6 Alicyclic Chemistry By N. S. SlMPKlNS Department of Chemistry Queen Mary College Mile End Road London El 4NS 1 General A variety of caged and strained structures continue to attract attention. Both f4] paracyclophane (1)’ and [4]metacyclophane (2)* have been generated from the corresponding ‘Dewar isomers’ and identified by spectroscopic and trapping methods. The secohexaprismane (3) has been synthesi~ed,~ and Mehta and Padma have also reported the first synthesis of the 1,4-bishomohexaprismane (4) (‘gar~dane’).~ Other hydrocarbons which have been synthesized include the tetracycle (5),’ and [4.4.4]propellahexaene (6).6Treatment of the diketone (7) with Tio gave the compound (S) presumably uia the desired diene (9).7 (7) (9) (8) ’ T. Tsuji and S.Nishida J. Chem. SOC.,Chem. Commun. 1987 1189. * G. B. M. Kostermans P. van Dansik W. H. de Wolf and F. Bickelhaupt J. Am. Chem. Soc. 1987 109 7887. G. Mehta and S. Padma J. Am. Chem. SOC.,1987 109 2212. G. Mehta and S. Padma J. Am. Chem. SOC.,1987 109 7230. R. Gleiter and U. Steuerle Tetrahedron left. 1987 28 6159. L. Waykole and L. A. Paquette J. Am. Chem. SOC.,1987 109 3174. J. E. McMurry and R. Swenson Tetrahedron Lett. 1987 28 3209. 133 N. S. Simpkins A number of reports detail further investigations of ring-expansion methods using sulphur- or selenium-stabilized carbanions.' The method described previously by Cohen for transformation of adducts such as (10) into the ring-expanded a-phenylthiobutane products can now be conducted under basic conditions (Scheme l).9 Similar products are also available by a novel ring-expansion described by Trost." Both a-phenylthio- and a-methoxy ketones e.g.(1 l) were formed by Lewis acid-mediated rearrangement of the intermediate sulphones. SOzPh i H X = SPh or OMe (11) Scheme 1 74% Scheme 2 Overman has reported an expansion reaction which converts certain cyclic vinyl acetals into fused tetrahydrofurans (Scheme 2).11 A number of different systems and reaction conditions were examined in this reaction which is thought to proceed via sequential Prins cyclization-pinacol rearrangement. Two other notable ring- expansions proceed uia radicals to give a variety of cyclic keto-esters.12 Further reports concern the cyclization reactions of unsaturated organolithiums derived from alkyl vinyl and aryl halides.13 Cyclic 1,2-and 1,3-diones are available by reduction of epoxy acetals with Zn/ClSiMe and with LiAlH4 re~pective1y.l~ A new asymmetric transformation of cyclic enones which corresponds to conjugate n R.C. Gadwood I. M. Mallick and A. J. Dewinter J. Org. Chem. 1987 52 774; A. Krief and J. L. Laboureur Tetrahedron Lett. 1987 28 1545; A. Krief J. L. Laboureur and W. Dumont Tetrahedron Lett. 1987 28 1549. 9 W. D. Abraham M. Bhupathy and T. Cohen Tetrahedron Lett. 1987 28 2203. 10 B. M. 'Trost and G. K. Mikhail J. Am. Chem. SOC.,1987 109 4124. 11 P. M. Herrington M. H. Hopkins P. Mishra M. J. Brown and L. E. Overman J. Org. Chem. 1987 52 3711. 12 P.Dowd and S.-C. Choi J. Am. Chem. SOC.,1987 109 3493; ibid. p. 6548. 13 M. P. Cooke jun. and R. K. Widener J. Org. Chem.. 1987 52 1381; W. F. Bailey T. T. Nurmi J. J. Patricia and W. Wang J. Am. Chem. SOC.,1987 109 2442. 14 Y. D. Vankar N. C. Chaudhuri and C. Trinadha Rao Tetrahedron Lett. 1987,28 551. Alicyclic Chemistry 135 addition of the acetaldehyde enolate utilises chiral phospholidines (Scheme 3).15 Several other phospholidines were examined in this reaction including a diastereomer of the compound shown but these were less successful. The reaction also worked well using cyclohexenone or cycloheptenone giving good chemical yields and 88% and 95% e.e. respectively. A 79% 98% e.e. Scheme 3 2 Three-membered Rings Mash has published further papers concerning the diastereoselective cyclopropana- tion of unsaturated chiral ketals.I6 A new cyclopropanation procedure for allylic alcohols uses samarium metal and is characterized by high yields and good diastereoselectivities (Scheme 4).” The procedure appears cleaner and more stereoselective than the Simmons-Smith reaction in certain cases; notably isolated olefins appear to be inert.Smor Sm(Hg) 6 M e + ‘4Me ‘4 Me CH,I,,THF ’ Bu’ But -78°C to r.t. But OH OH OH >200 1 (9970 yield) Scheme 4 Stereoselective reduction of gem-dichlorocyclopropanes is possible by use of potassium diphenylphosphide in DMS0.I8 Nucleophilic opening of suitably acti- vated cyclopropanes has been studied further using amines” and selenolate anions2* (Scheme 5).The reaction with amines provided a variety of functionalized dihy- dropyrroles and could be extended to provide products capable of elaboration to azabicyclic alkaloids. The ring-opening reaction of MeSeNa with diactivated cyclo- propanes contrasts with the 0-alkyl bond cleavage observed with the monoactivated system. A new preparation of vinylcyclopropanes such as (12) was reported last year. These products undergo pyrolytic rearrangement to the corresponding cyclopen- D. H. Hua R. Chau-Yu-King J. A. McKie and L. Myer J. Am. Chem. SOC.,1987 109 5026. 16 E. A. Mash K. A. Nelson and P. C. Heidt Tetrahedron Letr. 1987 28 1865; E.A. Mash and K. A. Nelson Tetrahedron 1987 43 679. 17 G. A. Molander and J. B. Etter J.Org. Chem. 1987 52 3942. ” G. F. Meijs J. Org. Chem. 1987 52 3923. 19 J. P. Celerier M. Haddad D. Jacoby and G. Lhommet Tetrahedron Lett. 1987 28 6597. 20 A. Krief and M. Trabelsi Tetrahedron Lett. 1987 28 4225. N. S. Simpkins C02Me I Ref. 19 PCO2Me 1.3 eq. MeSeM C02Me C0,Me (M = Na or L,) ' MeSeqC02Me Ref. 20 Scheme 5 Scheme 6 tenes. Now this conversion can be conducted by treatment with TMSI followed by base-induced ring closure (Scheme 6).2' Interestingly the endo isomer of (12) could be converted quantitatively into (13) via its silyl enol ether. These transformations were studied on a variety of bi- and tri-cyclic cyclopropanes. Both the stereoselective synthesis22 and regioselective addi- tion reactions23 of doubly activated vinylcyclopropanes have received further atten- tion.Piers has used the palladium-catalysed coupling of cyclopropyl zincs with vinyl iodides to prepare vinylcyclopropanes.24 This method was used to synthesize the sesquiterpenoids (*)-prezizanol and (*)-prezizaene. Cyclopropane intermediates feature in a new synthesis of pederol in which the cyclopropane assists in a key photolytic rearrangement as well as functioning as a masked gem-dimethyl 3 Four-membered Rings 4,4-Dichlorocyclobutenonederivatives readily available from dichloroketene have previously resisted efficient dechlorination. A new method which employs Zn/ EtOH/ AcOH/TMEDA conducts this transformation cleanly in good yields (Scheme 7).26 84% Scheme 7 21 A. Fleming G.Sinai-Zingde M. Natchus and T. Hudlicky Tetrahedron Lett. 1987 28 167. 22 J. E. Backvall J. 0. Vagberg C. Zercher J. P. Genet and A. Denis J. Org. Chern. 1987 52 5430. 23 K. Burgess J. Org. Chem. 1987 52 2046. 24 E. Piers M. Jean and P. S. Marrs Tetrahedron Lett. 1987 28 5075. 25 M. C. Pirrung and P. M. Kenney J. Org. Chem. 1987 52 2335. 26 R. L. Danheiser and S. Savariar Tetrahedron Lett. 1987 28,3299. Alicyclic Chemistry The cleavage of cyclobutanes using radical methods has been used in a new synthesis of phthalide~~~ and also in a modification of Crimmins’ silphinene syn- thesis.28As last year a great amount of interest has focused on intramolecular 2 + 2 cycloadditions. A number of examples of this type of reaction are outlined in Scheme 8.bv CuSO,CF, Et,O b LI Ref. 30 0 0 Ref. 31 Scheme 8 Pirrung has conducted a more detailed investigation of the cyclooctenone cyclo- additions reported last year.32 4 Five-membered Rings Two reports detail further extensions of Canonne’s work on annelations using bis-Grignard reagents.33 The usefulness of samarium for the stereoselective construc- tion of functionalized cyclopentanes has also been further demonstrated. Thus ketoesters or ketoamides bearing suitable appendages can be cyclized in good yield and with high diastereoselectivity by use of SmIz (Scheme 9). A very attractive ene-type cyclization of triene ethers has appeared which uses an easily prepared Feo catalyst.36 Scheme 10 outlines this reaction which utilizes 27 K.Kobayashi M. Itoh and H. Suginome Tetrahedron Lett. 1987 28 3369. 28 M. T. Crimmins and S. W. Mascarella Tetrahedron Lett. 1987 28 5063; M. T. Crimmins and L. D. Could J. Am. Chem. SOC.,1987 109 6199. 29 W. T. Brady Y.4. F. Giang L. Weng and M. M. Dad J. Org. Chem. 1987 52 2216. 30 S. Ghosh S. R. Raychaudhuri and R. G. Salomon J. Org. Chem. 1987,52 83. 31 A. R. Math and D. J. McGarvey Tetrahedron Lett. 1987 28 5087; A. R. Matlin T. C. Leckta D. J. McGarvey P. W. Jacob and H.A. Picken ibid, p. 5083. 32 M. C. Pirrung and N. J. G. Webster J. Org. Chem. 1987 52 3603. 33 P. Canonne R. Boulanger and M. Bernatchez Tetrahedron Lett. 1987 28 4997; P. Canonne and M. Bernatchez J. Org. Chem. 1987 52 4025. 34 G. A. Molander and C.Kenny Tetrahedron Lett. 1987 28 4367. 35 G. A. Molander J. B. Etter and P. W. Zinke J. Am. Chem. SOC.,1987 109 453. 36 J. M. Takacs and L. G. Anderson J. Am. Chem. SOC.,1987 109 2200. N. S. Simpkins BU'OH Me-8-Me SOEt SIIII~ HO CO2Et -78 "C + r.t. Me-' 15Yo y80% Ref. 35 Scheme 9 A Ph l-7 v :yM; ~~/C/OH;H' 71. 15% bpy.fe" ' Me 62% overall Scheme 10 SnBu3 10-15 mol '/o of catalyst and which is highly diastereoselective. Changing the geometry of the allylic ether double bond allows access to isomeric products having truns-substitution about the newly formed C-C single bond. Cyclic acyliron complexes are available by reaction of a,@-unsaturated acylirons with allylstannanes (Scheme 1l).37 The results contrast with the simple Michael addition products obtained using allysilane.Trost has published several reports concerning recent explorations of palladium-mediated cyclizations. Reductive cyclization of 1,6-enynes occurs nicely using a combination of (dba)3Pd3CHC13/ HOAc/ PMHS,38 whereas the correspond- ing unsaturated product was obtained using Pd(OAc) (Scheme 12).39An alternative 37 J. W. Herndon J. Am. Chem. Soc. 1987 109 3165. 3X B. M. Trost and F. Rise J. Am. Chem. SOC.,1987 109 3161. 39 B. M. Trost and D. J. Jebaratnarn Tetrahedron Lett 1987 28 1611. Alicyclic Chemistry Reagent i Pd(OAc)2- ii (dba),Pd,CHCI, HOAc PMHS-. saturated C(1)-C(2) Scheme 12 system for enyne cyclization uses a polymer-supported nickel-chromium catalyst and enables the preparation OF five- and six-membered dienes."' Intramolecular carbenoid cyclization of a-diazocarbonyl compounds has now been extended to phosphonate phosphine oxide and sulphone containing systems (Scheme 13).N2 3(Et0)2P11 0 0 67Yo Ref. 41 &SO,Ph -Rh(OAc) Uo 75% iO2Ph Ref. 42 Scheme 13 An increasing number of attractive building blocks are available in optically active form from enzymic reactions. Scheme 14 illustrates two such recent reports utilizing racemic and prochiral starting materials. Further transformation of chiral cyclopen- tanones such as (14) to bicyclic products e.g. (19 attractive For further synthesis was also demonstrated. Krief has described a cyclization reaction of benzyllithiums generated from selenides (Scheme 15).45 Interestingly either (16) or (17) can be obtained in good d.e.(96%)by selection of suitable reaction conditions whilst selenide (18) was obtained by use of 0.1 eq. of BuLi. Corey has described a novel one-pot annulation which gave bicyclic enone (19) in good yield (Scheme 16).46The tricyclic product was also obtained by the same procedure. The ready availability of (19) enabled the first total synthesis of 40 B. M. Trost and J. M. Tour J. Am. Chem. SOC.,1987 109 5268; B. M. Trost and G. J. Tanoury ibid. p. 4753. 41 B.Corbel 0. Hernot J.-P. Haelters and G. Sturtz Tetrahedron Lett. 1987 28 6605; H. M. L. Davies and L. V. T. Crisco ibid. p. 371. 42 H. J. Monteiro Tetrahedron Lerr. 1987 28 3459.43 Z.-F. Xie H. Suemune and K. Sakai J. Chem. Soc. Chem. Cornmun. 1987 838. 44 D.W. Brooks and K. W. Woods J. Org. Chem. 1987 52 2036. 45 A. Krief and P. Barbeaux J. Chem. SOC.,Chem. Cornmun. 1987 1214. 46 E. J. Corey and W. Su Tetrahedron Leu. 1987 5241 N. S. Simpkins Pseudomonas jluorescens lipase ' 0, AcO C02Et HO' C02Et 42% yield >99% e.e. Ref. 43 0 -B;t:aes:'s .&OH -O W0 (14) 75% yield (15) Ref. 44 Scheme 14 fFe-Ph Me Ph Me Ph Me Ph Me &CH3 + b4-CH. SeMe &, U MaBui t Bu'CECC0,Ph -M@ Me02C 0 Me02C 0 OLi Scheme 16 (19) 70% 0 0 CI 1. AICI,(CH,CI) Zn'/PhH/DMSO 0 ::o HG 2. HCECH H2O R' R2 RZ R2 3243% overall Scheme 17 (*)-bilobalide a member of the gingkolide family.47 Another cyclopentenone prepar- ation which has appeared combines two previous procedures involving Lewis acid mediated chlorocyclopentenone synthesis followed by reductive dechlorination (Scheme 17).48 Finally an interesting ring cleavage-ring forming sequence occurs on treatment of certain cyclic diketones with excess ethylene glycol-BF,.OEt e.g.Scheme 18.49 The reaction is thought to proceed via an initial aldol process followed by acetal- 47 E. J. Corey and W. Su J. Am. Chern. SOC.,1987 109 7534. 48 C. J. Rizzo N. K. Dunlap and A. B. Smith 111 J. Org. Chem. 1987 52 5280. 49 H. Suemune K. Oda and K. Sakai Tetrahedron Lert. 1987 28 3373. Alicyclic Chemistry 141 BF,.OEt, 7eq. ___ 80 :20 78% combined yield Scheme 18 initiated ring fragmentation.Although mixtures of products are obtained the method provides easy access to some unusually substituted cyclopentenes and cyclohexenes. 5 Six-membered Rings Further reports have dealt with the construction of six-membered rings by means of tandem reaction sequences for example one-sot sequential double Michael reactions (Scheme 19). moLi A OMM CO,Me THF-78"C+ -4O"C 10h 86% Ref. 50 HO 52% (+stereoisomer) Ref. 51 Scheme 19 The top example shows the efficient use of a chiral Michael acceptor in an intermolecular proce~s.'~ The second intramolecular process gave the indicated tricyclic intermediate which was further elaborated to (*)-pentalenic acid." Two more examples of note in this category are outlined below in Scheme 20.The formation of tricycle (20) in 80% yield is the best result from the examples tried. Other substrates gave mixtures of compounds including minor products having cyclopropanes cyclobutanes and medium-ring ethers.52 The synthesis of nitro-substituted decalones is one of three methods examined which gave variable stereochemical result^.'^ 50 H. Nagaoka K. Kobayashi T. Okamura and Y. Yamada Tetrahedron Lett. 1987 28 6641. 'I M. Ihara M. Katogi K. Fukumoto and 'T.Kametani J. Chem. Soc. Chem. Commtm. 1987 721. 52 J.-F. Lavallee and P. Deslongchamps Tetrahedron Lett. 1987 28 3457. 53 F. Richter and H.-H. Otto Tetrahedron Lett. 1987 28 2945. N. S. Simpkins (20) SO% Ref. 52 H I NO2 NO2 1 :4 45% yield Ref.53 Scheme 20 A tandem Michael-Claisen condensation has also been reported,54 whilst Posner has adapted his previous rnulticomponent annulation procedure to convert cyclo- alkenones into ring-expanded alkenolide~.~~ Annulation of a carbohydrate-derived ketone has been possible for the first time using the Stork modification of the Robinson annulation pr~cedure.~~ Both enantiomers of 5-trimethylsilyl-2-cyclohexenoneare available through reac- tion of the racemate with p-toluenethiol in the presence of ~inchonidine.~' These compounds are potentially very versatile intermediates for the preparation of many chiral cyclohexenone systems. A more detailed account of the enantioselective conversion of anthranilic acid derivatives into chiral cyclohexanes has appeared.58 Here the Birch reduction of the diazepine derivative (21) followed by alkylation gave the desired products (22) in good d.e.(Scheme 21). Scheme 21 A further development of Molanders annulation chemistry allows extension to the preparation of chiral 1,2-cyclohexanediols (Scheme 22).59 Thus chiral epoxy aldehydes prepared using the Sharpless procedure combine with 3-iodo-2-[ (trimethylsilyl)methyl]propene under the influence of SnF to give 54 T. H. Chan and C. V. C. Prasad J. Org. Chem. 1987 52 110. 55 G. H. Posner E. Asirvatham K.S. Webb and S. Jew Tetrahedron Lett. 1987 28 5071. 56 R. V. Bonnert and P. R. Jenkins J. Chem. Sac. Chem. Commun. 1987 6. 57 M. Asaoka K.Shima and H. Takei Terrahedron Lett.1987 28 5669; M. Asaoka and H. Takei ibid. p. 6343. 58 A. G. Schultz P. J. McCloskey and J. J. Court J. Am. Chem. Soc. 1987 109 6493. 59 G. A Molander and D. C. Shubert J. Am. Chem. Soc. 1987 109 576. Alicyclic Chemistry yields 0-67% Scheme 22 (24) Reagents i PhCOCl NaOH; ii PBrJBr,; iii MeSCH,SOMe KH; iv H30; v HX vi chiral lithium amide Scheme 23 the indicated products in moderate to excellent d.e. Chiral cyclohexanes have also been obtained starting from (S)-(-)-3-methyl piperidine (23),60 and by use of a chiral lithium amide base on the prochiral acid (24) (Scheme 23).61 Interest in cyclitols continues and especially in phosphates of myo-inositol an important cellular secondary messenger thought to mediate the release of Ca2+ from intracellular stores.Both enantiomers of myo-inositol 1,4,5-triphosphate (25) are available via a protection and resolution sequence using camphanic acid chloride.62 Similar chemistry has been used to prepare the corresponding 1-phosphate and 4-ph0sphate.~~ Another cyclitol-pinitol (26) has been synthesized in racemic form starting from diol (27) (Scheme 24).64 The starting material (27) was obtained by microbial oxidation of benzene. This method appears to have great potential for synthesis especially if substituted chiral derivatives of (27) can be used. Enzymic enantioselective hydrolysis of epoxides (28) and (29) has been studied and the chiral products used to synthesize (-)-chorismic acid (30) and (-)-shikimic acid (31).6’ Again this year a large number of reports focus attention on various aspects of the Diels- Alder reaction.66 The use of 2-and E-phenylsulphonylacrylateshas been 60 A.Thurkauf P. Hillery A. E. Jacobson and K. C. Rice J. Org. Chem. 1987 52 5466. 61 C. Duhaniel A. Ravard J.-C. Plaquevent and D. Davoust Tetrahedron Lett. 1987 28 5517. 62 J. P. Vacca S. J. deSolrns and J. R. Huff J. Am. Chem. SOC.,1987 109 3478. 63 D. C. Billington R. Baker J. J. Kulagowski and I. M. Mawer J. Chem. Soc. Chem. Commun. 1987 314. 64 S. V. Ley F. Sternfeld and S. Taylor Tetrahedron Lett. 1987 28 225. 65 J. L. Pawlak and G. A. Berchtold J. Org. Chem. 1987 52 1765. 66 For a recent review of the TMDA see D. Craig Chem. SOC.Rev. 1987 1& 187. N. S.Simpkins HO&OP03 Hz 0~.. OBZ MeOaOBz MeOaOH ?H ?H + -+ a::: ORz OBz HO’ OH I (27) OH i26) Scheme 24 examined in more detail by Parsons. The two isomers give complementary regiochemical control in reactions with dienes such as (32) (Scheme 25).67 A variety of 2-phenylsulphinyl-1 -nitroalkenes has been prepared and used as nitroacetylene equivalents in Diels-Alder reactions:* Dienylboronates constitute an attractive new group of dienes which can be used in the Diels-Alder reaction (Scheme 26).69 OAc OAc n,,SO2Ph + nSOzPh OAc C02Me C02Me OAc OAc COzEt PhS02 Scheme 25 67 A. D. Buss G. C. Hirst and P. J. Parsons J. Chem. SOC.,Chern. Comrnun. 1987 1836. M. E. Jung and D. D. Grove J. Chem. SOC.,Chem. Commun. 1987,753; For a related paper concerning the nitro group as a Diels-Alder regiocontrol element see N.Ono H. Miyake A. Kamimura and A. Kaji J. Chem. SOC.,Perkin Trans. 1 1987 1929. 69 M. Vaultier F. Truchet B. Carboni R.W. Hoffmann and I. Denne Tetrahedron Lett. 1987 28 4169. Alicyclic Chemistry 145 A' Scheme 26 The cycloaddition reaction was demonstrated only with maleic anhydride or N-phenyl maleimide although an additional feature is the stereoselective reaction of the allylboronate adducts with aldehydes as shown. Arabinose-derived auxiliaries for acrylate dienophiles have been examined with modest results.'' Much better diastereoselectivity can be obtained using menthyl acrylates such as (33) as demon- strated in a synthesis of lactone (34) a key intermediate for carbonucleoside synthesis (Scheme 27).71 + 'S COzMen ow SOPy 0 (33 1 (34) Scheme 27 High asymmetric induction has been observed in a photolytic 4 + 2 cycloaddition using chiral methoxymethylpyrrolidines as chiral auxi1ia1-y.~~ Further reports con- cerning the cycloadditions of optically active fumarates have appeared,73 as well as the use of chiral Lewis acids to effect asymmetric Diels-Alder reaction.74 Optimiz- ation of the tandem ene/intramolecular Diels- Alder (IMDA) process between 1,4-~yclohexadiene and singly or doubly activated acetylenes has been described (Scheme 28).75The reaction shown using DMAD occurred much more rapidly using microwave heating than conventional methods.With singly activated acetylenes the use of ZnC1 to mediate reaction was optimal.'* T. K. M.Shing and P. Lloyd-Williams J. Chem. SOC.,Chem. Commun. 1987,423. 71 Y. Arai Y.Hayashi M. Yarnamoto H. Takayama and T. Koizumi Chem. Lett. 1987 185. 72 D. Dopp and M. Pies J. Chem. SOC. Chem. Commun. 1987 1734. 73 K. Furuta S. Hayashi Y. Miwa and H. Yamamoto Tetrahedron Lett. 1987 28 5841. 74 H. Takemura N. Komeshima I. Takahashi S. Hashimotq N. Ikota K. Tomioka and K. Koga Tetrahedron Lett. 1987 28 5687. 75 R. J. Giguere A. M. Namen G. Majetich and J. Defauw Tetrahedron Lefr. 1987 28 6553. 146 N. S. Simpkins The IMDA reaction of several suitably substituted furans was found to proceed more efficiently in 2.OM calcium chloride solution than under other recommended condition^.'^ A novel tandem reaction sequence involves a one-sot oxidative cleavage of a furan followed by IMDA reaction of the resulting ene dione (Scheme 29).77 PCC/CH,CI 40% Scheme 29 C02Me 3OO0C U 85% 85 Yo (N.B.in situ decarbomethoxylation) Scheme 30 Three consecutive communications describe preliminary investigations of the transannular Diels- Alder reaction. A variety of tricyclic systems were prepared from the appropriate macrocyclic trienes (Scheme 30).78In some cases the transannular reaction appears more facile than the corresponding acyclic IMDA process. 6 Larger Rings Another annulation process from the Molander group allows for facile construction of ether-bridged seven- and eight-membered carbocycles in excellent yields (Scheme 3 l).79The reaction involves the now familiar stannous fluoride mediated reaction of a bifunctional allylsilane with either 1,4-or 1,5-dicarbonyl compounds.Wender's [4 + 41 cycloaddition approach to the cyclooctadienyl products described last year has been the subject of photolytic modification.80 The method was used in a formal total synthesis of coriolin. Marshall has published a series of papers highlighting the synthetic utility of the Wittig ring-contraction of cyclic ethers including syntheses of (*) aristolactone epimukulol and desoxyasperdiol.81 Finally 76 B. A. Keay J. Chem. Soc. Chem. Commun. 1987 419. 77 H-J. Wu and K. Pan J. Chem. Soc. Chem. Commun. 1987 898. 78 K. Baettig C. Dallaiere R. Pitteloud and P. Deslongchamps Tetrahedron Lett.1987 28 5249; K. Baettig A. Marinier. R. Pitteloud. and P. Deslongchamps ihid.. p. 5253 G. Beruhe and P. Deslong-champs ibid.,p. 5255. 79 G.A. Molander and D. C. Shubert J. Am. Chem. Soc. 1987 109,6877. 80 P. A. Wender and C. R. D. Correia J. Am. Chem. SOC.,1987 109 2523. J. A. Marshall J. Lebreton B. S. DeHoff and T. M. Jenson J. Org. Chem.,1987,52,3883; J. A. Marshall J. Lebreton B. S. DeHoff and T. M. Jenson Tetrahedron Lett. 1987 28 723; J. A. Marshall and J. Lebreton Tetrahedron Lett. 1987 28 3323; J. A. Marshall T. M. Jenson and B. S. DeHoff J. Org. Chem. 1987 52 3860; For related studies see also; J. A. Marshall R. C. Andrews and L. Lebioda J. Org. Chem. 1987 52 2378. 147 Alicyclic Chemistry 100% >10:1 ratio of diastereoisomers Phu -Ph-d-'H 63'/o Scheme 31 further syntheses of muscone have appeared using either a silyloxy-Cope ring- expansion,82 or radical ring-expansion methods.83 7 Bicyclics and Polycyclics A variety of fused cyclopentenones are available via a Mn"'-promoted annulation reaction of enol ethers.84 A new stereocontrolled synthesis of either the cis-or trans-hydroazulene skeleton utilizes alkylative trapping of oxy-Cope intermediates (Scheme 32).85 Q2qq& H H H 81% Br (35) Scheme 32 Thus attempted anionic rearrangement of (35) using KH was unsuccessful giving ether (36) whilst the desired transformation could be cleanly effected thermally in the presence of an acid scavenger.Another addition to the repertoire of tropone cycloadditions is the [6 + 31 variant described by TroskX6 The reaction involves the palladium-catalysed cycloaddition of a trimethylenemethane (TMM) precursor with tropone (Scheme 33).The sequence was also explored with a variety of substituted tropones and TMM precursors giving mainly very good yields. A number of bicyclic skeletons are accessible from conjugate addition products such as sulphoxide (37) (Scheme 34).87 82 R. W. Thies and K. P. Daruwala J. Org. Chem. 1987 52 3798. 83 H. Suginome and S. Yamada Tetrahedron Leu. 1987 28,3963. 84 E. J. Corey and A. K. Ghosh Tetrahedron Lett. 1987 28 175. M. Sworin and K.-C. Lin J. Org. Chem. 1987 52 5640. 86 B. M. Trost and P. R. Seoane J. Am. Chem. SOC.,1987 109 615; B. M. Trost and D.T. MacPherson ibid. p. 3483. 87 R. K. Haynes and A. G. Katsifis J. Chem. Soc. Chem. Comun. 1987 340; see also R. K. Haynes and S. C. Vonwiller ibid. p. 92. N. S. Simpkins 68% Scheme 33 Scheme 34 Hence bicycloheptanone (39) was obtained by treatment of (37) with KOBu' in THF at room temperature whilst use of LDA at -78 "C gave bicyclo[3.2.l]octano1 (38) via kinetically preferred deprotonation of the vinyl sulphoxide. Bicyclo[3.2.l]oct-6-enes are available via a [3 + 21 cycloaddition process which combines allylic chlorides with acetylenes (Scheme 35).88 The reaction works best when the acetylene is substituted with a phenylthio group. The method was used to synthesize an epimer of helmintho~poral.~~ A synthesis of (*)-8,14-cedranoxide (40) has been achieved in which the carbon skeleton was constructed using an electrochemical key-step ('Scheme 36).90 PhS Ph 80% Scheme 35 OMe --*lF.2 Anodic Oxidation r 77 OH 0' [ 0- Scheme 36 88 B.D. Gray C. M. McMillan J. A. Miller and M. Moore Tetrahedron Lett. 1987 28 235; B. D. Gray C. M. McMillan J. A. Miller and G. Mustafa Ullah Tetrahedron Left. 1987 28 689. 89 B. D. Gray and J. A. Miller J. Chem. SOC.,Chem. Commun. 1987 1136. 90 Y. Shizuri Y. Okuno H. Shigemori and S. Yamamura Tetrahedron Lett. 1987 28 6661. Alicyclic Chemistry 8 Natural Product Synthesis Polycyclopentanoid natural products continue to attract synthetic attention. This year a number of reports describe full details of methods suitable for synthesis of such compounds based on y-0x0-a-ester en~lates,~~ the de Mayo reaction (hir- s~tene),~~ A different formal synthesis and Panson-Khand cyclization (q~adrone).~~ of quadrone uses a highly regioselective cyclopropane opening reaction possible due to participation of a neighbouring carboxyl group (Scheme 37).94The enantio- specific synthesis of a suitably functionalized taxol A-ring (41) has been reported using an intramolecular closure of an epoxy-allysilane (Scheme 38).95 \/ Scheme 37 J+ - L-Arabinose + HO / C0,Et TBDMSO- TMS HO J CO,Et TBDMs0-Q ko (41) Scheme 38 Fragment (41) is obtained after a rather laborious sequence of over 20 steps starting from L-arabinose.Other taxane studies have centred on rapid construction of bicyclic frameworks corresponding to either the AB or BC skeleton.Thus Swindell has described an interesting route to the BC unit (42) which utilizes cleavage of known vinylogous imide photoproducts (Scheme 39).96 91 J. P. Marino and E. Laborde J. Org. Chem. 1987,52 1. 92 B. W. Disanayaka and A. C. Weedon J. Org. Chern. 1987 52 2905. 93 P. Magnus L. M. Principe and M. J. Slater J. Org. Chem. 1987 52 1483; see also N. E. Schore and M. J. Knudsen J. Org. Chem. 1987 52 569. 94 T. Imanishi M. Matsui M. Yamashita and C. Iwata J. Chem. Soc. 1987 1802. 95 L. Pattersson T. Frejd and G. Magnusson Tetrahedron Lett. 1987 28 2753; see also J. Lin M. M. Nikaido and G. Clark J. Org. Chern. 1987 52 3745. 96 C. S.Swindell B. P. Patel S. J. deSolms and J. P. Springer J. Org. Chem. 1987 52 2346. N. S. Simpkins 0 + ISOMERS I f=J) +--pJ-J ti H 0 (42) Scheme 39 The key step involved initiation of cyclobutane ring cleavage by a suitable group on nitrogen (R) following prior conversion of the ketone into a suitable leaving group. On a similar theme a different cycloaddition-cleavage sequence has been described which aEords a simple AB-type subunit.97 Both AB- and BC-type bicyclic taxane models are available by the [4 + 41 cycloaddition approach of Wender highlighted last year (Scheme 40)?8 Scheme 40 A formal synthesis of forskolin (43)has been reported by Ziegler which involves modifications of an intermediate (44) obtained previou~ly.~~ A very neat synthesis of a precursor to the AB portion of forskolin involves a one-pot tandem Michael- aldol reaction of (45) (Scheme 41).'0° Another novel approach involves an anionic oxy-Cope rearrangement and pro- vides a model ABC compound."" Finally efficient elaboration of the C-ring has been demonstrated using a compound with a model AB system (SCheme 42).'02 97 G.A. Kraus P. J. Thomas and Y.4. Hon J. Chem. SOC.,Chem. Commun. 1987 1849. 98 P. A. Wender and M. L. Snapper Tetrahedron Lett. 1987 28 2221. 99 F. E. Ziegler B. H. Jaynes and M. T. Saindane J. Am. Chem. SOC.,1987 109 8115. loo E. R. Koft A. S. Kotnis and T. A. Broadbent Tetrahedron Lett. 1987 28 2799. 101 1. A. Oplinger and L. A. Paquette Tetrahedron Left. 1987 28 5441.lo* S. Hashimoto M. Sonegawa S. Sakata and S. Ikegami J. Chem. SOC.,Chem. Commun. 1987 24. Alicyclic Chemistry 0 Forskolin (43) Scheme 41 C02Me C02Me _-_ + OH H ,,,,0SiPh2 &. OH Scheme 42 The first synthesis of the phorbol skeleton has been rep~rted.''~ Compound (46) a hybrid of the tigliane and ingenane structural types was prepared using an IMDA process and an intramolecular aldol reaction in the key ring-forming steps (Scheme 43). A very straightforward synthesis of the basic tricyclic framework of the ingenanes has been accomplished.'04 Another model study uses an intramolecular dioxolenone photocycloaddition developed earlier to prepare the same ske1et0n.I"~ More advanced studies have been reported by Paquette in which the tricyclic system (47) I03 P.A. Wender R. M. Keenan and H. Y. Lee J. Am. Chem. Soc. 1987 109 4390. I04 G. Mehta and V. P. Pathak J. Chem. SOC.,Chem. Commun. 1987 876. J. D. Winkler K. E. Henegar and P. G. Williard J. Am. Chem. SOC.,1987 109 2850. 152 N. S. Sirnpkins H I \ Br -Me09 cHo-w Me0 OMe Me0 TMSO -0Bn -0Bn H H Br HO OH OH OBn (46) Scheme 43 Me--- HO (47) (48) Scheme 44 was advanced to keto-tetrol (48) having all the functionality present in the natural product ingenol (49) (Scheme 44).'06 The synthesis of a number of other product types possessing fused seven-membered rings has been addressed. Rigby has used cyclopropyl ketones as inter- mediates in a synthesis of (&)-grosshemin (50),'07 and in a construction of the ophiobolane ring system (Scheme 45).'08 The same group has detailed more efforts in the synthesis of guaianolide~,'~~ and other work in this area has led to a total synthesis of (*)-gnididione."' Massive synthetic interest continues to centre on the synthesis of the antiparasitic agents the milbemycins and avermectins.Attention has now largely turned from the 106 R. J. Ross and L. A. Paquette J. Org. Chern. 1987 52 5497. I07 J. H. Rigby and C. Senanayake 1. Am. Chem. Soc. 1987 109 3147. 108 J. H. Rigby and C. Senanayake J. Org. Chem. 1987 52 4634. 109 J. H. Rigby and J. A. Z. Wilson J. Org. Chem. 1987 52 34. 110 C. P. Dell and D. W. Knight J. Chem. Soc. Chem. Commun. 1987 349.Alicyclic Chemistry OCOBu' o+0 OAc Ophiobolin F Scheme 45 spiroacetal grouping to the oxahindrene portion and to problems of coupling various fragments to give the natural products. Jung has used an elegant cycloaddition strategy to prepare fragment (51) in racemic form (Scheme 46).'" The initial cycloaddition furnishes (52) which has the required skeleton as well as functionality at all the necessary positions; the remaining steps involve reduction of the C-4 ester to a methyl and inversion of configuration at C-5. Simpler systems have been prepared by White'12 and by Dani~hefsky;"~ each of these products lacked one key feature needed for the natural product. The efficient preparation of the monocyclic lower portion of milbemyin p1in chiral form has also been described (Scheme 47).' l4 111 M.E. Jung Y. Usui and C. T. Vu Tetrahedron Lett. 1987 28 5971. I12 J. D. White and A. P. Dantanarayana Tetrahedron Left. 1987 28 6417. 113 D. M. Armistead and S. J. Danishefsky Tetrahedron Lett. 1987 28 4959. '14 N. J. Anthony T. Clarke A. B. Jones and S. V. Ley Tetrahedron Lett. 1987 28 5755. N. S. Sirnpkins (52) 53% +isomer Scheme 46 + + 0 OH 0 0 .0 0 4' PhSO2 PhSO2 0,H i 0,H I 0 OMe Scheme 47 OR x -OR /-Partial structure 2-epimer of avermectin or ivermectin 0; %- H OR Me Conjugated isomer Scheme 48 Ahcyclic Chemistry A key deconjugation step in Hanessian's relay synthesis of avermectin B, has become the subject of some controversy.From two subsequent reports it now seems that deconjugation of either A2-avermectin or A*-ivermectin directly to the natural products does not occur.'15 Rather the primary product of such a process is the 2-epi-isomer and the natural system can then result under certain conditions by epimerization (Scheme 48). 0 Other significant targets which have received attention include phyllanthocin (53),Il6 fredericamycin A (54),"' and ikarugamycin (55).Il8 Notably Corey has devised a synthetic route to the limonoid system"' and achieved the first synthesis of a ginkgolide (*)-bil~balide.~' 11s S. Hanessian D. Dube and P. J. Hodges J. Am. Chem. Soc. 1987 109 7063; B. Fraser-Reid H. Wolleb R. Faghih and J. Barchi jun.J. Am. Chem. Soc. 1987 109 933. 116 A. B. Smith 111 and M. Fukui J. Am. Chem. Soc. 1987 109 1269; S. F. Martin M. S. Dappen B. Dupre and C. J. Murphy J. Org. Chem. 1987 52 3706. I17 M. A. Ciufolini and M. E. Browne Tetrahedron Lett. 1987 28 171; G. Mehta and D. Subrahmanyam Tetrahedron Lett. 1987 28 479; D. L. J. Clive A. G. Angoh and S. M. Bennett J. Org. C'hem. 1987 52 1339. 118 G. Mehta A. N. Murthy and D. S. K. Reddy Tetrahedron Lett. 1987 28 1467; L. A. Paquette J. L. Romine and H.-S. Lin Tetrahedron Left. 1987 28 31. 11Y E. J. Corey J. G. Reid A. G. Myers and R. W. Hahl J. Am. Chem. Soc. 1987 109 918.