~~ Saturated and partially unsaturated carbocycles KEVIN I. BOOKER-MILBURN and ANDREW SHARPE School of Chemical Sciences, University of East Anglia, Nonvich, Nogolk NR4 7TJ, UK Reviewing the literature published between May 1995 and April 1996 Continuing the coverage in Contemporary Organic Synthesis, 1996, 3, 19 1 1.1 1.1.1 1.1.2 1.2 1.3 2 2.1 2.2 3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.3 3.4 4 4.1 4.2 4.3 4.4 4.5 5 5.1 5.2 6 7 8 Three-membered rings Metal carbenoid-based methods From dihaloalkanes From diazocarbonyl compounds Anion-based and related methods 0 ther met hods Four-membered rings Photochemical met hods 0 t her met hods Five-membered rings Free radical methods Me tal-based met hods Cobalt Palladium and nickel Zirconium and titanium Other metals Anion-based methods Cycloadditions, rearrangements and ring expansions Six-membered rings Diels-Alder reactions Free radical cyclisations Transition metal-mediated cyclisations Cationic cyclisations Other routes Seven-membered rings Cycloadditions and annulations Other methods Eight-membered rings Nine-membered and larger rings References optically active cyclopropanes.For example, Charette and Lebel' have reported the diastereo- selective cyclopropanation of allylic alcohols 1 using the modified Simmons-Smith reagent of diethylzinc and diiodomethane to give the desired products 2 in high yields and very high diastereomeric excesses superior to those obtained using the corresponding samarium-based cyclopropanation. Landais and Parra-Rapado' have used the same reagent to study 1,2-asymmetric induction in 2-silylalk-3-enols 3; similarly the resulting cyclopropanes 4 were obtained in high yields and high diastereomeric excesses.i. Etgn, CH2C12 - ')&R4 ii. CH212 R2 "J R4 R2 R3 1 2 Yield of syn syn : anti 86% 7: 1 97% 200: 1 96% 200: 1 R' = H; R2 = Ph; R3 = H; R4 = Me R1 = H; R2 = Ph; R3 = H; R4 = P i R' = Ph(CH2)2; R2 = H; R3 = H; R4 = Me SiMe2Ph SiMe2Ph Yield of anti anti : syn 1 Three-membered rings 1.1 Metal carbenoid-based methods 1.1.1 From dihaloalkanes The zinc carbenoid Simmons-Smith cyclopropana- tion remains one of the most useful methods available for the construction of the three- membered ring. Recent work has concentrated on the use of allylic or homoallylic alcohols to facilitate asymmetric induction; this coupled with the use of a chiral auxiliary has resulted in the preparation of Two research groups (Kobayash? and Charette4) have reported the Lewis acid-catalysed cyclo- propanation of the allylic alcohol 5 ; in both cases titanium tetrachloride was used as the Lewis acid and a good yield of the cyclopropylmethanol 6 was obtained.This principle was extended by both research groups to give enantioselection by the use of a chiral Lewis acid. Kobayashi used the Lewis acid 8 which was formed in situ from the C2 symmetric disulfonamide 7, whereas Charette used the titanium derivative 9. High yields of 6 were obtained with moderate to good enantiomeric excesses. Booker-Milburn and Sharpe: Saturated and partially unsaturated carbocycles 473LOH ii. C H ~ I ~ iii. Lewis acid Cu'Tf (5 mol%) ligand (15 rnol%) CHzCIz ooc+rt 05% 77% ee v 5 6 Lewis Yield ee acid 8 75% 68% 9 80% 90% H NHS02Ph Gyph Zn S02Ph a H NHS02Ph 7 8 9 1.1.2 From diazocarbonyl compounds The second metal carbenoid-based method of cyclo- propanation is by the treatment of an alkene with diazocarbonyl compounds in the presence of a metal catalyst. Demonceau and co-workers have demonstrated the use of the ruthenium-phosphine complex 11 and the osmium-phosphine complex 12 as catalysts5." as well as the osmium-aryl complex 137.Good yields of the product 10 were only achieved using styrene systems.Various research groups have been active in the dcvelopment of chiral catalysts for both intra- and inter-molecular enantioselective alkene-diazocarbonyl cyclo- propanations. The semicorrin-copper complex 16 has been reported' to effect the conversion of substrate 14 into the cyclopropyl ketone 15 in moderate yield with very good enantiomeric catalyst - phYco2Et Ph \= + N2CHC02Et 10 Catalyst Yield 12 OSCI2(PPhJ2 52% 11 RuCIp(PPh3 2 93% 13 [O~C1~(Cisopropyltoluene)]~ 59% 14 15 CN I CN 16 R = CMe20H excesses.A cobalt-salen complex, viz 18, has been reported' to catalyse the reaction between styrene and tert-butyl diazoacetate giving cyclopropanes 17a,b in good yield with good ee; a similar reaction has been described'" using an iron porphyrin as the catalyst. Shibasaki et aE." in their synthesis of the phorbol CD-ring skeleton have demonstrated an asymmetric intramolecular cyclopropanation of the enol silyl ether 19 using the chiral ligand 21 coupled with a copper catalyst to give the desired bicyclo- [4.1.0]heptane system 20 in very good yield and good ee.Doyle and Protopopova'2 have used the standard dirhodium tetraacetate catalyst in macro- cyclic lactone formation (22423). Finally, all four Ph L 17a catalyst CH2CIrMeOH rt, 24 h, 76% 1 + hYco2But 17b trans: cis 98 : 2 73% ee 18 N2' 4 0 OSiMe, 19 H H CMe3 CMe, 20 21 22 23 474 Contemporary Organic Synthesisdiastereomers of 4-(carboxymethy1)proline have been prepared via a dirhodium tetraacetate-induced cycIopropanation'-'. 1.2 Anion-based and related methods The familiar trimethylsulfoxonium ylide has been used by Gibson and co-workers14 as a reagent to convert the CrO complex 24 into the cyclopropane 25 in moderate yield. As a chiral alternative to the more usual trimethylsulfoxonium ylide, Hanessian et u1.l' have developed the new reagent 28 to prepare diastereomerically pure cyclopropyl ketones 27 from cqfi-unsaturated ketones such as 26.In the field of intramolecular anion reactions Nelson and Warren" have prepared cyclopropyl ketones 30 stereo- selectively from phosphine oxides 29. An intra- Me2(0)SCH2 61% 24 25 8 Me 28 BuLi, THF, -78 "C 73% 26 27 92%de 0 BU'OH Ph 29 30 R =Bu 83% trans: cis >95: 5 R = Ph 62% trans: cis >95: 5 molecular nucleophilic displacement has been used by Wicha et al. " to produce functionalised cyclo- propanes such as 32 from the iodide 31; elimination of benzenesulfinic acid from 32 then gave the cyclo- propene 33 in good yield. An intramolecular epoxide-ring opening has been reported]' in the enantioselective synthesis of cyclopropane a-amino acids, and a novel anion-induced ring contraction of cyclobutanes has been used as the key step in a preparation of an unusual cyclopropane nucleoside.19 Finally, Genet and co-workers"' have reported an asymmetric synthesis of the cis- and trans-vinylcyclopropanes 35 from the corresponding allylic esters 34.1.3 Other methods Two novel methods of cyclopropane ring formation starting from /I-haloesters have recently been N~N(S~MEI~)~ PhS02 C6H6 PhSO2 =!3iPh3 57% 32 trans : cis >96 : 4 31 BuLi 72% Et vSiPh3 33 34 35 reported. Thus, Tamaru et al." have developed a synthesis of the cyclopropane ketals 37a,b via a silyl chloride promoted cyclisation from /I-iodo esters such as 36 (moderate yields and stereoselectivities are obtained).Along similar lines, Fukuzawa et a1.22 found that treatment of 3-bromo esters 38 with a Grignard reagent -samarium iodide couple led to cyclopropanols 39 in excellent yield (this method has been adapted with less success to the prepara- tion of other cycloalkanols). Two other closely related methods of cyclopropanol formation, both utilising a titanium reagent, have recently been reported.'-' For example Cha and co-worker~~~ prepared the fused ring systems 41 from o-vinyl esters 40 via an intramolecular Kulinkovich hydroxycyclopropanation. The same research group has also rep~rted'~ the diastereoselective synthesis 0 i. Zn(Cu), THF ii. TBDMSCI I 36 37a 37b trans: cis = 12 : 1 RMgBr t ,xO" SmI2 (2 =I.) Br-C02Et THF-H MPA -78 "C -+ rt 38 39 R = BU 99% R = cyclohexyl 95% R = phenyl 99% OH 40 41 n = l 55% n = 2 62% n = 3 17% n = 4 0% Booker-Milburn and Shurpe: Saturated and partial& unsaturated carbocycles 475of cis- 1,2-dialkenylcyclopropanols using an intermolecular variation.The Cp2TiC12 complex has been used by Takeda et aLZ6 in the desulfuritive cyclopropanation of substituted 1,3-dithianes such as 42. A general method of small ring formation has been reported by Rieke and Sell27 in which, for example the cyclopropane 44 is prepared in good yield by reaction between Rieke barium, strontium, magnesium or calcium, the butadiene 43 and dichloromethane. A very neat synthesis of the cyclo- propane 46 has been described by Suzuki and co-workers28 starting from the homoallylic alcohol 45.This methodology has been used in the synthesis of a cyclopropane-containing icosanoid.29 Finally, a novel and highly efficient cyclopropane ring synthesis has been reported by Yus and Guijarro3" in which a 1,3-diol 47 is converted into a substituted cyclopropane 49 through the corresponding cyclic sulfate 48. CppTiC12 BULI (2 eq.) A * Ph3P Ph Ph 77% 42 M' ____f Ph A P h CHpClp 43 Brio+ 45 Ph - r v Ph 44 M=Ba 67% M = Sr 55% M=Ca 47% M=Mg 76% 46 0, ,o ,/s: 0 OH OH i. SOCI~, CCI~ I i. Li. 4.4'-di-tert-butvl- I biphenyl (cat.), YHF. o "C ii. H 2 0 "k R2 R3 49 Yield of 48 Yield of 49 R' = H; R2 = Me; R3 = CH2Ph 81% 60% 95% 84% R'R2 = CH2CH2CH2CH2; R3 = CH2Ph 93% 91 O/O R' = Me, R2 = CH2Ph; R3 = H 2 Four-membered rings 2.1 Photochemical methods The temporary silicon tether has again been used to good effect in [2 + 21 photocycloadditions.For example, Fleming et aZ. found that irradiation of the tethered enyne alkoxysilanes 50 followed by desilylation of the photoadducts led to high yields of the functionalised cyclobutene diols 51 with excellent levels of regio- and stereo-control.31 Overall the temporary silicon tether allows the synthesis of 'intermolecular' [2 + 21 photocyclo- adducts with the regio- and stereo-control normally associated with the intramolecular variant. Interestingly the diphenyl diyne 52 gave the naphthalene derivative 53 via an alternative cyclo- addition involving one of the phenyl moieties. Booker-Milburn et aZ.32 have reported that 3,4,5,6-tetrahydrophthalic anhydride 54 and the corresponding imide 55 underwent highly stereo- selective intermolecular [2 + 21 photocycloadditions with a variety of alkenols.For example irradiation of 54 with but-2-ene-174-diol gave the cyclobutane lactone 56 as a single product in excellent yield via spontaneous lactonisation of the initially formed cyclobutane anhydride. Irradiation of 55 with ally1 alcohol for example gave the diastereomeric cyclobutane imides 57 and 58 with a high de of 10 : 1. Similarly, a number of cyclobutene-anhydrides and imides were prepared in good yield by [2+2] photocycloadditions of 54 and 55 with a variety of acetylenic alcohols. Studies of the scope for intramolecular [2 + 21 photocycloadditions in synthesis have continued in earnest and a number of interesting examples have been reported over the review period.For example, Tenaglia and Barillk33 found that irradiation of the allenyl pyrone acetals 59 gave the corresponding exu-methylenecyclo- 50 L A 1 NH~F " O X HO 51 R=Ph 80% R=C02Me 75% ,Ph 52 53 476 Contemporary Organic Synthesis0 55 1.5 q H O v o H - hv. MeCN. 4 h, 83% 54 0 1.5 eq. doH hv, MeCN, 70 rnin, 89% 54, X L O 55, X=NH -O*l HO- 1 1 56 .&+:& HO- 1O:l 57 58 59 I I 60 n = i , R = M e 81% n = 2 , R = H 46% n = 2. R = Me 60% n = l , R = H 99% butanes 60 in good yield with excellent stereo- selectivity. In a study of the radical fragmentation of cyclobutanes, Reckwith and co-worked" found that irradiation of the pyridone 61 gave the highly functionaliscd cyclobutanc 62, as a single diastoreomer, in exccllcnt yield.In their studies towards as t e r i scan o 1 i de Boo ke r - M i 1 burn an d Cow c I 1 '' found t h at in t r am o I e cu 1 ar p h o t ocyclo - addition o f the x,/hnsaturated acid 63 gave the fused cyclobutane 64 with complete stereocontrol. Finally, Haddad and Abramovich"" have reported moderato to good diastereocontrol on irradiation of alkcnyl tethered cyclic acetals. 61 hv, Pyrex, MeCN c 76% H02C 63 62 R=HorMe H& H C02H 64 2.2 Other methods Padwa et al." have reported a very useful therrnal [2 + 2) cycloaddition reaction involving prop-2-ynyl sulfones. For example reaction of the alcohol 65 with benzenesulfenyl chloride gave the correspond- ing prop-2-ynyl sulfoxide which was then oxidised to the sulfone 66. Heating 66 with tricthylamine led to the metliylenecyclobutane 68 in excellent yield via thermal [2 + 21 cycloaddition of the transient allenyl sulfone 67.The Lewis acid promoted tandem intra- molecular Michael-aldol reactions of keto esters have bcen further investigated by FukumotoJX and a number of new examples reported (69-+70 and 71 4 7 2 ) . Jun has reported'" an interesting new i. PhSCI, Et3N ~ ii. Oxone@ \ \ \\ 65 \\ 66 EtSN, 80 "C 68 95% 67 TMSI or Bu2BOTf --OTMS 69 70 71 72 cyclobutane ring-forming process involving the reaction of quinoline-7-carbaldchydc with the Rh' bis-alkene dimer 73. The reaction probably proceeds by oxidative insertion of Rh into the aldehyde C-H bond followed by reductive cyclisation on treatment with trimethyl phosphite. Silyl substitution of vinyl allenes has been found to have a remarkable effect o n the rate and equilibrium of electrocyclisation; thus Ito et a/.'"' have found that a number of silyl substituted rnethylenecyclobutenes can be prepared in good yield under mild conditions (74-75).3 Five-membered rings 3.1 Free radical methods Free radical cyclisations remain a very popular method of tive-membered ring synthcsis; new work Boo kt.I--hlilhurri u t i d Sli urpe: Su tii ra t ed and partially u 11 sa ti iru t ed c-u rhocycles 477CHO I 2 73 I P(OMe)3, EtpO 82% Me H’ 83: 17 R’ -R’ SiRZ3 heat, xylene, 2 h 6 examples, 8549% 74 75 in this area comprises novel methodology, the use of chiral reagents to confer stereoselectivity and the application of existing methods to natural product synthesis. Two interesting developments reported recently involve the translocation via a 1,5-hydrogen abstraction by an aryl radical to form an alkyl radical which then undergoes cyclisation.For example Murphy and Roome” have generated aryl radicals from arenediazonium salts, such as 77, in the presence of tetrathiofulvalene 76 to afford ring systems, such as 78, in good yields. Curran and Xu41 have demonstrated the viability of a protccting- translocating group that generates a radical in the P-position relative to a protected alcohol, such that o-bromo-p-methoxyphenyl ethers 79 are converted successfully into cyclopentanes 80. Fu and Hays43 have described the use of catalytic tributyltin hydride for the radical-mediated reductive Bu3SnH Et02C Fe AlBN CGH6 R P OMe 79 cyclisations of enaIs arid enones, such as 81, giving good yields of cyclopentanes, e.g.82a,b. As alternative radical-generating methods, Chuang and Wang44 have reported the use of sodium toluene- p-sulfinate, while Hatem et al.4s have proposed the use of toluene-p-sulfonyl bromide in the cyclisations of allylallenes. Booker-Milburn and have published full experimental details of their iron( uI)-mcdiatcd ring expansion-cyclisation technique for the formation of [n.3.0] systems from cyclopropyl ethers. Enholm and Jia4’ have also made use of the radical ring openings of functionalised cyclopropanes; thus generation of the O-stannyl radical from the cyclopentanone 83 results in a fragmentation-cyclisation sequence of reactions to produce the angular triquinane skeleton 84. The same research group4’ has also studied the reactions of allylic O-stannyl radicals and excellent yields of cyclisation products 86a,b were achieved using tributyltin hydride radical-generation from the a,P-unsaturated ketone 85.Two examples of stercoselective radical cyclisations using a chiral aluminium-based Lewis acid have been reported by Nishida and co-workers.“””) Curran and Martinez- L 77 E t0pC & EtO& OMe - 45% t-- 1 ,&hydrogen abstraction I r 78 - Et02C E*2cT0 80 R = H 44% 89 : 11 cis: trans R = Br 71% 81 : 19 cis: trans 478 Con tetnporaiy Organic SynthesisC02Et BuoSnH (5 mol%) H o . , 6 C O 2 : a ''U PhSiH, AlBN * 0 71% 81 Bu3SnH AlBN C6H6 80 c 03 1.6: 1 82a 82b J 93% v H a4 0 A 193% 86a 86b 3 : 1 G r a d ' have used the unimolecular chain reactions of silicon hydrides such as 87 to give exclusively the E-alkene cyclisation product 88 (this methodology has also been applied to the synthesis of six- membered rings).The same principlei' has been utiliscd to prepare alkenes 90a,b predominantly as the Z-isomer 90a from the enantiomcrically pure alkyne-tethered oxime ethers 89. The final area of research involving free radicals that has attracted much interest is tandem cyclisations and cascade reactions. Pattendcn and Hayes" have dcviscd elegant methodology in which the sclcnoester 91 is convcrted into the bicyclic ketonc 94 in very good yield via the a,[,'-unsaturatcd acyl radical 92 and the 80% 87 88 BnO-N- W"" O X 0 89 H + O X 0 90a (Z) 69% 3% R = H 70% R=Ac R=TBDMS 45% 14% 91 90b (E) MOM0 Go 92 I 93 94 x-ketene alkyl radical 93.This is the first reported example of radical cyclisation onto a ketenc. An example of the unusual 5-endo-trig cyclisation in a radical cascade has been demonstrated by Malacrio and B ~ g e n ~ ~ in which alkynes 95 are converted into cyclopentanols 96 in very good yield. The uses of tandem radical cyclisations in natural product synthesis have been reported in the synthesis of ( & )-Y- and [Hiotol,55 and by Hoffmann and Booker-Milhurn and Sharp: Saturated and partially unsaturated carbocycles 47995 7 SiMe3 96 1 R' R2 (R4 R5) R3 Yield P i p i H Me BU' 88% p i PI-' H Me TMS 69% Et Et H H Bu' 21% Weltering" in their synthesis of dioxatriquinanes and doubly annulated glycosides. 3.2 Metal-based methods 3.2.1 Cobalt As in previous years the most commonly reported cobalt-based cyclisation method has been the Pauson-Khand reaction (PKR).Perhaps the most important recent development in the PKR has been reported by Livinghouse and Pagenkopf' who have found that under photochemical conditions the reaction can be made catalytic in cobalt with only 5 mol% Co,(CO), required. Cazes et af.58 have studied the intermolecular PKR with allenic compounds, and Veretenov and co-~orkers'~ have used the PKR to synthesise linearly fused triquinanes. Paquette and Borelly"" have prepared the angularly fused triquinane 98 from the cyclopentene 97 in their approach to the CD diquinane substructure 99 of 97 -+ 85% OTBDMS 98 OM@ Me 99 R'O R1O'* eR2 100 i. Co2(CO)e ii. A or B A 101 H A: MeCN, A 8: Me3N0, THF, rt R' = TBDMS; R2 = TMS 100 : 0 93% (A) R' = H; R2= Ph 92: 8 81% (B) R' = TBDMS; R2 = Bu' 97 : 3 84% (6) kalmanol.A highly diastereoselectivc construction of optically active bicyclo[3.3.0]octenones 101 from enynes 100 by an intramolecular PKR has been reported by Mukai et uf.61 Other uses of cobalt have been reported by Tyrrell and co-workersh2 who have utilized the intramolecular Nicholas reaction in an approach to fused carbocycles such as 103 from the alkynyl enol ether 102. Takacs and Mehrma# have developed the cobalt-mcdiated reductive cyclisation of ene dienes 104 to cyclopentanes, e.g. 105. 3.2.2 Palladium and nickel The familiar palladium-catalysed coupling of alkenes has been well represented in the literature recently, particularly in the area of natural product synthesis.On the methodology side, Larock and GuoM have studied the annulation of oxygen- substituted dienes with aryl iodides leading to benzo-fused cyclopentanes in excellent yield. The same research group" has also reacted aryl iodides 106 with vinylic cyclopropanes, including 107, to give benzo-fused cyclopentanes such as 108. The stereo- chemistry of the product 110 resulting from intra- molecular asymmetric allylation of the chiral enamine 109 has been investigated with some success by Hiroi and co-workers,b6 and Yamamoto 102 H 103 104 105 R=CHzPh 86% R = C02Et 74% 480 Contt.mporury Organic SynthesisC02Et I 106 107 Pd(0Ac) , NaOAc. Bu4NCI DMF. 3 Jays, a0 o c , 82% 108 i. Pd(dba)2 MeCN 82 "C + ii. 10% HCI 80% ee 65% 109 110 et aL6' have demonstrated a tandem palladium(o)- catalysed cyclization of 6-(alk-2-enyl)octa-2,7-dienyl acetate 111 giving the diquinane 112 with high diastereoselectivity.Palladium-catalysed cyclisation reactions directed towards the synthesis of natural products have been reported from the research groups of Fukumoto,"."' Shirahama"' (in their synthesis of kainic acid analogues) and Kihayashi" in which under controlled conditions the enyne 113 was found to give predominantly the single isomer 114, a key intermediate used in their synthesis of ( + )-streptazolin 115. Two research groups have studied organozinc/catalytic nickel(())-promotcd cyclisations. Thus, Knochel and Stadtmiiller7' have < OAc 111 112 Me 113 114 utilized this methodology in asymmetric syntheses of ( +)-methyl epijasmonate and (-)-methyl cucurbate, whereas Montgomery and Sauchenk~''.~~ have examined the cyclizations of bis-enones and the alkynyl enones 116 leading to products 117 in which the substituted double bonds have been introduced in a stereoselective manner.116 117 R=Me 82% R=Ph 61% 3.2.3 Zirconium and titanium The zirconium-mediated intramolecular cyclisation of 1,6-dienes, enynes and diynes is a well-known method for the formation of cyclopentanes proceding via zirconobicycles. Recently new methodology has been developed by Sato and co-workers7' in which the established zirconium reagent is replaced by a new titanium reagent, viz. a titanobicycle. Thus the diene 118 is converted in high yield into the cyclopentane 119 upon treatment with titanium tetraisopropoxide and iso-propyl- magnesium chloride.As with zirconium, the intermediate metallobicycle can be reacted with carbon monoxide to give a bicyclo[3.3.0]octanone; one advantage over zirconium is that single terminal alkynes can be used in the cyclisation. Sato's group have extended this work to include the stereo- selective synthesis of cycloalkylamines from unsaturated imines7' as well as to the cyclisation of conjugated dienes with alkyne~;'~ in the latter case it was found that the intermediate titanobicycle 121 derived from 120 reacts exclusively with electro- philes such as benzaldehyde through the allylic double bond to give the corresponding cyclopentane Ti(OPr'), Pr'MgCI * BnoxY BnO 77% BnO 118 119 B n O S Ti(OPr'), BnO* SiMea ::) - Ti-3 BnO , Pr'MgCI BnO .120 k 121 PhCHO 96% I BnO 122 Booker- M i l h rn and Sh arpe: Sa tit ra ted a ii d part ia /ly ii n sa tu ra ten ca rhocycles 48 1122 in excellent yield. Along similar lines, Buchwald and ~o-workers’~ have shown that dicyclopentene- titanium dichloride and butyllithium form a suitable alternative catalyst for the synthesis of bicyclic cyclopentenones and allylic amides; thus the enyne 123 can be converted into the amide 124 or the a,P-unsubstituted ketone 125. Zirconium-based cyclisations in conjunction with the zinca-cne-allene reaction have been used to synthesise linear and angular triquinane skeletons stereo~electively.~’ Returning to titanium-based methods, two research groups have studied the reductive cyclisations of &&-unsaturated ketones and aldehydes.Buchwald and Kablaoui””.“’ for instance have used a titanium catalyst with diphenyphosphine to prepare the cyclopentanol 127 from the enone 126, whereas Crowe and co-workers82’R’ have developed similar methodology that includes a carbon monoxide insertion reaction to synthesise fused bicyclic j+utyrolactones, such as 129, from enones e.g. 128. Ph cPh 123 i. Cp2TiCI2 BuLi ii. Et3SiCN D PPh3 toluene 64% 126 q y NH OAMe 124 & SiEt3 H30+ 66% I Ph do H 125 &Me 127 128 129 3.2.4 Other metals The familiar samarium diiodide coupling reactions of aldehydes and ketones with alkenes have been used for the synthesis of cyclopentanols notably by Holzaffel et al. 84 in their stereoselective synthesis from carbohydrates; this methodology has been extended to oxime ethers for the synthesis of aminocyclopentenols.85 Bennett and co-workersfi6 have used samarium diiodide to effect the trans- formation of alkynyl bromides to cyclopentanes i n very good yields.Forsyth and Huang” have reported the spirocarbomercuriation of a silyl enol ether in their synthesis of the spirocyclic sesquiterpenes erythrodiene and spirojatamol. Rieke et aLSS have reacted substituted (but-2-ene-1,4-diyl)magnesium complexes with carboxylic esters and lactones to generate cyclopentanols. In the field of alkene metathesis, Nugent et al.’” have used a tungsten catalyst to synthesize enantiomerically pure cycloalkenes e.g. 131 from the simple dienes 130, and Grubbs and Fuyimurago have had modest success with asymmetric ring-closure reactions using a chiral molybdenum catalyst.Finally, Taber and You” have used a diastereoselective rhodium carbenoid C-H insertion reaction (132 + 133) in their approach to the synthesis of the dendrobatid alkaloid 25 1 F. ArO.0 CI c, ,w.iAr (2 mol%) 1,2,Qtrichlorobenzene, 90 “C. 68% 130 Ar = 2,6-dibromophenyl 131 0 w, cat. Rh octanoate, CH2C12 89% Me02C 132 133 3.3 Anion-based methods Once again there have been many reports of five- membered ring synthesis using anion-based mcthods, including the standard aldol, Michael and Dieckman-like reactions, those of note leading to the syntheses of ( & )-Ia~rene’~ and ( & )-a~amide.’~,’~ There have also been a number of more novel methods including the reagent 134 devised by Katritzky et al.” to effect the transformation of esters 135 into 2-ethoxycyclopent-2-enones 136.Krief and co-workers’b have reported the stereo- selective synthesis of 1,2-dialkyl-l-phcnylcyclo- pentanes 138 by intramolecular carbolithiation of vinyl sulfides 137, and Taguchi et a1.” have used the chiral titanium reagent 141 to effect the catalytic asymmetric iodocarbocyclisation of diesters 139 to cyclopentane lactones 140, both in very good yield and with high ees. There have been several rcports of anion-based annulations, including two based on aldol condensations coupled with Wittig or Horner- Emrnons reactions to make 4-hydroxycyclopent- 2-en-1-ones 144. Thus, Bonadies et a1 ” have reacted diketones 142 with phosphonates 143 to achieve this 482 Contemporary Organic Synthesis134 1 NaH Ar&OEt 136 Ar = Ph 62% Ar = pMeOC6H4 57% Ar = pCIC6H4 55% t PhIGNOTf 86% SnBu3 1 45 Ill -Art +I " I ' Ph 146 LiN(SiMe& 66% &Me I Ts 1 47 i. BuLi Me,, PhMe Me., PhMe A particularly interesting and unusual example has - &sph + &SPh been devised by Padwa and co-workers'"' in which an a-diazo-yamido ketone such as 148 is treated 1 37 138 cisp : cisa = 3 : 1 C02Bn cat. 141, 12, CH,CI, 94% ee d C 0 2 B n 139 P6 Ph p{ 'Ph 140 141 ? LiOH*H,z j$,, "4~1 + (Me0)2P T R 2 MeOH " OH 0 0 142 143 144 R' = Et; R2= H R' = Ph; R2 = H R' = Ph; R2 = Bu 52% 64% 60% with rhodium( 11) acetate and an electron-deficient alkene or alkyne to give a spiro-epoxy cyclopentane such as 149.Lu and Zhang"'-' have developed a phosphine-catalysed cycloaddition reaction between buta-2,3-dienoate and electron-deficient alkenes, while Kurajima et af.104 have used the silyl enol ether 150 to prepare cyclopentanones from alkenes.A synthesis of diquinanes has been achieved by Iwato et af. Io5 using a novel cation radical-mediated intra- molecular [3 + 21 cycloaddition of cyclopropyl sulfides (151 +152a,b). Motherwell et af.'"6 have continued to develop their intramolecular [3 + 21 cycloaddi tions involving cyclopropanes which under palladium catalysis are converted into bicyclic systems. Lautens and c o - ~ o r k e r s ~ " ~ ~ ' ~ ) ~ have made cxtensive studies on cobalt- and nickel-catalysed [27r + 27r + 2711 cycloadditions; thus for instance bicyclo[2.2.l]hepta-2,5-diene 153 is converted into the enantiomerically pure cycloadducts 154 using Co(acac), in conjunction with a chiral phosphine ligand.Weinreb and co-workcrs1"" have reported a novel ene reaction involving allenylsilancs to synthe- sise cyclopentanols and cyclohexanols, while Normant et al." have used a similar zinca-ene-allene reaction t o prepare, for example, the cyclopentane 156 from the silylalkyne 155 in very good yield; this Yh Me, ,Ph 0 0 0 end, whereas Hatanaka and co-workers')' have reacted a phosphorane with chiral glyoxals. Another annulation reaction leading to the synthesis of bicyclic conjugated enediones has been described by G hera and co-workers.""' Finally, in a carbene-based cyclisation, Feldman et al."" have reacted the stannane 145) with base to produce the nitrogen- Ph * Rh" +HN2 0 70% Ph I alkynyliodonium salt 146 (derived from the alkynyl- 148 149 containing bicycle 147.OTlPS R MeS+OAc -2 EtAIC12 C10H21 CHzCIz 3.4 Cycloaddi tians, rearrangements and ring expansions 150 Many research groups have been active in the area o f five-membered ring formation viu cycloadditions. R = Ph 66% 89: 11 R = SPh 80% >99: 1 483151 + 153 3 b*SiMe3 155 T SiMe, 156 152a 152b 3 : 1 Co(aca& Et2AICI R' 154 C6H6 R = BU 83% 91% ee R = (CH2j40Ac 85% 85% ee i. Bu'Li THF * ii. ZnBr2 CuCN 72% SiMe3 TZnBr SiMe3 sequence in conjunction with zirconium chemistry has led to the synthesis of linear and angular tri- quinane carbon skeletons. An alternative synthesis of triquinancs has been devised by Moore and Santora'"' which features a novel tandem oxy-Cope- transannular ring closure to prepare, for example, the triquinane 158 from the ketone 157.Paquette and Doyen"' have continued to explore the fasci- nating chemistry of squarate esters to achieve full control of regioselectivity in their synthesis of linear and angular polyquinanes (159-+160). In the field of ring expansions, Fitjer et al."' have successfully prepared cyclopentanones from cyclobutyl phenyl sulfides (an asymmetric method has also been described), and Fukuzawa and Tsuchimoto] I ' have * Me3SiO& iii.NaHC03 ii. warm to rt Me3Si0 1 L 157 1 0 &p '0 H _67% Me3Sy@) 0 H HO- 159 1 60 developed a facile conversion of cyclobutanones into cyclopentanones using samarium diiodide and diiodomethane. Finally, Fukumoto et ~ l . " ' . " ~ have prepared cyclopentanones from vinyl cyclobutanols.4 Six-membered rings 4.1 Diels-Alder reactions The Diels-Alder reaction has continued to be the premier method for the formation of six-membered carbocycles, and again much work has been focused towards developing new methods for the construc- tion of enantiomerically pure cyclohexenes. The interest in asymmetric catalysis using binaphthol ligands has continued."" For example the cyclo- additions of eight different dienophiles were found to give very high ees with the boron-derived catalyst 161 and a number of cyclic and acyclic dienes."' Posner et a/.'1s have reported that the pyrone 162 undergoes cnantioselective cycloaddition using a BINOL [1.1 '-bi(2-naphthol)]-Ti catalyst. A very interesting kinetic resolution was reported by Larsen et al.ll' during the synthesis of angucyclinone antibiotics. It was found that brief exposure ( < 2 min) of 5-hydroxy-naphtho-l,4-quinone and the rucernic diene 163, to a catalyst prepared from (S)-3,3'-diphenyl-l,1 '-binaphthalene-2,2'-diol and borane, gave the Diels-Alder adduct 164 in good yield and greater than 98% ee.The use of chiral auxiliaries and diastereocontrol has continued to attract attention. For example Sommakia and Berliner have demonstrated"" that treatment of the acetals 165 with fluoroboric acid yields the cyclohex- enes 167 viu highly diastereosclective Diels-Alder cycloaddition of the vinyloxocarbenium ions 166. The continued interest of Agganval et ul.]" in chiral CF, 161 C02Me i. 1.3 eq. (R)-(+)-BINOL-TiC12(OPr')2 50 "C, toluene -oy&!: ii, _,OR ,-30°C 0 9243% ee o6 162 R = CH,naphthyl, SiMe2Bu' 158 4 84 Con temporary Orgu ri ic Synthesis@ :yMe I OMe OH 0 (*)-163 BH3-THF.(S)-3,3'-diphenyC1 ,l'- binaphthalene-2,2'-diol AcOH, THF, -78 "C, c2 min 69% 1 &M:8yoee \ OH 0 H : OMe 164 &OTOEt HBF4-OMe2 R' R' H 165 166 ii, TsOH, MeOH 0 R2 d=y;H 167 4&74% high des (20-2OO:l) sulfoxides has led to some promising results with the use of the enantiomerically pure sulfoxide 168 as a chiral ketene equivalent in diastereoselective Diels- Alder reactions. An entry to enantiomerically pure decalin structures has been reported by Chapleur and co-workers'" via the diastereoselectivc intra- molecular reaction of the carbohydrate derived triene 169. An interesting use of the retro Diels- n 4 EtCN, 83% rt, 18 h o--sTs-o >97:3 168 OTMS EtCN, rt, 2 h M%:20 0 >97:3 0 169 PhMe, 155°C hydroquinone 75% I Bu'02C 0 Alder reaction has been described in an enantio- selective synthesis"' of calcitriol.The toluene-p-sulfonyl selenoacetylene 170 has proved to be a useful masked ketene equivalent in a number of Diels-Alder reactions with unactivated dienes, leading to excellent yields of cycloadducts under mild conditions.I2" Grieco el af. 125.'26 have continued to report on the excellent results obtained with lithium perchlorate-accelerated Diels-Alder reactions. Of particular note is the use of LiNTf2 as a safer and equally efficient alternative to LiC104.'" Okamura et al.'2x have demonstrated that 3-hydroxy- 2-pyrone undergoes a base-catalysed Diels-Alder reaction with a number of dienophiles without the the need for high pressure e.g.171+172a,b. Furthermore, the resulting cycloadducts can be isolated without extrusion of CO?. Funk and Yost have shown that 2-acyloxyacroleins are excellent dienophiles for a number of different diene systems. Most importantly the tetrasubstituted dienes 173 lead to excellent yields of Diels-Alder cycloadducts under SnCI, catalysis, thus providing rapid access to functionalised Taxol A ring synthons."" R- f, + 1 - R - sTs -.-a \\ SePh 0 SePh 170 -C02Me '&C02Me - Et3N, CHC13, 12 h, 98% HO Ho C02Me OH 171 172a 172b (1 1:l) R' 3:l PhMe-CHzCI2 0 R2 0 173 R' = CH2C02Me; R2 = C5H1, 95% R' = OCOCSH11; R2 = OPr' 90% Booker-Milburn and Sharpe: Saturated and partially unsaturated carbocycles 485486 The intramolecular Diels-Alder (IMDA) reaction continues to be one of the most useful strategies in target molecule synthesis and a number of signifi- cant examples have been reported over the review period.Taber's synthesis of r-dictyopterol involved an efficient construction of the decalin framework via IMDA reaction of the vinylsilane 174 followed by Wittig olefination and oxidative desilylation.'"' Singleton and LeeI3' have continued their studies on the use of vinylboranes in the Diels-Alder reaction and have found that hydroboration of the acetylene 175 followed by IMDA of the intermediate vinyl- borane 176 yields the hydroxylated decalin 177 after oxidative work-up, all in a one pot reaction. It is interesting to note that 175 itself is constructed in good yield in a one pot reaction.In an approach towards the diterpene skeleton of the radarins either geometrical isomer of the tetraene 178 was found to undergo IMDA leading to the highly functionalised skeleton 179.'32 Baldwin and SiMezPh 250 "C ___) 0 c I 174 (E:Z = 4:l) i. Wittig ii. [O] t OH co-workcrs'33 have demonstratcd the viabiliy of an IMDA in the proposed biosynthesis of himgravine (180+181), and Deslongchanips and Hall'34 have used a tandem transannular Diels-Alder-aldol cyclisation sequence to good effect in a stereo- controlled approach towards ( + )-aphidicolin (182483). The temporary silicon connection has again been used as a powerful tool in the stereo- controlled formation of highly functionalised cyclo- hexenes.'35 For example Luh et a1.'36 found that the siloxane tethered bis-dienes 184 underwent IMDA reaction followcd by oxidative desilylation to yield the highly functionalised trans-cyclohex-3-ene- 1,2-diols 185 with complete stereocontrol.Finally, Stork and Chan13' have reported the remarkable observation that a magnesium or aluminium atom can serve as a temporary connection in an IMDA reaction, leading to good yields and stereoselectivi- ties. One of the fascinating features of this reaction is that it allows for the cycloaddition of unactivated , 0 180 TMSOCH2CH20TMS TMSOTf, CH~CIZ, -78 + 20 "C 2 h, 53% I &o H , ' 0 a-dictyopterol 181 i. (C6HI1)2BH, THF ii. 75 "C, 2.5 h 0 210"C, 18h, Et3N, PhMe 54% P TIPSO TIPSO 175 176 182 183 N aB 034H20 1 p 2 4542% R 184 177 KHCO3, H 0 2 , M~OH-T~F then KF, 7&75% SPh R 185 178 179 Z = 55%, E = 82% R = Ph, 4-MeOC6H4, Z-MeOC,H,, PhCH=CH Con temporury Orgartic Synthesis80 "C, 1 h Me / Me Me dienes and dienophiles under mild conditions.The reaction of 186 with vinylmagnesium bromide is illustrative. 4.2 Free radical cyclisation Nishida and co-workersI3' have reported the first example of an enantioselective radical cyclisation controlled by a chiral aluminium reagent. For cxample treatment of the vinyl iodide 187 with tributyltin hydride and triethylborane in the presence of the binaphthol catalyst 189 gave the methylenecyclohexcne 188 in 63% yield with an ee of 48%. Although in absolute terms this ee is moderate, the fact that enantioselectivity in a prochiral h-exu radical cyclisation (k, - 5.4 x 10' s - I ) can be controlled by added external Lewis acid is impressive.Chelation controlled 6-ex0 radical cyclisations of chiral oxazolidinone-derived alk- 2-enamides were found to proceed in good yield with moderate diastereoselect ion. I ") Pat t enden and ~ o - w ~ r k e t - s ~ ~ " papers o n their successful 6-endo multiple radical cyclisation reactions of polyenes (e.g 190+ 191). In a similar vein Zuretic et ~ 1 . " ' have shown that the Mn"' oxidativc cyclisation of the polyene 192 gives the tricyclic system 193 with excellent stereoselec- tivity. In an approach towards the huperzine skeleton White and Jeffrey"4 found that Mn"' oxida- have published a series of full I (c-Hex)02C 187 Et3B, Bu3SnH, 189 dry air, 63% CH~CIZ, -78 "C "i) 108 48% ee 190 Bu3SnH, AlBN 72% 1 191 f l Mn(0Ac)39 ~ ~ ~ 2 s 0 Et02C Et02C 'H 192 193 M~(OAC)~, Cu(OAc)z, HOAc, 33% EtHN 194 195 @/ 0 Bu3SnH, AlBN PhMe, 55% + fiH 0 SnBu3 196 197 C02Et COZEt - O T oa Bu3SnH,;N PhH.80 OC 198 199 tive cyclisation of the amide 194 gave the [3.3.1] bicyclic system 195. The rather unusual deethylation was a result of a sequence involving 1,5-hydrogen abstaction, oxidation, hydroxylation and loss of ace t alde hyde . A 6-endo r ad ical cy clisat ion, initiated by addition of thc tributylstannyl radical to an acety- Icnc. has been used in an approach to forskolin ( 196+197).145 Addition of Bu3Sn. to the carbonyl oxygen of the diquinane 198 followed by /$scission of the adjacent cyclopropane bond has been shown to provide novel access to the [3.2.1] ring system 199."" 4.3 Transition metal mediated cyclisations Balme et ul.terminated carbocyclisation for the formation of functionalised lactones. For example, treatment of have reported a useful palladium Booker- Mil bu rn a 11 (1 Sti (I rpe: Su tu ra t ed n ri ti partially U I I sn t i d ra t ed ca rbocy cles 487the carboxylic acid 200 with palladium acetate in the presence of base leads to the lactone 202 via cyclisa- tion of the Pd" intermediate 201. Malacria and co-~orkers'"~'~~ have used the Vollhardt cobalt mediated cycloaddition to good effect in the rapid construction of complex terpene skeletons. The rhodium-catalysed generation of sulfonium ylides from diazo esters, and the subsequent [2,3] sigma- tropic rearrangement "" have proved useful in the synthesis of highly functionalised cyclohexanones, as well as in a key step (203-204) in an approach to vernolepin'".A novel and very useful annulation (205 -207) reaction involving Fischer carbene '0 200 201 mo \ - Qf& 0 202 70% 4 examples C02Me Me0 203 10% Rh~(0Ac)d PhH. 80 "C, 77% 204 Mef + 205 111 Ph OMe 206 I.+ Me0 207 4 examples complexes and dienes leads to highly functionalised tricyclic ring systems in a one pot ~equence.'~' The reaction is thought to proceed via an initial [4 + 21 cycloaddition followed by benzannulation to yield the enarnine 206. Grubbs et al.'', have continued to report on the success of their ruthenium-catalysed metathesis reaction for the formation of fused 6,5- and 6,6-systems. Helquist et al. lS4 have demonstrated that iron carbene complexes undergo cationic polyene cyclisations leading to fused 6,6-systems (208-210).A useful feature of these reactions is that the intermediate iron complex 209 can be used to introduce further functionality into the cyclised products. Me30+ BF4-, MeN02 &25'C,2h = $@ H Cp(OC)2Fe Cp(OC)2Fe SPh 208 209 rn R 21 0 4.4 Cationic cyclisations Lewis acid-catalysed cyclohexane ring formation reactions have continued to attract interest and a number of research groups have reported significant results over the review period. For example, Jung et ~ 1 . l ~ ~ have shown that the allylsilane cyclisation of the Sharpless derived epoxy alcohol 211 leads to the enantiomerically pure diol 212 in good yield upon treatment with diethylaluminium fluoride. A similar BF,-catalysed allylsilane ring-opening reaction of an aziridine 213 was used to construct the amino substituted cyclohexanes 214a,b.Is6 Majetich and SieselI5' have used a BF,-catalysed cyclisation in their synthesis of nimbidiol.Cationic cyclisation of SiMe? 21 1 21 2 rSiMe3 2.7: 1 21 3 21 4a 214b 488 Contemporary Organic Synthesisthe silyl enol ether 215 gave the intermediate vinyl- mercury species 216 which underwent transmetalla- tion with palladium followed by carbonylation to yield the [3.3.1] bicyclic ketoester 2l7.Is8 Ley and co-workers'" have again used the selenium mediated cationic cyclisation to good effect in an approach towards the insect antifeedant jodrcllin (218+219). A high yielding iodine mediated trans- annular cyclisation of the bis-acetylene 220 has been shown to lead to the symmetrically functionalised'h" decalin system 221.OTMS w' 'Me HgC12,HMDS ~ \/"'Me 21 5 q 0 OH 21 8 220 CH& 21 6 PdCl CUC12 Lici, t o , M ~ O H M e O k i 0 I Me 21 7 i. NPSP, Znlp, CHpCIz, 95% ii. TBHP. Ti(OOPr')4, dihydropyran, CHzCIz, 95% 219 I 221 4.5 Other routes Yamaguchi et a1 16' have found that conjugate addition of hydride to the bis-a, /&unsaturated ester 222 promotes a Michael ring closure to form the cyclohexane diester 223 in good yield. In a similar vein Crimmins and co-workers'62 have reported on a useful annulation reaction involving the conjugate addition of zinc-copper reagents to acetylenic esters (224-+225). Functionalised 6,6-bicyclic systems have been constructed using a novel dehydrative cyclisa- tion of allylic alcohols under Mitsunobu conditions (226+227).Ih3 Mangion et al.Ih4 have demonstrated that the diene 228 undergoes a stereoselective photosensitised [4 + 21 cycloaddition to give the tricyclic system 229 in excellent yield.Paquette and Tsui'"-' have once again demonstrated the power of the anionic oxy Cope-rearrangemcnt for thc construction of complex carbocyclic structures from simple precursors. Thus, in their approach to the diterpene kaurane, the requisite dienol 230 was readily available in enantiomerically pure form and \CO2Me fJ' L-Selectride? d , . c o 2 u e THF, 4 0 "C, 82% 222 223 COVE1 IZnCu A C O z E t THF, EtpO, TMSCI. HMPA, 5040% R 224 225 H QSO Ph DEAD, Me3P, PhH S02Ph 82% - S02Ph2 HO S02Ph 226 227 Ph 228 hv, MeCN, PhH, 1,4-dicyanobenzene, 87% 1 G Ph 'H 229 \/ KH, 18-crown-6 THF, 80% H 0 / 230 231 1 0 232 underwent smooth rearrangement to the enone 232 via elimination from the intermediate enolate 231.The same research group reported the use of a stereoeontrolled oxonium ion-activated pinacol ring expansion (233+234) as the key step in the construction of ( + )-grindelic acid.'" Finally, Brown Hooker-Milbum und Shape: Saturated arid partially urisatiirated carhncycles 489490 CSA, CH2Cl2,20 "C 10 min. 76% 233 234 i. (ipc)BClp (cat.), Me3SiH, Et20 ii. 0.25 eq. LiAIHI iv. CI2CHOMe, Bu'OLi v. H202, NaOAc 0 235 236 77%; 299% ee and selective synthesis of trans-decalone 236, which involves treatment of the allylcyclohexene 235 with a remarkable succession of five different reagents resulting in an overall yield of 76% and an ee 2 99%.have reported a practical enantio- 5 Seven-membered rings 5.1 Cycloaddi t ions and annula t ion s The most frequently reported method for the synthesis of seven-membered rjngs has been via [3 + 41 cycloadditions or annulations. Harmata have been particularly prolific in the field of intramolecular cycloadditions; for example treat- ment of the ally1 alcohol 237 with triflourornethanc- sulfonic anhydride and 2,b-lutidine resulted in the formation of the bicycle 238 via cycloaddition of the intermediate vinylthionium ion. The tricycle 240 was prepared in high yield by Lewis acid-induced forma- tion of the alkoxyallylic cation from the enol ether 239. Molander and Ea~twood'~' have reported that the reaction of diones 241 with the bis(trimethy1- sj1yl)enol ether 242 gives the familiar oxygen- bridged carbocycle 243 which can then be readily converted into the cycloheptane 244.This method has also been adapted to [3 + 51 annulations. Takeda and co-worker~'~' have described the reaction of the the silane 245 with the lithium enolates of %,,%unsaturated ketones 246 to give the desired 168-I70 S S P h 237 PhS02 (3 Tf 0 cl-f$32 2,Wutidine -78 "C 63% & R3 PhS R' 0 241 TMSOTf 1 T M 4 E e 242 0 r R3 1 L 0 243 11 n H O G R2 R' 0 OLi 245 246 1 -80 -30 "C 0 TBDMSO 6; \ TMS 247 R' = H; R2 = CH2CH2Me; R3 = H R' = H; R2 = Me; R3 = Me R'R2 = CH2CH2CH2; R3 = H 73% 65% 73% products 247 in good yield. IIigher order cycloaddi- tions have also featured in the preparation of seven- membered rings. Lautens et ~ 1 . " ) ~ in their studies of the reactions of bicyclo[2.2.l]hepta-2,5-diene 248 have demonstrated the asymmetric [2n + 2n + 4x1 cycloaddition with diencs 249 using a cobalt catalyst and the chiral ligand R-l,2-bis(diphcnylphos- (aSPh 238 Ph2Pj-PPh2 Et AlCl &-HI3 R 248 249 B R 239 240 P-H : a-H = 2.4 : 1 Con temporary Orgu n ic Synthesis R=Me 66% 72%ee R = (CH2)30Ac 52% 73% ee\ / 80 “C R=Me 88% d R = H 84% 250 251 phino)propane (intramolecular cycloadditions have also been examined).Finally in this area, Rigby and co-worker~’~~ have described the intramolecular thermal cycloadditions of cycloheptatrienones 250 to give exclusively the exo product 251 in high yield, as well as the analogous photochemical and thermal cycloadditions of the corresponding chromium(o)tri- carbonyl complexes.5.2 Other methods Another popular method of seven-membered carbo- cycle synthesis is the Cope rearrangement of divinyl- cyclopropanes; the synthesis of the fused carbocycle 253 from the cyclopropane 252 is an example of the work of Cha et ~ 1 . ‘ ~ in this field. Along similar lines, Rarluenga and co-w~rkers”~ have prepared cyclo- heptane- 1,3-diones 256 from 2-arninobuta- 1,3-dienes 254 and vinylchromium Fischer-type carbenes 255 in very good yields; the total synthesis of desmarestene has also been reported175 using Cope rearrangement methodology. Alkene metathesis has also been used in the construction of seven-membered rings. For example Blechert et al. 17” have investigated the use of both rhenium 258 and ruthenium 261 catalysts in the synthesis of hydroazulenes e.g.259 from the I OTIPS 77% I J 1 ‘ TBDMSO TDMS C6H6 A \ heat 81% . OTBDMS OTBDMS 253 252 __c Ph 0‘ 254 255 256 R’ = Me; R2 = 2‘-furyl 82% R’ = CH2Ph; R2 = Ph 76% ? Me - 9:: 0 0 0 0 II 258 h 1.1.2-trichlorotrifluoroethane) A -. . . \ / 80q0 X V 257 259 cyclopentane 257. Grubbs et al.Is3 have also used the ruthenium catalyst 261 in their studies on the metathesis of dienynes, such as 260, to give fused bicyclic [n.m. 01 rings ( e g 262) in very good yields. Using an alternative stratcgy, Dowd and Zhang177 have extended their work on free radical ring expan- sions of fused cyclobutanones to fused rnethylene- cyclobutanes; for example 263 gave the 260 262 W”‘ 263 Bu3SnH 1 AIBN 91% 264 9218 cycloheptane 264 on treatment with tributyltin hydride and AIBN. Banwell and Ca~neron”~ have utilised a Beckwith-Dowd ring expansion in their enantioselective synthesis of the carbon skeleton of the sesquiterpene rnanicol. Also in the field of ring expansions Little et UE.~’~) have used a diyl cycloaddi- tion-fragmentation route to obtain bicyclic ring systems such as 265. This route has also been modified to include the synthesis of eight- and nine- membered rings.The radical tandem ring expan- sion-cyclisations of cyclopropylsilyl ethers described by 13ooker-Milburn and Thompson“6 also provides a facile entry into 7,s-bicyclic ring systems. New methodology for the synthesis of medium-sized rings in which cyclic /,’-keto phosphonates 266 are reacted with dimethyl acetylenedicarboxylate t o give good yields of the two-carbon ring-expanded products 267 has been developed.’”) The novel cyclisation of 2,3-epoxy alcohols reported by Marson and co-workers’” result in the formation polyfunctional seven-membered rings in excellent yiclds (2684269).The enantioselective synthesis of Rooker-Milburn and Sharpe: Saturated and partially unsuturuted curlwcycles 49 IL 266 0 268 qco2,. C4Me & - 94% H C02Me 1 i. Li, NH3, -78 "C ii. NH4CI, H20 72% .C02Me 265 OH C02Me ii. i. base Me02C-C02Me * n( @C02Me n=l 54% n=2 52% n = 3 60% n=4 57% OH OH I TiCI4 CH2CI2 98% 'cl 269 bicyclic tetrahydrofurancarbaldehydes from chiral 3-stannylbut-1 -enyl carbamates by tandem homoaldol-aldol reaction has been reported by Hoppe and co-workers (270+271).'8' Finally, Shea et a1.lg3 have developed a simple fused cycloheptane and cyclooctane synthesis by subjecting 272 to ozonolysis followed by an intramolecular aldol condensation to give, for example, the [5.3.0] bicyclic system 273 in excellent overall yield.This bridged-to-fused ring interchange methodology has been used in a neat total synthesis of the sesqui- terpene 1ed01.~~~ - Ph Bu& OCb 270 BF39Et PiOH quantitative I 94% ee H<,Me Cb = carbamoyl 271 6 Eight-membered rings Once again, this year has seen a heightened level of interest in eight-membered carbocycle constructions due to the intense synthetic activity towards Taxol and its congeners. Thus Danishefsky et al. have described the total synthesis of baccatin 111*85 and constructs"' using an intramolecular Heck reaction to construct the eight-membered B-ring (274+275). Blechert et al.'" have used a novel TMSI-promoted ring enlargement process (276+277) for the forma- tion of the taxane A,B-ring system.Swindell and his co-workers1"8-'90 have continued to publish promising results towards the taxanes using Ti- or Sm-mediated pinacol ring closure. Magnus et al.'"' have constructed the B,C-ring of the taxanes using an extremely efficient semi-pinacol type ring expan- sion under acid conditions (278+279). The seven- membered precursor 278 was readily constructed by pyrylium ylide cycloaddition. The cycloaddition chemistry of chromium carbonyl complexes has 0 OTBDMS 272 0 O'TBDMS 273 6' 274 0 275 H6 277 276 OTf 278 279 492 Contemporary Organic Synthesisbeen admirably demonstrated by Rigby et al.over the past few years and has recently been used to great effect in the construction of the taxane skeleton. For example, the photochemical [6 + 41 cycloaddition between the chromium tricarbonyl complex 280 and the diene 281 led to the adduct 282 which after some functional group interconver- sions gave the ketol epoxide 283. This epoxide was then subjected to an x-ketol rearrangement by treat- ment with aluminium isopropoxide which resulted in the formation of the taxane A,B-rings 284 in good yield.'" Other contributions to the formation of the taxane B-ring have come from a number of labora- tories including those of Wender,lg3 Kumar,lg4 Miesch,'" Paquette"' and Magnus.19"Finally, Nicolaou and Gray'9X have published a highly readable and personal account of their successful Taxol synthesis.280 282 Me& t(OP&.PhH M e w X = H 81% X=OT6S 65% H " H \x 284 283 A number of other cyclooctane-containing natural products have been investigated over the review period. For example Paquette and co-worker~'~~ reported full details of their ( + )-acetoxycrenulide synthesis which involved an oxidation-Claisen sequence as the key step (285-286). Booker- Milburn and Sharpe'" have described an approach to the related pachylactone skeleton where the key step involved an electrocyclic ring opening of the cyclobutene 287 followed by spontaneous lactonisa- tion to yield the cyclooctane 288. Borrelly and Paquette'"' also described a very neat Tebbe- Claisen sequence for the rapid construction of the kalmanol skeleton (2894290).An interesting Lewis acid mediated fragmentation-cyclisation sequence has been used as the key step in the synthesis of ( )-tetramethylmediterraneol B (291 -+292).*02 Me . . SePh TBSO "H 'Me TBSO 'Me 285 286 i. hv, prop-2-ynyl alcohol 77% ii. MeOH, cat. H'. 24 h 0 84% C02Me 287 xylene, reflux. 24 h 84% 1 C02Me 288 Me H I H B - O B n ' " S 0 - - ~ M e 0 0 Me' \ Me 289 i. Tebbe ii. pcymene, 120-130 "C 86% I TBSO-- OBn n Me U 290 291 I O---Lewis acid I L 1 J '0 292 Molander and EastwoodZu3 have used a [3 + 5 J cyclo- addition (293-294) as the key step in their total synthesis of (+)-dactyl01 . Piers and R ~ m e r o ~ " ~ have reported a useful oxidative cyclisation of bis-alkenyl- stannanes for the formation of carbocycles of various sizes. For example the bis-alkenylstannane 295 underwent oxidative coupling on treatment with CuCl in DMF to give the 6,8-system 296 in excellent yield.Booker-Milburn and Cowel13s used a novel aza deMayo reaction in their approach towards the Booker- Mil hu rn and Shave: Saturated and part ia li) unsaturated carbocy cles 493r " R 0 LHMDS, HMPA, THF Br 302 303 R = H; 95% R = CHZOTBDPS; 93% \ 293 ' 294 CO&t Me CrCl DM&O,307$ NiCh mMe Me0 OH Me0 ; ( I CHO .D 07% SnBu3 295 296 304 305 0 "a ii. i.Ru04 2 M H2SO4 d H-@ 2:, H N=C=O 55% ten-membered ring of the potent anti-inflammatory marine diterpenoid solenolide F (304 -305). Dowd and Zhang2'" have described a useful double ring expansion procedure for the formation of 11- and 12-membered rings. For example reductive cyclisa- tion ring expansion of the cyclobutanone 306 leads to the 6,8-system 307, which after Grob fragmenta- tion gives the 12-membered enone 308.Finally, Ma and Negishi211have disclosed exciting results on the cyclic carbopalladation of to-haloallenes. This promises to be a general route towards aryl fused medium and large rings and provides ready access 0 298 297 asteriscanolide skeleton (2974298). Further studies have been reported towards cyclooctane-containing lignans using biomimetic oxidative phenolic coupling catalysed by either ferric perchlorate2"s or phenyl- iodonium bis(trifluoroacetate).206 7 Nine-membered and larger rings Pfander et d 2 0 7 have used a Grob fragmentation of the toluene-p-sulfonate 300 [derived from (-)-HoJosParrish ketone 2991 in their synthesis of the optically active trans-cyclononenc 301.Continued studies towards the enediyne antitumour agents have yielded a number of new methods for ring closure. 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