H 31 Scheme 6 Reagents i 12 equivalents acrolein 1MLiOTf CH CN; ii CAN H O. usually required. However on complexation to pentammineosmium de-aromatises arenes and opens up a whole new range of chemistry for these substrates.Hence -arene—osmium complex 30 reacts with acrolein in molar lithium tri.ate in acetonitrile solution over 12 h at room temperature to give the endo-cycloadduct 31 in 97% yield as a single diastereoisomer (Scheme 6). The osmium can be readily oxidatively removed with ceric ammonium nitrate to give the fully aromatic compounds 32. Imino Diels–Alder reactions The Diels—Alder reaction of dienophiles derived from imines is common. However dienophiles derived from oximes are much rarer. Nitrosation of Meldrum’s acid in the 24 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OMe 32 OTs N OTs O N O O i or ii O O O O O 33 34 iii N CO2Et 35 Scheme 7 Reagents i benzene 80 °C; ii CH Cl Me AlCl,78 °C 4 h; iii NaOMe then NCS MeOH THF 1 1 overnight.presence of tosyl chloride gave an oxime toluene-p-sulfonate 33 in 57% yield. In thermal Diels—Alder reactions the regioselectivity of dienophile 33 is opposite to that of other imino dienophiles giving adduct 34 in low yield (Scheme 7). The low yield is in part due to the thermal instability of the cycloadduct 34. When the Diels—Alder reaction was conducted in methylene chloride at78 °C mediated by two equivalents of dimethylaluminium chloride 34 was obtained in 78% yield. The cycloadduct 34 can be readily converted to 2-methoxycarbonyl pyridines by elimination of the toluene-psulfonate and decarboxylation of the one of the esters. The overall yield for this pyridine synthesis is 57% from 33.Intramolecular Diels–Alder reactions When a 1Msolution of the polyene 36 was heated in toluene at 120 °C in the presence of dienophile 37 an exo-selective intramolecular and an exo-selective intermolecular Diels—Alder reaction took place giving 38 in 45% yield (Scheme 8). In one pot six new chiral centres were generated with the correct absolute stereochemistry for elaboration to ()-chlorothricolide. Taking into account all possible exo endo and regiochemical possibilities for these diene—dienophile combinations 96 di.erent Diels—Alder products are possible; the yield of 45% is therefore excellent. Intramolecular Diels—Alder reaction of substrate 39 has been used to simultaneously construct a six-membered ring and a macrocycle in the synthesis of pinnatoxin A (Scheme 9). There are eight possible products from the cyclisation but only three were formed.It was found that the choice of solvent in which the reaction was carried out had an e.ect on the relative amounts of these isomers. Dodecane proved to be the best solvent and heating a 0.2mM solution of 39 at 70 °C for 24 h gave a 78% combined yield of cycloadducts in the ratio of 1 0.9 0.4 of which the major exo-isomer 40 shown was the desired one. 25 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OTBDPS OTBDPS O O O O O i O But But CO2R CO2R 37 38 36 OMOM OMOM Scheme 8 Reagents i 1.0Min toluene 120 °C. Scheme 9 Reagents i 0.2mM in dodecane 70 °C 24 h. Intramolecular Diels—Alder reaction of unactivated alkynes with dienes usually requires high temperatures.Cationic rhodium complex 41 6mol% in methylene chloride at room temperature for 14 h catalyses the formal intramolecular Diels—Alder reaction giving the adduct 42 in 65% yield as a single diastereoisomer (Scheme 10). The reaction also works for alkene dienophiles but isomerisation to the enol ether is a 26 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Scheme 10 Reagents i CH Cl 25 °C 14 h 6mol% 41. side reaction. It is doubtful if this process is concerted but nevertheless the synthetic potential of these reactions has yet to be realised. 2 1,3-Dipolar cycloadditions Azomethine ylides Chiral azomethines 43 are generated by treating the corresponding secondary amine with aldehydes in boiling toluene.These species undergo regio- and stereoselective 1,3-dipolar cycloadditions with both imines and aldehydes (Scheme 11); for example the cycloadducts 44 and 46 were obtained in yields of 43 and 53% respectively as single diastereoisomers. In the chiral aldehyde case it is believed that the contributions to asymmetric induction from the chiral 1,3-dipole and chiral aldehyde are matched. Hydrogenolysis of the benzylic amines followed by hydrolysis of theN,Oand O,O-acetals gave the vicinal diamines 45 and vicinal amino alcohols 47 in yields of 83 and 95% respectively. This constitutes a very e.cient and elegant synthesis of polyoxamic acid 47. It has been demonstrated that unstabilised cyclic azomethine ylides 49 can be generated by treating 2,5-bis(trimethylsilyl) pyrrolidines 48 with two equivalents of silver .uoride in methylene chloride (Scheme 12). These transient species rapidly undergo 1,3-dipolar cycloaddition with methyl (E)-3-(6-chloro-3-pyridyl)prop-2- enoate giving mixtures of endo and exo stereoisomers 51 and 50 ratio 1 3 in 80% combined yield.The desired isomer was 51 but unfortunately the reaction was exoselective. Use of the corresponding cis-alkene gave a 62% yield of the exo-isomer in which the aryl group was equatorial. This intermediate has been converted to epibatidine. Intramolecular 1,3-dipolar cycloaddition of an azomethine ylide 53 has recently been employed as a key step in the synthesis of the tricyclic core of sarain A (Scheme 13). Hence heating amine 52 in boiling toluene containing paraformaldehyde gave 54 27 Annu.Rep. Prog. Chem. Sect. B 1999 95 19—38 Bn Bn N R N NH Ar 2 R N Ar Ph CO2H ii i Ar Ph N+ iii – NH2 44 O O O O R O 43 OH iv ii N Ph O CO2H HO O O iii OH NH2 O CHO O O 47 Pd(OH) ; iii HCl CH OH; iv 46 Scheme 11 Reagents i PTSA toluene 110 °C; ii H toluene 110 °C with H O removal. i – + N N TMS TMS Bn Bn N 49 48 Cl Bn Bn N Ar 45 CO2Et CO2Et EtO2C N Ar 50 51 Scheme 12 Reagents i 2 equivalents AgF CH Cl . in 97% yield presumably via the stabilised azomethine ylide 53. Three new chiral centres with the correct relative stereochemistry were established in one step. The yield dropped to 78% when the reaction was scaled to 7 g.Aza allyl anions Aza allyl anions are readily generated by treating the corresponding -stannyl imine with n-butyllithium at low temperature. These species undergo a variety of anionic cycloaddition reactions. Hence treatment of 55 with n-butyllithium in THF at78 °C gave aza allyl anion 56 which underwent intramolecular anionic cycloaddition and gave 57 in 45% yield as a single stereoisomer after an aqueous work up Scheme 14. The chirality at the protected secondary alcohols controls the absolute stereochemis- 28 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O CO2Et O CO2Et H NH2 i Bn N N + Bn N – OBn 52 OBn 53 O CO2Et H N Bn N H OBn 54 O) toluene 110 °C. Scheme 13 Reagents i (CH Scheme 14 Reagents i 4 equivalents n-BuLi THF,78 °C 2 h; ii H O.try at the three newly formed chiral centres in this concerted cycloaddition. Intermediate 57 was converted to coccinine. Nitrile ylides 60 in which the alkyl substituent R is not phenyl are rare. Recently synthetic equivalents to these species have been developed from heteroatom substituted 2-aza-allyl anions 59 Scheme 15. Hence when substrates 58a–c were treated with n-butyllithium in THF at 78 °C in the presence of an electron-rich dipolarophile in this case vinyltriethylsilane cycloaddition took place initially giving 61 followed by elimination of the heteroatom as the corresponding anion to give 62. Three di.erent heteroatoms oxygen nitrogen and sulfur were studied and oxygen gave the best yield of 62 97%.Normally nitrile ylides 60 react with electron-poor alkenes so these two methods to some extent complement each other. The chemistry can also be applied to cyclic systems 63 but in these cases the heteroatom cannot eliminate for geometric reasons. This chemistry gives rapid access to the biologically important azabicyclo[3.2.1]octane skeleton 64 in 90% yield. 29 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Scheme 15 Reagents i THF,78 °C BuLi. Ph O O i S S N Ph + N S S O O– O O 66 65 86% yield Scheme 16 Reagents i CH 67 Cl 25 °C. Nitrone cycloadditions The use of chiral C symmetric dipolarophile 66 in reactions with nitrones 65 has the advantage that the products arising from both the exo and endo transition states are identical.This drastically reduces the number of possible stereoisomeric products that can be formed. Hence reaction of 66 with 65 in dichloromethane at room temperature gave adduct 67 in 86% yield as a single diastereoisomer Scheme 16. Full experimental details on the preparation of dipolarophile dienophile 66 have recently been published. Catalytic asymmetric 1,3-dipolar cycloaddition of nitrones 68 to achiral ,-unsaturated imides derived from oxazolidinones 69 has been achieved Scheme 17. The catalyst is derived from binol ytterbium tri.ate and to get good enantioselectivity it is crucial to add 2 mol of amine shown per mol of catalyst. At present the catalyst loading is heavy 20 mol% but the results are remarkable.Nitrone 68 reacts with 69 in methylene chloride containing molecular sieves type 4Å and 20mol% of catalyst to give cycloadduct 70 in 92% yield. The endo exo selectivity for the cycloaddition is greater than 99:1 and the ee is 96%. Aza-C-disaccharides are emerging as new selective glycosidase inhibitors. A con- 30 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 + Yb(OTf)3 + N 2 O O O – i Bn +N N Ph 69 68 Scheme 17 Reagents i 20mol% ytterbium catalyst 4Å molecular sieves CH Cl 70 O 25 °C 5 h. AcO O + O– OAc 71 i or ii AcO O OAc Scheme 18 Reagents i toluene 110 °C; ii toluene 60 °C 10 kBar. venient entry to this class of compound involves 1,3-dipolar cycloaddition of cyclic nitrones 72 with carbohydrate derived enol ethers 71 followed by cleavage of the NO sigma bond Scheme 18. The cycloadditions are completely regioselective giving only the isomer 73 shown.73 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OH OH Catalyst O Bn N O Ph N O O OBut OBut N + 72 OBut OBut N O 31 COMe MeCO N2 EtO2C O – 2C R R + O i MeO2C EtO MeO2C O OTBDPS O OTBDPS OTMS OTMS 74 75 MeCO COMe EtO2C R O MeO2C O OTBDPS OTMS 76 Scheme 19 Reagents i 5mol% Rh (OAc) benzene 80 °C. The absolute stereochemistry is governed by the substituent on C3 on the glycal and C2 of the nitrone and in the case shown both are ‘matched’. With the purely thermal reaction the yield is 68% but when high pressure is applied the yield increases to 100%.Oxonium ylides Oxonium ylides are readily generated by reaction of carbenes derived from diazo compounds with carbonyl groups. To ensure good chemoselectivity ylide generation is usually intramolecular. Hence treatment of diazo compound 74 with 5mol% rhodium acetate in boiling benzene gave the transient oxonium ylide 75 which underwent 1,3-dipolar cycloaddition with electron-de.cient hex-3-ene-2,5-dione to give 76 in 47% overall yield. Substrate 76 contains the basic carbon skeleton of zaragozic acid Scheme 19. Trimethylene methanes Trimethylene methanes 78 are readily generated by heating an appropriately substituted vinyl cyclopropane 77 Scheme 20. These species behave as 1,3-dipoles and add to electron-de.cient O-benzyl oximes to give pyrrolidines 80 in good yield.Hence heating a neat mixture of 77 and 79 at 80 °C for 1.5 h gave 80 in 79% yield. Acetonitrile may be used as a solvent in these reactions. The vinyl acetals can be hydrolysed to give ester functionality. This represents one of the few dipolar cycloaddition methods for forming pyrrolidines in which the dipolarophile contains nitrogen. 3 22 Cycloadditions 22 Cycloadditions of stable trimethylsilyl ketenes with aldehydes have been used in the synthesis of the -lactone-containing natural products the panclinins Scheme 32 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 i O O O O O O + – + – 78 BnO N i CO2Me 79 O O N BnO CO2Me 80 Scheme 20 Reagents i 80 °C neat.O O TBSO 77 O TBSO O C i R H R1 R Me R1 3Si SiMe3 83 R1 = (CH2)6CH3 R = (CH2)7CH(CH3)2 + 81 82 O TBSO O SiMe3 R1 R 84 84% combined yield Scheme 21 Reagents i Et AlCl Et O,40—0 °C. 21. The cycloadditions are completely regioselective giving only -lactones as cis—trans mixtures of diastereoisomers. The absolute stereochemistry of the cycloaddition is controlled by the remote tributylsilyl protected secondary alcohol. Hence reaction of ketene 82 with aldehyde 81 in diethyl ether at40 to 0 °C in the presence of diethylaluminium chloride gave 83 and 84 in 84% combined yield and in the ratio of 4.9 1. Carbon desilylation was readily achieved using tetrabutylammonium chloride in THF at 90 °C and gave predominantly the trans-disubstituted -lactone which could be crystallised to isomeric purity.Photochemical Paterno—Buchi 22 cycloaddition of aromatic aldehydes with 33 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O O O i R R R N H Ph N N Ph Ph CO2Me 85 CO2Me CO2Me 86 Ph R N CO2Me O i N N Bn Bn N 90 89 87 ii HO O O O N N Bn Bn 88 Scheme 22 Reagents i h CH CN; ii H Pd/C. N N N 91 ii O N Bn N 92 Scheme 23 Reagents i h CH CN 1 h; ii HOAc pyridine CH CN 3 h re.ux. cyclic enamides has been used to prepare trisubstituted pyrrolidines regioselectively and with reasonable stereocontrol Scheme 22. Hence irradiation of benzaldehyde and cyclic enamide 85 in acetonitrile gave 86 and 87 in 65% combined yield ratio 1 4.4.Catalytic hydrogenolysis of the benzylic ether 87 gave 88 an intermediate in the synthesis of preussin. The central core of the manzamine alkaloids was rapidly constructed by a 22- 34 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Bu3Sn Bu3Sn i N N Ph BOC BOC H 94 Ph 93 Scheme 24 Reagents i 1.3 equiv. LDA THF—HMPA ratio 4 1 78 to 40 °C 20 h. – TfO S + S H i Me 95 96 Scheme 25 Reagents i LDA THF—N,N-dimethylpropylene urea 4 1,78 °C. photo-induced intramolecular cycloaddition of vinylogous amide with an alkene Scheme 23. Hence irradiation of 89 in acetonitrile for 1 h gave an unstable strained adduct 90 not isolated which underwent retro-Mannich reaction followed by cyclisation to give 91.Treatment of adduct 91 with pyridinium acetate in boiling acetonitrile gave the Mannich cyclisation product 92 in 58% overall yield from 89. 4 Sigmatropic rearrangements The 2,3-Wittig rearrangement has seen widespread usage in synthesis. However the aza version of this reaction is more di.cult and is usually only observed when there is substantial release of ring strain. The reasons for this are largely due to the fact that nitrogen is less electronegative than oxygen. However recently examples of this process have being appearing. The use of vinyl stannanes in this reaction helps give useful stereocontrol Scheme 24. Treatment of 93 with LDA in THF—HMPA 4 1 at 78 °C and then allowing to warm to 40 °C gives the aza-Wittig rearrangement product 94 in 71% yield as a single diastereoisomer.Since the tributyltin moiety can be replaced with a plethora of other functionalities this is synthetically a very useful group for directing the stereochemical outcome of a reaction. Thia Sommelet—Hauser rearrangement of sulfonium salt 95 takes place when it is treated with LDA in a solvent mixture of THF andN,N-dimethylpropylene urea ratio 4 1 to give 96 in 87% yield Scheme 25. What makes this reaction very special is that a quaternary chiral centre is generated with de 90% and the aromaticity of the ring is lost. 3,3-Sigmatropic rearrangements usually proceed at reasonably high temperatures. There have been numerous reports of anion accelerated 3,3-sigmatropic rearrangements.The .rst example of a radical accelerated rearrangement has now been reported Scheme 26. Treatment of substrate 97 with tributyltin hydride and a catalytic quantity of AIBN in re.uxing benzene gives the rearranged product 98 in 74% yield. A 35 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 • Bu3Sn Bu3Sn O Bu3Sn O O O O O [3,3] • • 97 Bu3Sn Bu3Sn H O O H CO2Et O OH i H 99 CO2Et 98 Scheme 26 Reagents tributyltin hydride catalytic AIBN benzene 80 °C. 90% yield 97% ee 2 CO2Et O BnO ii BnO OH H CO2Et 101 2 O iii H CO2Et 2 62% yield 98% ee CO2Et OH 100 Cl 0 °C. 102 Scheme 27 Reagents i 1mol% 7f CH Cl 0 °C 6 h; ii 1mol% 7f CH Cl 25 °C; iii 10mol% 7a CH possible mechanism is outlined in Scheme 26 though of course it is possible to draw other non-concerted pathways.5 Ene reactions Chiral Lewis acid 7f catalyses the ene reaction of a variety of alkenes with ethyl glyoxalate 2 Scheme 27. Hence treatment of methylenecyclohexane with aldehyde 2 in the presence of catalyst 7f 1 mol% in methylene chloride at 0 °C gave adduct 99 in 90% yield 97% ee. Good regioselectivity is observed for unsymmetrical alkenes. Hence reaction of alkene 100 with aldehyde 2 in methylene chloride at room temperature containing 1mol% 7f gave adduct 101 in 62% yield with ee 98%. Examples of 1,2-disubstituted alkenes are also reported. Hence treatment of cyclohexene with aldehyde 2 in methylene chloride at 0 °C in the presence of catalyst 7a 10 mol% gave 102 ratio endo exo 86 14 in 96% yield and 96% ee for the endo isomer shown.36 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O EtO N Scheme 28 Reagents i benzotri.uoride 5mol% 104 room temperature. 105 103 Me3Si Scheme 29 Reagents i toluene 110 °C 3 h. Previously reported ene reactions of 1,2-disubstituted alkenes were never catalytic in Lewis acid so this is a major advance in this area. Given the versatility of these copper catalysts it is remarkable that the reactions show such high chemoselectivities. Chiral Lewis acid catalysed ene reactions of electron-de.cient imines 103 with alkenes have also been employed for amino acid synthesis Scheme 28. Treatment of electron-de.cient 103 with 2-phenylprop-1-ene in the presence of 5mol% copper catalyst 104 in the unusual solvent benzotri.uoride at room temperature gave adduct 105 in 55% yield and 99% ee.The yield increased to 92% when two mol of alkene were employed. The N-tosyl group and ester groups were hydrolysed with hydrogen bromide in phenol. Under these conditions no racemisation or double bond isomerisation was observed. c X = SiEt3 yield 20% 2+ Tol2 N P Cu H P N Ph Tol2 Ts 2ClO4 – 104 i O Ph EtO N H Ts O O O O i OH OH Me3Si X X 106 107 a X = SnBu3 yield 90% b X = H yield 54% 37 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 6Electrocyclisations Heating trienes 106a–c in boiling toluene results in stereoselective electrocyclisation to give 107a–c Scheme 28. The yield is critically dependent on the nature of X with the best yield being obtained when XSnBu 107a 90%.It has been postulated that there is an attractive interaction between the tributyltin moiety and the secondary alcohol and this holds the molecule in the correct conformation for electrocyclisation however the silyl group and the oxygen group repel each other hence the low yield when XSiEt . References 1 Y. J. Hu X. D. Huang Z. J Yao and Y. L. Wu J. Org. Chem. 1998 63 2456. 2 S.E. Schaus J. Branalt and E. N. Jacobsen J. Org. Chem. 1998 63 403. 3 S.E. Schaus J. Branalt and E. N. Jacobsen J. Org. Chem. 1998 63 4876. 4 D.A. Evans G. S. Peterson J.S. Johnson D. M. Barnes K. R. Campos and K. A. Woerpel J. Org. Chem. 1998 63 4541. 5 S.L. Yao M. Johannsen R. G. Hazell and K. A. Jorgensen J. Org. Chem. 1998 63 118. 6 S.L. Yao M. Johannsen H. Audrain R. G. Hazell and K. A. Jorgensen J. Am. Chem. Soc. 1998 120 8599. 7 J. Thorhauge M. Johannsen and K. A. Jorgensen Angew. Chem. Int. Ed. Engl. 1998 37 2404. 8 D.A. Evans E. J. Olhava J. S. Johnson and J. M. Janey Angew. Chem. Int. Ed. Engl. 1998 37 3372. 9 D.A. Evans and J. S. Johnson J. Am. Chem. Soc. 1998 120 4895. 10 V. K. Aggarwal E. S. Anderson D. E. Jones K. B. Obiery and R. Giles Chem. Commun. 1998 1985. 11 S.R. Magnuson L. SeppLorenzino N. Rosen and S. J. Danishefsky J. Am. Chem. Soc. 1998 120 1615. 12 P. A. Grieco and Y. J. Dai J. Am. Chem. Soc.1998 120 5128. 13 J. E. Baldwin D. R. Spring and R. C. Whitehead Tetrahedron Lett. 1998 39 5417. 14 S.P. Kolis M. D. Chordia R. G. Liu M. E. Kopach and W. D. Harman J. Am. Chem. Soc. 1998 120 2218. 15 A. R. Renslo and R. L. Danheiser J. Org. Chem. 1998 63 7840. 16 W.R. Roush and R. J. Sciotti J. Am. Chem. Soc. 1998 120 7411. 17 J. A. McCauley K. Nagasawa P. A. Lander G. G. Mischke M. A. Semones and Y. Kishi J. Am. Chem. Soc. 1998 120 7647. 18 S.R. Gilbertson and G. S. Hoge Tetrahedron Lett. 1998 39 2075. 19 D. Alker L. M. Harwood and L. E. Williams Tetrahedron Lett. 1998 39 475. 20 L.M. Harwood and S.M. Robertson Chem. Commun. 1998 2641. 21 G. Pandey T. D. Bagul and A. K. Sahoo J. Org. Chem. 1998 63 760. 22 D. J. Denhart D. A. Gri.th and C. J. Heathcock J.Org. Chem. 1998 63 9616. 23 W.H. Pearson and B. W. Lian Angew. Chem. Int. Ed. Engl. 1998 37 1724. 24 W.H. Pearson and E. P. Stevens J. Org. Chem. 1998 63 9812. 25 V. K. Aggarwal R. S. Grainger H. Adams and P. L. Spargo J. Org. Chem. 1998 63 3481. 26 V. K. Aggarwal Z. Gultekin R. S. Grainger H. Adams and P. L. Spargo J. Chem. Soc. Perkin Trans. 1 1998 2771. 27 S. Kobayashi and M. Kawamura J. Am. Chem. Soc. 1998 120 5840. 28 F. Cardona P. Salanski M. Chmielewski S. Valenza A. Goti and A. Brandi Synlett 1998 1444. 29 F. Cardona S. Valenza S. Picasso A. Goti and A. Brandi J. Org. Chem. 1998 63 7311. 30 O. Kataoka S. Kitagaki N. Watanabe J. Kobayashi S. Nakamura M. Shiro and S. Hashimoto Tetrahedron Lett. 1998 39 2371. 31 S. Yamago M. Nakamura X. Q. Wang M. Yanagawa S. Tokumitsu and E. Nakamura J. Org. Chem. 1998 63 1694. 32 P. J. Kocienski B. Pelotier J. M. Pons and H. Prideaux J. Chem. Soc. Perkin Trans. 1 1998 1373. 33 T. Bach and H. Brummerhop Angew. Chem. Int. Ed. Engl. 1998 37 3400. 34 J. D. Winkler J. Axten A. H. Hammach Y. S. Kwak U. Lengweiler M.J. Lucero and K. N. Houk Tetrahedron 1998 54 7045. 35 J. C. Anderson and C. A. Roberts Tetrahedron Lett. 1998 39 159. 36 R. Berger J. W. Ziller and D. L. Van Vranken J. Am. Chem. Soc. 1998 120 841. 37 E. J. Enholm K.M. Moran P. E. Whitley and M. A. Battiste J. Am. Chem. Soc. 1998 120 3807. 38 D. A. Evans C. S. Burgey N. A. Paras T. Vojkovsky and S.W. Tregay J. Am. Chem. Soc. 1998 120 5824. 39 W.J. Drury D. Ferraris C. Cox B. Young and T. Lectka J. Am. Chem. Soc. 1998 120 11 006. 40 M. Bamba T. Nishikawa and M. Isobe Tetrahedron 1998 54 6639. 38 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38

ISSN:0069-3030    

DOI:10.1039/a808593e

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Synthetic methods Part (iii) Enzyme chemistry 2 A. J. Carnell Department of Chemistry Robert Robinson Laboratories University of Liverpool Liverpool UK L69 7ZD 1 Introduction The aim of this review is to provide the organic chemist with highlights of the literature in biocatalysis from the past year. It is by no means a comprehensive survey but represents a selection of transformations using novel or known biotransformations which might be of general interest to the synthetic organic chemist. Several general reviews have appeared,— in addition to reviews describing methods for improving biocatalyst performance and selectivity using cross-linked enzyme crystals (CLEC’s), immobilized and encapsulated biocatalysts. The preparation of highly sensitive biomolecules for the study of important biological mechanisms has been facilitated by some useful protecting group strategies which have been devised using hydrolytic enzymes. Speci.c reviews have appeared on Baeyer Villiger monooxygenases, — glycosidases and glycosyl transferases, enzymatic C—C bond formation, thiamine-dependent enzymes, and the application of -keto acid decarboxylases.2 Hydrolytic enzymes There seems to be almost no limit to the use of lipases for resolution of alcohols and carboxylic acids. All that is required is access to enough enzymes and the patience to test them under a variety of conditions in the hydrolysis and ester forming modes in aqueous organic or mixed solvents. For example Hiyama tested 84 commercially available lipases for the resolution of the acetoxyketone 1 (Scheme 1).The product hydroxyketone 2 can be transformed into 1-aminoindan-2-ol through oxime formation and diastereoselective hydrogenation. Of those tested Amano PS Meito QLand Fluka 62312 lipases were selected as optimal in terms of their E-values. Hydrolysis in phosphate bu.er (pH 7)—acetonitrile with Amano PS lipase led to highest selectivity (E250). By separation of the resolution products and hydrolysis of the acetoxyketone 1 using catalytic scandium tri.ate in order to avoid racemisation both 39 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 1 Scheme 2 enantiomers could be prepared in high yield and enantiomeric purity (45—47% 94—96% e.e.). A continuous chemoenzymatic process for the preparation of cypermethrine 6 involving four steps has been described by E.enberger (Scheme 2). The .rst step involves resolution of ( )-3-phenoxybenzaldehyde cyanohydrin acetate 3 with Lipase P in hexane using n-BuOH for the transesteri.cation.Highest selectivity was achieved using Celite-immobilized lipase where the immobilization had been performed at pH 4.5. The mixture of acetate 3 and alcohol 4 was then reacted with enantiomerically enriched acid chloride 5 to give a high yield of (1R,cis,S)-cypermethrine 6 with a 90% d.e. The unreacted acetate 3 could be recycled by distillation and racemization with triethylamine. The enantioselectivity of the enzyme was not a.ected by recycling although the activity diminished signi.cantly the reaction taking twice as long (15 h) on the fourth cycle as on the .rst.Adam and co-workers have carried out a comparative study of transesteri.cation 40 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 3 Scheme 4 versus hydrolysis for the resolution of synthetically useful threo-allylic diols (Scheme 3). Best results were obtained using Candida antarctica lipase fraction B (CAL-B) hydrolysis to a.ord enantiopure regioisomeric acetates 8 and 9 and highly enriched unreacted diacetate 7. In the nucleoside arena highly regio- and stereoselective deacylation of carbocyclic 3,5-di-O-acyloxetanocins has been achieved using lipases (Scheme 4). Treatment of the dibenzoyl derivative 10 with Lipase MY gave 3-monoprotected compound 12 with high regioselectivity and treatment of the diacetyl starting material 11 with lipase Type XIII from Sigma gave the 5-monoacylated derivative 13 with high enantioselectivity.These derivatives obviously have application in the synthesis of oligonucleotides. Understanding the roles of lipidated proteins in cell signalling processes is at the forefront of biological research. Waldmann has developed a clever and e.cient enzyme-labile blocking group strategy for assembling acid- and base-labile peptide conjugates containing palmitoyl thioesters and farnesyl thioethers. The N-terminus of a given peptide intermediate is protected as its p-acetoxybenzyloxycarbonyl (AcOZ) urethane derviative 14 (Scheme 5). Cleavage can be carried out under neutral conditions with acetyl esterase from oranges or Mucor miehei lipase.The lipase was used in cases where an organic co-solvent was required to solubilize the peptide in which case the esterase was inactivated. After cleavage of the acetate the resulting quinomethane 15 spontaneously fragments liberating the desired peptide conjugate 16. Characteristic S-palmitoylated and S-farnesoylated C-terminus peptides of the human N-Ras protein were synthesized using this very clean deprotection method. Combination with classical methodology allowed the synthesis of various .uorescent and modi.ed Ras 41 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 5 lipopeptides which were used for in vivo cell biology experiments. These experiments resulted in a model for the targeting of lipidated peptides and proteins to the plasma membrane by S-palmitoylation.In principle this enzymatic deblocking methodology is general since other acyl groups can be used with the appropriate hydrolytic enzyme. Waldmann has previously used PhAcOZ as a protecting group in phosphoglycopeptide synthesis cleaving with penicillin G acylase. In a highly e.cient approach to the synthesis of racemic and ()- and ()- conduritol C Ba� ckvall has used sequential palladium-catalysed 1,4-diacetoxylation and enzyme hydrolysis (Scheme 6). The palladium reaction used to convert the microbially derived diene 17 gave high trans selectivity for the production of the diacetate 18 when using phthalocyanine—O rather than the alternative MnO Chemical hydrolysis gave racemic conduritol C.Hydrolysis of the diacetate with Candida rugosa lipase gave a near perfect resolution. The diol 19 and diacetate 18 were then deprotected to give ()- and ()-conduritol C respectively. Key to the success of this strategy was the enzyme’s ability to recognize two acetates in one enantiomer of the substrate simultaneously. . N-Stearoyl-C -erythro-sphinganine diacetate 20 has been successfully resolved with regioselective primary acetate hydrolysis using immobilized Burkholderia cepacia lipase (SC lipase A) in a biphasic system (decane—phosphate bu.er; 10 1) in the presence of Triton X-100 (Scheme 7). The resemblance of this substrate to the natural triacylglycerol lipase substrates is noteworthy. The e.e. of the recovered (natural) ()-diacetate 20 could be enhanced by repeating the resolution.The native nonimmobilized enzyme showed low enantioselectivity but the high regioselectivity was 42 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 6 harnessed to a.ord the natural ()-monoacetate 21 from the ()-diacetate 20 which then could be selectively glycosylated at the primary position to form a glycosphingolipid. Due to the combination and relationship between functional groups in products of the Bayliss—Hillman reaction these materials provide valuable synthetic building blocks. Alcohols such as 22 and 23 have been successfully resolved using lipase PS acylation in acetonitrile to a.ord (R)-acetates 24 and 25 and unreacted (S)-alcohols. The acyl donor was isopropenyl acetate for 22 and vinyl acetate for 23.The E-values (349 for 22 and 424 for 23) obtained here were exceptionally high (Scheme 8). The lipase from Pseudomonas fragii has been little used in synthetic biotransformations. Crout has demonstrated its application in the preparation of a key intermediate 26 for the synthesis of carba-sugars (Scheme 9). Lipase catalysed acylation of alcohol 43 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—5Scheme 7 Scheme 8 Scheme 9 26 in a carefully selected solvent mixture (BuOMe containing 11% acetone) gave best results. The enantiopure acetate 27 could be obtained from the 91% e.e. material by recrystallizing the minor enantiomer from hot ethanol. 3Nitrile and epoxide hydrolysis Aliphatic ,-dinitriles 28 have been converted into -cyanocarboxylic acid ammonium salts 29 using either Acidovorax facalis 72W ATCC 55746 which contains a nitrilase or Comamonas testosteroni 5-M GAM ATCC 55744 containing nitrile hydratase and amidase activities.The acid salts were then converted directly to the lactams 30 by hydrogenation in aqueous solution without isolation of the intermediates. Only one of the two possible lactam products was produced from -alkylsubstituted ,-dinitriles resulting from -cyano group hydrolysis (Scheme 10). Conversions for both steps were generally high (80%) and no inactivation of the hydrogenation catalysts by microbial contaminants was observed. The microorgan- 44 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 10 ism Acidovorax facalis was heat treated (50 °C) for 1 hour before use in order to destroy an unwanted endogenous nitrile hydratase activity which was found to produce dicarboxylic acids.Rhone-Poulenc has patented the use of an immobilized recombinant E. coli strain containing a nitrilase from Alcaligenes faecalis for the enantioselective hydrolysis of 2-hydroxy-4-methylthiobutyronitrile to give the corresponding carboxylic acid. Furstoss discovered a surprising enantioselectivity enhancement e.ect when using a two-phase system for the enantioselective hydrolysis of p-bromo--methylstyrene epoxide 31 with Aspergillus niger crude cell extract. When carrying out the reaction in phosphate bu.er below the saturation point of the substrate the E value for the transformation was 20.However on using a substrate concentration way above the saturation point such that the substrate formed a second phase the E value increased 13-fold to 260 for the production of the (S)-epoxide 31 and (R)-diol 32 (Scheme 11). The authors ruled out the possibility of non-selective spontaneous hydrolysis occurring in the dilute system which might be lessened under biphasic conditions and so far have no explanation for the e.ect. The reaction was successfully carried out on 6 g of epoxide using only 75 ml of bu.er and 350mg of crude cell extract. 4 Oxidations Regioselective and asymmetric hydroxylations catalysed by enzymes continue to draw attention since these transformations are in many cases di.cult to control in chemical processes.Asymmetric -hydroxylation of long chain carboxylic acids 33 has been achieved using molecular oxygen catalysed by the -oxidase from peas (Pisum sativum). (R)-Hydroxyacids 34 were produced enantiomerically pure on up to a 1 mmol scale. Double and triple bonds oxygen and sulfur atoms were tolerated in the sidechain as long as they were at least three carbons away from the carboxylic acid group (Scheme 12). The major by-product was the next lower aldehyde formed presumably by decarboxylation of the intermediate -peroxyacid. Turner and Flitsch have shown that Cbz-protected piperidines are biohydroxylated with greater regioselectivity than the corresponding N-benzoyl analogues when incubated with the fungus Beauvaria bassiana ATCC 7159 (Scheme 13). Most substrates were regioselectively hydroxylated in the 4-position giving compounds 35 except N-Cbz-3-methylpiperidine and N-Cbz-2-methylpiperidine which underwent hydroxylation in both the 3- and 4-positions.Previous models proposed 45 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 11 Scheme 12 Scheme 13 for this organism emphasised the importance of a distance of 3.3—6.2Åbetween the site of hydroxylation and the carbonyl group which is the same for both N-Cbz and N-benzoyl protected piperidines. These results suggest that the distance to the aromatic side-chain is also important and that the active site of the enzyme contains a de.ned aromatic binding pocket. All of the biotransformations were run to completion leading the authors to suggest that enantioselectivity was unlikely.The commercially available chloroperoxidase is now showing promise for hydroxylation reactions. In combination with hydrogen peroxide or tert-butyl hydroperoxide it has been possible to hydroxylate a range of substituted alkynes 36 (Scheme 14). For R larger than methyl the e.e.’s of the product propargylic alcohols 37 were high (78—95%) although yields were in most cases disappointing due to substantial overoxidation of these products to the corresponding ketones 38. Two exceptions were RAcOCH and BrCH where alcohol yields were 52 and 65% respectively. Enantioselectivities with BuOOH as the oxidant were slightly lower although in contrast to hydrogen peroxide which must be added slowly owing to the catalase activity of the enzyme it has the advantage that it can be added at the beginning of the reaction.Stewart et al. have recently used their recombinant baker’s yeast strain which expresses cyclohexanone monooxygenase to examine 2- and 3-substituted cyclopen- 46 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 14 Scheme 15 tanones as substrates (Scheme 15). In contrast to 2-alkylcyclohexanones which from a previous study display high enantioselectivity where RMe or larger the 2-alkyl substituted cyclopentanones 39 required at least a four carbon substituent in which case optically pure (R)-ketone 39 and (S)-lactone 40 could be isolated from a single biotransformation (E200). As with the cyclohexanones the 3-substituted cyclopentanones 41 where RMe Et n-Pr or allyl were oxidized to give both regioisomeric lactones 42 and 43.However side-chains of n-butyl or larger gave regioselectively the 5-alkyl lactone 42 but the e.e.’s were low and absolute con.gurations were not determined. The di.erences between behaviour of cyclopentanones and cyclohexanones were ascribed to the relatively low energy barriers between alternative cyclopentane conformations and the accessibility of half-chair structures in this ring system. Hence for the 2-substituted series a larger side-chain which can be involved in additional active site interactions is needed for the cyclopentanones where energy di.erences between substituents in pseudoaxial and pseudoequatorial postions in the twist boat conformation are minimal.These additional interactions of the larger side-chains also appeared to be responsible for regioselectivity in the 3-substituted cyclopentanones. Brosa and co-workers have carried out microbial Baeyer Villiger reactions in 47 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 16 organic solvents and biphasic conditions. In phosphate bu.er the model substrate norbornanone 44 normally gives the regioisomeric lactones 45 and 46 in a 7 1 ratio with Pseudomonas putida ATCC 10007 a bacterium known to contain two types of monooxygenase enzymes MO1 and MO2. However on using 1 1 mixtures of bu.er and immiscible solvents the ratio of 45 46 was reduced to 2 1 (Scheme 16). Although reaction time was not greatly a.ected using water/octane use of toluene as cosolvent required longer reaction time (11 h).Conversion and reaction time using decanol either as a biphasic system or as a single solvent were not useful. The biotransformation also ran at a similar rate in toluene or octane and formation of lactone 45 was favoured being exclusive in the latter solvent. Chemical Baeyer Villiger reaction using tri.uoroperacetic acid gave a 14:1 ratio of lactones in favour of 45.No enantioselectivities were reported from this study. A chemoenzymatic method for enantioselective Baeyer Villiger reaction using a lipase enzyme Novozyme 435 has been devised by Guibe� -Jampel et al. The process is autocatalytic and uses dry media and urea—hydrogen peroxide as the primary oxidant. Lipase catalysed perhydrolysis of an -substituted cyclohexanone is enantioselective generating 6-substituted caprolactones and the corresponding hydroxyacids in enantiomericall enriched form. The intermediate hydroxyperacids generated by the lipase perhydrolysis are themselves oxidants for the Baeyer Villiger reaction making the process autocatalytic.The most widely studied Baeyer Villiger enzyme is cyclohexanone monooxygenase which has also been used for asymmetric sulfoxidation of aryl—aryl dialkyl sul.des and 1,3-dithioacetals in the past. A recent development has shown it to be e.ective for promoting enantioselective oxidation of organic cyclic sul.tes to sulfates. The requisite redox cofactor NADPH was recycled using the established glucose-6-phosphate dehydrogenase system.cis- and trans-4-benzyloxymethyl-1,3,2-dioxathiolane- 2-oxides 47 were resolved by CHMO both diastereoisomers giving the (4R)-cyclic sulfate 48 although the trans diastereomer reacted more slowly and with lower enantioselectivity. 48 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 17 Interestingly the relative rate and sense of enantioselectivity were reversed for the oxidation of 4-methyl-1,3,2-dioxathiane 2-oxides 49. trans sul.tes reacted faster than cis sul.tes and showed higher enantioselectivity (Scheme 17). A wide variety of alkyl aryl sul.des have been oxidized using the toluene dioxygenase (TDO) or naphthalene dioxygenase (NDO) systems contained in strains of Pseudomonas putida in order to provide more comprehensive data on this reaction.Notably the bioxidation of phenyl methyl sul.de with Pseudomonas putida UV4 was scaled up to give ca. 8 g (90% yield) of enantiopure (S)-sulfoxide. In general enantiocomplementary results were observed with TDO-catalysed (UV4) oxidation favouring the (R)-enantiomer and NDO (P. putida NCIMB 8859) favouring the (S)-enantiomer. Microbial cis dihydroxylation of azulene and non-aromatic polyenes has been demonstrated using P. putida UV4 (Scheme 18). Azulene 51 gave the enantiomerically pure (4R,5S)-diol 52 in 20% yield. A range of other trienes and dienes 53–56 gave (1R,2S)-diols 57–60 in around 30% yield all enantiomerically pure except the diol derived from cyclopentadiene which had a 20% e.e. Oxidation of cycloheptatriene gave dienediol 57 and achiral dienediol 61 in a 2 1 ratio.Interestingly dihydroxylation of these substrates with the Sharpless AD-mix- reagent gave much lower selectivities 5—40% e.e. NDO in P. putida strains 8859 or 9816/11 gave the same selectivity but lower yields for all substrates except for azulene and cycloheptatriene which were not transformed. Eupergit immobilized nucleoside oxidase from Stenotrophomonas maltophila was used to generate 5-carboxylic acid derivatives of nucleoside analogues. The enzyme had a broad speci.city for unnatural nucleosides and aristeromycin and neplanocin A were also good substrates. Substrates with a methyl group in the 2-position of the ribose ring or 2,3-acetonides of natural substrates were not accepted. The reaction 49 Annu. Rep. Prog.Chem. Sect. B 1999 95 39—58 Scheme 18 was scaled up to 20 gL and addition of quinol at 1 gL served to stabilize the enzyme enabling it to be recycled. 5 Reductions A novel cofactor recycling system for NADH and FMNH has been devised by Bhaduri et al. using H as the terminal reductant. This was coupled to lactate dehydrogenase and the conversion of pyruvate to lactate demonstrated with NADH being regenerated. The strategy is based on the relay of electrons from hydrogen via a platinum carbonyl cluster and the redox dye safranine O (Saf) 62 to NAD (Scheme 19). In order to overcome solubility and stability problems associated with cofactors and the cluster respectively a biphasic system was employed where the safranine O shuttled between the two phases.The salt [Saf] [Pt (CO) ] was prepared and used to supply the two redox components to the system. An enzyme called pyridine nucleotide transhydrogenase from Pseudomonas .uorescens NCIMB 9815 was cloned sequenced and overexpressed in E. coli allowing relatively easy preparation of large amounts of the enzyme. This enzyme catalyses transfer of reducing equivalents 50 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 19 between NAD(H) and NADP(H) and can be used to enhance a biotransformation process and in enzyme based analytical assays. Adam has obtained new isolates from soil for the enantioselective reduction of alkyl hydroperoxides. The organisms were selected using hydrogen peroxide to induce peroxidase transcription followed by addition of the hydroperoxide substrate.Of the strains isolated the best in terms of enantioselectivity was Bacillus subtilis which converted 1-phenylethyl hydroperoxide with modest enantioselectivity to a.ord the (S)-alcohol (30% e.e.) and the (R)-hydroperoxide (88% e.e.). Fungal systems Aspergillus niger Botrytis cinerea and Penicillium verrucosum carried out the conversion with opposite selectivity as does the previously used horseradish peroxidase which generally gives much higher e.e.’s. Fujisawa et al. have reported enantiocomplementary biocatalysts for the reduction of tri.uoroacetyl biphenyl derivatives 63 (Scheme 20). The chiral alcohol products have application in liquid crystals. Baker’s yeast in water—ethanol gave variable yields and e.e.’s depending on the R group in 63 for formation of the (R)-con.gured alcohols 64 resulting from Prelog selectivity.Geotrichum candidum acetone powder in phosphate bu.er—alcohol with supplementalNAD a.orded variable yields and high e.e.’s for formation of the (S)-con.gured alcohols 64. In most cases the alcohol co-solvent was octan-2-ol but where ROH or OMe propan-2-ol was optimal. A similar complementary set of biocatalysts has been determined by Fogagnolo and co-workers for accessing either enantiomer of a wide selection of 1-heteroaryl- and 1-arylpropan- 2-ols in high enantiomeric purity using microbial redox reactions (Scheme 21). Stereoselective oxidation of racemic alcohols 65 was achieved with Pseudomonas paucimobilis giving 40—47% yields of the (R)-alcohols in high enantiomeric purity (90—100% e.e.).The corresponding ketones 66 could be reduced using one of three microorganisms again giving high yields and exclusive selectivity for formation of the (S)-alcohols. The range of heteroaromatic groups in these substrates accepted by these organisms is particularly noteworthy. The use of redox enzymes for the deracemization of alcohols is an attractive approach. One can employ isolated enzymes with matched selectivity and the requisite cofactors in a two step procedure or a whole cell system which contains the necessary enzymes and cofactors to drive the deracemization to completion. Adam has reported the combination of glycolate oxidase from spinach and .-lactate dehydrogenase from Lactobacillus leichmannii for the deracemization of 2-hydroxyacids 67 via the - ketoacids 68 (Scheme 22).The .rst enzyme requires .avin mononucleotide and oxygen to function. The oxygen is reduced to hydrogen peroxide which can be decomposed with catalase in situ. The NADH required by the lactate dehydrogenase was recycled using the well established formate dehydrogenase system. Since it was necessary to run 51 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 20 Scheme 21 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 52 Scheme 22 Scheme 23 the second step (lactate DH) under nitrogen it was not possible to combine both steps and maintain high enantioselectivity (e.e.’s 67—91%) because under these conditions reduction of the ketoacid 68 to the opposite (S)-alcohol by the oxidase enzyme starts to compete.Notably phenyllactic acid was a poor substrate for this system and mandelic acid could not be transformed. Carnell et al. have recently shown that trans or cis indane-1,2-diols 69 and 70 can be deracemized using whole cells of Corynesporia cassiicola. As with the previously 53 Annu. Rep. Prog. Chem. Sect. B 1999 95 39—58 described substrate cyclohexane-1,2-diol the trans isomer reacted faster leading to 83% yield of the optically pure (S,S)-trans diol 69 (Scheme 23). The cis diol 70 underwent a similar transformation with both enantiomers being converted to the (S,S)-trans diol 69. Utaka has puri.ed a reductase enzyme to homogeneity (MW 37 KDa) from baker’s yeast and used it to carry out reduction of a range of typical substrates using the glucose-6-phosphate dehydrogenase system for cofactor recycling.1-Chlorohexan-2- one 1-acetoxyheptan-2-one methyl acetoacetate ethyl pyruvate 1-chloropentane- 2,4-dione and hexane-2,4-dione were all reduced to the corresponding alcohols in high e.e. (98%). Biotransformations with whole cells give signi.cantly lower selectivity in some cases. High speci.city constants (k/Km10—10 sM) and relatively low Michaelis constants (Km10 —10M) were measured for the substrates suggesting broad substrate speci.city of the enzyme. 6 Oligosaccharide synthesis The enzymatic synthesis of complex glycosides for the study of selectin binding continues to highlight the e.ciency of using biotransformations in this area.Thomas et al. have used galactosyl sialyl and fucosyl transferases to synthesize N-linked oligosaccharides terminating in multiple sialyl-Lewis (SLe)and GalNAc-Lewis determinants. Lubineau et al. have synthesized a 3 6 -disulfated Lewis pentasaccharide a candidate for human L-selectin using a chemoenzymatic approach. Wong et al. have synthesized .ve SLe dimers 73 and .ve SLe carboxylic acids 74 by coupling chemoenzymatically synthesized amino substituted SLe derivative 71 to homobifunctional cross-linkers 72 of varying chain length (Scheme 24). These derivatives were used in competitive binding assays to immobilized E- and P-selectin against a sialyl Lewis a polymer in order to probe the importance of multivalent interactions between the selectins and their natural glycosylated glycoprotein ligands.Particularly low IC values were observed for dimers where n3 and 6 and the strongest binding for the carboxylic acid derivative was where n2 for P-selectin. Hence optimal spacing between two SLe moieties could not be identi.ed. For the carboxylate a smaller entropy loss would be associated with n2 upon binding. Wong has also reported the use of a recombinant (13) galactosyl transferase for the synthesis of xenoactive -galactosyl epitopes. The interaction of epitopes bearing a Gal1—3Gal terminus on the surface of animal cells with anti--galactosyl antibodies in human serum is implicated in antibody-mediated hyperacute rejection in xenotransplantation.In a one-pot reaction an -galactosyl pentasaccharide was synthesized using the recombinant -(13) galactosyl transferase and -(14) galactosyl transferase both enzymes utilize the UDP-galactose donor. In situ cofactor recycling was employed to regenerate the expensive nucleotide donor and avoid product inhibition of the transferases. The e.ect of co-solvents on the stability and activity of -(1 4)-galactosoyl transferase from bovine colostrum and its ancillary enzyme UDP-galactose-4-epimerase was determined. Dimethyl sulfoxide and methanol could be used up to 20%v/v whereas tetrahydrofuran inactivated the transferase at 5%v/v. The former solvent mixtures were exploited for the galactosylation of the poorly water soluble coumarinic glucoside fraxin. 54 Annu.Rep. Prog. Chem. Sect. B 1999 95 39—58 Scheme 24 Montero and co-workers found that the regioselectivity of transgalactosylation of - and -xylose catalysed by -galactosidases depends on the source of the enzyme. Enriched mixtures of 4- 3- and 2-O--galactopyranosyl-xylose were obtained using the enzyme from E. coli bovine testes or Aspergillus oryzae respectively and for the corresponding -xylase derivatives the enzymes from A. oryzae lamb small intestine or Saccharomyces fragalis were required. A regioselective transglycosylation from p-NO--galactopyranoside to 1- deoxynorjirimycin was carried out using a-galactosidase from green coee beans. The major product was 6-O--galactopyranosyl-1-deoxynorjirimycin. Waldmann has reported the development of the tetrabenzylglucosyloxycarbonyl (BGloc) protecting group as an enzymatically removable urethane protecting function for peptide synthesis.BGloc amino acids are synthesized by converting amino acid allyl esters into the respective isocyanates followed by treatment with 2,3,4,6-tetra-O-benzylglucose and C-terminal allyl ester cleavage. The terminal urethane can be selectively cleaved by 55 Annu. Rep. Prog. Chem. Sect. B 1999 95 39¡X58Scheme 25 hydrogenation followed by hydrolysis with - and -glucosidase under mild conditions. 7 Carbon¡Vcarbon bond formation Kyoto Research Laboratories have scaled up an enzymatic process for the production of N-acetylneuraminic acid (Neu5Ac). A recombinant E. coli strain was used to overexpressN-acetylneuraminate lyase and -acyl-glucosamine epimerase. The two 56 Annu.Rep. Prog. Chem. Sect. B 1999 95 39¡X58enzymes were used simultaneously to convert 27 kg of N-acetylglucosamine (GlcNAc) and pyruvate into 29 Kg of Neu5Ac (77% conversion). 2-Keto-3-deoxy-6-phosphogluconate (KDPG) aldolase catalyses the reaction between 3-phosphoglyceraldehyde (3-PG) and pyruvate. -Glyceraldehyde is accepted as a substrate at 1% the rate of the phosphorylated substrate. Given the synthetic potential of 4-substituted-4-hydroxy-2-ketobutyrates Toone et al. investigated the variability of this component and the possibility that phosphorylated 3-PG analogues may serve as substrates. Using enzymes from E. coli and Z. mobilis there appeared to be no systematic universal variation in reaction rate in response to phosphorylation. Michaelis constants for the 3-PG analogues varied only modestly when compared with changes in turnover rates (k) showing that although the analogues were binding both the C-2 hydroxy and the C-3 phosphate are required for productive catalysis.Oikawa et al. have used a crude preparation of an enzyme from the fungus Alternaria solani to catalyse the two step conversion of prosolanapyrone II into ()- solanapyrones A and D (Scheme 25). The rst step is an oxidation catalysed by an oxidase activity evidenced by the requirement for molecular oxygen and the HO liberated. This gives a system containing an activated dienophile for the second step which is the rst example of an enzyme-catalysed Diels¡XAlder reaction. The E,Zisomer of prosolanapyrone II was oxidized but did not undergo cyclization. From partial purication and preliminary characterisation the authors propose that a single bifunctional enzyme is responsible for the two steps based on its chromatographic behaviour.References 1 S.M. Roberts J. Chem. Soc. Perkin Trans. 1 1998 157. 2 A. J. Carnell Annu. Rep. Prog. Chem. Sect. B Org. Chem. 1998 94 39. 3 J.B. Jones and C.-H. Wong Curr. Opin. Chem. Biol. 1998 2 67. 4 H. Holland Curr. Opin. Chem. Biol. 1998 2 77. 5 B. Schulze Spec. Chem. 1998 18 244. 6 T. Itoh Y. Takagi and H. Tsukube Trends Org. Chem. 1997 6 1. 7 M.T. Baust and P. Seufer-Wasserthal Spec. Chem. 1998 18 248. 8 A.R. Maguire and L. L. Kelleher Spec. Publ. ¡X R. Soc. Chem. 1998 216 116. 9 H. L. Holland J.-X. Gu D. Rie E. N. Vulfson and J. A. Khan Spec. Publ. ¡X R. Soc. Chem. 1998 216 128. 10 T. Pathak and H. Waldmann Curr. Opin. Chem.Biol. 1998 2 112. 11 J. D. Stewart Curr. Org. Chem. 1998 2 195. 12 S. M. Roberts and P.W. H. Wan J. Mol. Catal. B. ¡X Enzym. 1998 4 111. 13 J. Beecher and A.Willetts Tetrahedron Asymmetry 1998 9 1899. 14 D. H. G. Crout and G. Vic Curr. Opin. Chem. Biol. 1998 2 98. 15 W.-D. Fessner Curr. Opin. Chem. Biol. 1998 2 85. 16 U. Schorken and G. A. Sprenger Biochim. Biophys. Acta 1998 1385 229. 17 H. Iding P. Siegert K. Mesch and M. Pohl Biochim. Biophys. Acta 1998 1385 307. 18 A. Cipiciani M. Cittadini and F. Fringuelli Tetrahedron 1998 54 7883. 19 H. Kajiro S.-i. Mitamara A. Mori and T. Hiyama Tetrahedron Asymmetry 1998 9 907. 20 J. Roos U. Stelzer and F. Eenberger Tetrahedron Asymmetry 1998 9 1043. 21 W. Adam M. T. Diaz and C. R. Saha-MoÆØ ller Tetrahedron Asymmetry 1998 9 589. 22 N. Katagiri Y.Marishita and M. Yamaguchi Tetrahedron Lett. 1998 39 2613. 23 E. NaÆØ gele M. Schekaas N. Kuder and H. Waldmann J. Am. Chem. Soc. 1998 120 6889. 24 H. Yoshizaki and J.-E. BaÆØ ckvall J. Org. Chem. 1998 63 9339. 25 M. Bakke M. Takizawa T. Sugai and H. Ohta J. Org. Chem. 1998 63 6929. 26 N. Hayashi K. Yanagihara and S. Tsuboi Tetrahedron Asymmetry 1998 9 3825. 27 C. H. Tran and D. H. G. Crout J. Chem. Soc. Perkin Trans. 1 1998 1065. 57 Annu. Rep. Prog. Chem. Sect. B 1999 95 39¡X5828 J. E. Gavagon S. K. Fager R. D. Fallon F. E. Herkes A. Eisenberg E. C. Hann and R. DiCosimo J. Org. Chem. 1998 63 4792. 29 O. Faure-Bulle J. Rerrard C. David P. Morel and D. Horbez PCT Int. Appl.WO 98 18,941. 30 M. Cleiz A. Archelas and R. Furstoss Tetrahedron Asymmetry 1998 9 1839. 31 W.Adam W. Boland J. H. Schreier H.-U. Humf M. Lazarus A. Sa.ert C. R. Saha-Moller and P. Schreier 32 S. J. Aitken G. Grogan C. S.-Y. Chow N. J. Turner and S. L. Flitsch J. Chem. Soc. Perkin Trans. 1 1998 J. Am. Chem. Soc. 1998 120 11 044. 3365. 33 (a) S. Hu and L.P. Hager Biochem. Biophys. Res. Commun. 1998 253 544; (b) S. Hu and L.P. Hager J. Am. Chem. Soc. 1999 121 872. 34 M.M. Kayser G. Chen and J. D. Stewart J. Org. Chem. 1998 63 7103. 35 C. Brosa C. Rodriguez-Santamarta J. Salva and E. Barbera Tetrahedron 1998 54 5781. 36 B. K. Pchelka M. Gelo-Pujic and E. Guibe� -Jampel J. Chem. Soc. Perkin Trans. 1 1998 2625. 37 S. Colonna N. Gaggero G. Carrea and P. Pasta Chem. Commun. 1998 415. 38 D. R. Boyd N. D. Sharma S. A. Haughey M. A. Kennedy B. T. McMurray G.N. Sheldrake C. C. R. Allen 39 N. I. Bowers D. R. Boyd N. D. Sharma M. A. Kennedy G. N. Sheldrake and H. Dalton Tetrahedron H. Dalton and K. Sproule J. Chem. Soc. Perkin Trans. 1 1998 1929. Asymmetry 1998 9 1831. 40 M. Mahmoudian B. A. M. Rudd B. Cox C. S. Drake R. M. Hall P. Stead M. J.Dawson M. Chandler D. G. Livermore N. J. Turner and G. Jenkins Tetrahedron 1998 54 8171. 41 S. Bhaduri P. Mathur P. Payra and K. Sharma J. Am. Chem. Soc. 1998 120 12 127. 42 N. C. Bruce C. E. French PCT Int. Appl.WO 98 18,909. 43 W. Adam B. Boss D. Harmsen Z. Lukacs C. R. Saha-Moller and P. Schreier J. Org. Chem. 1998 63 7598. 44 T. Fujisawa Y. Onogawa A. Sato T. Mituya and M. Shimizu Tetrahedron 1998 54 4267. 45 M. Fogagnolo P. P. Giovannini A. Gurrini A. Medici P.Pedrini and N. Colombi Tetrahedron Asymmetry 1998 9 2317. 46 W. Adam M. Lazarus C. R. Saha-Mo� ller and P. Schreier Tetrahedron Asymmetry 1998 9 351. 47 A. J. Carnell P. C. B. Page and M. J. McKenzie Synlett 1998 774. 48 T. Ema Y. Sugiyama M. Fukumoto H. 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Kobayashi Y. Suzuhi and A. Ichihara J. Org. Chem. 1998 63 8748. 60 T. Kobayashi H. Oikawa M. Honma and A. Ichihara Biochim. Biophys. Acta 1998 1384 387. 58 Annu. Rep. Prog. Chem. Sect. B 1999 95 39&mdas

ISSN:0069-3030    

DOI:10.1039/a808596j

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

2 Synthetic methods Part (iv) Heteroatom methods Patrick J. Murphy Department of Chemistry University of Wales Bangor Gwynedd UK LL57 2UW 1 Introduction This report will focus on the organic chemistry of phosphorus sulfur silicon selenium and tellurium; the heterocyclic free radical and transition metal chemistry of these elements has been largely ignored as this will be covered elsewhere. 2 Organophosphorus chemistry The Baylis—Hillman reaction has attracted considerable attention and new methods for e.ecting this transformation are of current interest. Soai has reported the reaction of aldehydes 1 with acrylates using a range of chiral phosphines and has found that (S)-BINAP catalyses the reaction most e.ectively however only modest yields and ees are obtained (Scheme 1).The conjugate addition of LDA to vinylphosphonates 2 with in situ trapping of the enolate with an aldehyde and elimination of diisopropylamine leads to the formation of the Baylis—Hillman products 3 in good yields (Scheme 2). In a related process Warren has reported the addition of the amine 5 to vinylphosphine oxides 4 in the presence of TMSCl leading to the silylated intermediate 6 which on protodesilylation gave the -amino phosphine oxides 7 with excellent stereoselectivity (Scheme 3). TMSCl has also been reported to lead to improved yields for the addition of alkyl aryl and vinyl cuprates to -substituted vinylphosphine oxides. The phosphonium salts 8 have been shown to lead to predominantly E-alkenes in Wittig reactions with aromatic aldehydes;KHDMSwas found to be the base of choice for this process (Scheme 4). Tomioka and co-workers have reported an asymmetric HWE reaction mediated by the external chiral ligand 9; reaction of lithiated phosphonates 10 with 4-substituted cyclohexanones 11 in the presence of 9 led to the formation of the intermediate cis-alcohols 12 (together with the trans-isomers in 2—7% yield) which were eliminated to give the S-alkenes 13 in 51—84% ee (Scheme 5). Shibasaki has reported an interesting and potentially very useful Michael reaction of phosphonate ester 14 with enones 15 mediated by aluminium lithium bis(binaphthoxide) complex (ALB) in the presence of NaOtBu or n-BuLi leading to the adducts 16 59 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 —— CHCO R (S)-BINAP (20 mol%) CHCl 20 °C 62—327 h.RH Me; RMe Et i-Pr. Scheme 1 Reagents (i) CH CH 4-tert-butylcyclohexyl. Scheme 2 Reagents (i) RRC——O LDA THF 78 °C 30 min. R RH Me; REt Ph t-Bu PhCH Scheme 3 Reagents (i) 5 TMSCl (5 equiv.) THF,78 °C; (ii) TBAF THF. RPh p-MeOC H 2-furyl. with ees as high as 99% being obtained at the -position (Scheme 6). The combination of Sn(OTf) and N-ethylpiperidine in the HWE reaction of 2-.uoro-2-diethylphosphonoacetate with ketones has been reported to lead to high E-selectivities typically greater then 95 5 whereas the corresponding use of a magnesium based enolate system leads in some cases to the formation of Z-products (E:Z from 37 63 to 19 81). Nicolaou has reported the elaboration of a polymer supported methyl phosphonate to the precursors 17 which were cyclised to the macrocyclic lactones 18 by treatment with potassium carbonate.Further modi.cation of this methodology using 60 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 CH ; RPh 3,4,5-(MeO) C H . Scheme 4 Reagents (i) KHDMS 0 °C 2 h then 78 °C RCHO then rt 4 h. RMe Ph n-Bu PhCH Scheme 5 Reagents (i) n-BuLi hexane—PhMe,78—0 °C 1 h; (ii) NaOAc AcOH 30 min or KOH DMSO 50 °C 30 min. RPh vinyl aryl 1-naphthyl 2-naphthyl; RMe Ph t-Bu. Scheme 6 Reagents (i) ALB NaOt-Bu or n-BuLi THF rt—50 °C 72—140 h. a sort-pool combinatorial strategy led to a synthesis of ( )-muscone and a library of modi.ed muscones (Scheme 7).In two new variants of the HWE reaction the carbohydrate derived lactones 19 undergo reaction with the phosphonate 20 to give the ketene dithioacetals 21 (Scheme 8), whereas in a previously unprecedented reaction the phosphonate 23 undergoes reaction with the dithiocarbonate function of the substrate 22 leading to the TTF 24 in a reasonable yield (Scheme 9). 61 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 7 Reagents (i) K CO (5 equiv.) 18-crown-6 (5 equiv.) PhMe 65 °C 12 h. Scheme 8 Reagents (i) KHDMS THF,78—0 °C. Scheme 9 Reagents (i) 23 (10 equiv.) n-BuLi THF,78—0 °C. 62 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 10 Reagents (i) KHDMS 18-crown-6 (5 equiv.) THF RCHO 78 °C—rt 2h. RPh Bn PhCH—— CH C H i-Pr Cy.Scheme 11 Reagents (i) (EtO) (O)PCH Li (28) THF,78 °C 1 h; (ii) LDA RCHO 78 °C—rt 3 h. RAr 2-furyl cyclopropyl styryl. A new synthesis of Z-vinyl phosphonates has been reported using the bis(trifluoroethyl) phosphonate 25 which on reaction with aldehydes in the presence of KHMDS and 18-crown-6 leads to phosphonates 26 in excellent yields and moderate to good selectivity for the Z-isomer (Scheme 10). A related strategy has been reported for the synthesis of buta-1,3-dienyl phosphonates 30 in that bis-phosphonate 27 undergoes reaction with lithiated phosphonate 28 to give 29; reaction of this under standard HWE conditions leads to 30 as exclusively or predominantly the E,E-isomer (Scheme 11). Taillefer and Cristau have also reported the reaction of phosphonium diylide 31 with a range of electrophiles leading to the synthesis of styrylphosphines or the corresponding oxides or sul.des which depending on the electrophile used can be tailored to give either stereoisomer of the required compound (Scheme 12). A two step synthesis of -phosphonated cycloenones 33 can be e.ected by the alkylation of the dianion of -ketophosphonates 32 followed by ozonolysis and base-catalysed cyclisation (Scheme 13). Reaction of trimethylsilyl phosphites 34 with -haloacrylates has been reported to give the corresponding -phosphonoacrylates 35 in good yield under very mild conditions (Scheme 14). Tetramethylguanidine has been reported to be an e.ective catalyst for the 1,2-addition of dialkyl phosphites to imines aldehydes and ketones and 63 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 12 Reagents (i) Ph P(O)Cl then PhCHO; (ii) Ph PCl then PhCHO; (iii) Ph P(S)Cl then PhCHO; (iv) H O ; (v) S ; (vi) Si Cl . then Me S; (iii) NEt TsOH (65—88%). RRH Me Et. Scheme 13 Reagents (i) NaH THF then n-BuLi,CH ——CH(CH )Br (65—80% yield); (ii) O Scheme 14 Reagents (i) TMSCl NEt CH Cl 0 °C; (ii) 0 °C—rt 6 h. R REtO MeO Ph ()-menthyl; ZCN COMe CO Me; HalCl Br. the corresponding 1,4-addition to enones and acrylates. The presence of an electronwithdrawing group has also been shown to accelerate the uncatalysed addition of phosphites i-PrRPOH (Ralkenyl or alkynyl) to imines aldehydes and ketones and a Co(PMe ) mediated Reformatsky-type addition of -halomethylphosphonates to aldehydes and ketones has also been reported. Shioiri has reported that diethyl phosphorocyanidate [(EtO) P(O)CN] e.ects the homologation of carboxylic acids leading to the corresponding -hydroxycarboxylic acids 37 via the intermediates 36 (Scheme 15).64 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 15 Reagents (i) THF,20 °C (EtO) P(O)CN (2 equiv.) Et N; (ii) HCl (aq) 12h. Ralkyl aryl 2-naphthyl. Scheme 16 Reagents (i) n-BuLi THF,78 °C 1 h; (ii) electrophile (H O D O MeI allyl bromide TMSCl PhCHO). RMe Et i-Pr; RH Me alkyl; RRMe —(CH )— (n4 5); EH D Me CH —— CHCH TMS PhCH(OH).An unusual carbon to nitrogen migration observed during the reaction of lithiated alkyl phosphonates with N,N-dialkylcyanamides 38 leads to the formation of Nphosphorylamidines 39 (EH) in good yields; these products can be further modi.ed by reaction of the intermediate anion 40 with a range of electrophiles (Scheme 16). There continues to be interest in asymmetric organophosphorus chemistry including the appearance of a review on more recent aspects of the topic. The same author 65 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 17 Reagents (i) RCHO DBU; (ii) RCHO TMSCl; (iii) H. R()- menthyl ()-bornyl ()-1,2;5,6-di-O-isopropylidene--glucofuranosyl; Ri-Pr Ph Ar. has also reported the preparation of symmetric dialkyl 41 and trialkyl phosphites 42 which can be converted into the -hydroxyalkylphosphonic esters 43 with good des being obtained; the reaction is also applicable to aldimines with similar results being observed (Scheme 17).-Proline ethyl ester has also been reported to be useful as an auxiliary in the synthesis of chiral methyl p-nitrophenyl alkyl phosphonates [RP(O)(OMe)(pNOCH) Ralkyl Ph] via the corresponding N-prolinylphosphoramidates with des of 73¡X98% being obtained. Other reviews of note include reports on borane complexes of organophosphorus compounds and their use in the synthesis of chiral phosphine ligands and on the reaction of phosphorus acid halides with N-silylated organic compounds. 3 Organosulfur chemistry Kataoka has described a chalcogeno-variant of the Baylis¡XHillman reaction in which suldes and selenides act as catalysts for the reaction in the presence of a quantitative amount of titanium tetrachloride; for the example illustrated (Scheme 18) yields ranged from 69¡X85%.In a related process the thiolate or selenolate triggered tandem Michael/aldol reaction of acrylates with aldehydes leads predominantly to the synproducts 44 with modest stereoselectivity (Scheme 19). The regioselective opening of epoxides using (TIPS)SH in combination withDBUhas been reported to proceed with silyl migration to the oxygen oering a convenient synthesis of -silyloxythiols (9 examples 59¡X92%) (Scheme 20). The asymmetric Michael addition of thiols to ,-unsaturated ketones esters and thiolesters can be catalysed using (R)- LaNa tris(binaphthoxide) or the corresponding samarium complex; ees ranging from 56¡X90% were achieved.A controlled one-pot sequence of three Ad reactions can be initiated using ArSCl which after addition to an enol ether for example 45 undergoes reaction with a further enol ether substrate leading to the thiophanium ion intermediate 46 which is quenched with trimethylallylsilane to give 47 (Scheme 21). Other examples using silyl enol ethers and allylstannanes as quenches were also reported. 1,2-Dithiocyanates 66 Annu. Rep. Prog. Chem. Sect. B 1999 95 59¡X81Scheme 18 Reagents (i) Chalcogen TiCl CH Cl rt 1 h. XS Se; YS Se NBn; n0 1. Scheme 19 Reagents (i) RCHO PhSLi CH Cl 78 to 50 °C; (ii) (PhSe) MeLi—LiBr Et O 78 °C—rt.RMe Et t-Bu; RPh Ar 1-naphthyl 2-naphthyl C H C H ; XS Se. Scheme 20 Reagents (i) (TIPS)SH DBU THF 25 °C 12 h. Scheme 21 Reagents (i) p-TolSCl 78 °C CH Cl ; (ii) TiCl ; (iii) MeOCH——CH ; (iv) TMSCH CH——CH 0 °C 5 h. can be obtained from styrenes using CAN and ammonium thiocyanate in acetonitrile in good to moderate yields. A new method for the formation of silicon protected enethiols involves the deprotonation of thiirane S-oxides with LiHMDS leading to the rearranged intermediate lithium vinyl sulfenates which can be reduced in situ with 67 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 22 Reagents (i) 49 n-BuLi TMSCl; (ii) TMSOTf 2,6-lutidine,CH Cl ,78 to 25 °C.Scheme 23 Reagents (i) KHDMS 18-crown-6 THF,78 °C; (ii) BnBr. LiAlH and trapped with TBDMSCl (27—70% 7 examples). Magnus has reported that the benzylic sulfoxide 48 is an excellent substrate for the Pummerer reaction. For example the reaction with the -amino acid anion equivalent 49 led to the formation of 50 in quantitative yield o.ering an interesting synthetic strategy to the antibiotic gliovirin (Scheme 22). The addition of lithium bromide has been shown to lead to an increase in ee for the protonation of lithium enolates of ketones with chiral -sul.nyl alcohols. Treatment of bis-sulfoxide 51 with KHDMS has been found to lead to an e.cient desymmetrisation reaction leading to 52 a precursor in a total synthesis of the chitinase inhibitor allosamizoline (Scheme 23). A simple synthesis of chiral vinyl and dienyl sulfoxides can be e.ected by treatment of (S)-menthyl toluene-p-sul.nate 53 with two equivalents of methylenetriphenylphosphorane to yield the phosphorane 54 which on treatment with a range of aldehydes yields the E-Wittig products in reasonable yields and high ee (Scheme 24). An e.cient multi-gram resolution of p-tolyl vinyl sulfoxide has been reported based on the Michael addition of the sodium salt of menthol to the racemic material followed by separation of the two diastereoisomers and elimination of the menthol. Vinyl sulfoxides have been shown to be Michael acceptors in the reductive cyclisation of dienoates such as 55 (Scheme 25); stereoselectivity was high when the cis-derivatives were used and was less when trans-substrates were employed orHMPAwas used as an additive. 68 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 24 Reagents (i) PPh CH (2 equiv.) PhH rt 1 h; (ii) RCHO. RH vinyl E-CH CH——CH Ph Ar. Scheme 25 Reagents (i) Li(s-Bu) BH,30 °C 3 h then 10 °C 2 h. Scheme 26 Reagents (i) RLi or EtMgBr THF 78 °C 5 min. Rn-Bu t-Bu; RH PhCH CH Ar 1-naphthyl; RAr PhCH CH — 1-naphthyl alkyl. Sulfoxides have been employed in a new variant of the Julia—Lythgoe ole.nation whereby the -mesyloxy sulfoxides 56 (easily prepared from the corresponding sulfoxide and LDA followed by treatment with aldehyde RCHO and mesylation) undergo ligand exchange when treated with an alkylmetal (typically RLi) and elimination of the mesylate anion to give predominantly E-alkenes (Scheme 26). A modi.cation of the Julia reaction which employs 1-phenyl-1H-tetrazol-5-yl sulfones has been reported to give improved yields over the known benzothiazole variant when potassium or sodium hexamethyldisilazide are used as bases and DME is employed as the solvent. The intramolecular Michael addition of the carvone derived sulfone 57 leads to a stereoselective addition product 58 from which the sulfone functionality can be removed using samarium iodide leading to the overall formal addition of an acetate synthon via a temporary sulfur connection (Scheme 27). An interesting tandem reaction of the furan derived sultones 59 has been reported in which initial ring opening by an alkyllithium leading to 60 is followed by a 1,6-addition of a second equivalent of the base to give 61; subsequent alkylation and elimination leads to dienes 62 in good yields (Scheme 28). A convenient and high yielding synthesis of thiolesters involves the treatment of the corresponding alkyl thioacetylene with either tosic or tri.uoroacetic acid and silica in re.uxing dichloromethane. The coupling of thiols and acid chlorides mediated by activated zinc gives thiolesters directly in high yield and high purity. The conversion of secondary and tertiary amides to the corresponding thioamide can be e.ected by sequential treatment with tri.ic anhydride and hydrogen sul.de representing a useful alternative to traditional sulfuration methods. Symmetrical thiosulfonic S-esters 69 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 27 Reagents (i) DBU THF 0 °C; (ii) SmI THF MeOH. Scheme 28 Reagents (i) 2RLi THF 78—0 °C; (ii) ICH MgCl 70—25 °C. RH Me; RH n-Pr; RMe n-Bu. [RSO SR] can be prepared from the corresponding sulfonyl chloride by an acetyl chloride-activated zinc mediated reduction. Sul.nimines (thiooxime S-oxides) continue to attract attention indeed a recent review by Davis and co-workers details methods available for the synthesis of amino 70 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 29 Reagents (i) 63 (12 mol%) CuOTf PhMe 3Åmol. sieves 24 h. RPh 1-naphthyl 2-naphthyl ferrocenyl. acids using them as precursors. These intermediates readily undergo 1,2-addition reactions with a range of organometallics with recent examples including reactions with alkyllithiums, Grignard reagents and ester enolates. An indium metal mediated allylation of sulfonimines has also been reported. Other reviews of note include a comprehensive overview of the methods available for the synthesis of thiols selenols sul.des selenides sulfoxides selenoxides sulfones and selenones covering the literature published from mid 1997 to mid 1998. Reviews on the use of sulfur ylides in catalytic epoxidation and aziridation, the uses of sulfonyl 1,3-dienes in synthesis and the applications of 1,3-dithiane 1-oxide derivatives as chiral auxillaries have also appeared.4 Organoselenium and organotellurium chemistry It has been shown that the reductive coupling of selenocyanates can be e.ected using samarium diiodide in THF at low temperature the advantage of this method being that it tolerates substrates containing diverse functionality including esters ketones aldehydes cyanohydrins and enones. Catalytic asymmetric imidation of selenides is possible using TosN—— IPh in the presence of CuOTf and the bis(oxazoline) 63 with ees for the selenimides [RRSe——NTos] formed being in the range of 20—36% (5 examples).The reaction of allylselenides 64 proceeds with [2,3] rearrangement to give after aqueous hydrolysis the allylamines 65 in reasonable yield and with similar levels of enantiomeric enrichment (Scheme 29). Potassium 4-methylselenobenzoate acts as a selenating agent in the BF ·OEt mediated selenation of aliphatic or aromatic nitriles forming primary selenoamides [RC(Se)NH ] in high yields (11 examples 41—96% yield). ,-Unsaturated selenoamides 66 have been shown to react in a 1,4-fashion with alkyllithium reagents with diastereoselectivity of up to 94 4 at the -position; subsequent quenching of the intermediate adduct with allyl bromide gave 67 as the major diastereoisomer (Scheme 30). Reaction of corresponding saturated selenoamides with alkyllithiums leads to the net overall displacement of the amine function and deselenation to give ketones as products in high yields. Vinylselenides can be formed in reasonable yield by the Pd(..) catalysed hydroselenation of allenes, whilst 1-phenylthio-2-phenylselenation of alkynes can be e.ected using a (PhS) —(PhSe) binary system under photochemically generated free 71 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 30 Reagents (i) MeLi Et O 0 °C 10 min; (ii) allyl bromide 0 °C 1 h. Scheme 31 Reagents (i) DIBAH (PhSe) PhMe 50 °C 4 h; (ii) HCl (aq 1 M). RH Me Et n-Pr Ph vinyl; RH Me; RMe Et. Scheme 32 Reagents RNMe NHMe NEt pyrrolidin-1-yl NHCONMe ; RMe Et. radical conditions. The interesting allylselenides 69 have been prepared by treatment of the vinyl substituted acetals 68 with i-Bu AlSePh and are precursors to the - selenoaldehydes 70 (Scheme 31). Asymmetric oxyselenation of alkenes continues to attract considerable attention and the substrates 71, 72, and 73 all gave good yields in this reaction with reasonable to excellent selectivity being observed (Scheme 32).In addition oxyselenation of cycloalkenes with N-(phenylselenyl)phthalimide and (R,R)-or (S,S)-hydrobenzoin has been used in the synthesis of polyhydroxylated cycloalkanes however no stereoselectivity was observed in the addition step. Diselenide 74 has been found to be an e.ective mediator of arene—alkene cyclisation reactions giving excellent des; the presence of a catalytic amount of methanol was essential for the reaction to occur as it was found that the reaction proceeds via a -methoxyarylselenide intermediate (Scheme 33). An alternative method for the formation of -oxyarylselenides is the 72 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 AgOTf CHCl MeOH (3¡X5%),78¡X0 ¢XC 1 h. Scheme 33 Reagents (i) Br O¡Xpentane (4 1 1),100 ¢XC; (ii) RCHO; then RRC¡X¡XO; (iv) RCuMgBr THF 78 ¢XC 2¡X30 min. Rn-CH H n-CH Ph Tol aryl styryl; RPh Ar t-Bu i-Pr alkyl; RMe Scheme 34 Reagents (i) n-BuLi THF¡XEt (iii) CeCl n-C alkyl. BF¡POEt mediated ring opening of epoxides with tri-n-butylstannyl phenylselenoate which gives -hydoxyarylselenides in good to moderate yield. Transmetallation features heavily in organotellurium chemistry this year. Huang has reported that reaction of vinyltelluride 75a (XNHi-Bu) with two equivalents of n-BuLi leads to the intermediate organolithium species 76 which undergoes 1,2- addition reaction with aldehydes and ketones (on addition of cerium() chloride).The corresponding ester 75b (XOEt) has been shown to undergo 1,6-addition of organocuprates with concomitant elimination to give the E-products 77 in excellent yield (Scheme 34). The same group has reported that the organotellurium salts 78 undergo transmetallation with diethylzinc followed by addition to aldehydes ketones and esters in excellent yield. (Scheme 35) It has also been reported that aryltelluroesters [ArCOTeAr] undergo overall cis-1,2-addition to terminal alkynes on treatment with CuI in the presence of triethylamine followed by heating with trimethylamine hydrochloride. The reaction proceeds via an intermediate cuprous alkynylide which undergoes substitution at the telluroester function leading to an ,-alkynone which is susceptible to 1,4-addition of the arenetellurol formed in the second stage of the reaction; -aryltelluro-,-unsaturated ketones are thus formed in good yields.Telluroglycosides have been shown to be excellent glycosyl donors under neutral 73 Annu. Rep. Prog. Chem. Sect. B 1999 95 59¡X81 Scheme 35 Reagents (i) Et Zn RRC——O CH Cl rt. Rn-Bu i-Bu RH Ar vinyl; RAr alkyl; ECH —— CH TMSC—— — C Ph; XCl Br I BPh . conditions and it is possible to e.ect -or -selectivity through the choice of the C-2 sugar protecting group with benzyl leading to -selectivity and benzoyl to -selectivity. Reviews of note include monographs on the thioselenation of unsaturated C—C bonds using disul.de—diselenide binary systems, the synthesis of selenothioic and diselenoic acids, the isolation and stereochemistry of optically active selenium and tellurium compounds and the synthetic applications of organotellurium salts. 5Organosilicon chemistry Phenyldimethylsilyllithium [PhMe SiLi] 79 remains a versatile reagent for the introduction of a silyl group into organic moieties.Work of particular note has been performed by Fleming et al. who have investigated in detail the preparation and analysis of this reagent and its application in the cleavage of silyl enol ethers. They have also reported that the reagent will cleave the toluene-p-sulfonamides derived from secondary amines and indoles and also react with aziridine toluene-p-sulfonamides to give the products of ring opening in most cases. Their investigation of the reduction of -silyloxy ketones to ketones using this reagent has shown that the reaction proceeds via a Brook rearrangement leading to the formation of an intermediate silyl enol ether. Reaction of a slight excess of 79 with tertiary amides has been shown to lead to the formation of enediamines 80 in good yields; these intermediates are precursors to -amino ketones dienediamines and aminoenamines (Scheme 36). Investigations into the mechanism of this reaction have shown it to involve a carbene or carbenoid like intermediate. also e.ects 1,4-addition of the PhMe Si—group to enones (11 examples 35—100%). The metallation of the N-silylated benzyl carbamate 81 with a combination of In combination with a copper salt (typically CuCN) 79 has long been used for conjugate additions and epoxide ring openings however the need for a two fold equivalence of the reagent in forming (PhMe SiLi) CuCNLi and the use of stoichiometric amounts of copper have somewhat restricted its use.Lipshutz and co-workers have reported that the use of a stoichiometric amount of dimethylzinc in forming (PhMe Si)(Me) ZnLi followed by the addition of the higher order cuprate MeCu(CN)Li in a catalytic amount (3%) leads to e.ective formation of conjugate and ring opened products in high yields (9 examples 69—96%). In addition to this they found that Sc(OTf) had a remarkable catalytic e.ect on the reaction leading to an increase of rate to a level above that of the stoichiometric process. It has been reported that (PhMe Si) combined with a catalytic amount of (CuOTf) and P(n-Bu) n-BuLi and ()-sparteine leads to the formation of the corresponding -silylbenzyl- 74 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 36 Reagents (i) PhMe SiLi (79 1.1 equiv.) THF 78 to 20 ¢XC 1 h. Ralkyl aryl. Scheme 37 Reagents (i) s-BuLi ()-sparteine 78 ¢XC hexane or EtO. RMe i-Pr. Scheme 38 Reagents (i) RCHO CsF NaF or ZnBr DMSO DMF or THF 0.5¡X32 h. Ralkyl vinyl Ar Het-Ar. carbamate in excellent yield and with moderate ee (Scheme 37). The reduction of alkyl-1-(trimethysilyl)imine [n-PrC(¡X¡XNH)TMS] using lithium borohydride and -()- diethyl tartrate in THF leads to the formation of the corresponding -trimethylsilylamine [n-PrCH(NH )TMS] with a 60% ee.The tris-C,O,O-(trimethylsilyl)ketene acetal 82 reacts with aldehydes under Lewis acid or uoride catalysis to give E-alkenoic acids 83 in good to excellent yields and represents a mild alternative to more traditional methods for this transformation (Scheme 38). A Lewis acid catalysed [22] cycloaddition of crotylsilanes to methyl propiolate has been shown to be highly stereospecic leading cleanly to the cis-or transcyclobutene from the corresponding Z-or E-silane (Scheme 39). Allyl-tert-butyldiphenylsilane allyldiisopropylphenylsilane and allyltriisopropylsilane have been used in Lewis acid catalysed [32] cycloadditions to ,-unsaturated esters and ketones leading to silyl-substituted cyclopentenes which can be converted into the corresponding cyclopentanols using the Fleming¡XTamao oxidation protocol.The rst exclusive endo-dig carbocyclisation to be reported involves the HfCl catalysed allysilylation of the unactivated alkynes 84 which proceeds in moderate to excellent yields for a range of substrates (Scheme 40). The conjugate addition of allylsilanes to ,-unsaturated esters and ketones can be catalysed eciently using TMSN(OTf) generated in situ from HN(OTf) and the allylsilane employed. The bis-allylsilane 85 together with several related structures has been shown to be far superior in the TBAF mediated allylation of aldehydes than corresponding monoallysilanes; a stronger anity towards uoride ions leading to the chelate intermediate 86 is proposed (Scheme 41). Allylation of -hydroxyaldehydes with Z-crotyltrifluorosilane 87 in the presence of DIPEA leads predominantly to the formation of the 75 Annu.Rep. Prog. Chem. Sect. B 1999 95 59¡X81Scheme 39 Reagents (i) Methyl propiolate TiCl CH Cl ,78 to20 °C 19 h. Scheme 40 Reagents (i) HfCl (10 mol%) TMSCl (50 mol%) CH Cl 0 °C. RPh alkyl aryl; n0 1 2. Scheme 41 Reagents (i) TBAF. Scheme 42 Reagents (i) 87 (3 equiv.) DIPEA (3 equiv.),CH Cl 4Åmol. sieves 36 h. Rsubstituted alkyl. anti,anti-dipropionate stereotetrad 88 (Scheme 42). Allene 89 on treatment with t-BuLi undergoes -deprotonation followed by reverse Brook rearrangement to give enolate 90 which reacts with aldehydes leading to -hydroxy-,-unsaturated acylsilanes 91 in good yields (Scheme 43). Reaction of lithium enolates with -(2-pyridyl)acryloylsilanes 92 lead to the formation of the cyclopentenes 93 (major isomer) via a similar rearrangement process. A similar [43] annulation can be e.ected using lithium enolates of ,-unsaturated ketones 94 and -(trimethysilyl)acryloylsilanes 95 (Scheme 44). A [41] annulation of 76 Annu.Rep. Prog. Chem. Sect. B 1999 95 59—81 Scheme 44 Reagents (i) THF,80 to 30 °C. REt n-Pr i-Pr n-octyl. Scheme 45 Reagents (i) 96 97 98; 1.0 1.3 2.0 (C 78 °C 6 h. Scheme 43 Reagents (i) t-BuLi THF 78 °C 30 min; (ii) RCHO. Ralkyl vinyl styryl 1-naphthyl 1-furyl Ph Ar. F ) SnBr (0.2 equiv.) CH Cl 77 Annu. Rep. Prog. Chem. Sect. B 1999 95 59—81 30 ¢XC CHCl. Scheme 46 Reagents (i) SnCl Scheme 47 Reagents (i) TMSOTf Py CH CN,40 ¢XC¡Xrt; (ii) BF¡POEt.Ri-Pr Ph CH; n0 1. trialkylsilylvinylketenes with carbenoids providing a new route to cyclopentenones has also been reported. New methods for catalysing the Mukaiyama aldol coupling reaction continue to appear. The use of MgI SmI Bi(OTf) InCl (under aqueous conditions) polymer bound chiral Ti() complexes Sc(OSOCH) and bulky organoaluminium catalysts in combination with trialkylsilylsulfonates to mediate this reaction are all worthy of note. In addition Denmark has reported that readily prepared trichlorosilyl enolates react under chiral phosphoramide catalysis to give good levels of enantioselectivity. Otera has continued to investigate the strategy of ¡¥parallel recognition¡¦ in designing multi-component reactions and has demonstrated that discrimination between aldehydic and ketonic functions is possible in the one-pot reaction of substrate 96 with the ester 97 and ketone 98 derived silyl enol ethers catalysed by (CF)SnBr leading cleanly to the adduct 99 in 72% yield with no apparent cross over of reaction modes (Scheme 45).Anomeric silyl enol ethers for example 100 undergo rearrangement to give the -hydroxy ketones 101 in high yield and with moderate stereoselectivity 78 Annu. Rep. Prog. Chem. Sect. B 1999 95 59¡X81 (Scheme 46). In a process reminiscent of the Baylis—Hillman reaction enone 102 undergoes reaction with TMSOTf in the presence of pyridine to give the intermediate 103 which on treatment with cyclic acetals under Lewis acid catalysed conditions yields the enones 104 (Scheme 47). Addition of silyl enol ethers to imines and acylhydrazones has been catalysed in an enantioselective manner using a combination of Zr(Ot-Bu) (R)-Br-BINOL and either 1,2-dimethylimidazole in the case of imines or 1-methylimidazole for the acylhydrazones; ees as high as 98% being reported.Imines also react with silyl enol ethers under aqueous conditions in the presence of catalytic amounts of InCl and additions to acylhydrazones are catalysed by Sc(OTf) . Reviews of note related to organosilicon chemistry include a coverage of catalysed enantioselective aldol additions of latent enolate equivalents, a discussion of the use of bis(trimethylsilyl)acetamide and bis(trimethylsilyl)urea in synthesis, and overviews of counterattack reagents in organic synthesis and the chemistry of silylketenes.References 1 T. Hayase S. Shibata K. Soai and Y. Wakatsuki Chem. Commun. 1998 1271. 2 Y. Nagaoka and K. Tomioka J. Org. Chem. 1998 63 6428. 3 B. Bartels G. Martin A. Nelson M. G. Russell and S. 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ISSN:0069-3030    

DOI:10.1039/a808592g

出版商:RSC    

年代:1999

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2 Synthetic methods Part (v) Protecting groups Alan C. Spivey and Adrian Maddaford Department of Chemistry Brook Hill University of She.eld She.eld UK S3 7HF. E-mail a.c.spivey@she.eld.ac.uk Another excellent and comprehensive ‘update’ review of protecting group strategies in organic synthesis has appeared this year. Additionally a useful review focusing on enzymes as ‘reagents’ for protecting group manipulation (mainly esters and amides) has been published. O at 70°C (Kharasch—Sosnovsky 1 Hydroxy protecting groups The development of mild new methods for the cleavage of allyl ethers continues to attract attention. An interesting example is a new two-step procedure whereby sodium dithionate (Na S O )—sodium bicarbonate mediated (i.e.radical) addition of per- .uorohexyl iodide (C F I) in CH CN—H O (4 1) a.ords the corresponding -iodo- -per.uoroalkyl derivatives which undergo reductive elimination on treatment with Zn-powder and ammonium chloride in re.uxing EtOH to a.ord anomeric hemiacetals of carbohydrates, secondary alcohols and carboxylic acids from their respective allyl protected forms. Acetoxy and secondary hydroxy groups isopropylidene and benzylidene acetals thiophenyl ethers and trisubstituted double bonds are inert under these conditions (Scheme 1). Preliminary studies on the oxidative deprotection of allyl glycosides using tert-butyl hydroperoxide—copper(.) bromide in t-BuOH—H reaction via peroxyacetal intermediates) have also been disclosed but presently give moderate yields. Two new methods for the chemoselective O-methylation of phenols in the presence of alkyl alcohols have appeared LiOH·H O (1 equiv.) dimethyl sulfate (0.5 equiv.) in dry THF at 25 °C, and Cs CO (0.25 equiv.) in neat dimethyl carbonate at 120 °C. The former method which uses a minimum of dimethyl sulfate is compatible with benzylic primary amide and ester functionality and e.ciently methylates (R)-N-Boc tyrosine methyl ester without loss of optical purity.The latter avoids the use of dimethyl sulfate (which is toxic) and can also be applied to the preparation of methyl esters. 3-Pentyl ether protection of tyrosine has been advocated during segment coupling as it is compatible with both .uoren-9-ylmethyloxycarbonyl (Fmoc) and 83 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 Scheme 1 tert-butoxycarbonyl (Boc) based peptide synthesis strategies. Introduction employs NaH then 3-bromopentane in N,N-dimethylformamide (DMF) (no racemisation observed for N-Boc tyrosine) and cleavage employs neat tri.uoroacetic acid (TFA) 25 °C. Cleavage could also probably be e.ected using AlCl in CH Cl which has been reported to selectively cleave isopropyl aryl ethers in the presence of methyl aryl ethers. Phenolic triisopropylsilyl (TIPS) ethers are not stable to these conditions. The Boc group has been shown to be a useful group for the protection of highly hindered phenols such as 2,6-di-tert-butylphenol. The group is introduced using di-tert-butyl dicarbonate (Boc and deprotected using 3M aq.HCl—dioxane (1 1) at re.ux. Deprotection using TFA was unsatisfactory due to competing dealkylation and o-and p-realkylation by the liberated tert-butyl cation. O)—N,N-dimethyl-4-aminopyridine(DMAP) inCH CN orCH Cl Trityl ethers are popular acid labile protecting groups and a new method for their CH Cl. The expected selectivity for primary over secondary alcohols introduction under almost neutral conditions employs stoichiometric benzyl trityl ether (BTE) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) with 4Åmolecular sieves in ClCH is observed. Non-acidic deprotection of both trityl and monomethoxytrityl ethers can be e.ected using 1% iodine in MeOH allowing preservation of acetate and tertbutyldimethylsilyl (TBDMS) ethers providing the temperature is kept below 40 °C. A photo-labile trityl derivative the 9-phenylxanthen-9-yl (pixyl) group which undergoes heterolytic C—O bond cleavage on irradiation at 254 or 300nm in CH CN—H O in excellent yields has also been developed. Due to the enduring popularity of benzyl ether protection particularly in the .eld of oligosaccharide synthesis numerous new and selective methods for their deprotection continue to be reported.Of note is a new dual ‘primary benzyl ether deprotection and alkyl to thiophenylglycosyl’ conversion employing PhSSiMe ZnI Bu NI in ClCH CH Cl (a reagent combination introduced by Hanessian for the latter process).Of more general utility is the extensive work that has been reported this year on the e.ect of additives (both promoters and dopants) on palladium-catalysed hydrogenolysis. Thus Ti-loaded hexagonal mesoporous silica (TiHMS) signi.cantly accelerates the cleavage of primary and secondary benzyl ethers by hydrogen using 5% Pd—C in MeOH in the presence of acid-sensitive functionality such as TBDMS and 84 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 NAPO HO NAP = O O 10% Pd-C H2 EtOH 8 h BnO BnO BnO BnO 90% BnO OMe BnO OMe Scheme 2 tetrahydropyranyl (THP) ethers and dimethyl acetals. Elegant studies into the mechanistic details of hydrogenolysis with Pd—C (and homogeneous Pd systems) have highlighted the amphipolar nature of the Pd—H bond resulting in insights of use in synthesis. For example the use of speci.c amine dopants for tempering the reactivity of the Pd surface such that disubstituted alkenes benzyl esters and nitro functions can be reduced in the presence of phenolic benzyl ethers, mono- di- and tri-substituted alkene hydrogenation in the presence of O-benzyl and N-benzyloxycarbonyl (Cbz) groups, and the use of 2-naphthylmethyl (NAP) as a benzylic protecting group which is more labile to hydrogenolysis than the benzyl group thereby allowing sequential deprotection of the two (Scheme 2). Use of .uorous ‘tagged’ benzyl protecting groups during oligosaccharide synthesis has been shown to allow rapid .uorous-organic separation techniques although presently the yields of introduction of these groups leave much to be desired (51% for standard tribenzylation of a monosaccharide). Microwave thermolysis using clay supported ammonium nitrate (Clayan) in the absence of solvent o.ers a cost e.ective and environmentally benign method for the selective deprotection of alkyl and aryl p-methoxybenzyl (PMB) ethers in the presence of silyl ethers acetates esters double and triple bonds and benzyl ethers. O-2,4-Dimethoxybenzyl (DMB) protection of hydroxamic acids during parallel synthesis allows for clean deprotection by 5% TFA (triethylsilane as benzyl cation scavenger) in CH Cl . An economical method for the preparation of benzhydryl ethers would appear to be by re.uxing equimolar quantities of alcohol and benzhydrol with catalytic p-TSA in benzene in a Dean—Stark trap. In the area of ester protection of alcohols there have been further advances in non-enzymatic kinetic resolution of secondary alcohols via acylation using ‘synthetic’ chiral catalysts based on DMAP derivatives,— N-alkylimidazole containing tripeptides, TaCl —chiral diol complexes, and chiral diamines. Preparation of esters of highly hindered alcohols by reaction with an acid is frequently a challenging proposition but a number of excellent protocols have now been developed including the use of scandium tri.ate—DMAP and O,O-di(2-pyridyl) thiocarbonate —DMAP. An alternative protocol employs the acid anhydride with trimethylsilyl tri.ate (TMS-OTf). Selectivity for acylation of primary over secondary (or tertiary) alcohols is also challenging and stannoxane catalysed transesteri.cation with alkenyl esters (e.g.vinyl acetate), triphenylphosphine—carbon tetrabromide mediated transesteri .cation with ethyl acetate (or formate), and lanthanide tri.ate catalysed acylation with anhydrides all display useful levels of such selectivity. The utility of cerium(...) chloride (CeCl ) and copper(.) chloride for promoting selective C-10 [over C-7] acylation in 10-deacetylbaccatin III has also been investigated. Racemisation of optically labile secondary alcohols during esteri.cation can also prove troublesome and N-acylpyridinium tri.ates are recommended in such situations. Environment- 85 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 Ph Ph O O O O O AcO O AcO Bu4NNO2 (4 equiv.) Ac2O (1.5 equiv.) pyridine 0 °C O OMe O OMe O O NPh NHPh O N 93% Ac2O (1.2 then 1 equiv.) 40 °C Ph O O O AcO HO OMe Scheme 3 ally benign methods for the per-O-acetylation of polyols (particularly sugars) include using neat acetic anhydride (Ac O) with either Montmorillonite K-10 or Zeolite HSZ-360, both of which are cheap solids which can be readily recycled. A new ester group the 2,2-dimethylpent-4-enoate has been introduced as an oxidatively labile pivaloate equivalent. Use of pivaloate protection particularly for tertiary alcohols is often limited by the vigorous hydrolysis conditions required to e.ect cleavage.The 2,2-dimethylpent-4-enoate however can be removed by intramolecular 6-exo-trig lactonisation following either hydroboration—oxidation [9-borabicyclo[3.3.1]nonane (9-BBN)—H O ] or dihydroxylation [OsO —N-methylmorpholine oxide (NMO)]. The transformation of alcohols into N-phenylcarbamates using e.g. N-phenyl isocyanate is rarely considered as a protection step because deprotection requires drastic conditions (e.g. LiAlH in re.uxing THF or sodium ethoxide in re.uxing EtOH). However N-nitrosation of alkyl N-arylcarbamates at 0 °C in pyridine using acetic nitrous anhydride [AcONO generated in situ from Ac O—tetrabutylammonium nitrite (Bu NNO )] followed by addition of further Ac O and heating to 40 °C allows for e.cient deprotection of -.-glucofuranose derivatives without acetyl benzoyl pivaloyl or TBDMS migration. This innovation makes N-phenylcarbamate protection of alcohols much more attractive in the context of organic synthesis (Scheme 3).Toluene-p-sulfonates are generally prepared to enable S 2 type substitution rather than as an alcohol protection strategy. However following the development of interesting asymmetric ketone -tosyloxylation and alkene 1,2-tosyloxylation protocols using hypervalent iodine reagents mild methods for accomplishing their ‘deprotection’ have been developed utilising magnesium in dry MeOH. Methods for the selective deprotection of various silyl ethers are legion. Useful additions to the synthetic repertoire disclosed this year include the use of 1% iodine in MeOH and catalytic scandium tri.ate in CH CN—H O for selective deprotection of alkyl trialkylsilyl ethers in the presence of aryl trialkylsilyl ethers.Both systems are also successful for distinguishing di.erent alkyl trialkylsilyl ethers in favourable 86 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 SiMe3 O Me3Si 'SIL' O Si O O BASE O R H H O H H O MeO O O O P 'ACE' O O N O R = cyclooctyl for guanosine and uridine R = cyclododecyl for adenosine and cytidine O O 'TES' Uridine TrO Si Si O O iPr iPr iPr iPr H H H O O O NC 'THP' H P O N Tr = trityl Scheme 4 cases. Carbon tetrabromide in re.uxing MeOH or PrOH is also useful in this regard and can be used for deprotection of primary TIPS ethers in the presence of secondary ones. Tris(dimethylamino)sulfonium di.uorotrimethylsilicate (TAS-F) a commercially available anhydrous solid also appears to be a useful reagent for mild silyl ether removal in extremely base sensitive situations where alternative .uoride sources fail. This reagent has been used in DMF at 23 °C to successfully deprotect TBDMS and triethylsilyl (TES) ethers in complex natural product synthesis when tetrabutylammonium .uoride (TBAF) and HF—pyridine methods failed.Cerium(...) chloride heptahydrate (CeCl ·7H O)—sodium iodide in CH CN is also a useful reagent combination for nearly neutral deprotection of trialkylsilyl ethers in the presence of THP ethers. The versatility of pyridinium toluene-p-sulfonate (PPTS) as a cheap mild and selective acid catalyst has been highlighted by its use for primary TBDMS ether deprotection in the presence of primary N-Boc carbamates. Silyl protecting groups are gaining popularity for protection of 5-hydroxy positions during RNA synthesis using the phosphoramidite method.Traditionally this position is protected as an acid labile dimethoxytrityl (DMT) ether and the 2-hydroxy by a .uoride-labile TBDMS group. The ‘reversal’ of this orthogonality by employing .uoride-labile 5-protection and acid-labile 2-protection appears to produce cleaner RNA. Both 5-O-SIL-2-OACE and 5-O-TES-2-O-THP ribonucleoside phosphoramidites (Scheme 4) have been advocated although the former presently appears superior since .uoridolytic cleavage of the TES group induces partial cleavage of the 2-cyanoethyl phosporamidite group.Oxidative cleavage of silyl ethers yields either aldehydes or ketones. DDQ is 87 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 probably one of the mildest methods available for this transformation and is useful for the preparation of labile ,-unsaturated aldehydes from allylic TBDMS ethers and benzaldehyde derivatives from benzylic TBDMS ethers. A more vigorous procedure employs dinitrogen tetraoxide complexes of iron() nitrate [Fe(NO)¡PNO] and copper() nitrate [Cu(NO)¡PNO] either neat in CHCl or in CCl at 25 ¢XC. These conditions also eect oxidative cleavage of THP ethers acetals and thioacetals to give aldehydes and ketones.4,6-O-Phenylboronate diester protection of thioethylglycosyl donors during Niodosuccinimide (NIS)¡Xtriic acid (TfOH) mediated glycosylation appears to oer an interesting alternative to benzylidene acetal protection.A particular advantage is the easy introduction of this grouping by reuxing with phenylboronic acid in benzene with a Dean¡XStark trap and easy deprotection using the borate selective resin Amberlite-IRA-743 in dry CHCN at room temperature. The 1,1,3,3-tetraisopropyl-1,3- disiloxanediyl group can also be used for this same 1,3-diol protection. The advantage of this mode of protection is the ability to eect partial ring-opening at the sterically less hindered 6-position using polyhydrogen uoride. This and the chemistry of this group in a broader setting have been reviewed.A selective one-pot protection of the secondary alcohol of 1,2-diols using BuLi then di-tert-butylchlorosilane to form a cyclic silyl ether followed by Si¡XO ring-opening with BuLi at 78 ¢XC has been developed. This aords 2-(butyldi-tert-butylsiloxy)alkan-1-ols with excellent regioselectivities and as such represents an interesting alternative to the more readily accomplished selective protection of the primary alcohol. Selective mono-protection of the primary (i.e. 1-) position of 1,2-diols can be achieved by trityl protection (by virtue of the steric bulk of this protecting group) or benzylative or benzoylative ring-opening of dibutylstannylene acetals. However the large quantities of dibutyltin oxide required to form the stannylene acetals invariably present unwanted purication problems and so a new procedure employing just catalytic quantities of dimethyltin dichloride for the in situ formation of dimethylstannylenes during benzoylation should nd wide utility in synthesis (Scheme 5).2 Carboxy protecting groups TMS chloride catalyses the selective formation of aliphatic methyl esters from their corresponding acids in the presence of aromatic acids using 2,2-dimethoxypropane¡XMeOH at 25 ¢XC. As the reagents are cheap and all the by products are volatile this represents an attractive method. An intriguing new method for the synthesis of benzyl esters from their corresponding acids by simply heating in toluene with O-benzyl-S-propargyl xanthate (propargylprop-2-ynyl) has been described. The conditions are essentially neutral making the procedure useful for sensitive substrates and also for benzylation of other suitably acidic (pK below 8¡X10) functionality such as phenols and tetrazoles.Transesterication is another popular method for the preparation of esters and further mechanistic details of the alkali-metal alkoxide cluster catalysed procedure have appeared. Titanium() ethoxide has also been shown to be an eective catalyst for the preparation of hindered menthyl esters from ethyl or methyl ester precursors although the reaction fails for highly hindered tert-triphenylmethyl ester formation. Cleavage of highly hindered tert-butyl esters is 88 Annu. Rep. Prog. Chem. Sect. B 1999 95 83¡X95OBz OH OH PhCOCl (1.2 equiv.) Me2SnCl2 (0.01 equiv.) K2CO3 (2 equiv.) THF 25 °C 12 h OH OBz OH Ph Ph Ph Me 5% 90% via Me O Sn O Ph Scheme 5 generally achieved using excess TFA either neat or in concentrated CH Cl or CH CN solutions with cation scavengers such as anisole MeOH or trialkylsilanes added.A new method employs just two equivalents of commercial 100% nitric acid in CH Cl at 0 °C. As the liberated tert-butyl cation is rapidly scavenged by nitrate as 1,2-dimethylethyl nitrate (cf. poor scavenging properties of tri.uoroacetate) the addition of supplementary scavengers is unnecessary. Catalytic transfer hydrogenolysis of p-nitrobenzyl (PNB) esters using 10% Pd—C in MeOH with ammonium formate (or aqueous phosphinic acid) acting as hydrogen donor allows for clean deprotection in 3-cephems. 3-Cephems are notoriously prone to alkene isomerisation (to give 2- cephems) which occurred in this case when employing alkali-or .uoride-mediated hydrolysis.Alkaline hydrolysis is also problematic for the deprotection of peptide methyl esters as very careful control of pH is required to minimise racemisation in most cases. Tetrabutylammonium hydroxide (40% aqueous) in DMF or THF at 0 °C now appears to be the method of choice for this application particularly for poorly soluble non-polar peptide esters. These often hydrolyse very slowly and with unacceptable levels of epimerisation using alkali metal hydroxide hydrolysis. 3 Carbonyl protecting groups A new type of acetal protective group for aldehydes and ketones has been introduced the methylenephenylsulfone appended ethylene acetal. These are formed from 3- phenylsulfonylpropane-1,2-diol by re.uxing in benzene with a catalytic quantity of PPTS and can be readily cleaved by -elimination on treatment with 1,8-diazabicyclo[ 5.4.0]undec-7-ene (DBU 1.2 equiv.) in CH Cl .Such deprotection is complementary to conventional acid or Hg salt mediated cleavage of the ‘parent’ ethylene acetals (1,3-dioxolanes) for which a new protocol employing copper(..) chloride dihydrate in CH CN at 25 °C has been described. Catalytic quantities of CuCl ·2H O su.ce but the conditions do appear to be substantially acidic causing concomitant deprotection of TBDMS and THP ethers. A neutral and anhydrous alternative is the use of (trimethylsilyl)bis(.uorosulfuryl)imide [TMSN(SO F) (1.1 equiv.)] in CH Cl at 0 °C. This reagent can also be used in catalytic quantities (5 mol%) for the deprotection of dimethyl acetals of aromatic carbonyl compounds at 78 °C and aliphatic counterparts at 0 °C.1,1-Diacetates (acylals) are useful protective groups for aldehydes as they are particularly stable in basic media. Classical preparative procedures employ Ac O in conjunction with Brønsted or Lewis acids. Scandium tri.ate (2 mol%) in nitromethane has now been shown to catalyse this reaction, as has TMS iodide in CH CN or CHCl (generated in situ from TMS chloride and sodium 89 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 iodide), and commercially available zeolite-Y in neat Ac O. Aldehydes and ketones are occasionally protected as oximes during synthesis and furthermore the formation of an oxime from a carbonyl compound can often expedite its puri.cation and characterisation.Mild methods for regeneration of the carbonyl function from its corresponding oxime are still being sought. This year two new methods have been described one using silica-supported chromium trioxide (SiO —CrO ) and the other using the Dess—Martin periodinane to e.ect oxidative cleavage of the C——N bond. The former method gives excellent yields and involves pre-adsorption of the oxime onto the derivatised silica microwave (MW) irradiation for 45 s in a domestic 750W MWoven and elution from the silica. The latter method also gives excellent yields and employs 1.1 equiv.of the Dess—Martin oxidant in wet CH Cl at 25 °C for less than half an hour. It seems likely that the essentially neutral Dess—Martin reagent would be preferred in an acid sensitive molecule of some complexity for which pre-adsorption on silica would not be recommended. 4 Amine protecting groups In impressive studies directed towards the controlled synthesis of polyamine toxins isolated from the venom of spiders and wasps an orthogonal set of .ve independently removable amine protecting groups has been developed. The groups in question are i) Boc ii) N-(trimethylsilyl)ethanesulfonyl (SES) iii) N-allyl iv) N-phthalimido (Phth) and v) N-pyridine-2-sulfonyl. The conditions for their selective removal are as follows i) TFA—CH Cl 25 °C ii) CsF—DMF 90 °C iii) Pd(PPh ) —N,N-dimethylbarbituric acid (NDMBA)—CH 1.83mV (having previously removed the N-Phth group and reprotected as the tri.uoroacetate using TFA—Et be selectively deprotected using potassium carbonate in MeOH at 25 °C (Scheme 6).Cl 30 °C iv) N H ·H O EtOH re.ux and v) electrolysis N—CH Cl 0 °C). The tri.uoroacetate group can also 2-N-Ac Protection of .-glucosamine (GlcNH ) derived glycosyl donors during the synthesis of -GlcNAc and -GalNAc containing glycoconjugates is unsatisfactory due to the poor reactivity and poor anomeric -/-stereocontrol this group imparts (due to neighbouring group participation to give a 1,3-oxazolinium intermediate).Consequently numerous alternative protecting groups for the primary 2-amino group have been investigated.N-Phth protection in this context is widespread because of the -directing in.uence which the 2-N-Phth unit imparts to the glycosyl donor. However deprotection by prolonged heating with N H ·H O or ethylenediamine is often problematic in complex carbohydrates. The 4,4,5,5-tetrachlorophthaloyl (TCPhth) and 4,5-dichlorophthaloyl (DCPhth) groups have been advocated as alternatives which retain the advantageous -directing in.uence but allow cleavage under milder conditions. The DCPhth group is more stable towards basic conditions than the TCPhth group and has now been shown to survive deacetylisation benzylation benzylidenation and Lewis acid- silver salt- and iodonium ion-promoted glycosylation.The dimethylmaleoyl (DMM) group has also been touted for this role and appears to be an attractive choice in view of its good -selectivity stability during TMS-OTf mediated trichloroacetimidate glycosylation and ease of removal by treatment with NaOH and then dilute HCl (pH 5). The 2,5-dimethylpyrrole group has also been evaluated for use as a protecting group at this position and gives high yields 90 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 N O O S O N N N N BocHN O S O SiMe3 O Scheme 6 and high -selectivity in TMS-OTf promoted trichloroacetimidate glycosylation. The group is readily introduced using hexane-2,5-dione—Et N in MeOH is removed using hydroxylamine hydrochloride and is signi.cantly more base stable than Phth DCPhth or TCPhth groups.Interestingly it is stable to conditions required for the removal of the N-Phth group. The enhanced stability towards basic conditions of the 2,5-dimethylpyrrole group relative to Phth type groups also make this the group of choice for protection of anilines during nucleophilic aromatic substitution (e.g. copper( .) chloride mediated methoxylation of iodoaniline derivatives). E.cient protection of the side-chain primary amino functionality of lysine and ornithine residues during automated solid-phase peptide synthesis (SPPS) in a manner which allows for mild cleavage is also a challenge for which the Phth group falls short and for which solutions are valuable given current interest in the synthesis of cyclic and branched peptides.Monomethoxytrityl (MMT) and dimethoxytrityl (DMT) groups have been suggested for this role when using Fmoc based procedures but are incompatible with Boc based procedures. However the 1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl (Dde) group (the enamine of 2-acetyldimedone) is a promising alternative. It is stable to the acid (TFA) and base (20% piperidine—DMF) conditions employed during Boc and Fmoc based SPPS strategies but is readily removed with 2% v/v hydrazine in DMF. Furthermore providing allyl alcohol is added as a sacri.cial scavenger this hydrazinolysis is compatible with N-allyloxycarbonyl (Aloc) protection too. Two protecting groups closely related to Dde have been introduced this year the enamine of 2-isovaleroyldimedone (N-Ddiv), and the enamine of 2-acetyl-4-nitroindane-1,3-dione (N-Nde). The former displays slightly improved base stability and resistance to intramolecular NN migration relative to Dde and the latter has the advantage over Dde that its removal is readily monitored visually.All three groups show exquisite selectivity for introduction onto primary amines due to the formation of a strong intramolecular hydrogen bond making them attractive groups also for the synthesis of complex polyamines (e.g. spermidine derivatives) (Scheme 7). Another group which has been evaluated as a nitrogen protecting group which is orthogonal to Boc based peptide synthesis for the synthesis of cyclic peptides is the cyclohexyloxycarbonyl (Choc) group. This group is stable under the 1M TMSOTf —thioanisole/TFA Boc cleavage conditions but is removable with anhydrous HF.Selective N-benzoylation of less hindered amines in the presence of more hindered amines is possible using 2-chloro-N,N-dibenzoylaniline. The method is useful for discrimination between primary amines in sterically di.erent environments between primary amines and secondary amines and between secondary amines in sterically di.erent environments. The reagent which is an air-stable solid is readily prepared 91 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 Me Me O O H Me H Me Fmoc-(S)-Lys-OH FmocHN N O O R CO2H R O Dde R = Me Ddiv R = CH2CHMe2 H O O O Fmoc-(S)-Lys-OH H FmocHN N Me NO2 O O Me CO2H NO2 Nde Scheme 7 from 2-chloroaniline using BuLi¡Xbenzoic anhydride in THF at 25 ¢XC.A new and versatile method for the introduction of rigidifying constraints into amino acids and peptides is Ru-catalysed ring-closing metathesis. N-Allylation of amino acids and peptides is a relatively easy method for the introduction of the primary alkene functionality required for these reactions and has now been shown to be readily accomplished from N-Ts protected derivatives using allyl ethyl carbonate and 1 mol% allylpalladium chloride dimer. Should deprotection be required then a new method employing MeAl (3 equiv.) and (dppp)NiCl (4 mol%) in toluene can be employed. Diisobutylaluminium hydride (DIBAL 1.5 equiv.)¡X(dppp)NiCl (4 mol%) can be used for the analogous removal of N-allyl groups from primary or secondary amines.Deprotonated N-allyl- N-benzyl- and N-3,4-dimethoxybenzyl- methylbenzylamine are useful chiral ammonia equivalents for the synthesis of -amino acids via conjugate addition to acrylates. Selective deprotection to leave just the N-methylbenzyl group from these derivatives can be achieved by palladium or rhodium catalysed deallylation hydrogenolysis using Pearlman¡¦s catalyst [10% Pd(OH) on carbon] in MeOH and cerium() ammonium nitrate (CAN) in CHCN¡XHO or DDQ in CHCl¡XHO respectively. Further studies on the utility of the o-nitrobenzyl group as a photolabile benzyl protecting group have now established that this group can be eciently introduced onto (o-nitrobenzyl bromide¡XNaH¡XDMF) and removed from (h 300 nm) a number of indoles benzimidazoles and 6-chlorouracil.Carbamate protection remains one of the most valuable methods for the protection of amines both in natural product and peptide synthesis. Unsurprisingly therefore new methods for their introduction and removal continue to be developed. Of particular note is a new method for the introduction of common carbamate protecting groups simply by mixing the amine and appropriate chloroformate (ethyl isopropyl and benzyl) in benzene at 25 ¢XC in the presence of powdered zinc (1 equiv.). Excellent yields are observed and reaction times are generally under 20 min although electron decient anilines can take up to 6 h. Alkyl esters and tert-butyldiphenylsilyl (TBDPS) ethers are tolerated and the zinc can apparently be recovered and re-used. Six new 92 Annu. Rep. Prog.Chem. Sect. B 1999 95 83¡X95 methods for the deprotection ofN-Boc groups have been reported. Two closely related methods involving MW irradiation involve either pre-adsorption onto silica or pre-adsorption onto AlCl doped neutral alumina. Both methods are applicable to bothN-Boc amines and amides although the latter method appears to tolerate a wider range of potentially acid-and base-sensitive functionality (e.g. TBDMS ethers and benzyl ethers). A related method involving pre-adsorption onto Yb(OTf) doped silica followed by heating to 40 °C appears to be limited to the deprotection ofN-Boc amides which can be deprotected in the presence of N-Cbz carbamates and acetonides. Use of AlCl —anisole in CH Cl —MeNO (2 1) has been reported to successfully deprotect immobilised N-Boc-5-amino-2,5-dideoxynucleosides (on controlled pore glass CPG). The use of TFA in this instance resulted in unacceptable depurination at the 5-terminus.The use of TMS-OTf-2,6-lutidine in CH Cl at 25 °C is also su.ciently mild to allowN-Boc deprotection of peptides immobilised to resins via the Rink amide method (which is a TFA cleavable linkage). The strongly acidic ion-exchange resin Amberlyst-15 is also capable of deprotecting N-Boc amines and has the advantage that the released amino function becomes ionised and binds to the ion exchange resin thus allowing for separation and subsequent release from the resin by elution with ammonia-saturated methanol and evaporation. A specialised procedure for the introduction of carbamate protection onto the guanidino function of arginine via a silylated intermediate has also been disclosed. A one-pot conversion of N-Fmoc amino acids and dipeptides linked to Wang resin into N-Boc derivatives can be achieved in high yields using KF—Et N and either Boc O or S-Boc-2-mercapto-4,6-dimethylpyrimidine in DMF. This transformation is particularly valuable because unlike N-Fmoc derivatives N-Boc derivatives can be cleaved intact from Wang resin using trimethyltin hydroxide.A direct comparison of the e.cacy of the 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc) group and the Fmoc group with respect to N()-amino protection during the automated SPPS of peptides on PEG—PS and Wang-PS using standard (benzotriazolyloxy)tris- (dimethylamino)phosphonium hexa.uorophosphate (BOP)—diisopropylethylamine (DIEA) protocols has appeared. There appears to be very little to choose between the groups which are both base labile (via -elimination) although the Nsc protected peptides are substantially more polar than their Fmoc counterparts.Sulfonamide deprotection has again come under the spotlight and in particular some limitations to the thiolate cleavage of p-nitrobenzenesulfonyl (p-NBS) groups have been highlighted. Thus it has been found that deprotection (via S Ar substitution ipso to the sulfonamide) using thiophenol—DIEA in DMF is accompanied by signi.cant (up to ca. 11%) substitution ipso to the nitro group. This side reaction which seems to be most severe for cyclic amines generates 4-thiophenylbenzenesulfonyl protected amines which are essentially uncleavable.It was noted that the corresponding o-nitrobenzenesulfonyl (o-NBS) group did not su.er from this side reaction. The o-NBS group has also been examined as an alternative to Fmoc for SPPS. Advantages are reported to include i) deprotection liberates a yellow chromophore which allows visual or spectrophotometric con.rmation/quantitation of deprotection ii) the possibility of selective N-methylation of N-o-NBS protected nitrogen during peptide synthesis iii) the o-NBS amino acid chlorides couple more e.ciently to hindered amines than Fmoc ones and iv) o-NBS chloride is 10 times cheaper than Fmoc chloride. Furthermore since o-NBS groups cannot form 93 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 oxazolone intermediates it is possible that racemisation levels may be reduced. However it was noted that even for the automated synthesis of a hexapeptide a product of slightly lower purity relative to that prepared using Fmoc protection was obtained. Finally there has been an extensive study of methods for the cleavage of N-ptolylsulfonyl (N-Ts) from chiral aziridines (2-phenyl 2-benzyl and 2-carboxy-). Of the methods surveyed (M in liq. NH ,Mg in MeOH aromatic radical anions SmI hv) lithium with a catalytic amount of di-tert-butylbiphenyl (DTBB) in THF at 78 °C and Mg in MeOH at 25 °C with ultrasound were the best giving good yields of desulfonylated aziridines without detectable racemisation.Only the use of magnesium in MeOH was successful for the e.cient deprotection of sensitive 2-phenylaziridines. References 1 K. Jarowicki and P. Kocienski J. Chem. Soc. Perkin Trans. 1 1998 4005. 2 T. 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ISSN:0069-3030    

DOI:10.1039/a808598f

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

3 Organometallic chemistry Part (i) Palladium- and nickel-catalysed methods 1 Introduction Palladium and nickel salts/complexes are exceptionally versatile and robust catalysts for the construction of carbon—carbon and carbon—heteroatom bonds. A number of novel palladium and nickel catalysts have appeared in the literature this year. These include the discovery of novel homogeneous catalysts— 1 and 2 and heterogeneous catalysts 3 including palladium grafted molecular sieves. Palladacycle 2 proves to be an extremely active and robust catalyst in the Heck arylation of alkenes with turnover numbers of up to 5 750 000 and turnover frequencies up to 300 000. Novel .uorinated phosphine palladium complexes in supercritical carbon dioxide have also been used as catalysts in carbon—carbon bond forming reactions. Reviewed herein are the recent developments in palladium- and nickel-catalysed carbon—heteroatom bond formation cascade cycloadditions and cascade cyclisation reactions.Visuvanathar Sridharan a. R = 1- naphthyl X = OAc b. R = 1- naphthyl X = I c. R = 1- naphthyl X = Br Department of Chemistry Leeds University Leeds UK LS2 9JT R R P Pd 1 Ar'O OAr' X t-Bu Pd P R N Si 3 O P O Cl Pd 2 X R t-Bu 2 P Ar' = 2,4 -(t-Bu)2C6H3 Me Pd Me O P O 97 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 Me Me Me 2 Me PPh P 2 Fe P Me Me Me 4 5 2 2 Carbon–nitrogen bond formation Aromatic amines are an important class of compounds.They play a key role in a number of .elds which include pharmaceuticals agrochemicals photography and electronic materials. This section gives an update of the recent developments in palladium- and nickel-catalysed carbon—heteroatom bond formation as an extension to the last report. Hartwig’s and Buchwald’s groups have been engaged in developing novel second generation catalysts that can be used under mild conditions and have utilized them to increase the rate of carbon—nitrogen bond formation processes. Hartwig et al. have explored sterically hindered chelating phosphines 4–6 as ligands for palladium-catalysed carbon—nitrogen bond formation processes. P Me Me Me 2 Fe 2 P Me P Fe 2 6 Ligands 4–6 have two main advantages over conventional ligands that have been used in that they increase the rate of both oxidative addition (A) and reductive elimination (D) in the coupling processes (Scheme 1).The explanation for this increased activity with the ferrocenyl ligands (4–6) is that the sterically hindered alkylphosphines provide the required electron-rich metal centre while favouring ligand dissociation. This results in an increase in the rate of oxidative addition (A) the rate determining step in these catalytic processes. The catalytic cycle for the amination processes is presented in Scheme 1. Hartwig et al. have found remarkable rate enhancement for the coupling reactions with ligands 4–6. Unactivated aryl chlorides underwent coupling with aniline in excellent yield using 3mol% Pd(dba) and ligand 4 (Scheme 2).They also carried out amination of aryl toluene-p-sulfonates for the .rst time and synthesised mixed aryl—alkyl amines in high yield (Scheme 2). Ligand 4 allowed reactions between aryl bromides and aniline in excellent yield at room temperature (Scheme 3). Buchwald et al. have used the same hypothesis to develop ligand 7 for the amination of unactivated chlorides and bromides under mild conditions. Typical examples are shown in Scheme 4. 98 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 P P Pd NHR P P P Pd P A D Ar P P Pd Pd NHR P P t-BuOH C B Ar P Pd RNH2 O t-Bu P Cl + PhNH2 + BuNH2 OTs + hexylNH2 Scheme 1 Pd(dba) / ligand 4 NaOt-Bu dioxane 110 °C 4 h Pd(OAc)2 / ligand 6 NaOt-Bu toluene 85 °C 2 h Pd(OAc)2 / ligand 5 NaOC6H3-2,4,6 -(t-Bu)3 toluene 110 °C 2 h Br + PhNH2 Scheme 2 Pd(dba) / ligand 4 NaOt-Bu toluene rt 20 h Scheme 3 PCy2 Me2N 7 Annu.Rep. Prog. Chem. Sect. B 1999 95 97—115 X Ar X NaOt-Bu H Ph N 93% N Bu H 87% H N hexyl 83% H N Ph 94% 99 Pd2(dba)3 ligand 7 O N Cl R + HN O NaOt-Bu toluene 80 °C 91% O N DME rt 97% Me Br Me O + HN N O DME rt Me Me 97% MeO NC Me Scheme 4 Pd(OAc)2 P(t-Bu)3 Me R = OMe R = CN X + N NaOt-Bu xylene 120 °C N H X = Cl Br I 99% Br H Scheme 5 Pd(dba)2 N + NH2 OH OH ligand 9 NaOt-Bu toluene 60 °C <5 min 100% Scheme 6 Yamamoto et al. have used bulky electron-rich trialkylphosphine P(t-Bu) as a ligand for the amination of aryl bromides iodides and chlorides with diarylamines (Scheme 5).In the above processes use of BINAP as a ligand gave poor results. Kocovsky has also developed O—P N—P ligands 8 9 for amination processes. He found that these ligands exhibit a dramatic accelerating e.ect on palladium-catalysed amination of aryl bromides (Scheme 6). Several chelating aromatic phosphine based ligands have appeared in the past year for palladium-catalysed amination processes. Typical examples include Buchwald’s bis[2-(diphenylphosphino)phenyl] ether 10 and Uemura’s N-1-[2-(diphenylphosphino)--phenyl]ethyl-N,N-dimethylamine complex 11 (LPPh ).Palladium-catalysed amination processes have been carried out in water—methanol 100 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 R PPh PPh2 2 8 R = OMe 9 R = NMe2 PPh2 O 10 Me Br Me O + HN + X HN X = Cl Br mixtures using the water soluble chelating phosphine 12 in excellent yield (Scheme 7). Fort and Brenner have reported a liganded Ni catalyst for the amination of aryl bromides and chlorides under mild conditions (Scheme 8). Hartwig has further enhanced the scope of this process to synthesise azoles. Thus the combination of Pd(OAc) and DPPF catalysed the formation of N-arylazoles in the presence of Cs CO or NaOt-Bu with electron-rich neutral or electron-poor aryl halides in good yield (Scheme 9).For reactions of aryl halides possessing electrondonating substituents NaOt-Bu was a superior base to Cs CO . Beletskaya et al. have developed a similar Pd-catalysed process. Thus the arylation of benzotriazoles in water at 100 °C using TPPTS as the ligand proceeded in excellent yield (Scheme 10). Scheme 8 An intramolecular Pd-catalysed amination process has been successfully applied to the synthesis of functionalized pyrido[2,3-b]indoles in moderate yield (Scheme 11). One particular application of the amination process is found in the synthesis of indoles. Buchwald et al. have developed a novel Pd-catalysed cascade amination in combination with a Fischer indole process. This allows the synthesis of various substituted indoles in good yield (Scheme 12).Other applications are highlighted in the materials area. Polyaniline has attracted much attention in the .eld of organic conducting polymers due to its robust nature in the doped emeraldine state. Buchwald et Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 NMe2 PPh2 Cr(CO)2L 11 SO3Na Ar P Ar Ar P Ar SO3Na 12 Pd(OAc)2 / ligand 12 N Me Me O NaOH H2O / MeOH 75 °C Scheme 7 NaH t-AmOH 88% N 78% Ni(OAc)2 2,2' - bipyridine THF 65 °C 101 MeO NH Pd(OAc) or 2 / DPPF R Br+ Cs2CO3 or NaOt-Bu toluene 100 °C R = p-CN OMe t-Bu NC NH H N 2 N Ar = Ph p-MeC6H4 p-ClC6H4 SO3Na Cu(II) salt = P TPPTS = NaO3S Scheme 9 Pd(OAc)2 2 +N Ar2 IBF4 Cu(II) salt TPPTS NaOH H2O 100 °C SO3Na O O Br NH2 N Scheme 10 Pd2(dba)3 BINAP NaOt-Bu DMF 80 °C Me Scheme 11 al. have synthesised monodisperse controlled length and functionalized oligoanilines and triarylamine dendrimers via palladium-catalysed amination processes (Scheme 13).3 C–S C–P and C–C bond formation Zheng et al. have developed a palladium-catalysed C—S bond forming process using aryl tri.ates and thiols in the presence of Pd(OAc) and tolBINAP in toluene at 80 °C 102 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 N 98% N 98% Ar N N N 93 - 96% O Cu O Ph 2 O O N N Me 51% NH2 R N + Ph Ph Br R = Cl Me BOC N H2N H2N (i) Pd(OAc)2 6 mol% BINAP 7 mol% NaOt-Bu 2.8 eq toluene Et3N 90 °C (ii) (BOC)2O 3 eq DMAP 0.1 eq THF reflux R OTf R = t-Bu OMe Me R to generate phenyl sul.des (Scheme 14).Similarly Parker et al. and Saa et al. have reported a palladium-catalysed C—P bond forming process using Pd(PPh ) Et N in toluene at 130 °C in which phosphonate esters were formed in good yield (Scheme 15). Hartwig’s and Buchwald’s groups have independently reported the palladiumcatalysed arylation of amides esters and ketones. Typical examples of inter- and intramolecular -arylation of amides are shown in Scheme 16. The choice of base was Scheme 14 R TsOH•H2O Cl Pd(OAc)2 NH NH N Ph Ph n-C5H11 Me or O n-C Me 5H11 ketone O Me BOC N Scheme 12 NH2 + BINAP NaOt-Bu toluene 80 °C N 95% NH NCPh2 2 eq Br BOC BOC N NCPh2 (i) (ii) N 74% BOC 5 Scheme 13 Pd(OAc)2 n-BuSH + 83% S n-Bu tolBINAP NaOt-Bu toluene 80 °C 78-93% 103 Annu.Rep. Prog. Chem. Sect. B 1999 95 97—115 Ar Ar O N N Pd(PPh3)4 + Me Me P H N N Ph EtO Et3N toluene 130 °C Br P Ph OEt O 60% O NMe2 O Scheme 15 Pd(OAc)2 Me + Me N Me BINAP KHMDS Me Me 72% Me Me MeO Me Me Br Pd(OAc)2 O O N Me N Me BINAP KHMDS 80% O O Br Me Ar = p-t-BuPh Br MeO Me Scheme 16 Pd(OAc)2 + t-Bu BINAP NaOt-Bu toluene 100 °C t-Bu Scheme 17 crucial for the success of the above process.Best results were obtained when potassium hexamethyldisilazide (KHMDS) or lithium tetramethylpiperidide (LTMP) were used in dioxane as solvent. Buchwald et al. have also reported an asymmetric palladium-catalysed arylation of ketone enolates in good yields with good ee’s (Scheme 17) during the creation of the quaternary carbon centres. Other regiospeci.c palladium-catalysed arylation on the -position of , unsaturated carbonyl compounds with aryl bromides and arylation on the benzylic position of 4-alkylnitrobenzenes with aryl bromides have been reported (Scheme 18). 104 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 CHO Me + Me O2N Me+ R 2 2 1 X 1 one or two C component Table 1 Starter components for catalytic cascade cycloadditions Scheme 18 3' 2' 1 2 X two or three C component two C component 4 Cascade reactions The concept of cascade reactions involves careful design of multi-reaction ‘one-pot’ sequences so that the .rst step creates the functionality to trigger the second reaction and so on.This section is concerned with palladium- and nickel-catalysed processes in which two or more carbon—carbon/carbon—heteroatom bonds are formed. Cycloaddition cascades Grigg and Sridharan have proposed a new general scheme for palladium- and nickelcatalysed cascade cycloaddition processes in terms of ring sizes and applications. These processes involve combinations of a starter molecule which comprises a vinyl aryl allylic or benzylic halide tri.ate etc.with one (or more) acceptor molecules (alkene alkyne 1,2-diene 1,3-diene etc.). Carbon monoxide is also a valuable one carbon acceptor molecule and alkynes can function as the starter molecule via hydroor carbometallation. Some potential starter molecules are shown in Table 1. Five-membered rings. [41] processes. Several examples of nickel- and palladium-catalysed [41] processes have been reported by Negishi in which carbon monoxide was used as the one carbon component. Typical examples are shown in Scheme 19. Kundu et al. have successfully used alkynes as the one carbon component in the formal [41] cycloaddition palladium-catalysed process in which exocyc- Annu. Rep. Prog. Chem. Sect.B 1999 95 97—115 CHO Me Br Me Pd(OAc)2 PPh3 Cs2CO3 DMF 120 °C Br Pd(OAc)2 PPh3 Cs2CO3 H DMF 140 °C Y 70% 4 3 96% R O2N C 2 1 X X X three or four C component three atom component 105 CO2Et CO (40 atm) CO2Et CO2Et CO2Et I O 92% NiCl2(PPh3)2 Et3N MeCN 100 °C Pd(PPh3)2Cl2 82% CO2Et CO2Et CO (40 atm) CO2Et CO2Et n-Bu n-Bu I Ni(COD)2 PPh3 Et3N O 95% MeCN 100 °C H Ph I Scheme 19 Pd(0) / CuI HC CPh + O OH Et3N O O Scheme 20 lic alkenes were generated in moderate yields (Scheme 20). [32] processes. Most reported examples of .ve-membered ring formation have involved a [32] process. In this manner Larock et al. have developed a palladiumcatalysed regiospeci.c [32] cycloaddition process to synthesise 2,3-disubstituted indoles in excellent yield using disubstituted alkynes as acceptor molecules.Ujjainwalla and Warner have synthesised a 1H-pyrrolo[3,2-c]pyridine via a related process in good yield (Scheme 21). In this case Pd(dppf) Cl was found to be superior to Pd(OAc) as a catalyst. Back and Bethell have developed a palladium-catalysed [32] cycloaddition process to synthesise indolines in excellent yield using 1,3-dienes as the acceptor molecules (Scheme 22). The above process has been successfully transformed onto solid phase. Thus Wang and Huang synthesised indolines on Rink resin in good yield (Scheme 23). Alper and Yamamoto have developed novel palladium-catalysed [32] cycloaddition processes in which vinylic oxiranes react with unsymmetrical carbodiimides or activated ole.ns generating 1,3-oxazolidin-2-imine derivatives or tetrahydrofuran derivatives in excellent yield and high optical purity (Scheme 24).Reetz et al. have found nano structured nickel clusters catalyse the [32] cycloaddition of methylenecyclopropane and methyl acrylate in moderate yield (Scheme 25). A similar palladium-catalysed process has also been reported. Finally in the [32] theme 1,3-dipolar cycloadditions of nitrones and vinyl ethers have been found to be catalysed by palladium salts. Thus the diastereomeric adducts were obtained as a 1 1 mixture in 60% yield (Scheme 26). No reaction occurred without the catalyst in chloroform at 70 °C. 106 Annu.Rep. Prog. Chem. Sect. B 1999 95 97—115 N R NHX I CONH X = tosyl Six-membered rings. [42] processes. Larock et al. have used 1,2-dienes as acceptor molecules to prepare both novel nitrogen and oxygen containing heterocycles in excellent yield via palladium-catalysed [42] processes (Scheme 27). They have also synthesised both highly substituted isoquinolines and pyridines via a Pdcatalysed [42] process (Scheme 28). These processes utilise -iodoimines as the starter species and alkynes as the acceptor molecules. This process could also be adopted to synthesise analogous carbocycles via a [42] cycloaddition a typical Scheme 23 NHAc Pd(OAc)2 C C Me + I LiCl Na2CO3 NH2 DMF 100 ¡ÆC C C Si(Et)3 I I Scheme 21 Pd(OAc) Ts K2CO3 R2 Ts = tosyl + HOCH2CH2 R1 + NHCbz + Scheme 22 2 Pd(OAc) LiCl DIPEA DMF 100 ¡ÆC DMF / H2O H Annu.Rep. Prog. Chem. Sect. B 1999 95 97¡ª115 Ac N OH Pd(dppf)2 N Me 75% NH LiCl Na2CO3 SiEt3 Ts 60% R1 N R2 Cbz N DMF 120 ¡ÆC R 2 H N R = H R1 = R2 = H 83% R = CO2Me R1 = R2 = H 78% X O X N N 10% TFA / CH2Cl2 H O 90% 107 n-Bu N N O Cl Pd2(dba)3¡�CHCl3 N C N Cl + n-Bu O 92% ee 42% + Cl N O ¡© N n-Bu O L Pd+ H L 49% CN CN Pd(PPh3)4 + CN O O CN 90% (56:44) + 130 ¡ÆC THF rt CO2Me CO2Me 36% ¡© Me + N O + + OEt (S)¡©TolBINAP THF rt N O Scheme 24 Ni cluster Me Scheme 25 CHCl PdCl2(MeCN)2 3 Me N O OEt OEt 1 1 60% Scheme 26 example of which is shown in Scheme 29. Yamamoto et al. have published a series of papers concerning the palladium-catalysed [42] cycloadditions of enyne¡ªdiyne systems.These processes are regiospecic and occur characteristically in good yield (Scheme 30). They have also successfully developed an intramolecular version of the above process to prepare exomethylene paracyclophanes in excellent yield (Scheme 31). Palladium and nickel salts have also been found to catalyse intramolecular Diels¡ªAlder reactions (Scheme 32). A novel application of a palladiumcatalysed [42] cycloaddion process is reported in the synthesis of enantiopure 108 Annu.Rep. Prog. Chem. Sect. B 1999 95 97¡ª115 Me H Pd(OAc)2 N • + H H H I PPh3 Bu4NCl Na2CO3 DMF 80 °C O H H H Pd(OAc)2 OH • + MeO H Br H PPh3 Bu4NCl Na2CO3 DMF 80 °C t-Bu N EtO + I Me t-Bu N I HOH + 2C C C Scheme 27 Pd(OAc)2 2C C C PPh3 Na2CO3 DMF 100 °C Pd(OAc)2 PPh3 Na2CO3 DMF 100 °C X Pd(OAc)2 Scheme 28 C C + NaOAc Bu4NCl DMF 100 °C X = Br OTf TBSO 3)4 Bu + Scheme 29 Pd(PPh Bu (o-Tol)3P THF 100 °C Bu Hex Scheme 30 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 Me N 72% O O OMe 72% N CO2Et 99% Me N CH2OH 95% 86% OTBS Hex Bu 83% 109 O (OCH2CH2)n n = 2 3 O Me EtO2C TMS Br Br + R R = H R = OMe 110 Annu.Rep. Prog. Chem. Sect. B 1999 95 97—115 O O ( ) n Pd(PPh3)4 / PPh3 DMSO 100 °C n = 2 100% n = 3 95% Me O H 87% H EtO2C TMS Scheme 31 Pd(OAc)2 PPh3 THF 50 °C 10 min Ni(acac)2 Et2AlOEt P(o-FC6H4)3 70 °C 67% OtBu Br Scheme 32 OtBu Pd(OAc)2 PPh3 R 61 - 66% R R P Pd OAc 2 OtBu Bu4NOAc DMF / MeCN H H H R R = H 99% R = OMe 99% Scheme 33 NiCl2(PPh3)2 C60 + X C60 X Zn PPh3 toluene 90 ¡ÆC X = C(CO2Me)2 68% X = O 47% X = NTs 50% Scheme 34 CO2Me I CO2Me CO2Me I CO2Me ( ) n ( ) n [O] n = 1-2 80-90% CO2Me CO2Me ( ) n 90% ( ) n ¡� Scheme 35 Pd(OAc)2 I + NHBu N Bu X = C(CO2Me)2 X = O ¡� X = NTs CO2Me Pd(OAc)2 Et3N DMSO rt NHTs 80% E/Z (55:45) N Ts + PPh3 Bu4NCl Na2CO3 DMA 100 ¡ÆC 3 Pd(OAc)2 Bu PPh 4NCl I Na2CO3 DMA 100 ¡ÆC 57% E/Z (78:22) Scheme 36 estrone.Tietze et al. have synthesised the estrone precusor via a double Heck reaction in excellent yield (Scheme 33). They also prepared an aza heterocycle via a similar process in good yield. [222] process. Cheng et al. have described a nickel-catalysed [222] conversion of several ene diynes to C . These processes occur in good yield (Scheme 34). de Meijere et al. have reported a double Heck reaction on 1,2-dihalocycloalkenes.The initial adducts subsequently underwent a 6-electrocyclisation forming 111 Annu. Rep. Prog. Chem. Sect. B 1999 95 97¡ª115 OH NH2 + Me I NH2 O OMe Me Br O O OMe OMe Me OMe CO2Me Br CO2Me Br Pd CO2Me – CO2Me 112 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 Pd(OAc)2 LiCl i-Pr2NEt DMF 120 °C Me Scheme 37 Pd2(dba)3 (S)–BINAP Cs2CO3 Ag exchanged zeolite NMP 80 °C PdL O O Scheme 38 Pd(OAc)2 dppe KH THF 60 °C Pd Scheme 39 Me N 59% + NH2 OH Me 22% OMe Me O OMe 39% 63% ee (i) H2 Pd/C (ii) CAN O Me O O xestoquinone MeO2C CO2Me 70% MeO2C CO2Me Me AcO Me Me PdOAc H Br Br E E E = CO2Me benzene derivatives in good yield (Scheme 35).This is a formal [222] process leading to six-membered ring formation. Seven-membered rings. [52] processes. Larock et al. have described a palladium-catalysed [52] cycloaddition process to synthesise medium-size nitrogen heterocycles in good to excellent yields. In these examples 1,2-dienes were employed as the acceptor molecules (Scheme 36). Finally a formal palladium-catalysed [52] cycloaddition process has been developed by Dyker and Markwitz to synthesise benzazepine derivatives in moderate yield (Scheme 37). Scheme 41 Cyclisation cascades Shibasaki et al. synthesised ()-xestoquinone via asymmetric palladiumcatalysed cascade cyclisation reactions in moderate yield (Scheme 38).The use of silver O H Pd(PPh3)4 • Me AcOH CO 75 °C O O H Me O PdOAc PdOAc H O PdOAc Scheme 40 Pd(PPh3)4 E E E Bu4NCl xylene 80 °C E E E 68% 113 Annu. Rep. Prog. Chem. Sect. B 1999 95 97—115 exchange zeolite was found to be superior to Ag PO in obtaining high ee’s in this above process. A wide range of natural products have been synthesised utilising Pd-catalysed cyclisation processes as the key step. Such natural products include ()-physostigmine ()-physovenine, ()-laurequinone inhibitors of squalene synthase cp-225917 farnesyl transferase cp263114, antitumor antibiotic CC-1065, ()-crinamine, anatoxin, ()-valienamine, picrotoxinin, cardenolide and diazonamide analogues.Blame and Coudanne have reported in a series of papers a novel Pd-catalysed cyclisation process as an approach to the synthesis of hydrindane systems. These processes are similar to Wacker type cyclisation and occur in good yield (Scheme 39). In the cascade theme Yamamoto et al. have used allene and carbon monoxide as the relay species in their three-component cascade cyclisation process. These processes are regio- and stereospeci.c and occur in moderate yield (Scheme 40). Finally a novel bicyclic carbopalladation process with two geminal reaction centers has been used to construct bicyclic systems in good yield (Scheme 41). References 1 B.L. Shaw S. D. Perera and E. A. Staley Chem. 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ISSN:0069-3030    

DOI:10.1039/a808585d

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

3 Organometallic chemistry Part (ii) Transition metals in organic synthesis—stoichiometric applications Guy C. Lloyd-Jones School of Chemistry University of Bristol Cantock’s Close Bristol UK BS8 1TS 1 Introduction A selection of useful or unusual transition metal mediated reactions from the chemical literature of 1998 are reviewed below. Some reactions also involve transition metal catalysis in addition to the stoichiometric transition metal component. In all cases the reactions are organised by the transition metal group of the stoichiometric component with further subdivisions by reaction class or intermediates. 2 Applications Scandium ytterbium and the lanthanides Stoichiometric applications of these metals are scarce. However the dehydrogenative coupling of aromatic aldimines has been reported to occur on treatment with Yb metal and then an aromatic aldehyde as a hydrogen acceptor.Thus for example treatment of aldimine 1 with Yb and then 1-naphthaldehyde a.orded dimine 2 in 81% yield (Scheme 1). Titanium zirconium and hafnium Ole.nation. Ole.nations involving dithioacetal desulfurisation by titanocene reagents has been reviewed. Metallocenes. Zirconacyclopentadiene intermediates formed by reaction of zirconocene with acetylenes continue to be of interest. For example they may be crosscoupled with 3-iodopropenoates to a.ord cyclopentadienylacetate derivatives. Alternatively the two C—Zr bonds can be selectively cleaved by halogenating agents such as NCS NBS or I to a.ord 1,4-dihalogeno-1,3-dienes in good yield. Furthermore reaction with 2-iodothiophene in the presence of CuCl and DMPU furnishes thienyl dienes. The intriguing cyclophane 4 in which each pyridine is anti (X-ray crystallography) was prepared by reaction of zirconocene with bisacetylene 3 (Scheme 2).The 117 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 Ph N Ph i ii N Ph Ph Ph H N Ph 1 2 Scheme 1 Reagents (i) Yb; (ii) 1-naphthaldehyde. Cp Zr 2 TMS TMS TMS N N N i N N N TMS N TMS N Cp2Zr TMS TMS ZrCp2 TMS 3 4 Scheme 2 Reagents (i) Cp2Zr. i n-Hex ZrCp2 n-Hex Cl O N O Cl N 5 6 7 Scheme 3 Reagents (i) Ni(0) cat. dezirconated cyclophane (prepared by reaction with acetic acid) is much less rigid in solution according to comparative NMR experiments. Vinyl zirconocenes e.g.5 react smoothly with chloromethyl heteroaromatics e.g. 6 in the presence of Ni(0) to a.ord E-allylated heteroaromatics e.g. 7 in good yield (Scheme 3). 2-Bromophosphinines 8 react with zirconocene to a.ord 2-(phosphininyl)bromozirconocenes 9. These may then be transmetallated to Ni(0) resulting in dimerisation (to give 10) and subsequent decomplexation by addition of hexachloroethane a.ords 2,2-biphosphinine ligands 11 (Scheme 4). Azazirconocycles are the key intermediates in an e.cient process for meta-functionalisation of phenols protected with an ortho-lithiating group (Scheme 5). Thus lithiation of 12 followed by zirconocene addition and subsequent insertion of nitrile (RCN) a.ords 13 which on acidic hydrolysis gives 14. Diastereoselective synthesis of substituted dihydrofurans is facilitated by insertion of ketones into azazirconocycle 16 (prepared from cinnamaldehyde 15) and subsequent oxidative dezirconation then acidic cyclisation/dehydration to give 17 (98% de) (Scheme 6). Tricyclic compounds e.g.19 the skeleton of dolastane diterpenes can be constructed by elaboration of bicyclic zirconocenes 18 prepared by reaction of dibutylzirconocene with 1,6- or 1,7-dienes. 118 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 R2 R2 R3 R1 R3 R1 i P Br P Cp2(Br)Zr 9 8 ii R2 R2 R3 R3 R1 R1 R1 R1 R2 R2 P iii P P Ni PPh2 P R3 R3 Ph2P 11 10 Scheme 4 Reagents (i) Cp Zr; (ii) Ni(dppe)Cl; (iii) CCl. O O O O O O Zr(Cp)2 i ii iii iv N O R R 12 14 Scheme 5 Reagents (i) t-BuLi ; (ii) Cp Zr(i-Bu)Cl; (iii) RCN; (iv) HCl (aq).13 O Ar O iii iv v vi i ii N Zr Ph Ph Ph (¡Ó) 16 15 17 Scheme 6 Reagents (i) o-anisidine; (ii) Cp Zr; (iii) t-BuCOMe; (iv) pyr-N-oxide; (v) HCl THF; (vi) PPTS. H H O ZrCp2 HO n R H H O 20 19 18 The titanium() complex Cp TiPh promotes the reductive cyclisation of of - and -cyano ketones and also -ketoesters to give -hydroxy cycloalkanones e.g. 20 in good yield. Vinyl halides e.g. 21 are converted to allylic Ti() reagents on reaction 119 Annu. Rep. Prog. Chem. Sect. B 1999 95 117¡X136i ii Ph Cl OH Ph Ph 22 Scheme 7 Reagents (i) Cp TiCl and Me Al; (ii) PhCHO. with a reagent prepared from Cp TiCl and Me Al (toluene 3 days). The resultant Ti-allyl species react with carbonyl compounds.For example homoallylic alcohol 22 21 was prepared in 50% yield (Scheme 7). Miscellaneous. Reaction of vinyl zirconium species with phenyl iodanes a.ords vinyl iodonium salts which can be coupled with Grignard reagents in the presence of Cu(.) to a.ord E-1,2-disubstituted alkenes. The process occurs with retention of con.guration throughout the various steps. Lewis acids. TiCl strongly chelates -keto sulfones and allows their erythroselective reduction to -hydroxysulfones by pyridine—borane complex in non-coordinating solvent (CH Cl ) at low temperature. Vanadium niobium and tantalum Vanadium(.)-mediated deoxygenation and subsequent aldehyde elimination allows smooth conversion of -.uoro-,-dihydroxy acids 23 (and esters) to -.uorinated- ,-unsaturated acids 24 (and esters) with high selectivity for the Z isomer (Scheme 8). Chromium molybdenum and tungsten Carbene complexes.Fischer carbene complexes particularly of Cr continue to be of great interest and diverse application. For example MeC(OMe)——Cr(CO) reacts with keto-enynes such as 25 to a.ord aceto-furan derivatives e.g. 26 (Scheme 9). Similar processes with enediynes a.ord benzannulated products via Moore cyclisation. Chiral oxazolidinone bearing ene-carbamates 27 undergo diastereoselective photochemical reaction with a chromium ethoxycarbene complex to a.ord cyclobutanones e.g. 28 (RH) in high de (Scheme 10). By varying the R group in 27 the reaction can also be performed to generate -stannyl cyclobutanones (RBu Sn).The 2-alkoxycyclobutanones can be further elaborated by ring opening -bromination Baeyer—Villiger oxidation and photolysis in the presence of acetic acid to generate 2-acetoxy-5-alkoxytetrahydrofurans. Fischer carbenes undergo [3 2] cycloaddition with nitrilimines to produce -pyrazolinones. For example reaction of Nphenyl benzonitrilimine (generated in situ) with carbene 29 (Rmenthyl) a.ords 30 with high regio- and moderate diastereoselectivity. Intramolecular Friedel—Crafts type acylation reactions of Cr-carbene complexes are also possible. Thus treatment of 31 with ZnCl gave 32 in 67% yield (Scheme 11). A novel entry to the pyrimidine skeleton is provided by the reaction of ureas with alkynyl alkoxyWand Cr carbenes.120 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 OH OH CO2R i R R R F F CO2 R 23 Scheme 8 Reagents (i) VOCl 24 PhCl heat. R2 R2 O i O O R1 R1 25 26 Scheme 9 Reagents (i) MeC(OMe)——Cr(CO) . O O O R R i O O N N OEt Ph Ph Ph Ph 27 Scheme 10 Reagents (i) MeC(OEt)——Cr(CO) 28 h. OR OR Ph (OC)5Cr (OC)5Cr N Ph Ph Ph N 30 29 For example carbene complex 33 reacts with dimethylurea to a.ord alkylidenyl pyrimidine 34. Oxidative decomplexation a.ords the pyrimidinedione 35 (Scheme 12). Hydrostannylation and hydrosilylation of Cr-carbenes bearing an imidazolidinone chiral auxiliary proceed with high diastereoselectivity. Thus carbene 36 reacts with Ph SiH to a.ord 37 (96% de) (Scheme 13).The corresponding stannanes may be transmetallated and then alkylated. -Complexes. Enantiomerically pure substituted benzaldehyde—Cr(CO) derivatives e.g. 38 undergo samarium(..) diiodide mediated pinacol type coupling to produce after oxidative decomplexation with I solely the threo diols 39 as single enantiomers (Scheme 14). Apparently in the ketyl intermediates C—C rotation is restricted su.ciently such that no stereomutation occurs during coupling. Enantiomerically pure complex 40 underwent diastereoselective Suzuki coupling with 121 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 O Cr(CO)5 i O O MeO 32 31 MeO h CO. OEt O N O ii (OC)5W N N Ph Ph Ph 35 33 34 Scheme 12 Reagents (i) N,N-dimethylurea; (ii) CAN.OC SiPh3 O CO Cr O i OC Ph N Ph N Scheme 11 Reagents (i) ZnCl (OC)5W N O i CO N N Ph Ph 37 36 Scheme 13 Reagents (i) Ph SiH. O OH i ii H (OC)3Cr 38 39 THF; (ii) I . OH Scheme 14 Reagents (i) SmI boronic acid 41 giving 42 as a key step in the synthesis of atropisomerically pure O,O-dimethylkorupensamine A 43 (Scheme 15). The Cr(CO) -complex of anisole has been employed in a short enantioselective synthesis of ( )-ptilocaulin 44 with the key initial step being an asymmetric deprotonation—trimethylsilylation sequence. The bis-lithium amide base 45 was found to be highly e.ective in the enantioselective deprotonation of 1,3-dihydroisobenzothiophene chromium tricarbonyl complexes. Enantiomerically pure axially chiral Cr(CO) -complex generated from 5,6-dimethoxy- 1-tetralone was employed in an asymmetric total synthesis of putative helioporin D.The study allowed a revision of the structure of the natural product. A range of terpenoid-based chiral auxiliaries have been tested for diastereoselective induction in nucleophilic attack of alkoxyarene chromium tricarbonyl complexes. 2-Phenylisoborneol was found to be highly e.ective with de’s approaching 92%. The coordination of the Cr(CO) fragment to polycyclic aromatics (typically phenanthrene or anthracene) allows highly regioselective deprotonation—methylation. Aerobic oxidation 122 Annu.Rep. Prog. Chem. Sect. B 1999 95 117—136 Br O OMe OBn O MeO + Cr(CO)3 OMe B(OH)2 41 40 i OBn OMe OH OMe O O MeO MeO NH Cr(CO)3 OMe OMe 42 43 Scheme 15 Reagents (i) cat. Pd(0) Na CO . NH2 Li Ph NH HN H N Ph N Ph Ph Li H 45 44 decomplexes the products a.ording ring-methylated products in high yield. An ingeneous heterocycle construction sequence is facilitated by conjugate addition of salicylaldehyde to the Cr(CO) -complex of aryl allenyl phosphonates e.g. 46. On heating the resultant vinyl phosphonate 47 undergoes an intramolecular Horner—Wadsworth—Emmons ole.nation to give chromium-complexed heterocycle 48 in 87% yield (Scheme 16). The Do� tz benzannulation reaction of Cr(CO) —carbene complexes with hexyne has been employed for the generation of polycyclic arenes.For example 49 is converted into 50 in 62% yield (Scheme 17). A remarkable sequence involving [6 4] cycloaddition to Cr(0) complex 51 followed by oxidation a.ords the cycloadduct 52. Introduction of a bridgehead hydroxy group (via addition of Davis oxaziridine reagent to the enolate) then Tsuchihashi pinacol rearrangement a.ords the bicyclo[4.3.2]undecane structure 53 (Scheme 18). 123 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 EtO O EtO P H EtO i ii P(O) EtO . O O O Cr(CO)3 Cr(CO)3 Cr(CO)3 48 46 47 Scheme 16 Reagents (i) o-(OH)-PhCHO NaH; (ii) THF re.ux. OMe MeO OMe MeO i ii Cr(CO)5 TBDMSO Cr(CO)3 49 50 Scheme 17 Reagents (i) hex-1-yne; (ii) TBDMSCl Et N.O O iv v vi vii i ii iii H H Cr(CO)3 53 51 52 Scheme 18 Reagents (i) 1-acetoxybuta-1,3-diene; (ii) K CO ; (iii) Swern; (iv) KHMDS Davis reagent; (v) NaBH CeCl ; (vi) MsCl; (vii) Et AlCl. Miscellaneous. DMAP- and bpy-chlorochromates e.ect oxidative decomplexation of THP ethers to their corresponding carbonyl compounds in good yield. A short synthesis of ()-mitsugashiwalactone 54 has been developed utilising -tungsten alkynol chemistry. O H O H 54 Manganese technetium and rhenium Of these metals only manganese appears in mainstream organic synthetic applications. 124 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 Mn(CO)4 TMS ii i Ph N Ph N Ph N N N Ph Ph NH Ph 56 57 Scheme 19 Reagents (i) PhCH Mn(CO) ; (ii) TMS-acetylene.Organomanganese -compounds. Arylhydrazones undergo ortho-manganation in reasonable yields. Thus treatment of 55 with BnMn(CO) a.ords 56. Furthermore subsequent addition of alkynes leads to indenyl hydrazines e.g. 57 (Scheme 19). Allylation of aryl aldehydes by allyl chloride is readily e.ected in water by use of Mn metal in the presence of catalytic Cu (neitherMn nor Cu alone is e.ective). Interestingly aryl aldehydes react chemoselectively in the presence of aliphatic aldehydes and pinacol coupling is induced by acidic conditions. 55 Manganese ‘ate’ complexes. Treatment of 1,3-dihalopropene (halogenCl or Br) with n-Bu MnLi generates a butylated-allyl manganese complex which can be further reacted with electrophiles e.g.benzaldehyde. Iron ruthenium and osmium -Complexes. The reactivity and in particular the regioselectivity of attack of the Fe(CO) complex of cyclohepta-2,4-diene-1,6-dione (58) by nucleophiles and electrophiles has been explored. As part of the investigation 58 was converted to hinokitiol 59. Sequential addition of a cuprate Ac O and CO to iron-complex 60 O O O HO Fe(CO)3 58 59 a.ords azadiene complex 61. Meta-acyl aniline derivatives 62 are readily prepared from these by treatment withK CO (Scheme 20). Similar procedures can be used to generate meta-acyl alkyl benzene derivatives. Sodium triacetoxyborohydride e.ects decomplexation of -allyltricarbonyl iron lactone complexes.The resulting acyclic diols are obtained in reasonable yield and with high stereoselectivity (96% de). Intramolecular photothermal cyclisations of Fe—diene -complexes bearing a pendent alkene proceed in moderate yields. For example Fe-complex 63 is converted to pyrrolidinone 64 (in 12% yield) (Scheme 21). The reaction is hampered by isomerisation —in this case to give 65. The intramolecular cycloaddition (formally a Diels—Alder addition) of a diene tethered to a cyclobutadiene Fe-complex (66) gives tricyclic cyclobutene compound 67 (Scheme 22). A range of analogous reactions are also reported. Usage of the planar chirality of ferrocenes is a growing area. However 125 Annu. Rep.Prog. Chem. Sect. B 1999 95 117—136 Cu Li ; (ii) Ac O—CO; (iii) K CO . Ph Ph N N Ph H Ph 3Fe (OC)3Fe (OC)3Fe O O 65 63 64 Scheme 21 Reagents (i) hv. i (OC)3Fe O Scheme 20 Reagents (i) R Ph i N Ph (OC) O O 67 66 Scheme 22 Reagents (i) heat CAN. O H O CHO i ii N Fe Fe O 69 68 iii iv O O H R O HO v N R Fe H2N O (+ 68) 71 70 Scheme 23 Reagents (i) Na (S)-alaninate; (ii) Me COCl; (iii) LDA; (iv) RBr; (v) Amberlyst-15. 126 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 in the following example all of the chirality is central. Condensation of ferrocenecarbaldehyde 68 with (S)-alanine and then addition of pivaloyl chloride generates 69 in 98% de.This can be deprotonated with LDA and then alkylated by addition of RBr with complete retention of relative con.guration to a.ord 70. Hydrolysis a.ords a range of -alkyl--methyl amino acids 71 in very high enantiomeric excess (Scheme 23). The (-naphthalene)(-COD)Ru(0) complex 72 cleanly cyclotrimerises Ru 72 alkynes with loss of the naphthalene fragment to a.ord the corresponding (- arene)(-COD) complex. The -arene complexes of anisole with dicationic osmium pentammine have proved to be interesting substrates for a range of selective reactions that eventually generate functionalised cyclohexanones. For example reaction of complex 73 with CH (OEt) generates the electrophilic complex 74 which can then be reacted with silyl enol ethers to a.ord 75 (Scheme 24). Alternatively OEt CO2Me OEt MeO Me+O MeO [Os(NH3)5]2+ [Os(NH3)5]2+ [Os(NH3)5]2+ 73 75 Scheme 24 Reagents (i) CH (OEt) ; (ii) (CH ) C——C(OMe)(OTMS).74 HO O H iii iv MeO MeO [Os(NH i ii 3)5]2+ Me+O [Os(NH3)5]2+ 77 76 78 SO H; (ii) MVK; (iii) DMA; (iv) [Bu N][B(CN)H ]. i ii [Os(NH3)5]2+ Scheme 25 Reagents (i) CF tri.ic acid mediated reaction of 76 with methyl vinyl ketone instead of CH (OEt) forms 77 (Scheme 25). This may then undergo dimethylacetamide promoted deprotonation of the vinylogous methyl group resuing in cyclisation by attack of the ketone carbonyl and subsequent regioselective reduction with cyanoborohydride to a.ord a decalin type complex 78 with high stereoselectivity. Similarly naphthalene Os(..)-complexes can be dearomatised by sequential electrophile—nucleophile 1,4- additions. 127 Annu.Rep. Prog. Chem. Sect. B 1999 95 117—136 R R i ii R R O O 80 79 Scheme 26 Reagents (i) Fe(CO) NaBH AcOH; (ii) CuCl ·H O. HO O i ii H H H H 82 83 Scheme 27 Reagents (i) Co (CO) ; (ii) DME re.ux. Miscellaneous. Iron hydride reagents generated in situ can be used in conjunction with a Cu(..) oxidant to e.ect a one-pot conversion of alkynes to cyclobutenediones and ,-unsaturated carboxylic acids. The reagent [HFe (CO) ][Na] is highly selective for formation of cyclobutenediones.For example R-alkynes 79 are converted to cyclobutenediones 80 in 60—73% yields (Scheme 26). The nucleophilic metallate [Cp(CO )FeM] (MNa or K) adds cleanly to aldehydes (RCHO) and capture of the resultant alkoxy anion by TMS chloride a.ords (-siloxyalkyl)iron Cp complexes 81 in moderate to good yield. R Me3Si Fe Cp O OC CO 81 Cobalt rhodium and iridium Despite important catalytic reactions of Rh and Ir only Co appears in mainstream stoichiometric applications. -Complexes. The diastereoselective Nicholas reaction has been used in the construction of functionalised benzopyrans. High yielding decomplexation of Co—alkyne complexes is e.ected by excess (ca. 10 equiv.) ethylenediamine in THF e.g. diphenylacetylene was decomplexed from Co (CO) in 98% yield in 10 minutes. Acetylenic cyclopropanols rearrange to cyclopentenones with high stereoselectivity on heating after complexation with Co (CO) .For example 82 gave 83 in 86% yield (Scheme 27). Tetrahydrofurans tetrahydropyrans and oxepanes are formed by 128 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 O O O O Co O H O O O 84 85 Ar i ii Ar Nu Pt PPh3 Pt PPh3 PPh3 PPh3 87 86 88 Scheme 28 Reagents (i) ArH (e.g. C H NMe ); (ii) [Nu] (e.g. NaCH(SO Ph) . cyclisation of -cationic dihydroxycobaloximes. The ready complexation and removal of Co (CO) to the alkynes of the crown ether macrocyclic diyne 84 provide a general method for the modulation of the properties of the macrocycle.For example acting as a protecting group and blocking catenane formation by RCM with N,N- bis(hex-5-enyl)pyromellitic diimide. A sequential [4 2] then [2 2] cyclisation was employed in the construction of the AB taxane ring system utilising a Cp—Co template to generate 85. SparteineN-oxide has been used as a chiral promoter in the Pauson—Khand reaction of various alkynes with norbornene. Low to moderate ee’s were observed in the resultant cyclopentenones the highest being 33%. Nickel palladium and platinum The bulk of applications of Ni Pd and Pt involve catalytic quantities. Furthermore stoichiometric applications of Pd and Pt obviously su.er the issue of the high cost. However the regioselective addition of the C—H bonds of pyrrole indole and electronrich benzene derivatives to the central carbon of a cationic propargyl (prop-2-ynyl) complex of Pt 86 to a.ord a -allyl complex e.g.87 has been reported (Scheme 28). A mechanism involving platinacyclobutane intermediates is suggested. Subsequent addition of stabilised carbanion nucleophiles to 87 a.ords 88 the product of overall aryl vinylation of propargyl derivatives. Insertion of elemental sulfur into the Ar—Ni bond of 89 allows preparation of thiolate 90 (Scheme 29). 129 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 S N i N Ni Ni N N 90 89 OH O O i ii O Ph O Ph Ph Ph Me Me 92 91 93 Scheme 30 Reagents (i) MeLi—CuI Et O; (ii) PhCHO Et AlCl.Scheme 29 Reagents (i) S . O Cu(Me)Li O O O O i ii iii ii n-Bu TBDMSO n-Bu 94 95 ent-95 Scheme 31 Reagents (i) [n-Bu Cu(CN)Li ]; (ii) DBU; (iii) [n-BuCu(CN)Li]. Copper silver and gold Organocuprates. Moderate to good menthyl induced diastereoselectivity is observed in a three component synthesis of what are in essence Baylis—Hillman type adducts. For example addition of lithium dimethylcuprate to the menthyl ester of phenylpropiolic acid 91 a.ords intermediate vinyl cuprate 92 (Scheme 30). This is trapped with benzaldehyde (with Et AlCl as a Lewis acid accelerant) to a.ord 93 as an E/Z mixture and in 88 and 70% de respectively. The reaction of 98% ee TBDMSprotected hydroxycyclohexenone 94 with ‘higher order’ and ‘lower order’ cyano cuprates takes startlingly di.erent courses in terms of diastereoselectivity.Subsequent DBU-mediated elimination of the conjugate addition product allows the preparation of both enantiomers of cyclohexenone 95 in 97% ee (Scheme 31). The reaction proceeds analogously with a range of other cuprates and ketones. Miscellaneous. Silver(.) salts e.ect the oxidation of tertiary amines in toluene —water mixtures. A radical chain mechanism is proposed. A combination of silver tri.ate and phenyl chloroformate mediates the coupling of alk-1-ynylsilanes with quinoline derivatives to a.ord the corresponding alk-1-ynyl-1,2-dihydroquinoline derivative in good yield. Copper(..) salts promote highly e.cient O-arylation of phenols by aryl boronic acids at ambient temperatures.This has a great advantage in 130 Annu. Rep. Prog. Chem. Sect. B 1999 95 117—136 the arylation of phenolic amino acids since the process is racemisation-free. Cu() salts also promote the N-arylation of N¡XH containing compounds in the presence of triethylamine again by aryl boronic acids. Zinc cadmium and mercury O OP Addition of organomercury organozinc and organocadmium reagents to elec- trophiles. The asymmetric addition of dialkylzinc to aldehydes catalysed by e.g. amino alcohols is fast becoming a rather overworked reaction. However the addition of dimethylzinc to benzaldehyde catalysed by 2S-3-exo-(dimethylamino)isoborneol (DAIB) displays non-linear asymmetric phenomena and this has been studied in a quantitative kinetic sense in great detail by Noyori et al.Addition of dialkylzincs to ketones is promoted by the stoichiometric addition of Ti() isopropoxide. When the reaction is performed in the presence of catalytic amounts of camphor sulfonamide derivatives asymmetric induction is observed (up to 89% ee). The asymmetric addition (up to 92% ee) of dialkylzincs to imines is eected by stoichiometric addition of an azanorbornylmethanol type ligand. The ligand can easily be recovered and recycled. Acyclic congurationally-dened mixed dialkylzinc reagents can be prepared from trisubstituted alkenes by hydroboration (Et BH) then transmetallation (i-Pr Zn). Ph Ph Ph O O P N OO O O Ph Ph 97 96 98 Perfect anti selectivity is reported for the S2 and S2 type addition of dialkylzinc reagents to vinyl oxiranes catalysed by Cu().By use of the Feringa type 2,2-binaphthyl phosphorus amidite ligand 96 ecient kinetic resolution (allowing90% ee) is observed for the reaction of cyclic ,-unsaturated epoxides e.g. 97. Taddol derived phosphite ligand 98 is highly eective for the conjugate Cu-catalysed addition of diethylzinc to a range of enones. For example reaction of cyclohexenone in the presence of 0.5mol% Cu and 1mol% 98 aorded (S)-3-ethylcyclohexanone in 96% ee and 95% yield. Binaphthoxy phosphorus amidite ligands are also successful. A remarkable ee enhancement through the use of molecular sieves has been reported for the analogous reactions involving Taddol-phosphorus amidite ligands. Houk and Goldfuss have performed informative PM3 calculations of the transition states for enantioselective chiral -amino alcohol catalysed addition of EtZn to benzaldehyde.Highly enantioenriched propargylic mesylates 99 are smoothly converted to chiral non-racemic allenyl zinc reagents (100) on reaction with excess EtZn and 5mol% Pd(0). Reagents 100 may then be reacted with aldehydes (e.g. cyclohexanecarbaldehyde) to aord the anti adduct 101 in 90¡X95%ee (Scheme 32).UVlight induces 131 Annu. Rep. Prog. Chem. Sect. B 1999 95 117¡X136Scheme 32 Reagents (i) cat. Pd(0) Et Zn; (ii) c-CH-CHO. CO2Et Br Br ZnI I ii i ii CO2Me I IZn 106 103 102 CO2Et CO2Me 104 105 Scheme 33 Reagents (i) Zn powder; (ii) cat. Pd(PPh). catalyses the tandem coupling of Me selective phenylation of naphtho-1,4-quinones at the 2-position by reaction with diphenylmercury in acetonitrile. Readily prepared 2-bromophenylzinc() (103) can be used as the equivalent of an ortho cationic anionic reagent.Thus reaction of 2-iodobromobenzene 102 with zinc and then methyl 3-iodobenzoate 104 followed by ethyl 4-(iodozinc)benzoate 105 in the presence of Pd(0) catalyst aords terphenyl 106 (Scheme 33). Ni(acac) Zn with allyl- X¡XHC¡X ¡X¡XCR to aord predominantly allyl¡XCH¡X¡XC(R)Me (where allyl and R are trans). Organocadmium reagents (primary alkyl secondary alkyl and aryl) add selectively to just one of the carbonyl carbons of quinone derivatives¡Xallowing the selective synthesis of quinols. Zinc carbenoids. Enantiomerically pure trans-diaminocyclohexane bis-sulfonamide ligands are known to eect catalytic asymmetric cyclopropanation of cinnamyl alcohol by Et Zn ZnI and Zn(CHI). A solution state (NMR) and solid state (X-ray crystallography) study of the reaction and model systems has now identied kinetically active intermediates.Allylic stereocentres can induce diastereoselectivity in the EtZn mediated cyclopropanation of allylic alcohols. Remote aryl substituents can reverse the diastereoselectivity¡Xpossibly through -complexation. Theoretical studies on the Simmons¡XSmith cyclopropanation reaction of zinc carbenoids with olens reveal methylene transfer versus carbometallation as two possible pathways. Experimentally only the methylene transfer mechanism is observed¡Xhowever both processes can compete eectively with lithium carbenoids. Modication of Simmons¡XSmith reagents by reaction with enantiomerically pure chiral alcohols ROH aords reagents of the type ROZnCHI which eect cylopropanation of prochiral alkenes with modest enantioselectivity.For example E-PhCH¡X¡XCHMe was cyclopropanated in 51% ee. A three-component palladium-catalysed coupling of biszincio-methylenes and methylmethynes with propargyl and allylic electrophiles has 132 Annu. Rep. Prog. Chem. Sect. B 1999 95 117¡X136i ii iii iv Cl 107 108 Scheme 34 Reagents (i) CH CH(ZnI) ; (ii) cat. Pd(0)—tri-(3,5-(CF ) -phenyl)phosphine; (iii) CuCN; (iv) allyl bromide. i ii iii Br Zn Br 113 112 114 Scheme 35 Reagents (i) 2 BuLi; (ii) ZnCl ·OEt ; (iii) CuCl . H O O H i ii O O N N N N MeO MeO O O O O 115 116 Scheme 36 Reagents (i) Bu Sn-allyl; (ii) 2 eq. ZnCl ·OEt . been reported. Thus Pd-catalysed reaction of cinnamyl chloride 107 with CH CH(ZnI) followed by transmetallation (CuCN) then trapping with allyl bromide a.orded 1,6-diene 108 in 66% yield (Scheme 34). Lewis acids.Zinc(..) bromide is a useful Lewis acid for the formal [2 2] cycloaddition of selenosilyl alkenes with activated ethylene compounds. Highly enantioselective mercury cation induced cyclisation of allylic-homoallylic diol 109 reversibly gives 110 (which can be trapped by addition of Et B—LiBH ). This has been employed in a total synthesis of ( )-furanomycin 111. Miscellaneous. Biphenylene 114 and derivatives can be prepared in moderate to good yields via intramolecular coupling of zincacyclopentadiene 113 generated by lithiation then ZnCl -transmetallation of 2,2-dibromobiphenyl 112 (Scheme 35). Based on studies involving inhibition by galvinoxyl ZnCl ·OEt functions both as 133 Annu.Rep. Prog. Chem. Sect. B 1999 95 117—136 Ph i ii D Ph D 117 118 Scheme 37 Reagents (i) Et Zn 10mol% Ti(); (ii) DO. N N i ii iii OMe OMe O O 119 120 Scheme 38 Reagents (i) LDA; (ii) ZnBr; (iii) HO. radical initiator and chelating agent in the tin-based allylation of 115 to aord 116 with 86% de (Scheme 36). A T i()-catalyst prepared in situ from 10mol% Ti(i-PrO)Cl and 20 mol% EtMgBr allows carbozincation of enynes by Et Zn. For example enyne 117 is smoothly converted after deuterative work-up to 118 (Scheme 37). Functionalised pyrrolidines are readily prepared by diastereoselective intramolecular amino-zinc-enolate carbometallation.Thus for example lithiation of 119 followed by addition of ZnBr and then hydrolysis gave 120 in 70% yield (Scheme 38). Sequential oxymercuration¡Xreduction (Hg(OAc) then NaBH) eects conversion of mono- di- and tri-saccharide glycals into their corresponding 2-deoxy sugars. The process is mild and non-acidic thereby allowing the use of acid-labile groups such as silyl ethers. A combination of diethylzinc and air (CAUTION!) is eective as an initiator in tin hydride mediated radical reactions of organic halides. Activated zinc on a polymeric support can be prepared by addition of ZnCl solutions to polymeric supported alkali metals (prepared by evaporation of liquid ammonia solutions). 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ISSN:0069-3030    

DOI:10.1039/a808589g

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Aromatic chemistry 4 M. John Plater Department of Chemistry University of Aberdeen MestonWalk Aberdeen UK AB24 3UE 4 3 1 Theoretical and structural studies The existence of homoaromaticity in triquinacene 1 .rst suggested by Woodward in 1964 has been disproved. The enthalpy of formation was newly determined to be 57.51 kcalmol by measuring its energy of combustion in a microcalorimeter. This is identical to the value calculated at the RMP2/6-31G* level of theory and with AM1 semiempirical calculations. The previously reported value of 53.5 kcal mol was derived from the experimentalenthal py of hydrogenation of 1 to 4 of 78.0 kcalmol and the calculated enthalpy of formation of 4 of24.47 kcalmol . The lower than expected enthalpy of hydrogenation of 1 to 2 determined by Liebman is presumably an experimental error.2 1 The aromaticity and antiaromaticity of annelated .ve-membered ring systems pentalene 5 acepentalene 6 dicyclopenta[cd,gh]pentalene 7 and related compounds have been evaluated computationally using density functional theory (B3LYP/6- 31G*). The nucleus-independent chemical shifts (NICS) and magnetic susceptibility exaltations indicate 5 and 6 which have 8 and 10 electrons respectively to be antiaromatic as expected. In contrast 7 with 12 electrons is calculated to be aromatic. The dianions of all three have delocalised structures and are aromatic. 6 5 7 137 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 12 11 10 9 8 Homoaromaticity in some carbocations is well established such as for the 7- norbornenylcation 8 and the 8-endo-tricyclo[3.2.1.0]octylsystem 9.However until now no evidence for homoaromaticity in carbene intermediates has been found. An analysis of energies of stabilisation the molecular geometry and the singlet—triplet energy gap (E ) provides conclusive evidence that carbenes 10 11 and 12 are homoaromatic in character. The enhanced stabilities of singlet state carbenes 10 11 and 12 were evaluated at the B3LYP/6-31G*/B3LYP/6-31G* level correcting for zero-point energy di.erences. The stabilisation energies determined were 3.27 15.56 and 14.06 kcalmol respectively which compares with 20.91 kcal mol calculated for the 7-norbornenylcation 8. For carbene 11 the carbene carbon atom leans towards the double bond indicating the presence of conjugation.The singlet—triplet energy gaps for carbenes 10 11 and 12 were calculated as 8.33 27.82 and 25.74 kcal mol respectively. Hence for 10 only a modest stabilisation results but for 11 and 12 substantial stabilisation of the singlet carbene provides a large energy gap. Ha Cß Hb Hd Ca C1' C1 Hc 13a 13b The .rst synthesis of the molecular pinwheel [3 ](1,2,3,4,5,6)cyclophane 13 was reported by Sakamoto in 1996. This represented an important milestone in cyclophane chemistry. The trimethylene bridges invert rapidly at room temperature and a 10.9 kcalmol barrier for the degenerate interconversion 13a–13b was deduced from variable temperature NMR spectroscopy. It was proposed as a possible precursor to the unknown propella[3 ]prismane 14 which might be achieved by successive [22] 14 photochemical ring closures.Its molecular structure degenerate inversion and reaction to give 14 have now been studied by quantum chemicaltechniques. The geomet- 138 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 ries obtained for C symmetric 13 with various theoreticalmethods agree wellwith each other. In contrast to less symmetric cyclophanes which have bent or distorted benzene rings 13 has planar rings with equal C—C distances. Propella[3 ]prismane 14 which has six additional CC bonds is calculated to be 110.8 kcal mol higher in energy than 13. It is highly strained as its cyclohexane rings are severely distorted to achieve planarity.Calculations suggest that 13a interconverts with 13b by a sequential .ipping process with barriers at various levels which agree well with experiment. A synchronous mechanism involving a D symmetric structure is ruled out by its high energy of 43.5 kcalmol and seven imaginary vibrationalfrequencies. 15 17 16 18a 18b The X-ray crystallographic structures of .uorenylidenecycloproparenes 15 and 16 and of dibenzocycloheptatrienylidene 17 have been determined. Theoreticalstudies using ab initio methods have been used to study the structure charge distribution dipole moment and thermodynamic stability of these and related compounds. The X-ray crystalstructures of 15 and 16 reveala planar structure and a puckered structure is revealed for the seven-membered ring in dibenzocycloheptatrienylidene 17.The calculated dipole moments show that the cyclopropabenzene skeleton is positively charged as expected. However in benzotrifulvalene 18 the cyclopropabenzene ring is negatively charged owing to a stronger electron push from the non-benzo fused cyclopropene ring. 1H-Cyclopropa[b]naphthalene 19 was converted into novel polar ole.ns 21–25 by reaction of the disilyl derivative 20 with anthrone-like ketones (Scheme 1). The alkene products are crystalline polar compounds that range in colour from yellow to magenta. Calculated bond lengths and angles compared well with experimental values determined by X-ray crystallography. Calculated dipole moments for alkenes 21–23 and 25 have a positive pole on the cyclopropa[b]naphthalene ring.This is reversed for structure 24 which possesses the strongly electron-releasing amino group. A remarkably long bond length of 1.72Å was reported in 1994 for the C(sp )—C(sp ) bond in 1,1,2,2-tetraphenyl-3,8-dichloronaphthenocyclobutene 26. Variable steric and electronic factors have led to hexaarylethanes with bond lengths ranging from 1.54Å for 9,9-ditrypticyl 27 to 1.67Å for hexaphenylethane 28. A search of the Cambridge StructuralDatabase uncovered about 90 examples of C(sp )—C(sp ) benzocyclobutane bonds that are about 1.580.5Å in length. Owing to the exceptional world record for the above long bond length the crystallography was repeated collect- 139 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 SiMe3 (i) X SiMe3 19 20 21 X = CMe2 22 X = O 23 X = S 24 X = NMe 25 X = CO Scheme 1 Reagents (i) BuOK an anthrone.Cl Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Cl Ph 26 29 28 27 ing data at 90 K. Re.nement of the data gave a CC bond length of 1.710(2)Å in excellent agreement with the previous value determined at room temperature. Computations on 29 in a C conformation similar to that found crystallographically for 26 predict a bond length of 1.708Å in excellent agreement with the experimental observation for 26. Further structural analyses helped the authors conclude that the long bond length can be explained by a classical steric argument without the need to consider orbitalinteractions such as through bond coupling.1,10-Diiodophenanthrene 32 was prepared from phenanthrene 30 by dilithiation with n-BuLi to give the lithiated intermediate 31 followed by quenching with iodine (Scheme 2). The X-ray crystalstructure showed the dihedralangl e I—C—C—I to be 63° and a distance of only 3.61Å between the two iodine centers. This amounts to only 84% of the sum of the van der Waals radii. Computational calculations gave estimates of about 30 kJ mol for the iodine—iodine repulsion and about 10 kJ mol for the reduced delocalisation in the extremely twisted skeleton of 1,10-diiodophenanthrene. 6b,10b-Dihydrobenzo[j]cyclobut[a]acenaphthylene33 is a precursor for the generation of pleiadene 34 a reactive hydrocarbon that spontaneously dimerises upon formation. Bis-pleiadene derivatives 36 have been prepared which polymerise upon heating. The presence of side chain substituents increases the solubility and .lm forming properties.The alkoxy groups dramatically enhance the .uorescence. 12,15-Dichloro[3.0]orthometacyclophane 43 a highly strained biphenylophane has been prepared by the route shown in Scheme 3. Benzosuberone 37 was converted to diene 38 in four steps by a Mannich reaction Wittig methylenation alkylation and Ho.mann degradation. Diene 38 was converted to cyclophane 43 by the four steps shown. The HNMRspectrum indicated the presence of a single endo conformer only. The molecular strain in 43 is evidenced by facile cycloaddition with tetracyanoethene (TCNE) to give adduct 44. The kinetically stabilised [1.1]paracyclophane 51 has been prepared by the route 140 Annu.Rep. Prog. Chem. Sect. B 1999 95 137—156 (ii) (i) Li Li I I 30 32 31 Scheme 2 Reagents (i) n-BuLi; (ii) I . 33 35 34 36 shown in Scheme 4. Irradiation of 50 with a low pressure mercury lamp at 20 ¡ÆC gave the desired paracyclophane 51 and some of isomer 52 resulting from a secondary transannular [44] addition within the molecule. The enhanced kinetic stability of compound 51 was demonstrated by heating a dilute solution in the dark in the absence of air. The intensity of the UV¡ªVIS absorptions remained unchanged for 2 h at 50 ¡ÆC and decreased by only 8%after the solution was heated at 100 ¡ÆC for 1.5 h. Irradiation of 51 in solution with light of wavelength greater than 420nm transforms 51 into 52.On standing in the dark at room temperature the characteristic UV¡ªVIS absorption of 51 slowly developed. This indicates the greater thermal stability of 51 compared with 52. 2 Me Me Si Si Me Me Li Si Me Si Me Me Me Si Me Me Si Me Me Si Si Si Si Me Me Me Me Me Me Me Me Me Me Si Me Si Me 54 53 Treatment of hexasilylbenzene 53 with excess lithium metal in dry deoxygenated THF gave dianion 54 which could be isolated as an amorphous black solid. 141 Annu. Rep. Prog. Chem. Sect. B 1999 95 137¡ª156 Cl O (ii) Cl (i) + Cl Cl 37 38 40 39 (iii) Cl Cl Cl Cl (v) Cl (iv) Cl Cl Cl 42 41 43 (vi) Cl NC NC Cl NC 44 CN Scheme 3 Reagents (i) 4 steps (see text); (ii) BuOK HCCl ; (iii) FVP 495 °C; (iv) HCCl NaOH PTC; (v) BuOK—DMSO; (vi) TCNE rt.Performing the reduction in the presence of quinuclidine followed by recrystallisation from toluene gave single crystals of 54 [Li(C H N)] 54a. The molecular structure was determined by X-ray crystallography. One lithium cation is located above and below the plane of the benzene ring. Each is coordinated by one quinuclidine. The benzene ring is virtually planar. The EPR spectrum of a powder sample of 54a at room temperature is characteristic of randomly orientated triplets having approximately three-fold symmetry. The temperature dependence of the signal intensity was measured. The signalintensity increases with increasing temperature between 100 and 300 K as expected for a thermally excited triplet state.The energy gap between the triplet and singlet ground state was estimated to be only 1.0 kcal mol determined by curve-.tting with the Bleany—Bowers equation. Ab initio calculations of C constrained to the planar ring geometry have shown that the triplet state is lower in energy than the singlet state. This discrepancy between theory and experiment is ascribed to silyl-substituent e.ects insu.cient levels of ab initio MO calculations or the ion-pair interactions between the lithium cations and the benzene dianion. H 4,7-Dihydroacepentalene 58 can be generated in situ by protonation of the readily accessible and stable dipotassium acepentalenediide 57. This was prepared from triquinacene 56 by treatment with n-BuLi and KOBu.Treatment of 57 with moist ether gave a single product which was shown to be the dimer 59 by X-ray crystallogra- 142 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 O O O R R (ii) (i) R R R R O 45 46 47 O O (iii) CONMe2 O CONMe2 R C PhSe R R R (iv) R (v) R R R R R R R CONMe2 SePh 49 CONMe2 48 50 C O (vi) CONMe2 CONMe2 R R R h¥í R R R R R CONMe2 51 52 CONMe2 Scheme 4 Reagents (i) h/RC¡ª¡ª ¡ª CR (R CH SiMe ); (ii) h/RC¡ª¡ª ¡ª CR; (iii) Diazo transfer then h; (iv) PhSeNMe ; (v) H O /; (vi) h. phy. The highly reactive monomer intermediate 58 could not be observed by NMR spectroscopy even at 80 ¡ÆC.The intermediacy of monomeric dihydroacepentalene 58 in the formation of the dimer 59 was proved by interception with two other dienes. Reaction with cyclopentadiene and anthracene gave the respective [42] cycloadducts 60 and 61 respectively. Reaction of diide 57 with chlorotrimethylsilane gave 4,7-bis(trimethylsilyl)-4,7-dihydroacepentalene 62 which was puried by distillation. The bulky trimethylsilyl groups sterically hinder the central double bond which prevents the molecule from dimerising. Organic acids and alcohols can be readily added to the centraldoubl e bond to give the addition products 63 and 64 respectively. Since 57 has a bowl shaped negatively charged carbon skeleton for which only one singlet can be observed in the LiNMRspectrum at 25 ¡ÆC it must undergo rapid bowl to bowlinversion.Ab initio calculations predict an inversion barrier of 5.4 kcal mol for the acepentalene dianion in solution which rises to 9.8 kcal mol with two lithium 143 Annu. Rep. Prog. Chem. Sect. B 1999 95 137¡ª156 H 2 H H H H H 57 56 58 55 [4 + 2] 2 anthracene 59 60 57 61 Me3Si SiMe3 RCO2H 2 Me3Si RCO2 Me3SiCl 63 SiMe3 62 57 Me3Si ROH SiMe3 RO 64 counterions present. The NMR chemicalshifts of the ring protons of 6.09 and 6.16ppm suggest that the molecule is aromatic. Dibenzo[a,g]corannulene (C H ) 65 and dibenzo[a,g]cyclopenta[kl]corannulene (C H ) 66 undergo two-electron reductions with lithium metal to give stable solutions of purple dianions that were studied by H C and Li NMR spectroscopy.The dianion of dibenzo[a,g]corannulene 65 was found to be paratropic whereas the dianion of dibenzo[a,g]cyclopenta[kl]corannulene 66 was found to be diatropic. Further reduction with lithium metal gave the trianion radicals but not the tetraanions. However reduction with the more electropositive potassium metal gave both the dianions or on further reduction the tetraanions. The tetraanion of 65 was found to be diatropic and the tetraanion of 66 was found to be weakly paratropic. The terms paratropic and diatropic refer to the summation of the overall changes in C chemicalshifts of the neutral starting material compared to the reduced anions.For example for 65 50 ppm and for 66 178 ppm. Taking into account 144 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 66 65 the two-electron reduction process this gives 25 ppm and 89 ppm per unit of charge for 65 and 66 respectively. These values di.er markedly from those found for the corannulene dianion which has a total carbon chemical shift of 336ppm and a value of 168ppm per unit of charge. This was rationalised as a consequence of the paramagnetic or shielding e.ect of the ring current which is inversely related to the size of the HOMO—LUMO gap. 3,6,9,12,15,18-Hexaphenyldodecahydro[18]annulene 74 and related derivatives have been prepared by the route shown in Scheme 5. The molecular structure was determined by X-ray crystallography which showed that 74 has a planar -system with D symmetry.The linear C—C—C—C linkage has a unique short bond average of 1.217Å and the other two longer bonds average 1.390Å. 2 Aromatic ring syntheses Fischer carbene complexes have proved to be versatile reagents for selective carbon —carbon bond formation. The formal[3 21] cycloaddition of alkoxycarbene complexes with alkynes known as the Do� tz benzannulation is a striking example. The new alkenyl(amino)carbene chromium complex 77 bearing an electronwithdrawing group at the C-position reacts smoothly with di.erent alkynes to give the benzannulation products 79 (Scheme 6). Electron-poor alkynes also reacted e.ciently. The intramolecular reaction of alkynes with a Fischer carbene complex has been exploited for the synthesis of cyclophanes (Scheme 7). Precursors 82 were prepared by aldol condensation of a Fischer carbene complex with appropriate alkynyl aldehydes catalysed SnCl .Thermolysis at 60 °C for 14—18 h or at 100 °C for 0.2—4h gave the corresponding cyclophanes 83 84 and 85 shown. Treatment of enediyne 86 with chromium methylcarbene complex 87 followed by toluene-p-sulfonic acid gave benzofuran 89 and an E—Z mixture of butenylbenzofurans 90 (Scheme 8). A mechanism was proposed involving coupling of the carbene complex to the less hindered alkyne to give an intermediate enyne-ketene 91. This then undergoes a Moore cyclisation to give an intermediate chromium complexed diradical 92. Hydrogen abstraction from the solvent would give a phenol-ether which could cyclise to benzofuran 89 upon acid treatment.Formation of alkene-benzofuran derivative 90 occurs by intramolecular hydrogen atom abstraction followed by acid catalysed cyclisation. —Zn dust gave the cycloaromatised products 96 98 and 100 (Scheme 9). The reaction of but-3-en-2-one 94 with terminally substituted diynes 95 97 and 99 and NiCl The addition of ZnCl and Et N increased the reaction yields. 145 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 OMe Ar SiMe3 H Ar (i),(ii) (iii) COAr Me3Si THPO MeO H 68 67 OMe CHO (iv) 69 Ar MeO 70 Ar CHO OMe Ar OMe Ar O OH HO O (v) Ar Ar Ar MeO Ar MeO OMe OMe O OTHP 72 71 (vi) Ar OMe Ar HO OH Ar Ar Ph Ph (vii) Ar Ar Ar MeO Ar OMe Ph OH Ar 74 Scheme 5 Reagents (i) ethynylMgBr; (ii) n-BuLi then MeI; (iii) EtMgBr; HCO Me; then 70; (v) PPTS then 73 dihydropyran—PPTS; TBAF; (iv) EtMgBr then CeCl Dess—Martin reagent; (vi) PhMgBr; (vii) SnCl .A .exible route to substituted triphenylenes has been developed (Scheme 10). o-Terphenylcarboxylic acid derivatives 104 were prepared via a 6 electrocyclisation of a diene-ketene generated from acid 103 by treatment with ethylchl oroformate and 146 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 N (CO)5Cr CH3 75 Scheme 7 Reagents (i) SnCl Scheme 6 Reagents (i) n-BuLi; EtO CCHO; MsCl—Et N; (ii) DBU; (iii) various acetylenes/; (iv) SiO H (CH2)n 80a-e n a 2 b 6 c 8 d 10 e 13 OMe OH (CH2)n 83 a-e + (CO)5Cr=C(OMe)CH2 H 81 OMe OH (CH2)n HO OMe 84 a-e ; (ii) in di.erent solvents.MeO Cr(CO)5 (i) (CH2)n 82 (ii) OMe (CH2)n MeO HO OH OH (CH2)n (CH2)n OMe 85 a-e N (i) (CO)5Cr OMs CO2Et 76 N R2 R1 OH 79a R1 = Ph R2 = H 79b R1 = Bu R2 = H 79c R1 = CO2Et R2 = H 79d R1 = Ph R2 = Ph . O (CH2)n Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 N (ii) (CO)5Cr CO2Et 77 (iii) N Cr(CO)3 R2 (iv) CO CO R1 2Et 2Et OH 78 147 Bu HO Bu Me Me Bu O O (i) (ii) + MeO Me 86 88 89 90 Bu Cr(CO)3 O Me (iii) Me O C 89 86 + 87 MeO MeO (CO)3Cr 92 91 (iv) Cr(CO)3 Me HO (v) MeO 90 H 93 Scheme 8 Reagents (i) Me(MeO)C——Cr(CO) 87; (ii) TsOH; (iii) solvent H atom abstraction/TsOH; (iv) H atom abstraction; (v) TsOH.Et N. The hydroxy group can be removed reductively to give o-terphenylderivatives 105 which are precursors to substituted triphenylenes. An e.cient regiocontrolled synthesis of substituted 1,4-dimethoxynaphthalenes as precursors for 1,4-naphthoquinone systems has been developed (Scheme 11). Polynuclear quinones attract long standing interest owing to their occurrence in many biologically active natural products. The route involves the addition of 2,5- dimethoxybenzylmagnesium chloride 107 to acyclic and cyclic -oxoketene dithioacetals 108 followed by cycloaromatisation to naphthalenes 109 with BF ·OEt .Dethiomethylated naphthalenes 110 were obtained by treatment with Raney Ni. 2-Unsubstituted hydroquinone monoacetates 113 were prepared by the addition of a lithiated alkene to a tert-butyl or trimethylsilyl substituted cyclobutenedione 111. The addition of unsaturated carbon nucleophiles proceeded regiospeci.cally at the carbonylgroup distant from the bulky tert-butyl or trimethylsilyl group. Thermolysis of the adducts followed by removal of the bulky group with ZnCl furnished the hydroquinone monoacetates 113. This methodology is useful for the synthesis of 148 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 O O (i) CO2Et Me CO2Et CO2Et CO2Et 96 94 95 O (i) 94 O + O 97 98 O (i) + 94 100 Scheme 9 Reagents (i) NiCl /Zn/ZnCl /Et N.R' R' R' (ii) (i) CO2H CHO CO2Me R R R 102 103 101 HO2C (iii) HO CO2Me CO2Me (iv) R R R' R' 104 105 Scheme 10 Reagents (i) ClCO Et/Et N/NaBH then MnO ; (ii) dimethylsuccinate/ NaOMe; (iii) ClCO Et/Et N then NaOH; (iv) 2-chloro-1-phenyltetrazole/NiCl . 99 highly functionalised aromatic molecules. Arene containing vinylic iodides and tri.ates 114 undergo regioselective carboannulation with alkynes 115 catalysed by Pd(0). This gives the corresponding polycyclic 149 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 OMe R1 O + R2 SMe OMe 106 ClMg t t O Bu SMe Runsatd R1 R1 O R1 = Me or iPrO 111 107 Scheme 11 Reagents (i) BF Bu O Runsatd OAc R1 R1 OH t R1 Bu R2 114a R1 = I 114b R1 = OTf fused naphthalenes 116. The generality of this methodology makes it an attractive synthetic route to a range of polycyclic aromatic hydrocarbons.Alkynes 117 are cyclotrimerised to substituted benzenes 119 and 120 in water¡ªmethanol mixtures by the cyclopentadienyl-COD cobalt catalyst 118. The electron withdrawing ketone group enhances the reactivity of the catalyst and the alcohol group enhances the water solubility. Protection of the alkyne functional groups is not required even for amines and carboxylic acids. Water-soluble transition metal catalysts are attractive because water is a cheap environmentally friendly solvent and hydrophobic eects can provide substantialrate enhancements chemoselectivity and stereoselectivity.116a R1 = Ph R2 = Ph 116b R1 = Ph R2 = tBu 116c R1 = Ph R2 = SiEt3 150 Annu. Rep. Prog. Chem. Sect. B 1999 95 137¡ª156 OMe OH (i) R1 R2 SMe OMe SMe 108 R1 R2 ; (ii) Raney Ni. R3 ZnCl2 R2 OAc 112 113a R1 = Me R2R3 = OCH2CH2 113b R1 = Me R2R3 = OCH2CH2CH2 113c R1 = iPrO R2R3 = OCH2CH2 113d R1 = iPrO R2R3 = OCH2CH2CH2 R1 R1 115a-e OMe R1 R2 SMe OMe 109 (ii) OMe OMe 110 OH H R3 R1 R2 OAc 113 R1 R1 R2 R2 R1 R2 2 + H R 118/MeOH/H2O R2 R1 R2 R1 117 R1 R2 R1 = COCH2CH2CH2OH 120a-e 119a R2 = COCH3 119b R2 = CO2CH3 119c R2 = (CH2)2OH 119d R2 = CH2NHCH3 Co 118 Cp Co CpCo(C COCH2CH2CH2OH 2H4)2 122 121 123 SiMe3 CpCo(CO)2/Ph3P/h¥í SiMe3 SiMe3 SiMe3 124 125 Treatment of triynes 121 with CpCo(C H ) gave high yields of the metallacyclopentadienes 122 bearing a -bound alkyne ligand. Thermaldecomposition gave the expected angular phenylenes 123.Intermediate complexes 122 are the missing link in transition metal-catalysed alkyne cyclotrimerisations and have not been isolated 151 Annu. Rep. Prog. Chem. Sect. B 1999 95 137¡ª156 C14H29O I C14H29O OC14H29 127 OC14H29 I Pd(0)(Ph3P)4/CuI 126 128 R R Mo(CO)6/ArOH CH3 CH3 CH3 n R R 129 130 R = alkyl branched alkyl alkoxy previously.The isolation of the novel metallated dibenzodehydro[10]annulene 122 is probably facilitated by the molecular strain of the .nal angular phenylene. Helicene 125 was prepared by an intramolecular [222] cycloisomerism of triyne 124 catalysed by CpCo(CO) and Ph P/h. Further examples illustrated the generality of the method. Helicenes are comparatively di.cult to prepare traditionally requiring high dilution photochemical methods. The route developed here o.ers numerous advantages to di.erent structural types with helical chirality. 3 Functional polycyclics The pentiptycene-derived polymer 128 was produced by the palladium-catalysed cross-coupling of disubstituted diiodobenzene 127 with pentiptycene diacetylene 126. The steric bulk of the polymer backbone prevents close packing of the chains increasing the porosity.Nitrated aromatics such as 2,4,6-trinitrotoluene (TNT) are absorbed into thin .lms within seconds and cause .uorescence quenching. Direct methods of TNT detection are needed owing to the existence of about 120 million unexploded land mines worldwide. Conjugated poly(p-phenyleneethynylene)s 130 were formed from 1,4-dipropynylbenzenes 129 by alkyne metathesis with but-2-yne and Mo(CO) —4-(tri- .uoromethyl)phenol. The degree of polymerisation was determined by NMR spectroscopy from the integration of the propyne end group singlet at 2.04. The catalyst system is less sensitive to air and moisture compared to Schrock’s (BuO) WCBu.This method known as acyclic diyne metathesis (ADIMET) has some advantages over more conventional palladium couplings such as the absence of butadiyne defect structures. Poly(p-phenyleneethynylene)s are of interest for photonic devices such as 152 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 OC4H9 OC4H9 CH3 CH3 CH3 CH3 CH3 CH3 H9C4O H9C4O 131 Hg(TFA)2/I2 OC4H9 OC4H9 I I CH3 CH3 CH3 CH3 CH3 CH3 I I H9C4O H9C4O 132 LEDs and polymer based lasers. The ethynyl-substituted quinquephenyl 131 was prepared by an iterative coupling strategy. Electrophile induced cyclisation with iodine gave the extended fused-ring polycyclic 132 containing nine annelated aromatic rings. Conjugated molecular and polymeric materials are currently being exploited in advanced technologies involving molecule based sensors non-linear optical electroluminescence and photovoltaic devices.The shape persistent macrocyclic amphiphiles 133 134 and 135 were prepared by a combination of palladium-catalysed Hagihara and copper-catalysed Eglinton—Glaser couplings. The isolation and puri.cation of these macrocycles was straightforward owing to their restricted solubility. The compounds are all unsaturated and are all yellow in colour. The molecular .exibility allows rotation of the aromatic rings so that the nanometre-sized cavity can be either more or less polar depending upon the solvent and binding to guest species. In this respect they resemble the polycyclic crown 153 Annu.Rep. Prog. Chem. Sect. B 1999 95 137—156 OPr OPr OH OH OH OH OPr OPr 133 OPr OPr OH OH OH OH OPr OPr ether antibiotics such as monensin which can change conformation depending upon the polarity of the medium to facilitate the uptake or release of metal cations. The polar phenolic groups are also available for further functionalisation. The triptycene-substituted [3]- and [4]helicenes 137 and 138 were prepared as possible molecular versions of mechanical ratchets 136 where the triptycene serves as the ratchet wheel a and the helicenes as pawl b and spring c. Proton NMR was used to study the rotation around the triptycene—helicene single bond. At 20 °C rotation is frozen but the NMR of 137 revealed a plane of symmetry indicating that it cannot function as a unidirectional ratchet.In contrast NMR revealed that triptycyl[4] helicene 138 lacks the symmetry of 137 and has an energy barrier to rotation of 24.5 kcalmol . However spin polarisation transfer NMR experiments indicated that 138 rotates equally in both directions. Thermodynamics o.ers an explanation on the 135 154 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 PrO OPr HO OH OH HO PrO OPr 134 OPr OPr OH OH OH OH OPr OPr H C C (CH2)n H (i) EtO HOH2C CH2 OH 2C CO2Et EtO2C CO2Et H O (CH2)n H (CH2)n 141 139 140 (ii) (iii) ) ( CH2Cl ClCH2 H (CH2)n (CH2)n H 143 (n = 6,8,10) 142 ; (ii) SOCl ; (iii) BuOK. Scheme 12 Reagents (i) LiAlH grounds that it is only the height of the summit and not the steepness that matters.The principle of microscopic reversibility applies. A new family of soluble poly(p-phenylene vinylenes) 143 have been prepared by the route shown in Scheme 12. PPV polymers are of interest for light emitting diodes. The synthetic route involved cycloaddition of a long chain acetylene with cyclopentadienone 139 followed by reduction of the ester groups and conversion to chlorines with thionyl chloride. Polymerisation of precursor 142 was e.ected with KOBu. This synthetic route is versatile and will allow a range of di.erent DP-PPV derivatives to be prepared. References 1 S.P. Verevkin H. D. Beckhaus C. Ruchardt R. Haag S. I. Kozhushkov T. Zywietz A. de Meijere H. Jiao and P.von R. Schleyer J. Am. Chem. Soc. 1998 120 11 130. 2 T.K. Zywietz H. Jiao P. von R. Schleyer and A. de Meijere J. Org. Chem. 1998 63 3417. 3 P.K. Freeman J. Am. Chem. Soc. 1998 120 1619. 155 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156 4 Y. Sakamoto N. Miyoshi and T. Shinmyozu Angew. Chem. Int. Ed. Engl. 1996 35 549. 5 H.F. Bettinger P. von R. Schleyer and H. F. Schaefer III J. Am. Chem. Soc. 1998 120 1074. 6 Y. Apeloig R. Boese B. Halton and A. H. Maulitz J. Am. Chem. Soc. 1998 120 10 147. 7 B. Halton M. J. Cooney R. Boese and A. H. Maulitz J. Org. Chem. 1998 63 1583. 8 F. Toda K. Tanaka I. Sano and T. Isozaki Angew. Chem. Int. Ed. Engl. 1994 33 1757. 9 K.K. Baldridge Y. Kasahara K. Ogawa J. S. Siegel K. Tanaka and F. Toda J. Am. Chem. Soc. 1998 120 6167.10 H. Bock M. Sievert and Z. Havlas Chem. Eur. J. 1998 4 677. 11 P. Buchacher R. Helgeson and F. Wudl J. Org. Chem. 1998 63 9698. 12 M.J. van Eis F. J. J. de Kanter W. H. de Wolf and F. Bickelhaupt J. Am. Chem. Soc. 1998 120 3371. 13 H. Kawai T. Suzuki M. Ohkita and T. Tsuji Angew. Chem. Int. Ed. Engl. 1998 37 817. 14 K. Ebata W. Setaka T. Inoue C. Kabuto M. Kira and H. Sakurai J. Am. Chem. Soc. 1998 120 1335. 15 R. Haag F. M. Schungel B. Ohlhorst T. Lendvai H. Butenschon T. Clark M. Noltemeyer T. Haumann R. Boese and A. de Meijere Chem. Eur. J. 1998 4 1192. 16 A. Weitz E. Shabtai M. Rabinovitz M. S. Bratcher C. C. McComas M. D. Best and L. T. Scott Chem. Eur. J. 1998 4 234. 17 R. Suzuki H. Tsukda N. Watanabe Y. Kuwatani and I. Ueda Tetrahedron 1998 54 2477. 18 H.W. Fruhauf Chem. Rev. 1997 97 523. 19 J. Barluenga L. A. Lopez S. Martinez and M. Tomas J. Org. Chem. 1998 63 7588. 20 H. Wang and W.D. Wul. J. Am. Chem. Soc. 1998 120 10 573. 21 J. W. Herndon and H. Wang J. Org. Chem. 1998 63 4562. 22 S. Ikeda H. Watanabe and Y. Sato J. Org. Chem. 1998 63 7026. 23 E. Brenna C. Fuganti and S. Serra J. Chem. Soc. Perkin Trans. 1 1998 901. 24 B. K. Mehta O. Barun H. Ila and H. Junjappa Synthesis 1998 1483. 25 F. Liu and L. S. Liebeskind J. Org. Chem. 1998 63 2835. 26 R. C. Larock and Q. Tian J. Org. Chem. 1998 63 2002. 27 M.S. Sigman A.W. Fatland and B. E. Eaton J. Am. Chem. Soc. 1998 120 5130. 28 R. Diercks B. E. Eaton S. Gurtzgen S. Jalisatgi A. J. Matzger R. H. Raddle and K. P. C. Vollhardt J. Am. Chem. Soc. 1998 120 8247. 29 I. G. Stara I. Stary . Kollarovic F. Teply D. Saman and M. Tichy J. Org. Chem. 1998 63 4046. 30 J. S. Yang and T. M. Swager J. Am. Chem. Soc. 1998 120 11 864. 31 L. Kloppenburg D. Song and U. H. F. Bunz J. Am. Chem. Soc. 1998 120 7973. 32 M.B. Gold.nger K. B. Crawford and T. M. Swager J. Org. Chem. 1998 63 1676. 33 S. Hoger A.-D. Meckenstock and S. Muller Chem. Eur. J. 1998 4 2423. 34 T. R. Kelly J. P. Sestelo and I. Tellitu J. Org. Chem. 1998 63 3655. 35 B. R. Hsieh Y. Yu E. W. Forsythe G. M. Schaaf and W.A. Feld J. Am. Chem. Soc. 1998 120 231. 156 Annu. Rep. Prog. Chem. Sect. B 1999 95 137—156

ISSN:0069-3030    

DOI:10.1039/a808583h

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Heterocyclic chemistry 5 Mark F. Ward Department of Chemistry University of Aberdeen MestonWalk Old Aberdeen UK AB24 3UE This review covers the chemistry of heterocyclic compounds published during 1998 but focuses on the synthesis of such compounds rather than their reactivity. The subject is divided according to ring size and further grouped according to reaction type or nature of the heterocycle to guide the reader through the diverse material covered. Solid phase synthesis has largely been omitted because of the abstracting of much of this material in J. Chem. Soc. Perkin Trans. 1. 1 Three-membered rings Epoxides continue to receive substantial attention especially in the area of asymmetric synthesis. Further application of the dioxirane derived from 1 to asymmetric epoxidation has shown that it is e.ective in the asymmetric epoxidation of enynes (Scheme 1), dienes and silyl enol ethers or esters. Interestingly variations of the enantiomeric excesses with pH were observed for the epoxidation of alcohol-containing alkenes with 1. It was proposed that epoxidation by Oxone was facilitated by the hydroxy group in the substrate via hydrogen bonding thus allowing intramolecular attack.The ability of an -.uorine atom to in.uence the stereochemical outcome of an epoxidation has been demonstrated by treating alkenes with ketone 2 in the presence of Oxone (Scheme 2). Although research has focused on the use of chiral ketones as asymmetric mediators in this reaction iminium salts have also been used. Alkenes were converted to optically active epoxides in the presence of iminium salts 3 containing a chiral N-substituent (R) and Oxone (Scheme 3). In the search for structural types that would be amenable to asymmetric modi.cation 4 has been synthesised and shown to catalyse the epoxidation of alkenes (Scheme 4). Oxadiazepinium salt 4 shows a high rate of Oxone consumption as compared to cyclohexanone and high resistance to Baeyer—Villiger oxidation.Using salts 5 and 6 derived from Cinchona alkaloids phase-transfer catalysis has also been applied to this area in the guise of asymmetric epoxidations of ,-unsaturated ketones (Scheme 5) and asymmetric Darzens condensations (Scheme 6). The stereoselective preparation of cis-epoxyketones from cis-enones has proved troublesome because of the propensity of cis-enones to a.ord trans-epoxyketones during the oxidation process.Ytterbium based catalyst 7 has proved useful in applica- 157 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 Scheme 1 Reagents (i) Oxone 1 (20—30 mol%) NaHCO Na EDTA MeCN 0 or 10 °C. CO2Et N F H R3 R1 O 2 R2 Scheme 2 Reagents (i) Oxone 2 (10 mol%) NaHCO Na EDTA MeCN. R2 R3 R2 (i) 33-100% ee=29-83% BPh4 – N+ R1 3 (i) up to 78% ee=up to 73% R4 Scheme 3 Reagents (i) Oxone 3 (5—10 mol%) Na CO MeCN 0 °C. R4 + N O•H2O N+2TfO– 4 OBn (i) 96% conv. after 10h Scheme 4 Reagents (i) Oxone 4 (10 mol%) phosphate bu.er MeCN 0 °C. tion to this problem (Scheme 7), but a small amount of trans-epoxyketone is observed with some substrates.The current interest in immobilised reagents has led to the development of polymer linked versions of Jacobsen’s catalyst which epoxidise 1-phenylcyclohexene in up to 91% ee. Some notable methods for the asymmetric synthesis of epoxides by the use of ylides have been reported. Stoichiometric use of sul.mide 8 allows access to optically active epoxides or aziridines depending upon the nature of the heteroatom in the starting material 9 (Scheme 8). Another example of the stoichiometric use of sulfur ylides involves the generation of the C symmetric ylide in situ which reacts with aldehydes generating the trans-epoxide in most cases (Scheme 9). A particularly elegant catalytic procedure was provided by the copper(..) acetoacetate catalysed alkylidene transfer 158 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R3 R1 O R3 R2 O O OBn N BnO H Anthryl N+ O O Br– O 5 R2 R2 R1 R1 Scheme 5 Reagents (i) NaOCl 5 PhMe 25 °C. O H O O (i) 42-93% ee=69-87% N HO H N+ p-(CF3)C6H4 Br– 6 R Ph + Cl R O Ph O R2 R2 (i) 32-83% ee=42-79% Scheme 6 Reagents (i) LiOH·H O 6 Bu O 4 °C. OH O Yb(OiPr) O 7 R1 O O R1 Scheme 7 Reagents (i) MS 4Å 7 THF RT. X X (i) 51-80% ee=82-96% TsN– S+ Ar 8 R1 R2 R2 R1 9 Scheme 8 Reagents (i) NaH 8 DMSO usually 20 or 25 °C. O (i) up to 79% ee=6-70% S Me Me 10 PhCH RCHO 2Br + R Ph (i) 30-86% de=30-86% ee=86-94% (S,S) Scheme 9 Reagents (i) 10 NaOH H O BuOH RT.reaction to form a sulfur ylide derived from 11 which in turn reacts with benzaldehyde to form stilbene oxide (Scheme 10). Peroxycarboxylic acids such as m-chloroperbenzoic acid have various drawbacks because of the hazards associated with their preparation and use. Consequently there 159 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O + PhCHO O Ph Ph S 11 H Scheme 10 Reagents (i) Cu(acac) CH Cl RT. R2 O R1 R2 R1 + PhCHN2 O HN O 12 (i) 70-98% ee=68-94% O O H O R3 R3 R4 R4 Scheme 11 Reagents (i) 12 toluene or CH Cl or EtOAc usually 20 °C. Ph3N+ Br3 – R3 R3 R1 R1 13 NTs R2 R2 Scheme 12 Reagents (i) 12 TsNClNa MeCN 25 °C.H H N Mn (i) 98-100% N O R1 (i) 51-95% N O 14 Ts N R1 (i) 14-78% ee=31-94% Ph Ph R2 R2 Scheme 13 Reagents (i) 14 pyridine Ts O pyridine N-oxide CH Cl RT or 0 °C. is renewed interest in convenient methods for the epoxidation of alkenes. 5-(Hydroperoxycarbonyl) phthalimide 12 is a promising replacement for m-chloroperbenzoic acid (Scheme 11) because it is easy to prepare cheap and does not need bu.ering to overcome acid-induced side reactions. The use of carbodiimide promoted alkene epoxidation with aqueous hydrogen peroxide has also been reported. In a rare example of atom-transfer redox catalysis by a main group element bromine in the form of ammonium salt 13 catalysed the direct aziridination of alkenes in good to excellent yields (Scheme 12). Activation of nitridomanganese complex 14 by toluene-p-sulfonic anhydride causes it to e.ect the asymmetric transfer of an N-tosyl group to styrene derivatives (Scheme 13). Diastereoselective aziridination of alkenes with 16 has been shown to be greatly improved in the presence of titanium(..) tetra(tert-butoxide) (Scheme 14). It is postulated that chelation control is involved thus introducing a greater degree of steric control in the transition state.Intramolecular aziridination has been e.ected in high diastereoselectivity by the addition of iodine to the anion of N-tosyl allylamines (Scheme 15). Predominantly cis-vinyl aziridines have been prepared by the intramolecular closure of an N-sulfonylamine onto an -allyl complex(Scheme 16). Photolysis of N-alkylpyridinium 160 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 N N R1 15 tBu N (i) 53-85% dr>50:1 OH NHOAc ¡Ô R1NHOAc 16 H R2 Cl Ti(OBu) ,20 ¡ãC. TsN R1 R2 R3 I . R1 Scheme 14 Reagents (i) 15 CH R1 NHTs R2 (i) (ii) 63-95% R3 Scheme 15 Reagents (i) BuOK PhMe RT; (ii) I OCO2Me R1 (i) 50-88% cis:trans 94:6-98:2 N ArSO2NH SO2Ar Scheme 16 Reagents (i) Pd(PPh ) THF 60 ¡ãC. NR1 (i) 40-82% N+ Cl�C OH R1 17 O KOH externally cooled. OAc MeO2C MeO2C (ii) 48% (i) 80% N p-Tol N p-Tol Scheme 17 Reagents (i) h H 3 N 18 Scheme 18 Reagents (i) heptane reux; (ii) 1-acetoxybutadiene THF RT.salts yields aziridines 17 which have been elaborated to aminocyclopentanols (Scheme 17). Azirine 18 has been synthesised and shown to undergo Diels¡ªAlder reactions to produce bicyclic aziridines (Scheme 18). Tandem O,N-addition of hydroxamic acids to methyl propiolate produces N-acyloxaziridines (Scheme 19). N-Protected (trichloromethyl) oxaziridines have been synthesised and used as novel aminating agents (Scheme 20). A new and versatile method for the preparation of phosphirenes has been reported. Titanocene complexes and dialkoxytitanium complexes of alkynes react with dichlorophenylphosphine or phohorus trichloride to aord phosphirenes. (Scheme 21). Annu.Rep. Prog. Chem. Sect. B 1999 95 157¡ª182 CO2Me p-Tol 161 O O N R1 H O CO2Me (i) 86-95% + NHOH R1 CO2Me Scheme 19 Reagents (i) morpholine MeCN 40—45 °C. O (i) 93% Cl3C NBoc NBoc Cl3C Scheme 20 Reagents (i) Oxone K CO H O CHCl 0 °C. R5 (R1)2Ti(R2)2 P 19 R2 R2 R1 (i) 65-90% or (ii) 60-72% Scheme 21 Reagents (i) 19 (RCp RCi) BuLi THF alkyne PhPCl or PCl 78 then 50 °C; or (ii) 19 (RROPr) PrMgCl Et O alkyne PhPCl or R1 PCl 78 then50 °C. 2 Four-membered rings Highly sensitive oxetanes 20 and 21 have been isolated during investigations into the Mukaiyama crossed-aldol reaction (Scheme 22). These [2 2] cycloaddition intermediates form reversibly and prevent formation of the trimethylsilyl cation an achiral Mukaiyama catalyst thus in.uencing the enantioselectivity of the reaction.Enzymatic resolution has been used to prepare a .uorinated propiolactone in excellent optical purity (Scheme 23). Catalytic asymmetric [2 2] cycloaddition of silylketenes to aldehydes has been achieved using chiral titanium-TADDOL catalysts (Scheme 24). During the asymmetric syntheses of panclinins a silyloxy group has been shown to greatly in.uence the diastereoselectivity of the [2 2] cycloaddition process (Scheme 25). 4-Exo nickel-mediated radical cyclisation of 23 produced a -lactam (Scheme 26). -Lactam-4-ylidene based methodology was employed to prepare a benzo-fused oxapenem (Scheme 27). Standard [2 2] cycloaddition methodology was used to construct the -lactam core of a range of non-conventionally fused bicyclic -lactams 24 and 25.Subsequent functional group manipulation allowed incorporation of the fused ring (Scheme 28). Although these were of an interesting structural type they exhibited little or no antibacterial activity against a variety of micro-organisms. Employing a diastereoselective Staudinger reaction -lactam 26 was synthesised en route to the paclitaxel side-chain (Scheme 29). Oxazolidinone 27 combined with 2-chloro-1-methylpyridinium tosylate 28 as a dehydrating agent e.ected a stereoselective Staudingertype reaction (Scheme 30). Another chiral auxiliary based method allowed the asymmetric construction of -lactams by a three-component domino procedure (Scheme 31). 162 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 OSiMe3 + PhCHO OMe Scheme 22 Reagents (i) [Eu(hfc) ] C D 20 °C. O O C + H H H ClF2C (i) 67% (ii) ee=99.0% at 58% conv. ClF2C O Scheme 23 Reagents (i) ZnI Et O 30 °C. O O C + H H R1 SiMe3 R1 Scheme 24 Reagents (i) 22 (20 mol%) CH Cl 15 °C. O C tBuMe2SiO O + H R2 SiMe3 tBuMe2SiO (i) 57-84% dr=83:17-94:6 R1 Et O CH Cl 50 °C; (ii) Lipase PS n-C H OH (i) 39-79% dr=35:65->95:5 ee up to 80% major isomer Me R2 O O Ph Ph Ph Ph O O Ti Cl Cl 22 O O R1 SiMe3 O O R2 H SiMe3 Scheme 25 Reagents (i) EtAlCl Cl SPh N Bn 23 Cl (i) 60% O Scheme 26 Reagents (i) Ni AcOH PrOH re.ux.O Ph N Ph N O HO N O N (i) 53% O Ph Ph Scheme 27 Reagents (i) C H 100 °C. Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O Ph (i) 56% dr(20:21)=38:62 O Ph Et O 50 to 4 °C. Cl O NBn OSiMe3 OMe 20 + OMe OSiMe3 21 O 163 O R1 N N 24 25 H O R1N S O (i) 88%; (ii) 95% trans:cis 10:1 Ph + SBn N (iii) trans:cis 1:2 Cl R1 Ph H I Scheme 28 Reagents (i) Et N CH Cl 78 °C; (ii) I CH Cl re.ux; (ii) BuLi THF,78 °C then AcOH O . Ph Ph O N + AcO Et NH O MeO 26 N; (ii) recrystallisation; (iii) Ce(NH ) (NO ) MeCN R2 R1 O R1 N Cl TsO– (iii) 87% Cl N O N O N + (i) 78% dr=73:27 AcO (ii) 52% (S)-26 N+ Me 28 O R2 Ph Ph Ph Ph (i) 54-100% 81:19->99:1 27 Scheme 30 Reagents (i) Et N CH Cl 0 °C to RT.iPr R2 O (i) 60% trans:cis=100:0 ee(trans)=>99% or N (ii) 57% trans:cis=98:2 ee(cis)=>99% N O R1 Scheme 29 Reagents (i) Et H O. O CO2H S O O Scheme 31 Reagents (i) (a) Me CuLi Et O,78 °C (b) BocNCHPh THF 0 °C; (ii) (a) Me CuLi Et O,78 °C (b) (p-MeOC H )NCHCO Me THF 0 °C. 3 Five-membered rings Ring closing metathesis (RCM) has exerted considerable in.uence on the synthesis of heterocyclic rings of .ve atoms or more.A prominent example of RCM is the 164 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R1 tBu N Mo Me Ph O O O O Me Me tBu R2 R2 R3 R3 R3 30 Me R3 R4 (i) 28-91% ee=10-99% R4 (S)-29 R4 Scheme 32 Reagents (i) 30 (5 mol%) toluene 20 or22 °C. OBn OBn O O (i) 95% or BnO BnO (ii) 55% dr=4:1 O O R1 R1 OBn BnO BnO 31 ) RuCHPh toluene 60 °C; (ii) RMe OBn Scheme 33 Reagents (i) RH Cl (PCy Cl (PCy ) RuCHPh toluene 60 °C. MeO2C F3C (i) 50% N N MeO2C F3C Cbz Scheme 34 Reagents (i) Cl (PCy Cbz ) RuCHPh (11 mol%) CH Cl . desymmetrisation of achiral trienes via ring closing metathesis a.ording optically active dihydrofurans (S)-29 or (R)-29 (Scheme 32). The stereochemical outcome of the reaction appears to be determined by the size di.erential between R and the enantiotopic alkenyl moieties.Dihydrofuran (S)-29 is obtained whenRH however when a large group such as cyclohexyl is present predominantly (R)-29 is obtained. Pyranose spiroacetal derivatives 31 have also been prepared by ring closing metathesis of the corresponding non-conjugated acyclic dienes (Scheme 33). Modifying the ole.nic side-chains in the starting material allows the preparation of six- to eightmembered analogues of 31. Cyclic amino acid derivatives containing a tri.uoromethyl group have been prepared via RCM (Scheme 34). Five-membered N-heterocycles have been prepared by enyne metathesis which proceeds in substantially better yields if ethene is present (Scheme 35). Enyne metathesis followed by a Diels—Alder reaction has led to the e.cient formation of a highly substituted hydroisoindole ring system.The reaction sequence was performed on Wang resin and using a split/mix protocol to prepare a 104516 isoindoline combinatorial library (Scheme 36). A large number of palladium-catalysed methods for the synthesis of .ve-membered 165 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 CH (i) 21% or (ii) 90% N N Ts Ts ) RuCHPh (1 mol%) CH Cl Ar; (ii) R1 O R3 (i) (ii) N R4 Scheme 35 Reagents (i) Cl (PCy Cl (PCy ) RuCHPh (1 mol%) CH Cl CH CH .O R1 N O O R2 R2 ) RuCHPh (5 mol%) C H 75 °C; (ii) R3 CN CN O (i) 58-94% dr=52:48-61:39 R2 CN R2 R1 Scheme 37 Reagents (i) Pd(PPh ) THF 40 °C. R2 CH R1=Me R1=H Scheme 36 Reagents (i) Cl (PCy RCHCHR toluene 105 °C. CN R3 1 O R + R2 O HN CO2Me (i) 22-87% N Ts CO HN (ii) 23-66% 2R1 O Ts Scheme 38 Reagents (i) RX Pd(PPh or DMF 40—81 °C; (ii) RX Pd(OAc) Et Ts ) K CO or K CO —TBAC THF or MeCN or Pd(OAc) —PPh or Pd(PPh ) Et N or N—TBAC THF or MeCN 40—81 °C. heterocycles have appeared. Palladium-catalysed reaction of Michael acceptors with vinylic epoxides produced tetrahydrofuran derivatives as [3 2] cycloaddition products (Scheme 37). Using either the amino or acid functionality of acetylene-containing amino acids as a nucleophile O- or N-heterocycles were prepared (Scheme 38). Palladium-catalysed coupling of N-substituted 2-iodoaniline with a variety of internal alkynes results in 2,3-substituted indoles (Scheme 39). The reaction exhibits good regioselectivity with the less sterically demanding end of the alkyne being coupled to the aromatic ring.Indolines have been prepared from aryl Grignard reagents in a two-step sequence involving titanocene-based methodology followed by palladium catalysed aryl amination. In this way dibromo compound 32 was smoothly transformed into indoline 33 under the appropriate conditions (Scheme 40). The construction of complexmolecules by metal-mediated processes continues to 166 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R2 NHR1 N + R2 (i) 27-98% I R3 R3 Scheme 39 Reagents (i) Pd(OAc) (5 mol%) base DMF 100 °C. R3 R2 R2 R3 Br (i) 18-54% based on Cp2TiCl2 Br N Bn R1 32 R1 33 Scheme 40 Reagents (i) Pd (dba) P(o-tol) NaOBu BnNH PhMe. CH + X CH 34 Scheme 41 Reagents (i) Cp*Ru(cod)Cl 40 °C. R1 R1 O O O X (i) 50-90% 3 O Ph Cu R1 O O O R (i) 65-76% Scheme 42 Reagents (i) [Rh(DIPHOS)(CH Cl ) ]SbF CH Cl 25 °C.Me N O 2 35 O C R3OH + O C (i) Conv=83-99% R2 R1 R2 Scheme 43 Reagents (i) 35 toluene 25 °C. generate interest. Hepta-1,6-diynes undergo cycloaddition with allylic ethers in the presence of a ruthenium catalyst (Scheme 41). No cycloadduct is observed when 34 is substituted by cyclopentene or conformationally restricted allylic ethers which led the authors to postulate that ruthenium co-ordination of the oxygen atom and double bond in 34 is essential to the progress of the reaction. Rhodium—phosphine complexes have been used for the synthesis of variously substituted isobenzofuran derivatives (Scheme 42). Modi.cation of the phosphine ligand has made this a highly enantioselective process. Dihydrofuranones have been prepared by the copper-catalysed reaction of 1,2-bisketenes with alcohols (Scheme 43). No asymmetric induction was observed despite the use of a chiral catalyst.Nitrogen .xation has been used in the synthesis of N-heterocycles (Scheme 44). After sequestration of atmospheric nitrogen by the TiX —Li—Me SiCl system amination occurred across not only 1,4-diketones 167 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O O (i) 56% air O O NH or Ti(OPr) Li Me SiCl THF nitrogen or air. 3 2 HN 2 (i) 86% N2 MeNd SiMe 36 (i) 90% Scheme 44 Reagents (i) TiCl NH2 • D sealed tube 140 °C. O R1 R3 R1 (i) 54-92% dr=1:1->20:1 R2 OH O Scheme 45 Reagents (i) 36 C O X + R3M R2 Scheme 46 Reagents (i) MLi or MgBr or CeCl no other conditions given.O O (i) 78% H HO H 37 Scheme 47 Reagents (i) NaOH H O 25 °C. O R1O2C O O OSO2(3-NO2C6H4) (i) 41-70% ee=92-99% (R)-38 Scheme 48 Reagents (i) CH (CO R) CsF DMF. but from a ketone onto an activated acetylenic or an activated ester. Under catalysis by lanthanide complex 36 hindered alkenes have been intramolecularly hydroaminated to produce heterocyclic compounds (Scheme 45). Nucleophilic approaches to furans pyrrolidines and related compounds have seen some elegant developments. Stereocontrolled formation of tetrahydrofurans has been accomplished via S O-cyclisation (Scheme 46). Addition of an organometallic reagent to an aldehyde or ketone generates a nucleophilic alkoxide which attacks the allyl halide in an intramolecular sense to yield the product.The carbonyl group has also been reduced to the same ends. Bis-epoxide 37 has been regioselectively opened to produce an optically active tetrahydrofuran (Scheme 47). Sodium sul.de e.ected ring-opening of 37 to a.ord an inseparable 5 1 mixture of the corresponding tetrahydrothiophene via a 5-exo opening of the second epoxide and a tetrahydrothiopyran via a 6-endo opening of the second epoxide. Caesium .uoride promotes the addition of various malonate derivatives to (S)- or (R)-glycidyl nosylate 38 to produce cyclopropanolactones in good yields (Scheme 48). A small loss in optical purity indicates 168 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 O O OAlEt2 O (i) 45-76% + (ii) 81-99% R1 OtBu R1 ( )n ( )n Scheme 49 Reagents (i) THF,35 °C; (ii) TsOH·H O CHCl . Me CO2Me H CO2 Me SePh (i) 55-71% dr=71:29-93:7 O R1 SePh MeO2C O 39 40 Scheme 50 Reagents (i) MeLi Et O,70 °C then RCHO. I I R1 (i) 45-82% (ii) 40-75% CO CO R1 R1 2Me 2Me TsHN CO2Me N Ts N Ts 41 42 43 K CO MeCN; (ii) I MeCN. R3 R2 (i) 85-99% Me R1O2C Me N Scheme 51 Reagents (i) I OMs N R2 R1O2C R3 R1O2C R1O2C Cl DBU 0 °C. Scheme 52 Reagents (i) CH that initial displacement of the nosylate by the malonate can not be totally discounted. Spiro -lactones have been prepared by ring opening of spiroepoxides by aluminium enolates followed by acid catalysed lactonisation (Scheme 49). Using 2-selenofumarate 39 butano-4-lactone derivatives 40 have been assembled by a tandem Michael—aldol induced ring closure (Scheme 50). Methyllithium adds to 39 in an exclusively 1,4 fashion the resultant anion reacts with an introduced aldehyde and the resultant adduct undergoes an instantaneous lactonisation.Iodine has been used to activate double and triple carbon—carbon bonds to nucleophilic ring closure by an N-tosyl moiety. For example allylglycine derivative 41 undergoes ring closure to 2,5-trans-diastereoisomer 42 in the presence of iodine and base whereas in the presence of iodine alone the 2,5-cis-diastereoisomer 43 is formed (Scheme 51).Nucleophilic approaches to .ve-membered N-heterocycles usually involve a nucleophilic nitrogen atom with examples involving an electrophilic nitrogen somewhat less common. One such approach involving cyclisation onto an O-methanesulfonyl oxime by an active methine group a.ords dihydropyrroles (Scheme 52). Free radical methods have found use in the synthesis of nitrogen- and oxygencontaining .ve-membered rings. Radical cyclisations using a glucopyranosyl auxiliary have resulted in the construction of quaternary stereocentres with high stereopurity (Scheme 53). Mechanistic investigations into the pathway involved in the formation 169 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 CH Et O O O Br Me Me H O O OAc OR1 O (i) 61% O R1 ¡Ô OAc OAc OAc Scheme 53 Reagents (i) 1-ethylpiperidinium hypophosphite AIBN toluene reux.O Et 16O 2N NO2 18O (i) 49% MeO O OMe MeO O N O O S 45 Scheme 54 Reagents (i) h C 44 H reux. R1 R1 R2 O (i) 40-52% R2 dr=1.0:1-1.6:1 N N SO2Ph SO2Ph Scheme 55 Reagents (i) Bu SnH AIBN C H 80 ¡ãC. of spirodienone 44 have shown that the biaryl ether oxygen of the starting material 45 does not emerge as the carbonyl group oxygen in the product (Scheme 54). This and other evidence suggests that the spirocyclisation most likely involves the formation of a cyclohexadienyl radical which is subsequently trapped by a nitro group. Direct evidence of oxygen atom transfer from the nitro group to the carbon radical centre and hence to the carbonyl oxygen can not be realised until suitable methodology for the preparation of O labelled aryl nitro groups exists.Hydroxypyrrolidines have been prepared by tin hydride-mediated cyclisation of -amino aldehydes (Scheme 55). The use of -amino aldehydes under similar conditions aorded piperidines. Generation of acyl radicals from phenylselenocarbamates and subsequent 5-exo cyclisation leads to -lactams (Scheme 56). 2-Aziridinyl radicals undergo ring opening to generate a nitrogen centred radical which triggers o a cyclisation cascade to yield pyrrolizidines (Scheme 57). Five-membered heterocycles have been assembled using carbenes and carbenoids as 170 Annu. Rep. Prog. Chem. Sect.B 1999 95 157¡ª182 OMe OH O O R4 TsN SePh R1 TsN (i) 31-68% R2 R3 R4 R1 R2 R3 Scheme 56 Reagents (i) (Me Si) SiH AIBN PhMe re.ux. R1 R2 H R1 Me (i) 49-63% N R2 N Br Scheme 57 Reagents (i) Bu SnH AIBN C H heat. O O O (i) 58% O O 46 47 Scheme 58 Reagents (i) Me SiC(H)N BuLi DME hexanes. O O 48 O EtO2C R1 CO2Et Et3SiO (i) 53-87% dr=3:1->20:1 + N2 CHO R1 HO ·OEt 78 °C no solvent given. Scheme 59 Reagents (i) BF reactive intermediates. Addition of lithio(trimethylsilyl)diazomethane to ketal 46 followed by treatment with mild acid upon work up produced the bicyclic ether 47 (Scheme 58). Intermediate 48 was observed by NMR but was not isolated and indicates that this method may provide the basis for a synthesis of zaragozic acid/squalestatins.The Lewis acid induced reaction of ethyl diazoacetate and protected -alkyl--(triethylsilyl)oxyaldehydes has resulted in the synthesis of 2,3,4-trisubstituted tetrahydrofurans (Scheme 59). Generation of rhodium carbenoids from diazoesters and their N—H insertion reaction has been used in a modi.ed Bischler indole synthesis (Scheme 60). -Lactams 49 have been prepared from diazoketones 50 containing an N-tosylamine (Scheme 61). Wol. rearrangement of 50 leads to the corresponding ketene which is trapped in an intramolecular fashion by the nitrogen nucleophile. Cycloaddition processes including tethered Diels—Alder reactions and [3 2] 171 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 R2 (i) 60-89% R1 + CO R1 2R3 (ii) 31-87% N2 NHMe CO O 2R3 N Me Scheme 60 Reagents (i) Rh (OAc) PhMe or CH Cl heat; (ii) Amberlyst PhMe heat. NHTs O O R1 N R1 CHN2 (i) 81-93% 50 Ts 49 Scheme 61 Reagents (i) PhCO Ag Et N MeOH or THF. R1 R1 H BnN BnN (i) 69-83% SO2Ph SO2Ph 51 52 H re.ux. O (ii) 2.5:97.5 53 54 Scheme 63 Reagents (i) RH toluene or xylene 110 or 135 °C; (ii) RPh C toluene or xylene 110 or 135 °C. R2 N N R2 R1 C + CO2Me (i) 26-96% Scheme 62 Reagents (i) C (i) 100:0 or O R1N R1N R1 CO2Me 55 56 C H RT. Scheme 64 Reagents (i) PPh cycloadditions have been used in the construction of .ve-membered heterocycles.N-Tethered diene—dienophile systems have led to fused pyrrolidines. Diels—Alder reaction of amino acid derived triene 51 led exclusively to hydroisoindole 52 (Scheme 62). The size of the nitrogen substituent in 53 determined the position of the equilibrium between 53 and the cycloadduct 54 (Scheme 63). Cycloaddition processes have provided convenient approaches to nitrogen heterocycles. A novel phosphinecatalysed [3 2] cycloaddition of imines with methylbuta-2,3-dienoate 55 produced the cycloaddition product 56 regiospeci.cally (Scheme 64). It is postulated that the 172 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 R1 N R1 N R2 O (i) 55-91% R3 OH R4 Scheme 65 Reagents (i) PSP RCH——CHR CH Cl or CDCl .Ph O O S PPh3 (i) 58% S S 57 Scheme 66 Reagents (i) 600 °C 0.01 Torr. Me3Si SiMe3 Me3Si P P – P SiMe3 P P (i) 54% P Me3Si Me3Si 58 Scheme 67 Reagents (i) (Me Si) CHBr DME,78 °C. phosphine undergoes conjugate addition with 55 to produce a reactive dipolar intermediate which then goes on to react with the imine. Solid-supported reagents are of considerable importance in the solution phase synthesis of chemical libraries as they can be used in excess but obviate the need for extensive puri.cation of the product mixture. Polymer-supported perruthenate (PSP) has been used in mild and selective oxidations of secondary hydroxylamines to nitrones which undergo a [3 2] cycloaddition with dipolarophiles (Scheme 65). Other interesting approaches to .ve-membered heterocycles have been reported.Flash vacuum pyrolysis of phosphorus ylide 57 yielded benzothiophene (Scheme 66). Although extrusion of phosphines from stabilised ylides to give carbenes is unusual it is proposed that the carbene thus generated undergoes a 1,5-insertion process followed by homolytic degradation to yield the products. Phospholes are generally accepted not to be aromatic but alkylation of 3,5-bis(trimethylsilyl)-1,2,4-triphospholide anion 58 produced the .rst example of a fully delocalised 1,2,4-triphosphole (Scheme 67). 4 Six-membered rings Alkene metathesis has been found to be particularly applicable to the construction of polycyclic ether natural products.An elegant application of enyne metathesis has not only led to the synthesis of the desired cyclic enol ethers but has also extended the substrates known to undergo enyne metathesis to include alkynyl ethers (Scheme 68). An iterative approach to polycyclic ether systems involved conversion of ester 59 173 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 H H O PMP H H O PMP R1 (i) 20-77% O O O H O H R1 ) RuCHPh (10 mol%) CH Cl re.ux. BnO O BnO R1 (i) up to 65% of 70 BnO BnO O O 60 59 (iii) 15% (ii) up to 85% BnO O BnO R1 BnO O 61 Zn CH Br PbCl TMEDA THF 0 then 60 °C; (ii) bis(hexa.uoro-tert- R2 Scheme 68 Reagents (i) Cl (PCy BnO BnO O O R1 tBu N R1 Scheme 69 Reagents (i) TiCl (2,6-diisopropylphenylimido)neophylidenemolybdenum(..) butoxide) hexane 60 °C; (iii) conditions as for (i) but extended reaction time.N R1 + (i) 65-99% R3 I R2 R3 Scheme 70 Reagents (i) Pd(OAc) (10 mol%) PPh Na CO DMF 100 °C. into the enol ether 60 using Takai’s procedure and produced the desired cyclic enol ether 61 in low yield (Scheme 69). A two step procedure involving Schrock’s molybdenum alkylidene proved to be more e.cient. Isoquinolines and pyridines have been prepared via the palladium-catalysed iminoannulation of internal acetylenes (Scheme 70). Palladium methodology has previously been employed in the preparation of substituted isoquinolines but these older methods have been stoichiometric with respect to palladium.Intramolecular 1,4-dialkoxylation of cyclohexa-1,3-dienes under palladium catalysis has been shown to be an e.cient process for the preparation of fused pyrans (Scheme 71). Low valent early transition metal co-cyclisation of N-tethered enynes 62 produced piperidines 63 after hydrolytic workup (Scheme 72). Work up with carbon monoxide or iodine resulted in more highly functionalised N-heterocycles. Cyclohydrocarbonylation of heptadiene 64 under rhodium catalysis yielded dehydropiperidine 65 (Scheme 73). 4-Substitution of 64 with a methyl group resulted exclusively in the 174 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 (i) 76-96% 82->97% cis R1O O Scheme 71 Reagents (i) Pd(OAc) (5 mol%) MeSO H benzoquinone RT.R2 R1 OH + R1OH 2 N R R1 N (i) 30-90% R3 R3 63 62 Scheme 72 Reagents (i) Cp ZrBu THF,78 °C to RT then MeOH H O. 4 (i) 88% HNTs N Ts 64 65 CHO Scheme 73 Reagents (i) Rh(acac)(CO) BIPHEPHOS CO H THF 65 °C then SiO . Me HNTs CHO OHC 66 desired ring closed product after 16 h at 45 °C but the dialdehyde 66 was obtained as the predominant product at 60 °C after 24 h. Nucleophilic approaches to pyran and piperidine derivatives have used heteroatom and carbon nucleophiles to e.ect ring closure. The stability of -silyl cations has been harnessed in the synthesis of pyrans.Enantiomerically enriched allyl silanes 67 possessing a distal alcohol were treated with an aldehyde or ketone to yield optically active pyrans 68 (Scheme 74). Intramolecular attack of a nucleophile upon 2- phenyloxetan-3-ols led to heterocycles containing di.erent heteroatoms and having varying ring size. For example removal of the pivaloyl protecting group of 69 with methyllithium generated the corresponding lithium alkoxide which when heated yielded pyran 70 (Scheme 75). Some oxetane 71 was also recovered. Ring opening of epoxides 72 has been used to prepare pyrans 73 (Scheme 76). Stabilisation of propynyl cations by alkyne—dicobalt complexes caused ring closure to proceed via the endo mode rather than the normally expected exo mode. Preparation of an allenyl derivative of pipecolic acid utilised a chiral auxiliary to orchestrate the nucleophilic asymmetric intramolecular addition of a propargylsilane moiety onto an iminium ion 175 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 SiMe2Ph HO 2 O R R1 Bu (i) 72-99% 67 + Bu ee=91.5-93.6% trans/cis=9:1->99:1 O 68 R2 R1 Scheme 74 Reagents (i) Me SiOTf CH Cl 78 °C. O CO CO 2 tBu 2 tBu O O + (i) 54% (70) Ph 13% (71) Ph OH Ph OSiMe3 OH OH 69 71 70 Scheme 75 Reagents (i) MeLi DME then re.ux. OH (i) 65-98% O trans:cis=1:99-99:1 OH O R1 R1 (CO)6Co2 72 73 Scheme 76 Reagents (i) Co (CO) CH Cl then BF ·OEt ,78 °C to RT. SiMe3 OH OH H C N Ph NH Scheme 77 Reagents (i) CHOCHO THF H O RT.MeO NHBoc MeO NBoc MeO MeO (i) 70% Et – 75 Ph OH OTf Se+ SeAr (i) 66% de=79% 74 76 O,100 °C. Scheme 78 Reagents (i) 75 Et which was generated in situ (Scheme 77). Intramolecular aminoselenation of the alkene in 74 with the novel selenide 75 a.orded tetrahydroisoquinoline 76 (Scheme 78). It was established that the counter ion in.uenced the diastereomeric excess attained in the product. Using radical based methodology -lactones have been prepared from saturated alcohols and carbon monoxide (Scheme 79). The reaction is believed to involve a 1,5-hydrogen transfer from the -carbon to an alkoxy radical which is formed via a single electron oxidation of the alcohol.Subsequent carbonylation of the -carbon 176 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O R3 R1 O R4 (i) 32-75% R1 R4 R2 OH R2 R3 Scheme 79 Reagents (i) Pb(OAc) C H CO (80 atm) 40 °C. 2 R2 O Me3SiO H R (i) 65-98% + O ee=70-96% O OMe Scheme 80 Reagents (i) 77 4Å MS BuOMe then CH Cl and TFA. (i) 87-99% + R2 R2 OEt O O OEt O O Scheme 81 Reagents (i) 78 3Å MS THF 0 °C. P(p-Tol)2 P(p-Tol)2 OMe Ts R1 Ts R1 N ee=95-99% 81 N + O CO2Et (i) 68% ee=80% (ii) 70% ee=96% EtO2C Me3SiO R1 R1 79 ·4MeCN (1 mol%) THF,78 °C. 80 Scheme 82 Reagents (i) RH 81 CuClO·4MeCN (10 mol%) THF 78 °C; (ii) RMe 81 CuClO radical produces an acyl radical.Oxidation and deprotonation liberate the -lactones. Considerable advances in the area of hetero-Diels—Alder reactions have been made with a number of groups presenting work in this area. Chiral (salen)chromium complexes 77 catalyse the cycloaddition of Danishefsky’s diene and aldehydes in good to excellent enantiomeric excesses (Scheme 80). Copper complexes of C -symmetric bisoxazoline ligands brought about the addition of activated ketones to analogues of Danishefsky’s diene with high enantioselectivity. Asymmetric inverse electron demand hetero-Diels—Alder reactions of enol ethers with ,-unsaturated -ketoesters catalysed by 78 exhibit high enantioselectivities (Scheme 81). The reaction can tolerate reaction temperatures up to 0 °C without a large drop in enantiomeric excess and signi.cantly in the presence of .orisil the catalyst is adsorbed and may be recycled.An asymmetric variant of the aza-Diels—Alder reaction has been developed (Scheme 82), in which the ethyl glyoxylate-derived imine 79 reacts with 177 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R1 R2 R2 S S (i) 4-98% R4 R3 R4 R3 R2 R2 R1 R1 82 Cl 20 °C. O O + – N N Cr OTf N N Scheme 83 Reagents (i) CH Danishefsky’s and related dienes 80. Of the metal—ligand combinations screened 81—CuClO ·4MeCN proved to be the most active and to provide the best enantiomeric excesses. Thioketones underwent [4 2] cycloadditions to dienes to produce the corresponding cycloadducts 82 (Scheme 83). When monosubstituted dienes were used the preferred regioisomers obtained were ‘meta’ and ‘para’ cycloadducts 83 and 84 respectively.1,3-Dithia-2-ylium ions react with 1,3-dienes (Scheme 84). Mechanistic investigations suggested a stepwise process but did not rule out a concerted pathway involving highly unsymmetrical transition states. Bicyclic phosphines 85 have been prepared by [4 2] intramolecular cycloadditions involving in situ generated carbon —phosphorus dienophiles (Scheme 85). H H R1 R1 O O X tBu H2O Cu OH2 tBu OTf tBu tBu 78 77 3-Hydroxypiperidine N-oxide derivatives 87 have been synthesised via the reverse Cope cyclisation of -hydroxy hydroxyamines 86 (Scheme 86). Previously this reaction has been somewhat neglected due to its reversible nature.In this example the judicious placement of a hydroxy group may stabilise the amine oxide in 87 by hydrogen-bonding. 5 Seven-membered and larger rings Once again ring closing metathesis has been shown to be a versatile method for the construction of rings containing at least seven atoms. The .rst example of RCM on a phosphate template has led to the synthesis of six- to eight-membered heterocycles. For example triene 88 is smoothly transformed into 89 with Grubbs’ catalyst (Scheme 87). A traceless linker strategy allowed immobilised diene 90 to be cleaved by RCM to produce 91 (Scheme 88). Ring closing metathesis of functionalised alkyne derivatives has led to surprisingly good yields of twelve-membered or larger rings (Scheme 89). A range of functionality is tolerated in this transformation resulting in the formation of lactones lactams and cyclic silyl ethers.Finally RCM has been used to 178 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R2 S S R4 R3 R4 R3 83 84 R1 R1 BF4 S+ S+BF4 + (i) 64-84% S R2 R2 S Cl 25 °C. R1 R2 P R2 85 Scheme 85 Reagents (i) C H N,60 to 20 °C or Et N30 to 20 °C. R1 R1 HO (i) 51-82% Scheme 84 Reagents (i) CH Cl R1 P (i) H HO N Bn OH N+ Bn O– 86 87 re.ux. O O P O O P O Scheme 86 Reagents (i) CHCl O (i) 75% 88 89 ) RuCHPh (3 mol%) CH Cl re.ux.SO2(p-NO2C6H4) N SO2(p-NO2C6H4) (i) 54% CO2Me CO2Me 91 Scheme 87 Reagents (i) Cl (PCy O O N O 90 Scheme 88 Reagents (i) Cl (PCy ) RuCHPh (5 mol%) styrene PhMe 50 °C. 179 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 X X R2 R1 Scheme 89 Reagents (i) [W(— (i) 52-97% — — CCMe )(OCMe ) ] C H Cl 80 °C. X X Leu Aib Val Leu OMe Boc Val O O (i) 85% or (ii) 90% H BocN O O MeO2C Scheme 90 Reagents (i) XOHSer Cl (PCy ) RuCHPh (20 mol%) CHCl 25 °C; (ii) XOHHse Cl (PCy ) RUCHPh (20 mol%) CHCl 25 °C. cross-link peptides (Scheme 90). 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ISSN:0069-3030    

DOI:10.1039/a807597b

出版商:RSC    

年代:1999

数据来源: RSC