5 Aliphatic and Alicyclic Chemistry By PETER QUAYLE Department of Chemistry University of Manchester Manchester M 13 9PL UK 1 Introduction The application of modern synthetic methodology to the synthesis of complex natural products as exemplified by the total synthesis of bleomycin A (l),' swinholide A (2), zaragozic acid (3)3 and calyculin A (4),4has been truly outstanding this year. No doubt the limits of synthetic methodology will be further stretched in the near future by even more complex targets such as maitotoxin (5),5the largest natural non-polymer product yet isolated. The validation of synthetic methodology in this context is however coming under attack as demonstrated by a perceptible but real change in long term research goals of many groups.The rapid screening of potential medicinal agents by pharmaceutical companies has brought about the requirement for the development of automated synthetic sequences which enable the synthesis of chemical libraries. The development of such processes has begun to challenge the ingenuity of synthetic chemists as evidenced by the rapid growth of publications in this field.6 Recent advances in solid-phase oligosaccharide and glycopeptide synthesis7 will doubtless further blurr the boundaries between molecular biology and organic chemistry as multidisciplinary teams probe fundamental biological processes such as cellkell recognition phenomena.' The interplay between molecular biology and synthetic organic chemistry is also much in evidence as demonstrated by the use of catalytic antibodies as standard synthetic reagentsg and in approaches to the chemical synthesis of artificial enzymes." All of these developments are quite apt given that this year marks the centennial anniversary of Fischer's 'lock and key' paradigm for enzyme specificity.' One can envision that a similar interplay between synthetic chemistry and 1 D.L. Boger S. L. Colletti T. Honda and R. F. Menezes J. Am. Chem. SOC. 1994 116 5607. 2 I. Paterson K. Yeung R. A. Ward J.G. Cumming and J. D. Smith J. Am. Chem. SOC. 1994 116,9391. 3 E.M.Carreira and J. Du Bois J. Am. Chem. SOC. 1994 116 10825. 4 N. Tanimoto S. W. Gerritz A. Sawabe,T. Noda S.A. Filla and S. Masamune Angew. Chem. Int. Ed. Engl. 1994 33 673. S M. Murata H. Naoki S.Matsunaga M.Satake and T. Yasmuto J. Am Chem. SOC. 1994 116 7098. 6 M. Famulok and D. Faulhammer Angew. Chem. Int. Ed. Engl. 1994,33,1332; K. Burgess A. I. Liaw and N. Wang J. Med. Chem. 1994 37 2985. 7 M. Schuster P. Wang J.C. Paulson and C. Wong J. Am. Chem. SOC. 1994 116 1135. 8 A. Giannis Angew. Chem. Int. Ed. Engl. 1994 33 178. 9 K. Shokat T. Uno and P.G. Schultz J. Am. Chem. SOC. 1994 116 2261. 10 R. Breslow Red. Trav. Chim. PQJJS-EQS,1994 113 493; A.M. Reichwein W. Verboom and D.N. Reinhoudt ibid. 1994,113,343; L. G. Mackay R.S. Wylie and J. K. Sanders J.Am. Chem. SOC.,1994,116 3141. 11 F. W. Lichtenthaler Angew. Chem. Int. Ed. Engl. 1994 33 2364. 125 126 Peter Quayle materials science could lead to the development of new materials possessing useful bulk properties.Nevertheless the development of ‘new’ synthetic methodology continues to rise exponentially as witnessed by the number of review articles published annually. A broad range of topics has been discussed in a newly launched review journal which J.S. Miller and A. J. Epstein Angew. Chem. Int. Ed. Engl. 1994 33 385. Aliphatic and Alicyclic Chemistry 127 should have wide appeal to the community at large.I3 The development of new synthetic routes to a variety of natural and unnatural products of biological interest (including vitamin D3,14C-aryl glycosides,’ anticancer drugs,16 antitumour prod- rugs,17 anti-HIV agents,’ s oligonucleosides l9 glycoconjugates,20 peptidomimics,21 protein chemistry,22 molecular recognition phenomena,23 antimalarial^,^^ angioten-sin antagonist^,^ carbocyclic nucleosides,26 a-and p-amino acid^,^'.^' and enediyne antibiotic^^^) has attracted in-depth coverage this year.The study of enzyme-mediated biochemical pathways3’ and applications of enzymes in organic synthesis31 continue to be fertile areas of investigation as does the study of molecular recognition processes32 and supramolecular chemistry3 in general. The use oforgan~metallics,~~ free radicals,35 and carb be no id^'^^ in organic synthesis is now de rigueur. The impressive advances in asymmetric synthesis37 and the specific challenges which such processes present upon conversion to large-scale reactions38 have been Contemporary Organic Synthesis Royal Society of Chemistry Cambridge UK.l4 H. Dai and G. H. Posner Synthesis 1994 1383. lS C. Jaramillo and S. Knapp Synthesis 1994 1. l6 S.P. Gupta Chem. Rev. 1994 94 1507. l7 L.S. Jungheim and T.A. Shepherd Chem. Rev. 1994 94 1553. H. Laatsch Angew. Chem. Int. Ed. Engl. 1994 33,422. l9 W. J. Stec and A. Wilk Angew. Chem. Int. Ed. Engl. 1994 33 709. 2o T. Ogawa Chem. SOC.Rev. 1994 23 397. 21 R. M. J. Liskamp Angew. Chem. Int. Ed. Engl. 1994,33,305; R. M. J. Liskamp Red. Trav. Chim. Pays-Bas 1994 113 1. ” ‘3rd International Symposium on Protein Structure-Function Relationships’ Pure and Applied Chemistry 1994 66 1. 23 e.g. Y. Kuroda and H. Ogoshi Synlett 1994 319. 24 W. Zhou and X. Xu,Acc. Chem. Res. 1994 27 211. 2s D. Middlemiss and S. P. Watson Tetrahedron 1994 50 13 049.L. Agrofoglio E. Suhas A. Farese R. Condom S. R. Challand R. A. Earl and R. Guedj Tetrahedron 1994 50 10611. 27 R. 0.Duthaler Tetrahedron 1994 50 1539. 28 D.C. Cole Tetrahedron 1994 50 9517. 29 Tetrahedron 1994 50 1296. 30 V. Ullrich and R. Brugger Angew. Chem. Int. Ed. Engl. 1994,33 191 1; U. Pindur and G. H. Schneider Chem. SOC.Rev. 1994,23,409;T. A. Spencer Acc. Chem. Res. 1994,27,83;A. I. Scott Tetrahedron 1994 50 13315. 31 L. Kvittingen Tetrahedron 1994,50,8253;P. Besseand H. Veschambre ibid. 1994,50,8885;H. Waldmann and D. Sebastian Chem. Rev. 1994,94 911. 32 C. A. Hunter Chem. SOC. Rev. 1994,23 101 ;I. D. Kuntz E. C. Meng and B. K. Shoichet Acc. Chem. Res. 1994 27 117. ’’ V.V. Kane W.H. De Wolf and F. Bickelhaupt Tetrahedron 1994 50 4575; ‘Cyclophanes’ Top.Curr. Chem. 1994 172 1; T. Jorgensen T. K. Hansen and J. Becher Chem. SOC.Rev. 1994 23 41. 34 H. Butenschon Angew. Chem. Int. Ed. Engl. 1994,33,636;A. de Meijere and F. E. Meyer ibid. 1994,33 2379; C. Lambert and P. von R. Schleyer ibid. 1994,33,1129;A. Togni and L. M. Venanzi Angew. Chem. Int. Edn. Engl. 1994,33,497;‘OMCOS-7’ Pure and Applied Chemistry 1994,66,1415 et seq.; T. J. Collins Acc. Chem. Res. 1994,27,279; E. Negishi and T. Takahashi Acc. Chem. Res. 1994,27 124; Tetrahedron 1994 50 285; D. J. Burton Z. Yang and P.A. Morken ibid. 1994 50 2993; ibid. 1994 50 5845. 35 J. Iqbal B. Bhatia and N. K. Nayyar Chem. Rev. 1994 94 519; A. Albini M. Mella and M. Freccero Tetrahedron 1994 50 575. 36 A. Padwa and D. J. Austin Angew.Chem. Int. Ed. Engl. 1994,33 1797; H. Schmalz ibid. 1994,33,303;T. Ye and M.A. McKervey Chem. Rev. 1994 94 1091. 37 V.K. Aggarwal Angew. Chem. Int. Ed. Engl. 1994,33 175; T. Bach ibid. 1994,33,417; F. Effenberger ibid. 19994 33 1555; G. Kaupp ibid. 1994 33 728; H.C. Kolb M.S. VanNieuwenhze and K.B. Sharpless Chem. Rev. 1994,94,2483; C. S. Poss and S. L. Schreiber Acc. Chem. Res. 1994,27,9;W. Adam and M. U. Richter Acc. Chem. Res. 1994,27,57;T. G. Grant and A. I. Meyers Tetrahedron 1994,50,2297; Tetrahedron 1994 50 4235. 38 B. Cornils W.A. Herrmann and M. Rasch Angew. Chem. Int. Ed. Engl. 1994 33 2144; S. Kotha Tetrahedron 1994 50 3639. 128 Peter Quayle discussed in some detail. Despite these advances the use of non-racemic intermediates from the ‘chiral pool’ still remains an attractive proposition for many synthetic sequence^.^' As stated above the art of organic synthesis has in certain quarters become an undervalued currency those non-believers should consult the recent reviews on paclitaxel (Tax01)~’ and alkaloid4’ synthesis for rejuvenation.In a similar vein the chemistry of C6,and related systems has caught the imagination of theoretical and synthetic chemists alike as indicated by the frequency of reviews in this area.42 The current awareness of the synthetic community to environmental problems has evoked numerous responses including the investigation of aqueous reaction media,43 ~onochemical~~ and electrochemical technique^,^' and the solid state46 for conducting organic reactions.Toxicological properties of organochlorine compounds have been reviewed;47 curiously a recent study suggests that in seals at least that there is a preferential accumulation of ( + )-a-HCH in the brain:* 2 Aliphatic Chemistry General.-The theory of coarctate transition states has been re~iewed.~’ Overviews of hetero Diels-Alder reactions” including asymmetric variants,’ halohydrin~,’~ furan -+1,4-dicarbonyl inter conversion^,^ benzotria~oles,~~ MVP-type redox reaction^,^ a-oxoketene~,’~ and a refreshingly critical discussion of the now-fashionable Grif- fith-Ley TPAPS7 oxidant have appeared. Reductions.-Asymmetric hydrogenations are now becoming widespread in synthetic appeal. For example the DuPHOS-Rh system has been used to good effect in the synthesis of uncommon amino acids with uniformly high levels of asymmetric induction (>98.5% e.e.).” The Dupont have recently disclosed that either D-or L-ar-amino acids may be prepared by catalytic asymmetric reduction of the corresponding dehydroamino acids; again the degree of induction is high (96-97% e.e.) but more importantly the sense of induction is controlled by an easy modification of the chiral modifier which in this case was D-glucose.Related 39 e.g.,D. Tanner Angew. Chem. Int. Ed. Engl. 1994,33,599;H. Redlich Angew. Chem. Int. Ed. Engl. 1994 33 1345. 40 K.C. Nicolaou and D.J. Austin Angew. Chem. Int. Ed. Engl. 1994 33 15. “ U. Beifuss Angew. Chem. Int. Ed. Engl. 1994 33 1144. 42 e.g. E.C. Constable Angew. Chem. Int. Ed.Engl. 1994 33 2269. I3 A. Lubineau J. Auge and Y. Queneau Synthesis 1994 741. I4J. M. Pestman J. B. F.N. Engberts and F. deJung Red. Trau. Chim. Pays-Bas. 1994 113 533. 45 J. Yoshida Top. Curr. Chem. 1994 170 39. N. B. Singh R.J. Singh and N. P. Singh Tetrahedron 1994 50 6441. D. Henschler Angew. Chem. Int. Ed. Engl. 1994 33 1920. 48 K. Moller C. Bretzke H. Huhnerfuss R. Kallenborn J. N. Kinkel J. Kopf and G. Rimkus Angew. Chem. Int. Ed. Engl. 1994 33 882. 49 R. Herges Angew. Chem. Int. Ed. Engl. 1994 33 255. J. Streith and A. Defoin Synthesis 1994 1107. 51 H. Waldmann Synthesis 1994 535. 52 C. Bonini and G. Righi Synthesis 1994 225. 53 G. Piancatelli J. Auge and Y. Queneau Synthesis 1994 867. 54 A. R. Katritzky X. Lan and W. Fan Synthesis 1994 445.55 C. F. de Graauw J.A. Peters H. v. Bekkum and J. Huskens Synthesis 1994 1007. 56 C. Wentrup W. Heilmayer and G. Kollenz Synthesis 1994 1219. ” S.V. Ley J. Norman W. P. Griffith and S. P. Marsden Synthesis 1994 639. 58 M.J. Burk J. R. Lee and J. P. Martinez J. Am. Chem. SOC. 1994 116 10847. 59 T.V. RajanBabu T. A. Ayers and A. L. Casalnuovo J. Am. Chem. SOC. 1994 116,4101. Aliphatic and Alicyclic Chemistry 129 reductions of olefins,60 enamines,6' and ketones6 merely underscore the universal appeal of this approach to EPC synthesis (Scheme 1). Buchwald has developed a general approach to optically enriched amines and alcohols via the hydrosilylation of enamine~,~~ and ketones6' in conjunction with chiral titanocene catalysts irnine~,~~ (Scheme 2).Asymmetric borane reductions can provide functionalized alcohols with good/excellent levels optical purity66 (in certain cases >99% e.e.); one must always be aware however of the potential substrate dependence of these reductions upon the sense of induction67 (Scheme 3). Oxazaborilidine-mediated ketone reductions again have been used extensively for the enantioselective synthesis of alcohols.68",68b A highlight in this area is the observation by Heimstra and Speckamp that desymmetrization of meso-imides is possible using these reagents affording the corresponding imides with reasonable levels of optical purity (between 76% and 87% e.e.)69 (Scheme 4). Bullock has developed a highly efficient method for the ionic reduction of hindered 01efins.~' Oxidations.-The use of dimethyldioxirane (DMD) and its analogues as versatile oxidizing agents continues to gain acceptance.The major advantages of DMD over more conventional reagents such as peracids is that the by-product of the oxidation sequence acetone is relatively innocuous and that in many cases the oxidation reaction takes place under neutral mild reaction conditions. There are numerous examples of the use of this reagent in synthetic sequences this as depicted below (Scheme 5). Of note is the observation that oxidation of cyclohex-2-en-1-01 and its derivatives is uniformly trans-selective with this reagent78 (Scheme 6). Phot~lysis~~ of the diazo compound (6) in oxygen-saturated CFC1 at 183 K afforded the isolable dioxirane (7) in 55% yield as a crystalline solid (m.p.62-64 "C).Dioxirane (7) slowly decomposes to the ester (8) at the rate of 10% conversion per day (Scheme 7). Bolm"" has developed a Baeyer-Villiger-type lactone synthesis which utilizes molecular oxygen (at 1 atm. pressure) in conjunction with a variety of copper(I1) complexes. Incorporation of C,-symmetric ligands around the metal centre induces optical yields 6o J.N. Freskos S. A. Laneman M. L. Reilly and D. H. Ripin Tetrahedron Lett. 1994 35 835. 61 J. D. Armstrong 111 K. E. Eng J. L. Keller R. M. Purick F. W. Hartner W.-B. Choi D. Askin and R. P. Volante Tetrahedron Lett. 1994 35 3239. 62 D. M. Garcia H. Yamada S. Hatakeyama and M. Nishizawa Tetrahedron Lett. 1994 35 3325. 63 N. E. Lee and S.L. Buchwald J. Am. Chem.Soc. 1994 116 5985. 64 C. A. Willoughby and S. L. Buchwald J. Am. Chem. Soc. 1994 116 11 703. 65 M.B. Carter B. Schiott A. Gutierrez and S.L. Buchwald J. Am. Chem. Soc. 1994 116 1167. 66 D. A. Beardsley G. B. Fisher C. T. Goralski L. W. Nicholson and B. Singram Tetrahedron Lett. 1994,35 1511. 67 P. V. Ramachandran B. Gong and H. C. Brown Tetrahedron Lett. 1994 35 2141. (a)R. Hett R. Stare and P.Helquist Tetrahedron Lett. 1994,35,9375;(b)G. J. Qualich J. F. Blake and T.M. Woodall J. Am. Chem. Soc. 1994 116 8516. 69 R. Romagnoli E. C. Roos H. Hiemstra M. J. Moolnaar N. Speckamp B. Kaptein and H. E. Schoemaker Tetrahedron Lett. 1994 35 1087. 70 R.M. Bullock and J.-S. Song J. Am. Chem. Soc. 1994 116 8602. 71 J.T. Link S.J. Danishefsky and G. Schulte Tetrahedron Lett.1994 35 9131. 72 J.T. Link and S.J. Danishefsky Tetrahedron Lett. 1994 116 9135. 73 P. Bovicelli P. Lupattelli D. Fracassi and E. Mincione Tetrahedron Lett. 1994 35 935. 74 T. K. Park J. M. Peterson and S.J. Danishefsky Tetrahedron Lett. 1994 35 2671. 75 J. K. Crandall and T. Reix Tetrahedron Lett. 1994 35 2513. 76 X. Wang B. Ramos and A. Rodriguez Tetrahedron Lett. 1994 35 6977. 77 D. Kuck A. Schuster C. Fusco M. Fiorentino and R. Curci J. Am. Chem. Soc. 1994 35 2375. 78 M. Kurihara S. Ito N. Tsutsumi and N. Miyata Tetrahedron Lett. 1994 35 1577. 79 A. Kirschfeld S. Muthusamy and W. Sander Angew. Chem. Int. Ed. Engl. 1994 33 2212. (a)C.Bolm G. Schlingloff and K. Weickardt Angew. Chem. Int. Ed. Engl. 1994,33,1848; (b)G.-Z. Wang U. Andreasson and J.E. Backvall Tetrahedron Lett. 1994 35 1037. 130 Peter Quayle mH:rIMe (R R) -Pr -DuPHOS -Rh* CH;:? (ref 58) H2 Br Br >98.5% e.8. 0.05-0.1d% ‘qNHCoMe [LRH (COD)]Sb~ (ref 59) 30-40pSi C02Me H2 / THF 97.2% 8.e. Me 0 Me [Ru(R -BINAP) CIA * R0V!O2H (ref 60) MeOHI NEt3 155 “c H2 (S)-BINAP * (ref 61) RuCl2 70% (82%e.e.) Y a:Bw Y H H cgHlg% (ref 62) ((R)-BINAP] RuCl2 H2(1OOatm);(0.01 q) cgHlg5 OMe OMe MeOH; tt;40hr 100% yield (99%e.e.) Scheme 1 Aliphatic and AlicycEic Chemistry i -iii I (ref 63) R*Me 89 -96% e.e. vi -vii \ i,k-v L(.. R2 RR,, R~AN-R3 H 65-90% yield 67-88% yield (53-99% e.e.) (1 2 -97% e.e.) (ref64) (ref 65) Reagents i 2 eq.BuLi; ii 2.5 eq. PhSiH,; iii H,; iv Me,SiO[Me(SiO)H],SiMe; v TBAF; vi IOmol% Bu"Li; vii 15mol% PhSiH,; viii H, R'R2C=NR3 Scheme 2 in the region of 50-70% (Scheme 8). Clearly this methodology has many potential applications provided that the optical yields can be improved. A related methodsob for the oxidation of secondary alcohols to ketones has also appeared (Scheme 9). Sulfoxides are useful synthetic intermediates a number of reports have appeared this year detailing new or improved methods for their The use of a catalytic quantity of an optically pure sulfonylimine in conjunction with stoichiometric hydrogen peroxide as a reoxidant is particularly appealing.84 The development of catalytic oxidizing procedures using hydrogen peroxide as a reoxidant is a popular theme,85 as is the use of chemoenzymatic oxidation^^^-'^ (Scheme 10).W. B. Jennings M. J. Kochanewcz C. J. Lovely and D. R. Boyd J.Chem.SOC.,Chem. Commun. 1994,2569. 82 J. F. Bower and J. M. J. Williams Tetrahedron Lett. 1994 35,71 11. 83 K. M. Poss S. T. Chao E. .M. Gordon P. J. McCann D. P. Santafianos,S.C. Traeger R. K. Varma and W. N. Washburn Tetrahedron Lett. 1994 35,3461. 84 P. C. Bulman Page J. P. Heer D. Bethell E. W. Collington and D. M. Andrews Tetrahedron Lett. 1994 35,9629. '' W. P. Griffith A. M. Z.Slawin K. M. Thompson and D. J. Williams J. Chem.SOC.,Chem. Commun. 1994 569. 86 C.R.Johnson L. S. Harikrishnan and A. Golebiowski Tetrahedron Lett. 1994 35,7735. " C. R. Johnson A. Golebiowski M. P. Braun and H.Sundram Tetrahedron Lett. 1994 35 1833. " T. Hudlicky J. Rouden H. Luna and S. Allen J. Am. Chem. SOC. 1994 116 5099. 89 D. R.Bayd,N. D. Sharma S.A. Barr H. Dalton J. Chima G. Whited and R. Seemayer,J. Am. Chem.SOC. 1994 116 1147. 132 Peter QuayEe 2 &NR2 -L c'B(-&)2 81 -88% yieM (75-99% e.e.) (ref 66) 90% 8.8. OMe OH I 90% 8.8. (R) 92%e.e. (S) (ref 67) Reagents i rt 36 h; ii NaOH H,O,; iii H,O+ Scheme 3 Aliphatic and Alicyclic Chemistry 0.1 eq ?*F:ph 0.6 BH3- THF 8-0 i CHI Ph-0 c02Me 95% Ph 85%/NaHITMF cph/ 1 ""Wo+Ph Ph-O@' C02Me THF; A H HO Serevent' (ref 68a) Ph AcO Ph H'B-o (ref 69) 0soc-k8.DMw*Amy;Ac EH3.THF 0 ' ' Ph Ph 51%; 87%8.8.Scheme 4 134 Peter Quayle Ph’ 0% P H i NaH; CHGN iii. CHGN; R to refiux 42% (ref 72) 0 Reagents ii TBAF THF; iii NaH BnBu DMF Scheme 5 Aliphatic and Alicyclic Chemistry (ref 73) Bno F (ref 74) hi NaH BnBr DMF (72%) 0-Bn 0 (ref 75) T~NH' 56% TS'. - (ref 76) (ref 77) -20 oc 98% Scheme 5 (cont.) 6I_ 6,. 6 Peter Quayle + 0 trans :cis 77 23 OTBDMS OTBDMS 93 7 Reagents i oxone@ 2,6-dimethylcyclohexanone Scheme 6 Scheme 7 Synthetic applications of the Sharpless asymmetric dihydroxylation protocol attest to its fundamental importance in asymmetric ~ynthesis’~-~~ (Scheme 11).A particular-ly topical application of this methodology is that reported by Hawkinsg3 concerning the kinetic resolution of C70 C76 and CS4.Hale94 has observed anomalous stereochemical behaviour in the oxidation of 1,l-disubstituted alkenes with this system; such reports will add further interest to the mechanistic debate concerning these reaction^.'^ Jacobseng6 asymmetric epoxidation has also spawned a variety of 90 T.Nakarnura N. Waizumi Y. Horiguchi and I. Kuwajima Tetrahedron Lett. 1994 35 7813. 91 K.P. M. Vanhessche Z.-M. Wang and K. B. Sharpless Tetrahedron Lett. 1994 35 3469. 92 H.Wagner and U. Koert Angew. Chem. Int. Ed. Engl. 1994,33,1873. 93 J. M. Hawkins M. Nambu and A. Meyer J. Am. Chem. SOC. 1994,116,7642. 94 K.J. Hale S. Manaviazar and S. A. Peak Tetrahedron Lett. 1994 35 425. 95 A. Veldkamp and G.Frenking J. Am. Chem. SOC. 1994,116,4937;H.Becker P.T. Ho H.C. Kolb S. Loren P.-0. Norrby and K. B. Sharpless Tetrahedron Lett. 1994 35 7315. 96 W.Zang N. H. Lee and E.N. Jacobsen J. Am. Chem. SOC. 1994,116,425. Aliphatic and Alicyclic Chemistry cat+ = cu 1 Scheme 8 1 021 N2 __._3 i\ 0.5% A BU' BU' 00% 0 Scbeme 9 synthetic application^^'-^^ (Scheme 12). Kende' O0 has reported that diphenylphos- phinic anhydride mediates a high-yielding conversion of alkenes to epoxides whilst Aggarwal has developed a novel catalytic cycle for the synthesis of epoxides from aldehydes and sulfur ylides' O1 (Scheme 13). Olefins and Acetylenes.-The titanium-induced reductive coupling of aldehydes and ketones (McMurray reaction) provides a general method for the synthesis of olefins.97 J. F. Low and E.N. Jacobsen J. Am. Chem. SOC. 1994 116 12 129. 98 S. D. Rychnovsky and K. Hwang Tetrahedron Lett. 1994,35 8927. 99 S. Chang R. M. Heid and E. N. Jacobsen Tetrahedron Lett. 1994,35 669. loo A.S. Kende P. Delair and B. E. Blass Tetrahedron Lett. 1994 35 8123. V. K. Aggarwal H. Abdel-Rahman R. V. H. Jones H. Y. Lee,and B. D. Reid J. Am. Chem.SOC.,1994,116 5973. 138 Peter Quayle 8 S ArO 'Me ArO"Me (R) (ref 81) 34% 8.8. H (d.8. = 99 :1) 32% (ref 86) 90% (ref 87) Q -b TBSd Mannojirimyun (ref 89) Br)$-,& Bra:: OH >98% 8.8. Reagents i ButO2H Ti(OPr'), L-DET CH,Cl, -20 "C;24 h; ii isoprenyl acetate Pseudomonas cepacia lipase; iii Pseudomans putida 39D; iv H, Pd-C MeDH Scheme 10 Aliphatic and Alicyclic Chemistry OPiv OPW (ref 90) 00% 94%e.e.(R) (ref 91) 98% (ref 92) Reagents i OsO (1 rnol%) DHDQ-PHN K,Fe(CN), K,CO, Bu'OH H,O; ii MeN(H)CH,CH,N(H)Me Scheme 11 However a reinvestigation of the homocoupling of acetophenone conclusively demon- strates that the major product of this reaction is the 2 isomer and not the E isomer as originally claimedlo2 (Scheme 14). This reappraisal may be general for those couplings leading to tetrasubstituted double bonds. A general approach to the synthesis of 2 iodo-olefins using a-iodoalkyl ylides has many potential synthetic applications' O3 (Scheme 15). The syn elimination of hypoiodous acid from iodoso compounds leading to olefins was reported by Reich in 1978.Unfortunately this methodology has been somewhat upstaged by the use of related selenoxide/sulfoxide eliminations although application of this reaction in a real synthetic context by Fuchs clearly demonstrates the synthetic potential of this procedurelo4 (Scheme 16). In a related context the Ramberg-Backlund reaction has enjoyed a resurgence in interest of late as illustrated by its application in Trost's synthesislo5 of (+)-solamin (Scheme 17). lo2 P.G. Anderson Tetrahedron Lett. 1994 35 2609. '03 H. Chen T. Wang and K. Zhao Tetrahedron Lett. 1994 35 2827. lo4 S. Kim and P. L. Fuchs Tetrahedron Lett. 1994 35 7163. lo' B.M. Trost and Z. Shi J. Am. Chem. SOC.,1994 116 7459. 140 Peter Quayle OAC (ref 98) 0 0 35% 8.8.PI' (ref 99) 0-Qo 70% 8.8. Scheme 12 Organometallic-based approaches to olefin synthesis are legion; among the most impressive of these are the Matin'06 and Pandit'O' approaches to manzamine A which utilize a Grubbs metathesis reaction for the construction of the E and D rings respectively (Scheme 18). Heck,'08-''o Stille 111,112 Suzuki,"3*114 and Trost"' lo6 S. F. Martin Y. Liao Y.Wong and T. Rein Tetrahedron Lett. 1994 35 691. lo' B. C. Borer S. Deerenberg H. Bieraugel and U. K. Pandit Tetrahedron Lett. 1994 35 3191. lo' T. Jeffery Tetrahedron Lett. 1994 35 3051. lo9 D. C. Horwell P. D. Nichols and E. Roberts Tetrahedron Lett. 1994 35 939. Y. Koga M. Sodeoka and M. Shibasaka Tetrahedron Lett.1994 35 1227. A. Degl'Innocenti A. Capperucci L. Bartoletti A. Mordini and G. Reginato Tetrahedron Lett. 1994,35 208 1. 'I2 H. K. Patel J. D. Kilburn G. J. Langley P. D. Edwards T. Mitchell and R. Southgate Tetrahedron Lett. 1994 35 481. G. Mazal and M. Vaultier Tetrahedron Lett. 1994 35 3089. 'I4 K.K. Wang and Z. Wang Tetrahedron Lett. 1994 35 1829. K. Togashi M. Terakado M. Miyazawa K. Yamamoto and T. Takahashi Tetrahedron Lett. 1994,35 3333. Aliphatic and Alicyclic Chemistry PhCHO + Me2S + Rh2(0Ac) N&HPh H.A; (ref 101) 3hr Ph 70% Scheme 13 (ref 102) Scheme 14 reactions continue to be used extensively for the coupling of unsaturated fragments; illustrative examples are given in Scheme 19. Note should be made of the Jeffery'" and Buchecker' results concerning the development of aqueous and heterogeneous modes of the Heck and Suzuki reactions respectively.Elucidation of the factors controlling palladium-mediated asymmeric allylation reactions continues to be an active area of research.' '' The synthesis of functionalized unsaturated systems continues to be a growth area which relies almost exclusively upon transition-metal- based strategies for implementation' 18-' 24 (Scheme 20); notable exception^'^^"*^ to '16 G. Marck A Villiger and R. Buchecker Tetrahedron Lett. 1994 35 3277. '" C. Breutel P. S. Pregosin R.Salzmann and A. Togni J.Am. Chem. SOC.,1994,116,4067; B. M. Trost and R.C. Bunt J.Am. Chem.SOC.,1994,116,4089; A. Gogoll,J. Ornebro H. Grennberg and J.-E.Backvall J. Am. Chem. SOC. 1994,116,3631; P. Sennhenn B. Gabler and G. Helmchen Tetrahedron Lett. 1994,35 8595. F. Babudri V. Fiandanese L. Mazzone and F. Naso Tetrahedron Lett. 1994 35 8847. '19 S. Ikeda and Y. Sato J. Am. Chem. SOC.,1994 116 5975. 142 Peter Quayle (ref 103) (2 -major) Reagents i Bu"Li; ii I,; iii NaN(TMS),; iv R'CHO Scheme 15 Scheme 16 R20-P1 i -(ref 105) so2qo >95% R201r3 Reagents i Bu'OK Bu'OH CCl Scheme 17 this generalization are depicted in Scheme 21. The development of new routes to vinylstannanes,' 26 ~inylsilanes,'~~ and optically enriched ally1 silanes' 28 continues to be the focus of much attention (Scheme 22). The Cinderella area of polyacetylene 120 N. Chatani T.Morimoto T. Muto and S. Murai J. Am. Chem. SOC. 1994 116 6049. 121 L. Deloux E. Skrzypczak-Jankun B. V. Cheesman M. Srebnik and M. Sabat J. Am. Chem. SOC.,1994 116 10302. 122 B. M. Trost and T.J. J. Miiller J. Am. Chem. SOC. 1994 116 4985. 123 D. C. Harrowven and H. S. Poon Tetrahedron Lett. 1994,35 9101. 124 M. Alami B. Crousse and G. Linstrumelle Tetrahedron Lett. 1994 35 3543. 125 (a)B. M. Trost and C. Li J.Am. Chem. SOC.,1994,116,3167; (b)E. Doris L. Dechoux and C. Mioskowski Tetrahedron Lett. 1994 35 7943. 126 D. M. Hodgson L. T. Boulton and G. N. Maw Tetrahedron Lett. 1994,35 2231. 127 F.J. Blanco P. Cuardrado A. Gonzalez F. J. Pulido and I. Fleming Tetrahedron Lett. 1994,35 8881; D. M. Hodgson and P. J. Comina ibid. 1994,35,9469; J. A. Soderquist and J.C .Colberg ibid. 1994,35 27. 128 Y. Landais D. Planchenault and V. Weber Tetrahedron Lett. 1994,35,9549; Y.Hatanaka K. Goda F. Yamashita and T. Hiyama ibid. 1994 35 7981. Aliphatic and Alicyclic Chemistry (ref 107) [cat] = [ Scheme 18 chemistry' 29 has stimulated much interest in developing new routes to functionalized mono- and bis-acetylene starter units' 30-' 33 (Scheme 23). Alkylation Reactions.-Carbonyl Alkylation Afdof and Related Reactions. Enan-tioselective deprotonation of mem cyclic ketones is now a well established asymmeter- ization reaction and has been used to good effect this year in the synthesis of tropane alkaloids' 34 (Scheme 24). The initial deprotonation reaction proceeded with ca. 90% e.e. when conducted in the presence of 0.5 equivalents of LiC1.The synthesis of lZ9 J. Anthony C. Boudon F. Diederich J. Gisselbrecht V. Grarnlich M. Gross M. Hobi and P. Seiler Angew. Chem. Int. Ed. Engl. 1994 33 763. 130 D. Grandjean P. Pale and J. Chuche Tetrahedron Lett. 1994 35 3529. 13' C. H. Cummins Tetrahedron Lett. 1994,35 857. 13' J. S. Yadav and V. P. Prahlad Tetrahedron Lett. 1994 35 641. 133 Y. Fukue S. Oi and Y. Inoue J. Chem. SOC. Chem. Commun. 1994 2091. 134 M. Majewski and R. Lazny Tetrahedron Lett. 1994 35 3653. 144 Peter Quayle I PhI + 7c0,w c Ph~co,Me (ref 108) 96% (ref 111) OBn OBn b-FF 85% (ref 116) Reagents:i 5% [Pd(OAc),(PPh,),] K,CO or Na,CO, PTC H,O MeCN; ii SnBu,R PdCl,(MeCN),; iii Pd(o) HOAc; iv Pd/C Ph,P Na,CO, 17 h 80°C Scheme 19 novel C,-symmetric vicinal diamines for use in such asymmetric deprotonation reactions has also been described'35 (Scheme 24).Cahiez has demonstrated that manganese enolates undergo highly regioselective alkylation reactions; importantly over alkylation does not appear to be a problem in these systems'36 (Scheme 25).Silver triflu~roacetate'~~ has been used to promote the alkylation of silyl enol ethers under K. Bambridge M. J. Begley and N. S. Simpkins Tetrahedron Lett. 1994 35 3391. 13' G. Cahiez B. Figadere and P. Clery Tetrahedron Lett. 1994,35,3065; G.Cahiez K. Chau and P. Clery ibid. 1994 35 3069. 13' P. Angers and P. Canonne Tetrahedron Lett. 1994 35 367. Aliphatic and Alicyclic Chemistry 145 (ref 118) JMe + Bu"-H + Ph-SnEt3 80% (ref 1 1 9) pi(') Ec(ref 120) E R-H + (ref 121) Me02C+Y \ 0 Meo2cwR' \v 2.9 1 Reagents i Bu"Li -78°C; ii Cp,Zr(H)CI; iii E'; iv EZ Scheme 20 146 Peter Quayle Me02C *Me C02Me >-CH30bC02Me (ref 125a) <C02Me c02Me (ref 125b) Reagents i 0.3eq.Ph,P cat. HOAc cat. NaOAc toluene 80 "C Scheme 21 I (ref 126) =*= ll,IW (ref 127) 55% yield 35% yield Reagents i Bu,SnCHBr, LiI CrCl, DMF-THF 25 "C; ii (PhMe,Si),CuCNH,; iii Ef; iv (TMS),SiH CH,Cl, Rh,( OAc) Scheme 22 Aliphatic and Alicyclic Chemistry (ref 130) (ref 131) (ref 132) R1-H + COP + R2Br -vl R'-Co# (ref133) Reagents i Ph,P CBr,; ii NEt,; iii NaHDMS THF -100 "C; iv Ph,P CCl,; v Li THF; vi K,CO, Cu' Ag' Scheme 23 mild conditions.The stereoselective alkylation of enolates and related intermediates possessing chiral auxiliaries has been used extensively in natural product syn-thesis' 38-144 (Scheme 26). The use of Evans auxiliaries in asymmetric alkylation/aldol reactions 14'9 146 (Scheme 27) has been further bolstered by Da~ies's'~~ development of the related 'Quat' chiral auxiliaries (9),which offer the advantage of milder methods for auxiliary removal. Kobayashi14* has developed an anti-selective catalytic aldol sequence utilizing a chiral tin@) catalyst whilst Mikami14' has demonstrated that the related A.G. Myers B. H. Yang H. Chen and J. M. Gleason J. Am. Chem. SOC. 1994 116 9361. 139 D. Askin K.E. Eng K. Rossen R. M. Purick K. M. Wells R. P. Volante and P.J. Reider Tetrahedron Lett. 1994,35 673. 140 M. Mehlfuhrer H. Berner and K. Thirring J. Chem. SOC.,Chem. Comrnun. 1994 1291. R. M. Williams P. Colson and W. Zhai Tetrahedron Lett. 1994 35 9371. A. B. Smith A. Pasternak. A. Yokoyama and R. Hirschmann Tetrahedron Lett. 1994 35 8977. R. Cotton A. N. C. Johnstone and M. North Tetrahedron Lett. 1994 35 8859. M.T. Reetz F. Kayser and K. Harms Tetrahedron Lett. 1994 35 8769. H. Kigoshi M. Ojika T. Ishigaki K. Suenaga T. Mutou A. Sakarura T. Ogawa and K. Yamada J. Am. Chem. SOC. 1994 116 7443. K. G. Carson and B. Ganem Tetrahedron Lett. 1994 35 2659. S. G. Davies G. J. Doisneau J. C. Prodger and H. J. Sanganee Tetrahedron Lett. 1994 35 2369.S. Kobayashi and T. Kawasuji Tetrahedron Lett. 1994 35 3329. 149 K. Mikami and S. Matsulawa J. Am. Chem. SOC.,1994 116 4077. ''13 148 Peter Quayle (ref 134) Me (ref 135) -70 "C Scheme 24 OSiMe3(y i-iii * &Ph 09% (ref 136) iv ii iii ~ Ph+ 85% 61% 3.8:l Reagents i MeLi; ii MnC1,; iii PhCH,Br; iv LDA Scheme 25 Aliphatic and Alicyclic Chemistry (ref 138) (ref 139) But PhCON iv iii (ref 140) lYNMe 0 Ph v, L (ref 141) CBzNJo H *C02Me (co2Me vii. iii (ref 143) A A ZNH CO~BU' ZNH C02But (3:1) Reagents i 2eq. LDA LEI; E'; iii ally1 bromide; iv L,DA; v NaN(SiMe,),; vi RX; vii 2eq. LHMDS Scheme 26 150 Peter Quayle (ref 145) 60% (9) Scheme 27 titanium-promoted reaction proceeds via a closed transition state (Scheme 28).Functionalized allylboranes' and stannanes' 'l,' 52 continue to provide new path- ways for the asymmetric synthesis of a variety of functionalized intermediates (Scheme 29). The use of carbon-centred radicals in asymmetric synthesis is now a well- recognized phenomenon' 53*154 (Scheme 30).In certain cases154 the stereochemical outcome of these alkylation reactions is complementary to that observed using polar reagents. The use of transition metals as either temporary stereocontrol elements or as chiral modifiers in alkylation reactions has been used extensively of late,155*' 56 as illustrated below (Scheme 31). In certain cases' 56 the stereochemical outcome of the reaction may be radically affected by seemingly small changes in the ligand environment around the metal centre.Conjugate Additions. The role of copper additives in a number of carbon-centred conjugate addition reactions has come under scrutiny again this year.' Irrespective 150 A.G. M. Barrett M. A. Seefeld and D.J. Williams J. Chem. SOC.,Chem. Commun. 1994 1053. 15' S. J. Stanway and E. J. Thomas J. Chem. SOC. Chem. Commun. 1994 285. lS2 J. S. Carey and E. J. Thomas J. Chem. SOC.,Chem. Commun. 1994 283. 153 H. Nagno and Y. Kuno J. Chem. SOC.,Chem. Commun. 1994,987. 154 K. Haraguchi H. Tanaka S. Saito K. Yamaguchi and T. Miyasaka Tetrahedron Lett. 1994,35,9721. C.K. Wada and W.R. Roush Tetrahedron Lett. 1994 35,7351. 15' L. Schwink and P.Knochel Tetrahedron Lett. 1994 35,9007. 15' J. Kabbara S. Flemming K. Nickisch H. Neh and J. Westermann,Tetrahedron Lett. 1994,35,8591; A. S. Vellekoop and R. A. J. Smith J. Am. Chem. SOC.,1994,116,2902; N. Krause R. Wagner and A. Gerold ibid. 1994 116 381. Aliphatic and Alicyclic Chemistry 151 sn(OTf)n),/ *SIP OH 0 OH 0 cat. PhCHO + TBSOi(OSiMe3OPh PhvOPh + PhvOPh OTBS h S syn anti 6 9 4 (ref 148) (up to 95% e.e.) (ref 149) L Scheme 28 of finer mechanistic detail Michael reactions especially as their asymmetric variants have proved to be highly useful in a variety of synthetic (Scheme 32). Particularly impressive is Yamamoto's discovery'64 that a$-unsaturated aldehydes undergo site-selective conjugate addition reactions with organolithium and -mag- nesium reagents when conducted in the presence of the bulky Lewis acid ATPH.3 Alicyclic Chemistry Cyclopropanes-The isolation of FR-900848 (10) has served as a catalyst for heightened interest in the development of new synthetic methodology in this area especially for the synthesis of linear arrays of polycyclopropanes. Zer~her'~' has shown that the allylic alcohol (1 1) undergoes stereoselective cyclopropanation to Is* B. H. Lipshutz and M. R. Wood J. Am. Chem. Soc. 1994 116 11 689. lS9 Z. Jin and P. L. Fuchs J. Am. Chem. Soc. 1994 116 5995. 160 G. Li D. Patel and V.J. Hruby Tetrahedron Lett. 1994 35 2301. 16' M. Nomura and S. Kanemasa Tetrahedron Lett. 1994 35 143. G. Pain D. Desrnaele and J. d'Angelo Tetrahedron Lett.1994 35 3085. Z. Wang and L.S. Jirnenez J. Am. Chem. SOC.,1994 116 4977. 164 K. Muruoka H. Imoto S. Saito and H. Yamamoto J. Am. Chem. SOC. 1994,116,4131. C.R. Theberge and C.K. Zercher Tetrahedron Lett. 1994 35 9181. 152 Peter Quayle (reg 150) Bu3Snv iv. i R-(reg 151) NBn2 I NBn2 OH Reagents i RCHO; ii H,O, NaOH; iii H30+;iv SnBr, -78°C Scheme 29 afford the syn-bicyclopropanes (12) and (13) in good yields (65% and 72% respectively). The sense of induction in these cyclopropanation reactions is reagent controlled use of the (+)-tartrate dioxaborane (14) affords the syn isomer (12) whilst the (-)-tartrate-derived dioxaborane (15) leads to the anti isomer (13) (Scheme 33). Nobayashi has utilized a related catalyst system for the asymmetric synthesis of the tin-and silicon-substituted cyclopropanes (16).Enantioselectivities in the region of 70-80% were routinely observed in these investigations (Scheme 34).166 The use of copper and rhodium-catalysed cyclo-propanation reactions have again been much in evidence. Kanema~a'~~ has demon-strated that styrene derivatives undergo cyclopropanation with diazoesters in the presence of C,-symmetric 1,2-diamine-m0difiedcopper salts in moderate to excellent optical yields. This process has been applied to the synthesis of chrysanthemic acid (Scheme 35). Martin168has utilized intramolecular cyclopropanation reactions in the presence of chiral rhodium catalysts to prepare functionalized lactones with high levels of optical purity (Scheme 35).Alternatively Charette'69 has shown that glucose-derived allylic ethers undergo cyclopropanation reactions in good chemical yields (>90%0) and with useful levels of diastereoisomeric purity (11 :1 to 17 1). A simple synthesis' 70 of the cis-functionalized cyclopropane (17) the isolation' 71 of the highly 166 N. Imai K. Sakamoto H. Takahashi and S. Kobayashi Tetrahedron Lett. 1994,35 7045. 16' S. Kanemasa S. Hamura E. Harada and H. Yamamoto Tetrahedron Lett. 1994 35 7985. S. F. Martin M. R. Spaller S. Liras and B. Hartmann J. Am. Chem. SOC. 1994 116 4493. 169 A. B. Charette N. Turcotte and J. Marcoux Tetrahedron Lett. 1994 35 513. L. Dechoux and E. Dons Tetrahedron Lett. 1994,354 2017. 17' W. E. Billups W. Luo and M. Gutierrez J.Am. Chem. Soc. 1994 116 6463. Aliphatic and Alicyclic Chemistry (ref 153) major 0 t-* TBDM$ OTBDMS TBDM$ OTBDMS 10 :1 + 0 .. IS TBDMSO ~TBDMS Scheme 30 unsaturated system (18),and the intermediacy'72 of the related cyclopropene (19)have also been documented (Scheme 36).Merlic' 73 has reported the cyclopropanation of c6 using a Fischer carbene complex. Cyc1obutanes.-Rosini '74 has developed a facile procedure for the preparation of bicyclo[3.2.0]hept-3-en-6-onesbased upon an intramolelcular [2 +23 cycloaddition reaction. Photochemical'75 techniques have also been employed for the synthesis of related bicyclic structures in which a 'silicon tether' was used to control the regiochemistry of the cycloaddition reaction.Related intramolecular cycloaddition reactions of optically active allenes afford cycloadducts with high levels of isomeric purity.' 76 Fukumoto' 77 has utilized a tandem Michael addition-alkylation sequence for the preparation of donor-acceptor cyclobutanes which are of synthetic utility (Scheme 37). Cyclobutane derivatives of c~nduritol'~~ have been prepared from 172 P. A. Wade and P.A. Kondracki J. Chem. SOC.,Chem. Commun. 1994 1263. 113 C. A. Merlic and H. D. Bendorf Tetrahedron Lett. 1994 35 9529. 174 E. Marotta P. Righi and G. Rossini Tetrahedron Lett. 1994 35 2949. 175 M. T. Crimmins and L. E. Guise Tetrahedron Lett. 1994 35 1657. 176 E. M. Carreira C. A. Hastings M. S. Shepard L. A. Yerkey and D. B. Millward J. Am. Chem. SOC.,1994 116 6622.177 M. Ihara T. Taniguchi and K. Fukumoto Tetrahedron Lett. 1994 35 1901. 178 Y. Kara M. Balci S. A. Bourne and W.H. Watson Tetrahedron Lett. 1994 35 3349. 154 Peter Quayle 0J: MeMg I THF -40% C h$: (ref 155) OX0 93% OX0 OH C~QH&HO I * CIQHS~WM~ N(H)Tf 699'0 92% 8.8. I I" OH (ref 156) ginnol; 92% 8.8. Reagents i [Br(CH,),], Zn; ii Bu,Cu(CN)Li Scheme 31 cyclooctatetraene. The synthetic utility'" of cyclobutanes is exemplified in an approach to the perhydrohistrionicotoxin ring system which utilizes a fragmentation reaction of a cyclobutane derivative in a key step (Scheme 38). Cyclopentanes-The synthesis of cyclopentane derivatives remains a growth area. Significant advances this year include the use of the Pauson-Khand (PK) reaction in an asymmetric fashion,'80.'81 including its application to carbohydrate chemistry18* and the development of a catalytic process for intramolecular PK reactions'83 (Scheme 39).A mechanistic' 84 investigation into the stereochemistry of the thermal vinylcyc- lopropanesyclopentene rearrangement has appeared; the transition-metal-catalysed 17' D. L. Comins and X. Zheng J. Chem. SOC.,Chem. Commun. 1994,2681. lE0 V. Bernardes X. Verdaguer N. Kardos A. Riera A. Moyano M.A. Pericas and A.E. Greene Tetrahedron Lett. 1994 35 575. X. Verdaguer A. Moyano M. A. Pericas A. Riera V. Bernardes A. Greene A. Alvarez-Larena and J. F. Piniella J. Am. Chem. SOC. 1994 116 2153. N. Naz T.H. Al-Tel Y. Al-Abed and W.Voelter Tetrahedron Lett. 1994 35 8581. N. Jeong S.H. Hwang Y. Lee and Y.K. Chung J. Am. Chem. SOC. 1994 116 3159. 184 J.E. Baldwin K.A. Villarica D.I. Freedberg and F.A. Anet J. Am. Chem. SOC.,1994 116 10845. Aliphatic and AIicyclic Chemistry * i-ui (ref 158) I C6H13 A 82% Ph Ph )7 Br )7 ArYYN7fo(ref 160) hr'v -NKo 0 0 CH3 0 0 vl vH (ref 162) -MeO 60% 58Yo 8.0. viii. k (ref 163) QT+ -Qo H Nuc 0 0 50-90% (ref 164) Reagents i MeLi Me,ZnLi cat. Me,Cu(CN)Li,; ii 4-isopropylcyclohex-2-enone; iii hexanal; iv ArMgBr CuBr DMS; v NBS -78°C; vi methyl acrylate; vii H,O+; viii NaH; ix H,C=CHS+Ph,; x ATPH; xi Nuc-Scheme 32 156 Peter Quayle HO OH ".pH-oH ZnEt,. CHzI2 -/ Ph 67% (12) (ref 16!5) Ph ZnEt Ph 72% H-&;oH H Scheme 33 variant has been utilized in the preparation of functionalized cyc10pentene.s'~~ (Scheme 39).Zirconium-based methods for the preparation of cyclopentanes have received much attention of late as illustrated below.186 The mild conditions and non-polar nature of the intermediates involved in these transformations suggests that synthetic exploita- tion will ensue relatively rapidly. PiersI8' has described a novel cyclopentenone annulation procedure which should be of some synthetic utility (Scheme 40). The palladium-catalysed cycloaddition of TMM with C, has been reported. 88 Cyclohexanes-Diels-Alder approaches again figure extensively in the preparation of functionalized cycl~hexanes'~~-~~~ (Figure 1).The development of em-selective K. Hiroi and Y. Arinaga Tetrahedron Lett. 1994 35 153. 186 T. Luker and R. J. Whitby Tetrahedron Lett. 1994 35 785. E. Piers K. L. Cook,and C. Rogers Tetrahedron Lett. 1994 35 8573. "'L. Shiu T. Lin S. Peng G. Her D. D. Ju S. Lin J. Hwang C. Y. Mou and T. Luh J. Chem. Soc. Chem. Commun. 1994 647. K. Maruoka H. Imoto and H. Yamamoto J. Am. Chem. SOC. 1994 116 12115. Aliphatic and Alicyclic Chemistry Me2PhSi*O"H 81% 8.8. (16) Scheme 34 (R' = I -menthyl) t~s:&=8:12 (frans= 74% e.e.) Rhd(5S)-MEPyL (ref 168) 75% yield (>949/0e.8.) Scheme 35 158 Peter Quayle -i B&&o&R (reflss) BnO OH R3 major Reagents i ZnEt, CH,I, toluene -30 "C Scheme 36 cycloadditi~ns,'~~ new asymmetric catalyst and a variety of promoters have been documented.'99~200 The first direct evidence for a 'biological Diels-Alder' reaction has also been reported this year.Ig0 Medium Rings.-This area has been dominated by the development of synthetic strategies towards the total synthesis of paclitaxel (Tax01)~' and enediyne antitumour agents * O E..J. Corey S. Sarshar and D. Lee J. Am. Chem. SOC. 1994 116 12089. 19' M. W. Wright T. L. Smalley Jr. M. E. Welker and A. L. Rheingold J. Am. Chem. SOC.,1994,116,6777. 19' K. Mikami Y. Motoyama and M. Terada J. Am. Chem. SOC. 1994 116 2812. 193 K. Maruoka M. Akakura S. Saito T. Ooi and H. Yamamoto J. Am. Chem. SOC. 1994 116 6153. 194 W. Oppolzer B.M.Seletsky and G. Bernardinelli Tetrahedron Lett. 1994 35,3509. 19' P.A. Grieco S.T. Handy and J. P. Beck Tetrahedron Lett. 1994 35,2663. 196 I. E. Marko and G. R. Evans Tetrahedron Lett. 1994 35,2767. 19' 1. E. Marko and G. R. Evans Tetrahedron Lett. 1994 35,2771. 198 L.Meerpoel M. Vrahami J. Ancerewin and P. Vogel Tetrahedron Lett. 1994 35 111. 199 Z. Zhang F. Flachsmann F. M. Moghaddam and P. Riiedi Tetrahedron Lett. 1994 35,2153. 'O0 G.Jenner Tetrahedron Lett. 1994 35,1189. '01 D.A. Singleton and A.M. Redman Tetrahedron Lett. 1994 35,509. '02 Y. Motoyama and K. Mikami J. Chem. SOC. Chem. Commun. 1994 1563. H. Oikawa Y. Suzuki A. Naya K. Katayama and A. Ichihara J. Am. Chem. SOC. 1994 116 3605. ,04 M.D. Shair T. Yoon T. Chou and S.J. Danishefsky Angew.Chem. Int. Ed. Engl. 1994 33 2417. Aliphatic and Alicyclic Chemistry 0 k;M hv > 350nrn (ref 1 75) 70-80% %Me OH o'si-Me' 'Me 0-SiMe (ref 176) 1.2 1 92% 9.8. (91% 9.9.) (92% e.e.) (ref 177) H c02Me 67% Scheme 37 Large Rings.-The synthesis of large rings has enjoyed a resurgence of interest of late. This is primarily due to the interest in developing 'artificial enzymes' which require binding pockets afforded by molecules such as (20).205 In addition a number of groups are attempting to develop a rational de nouo synthesis of C, (Scheme 41) and its derivativeszo6 whilst others are interested in preparing cyclic polyunsaturated systems such as (21k(24)which may possess interesting physical properties.207 '05 H.L. Anderson A. Bashall K. Henrick M. McPartlin and J. K. M. Sanders Angew. Chem. Int. Ed. Engl. 1994 33 429. '06 P. W. Rabideau A. H. Addourazak H. E. Folsom Z. Marcinow A. Sygula and R. Sygula J. Am. Chem. Soc. 1994 116 7891. A. de Meijere S. Kozhushkov C. Puls T. Haumann R. Boese M.J. Cooney and L.T. Scott Angew. Chem. Int. Ed. Engl. 1994 33 869. 160 Peter Quayle 0 -hv 80% 1 Lii (ref 179) major Reagents i SmI, THF,DMPU; ii TFA Scheme 38 Aliphatic and AIicyclic Chemistry -Me02CQ0-ph - Me02C (ref 182) Me02C - MeO& ?7% 75% (ref 183) ". Me E m e8 \ (ref 185) hr Eas-0 Ph (89%ds) Reagents i Co,(CO), benzene; ii DMSO 50 "C; iii DME 120"C 24 h CO (3 atm) 3 mol% Co,(CO), 10mol% P(OPh),; iv Pd(o) MeCN 80°C Scheme 39 162 Peter Quayle 1 ii (ref 186) H 73% C02Me%b C02Me iii -p3OH 4- iii - &o H a OH Reagents i Cp,ZrBu,; ii LiC=CCH,Cl; iii Bu"Li THF -78 "C Scheme 40 Aliphatic and Alicyclic Chemistry ex0 > R= Ph 8x0 endo =96:4 (81% yield) R=Me,exo:endo =87:3 (72% yield) (ref 191) (ref 194) P I [Co]= Pyr(DMG)2 71% (ref 196 197) (ref 1 98) (ref 201) Me2PhSi (ref 201) Figure 1 164 Peter Quayle i,ii iii _3.Reagents i 2,4,6-Heptatrienone glycine (cat) norbornadiene-toluene reflux 72 h; ii PCI, toluene reflux 3 h; iii FVP 1OOO"C Scheme 41