9 Alicycl ic Chemistry ByJ. M. MELLOR Department of Chemistry The University Southampton SO95NH 1 Introduction The dominant theme in alicyclic chemistry continues to be the synthesis of natural products or their analogues which are expected to show important biological activity. The challenge to develop new synthetic methods parallels the discovery of novel skeletons. So a fresh challenge is provided by the discovery’ of for example naturally occurring cyclopropenone derivatives (1)and (2). An older challenge the synthesis of steroids can still be reawakened by a fresh insight. The recent studies based on the Kametani approach of an intramolecular Diels-Alder reaction using benzocyclobutene intermediates have been reviewed.2 The special position of the Diels-Alder reaction containing six-membered rings is emphasized by later examples and by a review3 describing the many possibilities of both inter- and intra-molecular reactions of heterosubstituted 1,3-dienes.A further review4 con- cerns both intramolecular cycloadditions and ene-reactions. Ring formation by cyclizations involving radical intermediates has been little used in target synthesis but a recent review5 emphasizing the regio- and stereo-selectivity of such cyclizations suggests an under-used potential. No naturally occurring benzvalenes have been reported but their easy synthesis has permitted the development of an extensive chemistry which is now reviewed.6 The first half’ of a ‘Symposium in print’ on ‘Perspectives in Small Ring Chemistry’ has appeared.‘ F. Bohlmann J. Jakupovic L. Muller and A. Schuster Angew. Chem. Znt. Ed. Engl. 1981 20 292. * T. Kametani and H. Nemoto Tetrahedron 1981 37 3. M. Petrzilka and J. I. Grayson Synthesis 1981 753. W. Oppolzer Pure Appl. Chem. 1981 53 1181. A. L. 3. Beckwith Tetrahedron 1981,37,3073. M. Christl Angew. Chem. Znt. Ed. Engl. 1981 20 529. ’ Israel1 Chem. 1981 21 95. 185 186 J. M. Mellor 2 Synthesis Monocyclic Compounds.-A gap in the methodology for cyclopropanation of alkenes has been an efficient procedure for introduction of a methyl carbene or dimethyl carbene equivalent. Now ethylidenations have been developed based on stable iron complexes. Thus treatment' of the stable complex (3)with trimethylsilyl triflate gives the triflate salt of the ethylidene complex (4).When (4) is generated in the presence of an alkene high yields of methyl cyclopropanes are obtained. The applicability of this method to the synthesis of a variety of alkylcyclopropanes seems probable but has yet to be demonstrated. In an alternative procedure' stable complex (5) with methyl fluorosulphonate gives an unstable sulphonium salt (6) which acts as an efficient agent for ethylidene transfer (Scheme 1).By generation Ph CP(CO)~F~CH(SP~)M~ +/ A Cp(C0)2FeCH(Me)S \ Reagents i Me,SiOSO,CF, CH,Cl, -78 "C; ii FSO,Me CH,CI, 25 "C Scheme 1 of dimethylcarbene at -70 "C low yields of cyclopropanation products" are obtained from 2,2-dibromopropane and n-butyl-lithium. Photolysis of di-iodomethane" has only modest advantages in certain cases over the conventional Simmons-Smith method but the selectivity observed with dienesI2 is very different using diazomethane and palladium(I1) acetate.Attack is selectively at the less hindered site and yields are excellent. A novel cyclopropane ~ynthesis'~ proceeds stereoselectively by an intramolecular ene-reaction (Scheme 2) termed 'an oxy- homodienyl hydrogen shift'. Acceleration by metallation of the hydroxy-group by analogy with the anionic oxy-Cope rearrangement has yet to be proved. CHZOH Gas phase 263 ' 85% Scheme 2 Photochemical routes to substituted cyclobutanes are extended by observation that 1,3-diacetylimidazolin-2-one(7) adds to alker~es'~ and to enol silyl ether^:'^ M.Brookhart J. R. Tucker and G. R. Husk J. Am. Chem. SOC.,1981,103,979. K. A. M.Kremer P. Helquist and R. C. Kerber J. Am. Chem. Soc. 1981,103 1862. lo P. Fischer and G. Schaefer Angew. Chem. Znt. Ed. Engl. 1981,20,863. P. J. Kropp N. J. Pienta J. A. Sawyer and R. P. Polniaszek Tetrahedron 1981,37 3229. M.Suda Synthesis 1981 714. F.-G. Klarner W.Rungeler and W. Maifield Angew. Chem. Znt. Ed. Engl. 1981,20 595. l4 K.-H. Scholz J. Hinz H.-G. Heine and W. Hartmann Liebigs Ann. Chem. 1981 248. Is R. A.Whitney Can. J. Chem. 1981,59,2650. Alicyclic Chemistry Ac I Ac (7) Hydrolysis of the former adducts leads to cyclobutane-cis -1,2-diamines and elabor- ation of a suitable adduct with an enol ether permits a short synthesis of biotin.The importance of keteneiminium salts in the synthesis of cyclobutanones by thermal addition has been recogriized for some time. Now improved procedures (Scheme 3) permit the efficient synthesis’6 of both cyclobutanones and cyclo- butenones. Further the remarkable reactivity of these salts is shown’’ by their ability to add to a,p-unsaturated carbonyl compounds. CF3S03-Ph 77% Ph o CF SO3-Ph’ ‘ 80O/O 0 ZnC1,-57% Reagents i (CF,SO,),O; ii PhCH=CH,; iii PhCGCPh; iv CH,=CHCO,Me Scheme 3 The ‘three-phase test’ the use of a polymer-bound reagent to release an unstable intermediate able to migrate through solution to be trapped by a second polymer- bound reagent has been used to investigate the chemistry of fleeting intermediates.Cyclopentadienone can be generated18 in this way and can be trapped by insoluble reagents via Diels-Alder additions in which the cyclopentadienone can act either as diene or dienophile. Substituted cyclopentadienones are possible synthetic pre- cursors of substituted cyclo-butadienes and -tetrahedranes. Elegant new syntheses are shown in Scheme 4. Although disubstituted (8) is readily dimerized flash J.-B. Falmagne J. Escudero S. Taleb-Sahraoui and L. Ghosez Angew. Chem. Znt. Ed. Engl. 1981 20,879. ” H.-G. Heine and W. Hartmann Angew. Chem. Int. Ed. Engl. 1981 20 782. ’* F.Gavina A. M. Costero P. Gil B. Palazon and S. V. Luis J. Am. Chem. SOC.,1981,103,1797. 188 J. M. Mellor C 3C-/ SiMe SiMe SiMe \(CH )4 CEC-SiMe SiMe Ref. 19 SiMe SiMe Me,Si-CCCH A pM:, + Me,sipo co Ref.19 pj 53% Me,St ,SiMe Me,%\ iii __* M (9) (10) Reagents i hv,THF [(q5-CsH,)Co(CO),]. -20 "C; ii MeCN n-CsH12 (NH,),Ce(NO,),; iii hv Scheme 4 pyroly~is'~ of the dimer of (8) at 550 "Cquantitatively regenerates the monomer. The trisubstituted (9) and (10) are more stable and have been used2' as prekursors of the tetrasubstituted (11) (Scheme 5). However in contrast to the photolysis2' of tetra-t-butylcyclopentadienone,which gives a tetrahedrane photolysis of (1 1) only gives2' a cumulene tetrakis(trimethylsily1) butatriene via an intermediate allenyl ketene. Tetramethylcyclopentadienone can be obtained by photolysis of l9 E. R. F. Gesing J. P. Tane and K.P. C. Vollhardt Angew.Chem. Int. Ed. Engl. 1980,19,1023. 2o G.Maier H. W. Lage and H. P. Reisenauer Angew. Chem. Int. Ed. Engl. 1981,20,976. *' G. Maier S. Pfriem U. Schafer K.-D. Malsch and R. Matusch Chem. Ber. 1981,114,3965. Alicyclic Chemistry SiMe SiMe 0 0 (10) (11) Reagents i Pyridinium perbromide n-C5HI2 -78 OC; ii 1,5-diazabicyclo[5.4.O]undec-S-ene;iii LiSiMe, CuI Scheme 5 cyclobutene dicarboxylic anhydride and in turn on photolysis givesz2 tetramethyl- cyclobutadiene. Silyl-substituted cyclopentadienones (9) and (10) are similarly prepared. Two features of the vinyloxycyclopropane rearrangement to give 3-cyclopen- tenols are likely to stimulate further studies. In contrast to typical vinylcyclopropane rearrangements requiring high temperatures as shown in Scheme 6 Reagents i *CHOCH,CH,Cl; ii n-BuLi Scheme 6 proceeds efficiently at 25 "C.Further and again in contrast to the conventional rearrangement reaction proceeds with high stereoselectivity.Trimethylsilylal- lene~*~ can act as a three-carbon unit which with a,@-unsaturated ketones affords regioselectively for example (12) from methyl vinyl ketone. Target synthesis of cyclopentanoid anti-tumour antibiotics is fashionable. These highly functionalized antibiotics are very unstable and must be generated under mild conditions. The key steps of some recent syntheses are shown in Scheme 7. Interest in new syntheses of prostacyclins and prostaglandins continues. Full details 22 G. Maier and H. P. Reisenauer Chem. Ber. 1981 114 3959.23 R.L.Danheiser C. Martinez-Davila and J. M. Morin J. Org. Chem. 1980,45 1340; R. L. Danheiser C. Martinez-Davila R. J. Auchus and J. T. Kadonaga J. Am. Chem. SOC., 1981,103,2443. 24 R. L. Danheiser D. J. Carini and A. Basak J. Am. Chem. SOC., 1981 103 1604. 25 A. J. H. Klunder W. Bos and B. Zwanenburg Tetrahedron Lett. 1981,22 4557. 26 Y.Kobayashi and J. Tsuji Tetrahedron Lett. 1981,4295. 27 Y.Takahashi K. Isobe H. Hagiwara H. Kosugi and H. Uda J. Chem. SOC.,Chem. Commun. 1981 714. 28 D. Boschelli R. M. Scarborough and A. B. Smith Tetrahedron Lert. 1981 19. 190 J. M. Mellor Ref. 25 %o 0 fterrein C0,Me sarkomycin vi Li Ref. 27 PhSxco2Me methylenomycin A 0 0 *%+ CO,CH CH SiMe 1vii Ref. 28 viii ix CO,H CO H desepoxydidehydro-methylenomycin A Reagents i 420°C; ii H,O'; iii [Pd(OAc),] PPh,; iv 7 steps; v CH,=CHCO,Me; vi 7 steps; vii AcCI Me,SiCH,CH,OH; viii 5% Na,CO,; ix H30+ Scheme 7 are published2' of the Salford/Glaxo route to a variety of prostaglandins by homoconjugate addition of organocuprates to (13) and of the Australian route3' to prostaglandins via (14) which is available from phenol in five steps.The highly stereoselective addition31 of carbomethoxychloroketene to cyclopentadiene to give 29 R. J. Cave R. F. Newton D. P. Reynolds and S. M. Roberts J. Chem. SOC.,Perkin Trans. 1 1981 646;J. Davies S.M. Roberts D. P. Reynolds and R. F. Newton ibid. p. 1317;M. A. W. Finch S. M. Roberts G. T. Woolley and R. F. Newton ibid. p. 1725;R.F. Newton D. P. Reynolds C. F. Webb andS. M. Roberts ibid, p. 2055. 30 M. Gill and R. W. Rickards Aust. J. Chem. 1981,34,1063;R. M. Christie M. Gill and R. W. Rickards J. Chem. SOC., Perkin Trans. 1 1981,593;M. Gill and R. W. Rickards ibid. p. 599. 31 S. Goldstein P. Vannes C. Houge A. M. Frisque-Hesbain C. Wiaux-Zamar L. Ghosez G. Germain J. P. Declercq M:Van Meerssche and J. M. Arrieta J. Am. Chem. SOC.,1981,103,4616. 191 AlicycEic Chemistry 0 X OSiMe2Bu' H (13) X = Br or SiMe2Bu' /CCo2R (16) (17) (15) makes (16) available from cyclopentadiene in only four steps. A similarly economical synthesis results32 from an improved methodology of organocuprate addition to the monoepoxide of cyclopentadiene. Although prostacyclin (PGI,) (17; Re= H) an inhibitor of blood platelet aggregation is extremely unstable analogues lacking the enol-ether functionality can have a similar profile of phar- macological activity.Hence in addition to a new of (17; R = Me) there will be considerable interest in the full details of the synthed4 of 6-thia-analogues and in the synthesis3' of 6-carba-analogues as both series show interesting activity. In spite of the many detailed studies of the Diels-Alder reaction improvements continue to be made in this remarkably useful reaction. The intramolecular version has recently led to many short syntheses of natural products and has been re~iewed.~ Jung and Hal~eg~~ provide a further example where the stereochemical control stems from the conrotatory opening of a cyclobutene intermediate (Scheme 8) in the synthesis of coronafacic acid (18).Lewis-acid catalysis of the Diels-Alder reaction has frequently been used to advantage but efficient catalysis of cases where both diene and dienophile are hydrocarbons has proved difficult. Aminium cation radicals3' may prove to be effective catalysts. Dimerization of cyclohexa- 1,3-diene at 200 "Cfor 20 h gives (19) in only 30% yield but an aminium salt permits much higher yield (70%)to be obtained at 0 "Cafter only 15min. Earlier studies of asymmetric induction in the Diels-Alder reaction have been frustrated by the inability to obtain high enantiomeric excesses easily. Rationally designed chiral acrylate esters3* and chiral dienes3' give sufficiently high enantiomeric 32 J.P. Marino and M. G. Kelly J. Org. Chem. 1981 46 4389. 33 R. F. Newton S. M. Roberts B. J. Wakefield and G. T. Woolley J. Chem. Suc. Chem. Commun. 1981,922. 34 K. C. Nicolaou W. E. Barnette and R. L. Magolda J. Am. Chem. Suc. 1981,103 3472. " W. Skuballa and H. Vorbruggen Angew. Chem. Int. Ed. Engl. 1981,20 1046. 36 M. E. Jung and K. M. Halweg Tetrahedron Lett. 1981,2735. 37 D.J. Belville D. D. Wirth and N. L. Bauld J. Am. Chem. Soc. 1981,103 718. W. Oppolzer M. Kurth D. Reichlin C. Chapuis M. Mohnhaupt and F. Moffatt Helv. Chim. Acta 1981,64 2802; W. Oppolzer M. Kurth D. Reichlin and F. Moffatt Tetrahedron Lett. 1981 2545. 39 B. M. Trost D. O'Krongly and J. Belletire J. Am. Chem. Suc. 1981,103,7595. 192 J. M. Mellor I C0,Et C02Et C0,Et Reagents i 100"C; ii 180"C; iii HCI Scheme 8 (19) endo :ex0 ratio 5 :1 excesses to suggest that Diels-Alder reactions with asymmetric induction will soon become important in target synthesis.Use of a disymmetric dienophile derived from a sugar alternatively permits highly selective formation of norbornene deriva- tive~~' that can easily be degraded to optically pure cyclopentane derivatives. A more recently discovered reaction now shown to have wide synthetic applica- tions is the oxyanionic Cope and related rearrangements (Scheme 9). Wender's permits a ring enlargement by an 8-carbon unit. The stereocontrol has been crucial in synthesis of the natural product m~ltifidene.~' Although (20; R = allyl) readily undergoes an oxyanionic Cope rearrangement (20; R = Me) with KH suffers dehydration to give (21) and (22).Crucial evidence45 that (21) arises by electrocyclization of a trienyl anion is the observation that (21)is exclusively formed when 18-crown-6 is added. Bicyclic Compounds.-Spirocyclization procedures are still limited. Welcome addi- tions are the regiospecific intramolecular alkylation of enolates generated by mild halide-ion-induced decarb~xylation~~ of w-halogeno-P-keto-esters used in the 40 D. Horton and T. Machinami J. Chem. SOC.,Chem. Commun. 1981,88. 41 P. A.Wender S. McN. Sieburth J. Petraitis and S. K. Singh Tetrahedron 1981,37 3967. 42 G.D.Crouse and L. A. Paquette J. Org. Chem. 1981,46,4272. O3 S. G.Levine and R. L. McDaniel J. Org. Chem. 1981 46 2199.44 S.L.Schreiber and C. Santini TetrahedronLett. 1981,4651. 45 L.A.Paquette and G. D. Crouse J. Am. Chem. SOC., 1981,103,6235. 46 R. G.Eilerman and B. J. Willis J. Chem. SOC.,Chem. Commun. 1981 30. Alicyclic Chemistry Ref. 41 Ref. 42 viii X ___) -* Ref. 44 Reagents i 9 steps; ii KH THF; iii NH4Cl; iv LiCH=CH-CH=CH,; v RMgX; vi Me,SiCl; vii 4 steps; viii 2 steps; ix KH 18-crownd; x 180 "C Scheme 9 (20) (21) (22) synthesis of P-vetivone a reductive cleavage4' of (23) obtained via photocycliz-ation to give (24) and a closure48 based on vinylsilanes (25) +(26). Yields49of spirolactones from treatment of cyclic anhydrides with a,odiGrignard reagents are surprisingly high (typically 75%) but the procedure is limited by lack of 47 W.Oppolzer L. Gorrichon and T. G. C. Bird Hefv. Chim. Actu 1981,64 186. 48 S. D. Burke C. W. Murtiashaw M. S. Dike S. M. S.Strickland and J. 0.Saunders J. Org. Chem. 1981,46,2400. 49 P. Canonne D. Belanger G. Lemay and G. B. Foscolos J. Org. Chem. 1981,46 3091. 194 J. M. Mellor (23) (24) (25) (26) stereoselectivity. Such selectivity5’ is the merit of acylation of ynamines by enol lactones. Syntheses of bicyclopentanoid and polycyclopentanoid natural products have been a focus of attention and are the subject of a symposium in print.5’ An important general procedure is the highly regioselective addition” of an organopalladium Reagents i [(Ph,P),Pd] Ph,P; ii TsOH CDCI, 50 “C Scheme 10 intermediate to a,&unsaturated ketones (Scheme lo) and the use of chiral phos- phines to effect the intramolecular Wittig reactions3 of (27) to give (28) in high (27) (28) (29) enantiomeric excess suggests a developing importance for such asymmetric induc- tions.Intramolecular ene-reactionsS4 and cyclization of acetylenic ketone^'^^^^ have been elegantly used in the synthesis of the propellane natural product modhephene (29) (Scheme 11). Bridged and PolycyclicCompounds.-Successive cyclizationsof ketone (30)aff ~rd~~ the propellane (31) which is readily converted into the triepoxides (32) and (33). Remarkably both epoxides are smoothly rearrangeds8 by BF3 to give a trioxa- J. Ficini G. Revial and J. P. Genet Tetrahedron Lett. 1981 629. ” ‘Recent Developments in Polycyclopentanoid Chemistry’ ed.L. A. Paquette Tetrahedron 1981 37 4357. ’* B. M. Trost and D. M. T. Chan J. Am. Chem. SOC.,1981,103,5972. ” B. M. Trost and D. P. Curran Tetrahedron Lett. 1981,4929. 54 W. Oppolzer and F. Marazza Helv. Chim. Acta 1981 64 1575; W. Oppolzer and K. Battig ibid. p. 2489. ’’ H. Schostarez and L. A. Paquette J. Am. Chem. SOC.,1981,103,722. ’‘ M. Karpf and A. S. Dreiding Helv. Chim. Acta 1981 64 1123. ’’ J. Drouin F. Leyendecker and J. M. Conia Tetrahedron 1980 36 1203. ’* L. A. Paquette and M. Vazeux Tetrahedron Lett. 1981 291; S. A. Benner J. E. Maggio and H. E. Simmons J. Am. Chem. SOC.,1981,103 1580. Alicyclic Chemistry A _* Ref. 54 Ref. 55 Ref. 56 Scheme 11 analogue of a hexaquinane (34).Conversion of (31) into (35) gives a racemate. 'H n.m.r. establishes that at +147 "C interconversion of the enantiomers occurs probably by a stepwise inversion. (33) (34) (35) (36) (37) 59 J. E. Maggio H. E. Simmons and J. K. Kouba J. Am. Chem. SOC.,1981,103,1578. 196 J. M. Mellor (38) (39) The synthesis of the much sought pentaprismane (36) has been achieved6’ at last. The key transformation is generation of the pentaprismane skeleton by Favor- skii rearrangement of (37). Although fenestrane (38)has not yet been synthesized some hope of a possible synthesis is given by the relative stability of (39)61and related62 broken window compounds. The details of the synthesis and valence isomerization of tetra-t-b~tyltetrahedrane~l.~~ to give the corresponding cyclo- butadiene have been published but it is proving diffic~lt~**~~ either to synthesize or to show unambiguously the transient generation of other substituted tetra- hedranes.Highly strained alkenes continue to evoke interest. The diene (40) having two double bonds that are both highly strained and constrained by their geometry into interaction has been by dimerization of (41) (Scheme 12). At 80°C I (42) (40) Scheme 12 (40) is equilibrated with (42) via a Cope rearrangement. Not surprisingly (40) is highly reactive. For example oxygen gives a bis-epoxide. Force-field calculations66 suggest that in some anti-Bredt alkenes the localization of the double bond at a bridgehead position may lead to extra stability relative to their positional isomers.In such cases -‘hyperstable’ alkenes -a lower reactivity can be expected. 6o P. E. Eaton Y.S. Or and S. J. Branca J. Am. Chem. SOC.,1981,103,2134. 61 K. B. Wiberg L. K. Olli N. Golembeski and R. D. Adams J. Am. Chem. SOC.,1980,102,7467. 62 S. Wolff and W. C. Agosta J. Chem. SOC., Chem. Commun. 1981 118. 63 G. Maier S. Pfriern K. D. Malsch H.-0. Kalinowski and K. Dehnicke Chem. Ber. 1981 114 3965. 64 E. H. White R. E. K. Winter R. Graeve U. Zirngibl E. W. Friend H. Maskill U. Mende G. Kreiling H. P. Reisenauer and G. Maier Chem. Ber. 1981 114 3906; G. Maier and H. P. Reisenauer ibid. p. 3916; G. Maier M. Schneider G. Kreiling and W. Mayer ibid. p. 3922; G. Maier W. Mayer H.-A. Freitag H. P. Reisenauer and R. Askani ibid.,p.3935. 6s K. B. Wiberg M. Matturro and R. Adams J. Am. Chem. SOC., 1981,103,1600. 66 W. F. Maier and P. Von R. Schleyer J. Am. Chem. SOC., 1981,103 1891. Alicyclic Chemistry 197 3 Structural Aspects Studies of Conformation.-Nuclear Overhauser experiments and in particular the study of conformational equilibria using kinetic nuclear Overhauser effects have not been greatly used in conformational analysis. In a study showing the potential of kinetic n.0.e.67 the preferred conformation of (43)was established [as shown in (43)].High-resolution solid-state I3C n.m.r. spectroscopy is yet another new technique with great potential. Rapid equilibration6' of enantiomeric conformers of (44)and other cis-fused diones has been established by means of this method.J-J) 0 (43) (44) Better spectra obtained in infrared studies of matrix-trapped cyclohexane the earlier observations and assignment of a minor component as the twist-boat form of cyclohexane. Synthesis7' of (45)permits X-ray characterization of a compound having a six-membered ring rigidly constrained to a twist-boat. (45) Photosensitized is~merization~' of cis-cycloheptene at -78 "C affords trans-cyclo- heptene. In methanol solution the strained alkene readily adds methanol to give methoxycycloheptane but in the absence of added acid thermal trans-cis isomeriz- ation also occurs. In neutral methanol at 0 "C trans-cycloheptene has a lifetime of several minutes. X-Ray diffraction studies e~tablish'~ the planarity of the central eight-membered ring in (46).The enhanced diamagnetism suggests double-bond delocalization of the 87r system.(46) 67 J. D. Mersh and J. K. M. Sanders Tetrahedron Lett. 1981 4029. C. A. McDowell A. Naito J. R. Scheffer and Y.-F. Wong Tetrahedron Lett. 1981 4779. 69 J. L.Offenbach L. Fredin and H. L. Strauss J.Am. Chem. SOC.,1981,103 1001. 70 D. J. Herbert J. R. Scheffer A. S. Secco and J. Trotter Tetrahedron Lett. 1981 2941. 71 Y. Inoue T. Ueoka T. Kuroda and T. Hakushi J. Chem. Soc. Chem. Commun. 1981 1031. 72 F. W.B. Einstein A. C. Willis W. R. Cullen and R. L. Soulen J. Chem. Soc. Chem. Commun. 1981 526. 198 J. M. Mellor Stereocontrolled development of chiral centres remote from other centres of chirality in acyclic systems is very difficult.One solution is the use of macrocyclic compounds in which first the ratios of diastereoisomers may be controlled leaving a problem then of generation of the acyclic system for example via Baeyer-Villiger oxidation. Such a strategy requires a better knowledge of the conformational demands of the different macrocyclic systems. Promising (Scheme 13) show that even a single methyl substituent provides enough control of possible conformers to permit highly stereoselective formation of new chiral centres. Reagents and Yields i Me,CuLi 72% (>99% trans);ii LiNiPr', MeI >go% (98% cis); iii Me,CuLi 82% (99% cis); iv Me,CuLi 95% (>99% cis) Scheme 13 Intramolecular hydrogen bonding to wsystems is often suggested. An X-ray now shows that in (47) the conformation of the hydroxyl-group is such that interaction occurs in the crystal.1.r. studies show that this interaction persists in solution. Bu" I (47) 73 W. C. Still and I. Galynker Tetrahedron 1981 37 3981. 74 W. B. Schweizer J. D. Dunitz R. A. F'fund G. M. R. Tombo and C. Ganter Helu. Chim.Acta 1981 64 2738. A licyclic Chemistry 4 Chemistry Neutral Species.-Flash techniques75 permit the sensitized photogeneration of the lowest triplet state of a cyclobutadiene (48). Thermolysis of either (49) or (50) generates a common product assigned to be (51) on the basis of the mode of formation and the photoelectron spectrum. It is suggested76 that (51) is formed via monothiobenzoquinone (52). (48) (49) The effective distinction between an unsaturated carbene and an allene [for example (53)and (54)] can be very difficult.The possibility of equilibration depends not only on their relative energies but also on the magnitude of the kinetic barrier separating them. An MNDO analysis77 predicts that (54) is substantially the more stable. Ph~togeneration~~ of (53) rather confirms that (53)behaves as a nucleophile with respect to alcohols whereas (55) behaves as an electrophile. The possible intermediacy of (54) in the chemistry of (53) has not been excluded. Dehydrobr~mination~~ of (56) gives (57) which can be trapped by 1,3-diphenyl- benzofuran. Isolation of an optically active adduct from optically active (56)strongly suggests the intermediacy of chiral (57).Similarly examination8' of the dehydro- bromination of (58) suggests that the twisted allene (59) is formed. Trapping 75 J. Wirz A. Krebs H. Schmalstieg and H. Angliker Angew. Chem. In?. Ed. Engl. 1981 20 192. 76 R.Schulz and A. Schweig Angew. Chem. Znt. Ed. Engl. 1981 20 570. 77 E. E. Waali J. Am. Chem. SOC.,1981,103,3604. 78 W.Kirrnse K. Loosen and H.-D. Sluma J. Am. Chem. SOC.,1981,103,5935. 79 M.Balci and W. M. Jones J. Am. Chem. SOC.,1980,102,7607. M. Balci and W. M. Jones J. Am. Chem. SOC.,1981,103 2874. 200 J. M. Mellur (60) (61) (62) experimentss1 suggest that reaction of (60) with potassium fluoride in DMSO leads first to the highly strained alkene (61) which then can rearrange to the cyclic triene (62). Diphenylbenzofuran traps both (61) and (62); the ratio of trapped adducts depends upon the concentration of the isobenzofuran.Carbenium Ions.-The detailed description of the 2-norbornyl cation continues to evoke interest. The group of Grob have summarizeds2 their extensive studies of the solvolysis of 6-substituted-2-exu- and -2-endu-norbornyl sulphonates. Solvoly- sis rates are clearly very sensitive to 6-ex0 substitution and indicate substantial 1,3-bridging. Donor substituents favour formation of 2-exu products and acceptor substituents facilitate formation of 2-endu products. The results rule out steric effects as the major factor causing high exu-endu product ratios. A further interest- ing test of the origin of high exu-endu rate ratios is providedS3 by the constrained epimeric sulphonates (63) and (64) and the epimeric benzoates (65) and (66).In &OTs QOTs hopNB contrast to the unconstrained 2-norbornyl system where a high exo-endu-rate ratio is observed only low rate ratios are observed for the epimeric pairs (63) and (64). The difference is attributed to the inability in (63) and (64) because of geometric constraints of a bridging stabilization to permit acceleration of the exu solvolysis. In sharp contrast high exu-endu-rate ratios are observed in (65)-(67) implying a common steric factor relatively facilitating solvolysis of the exu isomer. The successful application of the Saunders technique of deuterium-induced perturbation of 13C n.m.r. chemical shifts to the problem of the 2-norbornyl cation (Annu.Rep. Prog. Chern. Sect. B 1980 77 154) has highlighted a major new technique in the study of possibly equilibrating cations. Further successful uses of H.-G. Zoch G. Szeimies R. Romer and R. Schmitt Angew. Chem. Int. Ed. Engl. 1981,20,877. '* W. Fischer C. A. Grob R. Hanreich G. Von Sprecher and A. Waldner Helv. Chim. Acra 1981 64,2298;C. A. Grob B. Gunther and R. Hanreich ibid. p. 2312. 83 J. E.Nordlander J. R. Neff W. B. Moore Y. Apeloig D. Arad S. A. Godlesk and P. von R. Schleyer Tetrahedron Lett. 1981,4921. Alicyclic Chemistry 201 the method establish the symmetrys4 of the dication (68) the absence” of equilibra-tion and hence the necessity of hydride bridging in the cation (69) and the structures6 of the 9-barbaralyl cation (70).I Radical Species.-Low-temperature photolysis8’ of the aluminium halide com- plexes of tetramethylcyclobutadiene affords the monomeric tetramethylcyclo- butadiene radical cation. Details of the photolysis of pentamethylcyclopenta- diene88 giving the pentamethylcyclopentadienyl radical are reported. Radical cations with one electron situated between two bridgehead carbon atoms of a bridged system have been generated. y-RadiolysisS9 of [3,3,3]propellane (7 1) in carbon tetrachloride at 77 K affords a species to which the cation radical structure can be unambiguously assigned from the e.s.r. spectrum. Observation of such a radical cation in fluid solution has yet to be demonstrated. However formation of (72)from photolysisgO of (73) is suggested to involve the intermediacy of the cation radical (74).CF3 X- & &’ X- (74) Alkene cation radicals are typically highly reactive. Although the cation radical of adamantylideneadamantane (75) has previously been reported it is now that anodic oxidation of (75) affords via the intermediacy of the cation radical the dioxetane (76). Chemical of (75) by one-electron transfer 84 H. Hogeveen and E. M. G. A. Van Kruchten J. Org. Chem. 1981,46 1350. ” R. P. Kirchen K. Ranganayakulu A. Rauk B. P. Singh and T. S. Sorensen J. Am. Chem. SOC.,1981 103 588. 86 P. Ahlberg C. Engdahl and G. Jonsull J. Am. Chem. SOC.,1981 103 1583. ’’ Q. P. Broxterman H. Hogeveen and D. M. Kok Terrahedron Left. 1981 173. A. G. Davies and J. Lusztyk J. Chem.SOC.,Perkin Trans. 2 1981 692. 89 R. W. Alder R. B. Sessions and M. C. R. Symons J. Chem. Res. 1981,82. 90 P. Golitz and A. de Meijere Angew. Chem. Inf. Ed. Engl. 1981,20 298. 91 E. L. Clennan W. Simmons and C. W. Almgren J. Am. Chem. SOC.,1981,103,2098. 92 S. F. Nelsen and R. Akaba J. Am. Chem. SOC.,1981,103,2096. 202 J. M. Mellor (75) (77) oxidants can lead to epoxide (77) and ketone (78) via an at present obscure mechanism. The range of relatively stable cation radicals of sterically hindered alkenes has been extended by obser~ation~~ that (79; n = 1,2 and 3) are character- ized by reversible cyclic voltammograms with removal of a single electron from (79). Although the thermal isomerization and photoisomerization of substituted cyclo- propanes are well documented there has been no clear evidence of a catalysed thermal isomerization proceeding via the intermediacy of anion radicals.Isomeriz- ati~n~~ of (80)occurs at 20 "Cin the presence of a sodium-potassium alloy showing that arylcyclopropanes are readily isomerized. Carbanions.-Stable car bani on^^^ have been generated by reaction of 7-substituted cycloheptatrienes with KNHz in liquid ammonia. For example 7-carbomethoxy- cycloheptatriene gives anion (8l),which is assigned the non-planar structure on the basis of the 'H and I3C data. However this assignment seems to conflict with the observation of some paratropic character in (8l),implying delocalization of an 87~system. MNDO and ab initio calculations suggest that anion (82),initially considered to be the classic example of anionic homoaromaticity should not be considered as a Me 93 F.Gerson J. Lopez A. Krebs and W. Ruger Angew. Chem. Znt. Ed. Engl. 1981,20,95. 94 G. Boche and H. Wintermayr Angew. Chem. Znt. Ed. Engl. 1981,20,874. " A.W.Zwaard and H. Kloosterziel Red. Trav. Chim. Pays-Bas 1981,100,126. Alicyclic Chemistry homoaromatic system. Confirming recent doubts homoaromatic stabilization in carbanions is found96 to be unimportant. 5 Stereoselectivity of Attack at sp2 Centres The view has developed that the stereochemical outcome of nucleophilic addition at the carbonyl centre of substituted cyclohexanones is partly controlled by factors other than repulsive steric interactions in the transition state.A detailed present- ati~n~~ extends this view by the suggestion that in addition to a stericfactor favouring equatorial approach of a nucleophile in 4-t-butylcyclohexanone an axial approach is assisted by a transition-state stabilization. However in contrast to the earlier view98 that an axial transition state is stabilized by interaction of u* antibonding orbitals of axial C-H bonds this alternative view emphasizes an interaction with vicinal-occupied orbitals with the antibonding orbital of the developing bond. Stereoselection for the two possible modes of attack at an alkene has been explained by a view similar to that of Anh and Ei~enstein~~ for attack at carbonyl centres. Hence the structural relationship of allylic substituents controls the observed mode of attack.With this analysis99 ex0 attack on norbornenes and the relative rate of additions to cyclopentenes and to cyclohexenes are rationalized. 96 J. B. Grutzner and W. L. Jorgensen J. Am. Chem. SOC. 1981,103 1372; E. Kaufmann H. Mayr J. Chandrasekhar and P. von R. Schleyer ibid.,p. 1375. ’’ A. S. Cieplak J. Am. Chem. SOC.,1981 103,4540. 98 N. T. Anh and 0.Eisenstein Nouu. J. Chim. 1977 1,61. 99 P. Caramella N. G. Rondan M. N. Paddon-Row and K. N. Houk J. Am. Chem. Soc. 1981,103,2438.