5 Aliphatic and Alicyclic Chemistry By P. QUAYLE Department of Chemistry The Victoria University of Manchester Manchester M 13 9PL UK 1 Introduction This has been a good year for synthetic organic chemistry as shown by no less than three’ total syntheses of the immunosuppressive agent rapamycin (I).These embody a range of synthetic methodology which was only recently deemed esoteric including Stille cross-coupling reactions samarium-promoted Tischenko reactions and tita- nium-mediated aldol reactions. Application of the traditional skills of the synthetic organic chemist to increasingly more complex biological problems’ is well dernon- strated in Schreiber’s studies of the synthesis of FK-506 derived ligands capable of binding pr~teins.~ In a similar vein the use of biochemical techniques to solve chemical problems is ever more apparent as witnessed by the number of reviews in this area particularly noteworthy are appraisals of the use of catalytic antibodies4 in organic synthesis.On more familiar ground extensive reports on the use of enzymes in organic synthesis’ and a review on chemoenzymatic approaches6 to azasugars provide much useful information and stimulus. Other major research themes in recent years -supramolecular chemistry’ and molecular recognition* phenomena -have again enjoyed extensive coverage. In new synthetic methodology organometallic chemistry continues to provide K.C. Nicolaou T.J. Chakraborty A.D. Piscopio,N. Minowa and P. Berttnato,J. Am. Chem. SOC. 1993 115,4419;D.Romo,S.D.Meyer D.D. Johnson and S. L. Schreiber 1.Am. Ckem. Soc. 1993,115,7906; C. M.Hayward D. Yohannes and S.J. Danishefsky J. Am. Chem. Soc. 1993 115 9345. A.T. Sneden SYNLETT 1993 313; R.S. Varma SYNLETT 1993,621; G.G. Cross and T.M. Fyles SYNLETT 1993,449;R.S. Varma SYNLETT 1993,621;M Kahn SYNLETT 1993,821;A. Giannis and T. Kolter Angew. Chem. Int. Ed. Engl. 1993,32,1244;C.Unverzagt Angew. Chem.,Int. Ed. Engl. 1993,32 1691;C.A.A. van Boeckel and M. Petitou Angew. Chem. Int. Ed. Engl. 1993,32 1671. D.M.Spencer,T. J. Wandless S. L. Schreiber and G. R.Crabtree Science 1993,262,1019; M.B.Andrus and S. L. Schreiber J. Am. Chem. Soc. 1993 115 10420. ‘C. Laumann Angew. Chem. Int. Ed. Engl. i993,32,1291;P.G.Schultz and R.A. Lerner Ace. Chem. Res. 1993,26,391;D.Hilvert Acc.Chem. Res. 1993,26,552. D.H.G. Crout S. M. Roberts and J. B. Jones Tetrahedron Asymmetry 1993,4 757; 1081. G.C.Look,C.H. Fotsch and C.-H. Wong Acc. Chem. Res. 1993 26 182. ’S. Shinkai Tetrahedron 1993,49 8933; S. Anderson H. L. Anderson and J.K. M.Saunders Acc. Chem. Res. 1993,26,469;Top.Curr.Chem. 1993,165;R. M.Izatt and J. S. Bradshaw Pure Appl. Chem. 1993,65 355;D. N.Reinhoudt Pure Appl. Chem. 1993,65,2313;A.F.Danil De Namor Pure Appl. Chem. 1993,65 1457. * T.H.Webb and C.S. Wilcox Chem. SOC.Rev. 1993,22,383;K.E.Krakowiak J. S. Bradshaw and R.M. Izatt SYNLETT 1993,611;2.Asfari J. Weiss and J. Vicens SYNLETT 1993,719;N.T. Thuong and C. HeIene Angew. Chem. lnt. Ed. Engl. 1993 32 666. f 05 106 P. Quayle I H Me fruitful avenues for investigation,' especially in the development of new asymmetric reactions." Asymmetric methodology in general' 'continues to be a recurrent theme as is the use of free-radical reactions in organic synthesis.' Environmental consider- ations have prompted investigation of reactions carried out in the solid state13 and in aqueous s~lution'~ rather than in organic solvents.There has been renewed interest also in the application of photochemical' and electrochemica1l6 techniques to organic synthesis. The search for complex medicinal agents17 and the isolation of novel structural types,18 most notably from marine sources,19 continues to pose enormous rnethod- ological challenges,20 and few molecules are more challengingthan the enediyne family P.Knochel and R.D. Singer,Chern.Rev.,1593,93,2117;Y. Yamarnoto and N. Asao Ckem. Rev. 1993,93 2207; B. knnetau and J. Dunogues,SYNLETT 1993,171;S.G. Davies and T. J. Donohoe SYNLEJT 1993,323;U.Schuchardt W.A.Carvalho and E. V. Spinace SYNLETT 1993,713;P.Wipf Synthesis 1993,537;K.Ritter Synthesis 1993,735;G. G.Melikyan Synthesis 1993,833;A. Furstner Angew. Chem. Int. Ed. Engi. 1993,32,164;J. Sundermeyer Angew. Chem. Int. Ed. Engt 1993,32,1I44;Y.Nishigaichi A. Takuwa A. Tauwa Y.Naruta and K. Murayama Tetrahedron I993,49,7395;M.Schlosser,0.Desponds, R.Lehrnann E. Moret and G. RauchschwaIbe Tetrahedron 1993,49,10 175; A. J. Pearson Tetrahedron 1993,49 5415; 3.H-Rigby Acc. Chem. Res. 1993,26 579. lo J.M. Brown Chem. SOC. Rev. 1993 22,25; C.Bolm Angew. Chem.Int. Ed. Engl. 1993,32 232;W. Hernnann and C.W.Kohlpaintner Angew. Chem. Int. Ed. Engl. 1993,32,547;0.Reiser Angew. Chem. Int. Ed. Engl. 1993,32,547; A. pfaltz Acc. Chem. Rex 1993 26 39. A. H.Hoveyda D. A. Evans and G. C. Fu,Chem. Rev. 1993,93,1307;K.Fuji Chem. Rev. 1993,93,2037; M. Lautens SYNLETT 1993 177; S.W.McCombie 1993,807;L. Banfi Synthesis 1993,1029;H. Kunz and K. Riick Angew. Chem. Int. Ed. Engl. 1993,32,336;B. H. Kim and D. P.Curran Tetrahedron 1993 49,293;D.J. Ager and M.B. East Tetrahedron i993,4!?, 5683;K.Koja and T. Shioiri Tetrahedron 1993 49,1711; M.T.Reetz Acc. Chem. Res. 1993,26,462;K.Sakai and H. Suemune Tetrahedron Asymmetry 1!?93,4,2109. I' A.L. J. Beckwith Chem. Soc. Rev. 1993,22 143; P.Dowd and W.Zhang Chem. Rev. 1993,93,2091.l3 F.Toda SYNLETT 1993 303. l4 C.J. Li Chem. Rev. 1993,93 2023. l5 M. T. Crimrninsand T.L. Reinhold Org. Reuct. 1993,44,297;G.Pandey Top. Cum. Chem. 1993,168,175. l6 M.E.Niyazymbetov and D. H. Evans Tetrahedron 1993 49 9627. l7 P.W.Collins and S. W. Djuric Chem. Rev. 1993,93,1533;H.Kessler Angew. Chem. Int. Ed. Engf.,1993 32,543;S.F.Wunk Tetrahedron 1993,49,9877;S. L. Beacage and R.P. Iyer Tetrahedron 1993,49,10441. '* J. P.Michael and G. Pattenden Angew. Chem. Int. Ed. Engl. 1993,32 1. l9 D.J. Faulkner Cltem. Rev. I993,93 1671; D. J. Faulkner Top. Curr. Chem. 1993,167. 'O R. Gleiter and D. Kratz Angew Chem. Int. Ed. Engl. 1993,32,842. Aliphatic and AIicyclic Chemistry 107 of antitumour agents.” Recent advances in the development of more concise approaches to complex molecules are reviewed in two timely articles on double-Michael reactions22 and ‘sequential reactions’.23 Ultimately fundamental advances in synthetic design will depend upon a more quantitativez4 appreciation of stereochemi- cal and electronic factors controlling organic reactivity.These considerations are doubtless responsible in part for the continuing intense interest in the chemistry of C, and related compounds.2s The possibility of synthesizing molecular arrays possessing some characteristics of living organisms has been addressed.26 Advances in this area may have fundamental impIications but it is a sobering thought however that our understanding of complex biosynthetic problems (e.g. B 2) is still in~mplete.~’ 2 Alip&aticChemistry General.-The synthesis of planar four-coordinate carbon compounds has been reviewed.z8 OlahZ9 has presented a fascinating overview on his work on ‘super electrophiles’.Rearrangement reactions are frequently used in organic synthesis and several timely accounts of current progress in this area have appeared.30 The synthetic amine #l-la~tones,~* appIications of a-amino acids:’ alko~yallenes,~~ and organ~fluorine~~ compounds provide much interesting reading. Organic synthesis still relies heavily upon protecting group strategies for functional group differentiation and two excellent reviews dealing with use of silicon-based protecting groups for alcohobJ6 and with esters as a protecting group for carboxyl f~nctionality,~~ have appeared.Heteroatom-based rnethod~logies,~~ in particular those of phosphorus and selenium have transformed contemporary organic synthesis. Reich’s review39 on selenoxide eliminations in particular provides many useful pointers for the practising synthetic chemist. An extensive review of the Baeyer-ViIliger oxidation of aldehydes and ketones is also most welcome.** There have been theoretical studies on a number of text-book reactions including ” M.M. Campbell M. Sainsbury,and P.A. Wle Synthesis 1993,179; R. E. Wolf Pure Appf.Chem. 1993 65 1103; J.-C. Harmange and Figatere Tetrahedron Asymmetry 1993.4 1711. ” M. Ihara and K. Fukumoto Angew. Chem. Int. Ed. Engl. 1993,32 1010. ” L.F. Tictzc and U. Btifuss Angew. Chem. Int. Ed. Engl. 1993 32 131.’’ J.E. Eksterowicz and K.N.Houk,Chem. Rev. 1993 93 2439; 1. Ugi J. Bley A. Dengler A. Dietz E. Fontain B.Gruber R.Herges,M. Knauer,K.Reitsam and N. Stein Angew. Chem.,Int.Ed. Engf.,1993,32 201; C.D. Johnson Acc. Chem. Res. 1993 26,476. ’’ A. Hirsch Angew. Chem. Int. Ed. Engt. 1993,32,1138; H.Schwartz Angew. Chem. lnt. Ed. En& 1993.32 1412. 16 D. W.Urry Angew. Chenr. Int. Ed. Engl. 1993,32 819. ’’ A.1 Scott Angew. Chem. Int. Ed. Engl. f993,32 1223. M. Albrecht G. Erker and C.Kriiger SYNLETT 1993.26. 29 G.A. Olah Angew. Chem. int. Ed. En& 1993.32 767. S.R. Wilson Org. Reuct. 1993,43,93; R. F.C.Brown and F. W. Eastwood SYNLETT 1993 9; H. R. Sonawanc N. S. Bellur D. G. Kulkarni and J. R. Ahuja. SYNLETT 1993,875; J.-L. Ripoll and Y.Vallee Synthesis 1993,659; H.M.L.Davits Tetrohedron 1993,49 5203. ” A. Golebiowski and J. Jurczak SYNLETT 1993 241. ” R. Zimmer Synthesis 1993 165. 33 A. AIbini Synthesis 1393 263. ” A. Pommier and J.-M. Pons,Synthesis 1993,441. ” H. Uno and H. Suzuki SYNLETT 1993 91; G. Resnati Tetrahedron 1993 49 9385. 36 J. Muutrt,Synrhesis,1993.11; C.J. Salonton,E.G.Mata and 0.A. Mascaretti Tetrahedron 1993,49,3691. 31 A. Fava Pure Appf.Chem. 1993,65 595. 38 r. ugi Synthesis 1993 I. 39 H. J. Reich and S. Wollowitz Org. Rear. 1993,44,4. ” G.R. Krow Org. Reuct. 1993,43 251. 108 P.Quayle Michael additions:’ the SN2-E2 spectrum,42 pinacol rearrangement^:^ and elec- trophilic additions to alkene~.~~ Many stereocontrolled reactions involve the interac- tion of a carbonyl group with one or more metal centres.Much experimental evidence concerning the mode of such interactions has appeared this ~ear?~-~O The use of strong bases (e.g. Bu”Li/TMEDA) is now common place but often with little understanding of the nature of the species reacting in the medium. Recent mechanistic studiessi and an authoritative survey of organoalkali metal structuress2 should promote such understanding and perhaps encourage more efficient use. An evalu-ation of directing groups in ortho-lithiation reactions poses a number of interesting mechanistic questions. 53 A theoretical investigation into the generalized anomeric effects4 and further reports onthe transition state structures involved in cyclohexanone reductions have appeared.The ability to prepare probes containing chiral methyl groups has had a profound effect upon our understanding of a number of biosynthetic pathways. A personal account of work in this area is most instr~ctive.~~ Coupling Reactions.-Synthetic methods concerned with carbon-rbon bond forma-tion continue to be a major preoccupation. Variants on the Heck and StiHe cross-coupling reactions for the stereoselective formation of olefins are abundant (Schemes 1-1 l).57-68 A growing body of empirica1 evidence suggests that the addition of copper(i) salts as a cocatalyst in such reactions may have a pronounced effect upon the rate-determining transmetallation step.69 In several cases reaction times are L. Pardo R. Osman H. Weinstein and J. Rabinowitz J. Am. Chem.SOC. 1993,115 8263. ” S. Gronert J. Am. Chem. Soc. 1993 115 652. 43 K. Nakamura and Y.Osamura J. Am. Chem. Soc. 1993,115,9112. “ M. Fujita M. Ishida K.Manako K. Sato and K.Ogura Tetrahedron Lett. 1993,34,645. ‘’ S.E.Denmark and N.G. Almstead J. Am. Chem. Suc. 1993 115,3133. “ S. Castellino and W. J. Dwight J. Am. Chem. Soc. 1993 115,2986; P. G. Willard and Q.-Y. Liu J. Am. Ckem. Soc. 1993,115 3380. 47 H. Sasai T.Suzuki N. Itoh K.Tanaka T. Date K. Okamura and M. Shibasaki J.Am. Ckem. Soc. 1993 115 10372. ’* G. Quinktrt H. Becker M. Del Grosso G. Dambacher J. W. Bats and G. Durner Tetrahedron Letr. 1993 34 6885. 49 M.P.Bernstein and D. B. Collum J. Am. Chern. Soc. 1993 115 789. ” M.Sirnard J. Vaugeois and J.D. Wuest J. Am. Chem. Soc. 1993 115,370. ” F.E.Rosenberg M. P. Beernstein,J. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum,J. Am. Chem. Suc. 1993 115,3475; M. A Nichols and P.G. Willard J. Am. Chem. Soc. 1993,115 1568. ” E.Weiss Angew. Chem. Int. Ed. Engl. 1993 32 1501. ” P. Beak S-T. Kerrick and I).J. Gallagher J. Am. Chem. Soc. 1993 115 10628. s4 U. Salzner and P. Yon R. Schleyer J. Am. Chem. Soc. 1993 115 10231. ” 1. M.Coxon and R.T. Luibrand Tetrahedron Lett. 1993,34,7097; Y.Wu and K.N. Nouk J. Am. Ckem. Suc. 1993 115 10992. ’6 H.G. Floss and S. Lee Acc. Chem. Res. 1993 26 166. ” P. MeInyk J. Gasche and C. Thal Tetrahedron Lett. 1993 34 5449. A.R. Hunt S.K.Stewart and A. Whiting Tetrahedron Lett. 1993 34 3599. ” T. Sakamoto Y.Kondo N. Takazawa and H. Yamanaka Tetrahedron Lett.t993,34 5955. 6o D.A. Evans and T. Bach Angew. Chem. Int. Ed. Engl. 1993,32 1326. 61 H.Finch N.A. Ptgg and B.Evans Tetrahedron Lett. 1993,34 8353. ” J. P.Michael S.-F. Chang and C. Wilson Tetrahedron Lett. 1993,34,8365. D. Badone and U. Guzzi Tetrahedron Lett. 1993 34 3603. 2. Xu and J. S. Moore Angew. Chern. Int. Ed. Engl. 1993 32 1354. S. W. Lee and P. L. Fuchs Tetrahedron Lett. 1993,34,5209; Z.Jin and P. L. Fuchs Tetrahedron Lett. 1993 34 5205. ‘‘T. JeKery Tetrahedron Letr. 1993 34 1133. 67 M.Amat S. Hadida and J. Bosch Tetrahedron Lett. 1993,34,5005. K.F.McClure and S.J.Danishefsky J. Am. Chem. Suc. 1993 115 6094. 69 R.3. Hinkle G. T. Poutter and P.J. Stang J. Am. Chem. Soc. 1993 115 11 626; see also J. M.Saa and G. Martnrell .I Om Ch~m1993 9.1963 for related observations.Aliphatic and Alicyclic Chemistry 109 (ref 57) Reagents i Pd(OAc), Ph,P Bu,NBr K,CO, DMF Scheme 1 Reagents i Pd(OAc), NEt, CH3CN 80"C Scheme 2 (ref 59) Reagents i Zn*;ii ArX Pd(PPh3), THF 80"C scheme 3 Scbeme 5 110 P.Quayie (ref 62) Reagents i proton sponge Pd(OAc), DMF,80°C scheme 7 (ref 65) Reagents i P~(OAC)~, AgOAc DMF,45 "C Aliphatic and Alicyclic Chemistry Reagents i Pd(o) NEt, CH,CN 80°C scbeme 11 reduced and yields are higher especially in those reactions which are sluggish when using Pd(0) alone Scheme 12. Remarkably Piers has shown that in at least one system the palladium cataIyst can be dispensed with altogether if stoichiometric quantities of copper chloride are added Scheme 13.’* This result obviously warrants further investigation.(ref 69) Reagents i PdCIBn(PPh,), CuCI DMF,rt scheme 12 Reagents i CuCI (2.2 q),DMF 62 “C,3 min Scheme 13 ‘Contrasteric’ functionalization of 1,l-dihaloalkenes has been observed in Heck or Stille reactions by a number of workers.” The generation of chelated vinyl palladium species has been invoked in order to rationalize these observations (Scheme 14). The use of vinyl boronic acids72 (Suzuki crosscoupling) and vinyl ~iIanes’~ in Stille-type reactions continues to gain acceptance (Scheme 15). Cascade sequences which uti€ize 70 E. Piers and T. Wong J. Org. Cfiem. 1993 SB 3609. 7’ J. Suffert A. Eggcrs S. W. Scheupkin and R. Bnrckner Tetrahedron Lett.1993,34,4177; S. Toni H. Okumoto T. Tadokoro A. Nishimura and M.A. Rashid Tetrahedron Lett. 1993,34,2139; J. M. Nuss R. A. Rennels and 6.H. Lcvine J. Am. Chem.Soc. 1993,11S 6991; for related examples in organolithium chemistry see D. Grsndjcan and P. Pak TetrahedronLett. 1993,34,1155; M.Braun and K.Opdenbusch Angew. Cktn. Int. Ed. Engl. 1993,32 578. 72 N.Yrtsuda L. Xavitr D.L.Riegtr Y. Li A.E. DcCamp and U.-H. Dolling TetrahedronLett. 1993.34 3211. 73 K. Takahashi T. Minami Y. Ohara and T. Hiyama Tetrahedron Lett. 1993,34 8263. 112 P. Quuyb scheme 14 Reagents i Pd(dbq), THF KOHtaq) rt; ii TBAF P(OEt), Pd(o) Scheme IS sequential Heck and carbonylation reactions have been reported by Grigg (Scheme 15).74 The use of ketone enolates in palladium-mediated cross-coupling reactions has hitherto been neglected but a line example demonstrating the synthetic potential of this reaction is featured in Albizati's synthesis of (+ )-hapallindole Q (Scheme 17).7' (ref 74) Iso2m Isoph Rcsgents:i Pd(o) CO CH3CN TlOAc Scheme 16 The stereospecific cross coupling of a homochiral a-aIkoxystannane with an acyl halide has been reported by Fal~k'~ in his synthesis of(+ kgonifuranone (Scheme 18).The stereochemical course in this reaction wasopposite to that expected; further work in this area is required in order to ascertain the generality of this observation. Modifications77*78 of well-established copper-mediated carbon-carbonbond-form-'' R. Grigg and V. Sridharan Tetrahedron Left.1993 34,7471. " V. VaiIlancourt and K. F. Albizati J Am. Chem. Sac, 1993,115 3499. 76 J. Ye R.K. Bhatt and J. R. Falck Tetrahedron Lett.. 1993. 34,8007. " M. BergdahI M. Eriksson M. Nilssan and T. Olsson J. Org. Chem. 1993,58 7238. '' J. Westermann and K.Nickisch Angew. Chem. Int. Ed. Engl. 1993.32 1348. Aliphatic and Alicyclic Chemistry i (ref 75) Br& 50% + Brl--OAc I TIPS I TlPs Reagents i Bu,SnOMe Pd(o) toluene 100"C Scheme 17 (ref 76) Reagents:i PhCOCI PdCI,(PPh3), CuCN toluene 80°C Scheme 18 ing reactions continue to be the focus of attention (Scheme 19).A major advance this year includes the use of organolithium zincates as a 'soft' source of organoIithium reagents in the conjugate addition reactions of enones.Kn~chel~~ has published full experimental details of the preparation of the synthetically versatiIe functionalized organometalIics (2) (Scheme 20). Reagents i LiI TMSCI Scheme 19 (ref 79) (21 Reagents i Zn,THF 12°C; ii CuCN-2LiCI,3O0C,DMF;iii E+ Scheme 20 Asymmetric Catalytic CoupIing Reactions-Asymmetric Heck reactions as developed by Shibasaki have been utilized in the synthesis of indolizidine a~kaloidssOand in a '9 P. Knochel T.S. Chou C. Jubert and D. Rajapohal J. Org. Chem. t!393,58 508; M. J. Rozema C. Eiscnberg H. Lutjens R. Ostwald K. Belyk and P. Knochel Tetrahedron Lett. 1993 34,31 15. S.Nukui M.Sodcoka and M. Shibisaki Tetruhedron Lett. 1993 34,4965. 114 P. Quayle total synthesis of (-))-eptazocene (Scheme 21).81 Ligand systems which enable enantioselective palladium-catalysed allylic substitution reactions have again been the subject of numerous reports." Several authors have demonstrated that oxazo-line-derived ligands can induce high levels of enantioselectivity in these reactions (Scheme Z).82*83 Pfaltzg4has also demonstrated that ligands such as (3) enable the enantioselective 1,4-addition of Grignard reagents to enonesin poorto moderate levels of induction (1683% e.e.) (Scheme 23).(ref 81) Reagents i Pd*Lm, Ag'; ii Pd*(o) (ref 83) Reagents i 1 mol % [(Pd(C,H,)CI},J 2.5 mol % L*. BSA,KOAc. CH,Cl, 23 "C;ii [(Pd(C3H5)CI},]L* scheme 22 '* S.Takernoto M.Sodeoka H.Sasai and M.Shibasaki,J. Am.Chem. Soc. 1993,115,8477. 81 P.von Matt and A.Pfaltz Angew. Chem. lnt. Ed. Engf. 1993 32,556. '' G.J. Dawsoon C. G.Frost,C.J. Martin,J. M.J. WiIliarns and S. J. Coote TetrahedronLett. 1993.34,7793. Q.-L. Zhou and A. Pfaltz TetrahedronLett. 1993 34,7725. Aliphatic and Alicyclic Chemistry 0 0 Akenes and Polyeaes-Schlosser has developed a general method for the synthesis of Z vinyl halides8' using the modified Wittig reagents (4).Erythro phosphinyl alcohols (5) afford E olefins upon exposure to PCI and NEt, in a reaction similar to a Ramberg-Backlung rearrangement (Scheme 24).86 (ref 85) Reagents i,THF 50 "C; ii XI,,NE!,. CH,Cl, 0°C !scheme24 DenmarkB7 has reported a highly stereoselective synthesis of trisubstituted olefins,a structural motif present in many natural products but difficult to introduce in a stereoselective fashion using existing Wittig methodology (Scheme 25).Two OH BU' Reagents i THF 105 "C X.-p. Zhang and M.Schlosser,Tetrahedron Lett. 1393 34,1925. N. Lawrence and F. Muhammad 3. Chem. Soc. Chem. Comnnm. 1993 1187. S. Dcnmark and .I.Amburgey J. Am. Cfrem. Sm. 1993 115 10386. 116 P.Quayle i. ii 1 (>80% dc) (ref 88) (ref 89) Me02C H OTBDPS Reagents i KHMDS 18-C-6 -100°C; ii NaBH,; iii NaH -78 "C;THF Scheme 26 gro~ps~~~~~ have described the use of homochiral Wadsworth-Emmons reagents for the desyrnmetrization of meso carbonyl compunds (Scheme 26). Similarly,the kinetic resolution of xacemic ketones" using the phosphonate (6) afforded trisubstituted alkenes with usefuI Ievels of asymmetric induction (Scheme27).The use of homochird 0 ,-*z F% (ref 90) 38% (89%e.e.) (6) Reagents i KHMDS THF -80°C &kme 27 '' N. Kann and T. Rein J. Org. Chem. 1993 58 3802. 89 K. Tanaka Y. Ohta K. Fuji and T.Taga TetrahedronLett. 1993 34,407. 90 K. Narasaka E. Hidai Y. Hayashi and J.4. Gras J. Chem. Soc. Chem. Commun. 1993 102. Aliphatic and Alicyclic Chemistry bases in asymmetric elimination reactionsgi also appears to be an attractive route to scalemic exocyclic olefins (Scheme 28). Bu' 1 (ref 91) H02C' Qrganozirconiurn reagents have been used in several guises for the stereoselective synthesis of alkenes and polyenes (Scheme 29).92-94 In a ground-breaking develop- (ref 94) R-gents i 2 x EtMgBr; ii RC=CR; iii R,CHO; iv H,O+; v 35°C;vi H,O+ rt; vii cat.AgClO, Ff 30min; viii. H,Ot Scheme 29 ment two groupshave reported the use of anolefin metathesis strategy fur the synthesis of functionalized olefins (Scheme 3U).95+96Applications of this methodology will doubtlessarise in the nearfuture.The related Tebbe-mediated synthesis ofolefinsfrom unactivated carbonyl compounds (esters etc.) has been extensively re~iewed.~' 3. Vadecord J.-C. Plaquevent L. Duhamel and P. Duhamel J. Chem. Soc. Chem. CO~~UR., 1993 116. " T. Takahashi M. Kageyama V. Dcnisov R. Ham and E. Negishi Tetrahedron hrt. 1993,34 687. 93 T. Takahashi N. Suzuki,M. Kageyama D. Y. Kondakov and R.Hara TetrahedronLett. 1993,34,481I. '' H. Maeta and K. Suzuki Tetrahedron Lett.I993,34 341. 95 G. C. Fu and R. H. Grubbs,J. Am.Ckem.Soc. 1993,115,380O; G.C Fu S.T.Nguycn,and R.H.Grubbs,J. An.Chem. Soc. 1993 115,9856. 96 H. Junga and S. Blcchcrt Tetrahedron Lett. 1993,34,3731. " S.H. Pine Org. React. 1993 43 1. 118 P.Quayle (ref 95) Reagents i Mo catalyst benzene 20 "C;ii MTO/SiO, Ai,O, CH,€l, rt scbeme 30 Transfer hydrogenation ofacetylenesg8 has been shown to occur under mild reaction conditions to provide 2 olefins with levels of high stereochemical purity (typically Z E > 97 :3). y-Hydroxy-a,fLynones are cleanly transformed into E,E dienones upon treatment with triphenyf phosphine." SaladieloOhas reported a highly stereoselective synthesis of trienes uiu a 1,6 reductive4rnination sequence (Scheme 31).Reagents i TiCI, LiAlH, THF 65 "C scbeme 31 The Ramberg-Backlund reaction has been applied with good effect in the synthesis of unsaturated a-amino acids without loss of stereochemical fidelity (Scheme32)."' 1-Nitroalkenes are transformed into *unsaturated nitriles in a one-pot sequence (Scheme 33).Io2 98 K. Tani N.Ono,S. Qkamoto and F. %to J. Chem. Soc. Chem. Commun. 1993 386. '' G. Guo and X.Lu,J. Chem. Soc. Chem. Comn. 1993,394. loo G. Solladie G. B. Stone and A. Rubio Tetrahedron Lett. 1993 34,1803. 2.-X. Guo,M.J.Schaeffer and R.J. K. Taylor J. Chem. Soc. Chem. Commun. 1993,874. H.-W. Tso RA. Gilbert and J. R.Hwu J. Chem. Soc. Cfrem. Conrmun. 1993,669. Aliphatic and Alicyclic Chemistry DN0* -fil (ref 102) 10% Reagents i Me,SiCH,MgCl; ii XI, THF scheme 33 Stereoselective functionaiization of olefins continues to be an area of much methodological interest.*03 Of note this year is the report of a paIladium-catalysed asymmetric acetalization ofacryIamides (Scheme 34),"* the stereoselective cyclization t Ph-0 OMe (ref 1w 0U OI M e Reagents i MeOH PdCl, CuCi, O, rt; ii PhCH,OLi scbeme34 of 3-aminopent-1-en-5-01sto the corresponding tetrahydrofurans (Scheme 35),'05 and an asymmetric synthesis of a-amino acids via a stereoselective iodolactonization reaction (Scheme36).lo6 Details ofan asymmetric selenoetherification reaction have also appeared (Scheme 37).'*' Epxides Dids ad Related Compwds.-The Sharpless enantioselective dihyd- roxylation (ADHT)of achiral olefins has been the focus of mechanistic investigation; two distinct interpretations of kinetic data have been advanced.lo' Sharpless favours a non-concerted [Z + 23 cycloaddition-rearrangement reaction rather than a classical lo' J.Rodriguez and J.-P. Dulcert Synrhesis 1993 1177. lo4 T.Hosokawa and S.-i. Murahashi J. Chem. Soc. Chem. Convnun. 1993 117. lo' Y. Tarnura,H. Harayama and T. Bando J. Chem.Soc. Chpm. Cammun. 1993 1601. lo' 0.Kitigawa T.Hamno N. Kikuchi and T. Taguchi Tetrahedron Lett. 1993.34 2165. R. Dtzitl R.Goulet L. Grenier J. Bodeltau and J. Bernicr J. Org Chpm. 1!?93,S8 3619. IonE.J. Corty M.C.Noe and S.Sarshar,J. Am.Ch.Soc. 1993,115,3828; H.C. Kolb P.G. Andcrsson Y.L. Bcnnani G.A. Crispino K.4. Jeong H.-L.Kwong and K. B.Sharpless J.Am. Chem. Sm.,1993 115 12 226. 120 P. Quayle Reagents i I, NaHCO, O'C H,O Et,O Scheme 35 Scheme 36 9PMB i ii Oet SmfqB 51%(ca90%e.e) (ref 107) Reagents i pMBA; ii Ph,SnH AIBN Scheme 37 [3 + 21 cycloaddition process. Irrespective of mechanistic detail this experimentally simple reaction is now an indispensiblesynthetic tool as shown below (Scheme 38).'09 (+)-exo-brevicomin Reagents i OsO, (DHDQ),-PHAL; ii TsOH Scheme 38 J. A. Sodcrquist and A. M. Rane Tetrahedron Lett.. 1993 34,5034. Aliphatic and Alicyclic Chemistry Other workers have aIso developed both catalytic (Scheme 39)' and stoichiomet- 'On' ric (Scheme @)'I2 variations which in several instances are cornpIementary to the Sharpless system.L* = cG(R OH Y = neohexyl) R f Reagents i OsO, L* CHJl, -8 'C;ii Na,S,U Scheme 39 Reagents i OsO, L* toluene -90°C Scheme 40 Diastereoselective'' and enantioselective' I4 epoxidation reactions continue to be exploited synthetically (Scheme 41). Jacobsen's enantioselective epoxidation provides particularly rapid access to a range of functionalized olefins which are useful in Reagents i Bu'OOH 0.5 eq Ti(OPr'), L-( + )-DIPT -16 "C Scheme 41 'Io E.J. Corey M.C. Noe and W.-C. Shieh Tetrahedron tert. 1993 34 5995. 'I1 T. Oishi K. lida and M. Hirama Tetrahedron Lett. 1993,34,3573. 'I2 S. Hanessian P. Moffre M.Girard S. Beaudon J.-Y.Sanceau and Y. Bennani J. Org. Chem. 1993,518 1991. 'I3 J. Clayden E. W. Collington R. 3. Lamont and S.Warren Tetrnhedrun Lett. 1993 34 2203. 'I4 E.J. Allain L. P. Hager L. Deng and E. N. Jacobsen J. Am. Chem. Soc.. 1993 115 4415. f 22 P.Quayle 1 62%(!32%e.c.) 1 RO (CH2)3C02Me (ref 115) HQ-H Reagents i Mn cat NaOCI pH 11.5 !3cbeme 42 target-orientated synthesis as demonstrated by his synthesis of leukotriene A methyl ester (Scheme 42).' ' Ito' l6 has developed a potentiallypowerful method for the stereoselective synthesis of polyols which utilizes an intramolecular bis-silylation-xidation sequence (Scheme 43). Adam'" has adapted the photooxidation of aliylic alcohols into a tita-nium-catalysed epoxy-hydroxylation sequence in which the relative configuration of four contiguous chiral centres can be controlled in a single reaction sequence (Scheme 44).Reagents i Pd(OAc), RNC;ICI; ii KF,KHF, KHCO,; iii Ac,O scbeme43 f -&+ "3 -&-nmf (ref117) major isomer Reagents i O, TPP hv 0°C;ii. 0.05 eq TifOPr'), CH,Cl,. -25°C scheme44 'Is S.Chang N.H. Lec and E.N.Jacobsen,J. Org. Chem. 1993,58,6939. M. Murakami,M. Suginome K.Fujimoto H. Nakamura,P. G.Andersson and Y. Ito,J. Am.Chem. SOC. 1993,115,6487. (n.6.Foran improvement to the Fleming oxidative desilylation reaction see I. Fleming and S. B.D. Winter TetruhedronLett. 1993 34,7287). 'I7 W. Adam and B. Nestler Angew. Chem. lnt. Ed. Engf. 1993 32,733. Aliphatic and Alicyclic Chemistry Enantioselective aziridination1'8*1l9 of olefins has been achieved with high levels of asymmetric induction (up to 96% e.e.).Such compounds prove to be. useful synthetic intermediates (Scheme 45). Ts T" I I 63% (94% w.) 82% H COzMe NHTS Reagents i cat. CuOTf PhI=NTs rt; ii HCO,€€ Pd(o) McOH scbem 4s Alkyaes-Tetraethynylmethane (7) a high-carbon monomer whose polymerization could lead to a network homologous to diamond has been readily prepared from a dibromide (Scheme 45) in an eight-step sequence. *' Solid tetraethynylmethane decomposes rapidly at room temperature but a trimethylsilylated precursor could be handled under ambient conditions and an X-ray crystal structure of this material confirms the structure and reveals that bonds from the central C(sp3)to the C(sp) * D.A. Evans M.M.Fad M.T.Bilodeau B. A. Anderson,and D. M. Barnes,J.Am. Chem. Soc.1993,l IS 5328. *I9 Z. Li,K.R.Conscr and E. N.Jacobsen J. Am. Chem. Soc. 1993 115,5326. K.S. Feldman C. M.Kracbei and M.Parvez J. Am. Chem. Soc. 1993 115 3846. 124 P. Quayle atoms of the attached alkynyl units are lengthened by ca. 0.04A over standard values presumably reflecting steric compression at the central carbon. Medium ring and macrocydic acetylenic lactones are readily available (55-90%) from tosylhydrazones of vinylogous lactones upon treatment with NBS in aqueous Bu'OH (Scheme47).'" Acetylenes are versatile intermediates as demonstrated by synthetic applications of Livinghouse's amidornetallation reaction (Scheme 48)' ''and Takai's metallocydop- ropene functionalizationXz3 (Scheme 49). "HTS (ref 221) Reagents i Bu'OH NBS -10°C; ii NaHSO, 55°C Scheme 47 Reagents i TaCI, Zn;ii py THF; iii RCHO; iv NaOH DME Scheme 49 "' J.R.Mahajan and J.S. Resck 1.Chem. Suc.. Chem. Commun. 1993,1748. 12' P. L. McGrane and T. Livinghouse J. Am. Chem. Soc. 1993 115 11485. lZ3 M.E.Maier. B.-U. Hailer R. Stumpf and H. Fisher SYNLETT 1993,863. Aliphatic and Alicyclic Chemistry Enolrrte Aldoi and Related Reactioa-CoIlum '24 has demonstrated that the readily available hindered amide base (8) enolizes ketones with very high levels of E 2 selectivity (Scheme 50). Use of manganese'. *' and zinc'26 enolates in selective alkylation reactions has been amply demonstrated; asymmetric deprotonations and alkyhtions have found synthetic applications; lZ7 asymmetric protonation of thioi ester enolates has been reported128 to proceed with high levels of asymmetric induction future developments in this area are eagerly awaited.OTMS (AdhNLi + (ref 124) (8) Ad = Z-ada~~~~tyl E:Z 50 1 Reagents i TMSCL THF -20"C Scheme 50 Evans-type methodology is now commonplace for the synthesis of syn aldol products of high diastereoisomeric and enantiomeric purity. 29 Note however that there may be substrate control of the sense of induction as in the case of a,or,a-!-trifluoroketones, which afford 'non-Evans' syn aldol products (Scheme 5 1).' '* Lf Pr'" Reagents i Bu,BOTf PriNEt; ii 4-cyclobcxykrotonaldehyde; iii CF,CHU Scheme 51 ''* K. Sakuma J. H. Gilchrist F.E. Romesberg C. E. Cajthaml and D. B. Collum Tetrahedron Lett. 1993 34 5213.M.T. Reetz and H. Haning Tetrahedron Lett. 1993 34 7395. U. Groth T. Huhn and N. Richer Liebigs Ann. Cksm. 1993 49. A. J. Edwards,S. Hockey F.S. Mair P. R.Raithby R. Snaith and N. S. Simpkins,J.Org.Chem. 1993.58 6942; M. Sobukawa and K. Koja Tetrahedron Lett. 1993,34,5101; D. MiIne and P.J. Murphy J. Chem. Soc. Chern. Commun. 1993 884; Y. Hasegawa H. Kawasaki and K.Koga Tetrahedron Lett. 1993.34 1963. C. Fehr I. Stempf and J. Galindo Angew. Chem. Int. Ed. Engl. 1993 32 1043. lt9 B.D. Dorsey,K. J. Plzak and R.G. Ball Tetrahedron Lert. 1993 34 1851. K.Iseki S. Oisbi T.Taguchi and Y.Kobayashi. Tetrahedron Left. 1993 34,8147. 13' 126 P. Quuyie Subtle changes to the chiral auxiliary and of additives in the reaction can dso affect dramatically the stereochemical course of these reactions (Scheme 52).Reagents i TiCI, RCHO; ii Bu,BOTf RCHO Scheme 52 Evans132has shown that Z enolates derived from fl-hydroxy ketones undergo anti Felkin aldol reactions with high levels of double diastereodifferentiation (Scheme53). Bu' ,But i 156% Bu; ,Bu' _-(ref 133) Reagents i PhBCI, PriNEt CH2Cl, -7% "C scheme 53 Titanium enolates derived from glycine are observed to undergo aldoi reactions133 (presumablyoia a boat-type transition state) with high anti selectivity (up to >99 1 13' T.-H. Yan,C.-W. Tan,H.-C. Lee. H.-C. Lo and T.-Y. Huang. J. Am. Chem. Sm. 1993 115.2613. 13' D.A. Evans and M.A.Calter Telrahedron Lett. 1993 34,6871. 133 S. Kanemasa T.Mori and A.Tatsukawa Tetrahedron Lert. 1993 34,8293. Aliphatic and Alicyclic Chemistry (R4= CH2ph RS= H; >99 :1 d.e.) d.e.) (Scheme 54). In a related area intense interest has focused upon the Mukaiyama reaction,’34-* 35 with particular emphasis on the development of new catalyst systems (Scheme 55) and on synthetic applications of ally1 metat speciesi37(Scheme 56). OBIl OTBDMS -‘ UBn (84% dr) +y-CO*Me H UH (ref 135) Reagents i 3 mot *A LiCIO,. CH,CI, -30°C scheme 55 OH PH SDBU~ Ph (9S%C*.) h-\ (ref 138) Reagents i SnCI, CH,CI,; ii. RCHO; iii. I :1 (R)-BINAP-Ti(OPr’) scheme56 Realization that readiIy available BINOL-derived catalysts impart high levels of asymmetric induction in these reactions represents a major advance.’ ”The observa-tion that aIlyl stannanes undergo highly chemoselective alkylations (al-dehydes > ketones acid chlorides) in the presence of protic acids (2 M HCI) is also of some practical significance (Scheme 571.’ 39 The ene reaction especially when 13‘ K.Mikitmi and S. Matsukawua J. Am. Chrm. Soc. 1993 115 7039. ’” M.Reetz and D.N.A. Fox,Trrrctbdr4m Left.. 1993,34 I 1 19. K.Mikarni M. Terada. and T. Nakai J. Chrm. Soc. Chem. Commun. 1993 343. ‘37 A.H. McNeill and E.J. Thomas. Terrahrdrcm Lett. 1993 34,1569. IJnG.Keck. K.H. Tarbet. and L.S. Geraci J. Am. Chrm. Sw. 1993 115 8467. 13’ A. Yanagisawa H. Inoue M. Morodome. and H. Yamamoto J. Am. Chrm. SIX’..1993. IfS. 10356. 128 P. Quayle 0 (ref 139) Rcsgcnts i. HCI. THF.20°C scheme 57 conducted in a chelation-controlled mode has proven to be highly effective for the creation of up to three contiguous chiral centres in acyclic examples (Scheme 58).I4O EnantioseIective Ref~rrnatsky'~' and nitro-aldol reactions142 have been reported; and copper'44 homoenolates continue to be developed as useful synthetic reagents as do a-and b-heterQsubstituted organolithium ~eagents.'~' 1,7-Asyrnmetric induction has been observed in the reduction of 4-ketoalkylboronates (Scheme 59).146 Reagents i. SnCI,. -8 'C scheme 58 Reagents i. BH,.SMe,. O'C ii. NaOHtaq). H,02 Scheme 59 Radical Reactions.-The use of free radicals for the construction of carbon-carbon bonds continues to attract attention (Scheme A particularly interesting observationthis year is that scaIernic r-sulfinyIenones undergo conjugate addition with t 40 T.Nakamura.K.Tanino. and I. Kuwajima. Tetrahedron Lett.. 1993,34,7591; T. Nakamura. K.Tanino and I. Kuwajima. Tetrahedron Lerr.. 1993 34. 477; K. Mikarni and S.-i. Sakuda J. Chem. SOC. Chem. Commua. 1993. 710. 141 K.Soai. A. Oshio. and T. Saito. J. Chem. SOC..Chem. Commun.. 1993.121 Y.Yamamoto. M.Naito. Y. Uozumi. and T. Hayashi. Terrahedron Letr.-1993.34. 1468. t 41 H.Sasai. T.Suzuki. N.Itoh. S.Arai. and M.Shibasaki. Terrohedron Lerr.. 1993.34.2657 P.Wipf and S. Lim. J. Chem. Soc.. Chem. Commun.. 1993. 1654. t 43 R. F. W. Jackson and A. B.Rettic. Tetrahedron Lert.. 1993. 34.2985. I44 1. Ryu. K.Matsurnoto. Y.Kamcyarna. M.Ando. N.Kusumoto. A. Ogawa. N.Kamk. S. Murai. and Sonada. J. Am.Chem Soc.. 1993. 115. 12330. t45 3. Almcna. F.Foubelo.and M. Yus. Tetrahedron Lett.. 1993.34.1645 A. F.Burchat. J. M. Chong,and S. B. Park. Tetrabdrorr Lett.. 1993.34. 51 A. Guijarro and M.Yus TptrahedronLert. 1993.34. 3487; R. E. Gawky and Q. 2hang.J. Am. Ckenr. Sor.. 1993.115.7515 H. J. Rcich and R.R. Dykstra. Angew. Chem.. hr. €4.€Jig!.. 19!93.32,1459 W.H.Pearson. A. C. Lindbcck. and J. W. Kampf. f.Am. Chem. Sm.. 1993. 115.1521. 146 G.A. Molander and K.L. 3obbitt. J. Am. Cheni. Soc.. 1993. 115. 7517. 14-A. G. Myers. D. Y.Gin. and D.H.Rogers. J. Anr. Cheni. SOC.. 1993. 115. 2036 Aliphatic and Alicyclic Chemistry 129 (ref 147) Reagents i Bu,SnH BEt, 0°C; ii KF MeOH Scheme 60 carbon-centred radicals in a highly stereoselective fashion in the presence of bidentate Lewis acids (Scheme 61).14* The stereoselective functionalization of a-functionalized 50 radicals has also come under further in~estigation.'~'~' A potentially useful observation by AlperLslsuggests that carbon radicals may be trapped by carbon monoxide albeit at high pressure to afford carboxyl-containing products (Scheme 62). Reagents i TiC1,(OPr')2,CH,CI, 0°C; ii BR Scheme 61 d Reagents i CO (6OOpsi) OX Mn(OAc),-2H2O Scheme 62 14' T. Toru,Y. Watanabe M. Tasnaka and Y. Ueno J. Am. Chem. SOC. 1993 115,10464. 149 W.Damm J. Dickhaut F. Wellerich and 3. Giese Terrohedron Lett. 1993,34,431; C.Ferreri M. Ballesrri and C. Chatgilialoglu Tetrahedron Lelr. 1993 34,5147. 15' e.g.D. P.Curran and S.Sun Terrahedron Leu. 1993,34,6181;3.Giese W.Darnm F. Wetterich H.-G. Zeltz J. Rancourt and Y. Guindon Terrohedron Lerr. 1993 34,5885. 1. Ryu and H. Alper J. Am. Chem. Soc. 1993,115,7543. 130 P. Quayle Reductha-The use of oxazaboriIidine-derived reducing agents' 52 fur ketone reduction provides rapid access to a variety of functionalized alcohols with a predictable sense of induction (Scheme 63). Lithium aminoborohydrides' 53 have 0 i (sa%e+.) I (ref 152) I OH Reagents i. BH,-THF 25 T,cat Scheme 63 proved to be highly selective reducing agents. Williams'54 has developed a highly diastereoselective synthesis of syn 1,2-amino aIcohols from the corresponding oximes (Scheme 64). Matsuki has demonstrated that meso anhydrides may be desymrnetrized (ref 154) Reagents i 5 eq TABH CH,CO,H CH,CN 35'C scheme 64 by reduction with the LAH-EtOH-BINAL-H complex to afford lactones with high optical (84 to 95% e.e.1 (Scheme 65).EvanslS6 has developed a chiral samarium catalyst for the promotion of asymmetric Meerwein-Ponndorf-Verley reductions; high Ievels of induction (usually in excess of 97% ex.) are obtained for reduction of aryl alkyl ketones (Scheme 66). C. Boim and M.Feldcr TetrahedronLoft,,1993,34,6041; G.J. Quallich and T. M. Woodall Tefruhedron Leu. 1993 34 4145. J.C. Fuller E. L. Stageland C.T. Goralski and B. Singaram Zetrukedron Lett. 1993 34,257 Is* D. R. Williams M. H. Usterhout and J. P. Reddy Tetrahedron Lett. 1993 34 3271. lS5 K. Matsuki H.Inoue and M.Takeda Tetrahedron Left.,1993 34 1167. IJ6D.A. Evans S.C. Nelson M. R.Gagnc and A. R. Muci J. Am. Chem. Snc. fW3 IIS 9800. Aliphatic and Aficycfic Chemistry w BnNKNBn BnN NBn [ref 155) 75% (90%e.e.1 0 Reagents I (RkBINAL-H -78°C 10 rt Scheme 45 (ref 156) r Reagents i Me,CHOH 5% cat scheme 56 Asymmetric Hydrogenation and Related Reactions-Significdn t advances this year indude the use of the DUPHOS Iigand system (3)in conjunction with rhodium(1)for the enantioselective reduction (typically >99% e.e.) of dehydroamino acids (Scheme 67).157Buchwald158has developeda titanium catalyst for the asymmetric reduction of 4c02R (ref 157) R2 NHCOR' P2= Reagents i cat [ICOD)Rh(P,)]OTf H Scheme 67 trisubstituted olefins { >92% e.e.1.The synthesis and exploitation of novel phosphine Iigands continues to be fashionable.'59 BrownI6" has shown that the hybrid phosphine-isoquinoline ligand system (10) can be effectively employed in the asymmetric hydroboration' 6' of simple olefins (Scheme 681. Is' M.J. Burk,J. E. Feaster W. A. Nugent and R. L. Harlow J. Am. Chrm. Sric. 1993 115 I0 125. Is" R.D. Broene and S. L. Buchwald J. Am. Chem. Soc. 1993 115 2569. H. Brisset Y. Gourdel P. Pellon and M. Le Corre Trtruhedrnn Lett. t993 34,4523. lLr' J. M.Brown. D. I. Hulmes and T. P.Layzell 1.Chem. Soc. Chrm. Commun. 1993 1673. la' N. Sakai S.Mano K. Nozaki and H. Takaya J. Am. Chcm. Soc. 1993 115 7033. 132 P. Quayb + Rh(COD)(acac) + TMSOTf -[(quinoline)Rh(COD>l' CF3S03-catalyst (ref 150) OH I Reagents i Catalyst catechol borane; ii NaOH H,O Scheme 68 In a rather novel departure -asymmetric catalyst poisoning -Fallerls2 has demonstrated that hydrogenation of racemic cyclohexene-1-01 with racemic RuCl,(BINAPJDMF in the presence of (lR,2S)-ephedrine affords the alcohol (11) with high levels of induction (93% e.e.) at 72% conversion (Scheme 69).Reagents i H, (R)-Ru(BINAP) { -)-(1R,2S)-ephedrine2 Scheme 59 Pot Pourri.-Readily available scalemic a-epoxy alcohols,163 (hydroxymethy1)azi- ridine~,~~~ and a$-unsaturated epoxides' 65 continue to find novel uses in synthesis (Scheme 701 as do the now-fashionable oxidizing agents dialkyl dioxiranes166 and TPAP167(Scheme 71). The preparation of optically pure B-amino acids is presently an area of much methodologicaI interest.A particularly ready entry16* into this class of compounds utilizes an asymmetric conjugate addition ofhomochiral lithium arnides to or,fi-unsaturated carboxylic acid derivatives as outlined in Scheme 72. Finally a fascinating report by Yarnamotols9 details the preparation of stable Lewis acid complexes of reactive aldehydes using highly hindered aluminium alkoxide complexes. 162 J. W. Faller and M. Tokunaga Tetrahedron Lett. 1993,34,7359. '63 M.Poch M. Alcon A. Moyano M.A. Percas and A. Riera Tetrahedron Lett. 1993,34 7781. 16* T. Kawabata Y. Kiryu Y. Sugiura and K. Fuji Tetrahedron Lett. 1993,34 5127. 16s M. Miyashita K. Yoshihara K. Kawamine M. Hoshino and H. Irie Tetrahedron Lett.1993,34,6285. 166 R. Curci L. D'Accolti A. Detomaso C. Fusco K. Takeuchi Y. Ohga P. E. Eaton and Y.C. Yip Tetrahedron Lett. 1993,34 4559. 16' K. R. Guertin and A. S. Kende Tetrahedron Lett. 1993,114,5639. N. Asao N. Tsuda and Y. Yarnamoto J. Chem. Soc. Chem. Cornmun. 1993,1660. K.Maruoke A. B. Conqepcion,N. Murase M. Oishi,N. Hirayama,and H. Yamamoto J. Am. Chem.Soc. 1993 115 3943. A1iphatic and Alicycl ic Chemistry 13? (ref 163) TS I NHBOC HO (ref 164) OH (ref 165) Reagents i AlMe, H,O; -30 "C Scheme 70 (ref 164) (ref 167) Reagents i cat. TPAP NMO CH,CN Scheme 71 (ref 168) Scheme 72 The reaction ofsuch species with a variety of nudeophiles is also disclosed (Scheme 73). 3 Alicyclk Chemistry Cyciopropana-Keck' 70 has developed a facile synthesis of vinyl cyclopropanes (12) which themselves are useful synthetic intermediates (Scheme 74).CohenI7 has shown G. E.Keck and S.D. Tonnies Tetrahedron Lett. 1993,34 4607. C.A. Shook,M. L.Romberger S.-H.Jung M. Xiao J. P.Sherbine,B. Zhang F.-T. Lin and T. Cohen J. Am. Chem. Soc. 1993,115 10754. 134 P.Quayle R (ref 170) Reagents i TBSOTf CH,C12 0°C; ii KF,DMSO 18-C-6 scheme 74 that the cyclopropyl sulfides (I3) suffer sequential single-electron reduction alkyla- tion and Peterson olefination to generate the methylene cydopropanes rearrange- ment of which affords a general route to hydrazaazulenes (Scheme 75). Rather Reagents i e- CH,CH=CHCHO; ii KOBu'; iii 180°C scheme 75 unexpectedly,lf2 treatment of cqhnsaturated aldehydes with CrC1,-DMF complex provides a general synthesis of cyclopropanols (Scheme 76).Hoffmann"' has described a rare example of nucleophilic attack at the internal position of a Ir-allylpalfadium complex. Reaction of the complex (14) with a variety of ketone or ester enolates in the presence of TMEDA affords the cyclopropanes (15) in good isolated yields (Scheme 77). The generality of this reaction has yet to be established but it adds a further dimension to the reactivity of this most investigated class of organometallic reagent. Backvall' 74 has demonstrated high site selectivity in the cyclopropanation of 2-phenylsulfonyl-l,3-dieneswith nucleophilic and electrophilic cyclopropanating 172 D.Mongomery K.Reynolds and P. Stevenson J. Chem. Soc. Chem. Commun. 1993 363. A. Wilde A.R. Otte and H. M. R.Hohann J. Chem. Sac. Chem. Commun. 1993,515. J.-E. Backvall C. Liifstrom S. K. Juntuncn and M. Mattson Tetrahedron Lett. 1993 34,2007. Aliphatic and Alicyclic Chemistry 135 (ref 172) H Reagents i CrCl, DMF Reagents i LDA TMEDA 70°C scheme 77 agents; intramolecular cyclopropanations of iodonium ylides' ''have been utilized in the synthesis of a vitamin D ring-A synthon. Enantioselective rhodium-mediated cyclopropanation reactions have again come under much scrutiny. 76 Lee' 77 has developed a simple synthesis of functionalized vinylcyclopropanes which serve as precursors to cyclopentenones and furans (Scheme 78).Normant"* has utilized a \ EWG Reagents i PPh, TMSOTI THF 40"C;ii Bu"Li; iii CH,CH-EWG scbemtt8 metalla-Claisen rearrangement in the stereoselective elaboration of cyclopropanes (Scheme 79).A biomimetic synthesis' 79 of cyclopropane-containing eicosanoids utilized an intramolecular 5,2' substitution reaction of an allylic epoxide (Scheme80). Cyclobutanes-The synthesis ofthe tetraethynylcyclobutadienecomplex (16) has been R.M. Moriarty J. Kim and L. Guto Tetrahedron Lett. 1993,34 4129. M.P.Doyle W.R. Winchester J.A. Hoom U.1. Lynch S. H. Simonscn and R.Ghosh J. Am. Chern. Soc. 1994 115,9968. I" P.H. Lee,J.S. Kim,Y.C.Kim,and S. Kim Tetruhedron Lett. 1993,34,7583. If*D.&rubcn. I. Marek J.-F. Normant and N.Platzer Tetruhedron Lett. 1993.31 7575. J. D.White and M.S.Jenscn J. Am. Chem. SOC.,€993,115,2970. 134 P. Quayle (ref 179) Reagents t SnCI, MeNO, 0°C Scheme 80 (ref 180) described."* LiebskindIB' has developed a versatile route to the bisquaryl system (17) utilizing a Pd/Cu homocoupling procedure (Scheme 81). Organornetallic ap- proaches"' to cyclobutane synthesis have featured heavily this year as outlined in Scheme 82. Corey has described a novel samarium-mediated aldoI-type reaction in Reagents i,5% PdCIBn(PPh,), MeCN 50 "C Scheme 81 Reagents i Cp,ZrCl, BuLi BF,-OEt, -78°C Scheme 82 the synthesis of ( f )-paeoniflorigenin (Scheme 83); similarly Fuk~moto'~~ has *" U.H.F. Bunz and V. Enkelmann Angew. Chem. Int. Ed. Engl. 1993 32,1653. 18' L.S. Liebeskind M. S. Yu,R.H.Yu J.Wang and K.S. Hagen J. Am. Chem. SOC. 1993,115,9048. H. Ito T. Taguchi and Y. Hanzawa TetrahedronLett. 1993,34,7639; M. Hojo K. Tornita Y.Hirohara and A. Hosomi,Tetrahedron Lett. 1993,34,8123; B. M.Trost K. Imi and A. F. Indolese. J. Am. Chem. Soc. 1993,115 8831; B. M. Trost M.Yanai and K.Hoogsteen J. Am. Chem. SOC. 1993 115,5294; S. Kobbing and G. Raabe Chem. Ber. 1993 126 1849. E. J. Corey and Y.-J. Wu J. Am. Chem. Soc. 1993 115 8871. M. Ihara T. Taniguchi K. Makita M. Takano M. Ohnishi,N. Taniguchi,K. Fukumoto,and C. Kabuto J. Am. Chem. Soc. 1993 115 8107. Aliphatic and Alicyclic Chemistry OTIPS (ref 183) Reagents i SmI, THF -45°C Scheme 83 disclosed details of a tandem intramolecular Michael-Aldol reaction fur the synthesis of polycyclic cyclobutanes (Scheme 84).Reagents i TBDMSOTf NEt Scheme 84 [2 + 21-Cycloaddition strategiesls5-' " ha ve been employed in the synthesis of a variety of novel cydobutane systems (Scheme 85). The synthetic utility of the (ref 185) Reagents i 80°C; ii,hv Scheme 85 cydobutane ring system in natural product synthesis has been nicely exemplified by Crirnrnins'" in his synthesis of ( k)-bilobalide (Scheme 86). Cyc1opentanes.-The synthesis of cyclopentanes (and hexanes) from sugar derivatives A. Padwa M. A. Filipkowski M. Meske S.H. Watterson and Z. Ni J. Am. Chem. Soc. 1993,115,3775. F. Jin Y. Xu and W. Huang 3. Chem. Soc. Chem. Commun. 1993 814. W. G. Hollis W. C. Lappenbusch K. A. Everberg,and C. M. Woleben,TetrahedronLett. I993,34,7517.M.T. Crimrnins D.K. lung;and J.L. Gray J. Am. Chem. Soc. 1993 115 3146. 138 P. Qucryle OH Scheme 86 has been exhaustively reviewed by Ferrier.I8’ In keeping with recent trends radical 96 and radical-ani~n-based’~’ approaches to functionalized cyclopen- tanes have again been the subject of intense methodologicaI investigation (Scheme 87); the use of Mn3’ for the generation of rnal~nate-typel~~ radicals provides a useful alternative to more standard methods of radical initiation. In related studies cyclization of radical cationsf 99 provides a direct entry to spirocyclic systems. A novel two-fold addition-rearrangement reaction of vinyl anions to squarate esters generates tetracyclic cyclopentanoids in a single reaction sequence (Scheme 88).*’* A variety of organometallic-based strategies2*‘ have also emerged for the preparation of functionalized cyclopentanes (Scheme 89).Most notable amongst these is the Kn~cheI~~~-Normant~*~ cyclization of w-oIefinic organozinc reagents (Scheme 90),a zirconium-mediatedringcontraction of carbohydrate derivatives (Scheme 91 and a titanocene-catalysed conversion of eneynes into bicyclic cyclopentenones (Scheme 92).205The latter provides a useful alternative to the more common Pauson-Khand 1139 R.J. Ferrier and S. Middleton Chem. Rev. 1993,93,2779. 190 D.L,J. Clive and H. W. Manning J. Chem. Soc. Chem. Commun. 1993,666. 191 J. Fidalgo L. Castedo and D. Dominguez Tetrahedron Lett. I993,34 7317. 192 Y.-J. Chen C.-M. Chen and W.-Y. Lin Tetrahedron Lett.1993,34 2961. 193 V. H.Rawal V. Krishnamurthy and A. Fabre Tetrahedron Lett. 1993,34 2899. 19A C.-K. Shan C.-Y. Shen T.-S. Jean R.-T.Chiu,and W.-H. Tseng TetrahedronLett. 1993,34,7641;K.S. Feldman H. M. Berven and P. H. Weinreb J. Am. Chem. SOC. 1993,115,11 364;J. W.Grissom T.L. Calkins and M.Egan J. Am. Chem. Soc. 1993,115,11 744. 19s F.-H. Wartenberg H. Junga and S. Blechert Tetrahedron Lerr. I993,34 5251. 196 J. E.Brumwell,N. S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34,1215;D. F.Taker Y.Wang and S. J. Stacel Tetrahedron Lett. 1993,34,6209. 197 J. M.Aurrecoechea and A. Fernandez-Acebes Tetrahedron Lett. 1993,34,549;T.Gilhann Tetrahedron Lett. 1993,34,607;S. Arseniyadis D.V. Yashunsky M.Dorado R.B. Alves E.Toromanoff,L.Toupet and P. Poitier Tetrahedron Lett. 1993,34 4927. 198 J. Cossy and A. Bouzide Tetrahedron Lett. 1993,34 5583. I99 J. Cossy and A. Bouzide J. Chem. SOC.,Chem. Commun. 1993,1218. 200 J T. Negri T. Monvick J. Doyon P.D. Wilson E.R. Hickey and L.A. Paquette J. Am. Chem. Soc. 1993,115,12 189. 20I B.A. Anderson J. Bao T. A. BrandvoId C.A. Chatlener W. D. Wulff Y.-C. Wu Xu and A. L. Rhcingold J. Am. Chem. Soc. 1993,115 10671; M.Yarnaguchi M. Sehata A. Hayashi and M. Hirama J. Chem. Soc. Chem. Commun. 1993,1708;3. M.Trost and Y.Shi J. Am. Chem.Soc. 1993,115,9421;K. Takeda M. Fujisawa T. Makino E. Yoshii and K.Yamaguchi J. Am. Chem. Soc. 1993 115,9351; T.J.Katz A. M. Gilbert M. E. Huttenloch G. Min-Min and H. H. Brintzinger Tetrahedron Lett.1993,34,3551; H. Pellissier A. Tubul and M. SanteIli Tetrahedron Lert. 1993,34 827;M.Toyota Y.Nishikawa K. Motoki N.Yashida and K. Fukumoto Tetrahedron Lett. 1993,34,6099;X.-M. Wu K.Funakoshi and K. Sakai Tetrahedron Lett. 1993,34 5927; H.-J. Knoller and R. Graf Tetrahedron Lett. 1993,34,4765. 202 H. Stadtmiiller R.Lentz C. E. Tucker T. Stiidemann W.Darner and P. Knochel J. Am. Chem. Soc. 1993,115,7027. 203 C.Meyer I. Marek G. Courternanche and J.-F. Normant Tetrahedron Lett. 1993 34 6053;H. Stadmiiller C. E. Tucker A. Vaupel and P. Knochel Tetrahedron Lett. 1993,34 791 1. 204 H. Ito Y. Motoki T. Taguchi and Y.Hanzawa J. Am. Chem. Soc. 1993,115,8835. 20 5 S.E.Berk R.B. Grossman and S.L. Buchwald 1.Am. Chem. Soc. 1993 115,4912. Aliphatic and Alicyck Chemistry km@ (ref 193) OH 3:1 Reagents i Bu,SnH AIBN srbeme87 P.Quayle i-4*4 eSipi3 + 97% 0 0 0 (ref 201) 1 97% -'s PMBO PMBO \ OT3DMS Reagents i TiCl, -78 "C;ii Pd,(dba), CHCL, KOAc BDEDA Scheme 89 Reagents i Zn Et,O; ii E' Scheme 90 i ii (ref 204) Reagents i 'Cp,Zr'; ii BF,-UEt Scheme 91 (ref 205) Reagents i 'Cp,Ti',R"C; ii H,Ot Scheme 92 reaction which has aIso enjoyed continuing interest .*" 5-Endo-dig-cyclizationzo7 of acetylenic ethers promisesto provide a rapid entry into '06 S.-e. Yoo S.-H. Lee,N.Jeong and I. Cho Tetrahedron Letr. 1993,34,3435; M. E. Kraft I. L. Scott S.H. Romero S. Feibelmann and C. E. Van Pelt J. Am.Chem. SOC. 1993,115,7199.207 R. L. Funk G. L. Bolton K. M. Brummond K.E. Ellstead and J. B. Stallman J. Am. Chem. SOC. 1993 1IS,7023. Aliphatic and Alicyclic Chemistry a variety of cyclopentane derivatives as does the Enders''' diastereoselective intramolecular conjugate addition of SAMP-RAMP enolates to a,fl-unsaturated esters. FinaIly,'09 thermal reaction of a,w-bis-diazoketones affords a general synthetic route to both cyclohexenones and cyclopentenone derivatives (Scheme 93). (ref 209) %heme 93 Cyc1ohexanes.-The use of a-santonin in natural product synthesis has been re-viewed.210The 65th birthday ofthe Dieh-Alder reaction was celebrated in style with a review*' on recent developments and the numerous examples of synthetic applica- tions of existing and novel diene-dienophile partners (Figure 1).2' The use of tandem intramolecular Diels-Alder reactions (TIMDA) is a potentially powerful strategy if the timing of sequential cycloadditions can be contrdled.Synthetic applications of this process have appeared this year which shows that this is achievable (Scheme 94)'l 3,2'4 The development of effective catalysts for asymmetric intermolecular Diels-Alder reactions continues to be a major preoccupation2'5*216 and some examples are illustrated in Scheme 95. Of particular interest are the reports of and Sanders;2 the latter is concerned with the development of chemically engineered enzyme mimics which enhance both the rate of Diels-Alder reactions and promote D. Enders H.J. Scherer and J. Runsink Chem.Ber. 1993 126 1929. '09 S.Ohira M. Moritani T. Ida and M. Yamato J. Chem. Soc. Chem. Commun. 1993,1299; K.Nakatani K. Takada Y.Odagaki and S. Ism J. Chem. Soc. Chem. Commun. 1993 556. 'lo A. K. Bancjee W. J. Vera and N. C. Gonzalez Tetrahedron 1993 49 4761. 211 K. Krohn Angew. Chem. lnt. Ed. Engl. 1993 32 1582. '"(a)H. J. Reich I. L. Reich K. E. Yelm J. E. Holladay and D. Gschneider J. Am,Chem. SOC. 1993,115 6625; (bf B.L. Williamson P.J. Stang and A. M. Arif J. Am. Chem. Soc. 1993,115,2590; (c) M. E.Jung, C.N.Zimmerman C.T. Lowen and S.I. Khan Tetrahedron Lett. 1993,34,4453; (d)M. Nakagawa Y. Torisawa T. Hosaka K.Tanabe T. Da-te K Okamura and T.Hino Tetrahedron Lett. 1993,34,4543; (e)V. H. Rawal C. Michoud and R.F. Monstel J. Am. Chem. Soc. 1993,115,3030; u> M.C. Clasby D. Craig and A. Marsh Angew.Chem. Inr. Ed. Engl. 1993,32,144; @) Y.-F. Lu and A. G. FalIis Tetrahedron Lett. 1993,34,3367; (h)D. A. Singleton K.Kim and J. P. Martinez Tetrahedron Lett. 1993,34,3071; (i) J. Barluenga F. Aznar,C. Valdes A Martin S. Garcia-Granda and E. Martin J. Am. Chem.SOC. 1993 115,4403;0)J.-P. Duldre V. Agati and R. Faure J Chem. Soc. Chem. Commun. 1993 270; (k) J. E. Kerrigan P.G. McDougal and D. VanDerver TerralredronLett. 1993 34 8055; (1) J. Martynow M. Dimitroff and A.G. FaIlis Tetrahedron Lett. 1993 34 8201; (m)J.P. Konopelski and R.A. Kasar Tetrahedron Len. 1993,34,4587; (n)A. Kambuchi N. Miyaura and A. Suzuki. Tetrahedron Lett. 1993 34,4827. 2'3 I. E. Marko P. Seres G. R. Evans and T. M.Swarbick Tetrahedron Lett.1993 34 7305. D. R. Goldberg J. A. Hansen and R.J. Giguere Tetrahedron Lett. €993 34 8003. 'I5 E.J. Corey and Z. E.Wang Tetrahedron Lett. 1993 34,4001. 'Is K. Ishihara 0. Gao and H. Yamamoto Tetrahedron Lett. 1993 34 6917. 'I7 D.C. Braddock 3. M. Brown and P.Guiry J. Cfiem.Soc. Chem. Commun. 1993 1244. 'I8 C. J. Walter H. L.Anderson and J. K. Saunders J. Chem. Soc. Chem. Commun. 1993,458. 142 P. Qtcayle (ref 212) Figure I (ref 21 4) Reagents i BF,-OBt, CH,CI, 0°C exo-edu selectivity {Scheme 96). Photo-induced Diels-Alder reactions are also reported to be em elective.^'^ Free radical reactions have been exploited to good effect in the synthesisofa range of cyclohexane-contining systems (Scheme 97),2’* as have a variety of tandem Michael-typ reactions22* (Scheme 98).Harman222 has developed a novel dearomatization procedure via the intermediacy of osmium(rI)(q2-aryl)complexes (Scheme 99). This ‘19 B. Pandey and P. V. Dalvi Angew. Chem. Inr. Ed. Engl. 1993 32. 1612. D. L.J. Clivt and M.H.D. Postcma J. Chem. Soc. Chem. Commun. 1993,429. ’”C. Kuroda Y. Ohnishi and J.Y. Satoh,Tetrahedron Lett. f993,34 2613. 222 J. Gonzalez M. %bat and W. D. Harman J. Am. Chem. Sw. 1993 115,8857. 143 0+ 23 OO 0 (ref2I5) (ref 216) 0+Me++ OMe -.Q‘ +q0Me(d218) 0 S OMe 0 OMe 94 6 (BF-@E4:% (EJC13) tZ) Reagents i Lewis Acid CH,CI Schem% li SePh Reagents i Ph,SnH BEt, ‘air’ scbem97 0 8:l Reagents i TiCI, CHI,CI scbeme98 144 P.Quayle 0 (ref 222) 3 0 Reagents i TBSOTf PriNEt MeCN Scheme 99 methodology could have many synthetic applications; further developments are anticipated in this area. Medium Rings.-The synthesis of medium-sized ring systems has recently been extensively reviewed223 as have approaches to the highly functionalized enediyne family of antitumour agents." 223 C. J. Roxburgh Tetrahedron,1993,49 10 749.