6 Alicyclic Chemistry By P. QUAYLE Department of Chemistry University of Manchester Manchester M 139PL 1 Introduction Once again this area of chemistry has proven to be highly productive. In particular the application of pericyclic radical and organometallic-based strategies have proven to be extremely fruitful. Reviews detailing the seminal contributions of a number of workers have appeared.'-4 2 General Angle' has demonstrated that the p-quinomethide (1) (sometimes isolable) may be trapped in an intramolecular fashion to afford a range of functionalized carbocyclic ring systems (Scheme 1) in good overall yield (circa 70%). Rearrangement reactions have been utilized to good effect in the synthesis of cis-fused hydrindanes hydroazulenes and bicyclo-[6.3.O]-undecanes via a pin-nacol-type process6 (Scheme 2).In a related pro~ess,~ reaction of the bis-TMS enol ether (2) with an appropriate ketal in the presence of an excess of a suitable Lewis acid (BF3.0Et2) affords directly spirocyclic diketones (Scheme 3). In a similar manner reaction of the protected carbinols (3) with a suitable electrophilic trigger' results in a smooth rearrangement reaction to afford a variety of fused carbocyclic systems (Scheme 4).Derivatization' of the aldehydes (4)with TMS-SMe followed by activation with a strong Lewis acid (TMS triflate) affords the ring expanded systems (5) (Scheme 5) in good isolated yield for n = 5,8,12. In the case of n = 6 preferential migration of the TMS-methyl group is observed. Subsequent loss of trimethylsilanol affords the exocyclic thio-ether (6).However in the case of the unsaturated derivative (7) vinyl migration becomes more facile affording the cycloheptadiene (8) in excellent yield' (83%). Carbon-centred radical cyclizations have been put to good use in the synthesis of a number of carbocyclic systems. Of particular interest is the development" of ' B. M. Trost Angew. Chem. Int. Ed. Engl. 1989 28 1173. W. Oppolzer Angew. Chem. Int. Ed. Engl. 1989 28 38. For an interesting compilation of modem synthetic methodology see J. A. Gladysz and J. Michl (ed.) Chem. Rev. 1989,89 1413-1617. B. Geise Angew. Chem. Int. Ed. Engl. 1989 28 969. S. R. Angle and K. D. Turnbull J. Am. Chem. Soc. 1989 111 1136. G. C. Hirst P. N. Howard and L. E. Overman J.Am. Chem. Soc. 1989 111 1514. 'Y.-J. Wu and D. J. Burnell Tetrahedron Lett. 1989 30 1021. S. Kim and J. H. Park Tetrahedron Lett. 1989 30 6181. K. Tamino K. Sato and I. Kuwajima Tetrahedron Lett. 1989 30,6551. D. P. Curran M.-H. Chen and D. Kim J. Am. Chem. Soc. 1989 111 6265. 137 138 P. Quale 73% (1.8 1) Reagents i Ag,O CHC13 r.t.; ii ZnCI Scheme 1 TMSO qk -ib I OMe CH(OMe)2 H 82% 1 + -..,OM, H 80% 0 75% Reagents i SKI, CH2C12 -78 "C Scheme 2 Alicyclic Chemistry 139 81% Reagents BF3.0Et2 (excess) Scheme 3 OTBDMS i,ii --+ But&S;h B u' 96% Reagents i PhSCl; ii AgBF4 Scheme 4 TMsGHo i,ii 6'"' (7) (8) 83% Reagents i,TMS-SMe; ii TMS-OTf Scheme 5 140 I? Quale atom transfer processes leading to the preparation of functionalized hence poten- tially synthetically useful products (Scheme 6).Since the isolation of the novel antitumour antibiotic Fredericamycin A a number of strategies have appeared for the preparation of spirocyclic carbocyclic systems. A general method for the preparation of a number of such systems has appeared this year" based upon the intramolecular acylation reactions of a sulphoxide anion (9) (Scheme 7). 1 A R R = Me,E:Z = 54~44 Reagents i BuSnH (cat.)/PhH Scheme 6 0 Reagents i LDA THF -78 "C; ii PhS(CH,),CHO; iii NaIO,; iv Mn02 Scheme 7 The application of organometallics in organic synthesis continues to be an area of intense chemical interest.In particular the utilization of palladium-mediated carbon-carbon processes appears to be highly attractive due to the mild reaction conditions employed functional group compatability and potential for stereocon- trol. A recent example detailing tandem alkylation reactions is particularly M. Pohmakotr S. Popuang and S. Chancharunee Tetrahedron Lett. 1989,30 1715. Y. Zhang and E-i. Negishi J. Am. Chem. SOC.,1989 111 3454. Alicyclic Chemistry 141 noteworthy12 (Scheme 8) in that it illustrates the variety of ring systems which may be readily accessed from relatively simple substrates. An area of increasing interest is the utilization of electrochemical techniques to synthetic processes. For example electrochemical red~ction'~ of the mesylates (10) readily affords a variety of bicyclic substrates generally in good yield (Scheme 9) although cyclization to cyclobutanes is a particularly poor yielding reaction.0 &Ji& -72% yR EE 78% TMS E = CO,Et 56% Reagents i Pd'; ii CH,CHC02Me Scheme 8 3 Cyclopropanes Metallati~n'~ of the readily available cyclopropene (11) with Bu"Li in THF and subsequent trapping with ethylene oxide afforded the alcohol (12) in good yield. Oxidation of (12) to the acid was accomplished using Jones' reagent. 13 P. G. Gassman and C. Lee Tetrahedron Lett. 1989 30,2175. 14 N. D. Lenn Y. Shih M. T. Stankovich and H-W.Liu J. Am. Chem SOC.,1989 111 3065. 142 P. Quale COzEt CO2Et 88% COzEt 6% YOzEt ,COzEt H 81% Scheme 9 65% Reagents i BuLi/THF; ii fro; iii CrO,/H,SO,/AcOH Gassman has developed a number of routes to functionalized cyclopropanes.Conver~ion'~ of the sulphide (14) to the trans-cyclopropane (15) was accomplished in moderate overall yield by way of a Ramberg-Backlund reaction. Alternatively,16 electrochemical reduction of the vinyl phosphates (e.g. 16) readily affords the bicyclic cyclopropane (17) in moderate yield 58%. Presumably the reaction proceeds via a S.E.T. reaction to afford the radical anion (18) which upon fragmentation to the radical (19) cyclizes to the observed product. Reaction of di-iodomethane with esters in the presence of samarium metal provides rapid access to functionalized cyclopro- panes" (Scheme 10).H H Reagents i NCS; ii MCPBA; iii KO'Bu Is P. G. Gassman S. M. Bonser and K. M. Majerski J. Am. Chem. Soc. 1989 111 2652. l6 P. G. Gassman and C. Lee J. Am. Chem. Soc. 1989 111 739. l7 T. Imamoto Y. Kamiya T. Hatajima and H. Takahashi Tetrahedron Lett. 1989 30,5149. 143 Alicyclic Chemistry R OH RCOX 2 e.g. R = Ph 70% Reagents i Excess CH,12/Sm Scheme 10 wco2Me -0 C02Me 90% Reagents i KOH/MeOH/PhI(OAC)2; ii CuCl Scheme 11 Iodonium ylids18 are found to undergo efficient intramolecular cyclopropanation reactions when reacted with copper(1) chloride at 0 "C (Scheme 11). Vinyl boronic19 esters undergo smooth cyclopropanation to afford the cyclopro- panes (20). The synthesis of the novel cyclopropy12' amino acid (22) has been reported starting from the unsaturated amine (21).Reaction of the glucal (23) with (22) 18 R. M. Moriarty 0. Prakash R. K. Vaid and L. Zhao J. Am. Chem. Soc. 1989 111 6443. 19 P. Fantani B. Corboni M. Vautier and R. Came Tetrahedron Lett. 1989 30,4815. 20 R. C. Petter Tefrahedron Lett. 1989 30,399. 144 P. Quale (25) 81% NHTMS Reagents i EtAlC12; ~~o,,s = (24) a suitable nucleophile (24) afforded the unusual cyclopropanes (25) as a 1 :1mixture of diastereoisomers in high yield.21 Unexpectedly reaction of the diene (26) with an oxa-TMM equivalent afforded the cyclopropane (27) in moderate yield 56%.22 The synthesis of the plant growth regulator (29) from the imine (28) has been reported.23 Reagents KOBu'/THF/A The functionalization of 1,l -dihalocyclopropanes has been achieved by a number of worker^^^.^^ (Scheme 12).The synthesis of cyclopropanes with very high levels of diastereoselectivity has been the subject of a number of investigations. Hence Simmons-Smith cyclopropana- tion of the enol ether (30) proceeds in fair yields with excellent diastereoselectivity26 Scheme 12 21 M. Okabe and R-C. Sun Tetrahedron Lett. 1989,30 2203. 22 B. M. Trost and S. Schneider J. Am. Chem. SOC.,1989 111 4430. 23 N.De Kimpe P. Sulmon and N. Schamp Tetrahedron Lett. 1989 30 5029. 24 M. G. Banwell G. L. Gravatt J. S. Buckleton G. R. Clark and C. E. F. Rickard J. Chem SOC.,Chem Commun. 1989 865. 25 T. Harada K. Hattori T. Katsuhira and A. Oku Tetrahedron Lett.1989 30 6035. 26 T. Sugimura T. Futagawa M. Yoshikawa and A. Tai Tetrahedron Lett. 1989 30 3807. Alicyclic Chemistry (30) Reagents Et2Zn/CH212; -40 to 0 "C (>98%). Alternatively reaction of the homochiral Meldrum's acid derivative (31) occurs with complete facial selectivity to afford the chiral cyclopropanes (32) after removal of the chiral au~illary.~' Finally functionalized cyclopropanes have a rich and varied chemistry; for example the cyclopropyl carbene complex (33) upon reaction with olefin affords the isomeric cyclopropanes (34).28 R' R (32) E = CO,Me OMe R' R' < u (33) (34) ca. 60% Cyclopropanes such as (35) undergo oxidative ring cleavage to afford the peroxides (36) which upon reduction with SmI afford the syn-1,3-diols (37) with high levels of dia~tereoselectivity.~~ .via R R' R LR' (36) (37) Reagents i 02/Ph2S2; ii Srn12 27 M. Sato H. Hisamichi C. Kaneko N. Suzaki,T. Faruya and N. Inukai Tetrahedron Lett. 1989,30,5281. 28 J. W. Herndon and S. U. Turner Tetrahedron Lett. 1989,30 4771. 29 K. S. Feldman and R. E. Simpson Tetrahedron Lett. 1989 30 6985. 146 P. Quale 4 Cyclobutanes The chemistry of cyclobutanes has enjoyed a renaissance during the last year partly due to the quest for novel anti-viral agents. For example the di-acid (38) was converted in a one-pot procedure to the chloro-derivative (39). The acid (39) serves as a useful intermediate in the preparation of ‘surrogate’ n~cleosides.~~ Nternatively reaction of diethyl fumarate with the keten acetal (40) afforded the cyclobutane derivative (41) in 53% yield which again was transformed into a nucleoside analogue3 (42) (Scheme 13).I OH Reagents i SO,CI,/PhH 190-200 “C CO2Et Et02C OEt i_ bo+ CO,Et OEt I CO2Et (40) Conditions i ‘BuOH/A / 53% (41) HOW/’ (42) Scheme 13 has shown that photolysis of the chromium carbene complex (43), Heged~s~~ followed by aerial oxidation affords fair yields of the cyclobutanone (44).Further-more oxidation of the cyclobutanone (44)afforded the lactone (45) in moderate ’O G. A. Jacobs J. A. Tino and R. Zahler Tetrahedron Lett. 1989 30,6955. 31 W. A. Slusarchyk M. G. Young G. S. Bisacchi D. R. Hockstein and R. Zahler Tetrahedron Lett.1989,30 6453. 32 M. A. Sierra and L. S. Hegedus 1.Am. Chem. SOC.,1989 111 2335. Alicyclic Chemistry (44) 43% (45) 30% Reagents i hv/CH,CN; ii O2 Scheme 14 (30%) yield (Scheme 14). Cy~loaddition~~ of the amides (46) with the thioether (47) in the presence of a catalytic quantity of the chiral ligand (48) and TiC1 (0-iR) affords- the cyclobutanes (49) in high chemical (60-90%) and optical yields (>80% ee) (Scheme 15). This report represents the first example of a catalytic asymmetric cycloaddition reaction leading to a cyclobutane. (46) (49) SMe Reagents ==( (47) Ph f( OH)Ph2 (48) 90%; 93% e.e. SMe C(0H)PhZ Scheme 15 Unsaturated sugars have proven to be ideal substrates for achieving high levels of diastereoselection in [2 + 21-cycloaddition reactions with dichloroketen as illus- trated in Scheme 16 the sense of facial selectivity being determined by the nature of the substituent proximal to the vinyl ether moiety.34 Reagents i Cl,C=C=O; ii Zn/HOAc Scheme 16 33 Y.Hayashi and K. Narasaka Chern. Lett. 1989,793. 34 H. Redlich J. B. Lenfers and J. Kopf Angew. Chern. Ini. Ed. Engi. 1989 28 777. 148 P. Quale The synthesis of a range of cyclobutanones (50) has been disclosed by Pirr~ng~~ by way of a photolytic [2 3-21 cycloaddition strategy. Substrates such as (50) serve as useful intermediates as they undergo synthetically useful rearrangements upon phot~lysis,~~ (Scheme 17). An intramolecular [2 + 21-cycloaddition fragmentation strategy has been utilized in the synthesis of (-)-perhydrohistrionic~toxin~~ (51) (Scheme 18).H @Ow-!+ ( 1" ij ijj @+f (50) MeOzC Reagents i hvlacetone; ii MCPBA; iii MeONaIMeOH Scheme 17 I + 6kf 0 Ho J J (51) Reagents i hv 95% Scheme 18 Reaction of p-naphthols with ethylene at low temperature in the presence of aluminium chloride affords high yields of the corresponding cyclobutane derivative (52).38 3s M. C. Pirrung V. K. Chang and C. V. De Amicis J. Am. Chem. SOC 1989 111 5824. 36 C$ S. S. Rahrnan B. J. Wakefield S. M. Roberts and M. D. Dowle J. Clem. SOC.,Chem. Commum. 1989 303; 1696. 37 J. D. Winkler and P. M. Hershberger J. Am. Chem. SOC.,1989 111 4852. 38 M. Ue M. Kinugawa K. Kakiuchi Y. Tobe and Y. Odaira Tetrahedron Lett.1989 30,6193. Alicyclic Chemistry 149 Reagents i CZH4 AlC13 95% (52) A synthesis of (*)-1-fluorograndisol (54) has been accomplished from the cyclo- propane (53).39 5 Cyclopentanes The development of general strategies for the synthesis of 5-and 6-membered rings continues unabated. Motherwella has shown that the cyclopropene (55) undergoes an intramolecular cyclopentanullation reaction in the presence of Pd'. The homo- Diels- Alder reaction has received scant attention by synthetic chemists. However 5; i_ 40% MeOiC MeO& E (55) E = CO,Me E Reagents i Pdo Lautens4' has shown that certain nickel catalysts promote the cycloaddition reaction and thereby provide ready access to a number of polycyclic ring systems (Scheme 19).i!b+70Lto 62% (endo :ex0 = 2 :1) Reagents i Ph3P Et3AI Ni(acac)2 Scheme 19 39 S. Kanemoto M. Shimizu and H. Yoshioka J. Chem SOC.,Chem Commun. 1989,690. 40 S. A. Bapuji W. B. Motherwell and M. Shipman Tetrahedron Lett. 1989 30 7107. 41 M. Lautens and C. M. Crudden Tetrahedron Lett. 1989 30,4803; M. Lautens and L. G. Edwards Tetrahedron Lett. 1989 30 6613. 150 P. Quale The metallo-ene reactions continue to be actively investigated as a means of preparing highly functionalized polycyclic systems from acyclic precur~ors,~*~*~ (Scheme 20). I + E-gE I 0 AcO 74% 75% E:Z = 4:l 75% (1.3:1) Reagents i Pd(dba),/PPh,/HOAc/CO/MeOH/A; ii Pd(PPh,),/CH,CN/h Scheme 20 The Pa~son-Khand~~ reaction has been successfully utilized in the synthesis of furan-ether B.The reaction proceeded smoothly to afford a 2 1 mixture of exo-adducts which were processed into the title compound (56). 64% (2:1) I (56) Reagents (i) CH,CCH CO~(CO)~ CO PhH; reflux 44h 42 (a) W. Oppolzer T. H. Keller M. Bedoya-Zurita and C. Store Tetrahedron Lett. 1989 30 5883. (b) E-i. Negishi S. Iyer and C. J. Rousset Tetrahedron Lett 1989 30 291. M. E. Price and N. E. Schore Tetrahedron Lett. 1989 30,5865. 43 Alicyclic Chemistry Hernd~n~~ has demonstrated functionalized cyclopentanes may be prepared uia the reaction of ally1 stannanes with acyl iron complexes in the presence of aluminium trichloride (Scheme 2 1). SnBu3 Reagents i AlCl, r.t.; ii NBS/BnOH; iii Br,; iv NH,/MCPBA Scheme 21 OTBDMS OTBDMS 67% (4.2 1) Reagent i ‘TMM’-Pd Scheme 22 Trost has published a number of papers concerning additional applications of the TMM approach to cy~lopentanes,~~~~~ (e.g.Scheme 22). Dotz4’ has shown that upon reaction of the chromium carbene complex (57) with phenyl acetylene in refluxing di-n-butyl ether the indene complex (58) is produced in 45% yield as a single diastereoisomer with the phenyl moiety cis to the bulky chromium tricarbonyl moiety which is complexed to the aromatic portion of the indanone (Scheme 23). A number of reports have appeared concerning the cyclization of ene-ynes di-ynes and w-unsaturated imines (Scheme 24). 44 J. W. Herndon and C.Wu Tetrahedron Lett. 1989 30 6461. 45 B. M. Trost S. A. King and T. Schmidt J. Am. Chem. SOC.,1989 111 5902. 46 B. M. Trost and M. Acemoglu Tetrahedron Lett. 1989 30 1495. 47 K. H. Dotz H. G. Erben and K. Harms J. Chem. SOC.,Chem. Commun. 1989 692. 152 P. Quale Reagents i PhCCH Bu20 A Scheme 23 50% Reagents i ZrCp,; ii CO \ Br88% (~97% frans) Br 78% (>99% cis) Reagents i Cp,Zr BuLi; ii Br2; iii Cp*ZrCI -0' (Ref.50) 53% Reagents i Cp,Zr/n-BuLi; ii CO; iii I2 NHNMe -(Ref. 51) R qNNMe2 CL 71% R Reagents i Cp2Zr( Bu"Li) Scheme 24 48 E-i. Negishi P. J. Holmes J. M. Tour J. A. Miller F. E. Cederbaum D. S. Swanson and T. A. Takahashi J. Am. Chem. Soc. 1989 111 3336. 49 W.A. Nugent and D. F. Taber J. Am. Chem. Soc. 1989 111 6435. 50 C. J. Rousset D. R. Swanson F. Lamatay and E.4. Negishi Tetrahedron Lett. 1989. 30,5105. 51 M. Jenson and T. Livinghouse 1.Am. Chem. Soc. 1989 111 4495. Alicyclic Chemistry Tandem intramolecular 'Heck'-vinylation reactions prove to be highly effective for the construction of fused ring (Scheme 25). In a related reaction,54 treatment of the vinyl lithium (58) with MeZrCp2C1 afforded the zirconium complex (59) which upon reaction with the protected unsaturated alcohol (60) afforded the bicyclic ketone (61) as the sole product in 47% isolated yield (Scheme 26). Reagents i Pdo PhZnCl R = CO,Et 91% I (2:E= 8:l) R' Reagents i P~(OAC)~/P~~P, NaCH(CN)2 Scheme 25 +i -ZrCp 47% % (58) (59) OTBDMS (61) Reagents i MeZrCpzC1/PR3; ii CO (60) OTBDMS Scheme 26 Thermoly~is~~ of the w-acetylenic chromium carbene complexes (62) in the pres- ence of a suitable acetylene affords reasonable yields of the functionalized cyclopen- tenones (63) (Scheme 27).Clearly a reaction of some synthetic potential. Iron complexes56 of the type (64) undergo C-H insertion reactions upon reaction with Meerwein's reagent at ambient temperature. In certain cases high stereoselec- tivity is exhibited in such processes (Scheme 28). The intramolecular cis-carbolithiation of acetylenes and alkenes has been investi- gated in some detail by Bailey.57 For example reaction of the iodide (65) with Bu'Li 52 B. Bums R. Grigg V. Sridharan P. Stevenson S.Sukirthalingam and T.Worakun Tetrahedron Lett. 1989,30 1135. 53 R. Grigg and V. Sridharan Tetrahedron Lett. 1989.30 1139. 54 S. L. Buchwald R. T. Lum,R. A. Fisher and W. A. Davis J. Am. Chem. SOC.,1989. 111 9112. 55 Y.-C. Xu,C. A. Challener V. Dragisich T. A. Brandvold G. A. Peterson W. D. Wulff and P. G. Williard J. Am. Chem. SOC 1989 111 7269. 56 S.-K. Zhao C. Knors and P. Helquist J. Am. Chem. Soc. 1989 111 8527. 57 W. F. Bailey and K. Rossi J. Am.Chem. SOC.,1989 111 765; W. F. Bailey T. V. Ovaska and T. K. Leipert Tetrahedron Lett. 1989 30 3901. 154 P. Quale OMe (62) ca. 40% n = 1,2 Reagents i PhH A R'CCR' Scheme 27 O Fe(CO)2CP r Reagents i Me,OBF, CH,Cl, 0°C Scheme 28 rI- 1 Li 84% & Ai ii iv E (69) E = H SiMe, CO,H 60-80% Reagents i Bu'Li -78 "C; ii TMEDA -78 "C to r.t.; iii MeOH; iv E+ Scheme 29 at low temperature affords the lithio compound (66) which undergoes a tandem cyclization process to afford the spirocycle (67) in high yields (84%) (Scheme 29).Similarly,57 reaction of the iodide (68) with Bu'Li followed by a suitable electrophile (e.g. COz)affords good yield of the tricycles (69). Reactions performed on acetylenic iodides afford the corresponding exocyclic alkenes in good yield (8O%) (Scheme 30) with a high degree of stereochemical control.57 Alicyclic Chemistry CIR -mR E 80% Reagents i Bu'Li -78 "C; ii E+ Scheme 30 The synthesis of prostaglandins and related substances remains an area of intense interest.For example,58reaction of the diol (70) and the vinyl iodide (71) with a catalytic quantity of a Pdo catalyst (prepared in situ) provides a particularly concise approach to cyclopentanones of the type (72) (Scheme 31).Alternati~ely,~~ coupling of the vinyl iodide (73) with the stannane (74) proceeds smoothly to afford the prostanoid (75) with retention of stereochemistry about the olefinic side chain (Scheme 32). OH 0 HO (70) OTBDMS (72) 70% Scheme 31 (CH2)6C02Et (CH2)6CO?Et I I (73) OTBDMS (75) 75% Reagents trans-Bn(Cl)(Ph,P),Pd BuoSn 7 OTBDMS (74) Scheme 32 Radical cyclizations have been extensively used to prepare cyclopentanes a few examples are given in Figure l.6069 A significant advance has been the realization that heavily functionalized acyclic substrates derived from sugars can be cyclized under radical conditions to afford 58 R.C. Larock F. Kondo K. Narayanan L. K. Sydnes and M.-F. H. Hsu Tetrahedron Lett. 1989,30,5737. 59 J. K. Stille and M. P. Sweat Tetrahedron Lett. 1989 30 3645. 60 Y. Taura M.Tanaka K. Funakoshi and K. Sakai Tetrahedron Lett. 1989 30 6349. 61 H. Hemmerle and H.-J. Gais Angew. Chem. Znt. Ed. EngL 1989 28 349. 62 E. J. Enholm and G. Prasad Tetrahedron Lett. 1989,30 4939. 63 V. Yadav and A. G. Fallis Tetrahedron Lett. 1989 30 3283. 64 E. Lee C.-U. Hur and J.-H. Park Tetrahedron Letf. 1989 30 7219. 156 P. Quale (Ref. 60) 85% (cis :trans = 6 1) Reagents i TsCI (PhCO)20 PhH reflux TBDMSO TBDMSO s *I \ c!,' I Bu,SnH/AIBN/PhH reflux (Ref.61) Q Ow0 OW0 C02Me BU3SnH/AIBN/PhH 'O-b ,,+, %(Ref. 62) C02Me 81% HO Bu,SnH/NBN/PhH reflux 3+2 Q4-OH (Ref.63) 0 74% 0 i Bu,SnH/AIBN/PhH; ii H,O+ .g (Ref. 64) Pr' 80% (Ref. 65) Ph,S,/ NBN/ PhH/ hv & A-B (Ref. 66) ' R' R2 Trans-isomers major product Figure 1 Examples of cyclopentanes prepared by radical cyclization 65 A. P. Neary and P. J. Parsons J. Chem SOC.,Chem. Commun. 1989 1090. 66 K. S. Feldman R. E. Ruckle and A. L. Romanelli Tetrahedron Lett. 1989 30,5845. Alicyclic Chemistry (Ref. 67) 31% 40% CO2Me Sm12.THF/MeOH/-78"C ' [Ref. 69( a)] W""' 87% (>250 1) /v 60-70% (1,2-cis :trans >20 :1) Figure 1-continued D-(-)-Arabinose 30'' i Sml,/THF/MeOH/-78 "C 69% Bu,SnH/AIBN/PhH reflux+ ph-(IgR OV0 OBn tI 1,5-trans :cis =77 :23 Ph 32% Scheme 33 67 V.Reutrakul C. Poolsanong and M. Pohmakotr Tetrahedron Lett. 1989 30,6913. 68 T. Uruma S. Iwasa S. Kohmoto and K. Yamada J. Chem. Soc. Chem. Commun. 1989 1265. 69 (a) E. J. Enholm and A. Trivellas Tetrahedron Lett. 1989,30 1063; (b)G. A. Molander and C. Kenny J. Am. Chem. Soc. 1989 111 8236. 158 P. Quale functionalized cyclopentanes with a high degree of stereochemical control,70971 (Scheme 33). Alternative methods of 5-membered ring synthesis included intramolecular epoxide ring opening with an ally1 silane7* (Scheme 34) and tandem Michael addition reactions to a,P-unsaturated e~ter~~'~' (Schemes 35 and 36).OH +OH H -7 TMS 82% (trans cis) = 4 1 Reagents i SnCl2/CH2C1, -90 "C Scheme 34 qC02Et. YO2Et + TO2" CO2Et CO2Et c02et 26~7464% Reagents i LiN(Bn)TMS; ii Me1 Scheme 35 c02et TBDMSO \ C02Et . TBDMSO COzEt + 6-TBDMSO'cC02Et TBDMSO' R e.g. R = Me,92%(>99%d.e.) Reagents i RMgBr/CuI Scheme 36 Intramolecular acylation of the vinyl carbanion (76)" afforded the cyclopentenone (77) in moderate yield (50%) (Scheme 37). has demonstrated that intramolecular nitrone cycloaddition reactions can proceed with excellent diastereofacial selectivity affording functionalized cyclopentanes in high yield (Scheme 38). Ti~s~~ has developed a novel cationic cyclopentannulation procedure as exemp- lified in the recent synthesis of (*)-xanthocidin [Scheme 39(a)].70 E. J. Enholm and A. Trivellas J. Am. Chem. SOC.,1989 111 6463. 71 T. V. RajanBabu T. Fukunaga and G. S. Reddy J. Am. Chem. SOC.,1989 111 1759. 72 S. Hatakeyoma K. Osani H. Numata and S. Takano Tetrahedron Lett. 1989 30 4845. 73 T.Uyehara N. Shida and Y. Yamamoto J. Chem. SOC.,Chem. Commun. 1989 113. 74 S. Saito Y. Hirohara 0. Narahara and T. Moriwake J. Am. Chem. SOC.,1989 111 4533. '' M. T. Crimrnins and J. B. Thomas Tetrahedron Lett 1989 30 5997. 76 T. K. M. Shing D. A. Elsley and J. G. Gillhouley 1.Chem. SOC.,Chem. Commun. 1989 1280. 77 M.A. Tius and D. P. Astrab Tetrahedron Lett. 1989 30 2333. Alicyclic Chemistry OMOM (76) OMOM (77) 50% Reagents i LDA/THF/-78 "C Scheme 37 O"0 \ 94% Scheme 38 I1 Ph C02H A Ph Ph 72% Reagents i 2,6-lutidine/TFAA -10 to 0 "C Scheme 39(a) Meyers" has developed a particularly effective protocol for the synthesis of homochiral cyclopentenones from the lactam (78) as exemplified in [Scheme 39(b)].A~ymmetric'~ deprotonation of the meso-ketone (79) with a chiral base and subsequent trapping with TMSCl afforded the enol ether (80) in 94% enantiomeric excess (Scheme 40). 78 A. I. Meyers and C. A. Busacca Tetrahedron Lerr. 1989 30,6977. 79 H. Izawa R. Shirai H. Kowasaki H.-d. Kim,and K. Koga Tetrahedron Lett. 1989 30,7221. 160 I? Quale (78) O 0 0 Reagents i ,ZnBr / Y Scheme 39(b) n n E+ I,.I1 .. -H EH -H@E v OTMS 0 (80) 93% 94% ee (1S,5 R) Reagents i MeN' Ph; ii TMSCI NLi But Scheme 40 NC OTBDMS -i +TBDMs (81) 96% ee 'C N (82) 74% Reagents i LHMDS/THF/-78 "C Scheme 41 Finally,80 the functionalized cyclopentane (82) was obtained in good yield from the homochiral epoxy-nitrile (81) upon exposure to LHMDS (Scheme 41). 6 Cyclohexanes The stereocontrolled functionalization of polyhydroxylated cyclohexanes has been the subject of intense interest due to the pharmacological properties of myo-inositol phosphates. This area of chemistry has been comprehensively reviewed.81 A number of reports concerning the preparation/reactivity of novel dienes/dienophiles have appeared a selection of which are included in Figure 2 (references 82-1 02).S. G. Levin and M. P. Bonner Tetrahedron Lett. 1986 30,4567. " D. C. Billington Chem. SOC.Rev. 1989 18 83. Alicyclic Chemistry \ (Ref. 82) 4-L so (Ref. 86) OR 6 (Ref. 89) (Ref. 92) PhSOz (Ref. 83) II A TMS SOPh (Ref. 90) P SePh 1R (Ref. 85) (Ref. 84) SMe (Ref. 91) 0 (Ref. 93) 0 (Ref. 94) Figure 2 Novel dienes and dienophiles 82 C. W. Bird and A. Lewis Tetrahedron Lett. 1989 30 6227. 83 J. E. Backvall and F. Rise Tetrahedron Lett. 1989 30 5347. 84 J. P. Konopelski and M. A. Boehler J. Am Chem. SOC.,1989 111 4515. M. Ishida T. Aoyama and S. Kato Chem. Lett. 1989 663. 86 A. M. Naperstkow J. B.Macauly R. J. Newlands and A. G. Fallis Tetrahedron Lett. 1989 30 5077. ” J. R. Bull and K. Bishofberger J. Chem. Soc. Chem. Commun.,1989 1405. Y. Haazawa M. Suzuki and Y. Kobayashi Tetrahedron Lett. 1989 30 571. 89 F. Kiengle J. Stadweiser and I. Mergelslberg Helv. Chim Actu 1989 72 348. 90 R. V. Williams and X. Liu J. Chem SOC.,Chem Commun. 1989 1872. 91 J.-L. Boucher and L.Stella J. Chem. SOC,Chem Commun. 1989 187. 92 M,. Sato C. Oris J.4. Sakaki and C. Kaneko J. Chem SOC.,Chem. Commun. 1989 1435. 93 P.G. McDougal J. M. Jump C. Rojas and J. G. Rico Tetrahedron Lett. 1989 30,3897. 94 M. C. Carreno J. L. G. Ruano and A. Urbano Tetrahedron Lett. 1989 30,4003. 95 A. Schoning and W. Friedrichsel Chem. Ber. 1989 122 1119. 96 J. Matlay J. Mertes and G.Maer Chem. Ber. 1989 112 327. 97 J. Lee and J. K. Snyder J. Am. Chem. SOC,1989 111 1522. 162 P. Quale 0 (Ref. 96) (Ref. 97) PhSOz \ TQCOzMe (Ref. 99) (Ref. 98) (Ref. 100) 0 QqPh 0 0 (Ref. 101) (Ref. 102) Figure >continued Wenderlo3 has shown that Diels- Alder reactions occur readily with unactivated substrates when suitable transition metal catalysts are added (Scheme 42). A number of catalysts have been developed which enable asymmetric Diels- Alder reactions to be carried out with good enantiomeric excess (Scheme 43). Gassmanlo6 has reported that orthoesters undergo 'ionic' Diels- Alder reactions under mild conditions (Scheme 44). y0TBDMS @OTBDMS TMS TMS 98% Reagents i Ni(COD) (10 mol YO),r.t.Scheme 42 98 A. H. Davidson and B. A. Maloney J. Chem. SOC.,Chem. Commun. 1989 445. 99 P. M. Fresneda and M. Vaultier Tetrahedron Lett. 1989 30 2929. 100 K. A. Parker and S. M. Ruder J. Am. Chem. SOC.,1989 111 5948. lo' A. I. Meyers and C. A. Busacca Tetrahedron Lett. 1989 30 6973. 102 A. Waldner Tetrahedron Lett. 1989 30 3061. 103 P. A. Wender and T. E. Jenkins J. Am. Chem. SOC.,1989 111 6432. 104 K. Narasaku N. Iwasawa M. Inoue T. Yamada M. Nakashima and T. Sugimori J. Am. Chem. SOC. 1989 111 5340. 105 E. J. Corey R. Imwinkelreid S. Pikul and Y. B. Xiang J. Am. Chem. SOC.,1989 111 5493. '06 P. G. Gassman and S. P. Chava J. Chem. SOC.,Chem. Commun. 1989 837. Alicyclic Chemistry 00 C02Me (Ref.104) a *CONR2 85% ee Ph Ph Reagents i 3PhH; r.t.; ii cat. Ph Ph CONR2 92% 91%ee cat. = CF3S02N ,NS02CF3 A1 I Me Scheme 43 CO2H 74% Reagents i BF3.0Et2; ii HCl/H20 -72" to 0 "C Scheme 44 S~therland''~has utilized an electrocyclic ring closure reaction to afford highly functionalized systems possessing structural similarities to the quassinoids (Scheme 45). The Diels-Alder reaction is an immensely powerful reaction and there is little wonder that a number of groups have used this basic strategy in approaches to forskolin."* Reagents i Mukaiyama's reagent CH2Cl, Et,N r.t. 72% Scheme 45 L. Larsen and J. K. Sutherland J. Chem. Soc. Chem. Commun. 1989 784. e.g. B. M. Trost and R. Holcomb Tetrahedron Lett. 1989 30 7157; E.J. Corey and P. Da Silva Jardine Tetrahedron Lett. 1989 30 7297; K. Kanematsu and S. Nagashima J. Chem. SOC.,Chem. Commun. 1989 1028. 164 I? Quale The IMDA reaction of furan as a potential route to polyoxygenated systems is usually hampered by the reversible nature of this reaction. However Keay"' has investigated the subtle effects of substituents on the course of this reaction and demonstrated that under mild conditions and correct substitution pattern the reaction can be of some synthetic utility (Scheme 46). 0 c 1 Reagents i Florid CH2C12 Scheme 46 The IMDA reaction has been used successfully to construct the tricycles (83) and (84) which serve as model compounds for the synthesis of the manzarnines1lo and quassinoids"' respectively (Scheme 47).Scheme 47 The use of a novel homochiral catalyst in an asymmetric IMDA reaction leading to the isolation of the bicycle (85) in 92% enantiomeric excess (84% yield) has been disclosed,"2 (Scheme 48). A paper detailing the synthetic utility of cation-radical promoted Diels-Alder reactions has also a~peared."~ Carle~s"~ has illustrated the utility of the diol (86) in the synthesis of inositol derivatives (Scheme 49). 109 B. A. Keay and P. W. Dibble Tetrahedron Lett. 1989,30 1045; C. Rogers and B. A. Keay Tetrahedron Lett. 1989 30 1345. 110 K. M. J. Brands and V. K. Pandit Tetrahedron Lett. 1989 30 1423. 111 T. K. M. Shing Y. Tang and J. F. Malone J. Chem. SOC.,Chem. Commun. 1989 1194. 112 K. Furuta A.Kanematsu H. Yamamoto and S. Takaoda Tetrahedron Lett. 1989 30,7231. 113 B. Harirchian and N. L. Bauld J. Am. Chem. SOC.,1989 111 1826. H. A. J. Carless and 0. Z. Oak Tetrahedron Lett. 1989 30 1719. Alicyclic Chemistry (85) 84% 92%ee (99 :1 endo :exo) Reagents i 10 mol. % cat. CH2C12 -40 "C cat. = Scheme 48 aoH ?H + + i ii aoH CH ' OH OH I OH I Reagents i loz;ii Thiourea Major product OH Scheme 49 (+)-Albicanol Scheme 50 A synthesis of (+)-albicanol demonstrates the potential for stereochemical control in intramolecular nitrile oxide cycloaddition reactions,' Is (Scheme 50). Radical cyclizations have also been used to good effect to prepare functionalized cyclohexanes. For example,'16 the sugar derivative (87) underwent cyclization to the carbocycle (88) in moderate yield (50%).Crich"' has prepared the ketone (go) an intermediate for the synthesis of vitamin D3 uia cyclization of the acyl radical (89) (Scheme 51). Chirality transfer by way of pericyclic processes have been used extensively. Hence,' l8 the functionalized cyclohexane (92) a component of FK506 was prepared via an Ireland-Claisen rearrangement of the lactone (91). An example' l9 of remote asymmetric induction is nicely exemplified by orthoester- Claisen rearrangement of the alcohol (93) to the ester (94) (Scheme 52). 115 K. Shishido Y. Tokunaga N. Omachi K. Hiroya K. Fukumoto and T. Kametani J. Chem. Soc. Chem Cornmun.,1989 1093. 116 B-W. A. Yeung J. L. M. Conlettes and B.Fraser-Reid J. Chem. Soc. Chem Commun. 1989 1160. 117 D. Batty D. Crich and S. M. Fortt J. Chem. Soc. Chem. Commun. 1989 1366. 118 S. L. Schreiber and D. B. Smith J. Org. Chem. 1989 54 9. 119 P. M. Wovkalich P. C. Tang N. C. Chadha A. D. Batcho J. C. Barrish and M. R. Uskokovic J. Am. Chem. Soc. 1989 111 2596. 166 P. Quale OR OR 0 I PhS SePh --PhS RO Reagents i Bu,SnH/AIBN/PhH reflux (90) 91% Scheme 51 Ho2cuoM 0qMe-(91) (92) Scheme 52 Pearson12' has prepared a number of functionalized cyclohexanones effectively utilizing the stereodirecting effect of the .rr-allyl-Mo(C02)Cp moiety (Scheme 53). In a similar manner,'21 the use of a sterically demanding but readily released TMS group has been utilized in the synthesis of homochiral cyclohexenones (Scheme 54).gSPh OH Nu- Scheme 53 A. J. Pearson and R. Motezaei Tetrahedron Lett. 1989 30 5049. M. Asaoka T. Aida S. Sonada and H. Takei Tetrahedron Lett. 1989 30 7075. Alicyclic Chemistry TMS' R2 Scheme 54 In an extension of earlier work Frater'22 has shown that alkylation of the dianion (95),derived from readily available P-hydroxy esters (in optically pure form) affords diastereomerically pure products (961 (Scheme 55). Reagents i 2 x LDA; THF;-78 "C;ii E+ Scheme 55 7 Cycloheptanes A novel [4 + 31 cycloaddition reaction has been disclosed'23 enabling the facile preparation of functionalized cycloheptanes (97) (Scheme 56). (97) 70% Reagents i [(PriO),P],Pdo (cat.) PhH reflux AcO &TMS Scheme 56 Lewis acid promoted reaction of the Chan diene (98) with p-dicarbonyl com- pounds afforded the [3 + 41 adducts in good overall yield,'24 (Scheme 57).12' G. Frater W. Gunther and U. Miller Helu. Chirn. Acfa 1989 72 1846. 123 B. M. Trost and S. Schneider Angew. Chem. Inf. Ed. Engl. 1989 28 213. 124 G. A. Molander and S. W. Andrews Tetrahedron Lett. 1989 30,2331. 168 P. Quale 0 TMSO OMe + R 1 y A &-R C02Me -oms R Rl-0 (98) 7680% Reagents i TiCL, -78 "C (R R' = various) Scheme 57 The synthesis of hydrazulenes has been achieved by rearrangement of either the cyclopropyl ~arbinols'~~ (99) or via an oxy-Cope rearrangement'26 of the 1,5-dienes (100). In the latter case the trans-[6.4.0] system was isolated upon treatment with base (Scheme 58).d q H (99) Ii @ (32 H R 8690% 80% Reagents i NaH/THF; ii 210°C; iii NaOH Scheme 58 8 Cyclooctanes B~eckman'~~ has reported that cyclooctanes may be prepared via a methoxide induced Grob fragmentation of a bicyclo-[3.3.1] system (Scheme 59). Alterna-tively,12* an intramolecular Barbier coupling reaction of the iodo-aldehyde (101) afforded the cyclooctane (102) in good yield as a single diastereoisomer (Scheme 60). Reagents i NaOMe/MeOH [R= (CH2)2C02Me] 73% Scheme 59 125 V. Reydellet and P. Helquist. Tetrahedron Lett. 1989 30,6837. 126 M. Sworin and K.-C. Lin .L Am. Chem. Soc. 1989 111 1815. 127 R. K. Boeckman A. Arvantis and M. E. Voss J. Am. Chem. Soc. 1989 111 2737.128 M. Rowley M. Tsukamoto and Y.Kishi J. Am. Chem. Soc. 1989 111 2735. Alicyclic Chemistry ?Ho R - I 73% PhzBu'SiO (101) Reagents i CrCIJ NiCI Scheme 60 9 Larger Ring Systems A few reports have detailed the preparation of medium-sized ring systems via organometallic and radical ring closure methodologie~.'~~ A notable example is the synthesis of an analogue of Neocarzinostatin via an intramolecular palladium coupling rea~tion,'~' (Scheme 61). 72% Reagents i Pd(Ph,P), THF reflux Scheme 61 10 Natural Products A number of outstanding contributions have appeared this year including the total synthesis of (*)-~eroplastol,'~~ (+)-ophiobotin,'28 and sarcophytol B,13' phorb01,'~~ (*)-pleur~mutilin.'~~ The synthesis of model compounds related to the unusual calicheamicin/esperamicin family of antibiotics continues at a high level of interest.'34 129 J.E. McMurray and J. G. Rico Tetrahedron Lett. 1989 30 1169; J. E. McMurray Chem Rev. 1989 89 1513; N. A. Porter B. Lacher V. K.-T. Chang and D. R. Magnin J. Am. Chem SOC.,1989 111 8309; B. M. Trost S. Matsubara and J. J. Caringi J.-Am. Chem. Soc. 1989 111 8745; N. J. G. Cox G. Pattenden and S. D. Mills Tetrnhedron Lett. 1989 30,621. 130 M. Hirama K. Fujiwara K. Shigematu and Y. Fukazawa J. Am. Chem SOC.,1989 111,4120. 131 J. E. McMurray J. G. Rico and Y-n. Shish Tetrahedron Lett. 1989 30 1173. 132 P. A. Wender H.Y. Lee R. S. Wilhelm and P. P. Willcom J. Am. Chem. SOC.,1989 111 8954. 133 R.K. Boeckman D. M. Springer and T. R. Alessi J. Am. Chem. SOC. 1989 111 8284. 134 cf J. N. Haseltine S. J. Danishefskey and G. Schulte J. Am. Chem SOC.,1989 111 7838.