9 Synthetic Methods By D. R. KELLY School of Chemistry and Applied Chemistry University of Wales College of Cardiff PO Box 912 Cardiff CF13TB 1 Introduction ‘The problem with organic synthesis is that it is literally creative and that its practitioners range from the master builder who uses only the best materials (in extreme cases only materials and methods he has invented) to the scrap merchant who is prepared to knock you up a molecule out of any old synthons.” The award of the Nobel prize to E. J. Corey2 in 1991 possibly marks the maturation of organic synthesis3 from a pure science with internal goals to an applied science which can tackle significant problems in biology and make new materials with predictable proper tie^.^ There is certainly a wealth of techniques available particularly for asymmetric transformations.Artificial (abiotic) catalysts are now competitive with yeast5 and enzymes6 in terms of selectivity and yield. But the ability to change the reactivity of enzymes using protein enginee~ing,~ substrate imprinting’ and non-aqueous solvents’ means they are currently more versatile and this position will be augmented when catalytic antibodies (abzymes)” are available ‘off the shelf ’. ‘Biotransforma-tions’” have a further advantage that (with some exceptions) they all act under more or less the same conditions and so it is possible to perform multiple reactions S. Warren Chem. Ind. 1991 796. ’ E. J. Corey Angew. Chem. Znt. Ed. Engl. 1991 30,455. J. Mulzer H.J. Altenbach M. Braun K.Krohn and H. U. Reissig Organic Synthesis Highlights VCH Weinheim 1991. G. W. Gokel J. C. Medina and C. Li SYNLEZT. 1991,677. R. Cszuk and B. I. Glanzer Chem. Rev. 1991 91 49. Biocatalysis in Organic Chemistry ‘a symposium in print’ Red. Trau. Chim. Pays-Bas. 1991 110 (5) 151-263 63; Biotransformations of organometallics A. D. Ryabov Angew. Chem. Znt. Ed. Engl. 1991 30,931. ’ Z. Zhong J. L-C. Liu L. M. Dinterman M. A. J. Finkelman W. T. Mueller M.L. Rollence M. Whitlow and C.-H. Wong J. Am. Chem. SOC,1991,113,683; Z. Zhong J. A. Bibbs W. Yuan and C.-H. Wong 1.Am. Chem SOC.,1991 113 2259. M. Stahl U. Jeppsson-Wistrand M.-0. Mansson and K. Mosbach J. Am. Chem. Soc. 1991,113,9366. E. Rubio A. Fernandez-Moyorales and A. M. Klibanov J. Am. Chem. SOC.,1991 113 695; A.L. Gutman and M. Shapka J. Chem. SOC.,Chem. Commun. 1991 1467; P. Z. Fitzpatrick and A. M. Klibanov J. Am. Chem. SOC.,1991 113 3166; S. Panda and J. S. Dordick J. Am. Chem. SOC.,1991 113 2253. ‘Catalytic Antibodies’ Ciba Foundation Symposium 159 Chairman W. P. Jencks Wiley Chichester 1991; R. A. Lerner S. J. Benkovic and P. G. Schultz Science 1991 252 (5006),659. The activity in this area can be judged by the launch of the new journal Preparative Biotransformations. 219 220 D. R. Kelly in one pot e.g. ester hydrolysis,12 oxidation of the alcohol to an aldehyde cis-trans is~merization,'~ and carbon-carbon bond formation with an aldolase could all be achieved concurrently. There are intriguing possibilities offered by molecular recognition using or self assembling struct~res'~ supramolecular ~ystems'~ such as micelles or monolayers which can be visualized and modelled using computer graphics.16 However although there are a plethora of supramolecular abiotic systems capable of selective binding precious few are capable of effecting a chemical change." One system with enormous potential is the carcerands which are large hollow spherical molecules constructed by dimerization of two hemispherical units (cavitands18).At least one molecule of solvent is always impri~oned'~ during closure and if a solvent mixture is used the most polar solvent (assuming it is small enough) is preferentially incorporated. The linkages between the cavitands are typically acetals2' or thioethers21 which are formed by nucleophilic substitution on alkyl chlorides.The imprisoned solvent molecule( s) stabilize the polar SN2transition state which other- wise would have to take place in a vacuum. Cram has revolutionized isolation technology by infiltrating a-pyrone (2) into a hemicarcerand (1)22at high tem- perature and then photolysing it to give a trapped molecule of cyclobutadiene (3) and carbon dioxide which escaped. Prolonged photolysis effected retro [2 + 21 cycloaddition to give acetylene which also escaped the confines of the hemicarcerend (1).23 The hemicarcerends have much larger portals than the carcerands and guests as large as ferrocene can be in~orporated,~~ with discrimination between enan-ti0me1-s.~~ 12 I. Weinhouse R. A.Lerner R. A. Gibbs P. A. Benkovic R. Hilhorst and S. J. Benkovic J. Am. Chem. SOC.,1991 113 291; K. D. Janda M. I. Weinhouse T. Danon K. A. Pacelli and D. M. Schloeder J. Am. Chem. Soc. 1991 113 5427; S. Ikeda M. I. Weinhouse K. D. Janda R. A. Lerner and S. J. Danishefsky J. Am. Chem. SOC.,1991,113,7763; T. Kitazume J. T. Lin M. Takeda and T. Yamazaki J. Am. Chem. Soc. 1991 113 2123. l3 D. Y. Jackson and P. G. Schultz J Am. Chem. Soc. 1991 113 2319. 14 F. Vogtle 'Supramolecular Chemistry an Introduction' Wiley Chichester 1991; ed. H.-J. Schneider and H. Durr 'Frontiers of Supramolecular Organic Chemistry and Photochemistry' VCH Weinheim 1991. Is F. M. Menger Angew. Chem. Znf. Ed. Engl. 1991 30 1086. 16 Interactions computation W. L. Jorgensen Chemtracts Organic Chemistry 1991 4 91; W.C. Ripka and J. M. Blaney Top. Stereochem. 1991 20 1. l7 Ten news items and articles describing prospects for nanotechnology Science 1991 254(5036) 1300- '* These are essentially calixarenes with functional groups on one face see J. Vicens and V. Bothmer 1342. 'Calixarenes a Versatile Class of Macrocyclic Compounds' (Topics in Inclusion Science 3) Kluwer Dordrecht 1991. 19 'Host-Guest molecular Interactions From Chemistry to Biology' Ciba foundation Symposium 158 Chairman I. 0. Sutherland Wiley Chichester 1991. 20 J. C. Sherman C. B. Knobler and D. J. Cram J. Am. Chem. SOC.,1991 113 2194. 21 J. A. Bryant M. T. Blanda M. Vincenti and D. J. Cram J. Am. Chem. SOC.,1991 113 2167. 22 Hemicarcerands differ from carcerands in having portals through which guests can enter and leave.23 D. J. Cram M. E. Tanner and R. Thomas Angew. Chem. Inf. Ed. Engl 1991 30 1024; H. Hopf Angew. Chem. Int. Ed. Engl. 1991 30 1117. 24 M. L. C. Quan and D. J. Cram J. Am. Chem. SOC.,1991 113 2754; D. J. Cram M. E. Tanner and C. B. Knobler J. Am. Chem. SOC.,1991 113 7717. 25 J. K. Judice and D. J. Cram J. Am. Chem. Soc. 1991 113 2790. Synthetic Methods 22 1 Buckminsterfullerene.-The most vigorous area of research (as judged by citation analysis of papers published in 1991) continues to be the chemistry of buckminster- fullerene.26 The simple construction of the carbon spark generator27 enables even a novice to make practical amounts of fullerite (the raw mixture of c60 C70 and higher homologues) which can be separated crudely by soxhlet extraction28 and purified by HPLC.29 The spark generator appears to operate by formation of individual carbon atoms because mixtures of 12C and 13Cgraphite give C60in which the 13C atoms are randomly in~orporated.~' 26 Reviews H.W. Kroto A. W. Allaf and S. P. Balm Chem. Rev. 1991 91 1213; J. F. Stoddart Angew. Chem. Znt. Ed. Engf. 1991 30 70; A. Moody Chem. Ind. 1991 (lo) 346; R. Lee ibid. 349; J. S. Miller Adu. Mater. 1991 3 262; F. Diederich and R.L. Whetten Angew. Chem. Znt. Ed. Engl. 1991 30 678. 27 A. S. Koch K. C. Khemani and F. Wudl J. Org. Chem. 1991 56 4543. 28 D. H. Parker P. Wurz K. Chatterjee K. R. Lykke J. E. Hunt M. J. Pellin J. C. Hemminger D. M. Gruen and L.M. Stock J. Am. Chem. SOC.,1991 113 7499. 29 W. Pirkle and C. J. Welch J. Org. Chem. 1991 56 6973. 30 J. M. Hawkins A. Meyer S. Loren and R. Nunlist J. Am. Chem. SOC.,1991 113 9394; C. S. Yannoni P. P. Bernier D. S. Bethune G. Meijer and J. R. Salem J. Am. Chem. SOC.,1991,113,3190; for complete 2D NMR studies see J. M. Hawkins S. Loren A. Meyer and R. Nunlist J. Am. Chem. SOC.,1991 113 7770; R. D. Johnson G. Meijer J. R. Salem and D. S. Bethune J. Am. Chem. SOC.,1991 113 3619. 222 D. R. Kelly c60 and CT0 have eluded structyral characterization by X-ray crystallography because these nearly spherical molecules spin too quickly in the crystal lattice,31 however the cyclohexanone solvates reduce this rotation sufficiently to define the positions and general shape32 and the osmium tetraoxide dipyridine adduct was sufficiently ordered that the ‘football’ structure could finally be proven.33 A hexa(diethy1phosphino platinium) adduct of C60 is formed with octahedral symmetry and n2-bonding at the electron rich 6:6 fusions;34 similarly C70 reacts with Ir(CO)Cl(Ph3P)2 to give a mono n2-adduct at the most non-planar 6:6 fusion.35 In both cases the adducts were characterized by X-ray crystallography.The situation for p-block derivatives is much less satisfactory. The C600 and C700,36 the monoepoxides have been characterized well but other derivatives such as c~~(cH~)~-~~ c~~F~~, ,37 c~~F~() ~70~40, ,38 amongst other fluoro derivative^,^^ C6Oc112 ?o c60c12 C60Br~ C60(OCH3)1-26 C60Ph>22 C60HPh12 ,42 C60(morpho-line)643 are only characterized as amorphous mixtures.c60 readily forms stable radical anion saltsu which are semiconductors. It is reduced to a trianion4’ with alkali metals46 to produce materials that are supercon- ducting at 18 K which is unprecedentedly high for an ‘organic supercond~ctor’,4~ 31 J. M. Hawkins T. A. Lewis S. D. Loren A. Meyer J. R. Heath R. J. Saykally and F. J. Hollander J. Chem. Soc. Chem. Commun. 1991,775; W. I. F. David R. M. Ibberson J. C. Matthewman K. Prassides T. J. S. Dennis J. P. Hare H. W. Kroto R. Taylor and D. R. M. Walton Nature 1991 353 147 32 S. M. Gorun K. M. Creegan R. D. Sherwood D. M. Cox V. W. Day C. S. Day R. M. Upton and C. E. Briant J. Chem. Soc. Chem. Comrnun. 1991 1556. 33 J. M. Hawkins A.Meyer T. A. Lewis S. Loren and F. J. Hollander Science 1991 252(5003) 312. 34 P. J. Fagan J. C. Calabrese and B. Malone J. Am. Chem. Soc. 1991 113 9408; J. M. Hawkins A. Meyer T. A. Lewis S. Loren F. J. Hollander Science 1991 252 312; P. J. Fagan J. C. Calabrese and B. Malone Science 1991 252 1160. 35 A. L. Balch V. J. Catalano J. W. Lee M. M. Olmstead and S. R. Parkin J. Am. Chem. Soc. 1991 113 8953. 36 F. Diederich R. Ettl Y. Rubin R. L. Whetten R. Beck M. Alvarez A. Anz D. Sensharma F. Wudl K. C. Khemani and A. Koch Science 1991 252 548. 37 J. W. Bausch G. K. S. Prakash G. Olah D. S. Tse D. C. Lorents Y. K. Bae and R. Malhotra J. Am. Chem. Soc. 1991 113 3205. 38 J. H. Holloway E. G. Hope R. Taylor J. Langley A. G. Avent T.J. Dennis J. P. Hare H.W. Kroto and D. R. M. Walton J. Chem. Soc. Chem. Comrnun. 1991,966. 39 H. Selig C. Lifshitz T. Peres J. E. Fischer A. R. McGhie W. J. Romanow J. P. Cauley Jr. and A. B. Smith 111 J. Am. Chem. Soc. 1991 113 5475. 40 F. N. Tebbe J. Y. Becker D. B. Chase L. E. Firment E. R. Holler B. S. Malone P. J. Krusic and E. Wasserman J. Am. Chem. SOC. 1991 113,9900. 41 G. A. Olah I. Bucsi C. Lambert R. Aniszfeld N. J. Trivedi D. K. Sensharma and G. K. S. Prakash J. Am. Chem. Soc. 1991 113 9385. 42 G. A. Olah I. Bucsi C. Lambert R. Aniszfeld N. J. Trivedi D. K. Sensharma and G. K. S. Prakash J. Am. Chem. SOC.,1991 113,9387. 43 A. Hirsch Q. Li and F. Wudl Angew. Chem. Znt. Ed. Engl. 1991 30,1309. 44 P.-M. Allemand G. Srdanov A. Koch K. Khemani F. Wudl Y.Rubin F. Diedrich M. M. Alvarez S. J. Anz and R. L. Whetton J. Am. Chem. Soc. 1991 113 2780. 45 D. M. Cox S. Behal M. Disko S. M. Gorun M. Greaney C. S. Hsu K. B. Kollin J. Millar J. Robbins W. Robbins R. D. Sherwood and P. Tindall J. Am. Chem. Soc. 1991 113 2940; P.-M. Allemand A. Kochi F. Wudl Y. Rubin F. Diederich M. M. Alvarez S. J. Anz and R. L. Whetten J. Am. Chem. SOC.,1991 113 1050. 46 J. P. McCauley Jnr. Q.Zhou N. Coustel 0. Zhu G. Vaughan S. H. J. Idziak J. E. Fischer S. W. Tozer D. M. Groski N. Bykovetz C. R. Lin A. R. McGhie B. H. Allen W. J. Romanow A. M. Denenstein and A. B. Smith 111 J. Am. Gem. Soc. 1991 113 8537; R. M. Fleming A. P. Ramirez M. J. Rosseinsky D. W. Murphy R.C. Haddon S.M. Zahurak and A. V. Makhija Nature 1991,352 787.47 A. F. Hedard et al. Nature 1991 350(6319) 600; This was the most highly cited paper published in 1991 with 89 citations; see also R. C. Haddon et al. Nature 1991 350(6318) 920; J. H. Weaver et al. Chem. Phys. Lett. 1991 66 1741. Synthetic Methods whereas the tetra-anions are not superconductors.48 c60+and c6()-can be generated reversibly but only in ben~onitrile.~~ c60 and C70 are stable to light and readily yield the triplet states” which are good sensitizers for singlet oxygen formation.” Species such as AgC60 ,52 FeC60+,53and the ‘dumbbell’ Ni( C60)2+ 54 have the metal bound on the outer surface of the fullerene however C6,He’+ 55 and C60Ne-+ produced by collision in ion beamss6 may be the long sought after endohedral complexes.57 In another surprise in this area c76 (4)” and Cgqs9 both appear to have D2 symmetry and exist as pairs of enantiomers.By analogy with the helicenes they are expected to have extremely high optical rotations. The carbon oxides (5) are precursors of ‘cyclic carbon’ (6) (7).60 Ab initio calculations suggest that the most stable valence isomer of C18 is the cummulene (7) rather than the polyacetylene (6).61 Intriguingly the C30 (6c) (7c) homologue gives an extremely intense peak at 720amu in the positive ion laser desorption Fourier transform mass spectrum implying dimerization to c60. A new synthesis of corannulene (13) ([5]circulene) has two particularly striking steps (Scheme 1) Double Knoevenagel condensation yields a cyclopentadienone 48 R.M. Fleming M. J. Rosseinsky A. P.Ramirez D. W. Murphy J. C. Tully R. C. Haddon T. Siegrist R. Tycko S. H. Zahurak A. V. Makhija and C. Hampton Nature 1991 352 701. 49 D. Dubois K. M. Kardish S. Flanagan and L. J. Wilson J. Am. Chem. SOC.,1991 113 7773. M. R. Wasielewski M. P. O’Neil K. R. Lykke M. J. Pelin and D. M. Gruen J. Am. Chem. SOC.,1991 113 2774. 51 J. W. Arbogast and C. S. Foote J. Am. Chem. SOC.,,1991 113 8886. 52 J. A. Howard M. Tomietto and D. A. Wilkinson J. Am. Chem. SOC.,1991 113 7870. 53 L. M. Roth Y. Huang J. T. Schwedler C. J. Cassady D. Ben-Amotz B. Kahr and B. S. Freiser J. Am. Chem. SOC.,1991 113 6298. 54 Y. Huang and B. S. Freiser J. Am. Chem. SOC.,1991 113 8186. 55 T. Weiske D. K. Bohme J. Hrusak W. Kratschmer and H.Schwarz Angew. Chem. Znr. Ed. Engl. 1991,30 884. 56 K. A. Caldwell D. E. Giblin C. S. Hsu D. Cox and M. L. Gross J. Am. Chem. SOC.,1991 113 8519. 57 J. Cioslowski and E. D. Fleischmann J. Chem. Phys. 1991,94 3730; J. Cioslowski J. Am. Chem. SOC. 1991 113 4139; J. Cioslowski and S. T. Mixon J. Am. Chem. SOC.,1991 113 4142. 58 R. Etti I. Chao F. Diederich and R. L. Whetten Nature 1991 353 149. 59 P. W. Fowler J. Chem. SOC.Faraday Trans. 1991 87 1945. 60 Y. Rubin M. Kahr C. B. Knobler F. Diederich and C. L. Wilkins J. Am. Chem. SOC.,1991 113 495. 6’ V. Parasuk J. Almlof and M. W. Feyereisen J. Am. Chem. SOC.,1991 113 1049. 224 D. R. Kelly a n=l b n=2 c n=3 0 & \/ \/ (9) I @R&Eg c-\/ iv \/ \/ a R=E -'Jii b R=CH=CBr c R=C==CHd iii Reagents i Glycine norbornadiene; ii (a) LiAIH4 (b) PCC (c) Ph,P,Zn,CBr,; iii LDA; iv Flash vacuum pyrolysis Scheme 1 Synthetic Methods 225 (9) which undergoes a Diels-Alder reaction in situ with nonbornadiene.The adduct (10) eliminates cyclopentadiene by a retro Diels-Alder reaction and extrudes carbon monoxide to give diester (12a). This was converted to the tetrabromide (12b) or the diacetylene (12c) both of which gave corannulene (13) in about 10% yield upon flash vacuum pyrolysis.62 Low temperature NMR studies show that corannulene has a bowl like structure which inverts rapidly through the planar form at room temperat~re.~~ Thiophenes-There has been a renaissance in the chemistry of olig~thiophenes~~ due to their potential as electrical conductor^^^ and occurrence in plants of the Compositae family66 where they act as photo to xi^^^ nematocides (e.g.a-terthiophene (14a) and a-quinquethiophene (14b)68).Typically these systems are prepared by acylation of thiophenes with succinyl chloride to give 1,4 diketones which are converted to a thiophene ring with Lawesson's reagent. The longest characterized oligothiophene is the undecithiophene (19 which was substituted with aliphatic r 1 (14) a n=l b n=3 R' RZ R' (15) a R' = R2= C,,H2 b R' = n-C12H25,R2= "-C,H sidechains to enhance solubility69 and has comparable conductivity to polythiophene or poly(benzo[ ~]thiophene).~' The bis(terthi0phene) (16) in which the two .rr-systems are orthogonal has been proposed as a molecular switch7' and an extraordinary 'insulated wire' consisting of a fully conjugated porphyrin core almost 65 A long with an insulating sheath of t-butyl groups has been prepared.72 62 L.T. Scott M. M. Hasemi D. T. Meyer and H. P. Warren J. Am. Chem. SOC.,1991,113,7082. Although corannulene ws first made in 1966 the synthesis has apparently never been repeated and so for example the 13C NMR spectrum had never been recorded prior to the current work. 63 For a comparable study of [7]circulene and [7.7]circulene see K. Yamamoto Y. Saitho D. Iwaki and T. Ooka Angew. Chem. Znt. Ed. Engl. 1991 30 1173. 64 S.Gronowitz 'Thiophene and its Derivatives Pt 4' (Chemistry of Heterocyclic Compounds 44),Wiley New York 1991.65 Review of organic conductors K. Davidson Educ. Chem. 1991 28 155. 66 J. Kagan Prog. Chem. Org. Naf. Prod. 1991 56 88. 67 D. M. Perrine D. M. Bush E. P. Komak M. Zhang Y. H. Cho and J. Kagan J. Org. Chem. 1991 56 5095. A. Men and F. Ellinger Synthesis 1991 462. 69 W. ten Hoeve H. Wynberg E. E. Havinger and E. W. Meijer J. Am. Chem. Soc. 1991 113 5887. 70 T. Iyoda M. Kitano and T. Shimidzu J. Chem. SOC.,Chem. Commun. 1991 1618. 71 J. Nakayama and T. Fujimori J. Chem. SOC.,Chem. Commun. 1991 1614; For the benzanoid analogue see N. Harada H. Ono Y. Nishiwaki and H. Uda J. Chem. SOC.,Chem. Commun. 1991 1753. 72 M. J. Crossley P. L. Bum S. S. Chew F. B. Cuttance and I. A. Newsom J. Chem. SOC., Chem. Commun. 1991 1564; M.J. Crossley P. L. Bum S. J. Langford S. M. Pyke and A. G. Stark J. Chem. SOC.,Chem. Commun. 1991 1567; M. J. Crossley and P. L. Burn J. Chem. SOC.,Chem. Commun. 1991 1569. 226 D. R. Kelly Natural Products Synthesis.-Evans has achieved the synthesis of Ferensimycin B which bears a total of 16 chiral centres on a 24 carbon backbone. In the last step aldol reaction of the zinc enolate (17) and aldehyde (18) gave a mixture of adducts (65% yield) in which Ferensimycin (19) (the threo-Cram adduct) was the largest r 1 ClZn ~t $e OM OM component (41Y0).~~ Nicolaou has completed the synthesis of the FGHIJ rings of brevetoxin A74in about 100 steps starting from common sugars.75 The ABCD and E ring fragments were finished last year. Assembly and a one carbon homologation at the aldehyde terminus should complete this monumental task.A nine year study has culminated in the syntheses of all members of the phyllanthostatin family (23). A key bond construction was addition of the vinyl lithium (21) to the aldehyde (20) to give the pivitol intermediate (22).76 73 D. A. Evans R. P. Polniaszek K. M. DeVries D. E. Guinn and D. J. Mathre J. Am. Chem SOC,1991 113 7613. 74 For a review of polyether antibiotics see J. A. Robinson Bog. Chem. Org. Not. Prod. 1991 58 1. ’’ K. C. Nicolaou A. C. Veale C.-K. Hwang J. Hutchinson C. V. C. Prasad and W. W. Ogilvie Angew. Chem Int. Ed. EngL 1991 30,299. 76 A. B. Smith 111 M. Fukui H. Vaccaro and J. R. Empfield J. Am. Chem SOC,1991 113 2071; A. B. Smith 111 R.A. Rivero K. J. Hale and H. Vacarro ibid. 2092; A. B. Smith K. J. Hale H. Vaccaro and R.A. Rivero ibid 21 12. Synthetic Methods I R4 I Me 0 AcO OH (23) Phyllanthoside R’ = RZ= H R3= Ac R4,R5= 0 (epoxide) Phyllanthostatin 1 1 Rz= Ac R3= H Phyllanthostatin 2 1 R’ = OH Phyllanthostatin 3 1 R4= R5= OH Chiral Analysis.-The developments in ~hiral~~ synthesis78 have severely tested the techniques for the determination of enantiomeric excess. HPLC,79,80SFC,81GLC,82 and capillary zone electrophoresis (CZE)83give the most accurate results but NMR spectro~copy~~ is usually quicker. Circular dichroism is restricted to compounds with good chromosphores but enables the absolute configuration to be determined.85 2,2,2-Trifluoro-1-(9-anthryl)ethanol(24) (which is widely used as a chiral solvating agent and as the stationary phase in chiral HPLC) adopts a conformation in solution which places the trifluoro group orthogonal to the anthracene ring and locks the 77 ‘New Developments in Molecular Chirality’ ed.P. C. Mezey Kluwer Academic Publishers Dordrecht 1991. 78 For industrial chiral synthesis see J. Crosby Tetrahedron 1991 47 4789. 79 ‘Chiral Separations by Liquid Chromatography’ ed. S. Ahuja ACS Symposium series 471 ACS Washington 1991; N. Krause and G. Handke Tetrahedron Lett. 1991 32 7225; W. H. Porter Pure Appl. Chem. 1992 63 1119; J. N. Kinkel U. Gysel D. Blase and D. Seebach Helu. Chim. Acta 1991 74 1622. 80 For the determination of absolute configuration by HPLC see K.S. Rein and R. E. Gawley J. Org. Chem. 1991,56 839; K. Nilsson A. Hallberg R. Isaksson and J. Sandstrom Acta Chem. Scand. 1991 45 716. 81 V. Schurig D. Schmalzing and M. Schleimer Angew. Chem Znt. Ed. EngL 1991 30,987. 82 Y. Dobashi K. Nakamura T. Saeki M. Matsuo S. Hara and A. Dobashi J. Org.Chem. 1991,56,3299. 83 P. Camilleri and G. N. Okafo J. Chem. Soc. Chem. Commun. 1991 196. 84 D. Parker Chem Rev. 1991,91 1441; for a new techniques using 77Se NMR see L. A. Silks 111 J. Peng J. D. Odom and R. B.Dunlap J. Chem Soc. Perk Trans. I 1991 2495. 85 H. E. Smith and L. P. Fontana J. Org. Chem. 1991 56 432; T. Hargitai P. Rheinholdsson and J. Sandstrom Acta Chem Scand. 1991,45 1076; D. F. Colon and S.T. Pickard J. Org. Chem.1991,56 2322. 228 D. R. Kelly A HN NH HOOCd kCOOH // HOOC COOH (25) hydroxyl group in a highly asymmetric environment.86 In the solid state homochiral material forms face to face dimers with the hydroxyl groups facing inwards and the hydroxyl proton engaged in an unusual .rr-facial hydrogen bond.87 Chiral lanthanide shift reagents are convenient to use but are highly unpredictable cause line broadening and can only be used in very dry organic solvents. However the Europium( 111) complex of (S S)-ethylenediamine-N,N'-disuccinicacid (25) discriminates the 'H NMR signals of enantiomeric amino acids in aqueous solution.88 It is remarkable that after 22 years Mosher's acid chloride (26)89 is still the paramount derivatizing reagentg0 for assessing enantiomeric purity and for determin- ing absolute stereo~hemistry.~' The cyano fluoro analogue (27) has been suggested CF F I I Ph-C-COOH Ph-C-COOH I I OMe CN (26) (27) as a substitute because it gives larger A6 values in the 19F NMR spectrum.92 Chiral derivatives are not necessarily required.Achiral diphenyldichlorosilane forms diastereomeric silyl acetals with chiral alcohols. If the dl and meso compounds can be distinguished the enantiomeric ratio can be ~alculated.~~ Similarly if the enan- tiomers associate in solution (e.g.by hydrogen bonding) the enantiomeric ratio can be determined in the same way!94 Cholesteric liquid crystals attached to steroidal crown ethers change colour when they bind enantiomeric ammonium salts.In the best case the difference in (A)(A)max was only 81 nm but it is not difficult to imagine that this could be developed into the chiral equivalent of pH paper!95 86 C. Jaime A. Virgili R. M. Claramunt C. Lopez and J. Elguero J. Org. Chem. 1991 56 6521. 87 H. S. Rzepa M. L. Webb A. M. Z. Slawin and D. J. Williams J. Chem. Soc. Chem. Cornmun. 1991 765. 88 J. Kido Y. Okamoto and H. G. Brittain J. Org. Chem. 1991 56 1412. 89 J. A. Dale D. L. Dull and H. S. Mosher J. Org. Chem. 1969 34 2543. 90 D. E. Ward and C. K. Rhee Tetrahedron Lett. 1991 32 7165. 91 I. Ohtani T. Kusumi Y. Kashman and H. Kakisawa J. Am. Chem. Soc. 1991 113 4092; T. Kusumi Y. Fujita I. Ohtani and H. Kakisawa Tetrahedron Lett. 1991 32 2923; I. Ohtani T.Kusumi Y. Kashman and H. Kakisawa J. Org. Chem. 1991 56 1296; T. Kusumi T. Fukushima I. Ohtani and H. Kakisawa Tetrahedron Lett. 1991 32 2939. 92 Y. Takeuchi N. Itoh H. Note T. Koizumi and K. Yamaguchi J. Am. Chem. Soc. 1991 113 6318. 93 X. Wang Tetrahedron Lett. 1991 32 3651. 94 C. Giordano A. Restelli M. Villa and R. Annunziata J. Org. Chem. 1991 56 2270. 95 T. Nishi A. Ikeda T. Matsuda and S. Shinkai J. Chern. Soc. Chem. Cornmun. 1991 339; F. Vogtle and P. Knops Angew. Chem. Znt. Ed. EngZ. 1991 30,958. Synthetic Methods New Publications.-The Organic Syntheses Reaction Guide96 has been brought up to date and collectives will occur at five yearly intervals in future rather than ten yearly as at present. Wilen’s excellent review of reviews is also appearing more freq~ently.~’ A reasonably priced 4 volume compilation of drug syntheses98 has been published as well as second editions of Greene’s ‘Protective Groups in Organic Synthesis’99 and Lowenthal’s ‘Guide for the Perplexed Experimentalist’.’00 2 CC Connection and Disconnection Ketones.-A careful study has for the first time given convincing proof that chelation increases the rate of nucleophilic addition to ketones.”’ Thus the chelating benzyl ether (28a) reacts 140 times faster with dimethyl magnesiumlo2 at -78 “C than the non-chelating silyl ether (28b).In fact the latter is about as reactive as methyl butyl ketone (28c). A similar study with the chiral ethers (29a-c) showed a direct correla- tion between diastereoselectivity and reaction rate.’03 LRa R=OBn b R=Pr c R=OSi(Pri) OR 0rganolithiums.-When the 0-deutero quinoline (30) was treated with butyl lithium and then quenched with H20 the C-deutero quinoline (31) (66% incorporation of deuterium) was f~rmed,”~ repetition of this work under slightly different conditions gave a 27-32% incorp~ration.’~~ This result was attributed to initial halogen-lithium exchange followed by intramolecular transfer of deuterium however it is also possible that individual molecules undergo alkoxide formation followed by halogen-lithium exchange and the aryl lithium is quenched by unreacted 0-deuteroquinoline (30).These two possibilities can only be resolved by a double labelling experiment which shows the extent of intermolecular transfer of deuterium.96 D. C. Liotta and M. Volmer ‘Organic Syntheses. Reaction Guide’ Incorporating Collective Volumes 1-7 and Annual Volumes 65-68 John Wiley and Sons Inc. New York 1991. 97 S. H. Wilen J. Org. Chem. 1991 56 477 2597 4580 5966; 1992 57 412 2203. 98 D. Lednicer and L. A. Mitscher ‘Organic Chemistry of Drug Synthesis’ Wiley New York 1991. 99 T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ Wiley New York 1991. 100 H. J. E. Loewenthal ‘Guide for the Perplexed Experimentalist’ J. Wiley and Sons Chichester 2nd edition 1990. 101 For acyl silanes see S. Bienz and A. Chapeaurouge Helv. Chim. Acta 1991,74 1477; aldol condensation R. Carlson A. Nordahl and W. Kraus Acta Chem Scand. 1991 45 46. 102 For boron enolates as nucleophiles see A.Bernardi A. M. Capelli A. Comotti G. Gennari M.Gardner J. M. Goodman and I. Paterson Tetrahedron 1991 47 3471. 103 E. L. Eliel S. V. Frye E. R.Hortelano X. Chen and X. Bai Atre Appl. Chem. 1992 63 1591. 104 N. S. Narasimhan N. M. Sunder R. Ammanamanchi and B. D. Bonde J. Am. Chem. SOC.,1990 112 4431. 105 D. J. Gallagher and P.Beak J. Am. Chem. Soc. 1991 113 7984. 230 D. R. Kelly OH Ph Ph Bun Bun An intriguing similar result has been obtained during the addition of butyl lithium to benzoic acid (32) which yields roughly equal amounts of the ketone (33) and the alcohol (34). The conventional wisdom is that deprotonation is followed by nucleophilic attack to give the stable dialkoxide (35).It has been suggested in this case that nucleophilic attack occurs prior to deprotonation (36) and that loss of lithium hydroxide gives the ketone (33) which then undergoes a second addition but it is also possible that lithium oxide is eliminated from the dialkoxide (35).'06 Dihalo-organ~lithiurns~~~ (37) add to diesters (38) without elimination of the ,alkoxy group (39) (40),'08 as do acyl anions.'09 C02Me x)--Li+ ( - X C02Me C02Me C02Me (37) X = C1 Br Lithium naphthalenide and lithium p,p'-di-tert-butylbiphenyl(LiDBB)"' are nor- mally used stoichiometrically for the preparation of organolithium'll reagents from alkyl halides but a new catalytic procedure is claimed to be equally efficient."* para-Dilithium hexakis(trimethylsily1)benzenide has been isolated as a bis-THF adduct113 with both lithium atoms located on the concave side of the boat shaped aromatic ring."4 Addition of D,O gives the expected 'Birch' 1,6dihydrobenzene.Association between cation and carbanion,' l5 and the degree of aggregation116 106 C. Einhom J. Einhom and J.-L. Luche Tetrahedron Lezt. 1991 32 2771. 107 a,a-halolithiums are configurationally stable at -120 "C R. W. Hoffmann T. Ruhland and M. Bewersdorf J. Chem. SOC.,Chem. Commun. 1991 195. 108 J. Barluenga L. Llavona M. Yus and J. M. Concellon Tetrahedron 1991 47 7875; J. Barluenga L. Llavona J. Concellon and M. Yus J. Chem. SOC.,Perk Trans. I 1991 297. 109 D. Seyferth R. M. Weinstein R.C. Hui W.-L. Wang and C. M. Archer J. Org. Chem. 1991,!% 5768.110 D. J. Rawson and A. I. Meyers Tetrahedron Lett. 1991 32 2095; N. J. R. van Eikern Hornmes F. Bickelhaupt and G. W. Klumpp J. Chem. SOC.,Chem. Commun. 1991,438. For a new analytical method see H. Kiljunen and T. A. Hase J. Org. Chem 1991 56 6950. 112 M. Yus and D. J. Ramon J. Chem. Soc. Chem. Commun. 1991 398. 113 A. Sekiguchi K. Ebata C. Kabuto and H.Sakurai J. Am. Chem. SOC.,1991 113 1464. 114 A. Sygula and P. W. Rabideau J. Am. Chem. SOC.,1991 113 7797. 115 H. J. Reich and J. P. Borst J. Am. Chem. Soc, 1991 113 1835. 116 M. Buhl N. J. R. van Eikema Hornmes P. von R. Schleyer U. Fleischer and W. Kutzelnigg J. Am. Chem. SOC.,1991 113 2459; L. M. Jackrnan E. F. Rakiewicz and A. J. Benesi J. Am. Chem. SOC.,1991 113 4101; H.-J. Gais J.Muller J. Volhardt and H. J. Lindner J. Am. Chem. SOC.,1991 113 4002. Synthetic Methods 23 1 profoundly affect the reactivity of organometallics but these factors are not readily predictable. The enthalpies of deprotonation of isopropanol by alkyl lithiums and lithium amides in the presence and absence of lithium t-butoxide are the same indicating that the alkoxide does not associate with the base.'17 But the rates of deprotonation of toluene and ethyl benzene increase when more sterically hindered potassium alkoxides are used with alkyl lithiums."' Dithioacetals derived from aromatic ketones (41) undergo reductive cleavage by alkyl lithiums to give a benzylic anion (42);l19similarly the allyl thioether (44)is cleaved by lithium 1-(dimethy1amino)naphthalenideto give the allyl methyl anion (45) which is a useful reagent for terpene synthesis.'** In a more complex example -RsxLi RsxsR E+_ RsxE Ph Me Ph Me Ph Me (41) (42) (43) R= Me Ph or R-R= -(CH2)2 -(CH2)3- addition to the aldehyde (46) gives an alkoxide (47) which undergoes deprotonation adjacent to one thioether and intramolecular nucleophilic displacement of the other thioether group.A second deprotonation directed by the alkoxide gives the cis-dilithiocyclopropane (48) which can be trapped with dimethylformamide to give the lactol (49).12'Reductive cleavage of BF,-THF complex (50) with LDBB at room temperature yields a versatile 8-alkoxy organolithium (51) used in a synthesis of PhS&H 2BuLi I phs>CHO ___* \ Li ?Me PhS PhS (46) / Lid Li (47) 117 E.M. Arnett and K. D. Moe J. Am. Chem SOC,1991 113 7068. 118 L. Lochmann and J. Petranek Tetrahedron Lett. 1991 32 1483. 119 A. Kreif B. Kenda and P. Barbeaux Tetrahedron Lett. 1991 32 2509. 120 D. W. McCullough M. Bhupathy E. Piccolino and T. Cohen Tetrahedron 1991 47 9727. 12' K. Tanaka H. Matsuura I. Funaki and H. Suzuki J. Chem SOC.,Chem. Commun. 1991 1145. 232 D. R. Kelly the olive fly sex pheromone (52).122 N-methyl tetrahydroisoquinoline (53) is deprot- onated by butyl lithium at C-4 (54) but the BF3 complex (55) is deprotonated adjacent to the amino group by lithium tetramethyl ~iperidide.'~~ -BF3 (55) -The diene (57) undergoes initial deprotonation to give an ally1 lithium (58) which eliminates lithium h~dride'~~ to give the triene (59).Double deprotonation then gives a product best formulated as the p-xylene dianion (60).'25 Bu"Li 4 _7 2BuLi 0-QLi 0 ,$ TMEDA TMEDA \ Intermolecular addition of organolithiums to unactivated alkenes is generally very but the kinetically controlled 5-exo-trig cyclization of 5-hexen-1 -yl lit hi urn^'^^ is much faster and has been used in a novel synthesis of racemic 122 B. Mudryk and T. Cohen J. Am. Chem SOC.,1991 113 1866; for a related cleavage of oxetane with K+(18-Crown-6)K-see Z. Jedlinski A. Misiolek A. Jankowski and H. Janeczek J. Chem. SOC.,Chem. Commun. 1991 1513. 123 S. V. Kessar P. Singh R. Vohra N. P. Kaur and K. N. Singh J. Chem. SOC.,Chem. Commun. 1991 568;S.V.=Kessar P.Singh K. N. Singh and M. Dutt J. Chem. SOC.,Chem Commun. 1991 570. 124 J. J. Novoa M.-H. Whangbo and G. D. Stucky J. Org. Chem. 1991,56 3181. 125 S. D.Meyer N. S. Nills J. B. Runnels B. de la Torre C. C. Ruud and D. K. Johnson J. Org.Chem. 1991,56 947. 126 B. 0.T. Kammermeier G. W. Klumpp K. Kolthof and M.Vos Tetrahedron Lett. 1991 32 3111; T.Hattori T.Suzuki and S. Miyano J. Chem. SOC.,Chem. Commun. 1991 1375. 127 W.F. Bailey A. D. Khanolkar K. Gavaskar T. V. Ovaska K. Rossi Y. Thiel and K. Wiberg J. Am. Chem SOC.,1991,113 5720; for a comparable epoxide cyclization see V. Cere C. Paolucci P. Pollicino E. Sandri and A. Fava J. Org. Chem. 1991 56,4513. Synthetic Methods I' -OMLi cuparene.I2' Cyclization of the vinyl ether (61) effected p-elimination of the alkoxide (62) to give a novel [1,4]-Wittig reat~angement'~~ to (63).Similarly dihydropyran (64) can be deprotonated to give the a-lithiated vinyl ether (65),l3' which undergoes nucleophilic addition of alkyl lithiums to the carbanionic centre (!) and alkoxide elimination to give the ring opened vinyl lithium (66).131 Polylithio aromatics have been sought by several groups but at present dilithio derivatives132 seem to be the practical limit. Treatment of 1,3,5-trimethoxybenzene (68) with 6 equivalents of BuLi/TMEDA complex and trapping with propyl disulfide gave only the bis adduct (69) but in situ repetition of the reaction allowed a third group to be introduced (70).'33 Direct lithiation of the diphenol (71a) gave insoluble MeovoMe SPr - SPr i 6 BuLi/TMEDA Meo@oMe BuLi ii (RS) PrS (W PrS SPr OMe OMe OMe (68) (69) (70) TMEDA = N,N,Nt,Nt-tetramethyl-l,2-ethane diamine precipitates but halogen-lithium exchange'34 gave the sulfide (73) via (72) plus reduced starting material (71a).135 Attempted halogen-lithium exchange with the sterically congested bromide (74) gave the unexpected plumbane (75) a diplum- bane and the alcohol (76) presumably via single electron transfer and hydrogen 128 W.F. Bailey and A. D. Khanolkar Tetrahedron 1991 47 7727. 129 W. F. Bailey and L. M. J. Zarcone Tetrahedron Lett. 1991 32 4425. 130 N. J. Harris and J. F. Sebastian Tetrahedron Lett. 1991 32 6069. 131 T. Nguyen and E.Negishi Tetrahedron Lett. 1991 32 5903. 132 L. Lochmann M. Fossatelli and L. Brandsma Red. Trav. Chim. Pays-Bas. 1990 109 529; T. Lund and H. Lund Acta Chem. Scand. 1991,45 655. 133 S. Cabiddu L. Contini C. Fattuoni C. Floris and G. Gelli Tetrahedron 1991 47 9279. 134 H. J. Reich D. P. Green and N. H. Phillips J. Am. Chem. SOC.,1991 113 1414. 135 J. M. Saa J. Motey G. Suner A. Frontera and A. Costa Tetrahedron Lett. 1991 32 7313. D. R. Kelly OH OH OLi Li OH OH (71) a X=H (72) (73) b X=Br c X=I (74) (75) radical migrati~n.'~~ n-Deficient aromatics normally undergo nucleophilic addition of organolithi~ms,'~~ but if a directing group is present ortho metallation occurs.138 Grignard Reagents.-Butyl magnesium bromide and butyl lithium react in surpris- ingly different ways with para-substituted benzophenones.BuMgBr produces increasing amounts of 1 -phenyl ethanols as the electronegativity of the substituents increases and the rate increases (p = 1.45) whereas the late of reaction of BuLi is virtually independent of the substituents and the ratio of addition to reduction is more or less constant (70 30).'39 Dry magnetic stirring of magnesium powder under an inert atmosphere causes fragmentation to give a micro-crystalline powder which is much more reactive than conventional 'turnings'. This enables 0.4M solutions of Grignard reagents to be produced free from coupling products." Cyclopropyl magnesium bromide is notorious difficult to prepare because the intermediate cyclopropyl radical^'^' attack the solvent to give cyclopropane but if it is prepared in the presence of hexyl bromide or hexyl magnesium bromide (entrainment) the yield is greatly enhanced.14* Reduction of magnesium chloride with lithium naphthalenide gives extremely fine magnesium powder which undergoes cycloaddition to 1,4 dienes to give a magnesium rnetall~cycle,'~~ which in turn reacts with dihalides to give fused'44 or 136 R.Okazaki K. Shibata and N. Tokitoh Tetrahedron Lett. 1991,32,6601; cf. B. Dhawan and D. Redmore J. Org. Chem. 1991 56 833. 137 For addition reactions of Grignard reagents see T. Holm Acta Chem. Scand. 1991 45 276 or thiols see S. Prachayasittikul G. Doss and L. Bauer J. Her. Chem. 1991 28 1051. 138 G. Queguiner F.Marsais V. Snieckus and J. Epsztajn Ada Het. Chern 1991 52 189; J. A. Lepoivre Janssen Chernica Acta 1991 9(1) 20. 139 H. Yamataka N. Miyano and T. Hanafusa J. Org. Chem. 1991 56 2573. 140 K. V. Baker J. M. Brown N. Hughes A. J. Skamulis and A. Sexton J. Org. Chern 1991 56,698. 141 J. F. Garst Acc. Chem. Rex 1991 24 95. 142 J. F. Garst F. Ungvary R. Batlaw and K. E. Lawrence J. Am. Chem. Soc. 1991 113 5392 6697. 143 o-Phenylenemagnesium tetramer M. A. G. M. Tinga 0. S. Akkerman F. Bickelhaupt E. Horn and A. L. Spek J. Am. Chem. SOC.,1991 113 3604. 1J4 R. D. Rieke and H. Xiong J. Org. Chem. 1991,56 3109. Synthetic Methods 235 (77) ~piro'~~ carbocycles. A curious double metallation was observed during zirconocene dichloride catalysed addition of ethyl magnesium halides to the ally1 pyrrolidine (77).'46 Amide Bases.-Crystalline LDA exists as a helical polymer'47 in which the 'backbone' consists of unprecedented near linear N-C-N bonds.'48 In hexane it exists as a mixture of at least five different types of aggregate however in THF solution it is present exclusively as the cyclic dimer (80a).'49 Addition of lithium chloride gives the dimer adduct (81) at low concentrations and the monomer adduct (82) at high concentrations whereas addition of an enolate gives the 1:1 dimer (83).'" HMPA is purported to enhance reactivity by acting as a disaggregating agent; however X I I Y (80) a X=THF Y=THF b X =THF Y = HMPA c X = HMPA Y = HMPA 14' 145 H.Xiong and R.D. Rieke Tetrahedron Lett. 1991 32 5269. 146 D. P. Lewis P. M. Muller R. J. Whitby and R. V. H.Jones Tetrahedron Lett. 1991 32 6797; CJ P. Canonne R. Boulanger and P. Angers Tetrahedron Lett. 1991 32 5861. R. E. Mulvey Chem. SOC.Rev. 1991,20 167; U. Olsher R. M. Izatt J. S. Bradshaw and N. K. Dalley Chem. Rev. 1991,91 137; cf:organomagnesium compounds P. R.Markies 0.S. Akkerman F. Bickel-haupt W. J. J. Smeets and A. L. Spek Adv. Organometallic Chem. 1991 32 147. 148 N. D. R. Barnett R. E. Mulvey W. Clegg and P. A. O'Neil J. Am. Chem. SOC.,1991 113 8187. 149 The crystal structure of this dimer has been reported but the details were not published however comparable structures have been reported for bis(trimethylsily1) amide bases P. G. Williard and M.A. Nichols J. Am. Chem. SOC.,1991 113; 9671; and a sodium amide P. C. Andrews D. R. Armstrong W. Clegg M. MacGregor and R. E. Mulvey J. Chem. SOC,Chem. Commun. 1991,497. For a comparable study of silaamidide salts see G. E. Underiner R P. Tan D. R. Powell and R. West J. Am. Chern. SOC.,1991 113 8437. A. S. Galiano-Roth Y.-J. Kim J. H. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum J. Am. Chem. Soc 1991 113 5053. 236 D. R. Kelly spectroscopic studies demonstrate that it sequentially (80b) (80c) replaces the THF ligands in the dimer (80a) without changing the state of aggregati~n.'~' In fact even an amide base incorporating a crown ether group exists as the dimer in the solid state.'52 Crystalline unsolvated enolates can be isolated from hexane solutions of LDA'53 (up to 0.1 M at -78 "C) and ketones esters or carbo~amides.'~~ The elusive isoprene'55 anion'56 has now been prepared using LDA and potassium t-butoxide.Cuprates.-Organocoppers can be prepared directly by the reaction of alkyl halides and dispersed Cu(o). In a new procedure lithium napthalenide reduction of CuCNe2LiBr rather than copper iodide phosphine complexe~,'~~ enables the prepar- ation of organocopper reagents free from phosphine ligands which are appreciably more reactive particularly in conjugate additi011s.l~~ The cuprate reagent prepared from 13Clabelled ethyl lithium and 13C labelled copper cyanide has a 13C-13C two bond NMR coupling. This indicates that both moieties are attached to the copper atom (Et(CN)CuLi) however addition of further ethyl lithium abolishes the coup- ling to the cyanide carbon and so this reagent must be formulated as a dialkyl cuprate lithium cyanide complex (Et,CuLi.LiCN) rather than a higher order cuprate; R2(CN)CuLi2 .159 Curiously when lithio silanes are added to these com- plexes an alkyl lithium is displaced and can be detected uncomplexed in solution.16' Considerable effort has been expended in the design of chiral amino16' and phosphine'62 ligands for asymmetric conjugate addition.One extremely successful example is the synthesis of the highly prized fragrance muscone. Conjugate addition of dimeric chiral complex formed from the ligand (84) and dimethyl cuprate to the enone (85) gives (R)-( -)-muscone (86) enantiomerically pure with non-0 0 Me (84) 151 F.E. Romberg J. H. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum J. Am. Chem. SOC,1991 113 5751. 152 D. Barr D. J. Bemsforb L. Mendez A. M. Z. Slawin R. Snaith J. F. Stoddart D. J. Williams and D. S. Wright Angew. Chem. Int. lid. Engl. 1991 30 82. 153 For a new analytical method see R.$. Ireland and R. S. Meissner J. Org. Chem. 1991 56 4566. 154 Y.-J. Kim M. P. Bernstein A. S. Galiano-Roth F. E. Romesberg P. G. Williard D. J. Fuller A. T. Harrison and D. B. Collum J. Org. Chem. 1991 56 4435. 155 M. Bertrand B. Waegell and J. P. Zahra Bull. SOC.Chim. Fr. 1991 128 904. 156 P. A. A. Klusener L. Tip and L. Brandsma Tetrahedron 1991 47 2041. 157 G. W. Ebert and W. R. Klein J.Org. Chem. 1991 56 4744. 158 D. E. Stack B. T. Dawson and R. D. Rieke J. Am. Chem. SOC.,1991 113 4672. 159 S. H. Bertz J. Am. Chem. SOC.,1991 113 5470; S. H. Bertz G. Dabbagh and A. M. Mujsce J. Am. Chem. SOC.,1991 113 631. 160 R. D. Singer and A. C. Oehlschlager J. Org. Chem. 1991,56,3510; S. Sharma and A. C. Oehlschlager J. Org. Chem. 1991 56 770; S. Sharma and A. C. Oehlschlager Tetrahedron 1991 47 1177; R. D. Singer M. W. Hutzinger and A. C. Oehlschager J. Org. Chem. 1991 56 4933. 161 B. E. Rossiter M. Eguchi A. E. Hernandez D. Vickers J. Medich J. Marr and D. Heinis Tetrahedron Lett. 1991 32 3973. 162 A. Alexakis S. Mutti and J. F. Normant J. Am. Chem. SOC.,1991 113 6332. Synthetic Methods 237 enantiomerically pure ~ata1yst.l~~ This phenomenon known as chiral amplification comes about when the heterodimeric catalytic complex is more stable and the homodimeric complex is more reactive and enantioselective.In essence all of the less abundant enantiomer is trapped in the heterodimeric complex and hence the reactive homodimer is enantiomerically pure. Zinc.-The formation of organozincs by reaction of an organohalide and zinc metal is normally very slow however the reaction with alkyl iodides is accelerated by primary amine~'~~ and using precipitated zinc'65 even alkyl chlorides can be conver- ted quantitatively. Diorganozincs are unreactive with aldehydes however the complexes'66 formed with catalytic amounts of amine ligands (e.g. (87),'67 (88),16* (89),'69 (9O)l7O) or the titanium complex (91)171 promote highly enantioselective addition.&/ OH OH 3.' CH (87)=( -)-DAIB ( -)-3-exo-(dimethylamino)isoborneol Li (89) " xu (1R,2S)-(+)-dibutyl Li Ph Ph norephedrine (90) The reactivity of organozinc halides can be modified by transmetallation with a mixture of lithium chloride and copper cyanide to give reagents'72 with a similar but attenuated reactivity reminiscent of organocoppers or cuprates such as syn 163 K. Tanaka and H. Suzuki J. Chem. SOC.,Chem. Commun. 1991,101; K. Tanaka H. Ushio Y.Kawabata and H. Suzuki J. Chem. SOC.,Perk. Trans. I 1991 1445; K. Tanaka J. Matsui Y. Kawabata H. Suzuki and A. Watanabe J. Chem. SOC.,Chem. Commun. 1991,1632; for an alternative approach see T. Ogawa C.-L.Fang H. Seumune and K. Sakai J. Chem. SOC.,Chem. Commun. 1991 1438. 164 H. P. Knoess M. T. Furlong M. J. Rozeman and P. Knochel J. Org. Chem. 1991 56 5974. 165 L. Zhu R. M. Wehmeyer and R. D. Rieke J. Org. Chem. 1991 56 1445. 166 For an X-ray crystal structure of a zinc aldehyde complex see M. Bochmann K. J. Webb M. B. Hursthouse and M. Mazid J. Chem. SOC.,Chem. Commun. 1991 1735. R. Noyori and M. Kitamura Angew. Chem. Int. Ed. Engl. 1991 30 49. 168 M. Hayashi T. Kanekp and N. Oguni J. Chem. SOC.,Perk. Trans. I 1991 25. 169 K. Soai Y. Kawase and A. Oshio J. Chem. SOC.,Perk. Trans. I 1991 1613; S. Niwa T. Hatanaka and K. Soai J. Chem. SOC.,Perk. Trans. I 1991 2025; P. Chaloner E. Langadianou and S. A. R. Perera J. Chem. SOC.,Perk.Trans. I 1991,2731; for conjugate additions to enones see K. Soai M. Okudo and M. Okamoto Tetrahedron Lett. 1991 32 95. 170 S. Niwa and K. Soai J. Chem. SOC.,Perk. Trans. I 1991 2717; T. Shono N. Kise E. Shirakawa H. Matsumoyo and E. Okazaki J. Org. Chem. 1991 56 3063. 171 B. Schmidt and D. Seebach Angew. Chem. Int. Ed. Engl. 1991,30 99 1321; D. Seebach L. Behrendt and D. Felix Angew. Chem. Int. Ed. Engl. 1991 30 1008. 172 S. A. Rao and P. Knochel J. Org. Chem. 1991 56 4591. 238 D. R. Kelly addition to acetylene^,'^^ addition-elimination with nitroalkene~'~~ and coupling with vinyl halides.'75 Ally1 Silanes and Stannane~."~-An ultrasonicated mixture of allyl bromide and tin powder in ethanol-water effects diastereoselective addition (threo :erythro approx 5 1) of an allyl group to aldoses with good to excellent yields.'77 Similar results can be obtained with aldehydes and ketones by blending them with allyl br~mide"~ or propargyl bromide,'79 zinc and ammonium chloride in a mortar and pestle.The triene disilane (92) was acylated twice in one pot to give a diketotrienes (93)lg0and the distannane (94) reacted with oxalyl chloride in refluxing THF to give the useful cyclopentanone (95).18' 0 Me3Sn SnMe reflux (94) (95) The addition of alkoxy substituted allyl species18* to aldehydes'83 and a$ un-saturated ketones'84 has been a major theme this year and some perplexing results have been obtained. Addition of a-alkoxyallyl silanes and stannanes (96) to aliphatic aldehydes (97a) gives predominantly the syn E-isomer (98a) whereas aromatic aldehydes (97b) give the syn 2-isomer (99b) with the opposite facial sele~tivity,'~~ which was attributed to diastereomeric boron trifluoride complexes (102) (101).'86 But in general bidentate Lewis acids (e.g.TiC14'") give much better stereoselectivity 173 S. A. Rao and P. Knochel J. Am. Chem. SOC.,1991,113,5735; cf G. Courtemanche and J.-F. Normant Tetrahedron Lett. 1991 32 5317. 174 C. Retherford and P. Knochel Tetrahedron Lett. 1991 32 441. 175 S. A. Rao and P. Knochel J. Org. Chem. 1991 56,4593. 176 V. J. Jephcote and E. J. Thomas J. Chem. SOC.,Perk Trans. I 1991,429; see also allyl indiums S. Araki T. Shimizu P. S. Johar S.-J. Jin and Y. Butsugan J. Org. Chem. 1991 56 2538; allyl bariums A.Yanagisawa S. Habaue and H. Yamamoto J. Am. Chem. SOC.,1991 113 8955; and allyl tri- fluorosilanes Y.Hatanaka Y.Ebina and T. Hiyama J. Am. Chem. SOL 1991 113,7075. I77 W. Schmid and G. M. Whitesides J. Am. Chem. SOC.,1991 113 6674. 178 K. Tanaka S. Kishigama and F. Toda J. Org. Chem. 1991 56 4333. I79 J. J. DeVozz J. F. Jamie J. T. Blanchfield M. T. Fletcher M. G. O'Shea and W. Kitching Tetrahedron 1991,47 1985; C. Chen and D. Crich J. Chem. SOC.,Chem. Commun. 1991 1289. 180 F. Babudri V. Fiandanese and F. Naso J. Org. Chem. 1991 56 6245. 181 A. Degl'Innocenti P. Dembach A. Mordini A. Ricci and G. Seconi Synthesis 1991 267. lS2 J. A. Marshall and G. S. Welmaker Tetrahedron Lett. 1991 32 2101; J. A. Marshall G.S. Welmaker and B. Gung J. Am. Chem. SOC.,1991 113,647. 183 J. A. Marshall and D. V. Yashunsky J. Org. Chem 1991 56 5493; J. A. Marshall and G. P. Luke J. Org. Chem. 1991 56 483. 184 L. 0.Jeroncic M.-P. Cabal S. J. Danishefsky and G. M. Schulte J. Org. Chem. 1991 56 387. 185 B. W. Gung D. T. Smith and M. A. Wolf Tetrahedron Lett. 1991 32 13; B. W. Gung A. J. Peat B. M. Snook and D. T. Smith Tetrahedron Lett. 1991 32 453. 186 B. W. Gung Tetrahedron Lett. 1991 32 2867. 187 C. Nativi G. Palio and M. Taddei Tetrahedron Lett. 1991 32 1583. Synthetic Methods Ye Me OR‘ (97)RCHO R +OR’ + R+ BF,.Et,O IOH OH R’= (8-phenylmethy1)oxymethyl a = cyclohexyl SY n-(E 1 82 sYn-(Z) 18 b = C6HS <1 95 antiperiplanar ‘outside alkoxy’ than modentate Lewis acids (e.g.BF3),in which the stereocontrol results solely from steric interactions.’88 The stereoselectivity of ring opening of acetals (104) to (106) and (107) is lower with allyl silanes than allyl stannes (105p9 because the acetals undergo reversible ring ~pening’’~ prior to attack of the less reactive allyl silanes.”l Similar oxonium ion intermediates can be generated in situ from aldehydes and trimethylsilyl ethers’” and the intramolecular reaction has been used for a synthesis of medium ring ethers.193 188 Y. Nishigaichi A. Takuwa and A. Jodai Tetrahedron Lett. 1991,32,2383; J. A. Marshall and X.Wang J. Org. Chem. 1991 56 3211; 6264. 189 G. Hagen and H. Mayr J. Am. Chem. Soc. 1991 113 4954. 190 S.E. Denmark and N. G. Almstead J. Am. Chem. SOC.,1991 113 8089. 191 S. E. Denmark and N. G. Almstead J. Org. Chem. 1991 56 6458 6485. 192 A. Mekhalfia and I. E. Marko Tetrahedron Lett. 1991 32 4779. 193 R. Chakraborty and N. S. Simpkins Tetrahedron 1991 47 7689; for other cyclizations involving imminium ions H. H. Mooiweer H. Hiemstra and W. N. Spekamp Tetrahedron 1991,47,3451; epoxides M.Yoshitake M. Yamamoto S. Kohmoto and K. Yamada J. Chem. Soc. Perkin Trans. I 1991 2157 2161; enones G. Majetich J.-S. Song C. Ringold G. A. Nemeth and M. G. Newton J. Org. Chem. 1991 56 3973. 240 D. R. Kelly Cy~loadditions.'~~-[2+ I]. A stable crystalline carbene has been prepared it melts at 240-241 "C without decompo~ition'~~ and gives a 'reverse' ylide with iodopenta- flu~robenzene'~~ but no reactions with alkenes have been reported thus far.It was anticipated that methoxytrifluoromethylcarbene would be stabilized by a push-pull effect(cf:captodative radicals) but in fact it is much more reactive than most other carbenes and fails to discriminate between electron deficient and electron rich alkene~.'~' Highly reactive Simmons-Smith reagents'98 can be prepared from chloroiodomethane and diethylzinc in 1,2 di~hloroethane,'~~ but the reagents are less stable than in ethereal solvents2" and less regioselective.201 This method can also be applied to iodoform for the generation of iodocarbene.202 The metal complex catalysed203 asymmetric cyclopropanation of alkenes with diazoalkenes is a notoriously difficult reaction.The enantioselectivity is usually poor and cis/trans mixtures are produced. Accordingly most workers have effected double differentiation by using both a chiral catalyst and a chiral diazoester. However the technology has now progressed sufficiently far that the chirality in the diazoester can be dispensed with204 although a sterically hindered ester (108) is still required for trans/& selectivity. In the best case styrene (109) gave 95% of the trans cyclopropane (11 1) (97% ee).205 Intramolecular cyclopropanation206 with rhodium catalysts does not seem to suffer from the formation of &/trans mixtures and the enantioselectivities are excel~ent.~" 194 Enantiocontrolled Cycloadditions ed. L. M. Harwood a 'symposium in print' Tetrahedron Asymmetry 1991,2 1173-1444.195 A. J. Arduengo 111 R. L. Harlow and M. Kline J. Am. Chem. Soc. 1991 113 361 2801; M. Regitz Angew. Chem. Znt. Ed. Engl. 1991 30 674. 196 A. J. Arduengo 111 M. Kline J. C. Calabrese and F. Davidson J. Am. Chem. SOC.,1991 113 9704. 197 R. A. Moss T. Zdrojewski and G.-J. Ho J. Chem. SOC.,Chem. Commun. 1991 946. S. Durandetti S. Sibille and J. Perichon J. Org. Chem. 1991 56 3255. 198 199 S. E. Denmark and J. P. Edwards J. Org. Chem. 1991 56 6974. 200 The crystal structure of bis(iodomethy1) zinc coordinated to a bornane ether has been determined. S. E. Denmark J. P. Edwards and S. R. Wilson J. Am. Chem. Soc. 1991 113 723. 201 E. C. Freidrich and F. Niyati-Shirkhodaee J. Org.Chem. 1991 56 2202. 202 E. V. Dehmlow and J. Sutten Tetrahedron Lett. 1991 32 6105. 203 Review M. P. Doyle Red. Trav. Chim. Pays-Bas. 1991 110 305; for reusable polymer bound rhodium carboxylates see D. E. Bergbreiter M. Morvant and B. Chen Tetrahedron Lett. 1991 32 2731. 204 R. E. Lowenthal and S. Masamune Tetrahedron Lett. 1991,32,7373; some ofthe structural assignments in this paper have been criticised see D. A. Evans et al. next citation. 205 D. A. Evans K. A. Woerpel M. M. Hinman and M. M. Fad J. Am. Chem. SOC.,1991 113 726. 206 For racemic and achiral examples see 3. Adams C. Lepine-Frenette and D. M.Spero J. Org. Chm. 1991,56 4494; W. Kirmse and G. Homberger J. Am. Chem. Soc. 1991 113 3925. 207 M. P. Doyle R.J. Peiters S. F. Martin R.E. Austin C.J. Oalmann and P. Muller J. Am. Chem SOC. 1991 113 1423. Synthetic Methods 241 Dichlorocarbene is easily generated under phase transfer conditions by the deprotonation of chloroform with aqueous sodium hydroxide and subsequent elimi- nation of chloride;208 however difluorocarbene generated under the same conditions reacts with water before it can be intercepted by an alkene. Consequently in an attempt to generate it in the organic bulk phase dibromomethane anion (1 12) was used as a halogenophile to generate the difluorobromo anion (113) elimination of bromide gave difluorocarbene (1 14) which was efficiently trapped by alkene~.~'~ Alternatively treatment of the phosphonium salt (1 15) with potassium fluoride gives difluorocarbene which was trapped with alkynes to give difluorocyclopropenes (116).210 TBAH =tetrabutyl ammonium hydrogen sulfate -CHBr + -CHBr3+CBrF +:CF,+ Br- Br' 'F (113) (114) (112) [Ph3h-CF,Br] Br- -(115) FF [2 +21 Thermal.Cycloaddition of the cyanoketene (117) to the alkene (118) gave the expected cyclobutanones (1 19) plus the regioisomeric ene reaction products (120).211These were attributed to the anion stabilizing ability of the cyano group212 which enables a stepwise zwitterionic mechanism to operate.213 Ab initio calculations now favour a [~2s+ (1~2s+572s)] description over the Woodward-Hofmann [7r2s + v2a] mechanism for ketene-alkene cyl~additions.~~~ Whatever the precise 0 0 NC& + + Los(+ 208 J. D. Winkler and E. A. Gretler Tetrahedron Lett.1991 32 5733. 209 P. Balcerzak M. Fedorynski and A. Jonczyk =I. Chem. SOC.,Chem. Commun. 1991 826. 210 Y. Bessard and M. Schlosser Tetrahedron 1991 47 7323; H. Burger and S. Sommer J. Chem. SOC. Chem. Commun. 1991 456. 211 A H. Al-Husaini M. Muqtar and Sk. A. Ali Tetrahedron 1991 47 3845 7719. 212 For a general discussion of the effect of substituents on ketene structure see L. Gong M. A. McAllister and T. T. Tidwell J. Am. Chem. SOC 1991 113,6021. 213 W. T. Brady and M. M. Dad J. Org. Chem. 1991 56 6118; T. Gotoh A. B. Padias and H. K. Hall Jr. 1. Am. Chem. SOC.,1991 113 1308. 214 E. T. Seidl and H. F. Schaefer 111 J. Am. Chem. SOC.,1991 113 5195. 242 D. R. Kelly nature of the transition state it is clearly highly ordered.The addition of oxazolidine substituted ketenes to imines is essentially stereo~pecific~~~ (>97% absolute stereochemistry unknown) and similarly the cycloaddition of the keteniminium salt gives a single stereoisomer at the bridgehead positions completely overwhelming the stereorandom elements present.216 Electrocyclic ring opening of cyclobutenes has been used in two novel ring transformation reactions.217 Thermolysis of the cyclobutenone (121) gives the vinyl ketene (122) which undergoes cycloaddition to the distal alkene to give (123) a bicyc10[3.2.0]heptanone.~~~ Similarly Trost used palladium catalysed olefin meta- thesis219 to give the tricyclic complex (125) which underwent ring opening to give the bicyclo[6.2. llundecane (126) .220 + Me0a h Me0*-OMe Me3Si0 + Me3si0Q =-C02Me (124) i Me0,C-N=N-C0,Me The sulfonyl allene framework (127) demonstrates the subtle balance between the [2 + 21 and [4 + 2) cycloaddition pathways.221 When there is no substituent at C-2 (127a) fast (2 + 2) cycloaddition gives the cyclobutene (128a) whereas with a methyl substituent (127b) slow [4 + 21 cycloaddition gives the decalin (129b).222 215 L.S. Hegedus J. Montgomery Y. Narukawa and D. C. Snustard J. Am. Chem. SOC.,1991 113 5784; cf B. C. Borer and D. W. Balogh Tetrahedron Lett. 1991 32 1039. 216 L. Chen and L. Ghosez Tetrahedron Asymmetry 1991 2 1181. 217 H. Hesse Ring Enlargements in Organic Chemistry VCH Weinheim 1991. 218 S. L. Xu H. Xia and H. W.Moore J. Org. Chem. 1991 56 6094. 219 R. Hertel J. Mattay and J. Runsink J. Am. Chem. SOC.,1991 113 657. 220 B. M. Trost and M. K. Trost J. Am. Chem. SOC. 1991 113 1850; for the metal mediated [2 + 21 dimerization of benzene see R. L. Thompson S. J. Geib and N. J. Cooper J. Am. Chem. Soc. 1991 113 8961. 221 S. J. Getty and W. T. Borden J. Am. Chern. SOC.,1991 113 4334. 222 K. Kanematsu N. Sugimoto M. Kawaoka S. Teo and M. Shiro Tetrahedron Lett. 1991 32 1351 for intermolecular [2 + 21 cycloadditions to allenes see D. J. Pasto K. D. Sugi and J. L. Malandra J. Org. Chem. 1991 56 3781 3795; 6216. Synthetic Methods 0 0 0 II II (127) (128) (129) a R=H (l10°C,5hrs) b R=Me (160 "C,48 hrs) [2 + 21 Photochemical. Photolysis of the bis-styrene (130) gave a mixture of all the possible cis cyclobutane stereoisomers (131) in low yield however the mixture was quantitatively converted to [4.4] metacyclophane (132) by Birch reduction.223 Photoenolization of the ketone (133) and thermal ring closure gives the cyclo- butenols ( 135) as single diastereoi~omers;~~~ in contrast photochemical ring disrota- tory opening of cyclobutenes is only partially stereo~elective.~~~ (133) The photoaddition226 of alkenes to enones is particularly useful because it can give the highly prized trans adducts but the reaction is frequently complicated by isomerization of the alkene.In an attempt to overcome this intramolecular photo- addition of the 2-alkene (136) (or the E-isomer) was attempted but an equal amount of diastereomeric products ( 137) were obtained due to non-stereospecific ring closure of the 1,4 diradical intermediate.227 The photoaddition of cyclopentene to cyclohexenone gives four adducts (138)-( 141) (68 :41 :7 :25) which were isomer- 223 J.Nishimura Y. Horikoshi Y. Wada H. Takahashi and M. Sato J. Am. Chem. SOC. 1991 113 3485 see also K. Nakanishi K. Mizuno and Y. Otsuji J. Chem. Soc. Chem. Commun. 1991 90. 224 P. J. Wagner D. Subrahmanyam and B.-S. Park J. Am. Chem. Soc. 1991 113 709. 22s W. J. Leigh and K. Zheng J. Am. Chern. Soc. 1991 113 4019. 226 D. I. Schuster G. E. Heibel and J. Woning Angew. Chern. Znt. Ed. EngZ. 1991 30 1345. 227 D. Becker M. Nagler Y. Sahali and N. Haddad J. Org. Chem. 1991 56,4537. 244 D.R. Kelly 0 hv ___+ HH HH b b HH HH ized by base to the cis-isomers (138) (139) (75:25) in contradiction to an earlier report.228 [3 + 2). The [2 + 21 cycloaddition of a$-unsaturated ketones and alkenes has been extended in a novel way by placing an alkyne group at the p-position of the enone. 1,5 closure gives the carbene (146) which abstracts hydrogen to give a mixture of dienes or reacts with excess alkene to give a cy~lopropane.~~~ Reviews have appeared of the addition of diazomethane to nitrogen heterocycle^^^' and the Weiss reaction.231 [4 + 2). There have been two major issues in Diels-Alder chemistry this year the use of novel solvents232 and enantioselective catalysis.233 Several reactions including the Diels-Alder reaction are accelerated if run in ~ate8’~ or laterly lithium perchlor- 228 D.I. Schuster N. Kaprinidis D. J. Wink and J. C. Dewan J. Org. Chem. 1991 56 561. 229 H.-J. Rathjen P. Margaretha S. Wolff and W. C. Agosta J. Am Chem. SOC.,1991 113 3904. 230 B. Stanovnik Tetrahedron 1991 47 2925; for other heterocyclic [3 + 21 cycloadditions see A. Ando M. Kato and T. Akasaka J. Am. Chem. SOC.,1991 113 6286; T. Hudlicky and G. Barbieri J. Org. Chem. 1991 56 4598; H. H. Karsch K. Zellner and G. Muller J. Chem. SOC.,Chem. Commun. 1991 466; P. J. Smith D. J. Soose and C. S. Wilcox J. Am. Chem. SOC.,1991 113 7412; P. A. Wender and J. L. Mascarenas J. Org. Chem. 1991 56 6267. 231 A. K. Gupta X. Fu J. P. Synder and J. M. Cook Tetrahedron 1991 47 3665; for other carbocyclic [3 + 21 annulations see F.Fellga P. Nitti G. Pitacco and E. Valentin J. Chem. SOC.,Perk. Trans. I 1991 1645; J. Boivin C. Tailhan and S. Z. Zard J. Am. Chem. SOC.,1991 113 5874; D. A. Singleton C. C. Huval K. M. Church and E. S. Priestly Tetrahedron Lett. 1991,32 5765; M. P. Collins J. Mann N. Capps and H. Finch J. Chem. Soc. Perk. Trans. I 1991 239. 232 C. Reichardt ‘Solvents and Solvent Effects in Organic Synthesis’ VCH Weinheim 1988. 233 K. Naraska Synthesis 1991 1. 234 R. Breslow Acc. Chem. Res. 1991 24 159; W. Blokzijl M. J. Blandamer and J. B. F. N. Engberts J. Am. Chem. SOC.,1991 113 4241; A. Lubineau J. Auge and N. Lubin Tetrahedron Lett. 1991 32 7529; I. Hunt and C. D. Johnson J. Chem. SOC.,Perk Trans. 11 1991 1051. Synthetic Methods I I-60'C 40°C ate-diethyl ether.235 This has been attributed to solvoconstriction (hydrophobic effect); the forcing together of the reactants by the cohesive forces between the water molecules,236 hydrogen bonding,237 and catalysis by lithium ions.238 Similar effects are claimed for the surface of clay239 (in non-aqueous solvents).The current strength of chiral Diels-Alder technology can be demonstrated by three syntheses of the prostaglandin intermediate (149). C~rey~~' used the achiral amide (148a) and either of two chiral catalysts (150)241 (151)242 and in both cases obtained the endo adduct (149) (>95% endo >95% ee). Whereas Arai used the chiral ester (148b) and titanium tetrachloride243 as catalyst and obtained essentially identical results (endo adduct only de 9%0).~~ a-Methylene p-lactones (152)245 are versatile substitutes246 for allene~.*~~ They 235 P.A. Greico Aldrichimica Acta 1991 24 59; H. Waldmann Angew. Chem. Znt. Ed. Engl. 1991 30 1306; P. A. Greico R. J. Cooke K. J. Henry and J. M. VanderRoest Tetrahedron Lett. 1991,32 4665; P. A. Greico J. D. Clark and C. T. Jagoe J. Am. Chem. Soc. 1991; 113 5488; A. Thaler D. Seebach and F. Cardinsux Helu. Chim. Acta 1991 74 617 628. 236 R. Brewlow and C. J. Rizzo J. Am. Chem. Soc. 1991 113 4340. 237 J. F. Blake and W. L. Jorgensen J. Am. Chem. Soc. 1991 113 7430. 238 M. A. Forrnan and W. P. Dailey J. Am. Chem. SOC. 1991 113 2761; G. Desimoni G. Faiti and P. P. Righetti Tetrahedron 1991,47,5857; G. Desimoni G.Faita P. P. Righetti and G. Tacconi Tetrahedron 1991 '47 8399; D. A. Smith and K. N. Houk Tetrahedron Lett. 1991 32 1549. 239 C. Collet and P.Laszlo Tetrahedron Lett. 1991 32 2905. 240 For closely related studies using other catalysts see E. J. Corey N. Imai and H.-Y. Zhang J. Am. Chem. .Soc. 1991 113 728; E. J. Corey and T.-P. Loh J. Am. Chem. Soc. 1991 113 8966. 24 1 E. J. Corey N. Imai and S. Pikul Tetrahedron Lett. 1991 32 7517; for borane based catalysts and auxilaries see J. M. Hawkins and S. Loren J. Am. Chem. Soc. 1991 113,7794; X. Wang J. Chem. Soc. Chem. Commun.,1991 1515. 242 E. J. Corey and Y. Matsumura Tetrahedron Lett. 1991 32 6289; for the use of this catalyst with 1,4 benzoquinones see T. A. Enger M. A. Letavic and J. P.Reddy J. Am. Chem. Soc. 1991 113 5068; and BINOL titanium dichloride M. Terada K. Mikami and T. Nakai Tetrahedron Lett. 1991,32,935. 243 R. C. Corcoran and J. Ma J. Am. Chem. Soc. 1991 113 8973. 244 K. Miyaji Y. Ohara T. Tabahashi T. Tsuruda and K. Arai Tetrahedron Lett. 1991 32 4557. 245 W. Adams R. Albert N. D. Grau L. Hasemann B. Nestler E.-M. Peters K. Peters F. Prechtl and H. G. von Schnering J. Org. Chem. 1991,56 5778. 246 For the use of vinyl sulfoxides as allene equivalents see R. V. Williams and K. Chauhan J. Chem. Soc. Chem. Commun. 1991,1672or as acetylene equivalents see A. Sekiguchi I. Maruki E. Ebata C. Kabuto and H. Sakurai J. Chem Soc. Chem. Commun. 1991 341. 246 D. R. Kelly 0 (149) b R= do 6 Mexoco; Ar Ar CF,SOz-N N-SOzCFS TiClz Ar = A< Ph 0 0 Me ' I H Me Me Ar Ar (150) (151) readily undergo cycloaddition and cleanly generate either allenes (155) or alkenes (154) albeit at high temperature^.^^' The furan (156) undergoes cycloaddition with ethyl a~rylate~~~ at room tem- perature to yield (157) whereas the phorbol precursor (158) required 19 kbar pres- sure25o to produce (159) but with a shorter tether cyclization occurred so readily that the open chain compound (160) could not be isolated.251 247 D.L. Boger and M. Zhang J. Am. Chem. SOC., 1991 113 4230. 248 W. Adam R. Albert L. Hasemann V. 0. N. Salgado B. Nestler E.-M. Peters K. Peters F. Prechtl and H. G. von Schnering J. Org. Chem. 1991 56 5782. 249 J. J. McNally and J. B. Press J.Org. Chem. 1991,56,245; K. Ando N. Akadegawa and H. Takayama J. Chem. SOC.,Chem. Commun. 1991 1765. L. M. Harwood T. Ishikawa H. Phillips and D. Watkin J. Chem. SOC.,Chem. Commun. 1991 527 for other examples of high pressure Diels-Alder reactions see R. W. M. Aben L. Minuti H. W. Scheeren and A. Taticchi Tetrahedron Lett. 1991 32 6445; V. Branchadell M. Sodupe R. M. Ortuno A. Oliva D. Gomez-Pardo A. Guingant and J. d'Angelo J. Org. Chem. 1991 56 4135. 2s1 M. E. Jung and J. Gervay J. Am. Chem. SOC. 1991 113 224; see also A. P. Kozikowski and W. Tuckmantel J. Org. Chem. 1991 56 2826. Synthetic Methods SCHzPh CH,CI - 13h 68% R= Me R,R=(CH,), R= Et COOMe (160) (161) Other Cyc1oadditions.-The nature of the current frontier in organic synthesis is well illustrated by Taxol (162).’” It is obtained in very small quantities from yew bark and has exciting anti-tumour and anti-leukaemic activity.There are no par- ticularly bizarre functional groups present; it is the number of groups and their cocatenation that poses the problem. Moreover synthesis of a few milligrams has no practical value. Kilograms are required for clinical studies. An interesting approach to the fused central bicycle uses the [4 + 41 photodimerization of bis- pyridones (163) to give (164) which instals four new chiral centre^."^ There have 252 S. Blechert and A. Kleine-Klausing Angew. Chem. Int. Ed. Engl. 1991,30,412; J.-N. Denis A. Correa and A. E. Greene J. Org. Chem. 1991 56 6939. 253 S. McN. Sieburth and J.Chen J. Am. Chern. Soc. 1991 113 8163. 248 D. R Kelly hu __+ 63% f OH only been sporadic reports of [6 + 21 cycloadditions but by photolysing a chromium(0) tricarbonyl triene complex (165) in the presence of an electron deficient diene (166) good yields of the deligated adduct (167) can be obtained (36-93%) and prolonged photolysis gives the cyclobutene (168).254The two previous examples 0 I u I’ 58% CdCOL 2.5 mol% (dba),Pd,CHCl, 10 mol% Ph,Sb 10 mol% AcOH 86% yield demonstrate the rapid elaboration of complexity that can be achieved by cycloaddi- tion. Other vivid examples are provided by Trost’s synthesis of five rings (170) in a single step from (169) by what he terms ‘polyolefin polycycloisomerization’ using palladium and the construction of the entire steroid ring system (173) by Diels-Alder reaction (171) (172) (ring A) carbonylation and electrocyclic ring closure (ring c) (Scheme 2).256 254 J.H. Rigby and J. A. Henshilwood J. Am. Chem. SOC.,1991,113 5122. 255 B. M.Trost Janssen Chimica Acta 1991,9(1),3; B. M.Trost and Y. Shi J. Am. Chem. SOC.,1991,113 701. 256 J. Bao V. Dragisich S. Wenglowsky and W. D. Wulff J. Am. Chem. SOC 1991,113 9873. Synthetic Methods Me Reagents i CH3CN CO 25 "C 16 h; ii 110 "C 23 h Scheme 2 3 Functional Group Manipulation Oxidation.-Hydroxylution. It would be highly desirable to be able to emulate the ability of micro-organisms to introduce a iunctional group at a remote unfunctional- ized carbon centre.Progress in this area has been slow but practically useful methodology has been achieved. Ruthenium tetraoxide selectively oxidizes2" adamantane to 1-adamantanol in 62% yield with no isomeric contaminants.2s8 Metal insertion into unactivated C-H occurs via a concerted C-H oxidative addition pathway2s9 which may be followed by oxygen insertion,260 C-C bond cleavage,261 or by hydrogen elimination. The power of this technology is demonstrated by the elimination of 3 moles of molecular hydrogen from methylcyclohexane by the ruthenium complex (174) to give (175).262 I -H2,-3H Ru P/\ P W (175) 257 For general reviews of methane and hydrocarbon oxidation H. Schwarz Angew. Chem. Int. Ed. Engl. 1991 820; K. Eller and H. Schwarz Chem. Rev.1991 91 1121; D. H. R. Barton and D. Doller Coll. Czech. Chem. Commun. 1991 45 984; idem. fire Appl. Chem. 1992 63 1567. A comprehensive description of Barton's work in this area was given in last years Annual Report. 258 J. M. Bakke and J. E. Braenden Actu Chem. Scund. 1991 45 418; for a similar iodosyl benzene oxidation catalysed by a manganese complex C.-M. Che W.-T. Tang K.-Y. Wong W.-T. Wong and T.-F. Lai J. Chem. Rex 1991 (S) 30 (M)401; osmium trichloride S.-I. Murahashi T. Sato T. Naota H. Kumobayashi and S. Akutagawa Tetrahedron Lett. 1991 32 2145; a binuclear iron complex N. Kitajima M. Ito H. Fukui and Y. Moro-oka J. Chem. SOC.,Chem. Commun. 1991 102. 259 M. R. A. Blomberg P. E. M. Siegbahn U. Nagashima and J. Wennerberg J. Am. Chem. Soc. 1991 113 424.260 L.-C. Kao A. C. Hutsoj and A. Sen J. Am Chem SOC,1991 113 700. 261 P. A. M. van Koppen J. Brodbelt M. T. Bowsers D. V. Dearden J. L. Beauchamp E. R. Fischer and P. B. Armentrout J. Am. Chem. Soc. 1991 113 2359. 262 J. D. Koola and D. M. Roddick J. Am. Chem. Soc. 1991 113 1450. 250 D. R. Kelly The efficient conversion of benzene derivatives263 to enantiomerically pure264 cis-benzene glycols (177b-d) by Pseudomonus putidu is still unmatched by abiotic chemical synthesis. Most functional groups are tolerated at C-1 but those that are not (177d) can be introduced by substitution of the bromo (176b) or iodo compounds (176c) using the requisite stannane under palladium catalysis.265 The plane of symmetry in the meso-diol (176a) is removed by enantioselective galactosyl transfer using E.coli P-galactosidase266 or by P. cepuciu lipase catalysed hydrolysis of a tetrol derivative.267 R R (176) (177) a R=H d R=vinyl allyl alkyne b R=Br nitrile thiomethoxide c R=I Dihydroxylution. The cinchona alkaloid catalysed osmium tetraoxide dihydroxyla- tion of alkenes can now be applied to terminal alkenes268 by using a new rate enhancing ligands (e.g. 178),269 which seem to be evolving towards a BINAP type structure. The increased reactivity allows as little as 0.5 mol% of osmium tetraoxide (or the safer potassium osmate(v1) dihydrate) to be used with potassium ferricyanide as re~xidant.~~' The diene (179) undergoes diastereoselective hydroxylation to give the syn anti tetrol (180) (94%) and the syn syn stereoisomer YO).^" 263 For applications of this micro-organism to other aromatics see D.R. Boyd D. R. Bushman R. J. H. Davis M. R. J. Dorrity L. Hamilton D. M. Jerrina W. Levin J. J. McCullough R. A. S. McMordie J. F. Malone and H. P. Porter Tetrahedron Lett. 1991 32 2963; D. R. Boyd N. D. Sharma P. J. Stevenson J. Chima D. J. Gray and H. Dalton Tetrahedron Lett. 1991 32 3887. 264 D. R. Boyd M. R. J. Dorrity M. V. Hand J. F. Malone N. D. Sharma H. Dalton D. J. Gray and G. N. Sheldrake J. Am. Chem. SOC.,1991 113 666. 265 D. R. Boyd M. V. Hand N. D. Sharma J. Chimica H. Dalton and G. N. Sheldrake J. Chem. Soc. Chem. Commun. 1991 1630. 266 D. H. G. Crout D. A. MacManus and P. Critchley J. Chem. SOC.,Chem. Comun. 1991 376.267 C. R. Johnson P. A. Ple and J. P. Adams J. Chem. SOC.,Chem Commun. 1991 1006; cj H. A. J. Carless and 0.Z. Oak J. Chem. Soc. Chem. Commun.,1991 61. 268 K. B. Sharpless W. Amberg M. Beller H. Chen J. Hartung Y. Kawanami D. Lubben E. Manoury Y. Ogino T. Shibata and T. Ukita J. Org. Chem. 1991 56 4585. 269 Y. Ogino H. Chen E. Manoury T. Shibata M. Beller D. Lubben and K. B. Sharpless Tetrahedron Lett. 1991 32 5761. 270 Y. Ogino H. Chen J.-L. Kwong and K. B. Sharpless Tetrahedron Lett. 1991 32 3965. 271 C. Y. Park B. M. Kim and K. B. Sharpless Tetrahedron Lett. 1991,32,1003; cf M. Burdisso R. Gandolfi and A. Rastelli Tetrahedron Lett. 1991 32 2659. Synthetic Methods 251 OH OH Ph '''4,ph)-,+Ph Ph-NMO (179) OH OH NMO = N-methylmorpholine N-oxide (180) The dihydroxylation (and cleavage) of alkenes by permanganate is entirely sup- pressed by the addition of oxalyl chloride and trans vicinal dichlorides are formed instead.272 Stereospecific trans addition of dinitrogen tetraoxide to dimethyl cyclo- hexene (181) gives the dinitro adduct (182a) which is readily reduced to the diamine (182b Scheme 3).273 X (181) (182) a R=N02 b R=NH Reagents i N204 Et20; ii H2 RhCI(PPh,) Scheme 3 Epoxidation.A general method for the enantioselective epoxidation of unfunctional-ized alkene~~~~ continues to be elusive. The observation that cytochrome P450,, (which has an iron porphyrin prosthetic group) and related systems are capable of epoxidation of alkenes prompted the synthesis of model systems based on manganese275 and iron porphyrin~.~~~ But unfortunately most of the abiotic systems require aggressive regenerating reagents such as sodium hypochlorite (bleach) and peroxides or ozones which damage the p~rphyrin~~~ frequently the stereochemistry of the alkene is scrambled during epoxidation.The 'natural' substrate for Cytochrome P450,, is camphor but other substrates are accepted. For example cis-P-styrene is epoxidized with retention of alkene stereochemistry in 78% enan- tiomeric excess278 and an essentially identical result has been obtained using an abiotic tetraphenyl porphyrin with D4 symmetry.279 The most generally useful catalysts at present are those based on manganese(I1I) di-imine complexes280 (183). P-Methyl styrene is epoxidized with good stereoselectivity (92% ee 81% yield) and uniquely for these systems the electron deficient alkene cis-methyl cinnamate also gives good results (89% ee 65% yield).281 Non-metallic reagents in this area are 272 I.E. Marko and P. F. Richardson Tetrahedron Lett. 1991 32 1831. 273 W. Zhang and E. N. Jacobsen Tetrahedron Lett. 1991 32 1711; for the synthesis of vicinal diamines from diols see R. Oi and K. B. Sharpless Tetrahedron Lett. 1991 32 999. 274 Review; C. Born Angew. Chem. Int. Ed. Engl. 1991 30 403. 275 S. Campestrini A. Robert and B. Meunier J. Org. Chem. 1991 56 3725. 276 G.-X. He and T. C. Bruice J. Am. Chem. SOC.,1991 113 2747. 277 For the use of t-amine N-oxides in place of hydrogen peroxide see A.M. d'A. R. Gonsalves R. A. W. Johnstone M. M. Pereira and J. Shaw J. Chem. SOC.. Perkin Trans. I 1991 645; R. Ire Y. Ito and T. Katsuki SYNLEn 1991 266. 278 P. R. Ortiz de Montellano J. A. Fruetel J. R. Collins D. L. Camper and G. H. Loew J. Am. Chem. SOC.,1991 113 3195. 279 R. L. Halterman and S.-T. Jan J. Org. Chem. 1991 56 5253. 280 Review of C2 diamines as chiral catalysts C. Bolm Angew. Chem. Int. Ed. Engl. 1991 30 542. 281 E. N. Jacobsen W. Zhang A. R. Muci J. R. Ecker and L. Deng J. Am. Chem. SOC. 1991 113 7063; W. Zhang and E. N. Jacobsen J. Org. Chem. 1991 56 2296. 252 D. R. Kelly rare but useful enantiomeric excesses have been achieved with N-sulfonyl oxaziridines.282 The Katsuki-Sharpless rules for enantioselective epoxidation (Figure 1)283have remained essentially unbreached for the past 11 years but an exception has now been found.The combination of allylic and homoallylic hydroxyl groups in the D-( -)-DET L-( + )-DET 'f 'f 'E 11 I1 I1 /I I1 II L-( + )-DET D-( -)-DET L-(+)-DET Figure 1 (184) a R=H b R=Bn diene (184a) gives the unexpected (S)-epoxide (185) with D-( -)-diisopropyl tartrate (DIE) and no reaction with L-(+)-DIPT.Participation of the homoallylic hydroxyl group in the coordination sphere of the titanium complex284 is clearly demonstrated by the normal behavior of the monobenzyl derivative (184b) which gives the (R)-epoxide (186).285The success of the Katsuki-Sharpless methodology has 282 F. A. Davis R. ThimmaReddy J. P. McCauley Jr.R. M. beslawski M. E. Harakaland and P. J. Carroll J. Org. Chem. 1991 56 809; F. A. Davis A. Kumar and B.-C. Chen J. Org. Chem. 1991 56 1143. 283 Review of asymmetric epoxidation Y. E. Raifel'd and A. M. Vaisman Russ. Chem. Rev. 1991,6Q 123; for an alternative approach to the large scale synthesis of chiral epoxides see J. Dunigan and L. 0. Weigel J. Org. Chem. 1991 56 6225. 284 Mechanistic studies B. H. McKee T. H. Kalantar and K. B. Sharpless J. Org. Chem. 1991 56 6966; S. S. Woodward M. G. Finn and K. B. Sharpless J. Am. Chem. SOC.,1991 113 106; M. G. Finn and K. B. Sharpless J. Am. Chem. SOC.,1991 113 113. 285 S. Takano Y. Iwabuchi and K. Ogasawara J. Chem. SOC. Chem. Comrnun. 1991 820; S. Takano Y. Iwabuchi and K. Ogasawara J. Am. Chem.SOC.,1991 113 2786. Synthetic Methods 253 spawned a wealth of new methodology for the functionalization of epoxy alcohols286 and in particular the 'parent epoxy alcohol' glycid01.~~~ For those rare cases where it is simply not possible to make the epoxide enan- tiomerically pure Julia has developed a resolution technique in which the epoxide undergoes ring opening with dimethyl sulfide to give sulfonium salts which are resolved as dibenzoyl tartrate sulfonium salts. Base treatment regenerates the original epoxides.288 The dioxiranes (187a-~)~~~ are the most mild efficient reagents available for the epoxidation of alkene~~~' and this has enabled the synthesis of epoxides of unpre- cedented reactivity. Electron donating groups and ring strain both greatly increase the reactivity of epoxides but using DMD even two oxygen substituents (188) are 0-0 OSiMe3 OSiMe3 1 R' R2 -30°C.3 hrs OSiMe, (187) a R' = R2 = Me GosiMe3 b R'=Me,R2=CF3 (188) (189) c R'=R2=CF3 tolerated291 and the previously unknown flavonoid ep~xides,~~~ benzofuran ep~xides,~~~ have been isolated. Similarly lithio and fulvene endocyclic ep~xides~~~ enolates are converted to a-hydroxy ketones295 and phenols to orthoq~inones.~~~ Perhaps the most stunning application has been the steroselective conversion of allenes (190) to crystalline spiro-epoxides (191) which undergo regioselective SN2 substitution (192).297 Treatment of the cyclopropene (193a) with pera~id~~~ gives the fused epoxycyclopropane (194) which rapidly rearranges to an alkene which in turn undergoes a further epoxidation (195) in contrast dimethyl dioxirane has 286 Conversion of epoxy alcohols to aldols K.Maruoka J. Sato and H. Yamamoto J. Am. Chem. Soc. 1991,113 5449;2,3-epoxy-1,4-butanediols, Y. Aoyama H. Urabe and F. Sato Tetrahedron Lett. 1991 32; 6731;triols by kinetic resolution A. Ishikawa and T. Katsuki Tetrahedron Lett. 1991,32 3547; enantiomeric epoxy alcohols V.Jager D. Schroter and B. Koppenhoefer Tetrahedron 1991,47 2195. 287 Review of applications of glycidol R. M. Hanson Chem. Rev. 1991,91 437. 288 B. Cimetiere L. Jacob and M. Julia Bull. SOC.Chim. Fr. 1991 128 926. 289 W. Adam S. E. Bottle and R. Melo J. Chem. SOC.,Chem. Commun. 1991 770; W. Adam R. Curci M.E. G. Nunez and R. Mello J. Am. Chem. Soc. 1991,113 7654. 290 Mechanism; R. W. Murray D. L. Shiang and M. Singh J. Org. Chem. 1991,56 3677; A. Messeguer F.Sanchez-Baeza J. Casas and B. D. Hammock Tetrahedron 1991 47 1291. 291 W. Adam L. Hadjiarapoglou and X. Wang Tetrahedron Lett. 1991,32 1295. 292 W. Adam D. Golsch L. Hadjiarapoglou and T. Patonay Tetrahedron Lett. 1991,32 1041. 293 W. Adam L. P. Hadjiarapoglou T. Mosandl C. R. Saha-Moller and D. Wild J. Am. Chem. SOC.,1991 113,8005; furan epoxides rearrange to 1,4enediones before isolation B. M. Adger C. Barrett J. Brennan M. A. McKervery and R. W. Murray J. Chem. SOC.,Chem. Commun. 1991 1553. 294 W.Adam L. P. Hadjiarapoglou and A. Meffert Tetrahedron Lett. 1991,32 6697. 295 K. R. Guertin and T.-H.Chan Tetrahedron Lett. 1991,32 715. 296 J. K. Crandall M. Zucco R. S. Kirsch and D. M. Coppert Tetrahedron Lett. 1991,32 5441. 297 J. K.Crandall D. J. Batal D. P. Sebestra and F. Lin J. Org. Chem. 1991,56 1153. 298 K. W.Wood and P.Beak J. Am. Chem. SOC.,1991,113,6281;R.D. Bach A. L. Owensby C. Gonzalez H. B. Schlegel and J. J. W. McDouall J. Am. Chem. SOC.,1991,113 2338 254 D. R. Kelly (193) a R=CH b R=COOH (194) no effect on the alkene bond and instead oxidizes a methyl group to a carboxylic acid (193b).299 The oxidation of alcohols to ketones and carboxylic acids implicit in this reaction has been developed into a synthetically useful procedure using trifluoromethylmethyl di~xirane[b]~~' and goes by a mechanism in which oxygen is inserted directly into the a C-H bond.301 Dioxiranes also oxidize other heteroatom bonds.Diazoketones are converted to a-ket~aldehydes,~'~ hindered oxazolidines to hydro~yamines,3~~ and arenes can be released from chromium tricarbonyl arene complexes.304 Reduction.-Heterogeneous Hydrogenation.305 It is common knowledge that the reduction of alkenes on noble metal catalysts results from the cis addition of surface bound hydrogen to the less hindered side of the alke~~e,~'~ but beyond this almost nothing else is known. Whitesides has shown that soluble platinium alkene complexes are reduced on platinium black with incorporation of deuterium with retention of configuration of the platinium alkene bonds. If metathesis of the alkene between the 'soluble' platinium and the platinium surface also proceeds with retention of configuration then the reduction must also occur with overall retention of stere~chemistry.~'~ The incorporation of excess deuterium or tritium in saturated groups during reduction of alkenes is a common problem and a new system using platinium black in deuterium oxide and THF reduces cycloalkenes to predominantly the perdeuteroalkanes e.g.cyclodecene was converted to Cl0DZ0 in 60% yield.308 The mechanism for this process probably involves a r-ally1 or alkyl platinium complex similar to that implicated in the montmorillonite-diphenylphosphinepal-ladium(11)~'~ reduction of l,4-butyne-diol to cis-butene-l,4-diol and isomerization to 2-hydro~ytetrahydrofuran.~~~ Rieke zinc prepared from zinc bromide and potassium reduces alkynes to cis alkene~,~~' without using hydrogen!312 299 G.D. Maynard and L. A. Paquette J. Org. Chem. 1991 56 5480. 300 R. Mello L. Cassidei M. Fiorentiono C. Fusco W. Hummer V. Jager and R. Curci J. Am. Chem. SOC.,1991 113 2205. 30 1 B. A. Marples J. P. Muxworthy and K. H. Baggaley Tetrahedron Lett. 1991 32 533. 302 H. Ihmels M. Maggini M. Prato and G. Scorrano Tetrahedron Lett. 1991 32 6215. 303 C. Bonvalet F. Bourelle D. Scholler and A. Feigenbaum J. Chem. Rex 1991 (S) 348. 304 A.-M. Lluch F. Sanchez-Baeza F. Camps and A. Messeguer Tetrahedron Lett. 1991 32 5629. 305 For a review of chiral heterogenous catalysis H.-U. Blaser Tetrahedron Asymmetry 1991 2 843. 306 N.Ravasio and M. Rossi J. Org. Chem. 1991 56 4329. 307 T. R. Lee and G. M. Whitesides J. Am. Chem. SOC.,1991 113 368; T. R. Lee P. E. Laibinis J. P. Folkers and G. M. Whitesides Pure Appl. Chem. 1992 63 821. 308 T. R. Lee and G. M. Whitesides J. Am. Chem. SOC.,1991 113 369. 309 For other chiral phosphine ligands see H.-J. Zeiss J. Org. Chem. 1991 56 1783; M. J. Burk J. Am. Chem. SOC.,1991 113 8518. 310 J. S. Chickos J. Y.-J. Uang and T. A. Keiderling J. Org. Chem. 1991 56 2594. 311 W. N. Chou D. L. Clark and J. B. White Tetrahedron Lett. 1991 32 299. 312 For transfer hydrogenolysis in which no hydrogen gas is released see H. Weiner J. Blum and Y. Sasson J. Org. Chem. 1991 56 4481; 6145. Synthetic Methods Carbonyl The oxazaborolidine (~6)~~~ is emerging as a general catalyst for the enantioselective reduction of ketones315 and particularly aryl alkyl ketones.316 The lithium borohydride reagent derived from the 9BBN hydroboration of nopol reduces dialkyl ketones with good to excellent enantioselectivities but the stereoselectivity and reactivity drop if a potassium counter-ion is used.This presum- ably reflects the role of the lithium ion in coordination to the carbonyl Regioselectivity in the reduction of the diester (197) to the aldehyde (198) is achieved by selective formation of a five rather than a six membered chelate with magnesium bromide etherate and then reduction with di-isobutyl aluminium hydride (DIBALH),318similarly zinc bromide was used to organize the y-ketoacid (199) for reduction to (200).319 OMe H MeO#o MgBr2.0Et2DIBALH ~ 78% iOBn OBn 0 Protecti~n.~~-The migration of acyl groups from secondary or tertiary alcohols to primary alcohols or amines is commonly observed in partially protected aminols.The reverse migration can be induced by treatment with triphenyl phosphine-carbon 313 J. Seyden-Penne ‘Reductions by the Alumino- and Borohydrides in Organic Synthesis’ VCH New York 1991; G. D. Paderes P. Metiver and W. L. Jorgensen J. Org. Chem. 1991 56 4718. 314 Preparation D. J. Mathre T. K. Jones L. C. Xavier T. J. Blacklock R. A. Reamer J. J. Mohan E. T. T. Jones K. Hoogsteen M. W. Baum and E. J. J. Grabowski J. Org. Chem. 1991 56 751. 315 T. K. Jones J. J. Mohan L. C. Xavier T. J. Blacklock D.J. Mathre P. Sohar E. T. T. Jones R. A. Reamer F. E. Roberts and E. J. J. Grabowski J. Org. Chem. 1991 56 763. 316 E. J. Corey X.-M. Cheng K. A. Cimpich and S. Sarshar Tetrahedron Lett. 1991 32 6835; E. J. Corey and J. 0. Link J. Org. Chem. 1991 56 442. 317 M. M. Midland A. Kazubski and R.,E. Woodling J. Org. Chem. 1991 56 1068; for borane reagent based on aminohydroxyboranes see K. Tanaka J. Matsui and H. Suzuki J. Chem. Soc. Chem. Commun. 1991 1311; K. Soai S. Yokoyama and T. Hayasaki J. Org. Chem. 1991 56 4264. 318 G. E. Keck M. B. Andrus and D. R. Romer J. Org. Chem. 1991,56,417; for the use of DIBALH-BuLi”ate complexes see A. Anantanarayan and H. Hart J. Org. Chem. 1991 56 991. 319 R. Frenette M. Monette R. N. Young and T. R. Verhoeven J.Org. Chem. 1991 56 3083. 256 D. R. Kelly tetrabromide and indeed this is a convenient procedure for 0-acylation in the presence of primary amine~.~~' Ethers. It is a textbook paradigm that tertiary carbonium ions are more stable than primary or secondary carbonium ions.321 However the diol (201) (and its epimer at C-1) cyclizes with retention of configuration at the tertiary centre (202). Presumably a carbonium ion at C-1 is disfavoured by the adjacent electron withdrawing methoxyl and retention of the "0 label rules out direct neighbouring group parti~ipation.~~~ PH n 18 I I p-TsOH uivie PhCH,,A '\/) .'Me The Williamson synthesis of oxetanes (205) from 4-halo alcohols gives poor yields because the intermediate alkoxide fragments; however 3-chloropropyl acetate (203) cyclizes much more readily by rearrangement of the ortho-ester (204).324 n cola -&-H Homoallyl alcohols (206) and aldehydes undergo an intramolecular Prins reaction to give dihydropyrans (209);325however if a hydroxyl group is vicinal to the carbonium ion centre pinacol ring contraction gives an acyl tetrahydrofuran (210).326 The cleavage of ethers by acyl halides is greatly improved by catalysis with cobalt(11) chloride consequently even diethyl ether is cleaved in fair yield (49%).327 320 P.K. Dutta C. Chaudhuri S. B. Mandal A. K. Banerjee S. C. Pakrashi and B. Achari J. Chem. Res. 1991 (S) 201 (M) 2180. 321 For a related cyclisation with a secondary to tertiary carbonium ion rearrangement see A.F. Mateos C. M. Almena J. de P. Teresa and R.R.Gonzalez Bull. Soc. Chim. Fr. 1991 128 898. 322 Review of electronegatively substituted carbocations X. Creary Chem. Rev. 1991,91,1627; M. Saunders and H. A. Jimenez-Vazquez Chem. Rev. 1991 91 375. 323 L. A. Paquette and J. T. Negri J. Am. Chem. Soc. 1991 113 5072; J. T. Negri R. D. Rogers and L. A. Paquette J. Am. Chem. Soc. 1991 113 5073. 324 J. Dale and S. B. Fredricksen Acta Chem. Scund. 1991 45 82. 325 A. C. Razus M. D. Gheorgiu and E. Bartha Rev. Roumaine. Chem 1991 36 215; F. Perron-Sierra M. A. Promo V. A. Martin and K. F. Albizati J. Org. Chem. 1991 56 6188. 326 M. H. Hopkins L. E. Overman and G. M. Rishton J. Am. Chem. SOC.,1991 113 5354; M. J. Brown T. Hamson P. M. Hemngton H.H. Hopkins K. D. Hutchinson P. Mistra and L. E. Overman J. Am. Chem. Soc. 1991 113 5365; M. J. Brown T. Hamson and L. E. Overman J. Am. Chem. Soc. 1991 113 5378. 327 J. Iqbal and R. R. Srivastava Tetrahedron 1991 47 3155. Synthetic Methods (206) (207) (a) R'=R2=R3=H (b) R' =OH RZ= R3 = alkyl (211) a R'=R2=Me b R' = R2 = CHMe c R'=H,R2=Me d R'=H R2=CHMez (21 la) and isopropyl (21 lb) pyridine diethers are cleaved selectively at the 4-position by sodium thiomethoxide and aluminium chloride respectively.329 Terminal acetonides (212) are cleaved regioselectively to vinyl ethers (2 13) which are readily cyclopropanated. The 1-methyl cyclopropyl ethers (214) so formed are stable to strong base moderate acid and reduction but are cleaved by NBS or DDQ (Scheme 4).330 Silyl Ethers and Fluoride Reagents.It is a general perception that fluoride based reagents are the best choice for cleaving silyl ethers but all the various methods have disadvantages. Tetrabutylammonium fluoride is difficult to dry KF and CsF are not sufficiently reactive HF is difficult to handle and BF3-OEt2 is too acidic. Consequently several new reagents and old reagents in new guises have been 328 For the suppression of radical hydrogen abstraction by the use of trideutereromethyl ethers see D. L. J. Clive A. Khodabocus M. Cantin and Y. Tao J. Chem. Soc. Chem. Commun. 1991 1755; D.L.J. Clive A. Khodabocus P. G. Vernon A. G. Angoh L. Bordeleau D. S. Middleton C. Lowe and D. Kellner J. Chem. SOC.Perkin Trans.I 1991 1757. 329 S. G.Hedge J. Org. Chem. 1991,56 5726. 330 S. D. Rychnovsky and J. Kim Tetrahedron Lett. 1991,32 7219 7223. 258 D. R Kelly proposed. Tetrabutylammonium difluorotriphenylstannate is non-hydroscopic and is 18 times more reactive as a nucleophile to benzyl bromide than CSF.~~~ Another 'naked' fluoride reagent phosphazenium fluoride (216) shows unique E2 activity and readily gives 1-alkenes from 1-halides however it is sufficiently nucleophilic to effect coupling of ally1 silanes and l-i~doalkanes.~~~ Catalytic transfer hydrogena- tion is selective for the cleavage of primary t-butyl dimethylsilyl (TBDMS) ethers333 NMe NMe, I+l Me2N-P=N=P-NMe F-I I NMe NMe (216) and the acidity of BF3-OEt2 has been used to advantage334 in the elimination of tertiary silyl ethers and alcohols to alkene~,~~~ one pot cleavage and oxidation to a ketone has been achieved by photolysis w~~~DDQ.~~~ Phenols and alcohols and primary alcohols are converted to TBDMS ethers upon treatment with t-butyl- dimethylsilanol under Mitsunobo conditions337 and phenolic silyl ethers are selec- tively cleaved by potassium fluoride supported on alumina and irradiated with ultrasound.338 Despite the disadvantages mentioned above a column packed with glass helices covered in tetrabutyl ammonium fluoride sufficed to effect elimination from the silyl chloride (217) to give spiropentadiene (218) which was trapped in a Diels-Alder reaction to give (219).339 25 "C x-Q Bu,NF -78 "C 4 New Reaction Conditions If synthesis of a single natural product is a challenge then consider the possibilities of making hundreds at a time! Parallel synthesis is currently used by immunologists to prepare polypeptides as candidate antigens.The chemistry is similar to conven- 331 M. Gringas Tetrahedron Lett. 1991 32 7381. 332 R. Schwesinger R. Link G. Thiele H. Rotter D. Honert H.-H. Limbach and F. Mannle Angew. Chem. Znt. Ed. Engl. 1991 30 1372; for a study of fluoride solvation see G. T. Hefter fire Appl. Chem. 1992,63 1749. 333 J. F.Cornier Tetrahedron Letf. 1991 32 187. 334 Siloxanes and silyl ethers are appreciably less basic than dialkyl ethers J. F. Blake and W. L. Jorgensen J. Org. Chem. 1991 56 6052. 335 G.H. Posner E.M. Shulman-Roskes C. H. Oh J.-C. Carry J. V. Green A. B. Clark H. Dai and T. E. N. Anjeh Tetrahedron Lett 1991 32 6489. 336 0.Piva A. Amougay and J.-P. Pete Tetrahedron Left. 1991 32 3993. 337 D. L. J. Clive and D. Kellner Tetrahedron Left. 1991 32 7159. 338 E.A. Schmittling and J. S. Sawyer Tetrahedron Lett. 1991 32 7207. 339 W.E. Billups and M. M. Haley J. Am. Chem. SOC.,1991,113,5084;'for other triangulanes see K. A. Lukin S. I. Kozhushkov A. A. Andrievsky B. I. Ugrak and N. S. Zefirov J. Org. Chem. 1991,56,6176. Synthetic Methods 259 tional solid phase peptide synthe~is~~ except that the growing chains are attached to plastic pins (typically 96) on a backboard. Each synthetic step is conducted in a new plate with an individual well for each pin containing the requisite reagent.A new variant of this technique uses light cleavable protecting groups and an optical mask to differentiate the individual areas of a glass plate. The preparation of 1024 peptides on a single slide has been demonstrated and 250 000 syntheses per square centimetre are possible in principle using currently available masking technology.341 Techniques such as photocherni~try~~~ have been universally adopted but there are wealth of opportunities waiting to be discovered with other forms of energy such as ultrasound microwaves radioly~is,~~~ and electrochemistry. Ultrasound promoted reaction^'^ can be divided into two types heterogenous systems in which the effect of the ultrasound is to increase surface area by dispersion or ‘cleaning’.These typically involve metals such as lithium,345 Li/TiC13 ,346 potassium,347 magnesium zinc,349 or zinc-copper couple.350 This cleaning effect was used to destroy disordered domains on the surface of Raney Nickel in preference to the more robust crygalline domains prior to modification with tartaric acid.351 ‘True’ sonochemical reactions proceed exclusively via radicals or radical ions.352 But it is frequently difficult to distinguish the latter possibility because ultrasound also causes localized (and unquantifiable) heating which may promote ionic reactions.353 The dilemmas that this area presents are illustrated by the free radical polymerization of vinyl carbazole. The rate was studied as a function of ultrasound intensity.At the highest settings (100 Wcm-2) polymerization stopped but recommenced when the ultrasound was turned off .354 Equally what conclusions can be drawn from the observation that the 5’ acylation of adenosine by subtilisin is accelerated by ultrasound?355 340 T. Weiland and M. Bodansky ‘The World of Peptides A Brief History of Peptide Chemistry’ Springer- Verlag Heidelberg 1991. 341 S. P. A. Fodor J. L. Read M. C. Pirrung L. Stryer A. T. Lu and D. Solas Science 1991 251 767; G. von Kiederowski Angew. Chem. Int. Ed. Engl. 1991,30 822. 342 N. Turro ‘Modem Molecular Photochemistry’ University Science Books Mill Valley 1991. 343 For homolytic aromatic hydroxylation using radiolysis see M. K. Eberhardt in Reviews on Heteroatom Chemistry 4 ed.S. Oae MYU K. K. Tokyo 1991 and high pressure radiolysis for Co-C bond formation see R.van Eldik H. Cohen and D. Meyerstein Angew. Chem. Int. Ed. Engl. 1991 30 1158. 344 K. S. Stslick Science 1991 253 1397; K. S. Suslick Roc. Natl. Acad. Sci. USA 1991 88 7708; W. Worthy Chem. Eng. News 1991 Oct. Sth 18. 345 G. J. Price and A. A. Clifton Tetrahedron Lett. 1991 32 7133. 346 S. N. Nayak and A. Banerji J. Org. Chem. 1991 56 1940. 347 T. Chou S.-H. Hung M.-L. Peng and S.-J. Lee Tetrahedron Lett. 1991 32 3551. 348 K. S. Suslick S.-B. Choe A. A. Cichowlas and M. W. Grinstaff Nature 1991 353 414. 349 G. Etemand M. Rifqui P. Layrolle J. Berlan and M. Koenig Tetrahedron Lett. 1991 32 5965; A. P. Marchand and G. M. Reddy Synthesis 1991 198. 350 L.A. Sarandeses A. Mourino and J.-L. Luche J. Chem. Soc. Chem. Commun. 1991 818. 351 A. Tai T. Kikukawa T. Sugimura Y. Inoue T. Osawa and S. Fujii J. Chem. SOC. Chem. Commun. 1991 795; 1324. 352 M. J. Dickens and J.-L. Luche Tetrahedron Lett. 1991 32 4709. 353 T. Ando P. Bauchat F. Foucaud M. Fujita T. Kimura and H. Sohmiya Tetrahedron Lett. 1991 32 6379. 354 J. P. Lorimer T. J. Mason and D. Kershaw J. Chem. SOC.,Chem. Commun. 1991 1217; cf M. J. S. M. Moreno M. L. Sa e Malo and A. S. Campos Neves Tetrahedron Lett. 1991 32 3201 (perruthenate oxidations); B. C. Ranu and M. K. Basu Tetrahedron Lett. 1991,32,3243 (zinc borohydride reductions). 355 M. Criton GJ Dewynther and J.-L. Montero Recl. Trav. Chim. Pays-Bas. 1991 110 443. 260 D.R. Kelly The cycloaddition of aryl sulfonyl azides (220) to enol ethers (221) is promoted both by ultrasound356 and high pressure.357 It was assumed that the high pressures that result from the collapse of cavitation bubbles mimic the conditions of bulk high pressure reactions. A wide range of esters were cleaved by almost stoichiometric amounts of water and di-isopropyl ethylamine (Hunig's base) in acetonitrile at 8 Kba~-.~" N3 Br (221) (220) 46 hrs neat 35 "C ))) 78% 24 hrs CH,CN 80 "C <lo% 18 hrs CH,CN 25 "C 10kbar 85% The use of microwave ovens359 continues to attract controversy. The esterification of propan-1-01 with ethanoic acid proceeds at the same rate in a microwave oven as when heated con~entionally.~~~ In other cases the even heating that can be achieved with microwaves gives better and fasterS6' results than can be obtained conventionally particularly if the substrate rather than the solvent preferencially absorbs the microwaves.362 For example the p-lactam (223) undergoes hydrogena- tion and hydrogenolysis in 45 secs at 110 "C (Scheme 5).363 OMe Reagents i HC02NH4 Pd/C 10% (224) Scheme 5 356 D.Goldsmith and J. J. Soria Tetrahedron Lett. 1991 32 2457. 357 For general reviews of high pressure reactions see N. S. Isaacs Tetrahedron 1991,47,8463; K. Matsumoto and K. M. Acheson 'Organic Synthesis at High Pressure' Wiley New York 1991; M. Buback Angew. Chem. Int. Ed. Engl. 1991 30 641. 358 Y. Yamamoto T. Furata J. Matsuo and T. Kurata J. Org. Chem. 1991 56 5737; for the use of LiBr/DBU see D.Seebach A. Thaler D. Blaser and S. Y. Koo Helu. Chim. Acta 1991 74 1102. 359 General reviews D. M. P. Mingos and D. R. Baghurst Chem. SOC. Reu. 1991,20 1; R. A. Abramovitch Org. Preps. Proc. Int. 1991 23 683. 360 S. D. Pollington G. Bond R.B. Moyes D. A. Man J. P. Candlin and J. R. Jennings J. Org. Chem. 1991 56 1313. 361 A. K. Bose M. S. Manhas M. Ghosh V. S. Raju K. Tabei and Z. Urbanczyk-Lipowska Heterocycles 1990 30 741. 362 R. A. Abramovitch D. A. Abramovitch K. Iyanar and K. Tamareselvy Tetrahedron Lett. 1991,32,5251. 363 A. K. Bose M. S. Manhas M. Ghosh M. Shah V. S. Raju S. S. Bari S. N. Newaz B. K. Banik A. G. Chaudhary and K. J. Barakat J. Org. Chem. 1991 56 6968. Synthetic Methods 261 Electro~hemical~~~ of the diyne (225) to (226) in a single compart- carb~xylation~~~ ment cell is regio- and steroselective (Scheme 6).366 R Reagents i Ni” (lo%) Ligand Mg anode DMF Bu:N+BF4-; ii H20 Scheme 6 Many racemic compounds resolved spontaneously367 by chance cry~tallization~~~ of a single enantiomer and a recent report suggests that the enantiomeric excess may be improved by magnetically stirring the solution!369 This apparently implaus- ible observation has been attributed to fragmentation of the first seed crystal by the stirrer bar resulting in a much faster crystallization than normal.370 Solid state reactions in crystals frequently have different selectivities to the corres- ponding reactions in solution.Crystals of the alcohols (227a) (227b) were crushed with a mortar and pestle to give a c~crystal~~~ which was then mixed with p-toluenesulfonic acid to give exclusively the ‘mixed’ ether (228) whereas in refluxing toluene a statistical mixture of the possible products was formed.372 CI pTsOH Ph+ H OH (227) a R=H b R=C1 364 T.Shono Electroorganic Synthesis Best Synthetic Methods series Academic London 1991 ; J. S. Swenton and G. W. Morrow ‘Synthetic Applications of Anodic Oxidations Tetrahedron Symposia-In- Print’ 42 Tetrahedron 1991 47 531. 365 Review G. Silvestri S. Gambino and G. Filardo Acta Chem. Scand. 1991 45 987. 366 S. Derien J.-C. Clinet E. Dunach and J. Perichon J. Chem. Soc. Chem. Commun. 1991 549. 367 For rationale crystal engineering of diastereoisomers see F.J. J. Leusen H. J. B. Slot J. H. Noordik A D. van der Haest H. Wynberg and A. Bruggink Red. Trav. Chim. Pays-Ras. 1991 110 13; G. Coquerel N. Mofaddel M. N. Petit and R. Bouaziz Bull. SOG Chim. Fr. 1991 128 419 773. 368 For automated crystallization see M. Caron C. M.Moren J. C. Bondiou J. P. Bourgogne C. Porte and A. Delacroix Bull. SOC.Chim. Fr. 1991 128 684. 369 This should not be confused with the now discredited observation of chiral induction by spinning a reaction vertically relative to the earths gravitational field D. Edwards K. Cooper and R. C. Dougherty J. Am. Chem. Soc. 1980 102 381. 370 J. M. McBride and R.L. Crandall Angew. Chem. Int. Ed. EngL 1991 30,293. 371 For the use of triphenyl phosphine oxide as a crystallization aid see A.L. Llamas-Saiz C. Foces-Foces J. Elguero P. Molina M. Alajarin and A. Vidal J. Chem. SOC.,Chem. Commun. 1991 1694; for cholic acid inclusion complexes see K. Miki N. Kasai M. Shibakami K. Takemoto and M. Miyata J. Chem. Soc. Chem. Commun. 1991 1757 and tartaric acid inclusion complexes F. Toda A. Sato L. R. Nassimbeni and M. L. Niven J. Chem. Soc. Perk. Trans. ZZ 1991 1971. 372 F. Toda and K. Okuda J. Chem. Soc. Chem. Commun. 1991 1212. 262 D. R. Kelly 5 Epilogue This is my last year on the synthetic methods review and I think my attitude to the difficulties in compiling it can be encapsulated in another quote from Warren '. . .you have a nagging worry in the back of your mind that everything in the literature is interesting'.'