6 Alicyclic Chemistry By N. S. SlMPKlNS Department of Chemistry Queen Mary College Mile End Road London E14NS 1 General An issue of Chemical Reviews has been devoted to 'Emerging Organic Reactions' and covers many topics relevant to alicyclic synthesis.' Meyers has developed a number of chiral bicyclic lactam systems which are suitable for synthesis of alicyclic compounds in optically pure form. The versatility of this method has now been further demonstrated by synthesis of chiral 4,4-disubstituted cyclohexenones,2 cycl~pentenones,~ and cyclobutanones? e.g. (-)-grandisol (Scheme 1). yp&MeL@p2+ 05 Me MeOzC "1 IMe H 0 H 0 (93%) 12 1 ratio iii *--Me02C I Ho be Me (-) -grandisol iv v . Ph 0 &7 -i";l Rl R diastereoisomeric ratio 4748% 75~25to 97:3 >95% e.e.Reagents i CH,=CH2 hv -78 "C; ii H2S04 MeOH; iii Ph,P=CH2; iv LDA RX;v LDA HMPA R'X; vi Red Al;vii Bu4NH2P04 Scheme 1 ' See Chem. Rev. 1986,86 No. 5. A. I. Meyers B. A. Lefker K. T. Wanner and R. A. Aitken J. Org. Chem. 1986 51 1936. A. I. Meyers and B. A. Lefker J. Org. Chem. 1986 51 1541. A. I. Meyers and S. A. Fleming J. Am. Chem. Soc. 1986 108 306. 123 124 N. S Simpkins Another asymmetric synthesis of grandisol also involves the use of an easily detachable chiral auxiliary and allows for synthesis of both enantiomers.' A new general method for synthesis of cycloalkenones involves cyclization of dialkylamides bearing a vinyl iodide appendage using Bu'LL6 The method gives good yields and is especially suitable for preparation of a-silylenones.A Lewis acid mediated version of the Nicholas reaction yields cobalt-complexed cycloalkynes of varying ring sizes.7 Decomplexation to give the cycloalkyne is not yet possible however subsequent Pawson-Khand reaction provides an elegant and stereoselective route to polycyclics with potential for natural product synthesis (Scheme 2).CO benzene 75 % 8 85% Scheme 2 A facile Lewis acid rearrangement of epoxy silyl ethers allows for 1-carbon ring-expansion of suitable cyclic systems.8 Another ring-expansion method uses the reaction between a cyclic P-hydroxyselenide and TlOEt (5.5 eq.)' (e.g. Scheme 3). &J PhSef ___, '8"" 95:5 Scheme 3 Contrary to the usual trend migration of an alkyl group in preference to a vinyl group is observed although the outcome is somewhat substituent-dependent.Other new general methods which have been largely illustrated using cyclic compounds include a regioselective entry to vinyl tins via enol triflates," and a method for P-functionalization of enones involving 'phosphoniosilylation'." M. Demuth A. Palomer H.-D. Sluma A. K. Dey C. Kruger and Y.-H. Tsay Angew. Chem. Int. Ed. Engl. 1986 25 1117. H. Sawada M. Webb A. T. Stoll and E. Negishi Tetrahedron Lett. 1986 21 775. 'S. L. Schreiber T. Samrnakia and W. E. Crowe J. Am. Chem. Soc. 1986 108 3128. K. Maruoka M. Hasegawa H. Yarnarnoto K. Suzuki M. Shimazaki and G. Tsuchihashi J. Am. Chem. Soc. 1986 108 3827. A. Krief and J. L. Laboureur J.Chem. Soc. Chem. Commun. 1986 702. 10 W. D. Wulff G. A. Peterson W. E. Bauta K.4. Chan K. L.Faron S.R. Gilbertson R.W. Kaesler D. C. Yang and C. K. Murray J. Org. Chem 1986,51 277. 11 A. P. Kozikowski and S. H. Jung J. Org. Chem. 1986 51 3400. Alicyclic Chemistry A report covering the synthesis of non-natural products has appeared,12 and another review which discusses strained molecules has also been p~b1ished.l~ Interest in novel cumulenes continues particularly in the synthesis of strained compounds which are stabilized by incorporation of bulky groups. Amongst compounds recently synthesized are the t-butyl-8-membered ring allene (1),14 the first ever bicyclic cumulatriene (2)," and the tetramethyl benz-fused cyclooctatrienyne (3).16 The first known bicyclo[l.l.l]pentane with sp2 carbon atoms at each bridge is the very strained ketone (4) with a half-life of 90 min at -30 'C.17 Me Me Me he hu 260nm hu 334 nm ___c_, -10 K 17 K Sensitizer Matrix Photolysis of (4) at 10K in the presence of a photosensitizer produces the ground-state triplet hydrocarbon (5),'* as does photolysis of (6).19Similarly cyclopro- pen-3-yl has been generated at low temperature in a matrix and characterized by e.p.r.spectroscopy.20 Addition of an alkyne to a cyclobutylidene results in formation of several novel products (Scheme 4).21 I Scheme 4 l2 P. E. Eaton (ed.) Tetrahedron 1986 42 No. 6. l3 K. B. Wiberg Angew. Chem Znt. Ed. Engl. 1986 25 312. 14 J. D. Price and R.P. Johnson Tetrahedron Lett. 1986 27 4679. 1s R. S. Macomber and T. C. Hemling J. Am Chem. SOC.,1986 108 343. 16 T. L. Chan T. C. W. Mak C.-D. Poon H. N. C. Wong J. H. Jia and L. L. Wang Tetrahedron 1986 42 655. P. Dowd and Y. H. Paik Tetrahedron Lett. 1986 27 2813. P. Dowd and Y. H. Paik J. Am. Chem SOC.,1986 108 2788. 19 G. J. Snyder and D. A. Dougherty J. Am. Chem SOC.,1986 108 299. 2o G. L.Closs and 0.D. Redwine J. Am Chem. Soc. 1986 108 506. 21 U. H. Brinker and J. Weber Tetrahedron Lett. 1986 27 5371. 126 N. S. Simpkins Studies on strained pyramidalized olefins have resulted in successful matrix isolation and characterization of (7),22whilst (8) has been detected by trapping with diphenylisoben~ofuran.~~ (7) n = 2 6 8% McMurry has published further details concerning the synthesis and properties of the unusual cyclic olefins (9) and (10).Whilst in (9) there appears to be little interaction between the carbon-carbon double bonds,24 (10) forms a static silver olefin 7r-complex when treated with AgOTf.25 2 Three-membered Rings Schollkopf has reported a straightforward synthesis of 1 -amino- l-cyclopropanecar- boxylic acids which involves reaction of t-butylisocyanoacetate with epoxides26 (Scheme 5). But02C' 2. BF,.OEt 2. KOBu' A 4 CNC02Bu' CN C02Bu' Scheme 5 In another paper from the same group these products are again prepared stereoselectively using a carbene derived from a chiral bislactim-ether.27 Dichlorocar- bene cyclopropanation of allylic alcohols is possible in highly stereoselective fashion regardless of the olefin substitution pattern.28 The use of homochiral ketals for asymmetric cyclopropane synthesis has been extended to bicyclic and applied to large rings in a synthesis of (R)-m~scone.~' Asymmetric cyclopropanation of olefins using diazo-compounds catalysed by chiral copper semicorrin complexes has also received more attenti~n.~' Vinylcyclopropanes have been prepared by a new method which relies on conju-gate addition of a-bromoester dienolates to enones3* (Scheme 6).22 J. E. Radziszewski T.-K. Yin F. Miyake G. E. Renzoni W. T. Borden and J. Michl J. Am. Chem. SOC.,1986 108 3544. 23 G. E. Renzoni T.-K. Yin and W. T. Borden J. Am. Chem. Soc. 1986 108 7121. 24 J. E. McMurry G.J. Haley J. R. Matz J. C. Clardy G. V. Duyne R. Gleiter W. Schafer and D. H. White J. Am. Chem. Soc. 1986 108 2932. 25 J. E. McMurry G. J. Haley J. R. Matz J. C. Clardy and J. Mitchell J. Am. Chem. Soc. 1986 108 515. 26 U. Schollkopf B. Hupfeld and R. Gull Angew. Chern Znt. Ed. Engl. 1986 25 754. 27 U. Schollkopf M. Hauptreif J. Dippel M. Nieger and E. Egert Angew. Chem. Znt. Ed. EngL 1986 25 192. 28 F. Mohamadi and W. C. Still Tetrahedron Lett. 1986 27 893. 29 E. A. Mash and K. A. Nelson Tetrahedron Lett. 1986 27 1441. 30 K. A. Nelson and E. A. Mash J. Org. Chem. 1986 51 2721. 31 H. Fritschi U. Leutenegger and A. Haltz Angew. Chem. Znt. Ed. Engl. 1986 25 1005. 32 T. Hudlicky L. Radesca H. Luna and F. E. Anderson 111 J. Org.Chem. 1986 51 4746. Alicyclic Chemistry The products such as (11) have considerable synthetic application including the well known pyrolysis to furnish cyclopentenes (1 2). High-temperature chemistry such as this has been recently reviewed.33 New and useful applications of vinylcyclopropane chemistry include a radical- mediated stereoselective ~xygenation~~ (Scheme 7) and a convenient synthesis of substituted cycl~heptenones~~ (Scheme 8). 63% Scheme 7 / R 0Si.-Scheme 8 Et,AlCl effectively mediates the aminolysis of activated cyclopropanes allowing regioselective opening of suitable substrates even with primary amine~.~~ A sequence combining stereoselective cyclopropanation of an allylic alcohol followed by regioselective oxymercuration offers an attractive route to systems having alternating hydroxyl and methyl substituents (Scheme 9).37 Scheme 9 33 M.Karpf Angew. Chem. Int. Ed. Engl. 1986 25 414. 34 K.S. Feldman R.E. Simpson and M.Parvez J. Am. Chem. Soc. 1986 108 1328. 35 E.Piers M.S.Burmeister and H. V. Reissig Can. J. Chem. 1986 180. 36 L. A. Blanchard and J. A. Schneider J. Org. Chem. 1986 51 1372. ’’ D. B. Collum W. C. Still and F. Mohamadi J. Am. Chem. SOC.,1986 108 2094. N. S. Simpkins The Ni( CO),-induced reductive carbonylation of gem-dibromocyclopropanes is a versatile method for the synthesis of cyclopropanecarboxylic acid derivative^^^ (Scheme 10). 0 Br Br PrNH Ni(CO), 75 "C Ph Ni(CO), DMF ,PhYEpr gyHa. Br 82Yo 78% mixture of cis and trans Scheme 10 A tetracyclic intermediate related to lycorine has been synthesized by an elegant application of the cyclopropyl iminium ion rearrangement39 (Scheme 11).Scheme 11 Thermal rearrangement of a cyclopropene azide (13) has allowed the preparation of the first kinetically stable azacyclobutadiene (14)? cycZo-C,I is a readily prepared and explosive compound which appears to be a salt-like halogenocarbon best formulated as (15):l 38 T. Hirao Y. Harano Y. Yamana Y. Hamada S. Nagata and T. Agawa Bull. Chem. SOC.Jpn. 1986 59 1341. 39 R. K. Boeckman jun. J. F.Sabatucci S. W. Goldstein D. M. Springer and P. F. Jackson J. Org. Chem 1986 51 3740. U. J. Vogelbacher M. Regitz and R Mynott Angew. Chem Int.Ed. EngL 1986 25 842. 41 R. Weiss G.-E. Meiss A. Haller and W. Reinhardt Angew. Chem Inr. Ed. EngL 1986 25,103. Alicyclic Chemistry 3 Four-membered Rings A number of reports have concerned intramolecular [2 + 21 cycloadditions as a method of cyclobutane constyction. Pirrung has investigated photolysis of cyclooc- tenes such as (16) and obtained mixtures of products in rather low yield?2 In related studies the use of an acetal as a link between enone and olefin was found more ~atisfactory~~ (Scheme 12). The regiocontrol in such cycloaddition reactions of carbonyl-substituted 144- alkeny1)-1-cyclopentenes has been thoroughly examined,44 allowing some generaliz- ations concerning the favoured mode of ring-closure. A strategy involving intramolecular [2 + 21 photocycloaddition and subsequent cyclobutane fragmenta- tion has proved effective for the synthesis of a number of angular triquinanes4’ (Scheme 13).F02R (*)-pentalenene % *zo2Et __* --, hu (*)-pentalenic acid CO2Et ,t Mew 73% (and minor isomer) Scheme 13 Another method utilizes a copper-catalysed photobicyclization followed by cationic rearrangement as a general stereoselective and high yielding route to fused norbornanes.& Lewis acid mediated [2 + 21 cycloadditions have also been examined. Di-t-butylmethylenemalonateadds effectively to vinyl ethers at low temperature in the presence of ZnBr2.47 Allenic esters also undergo this type of reaction with simple alkenes (reaction times 1-25 days) to give mixtures of stereoisomeric products and again the intramolecular version has been examined48 (Scheme 14).Johnson has examined the generation and rearrangement of oxonium ylides. Thus treatment of substituted diazo-ketones with Rh(OAc) gives a mixture of products in which cyclobutanones often pred~minate~~ (Scheme 15). 42 M. C. Pirrung and N. J. G. Webster Tetrahedron Lett. 1986 27 3983. 43 M. C. Pirrung and S. A. Thomson Tetrahedron Lett. 1986 27 2703. 44 A. R..Matlin C. F. George S. Wolff and W. C. Agosta J. Am. Chem. SOC,1986 108 3385. 4s M. T. Crimmins and J. A. DeLoach J. Am. Chem SOC.,1986 108 800. 46 K.Avasthi and R G. Salomon J. 0%.Chem. 1986 51 2556. 47 M. R. Baar P. Ballesteros and B. W. Roberts Tetrahedron Lett. 1986 27 2083.48 B. B. Snider and E.Ron J. Org. Chem 1986 51 3643. 49 E. J. Roskamp and C. R. Johnson. J. Am. Chem. SOC.,1986 108,6062. 130 N. S. Simpkins CO2Et CO2Me CH,CI 25 "C "i 56% 21O/o and a bridged adduct (16%) Scheme 14 0 A0 PN2 Rh(OAc) 1 mol% + &OM' benzene RT OMe 45O/O 10% Scheme 15 Applications of the cyclobutenyl phosphorane (17) appear limited to reaction with two equivalents of an aromatic aldehyde." Danheiser has nicely demonstrated his cyclobutenone strategy for preparation of polysubstituted aromatics with a total synthesis of mycophenolic acid (18p (Scheme 16). Another elegant use of cyclobutanes in synthesis involves titanium reagents in a synthesis of A9*'2-capnellene52 (Scheme 17).A total synthesis of (-)-punctatin A has been accomplished in which the cyclo- butane ring was formed by a photolytic Norrish type I1 processs3 (Scheme 18). 4 Five-membered Rings Details have appeared concerning a number of five-membered ring-forming reactions which are mediated by silicon groups. Denmark has further examined the stereocon- trol possible in the silicon-directed Nazarov cyclization thus treatment of j3-silyl enone (19) with FeCl gives predominantly the bicyclic enone (20)54(Scheme 19). 50 T. Minami N. Harui and Y. Taniguchi J. Org. Chem. 1986 51 3572. 51 R. L. Danheiser S. K. Gee and J. J. Perez J. Am. Chem SOC.,1986 108 806. 52 J. R. StiIIe and R. H. Grubbs J. Am. Chem. Soc. 1986 108 855. 53 L. A. Paquette and T.Sugimura J. Am. Chem. SOC.,1986 108 3841. 54 S. E. Denmark K. L. Habermas G. A. Hite and T. K. Jones Tetrahedron 1986.42 2821. Alicyclic Chemistry 131 / -SiO + benzene-(sealed120tube)"C-14 h @%-% Me0 O,,OMe 73'/o Me <OOMe COiH ,' 4 steps Me0 Me (18) Scheme 16 I + % TiCp 9 steps (*)-A9.''Capnellene +- - - - - - -81% overall Reagents i Cp2TiAA1Mel DMAP; ii HO/\/OH p-TSA benzene A \/ c1 Scheme 17 M& -Hfl hv 254nm --+ II SEMO SEMO 49yo (-)-Punctatin A Scheme 18 N. S. Simpkins + P R ‘H R R (19) R = Me CH=CH, Ph erc. (20) major minor combined yields 40-99% Scheme 19 In a study of the reactions of cis-silyl tin olefins such as (21) it was found that BF,-promoted Nazarov cyclizations occurred with retention of the bulky silicon group” (Scheme 20).(21) R = (CH2)3CI 80% Scheme 20 More details of the intramolecular cyclizations of allylS6 and propargyl” silanes to give five-membered ring products have appeared. Allylsilanes also feature in an annulation sequence described by Lee.58 A silyl enol ether is reacted with reagent (22) to produce an intermediate which then cyclizes under harsher Lewis acid conditions (Scheme 21). The method suffers from lack of regioselectivity in most OMe YOMe TMSOTf @+ & OSiMe3 I. (22) + 2. TiCl, -78 “C OMe 48% combined yield Scheme 21 cases but is interesting in that TMSOTf is shown selectively to activate an enol silane in the presence of an allylsilane.A highly stereocontrolled addition of the iodinated allylsilane (23) to 1,2-diones has been described by M01ander~~ (Scheme 22). 55 B. L. Chenard C. M. Van Zyl and D. R. Sanderson Tetrahedron Lett. 1986 27 2801. 56 G. Majetich R. W. Desmond jun. and J. J. Soria J. Org. Chem. 1986 51 1753. 57 D. Schinzer J. Steffen and S. Solyom J. Chem SOL Chem Commun. 1986 829. T. V. Lee K. A. Richardson and D. A. Taylor Tetruhedron Lett. 1986,27 5021. 59 G. A. Molander and D. C. Shubert J. Am. Chem. Soc. 1986 108,4683. 133 Alicyclic Chemistry II Scheme 22 Intramolecular olefin cyclization of hmmerer reaction products is possible yielding sulphur-substituted cyclopentanones which can then be further transformed into dienonesm (Scheme 23).The method appears limited to substrates having a fairly nucleophilic double bond and can lead to other products resulting from carbocation capture by CF3C02-,although some general applicability to five- six- and seven-membered rings is evident. 0 &,Me II 0 CH,CI, 0 "C 7 8 '10 72'/o Scheme 23 Snider has disclosed details of the EtAlC1,-catalysed reaction of alkenes with electrophilic cyclopropanes which gives good yields of cyclopentane products.61 In an extension of earlier work Canonne has used bis-Grignard reagents having one secondary terminus in a high yielding and stereoselective preparation of cylopen-tanols6 (Scheme 24). + FMe R = H alkyl aryl I minor major combined yields 70-88% Scheme 24 A similar sequence using an homologous bis-Grignard reagent gave disappointing yields of cyclohexanols.Polyfunctionalized cyclopentanes are obtained when suitably activated olefins are treated with (2-carbamoylallyl)lithium reagents63 (Scheme 25). Significant propor- tions of uncyclized products are also usually formed. Vinyl lithiums generated from aryl sulphonyl hydrazones undergo efficient and highly stereoselective cyclization onto olefinic appendages. Subsequent in situ inter-molecular quenching of the resulting cyclized alkyl lithium has been accomplished 60 H. Ishibashi S.Harada M. Okada M. Ikeda K.Ishiyama H. Yamashita and Y. Tamura Synthesis 1986 847. R.B. Beal M. A. Dombroski and B. B. Snider J. Org. Chem. 1986 51 4391. 62 P.Canonne and M.Bernatchez J. Org. Chem 1986,51 2147. 63 P.Beak and K. D. Wilson J. Org. Chem 1986,51,4627. N. S. Simpkins R' R2N I 8-8 1Yo EWG = CONR Scheme 25 for the first time,@ thus offering an attractive alternative to the analogous radical sequence (Scheme 26). A review highlights the utility of cy -chlorosulphides in organic synthesis,65 includ- ing Ramberg-Backlund reactions of cyclic a-chlorosulphones to give cyclic olefins. A new variant of this approach constitutes a useful multistep route to substituted ~yclopent-3-enones~~ (Scheme 27). IE+ x?' H 49-6 1Yo Tris = triisopropylbenzene E = Br CHO CO,H CH2CH20H Scheme 26 n n ___ 02 02 R R 83% Reagents i NCS py; ii TolSO,Na HCI EtOH; iii HOkoH H+ benzene; iv rn-CPBA; v base RX;vi NaH KH; vii p-TSOH-py HzO acetone Scheme 27 64 A.R. Chamberlin and S. H. Bloom Tetrahedron Lett. 1986 27 551. " B. M.Dilworth and M. A. McKervey Tetrahedron 1986,42 3731. 66 H. Matsuyama Y. Miyazawa and M. Kobayashi Chem. Lett. 1986 433. Alicyclic Chemistry An intramolecular nitrone-alkene cycloaddition yields a stereoisomeric mixture of bicyclic isoxazolidines (24) which can then be cleaved to give substituted aminocycl~pentanols~~ (Scheme 28). The method appears to offer a direct and operationally simple route to a variety of prostanoid analogues although as yet the cycloaddition is not stereoselective. NHPh H I H OSiPh3 (24) and diastereomer Scheme 28 Full details have appeared concerning the photoreductive cyclization of a,&-unsaturated ketones including stereochemical aspects and comparison with chemical methods?* The reaction has the advantage of being conducted under homogeneous conditions and will tolerate additional functionality as in conversion of ketoester (25) (Scheme 29).solvent = HMPA (80%) Scheme 29 = tt,N-MeCN (86%) Several papers have dealt with the application of cobalt reagents to the preparation of cyclopentenones for example in a synthesis of cyclocolorenone (26),69initially thwarted by an unexpected ‘mislocation’ in cyclopropanation of ketal (27).70 Br Br Br (27) (26) A rhodium cluster effects catalytic hydroformylation and hydrocarboxylation of certain enynes giving mixtures of products including cyclopentenones and b~tenolides.~’ A more selective method which utilizes a catalytic amount of Pd(OAc) allows oxidative cyclization of hexa-l,Sdienes as in Scheme 30.72 67 J.R. Hwu and J. A. Robl J. Chem. SOC.,Chem. Commun. 1986 704. D. Belotti J. Cossy J. P. Pete and C. Portella J. Org. Chem. 1986 4196. 69 M. Saha B. Bagby and K. M. Nicholas Tetrahedron Lett. 1986 915. 70 M. Saha S. Muchmore D. Van der Helm and K. M. Nicholas J. 0%.Chem. 1986 1960. ” K. Doyama T. Joh S. Takahashi and T. Shiohara Tetrahedron Left. 1986 27 4497. 72 T. Antonsson A. Heumann and C. Moberg J. Chem. Soc. Chem. Cornmun. 1986 518. N. S. Simpkins 70‘/o (> 95 % stereoselective) Scbeme 30 The area of cyclopentane annelation has been reviewed.73 Annulating reagents utilized very recently include the sulphone (28),74 the phosphonate (29),” the dithiane (30) and the iodide (31) in which the vinyl silane acts as a masked ketone.76 OEt Vinyl tin compounds are attractive reagents in a variety of ring-forming reactions.Piers has investigated several applications to preparation of cyclopentanoid systems77 and succeeded in synthesizing the dolostane diterpene (32) Scheme 31.78 1. LDA THF HMPA FL.1 2. PhN(SO,CF,) 3. (Ph,P),Pd steps Scbeme 31 73 B. M. Trost Angew. Chem Int. Ed. EngL 1986 25 1. 74 S. De Lombaert I. Nemery B. Roekens J. C. Carretero T. Kimmel and L. Ghosez Tetrahedron Lett. 1986 27 5099. 75 S. C. Welch J.-M. Assercq and J.-P. Loh Tetrahedron Lett. 1986 27 1115.76 D. R. St. Laurent and L. A. Paquette J. Org. Chem. 1986 51 3861; L. A. Paquette R. A. Galemmo jun. J.-C. Caille and R. S. Valpey ibid. p. 686. 77 E. Piers and R. T. Skerlj .IChem. Soc. Chem. Commun. 1986 626. E. Piers and R. W. Fnesen J. Org. Chem 1986,51 3405. Alicyclic Chemistry 5 Six-membered Rings Cytochalasins G and H,79(+)-compactin,80 and 3-oxosilphinenes1 are recent examples of molecules which have succumbed to total synthesis uia application of the intramolecular Diels-Alder reaction. Asymmetric Diels-Alder chemistry also continues to attract interest; Davies has nob illustrated the use of an unsaturated chiral iron acyl to obtain a Diels- Alder adduct in useful diastereoisomeric excess.82 A new and elegant approach to this problem involves mediating the cycloaddition process with a chiral Lewis acid.Kelly has found that the chiral quinone complex (33) undergoes highly selective reaction with diene (34) to give the expected product in 98% enantiomeric excess83 (Scheme 32). OMe 0 98% e.e. (33) Scheme 32 The reaction worked equally well with several other reaction partners allowing an enantioselective synthesis of (-)-bostrycin. A chiral titanium reagent also effects asymmetric Diels- Alder reactions to give products in high e.e. Remarkably this reagent works equally well in catalytic (10%) quantities providing the reaction is carried out in the presence of 4A molecular sieves84 (cJ the Sharpless epoxidation). A full paper concerns the use of chiral Lewis acids to effect cationic cyclization of unsaturated aldehyde^.^' Further examples of the Posner 2 + 2 + 2 one-pot construction of cyclohexane systems have appeared.86 In another method involving 79 H.Dyke R. Santer P. Steel and E. J. Thomas J. Chem. Soc Chem Commun.,1986,1447; E. J. Thomas and J. W. F. Whitehead ibid. p. 727. 80 G. E. Keck and D. F. Kachensky J. Org. Chem. 1986 51 2487. 81 M. Ihara A. Kawaguchi M. Chihiro K. Fukumoto and T. Kametani J. Chem. SOC Chem. Commun. 1986 671. '* S. G. Davies and J. C. Walker J. Chem Soc. Chem. Commun. 1986 609. 83 T. R. Kelly A. Whiting and N. S. Chandrakumar J. Am. Chem. Soc. 1986 108 3510. 84 K. Narasaka M. Inoue and N. Okada Chem Lett. 1986,1109; K. Narasaka M. Inoue' and T. Yamada ibid p.1967. 85 S. Sakane K. Maruoka and H. Yamamoto Tetrahedron 1986 42 2203. 86 G. H. Posner S.-B. Lu E. hirvatham E. F. Silversmith and E. M. Schulman J. Am Chem. SOC.,1986 108 511; G. H. Posner S.-B. Lu and E. Asirvatham Tetrahedron Lett. 1986 27 659. N. S. Simpkins a double Michael reaction Mukaiyama has reacted siloxydienes with a,P -unsatur-ated ketones in the presence of trityl perchlorate" (Scheme 33). The method has the advantage of operating under very mild conditions and gives products of kinetic control. 55% Scheme 33 The problem of stereoselective construction of exocyclic tetrasubstituted double bonds has been addressed allowing the first stereospecific synthesis of E-y-bisabolene" (Scheme 34). The key feature of this synthesis is a stereospecific 84% overall isomerically pure Reagents i BuLi B U I 3 ; ii TMSOTf; iii BuLi CuI; (MeO),P-HMPA-Mel; iv TBAF; TiCI,-methylaniline complex Scheme 34 T.Mukaiyama Y. Sagawa and S. Kobayashi Chem. Lett. 1986 1821. an E. J. Corey and W. L. Seibel Tetrahedron Lett. 1986 27 905. Alicyclic Chemistry 139 migration of a carbon chain from boron to carbon. Similar chemistry also allows for preparation of Z-y-bisabolene but with lower ~electivity.'~ In a series of papers Livinghouse has described new procedures for arene-alkene carboannulati~ns~~ (Scheme 35). These methods appear limited to systems having the right combination of nucleophilic arene and/or alkene groups. OMe OMe OMe PhS+BF,-NC y or PhSCl then AgBF /R R OMe NC X NC Meo&R R R = H or Me R = Me 30:l (combined yield 48%) Scheme 35 The two conformers of the fully substituted cyclohexane (35) are separable by chromatography have distinct melting points and are stable indefinitely in solution at room temperature." The barrier to cyclohexane inversion is much higher than any hitherto observed.6 Larger Rings In a continuation of studies on trans cycloalkenes 1-methoxy- trans-cyclooctene has been synthesized by a Peterson elimination route.92 89 E. J. Corey and W. L. Seibel Tetrahedron Lett. 1986 27 909. YO E. Edstrom and T. Livinghouse J. Chem. Soc. Chem. Commun. 1986 279; E. D. Edstrom and T. Livinghouse Tetrahedron Lett. 1986 27 3483; E. D. Edstrom and T.Livinghouse J. Am Chem. SOC. 1986 108 1334. 91 D. Wehle and L. Fitjer Tetrahedron Lett. 1986 27 5843. 92 M. J. Prior and G. H. Whitham. J. Chem. Sac.. Perkin Trans. I 1986 683. 140 N. S. Simpkins A new method for the synthesis of polycycles incorporating 8-membered rings has been described by Wender; thus nickel-catalysed [4 + 41 cycloaddition of suitable substrates gives cyclooctadienyl products in stereoselective fashiong3 (Scheme 36). 100% cis :trans 19 1 70% yield C02Me H Reagents i base Brw 84% ;ii 11% Ni(COD)2 33% Ph,P toluene 60 "C Scheme 36 The use of chemically modified KH (using iodine to remove potassium metal) improves yields in oxy-Cope rearrangement^.^^ Acetylenic oxy-Cope rearrangements feature in recent total syntheses of Phoracantholide 1 Poitediol and Dactylolgs (Scheme 37).Ireland ester enolate-type ring contraction of macrocyclic lactones to give car- bocycles and heterocycles has been more fully described.% This method has now MEMoG -O ***\ 170°C Me --_ ~ -..& OMEM HO 0 Phoracantholide 62% Dactylo1 Scheme 37 93 P. A. Wender and N. C. Ihle J. Am. Chem. SOC.,1986 108,4678. 94 T. L. Macdonald K. J. Natalie jun. G. Prasad and J. S. Sawyer J. Org.Chem. 1986,51 1124. 95 T. Ohnuma N. Hata N. Miyachi T. Wakamatsu and Y.-Ban Tetrahedron Lett. 1986 27 219; R. C. Gadwood R. M. Lett and J. E. Wissinger J. Am. Chem. SOC 1986 108 6343. % A. G. Cameron and D. W. Knight J. Chen SOC.,Perkin Trans. I 1986,161; R. L. Funk M.M. Abelman and J. D. Munger jun. Tetrahedron 1986,42 2831. Alicyclic Chemistry enabled the synthesis of a known quadrone precursor.97 A similar strategy has now been applied to 13- and 17-membered ring ethers. Thus low-temperature [2,3] Wittig rearrangement of compounds (36) and (37) is effected on treatment with alkyllithiums at low temperature (Scheme 38). OH '1 94% from (E,E) 96% from (Z,Z) major isomer 4.5 :1 mixture 85% combined yield Scheme 38 7 Bicyclic Compounds There is continued interest in methods for the rapid assembly of cyclic systems of various types involving sequential Michael additions.w The first three-component triple conjugate addition process gives fair yields of substituted bicyclo[2.2. llhep- tanones in stereoselective fashion'"" (Scheme 39).,C02Me [I p-Qo Ph Ph Me02C Ph 68% NU =-SPh Scheme 39 40% Nu =fCo,Me The use of an allylic alcohol or ether as an allylic cation precursor allows control of regioselectivity in the 'ionic Diels- Alder reactions' described by Gassman"' (Scheme 40). 97 R L. Funk and M. B. Abelman J. Org. Chem 1986,51 3241. 98 T. Takahashi H. Nemoto Y. Kanda J. Tsuji and Y. Fujise J. Org. Chem. 1986 51 4315; J. A. Marshall J. M. Jenson and B. S. DeHoff ibid. p. 4316. H. Hagiwara and H. Uda J. Chem Soc Perkin Trans. I 1986,629; M. Ihara M. Toyota K. Fukumoto and T. Kametani ibid p. 2151. C. Thanupran C. Thebtaranonth and Y. Thebtaranonth Tetrahedron Lett. 1986 27 2295. lo' P. G. Gassman and D. A. Singleton J.Org. Chem. 1986 51 3075. N. S. Simpkins I 31% I I TI known y-cadenane precursor Scheme 40 Although the reaction is stereospecific the yields appear variable and the reaction conditions have been adjusted for each substrate. An efficient strategy for the synthesis of stereodefined exocyclic alkenes has been described by Negishilo2 (see also the Corey example above) and uses a combination of organometallic reactions developed previously. Thus regio- and stereospecific introduction of an ally1 group to a propargyl alcohol allows preparation of vinyl iodides (38),which are then further reacted with organozinc halides using catalytic Pd(PPh3)4 to give (39) (Scheme 41). Further transformation then gives the desired bicyclic enones such as (40) in stereospecific fashion.iii iv R-C-CCH20H R)=qo +L R;G \ __ -%Me3 R2 SiMe3 (40) Reagents i eMgBr* 10% CuI; ii 12; iii Bu'Me2SiCl imidazole; iv R'ZnX 1% Pd(PPh3)o; v C12ZrCp2 BuLi; CO Scheme 41 8 Polycyclic Compounds Decarbonylation of tricyclic bridgehead acid chlorides can be effected under remark- ably mild conditions to give alkene products presumably uia bridgehead alkeneslo3 (Scheme 42). A re-examination of the decomposition products of diazo ketone (41) confirms the identity of the strained cyclopropanobicyclo[3.2.l]octanone (42),'O" although 102 E. Negishi Y.Zhang F. E. Cederbaum and M. B. Webb J. Org. Chem. 1986 51 4080. 103 K. Hori M. Ando N. Takaishi and Y. Inamoto Tetrahedron Lett. 1986 27 4615.'04 P. Ceccherelli M. Curini M. C. Marcotullio and E. Wenkert J. Org. Chem. 1986 51 738. Alicyclic Chemistry 1% Pd". Bu,N 130 "C Scheme 42 (42) 41% Scheme 43 the product of subsequent reaction with Li-NH3 is (43) and not (44) as previously described (Scheme 43). The direct formation of a tricyclic cycloheptanone-containingsystem has been observed when cyclopropanone hemiacetal (45) is treated with MeMgBr followed by cyclohexanone lithium en~late'~' (Scheme 44). -78" +25 "C 14% Scheme 44 Cationic rearrangement of [3.3.3]propellanes furnishes mixtures of tricyclic enones suitable for further elaboration to natural products including quadrone.'06 Further synthetic activity in the area of linear triquinane natural products has resulted in the first total synthesis of (-)-c~riolin,'~' and two A9('2)-Capnellanes,'08 as well as other members of this family synthesized previo~sly.'~~ A very nice example in this area is a simple four-step synthesis of hirsutene'" (Scheme 45).More Diels-Alder chemistry aimed at synthesis of taxane targets has appeared."' The synthesis of mevinic acids has been the subject of a tetrahedron report."* Two lo' J. T. Carey C. Knors and P. Helquist J. Am. Chem SOC.,1986 108 8313. G. Mehta K. Pramod and D. Subrahmanyam J. Chem. SOC.,Chem..Commun. 1986 247. 107 M. Demuth P. Ritterskamp E. Weigt and K. Schaffner J. Am Chek Soc. 1986 108 4149. 108 M. Shibasaki T. Mase and S. Ikegami J. Am. Chem Soc. 1986 108 2090. 109 P. F. Schuda J.L. Phillips and T. M. Morgan J. Org. Chem. 1986,51,2742; G. Mehta A. N. Murthy D. S. Reddy and A. V. Reddy J. Am Chem. SOC 1986 108 3443. 110 M. Iyoda T. Kushida S.Kitami and M. Oda 1.Chem. SOC.,Chem. Commun. 1986 1049. Ill P. A. Brown and P. R Jenkins J. Chem. Soc. Perkin Trans. 1 1986 1303; K. J.' Shea J. W. Gilman C. D. Haffner and T. K. Dougherty J. Am. Chem. SOC.,1986 108 4953; A. S. Kende S. Johnson P. Sanfilippo J. C. Hodges and L. N. Jungheim J. Am. Chem. SOC,1986 108,3513. T. Rosen and C. H. Heathcock Tetrahedron 1986 42 4909. 144 N.S. Simpkins @-Me,SiI H H 0 80% Ph,P=CH -H H H 47 % Scheme 45 73% R = Me 92% 58% R = Pr' (46) Scheme 46 examples of Lewis acid catalysed intramolecular heterocycloaddition reactions have been explored"' (Scheme 46).These constitute relatively rare examples in which ketones (rather than aldehydes) participate effectively in this type of process subsequent cleavage of the oxygen bridge to give (46) was cleanly effected using lithium in methylamine. Wender has described another application of his arene olefin cycloaddition reaction,' l4 which constitutes the first total synthesis of the antileukaemic pseudoguaianolide Rudmollin (47) (Scheme 47). Both isomeric products from the photocycloaddition are efficiently converted through into the same tricyclic ketone by the use of Hg(OAc);?. The synthesis is then completed by a rather lengthy sequence involving a further ring fragmentation. Several groups have disclosed chemistry involving cycloaddition reactions of tropone derivatives.The intramolecular [6 + 21 photocycloaddition of alkenyl tropones such as (48) has been examined with mixed res~lts"~ (Scheme 48). None of the desired adduct could be isolated on irradiation of (48) in aprotic solvents. Mixtures of products resulting from [6 + 21 and [8 + 21 cycloaddition could be obtained in acidic medium thus implicating the hydroxytropylium ion (49) as the effective 67r component. Unfortunately yields in all cases were rather low- ca. 20% isolated. By contrast the thermal [4 + 21 and [6 + 41 cycloadditions of tropone 113 J. H. Rigby J. Z. Wilson and C. Senanayake Tetrahedron Lett. 1986 27 3329. 114 P. A. Wender and K. Fisher Tetrahedron Lett. 1986 21 1857. K.S. Feldman J. H. Come A. J. Freyer B. J. Kosmider and C. M. Smith J. Am. Chem. SOC.,1986 108 1327. Alicyclic Chemistry 145 I I -SiO -SiO '+ '+ 63% combined vield \H.~(oA~),,~~.THF H\ +________ -sid Ho OH /I (47) Rudmollin -I-Scheme 47 mR1 H+,McOH --, / R' RZ *. R3 RZ -r mR1 + @, R2 R3 [6 +21 Scheme 48 derivatives appear facile and high yielding especially in intramolecular examples. Intermolecular reaction of dienes with tropone gave mainly [4 +21 addition however 1-acetoxybutadiene gave the [6 +41 adduct (5O)ll6 in 55% yield. The intramolecular process favours [6 +41 addition (51) being the only product obtained from the diene-substituted tropone (52). Funk examined these intramolecular reactions in some detail,"' obtaining high (67-92% ) yields and J.H.Rigby T. L. Moore,and S. Rege J. Org. Chem 1986,51 2398. R. L. Funk and G. L. Bolton J. Am. Chem. SOC.,198% 108,4655. 146 N. S. Simpkins (50) (52) (51) finding that more substituted olefinic appendages will react smoothly if 0.1 eq. of Et,AlCl is included (Scheme 49). This strategy appears ideally suited for the synthesis of several polycyclic natural products notably those of the ingenane group. Vollhardt has extended his cobalt-mediated method for steroid synthesis to allow direct one-step preparation of B-ring aromatic steroids from acyclic precursors' '* (Scheme SO). Two other publications indicate the potential of this chemistry for synthesis of fused indole ~ystems.''~ -y 80°C.6h (92%) ' a-; OSi-X 20O0C 60h (86%) or llO"C 36h (79%) 0.1 eq. Et,AICI d? OSi-X without Et,AlCl a :p ratio 3 :1 with Et,AICl a :p ratio >20 1 Scheme 49 80-90% Scheme 50 118 S. H. Lecker N. H. Nguyen and K. P. C. Vollhardt J. Am. Chem. SOC.,1986 108 856. 119 G. S. Sheppard and K. P. C. Vollhardt J. Org. Chem. 1986 51 5496; D. B. Grotjahn and K. P. C. Vollhardt J. Am. Chem. Soc. 1986 108 2091.