~~ Saturated and partially unsaturated carbocycles CHRISTOPHER D. J. BODEN and GERALD PATTENDEN Department of Chemistry, Nottingham University, University Park, Nottingham NG 7 2RD, UK Reviewing the literature published between January 1994 and April 1995 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 433 1 1.1 1.1.1 1.1.2 1.2 1.3 1.4 2 2.1 2.2 2.3 3 3.1 3.1.1 3.1.2 3.1.3 3.1.4 3.2 3.3 3.4 3.5 3.6 4 4.1 4.2 4.3 4.4 4.5 5 6 7 8 9 Three-membered rings Metal carbenoid-based methods From dihaloalkanes From diazocarbonyl compounds Free radical methods Ylide-based methods Other routes to three-membered rings Four-membered rings Photochemical met hods Other routes to four-membered rings Cyclobutenes Five-membered rings Transition metal-based methods Cobalt Palladium and nickel Zirconium Other transition metals Free radical-based methods Cationic methods Anionic methods Other routes to five-membered rings Polyquinanes and 'cascade' polycyclisations Six-membered rings Diels-Alder reactions Other cycloaddition routes Free radical cyclisations Electrophilic polyene cyclisations Other routes to six-membered rings Seven-membered rings Eight-membered rings Nine-membered and larger rings General carbocycle synthesis References 1 Three-membered rings 1.1 Metal carbenoid-based methods 1.1.1 From dihaloalkanes The familiar zinc carbenoid-based Simmons-Smith cyclopropanation remains a popular method for the formation of three-membered rings, allowing as it does the induction of chirality through transition state interactions with chelating heteroatoms (usually oxygen).Allylic alcohols such as 1 are the most commonly used starting materials, and a number of new chiral auxiliaries and/or catalysts have been developed to facilitate their asymmetric cyclopropanation. The most notable examples are the tartrate-derived dioxaborolane ligands 3 and 4 reported by Charette et al. prior to treatment with the conventional Simmons- Smith reagent (Zn/CH21,), give the corresponding cyclopropyl methanols 2 with excellent yields and enantiomeric excesses. Care is, however, required for the safe use of this method.2 The method has also been used by Zercher et al.3 and by Barrett et al. for the preparation of vicinal cyclopropanes; for example the conversion of the diene 5 into either 6 or 7, in which it was found to be markedly superior to other method^.^ which, when added to 1 R t q o H ii. i.Zn(CH& 3, CH2CI2 (2.2 q.) RJ+oH R3 R3 CH&I, 25 "C, 2 h 1 2 280% yield 9144% 88 Me,NOCh CONMe, Me2NOC,,dCONMe2 O?/O o.B/o I Bu Bu 3 4 HO 5 \\i. 3; ii. Zn(CH2Q2 OH 1. 4;ii. Zn(CH,Q2 Hov -.: \' \ 6 \ H O m o H 7 A more conventional approach to such vicinal cyclopropanes (which form part of the natural product FR-900848) has been reported by Armstrong et al.' In a similar vein Denmark et al. have studied the use of auxiliaries derived from the chiral diamines 8 and 9,6,7 obtaining moderate to Boden and Pattenden: Saturated and partially unsaturated carbocycles 1910 good enantiomeric excesses. The new acetal-type auxiliary 10 derived from fructose has been described for the cyclopropanation of 2-alkenal~.~ An unusual route into terpenoid-derived bicyclo[4.1.0] systems such as carene 12 from acyclic terpenoid enals, e.g.citral 11, has been described by Motherwell et aL9 The outcome appears to be independent of the alkene geometry in the substrate. Lautens has studied the samarium-based cyclopropanation of a range of mono- and bi- metallic alkenols 13, with the syn cyclopropanes 14 being obtained in very good yields and with high diastereoselectivity." The same procedure was also applied" to the regioselective cyclopropanation of a-allenyl alcohols 15, giving the synthetically useful cyclopropylmethylenes 16. It is noteworthy that in the latter case conventional zinc carbenoid methods completely failed to give the required chemoselectivity .0 CISiMe2(CH2)&Me2CI --H singleisom 11 12 13 14 R' = alkyl; R2, R3 = H, alkyl, TMS, BuoSn OH 15 R' = alkyl; R2 = H, alkyl, Me0 OH 16 1.1.2 From diazocarbonyl compounds The other classical method for effecting metal- carbenoid mediated cyclopropanations - treatment of alkenes with diazocarbonyl compounds in the presence of a metal catalyst - has also received considerable attention recently. Nishiyama has reported the use of the chiral ruthenium bis(oxazoliny1)pyridine catalyst 17 for the asymmetric cyclopropanation of terminal alkenes.12 In a similar vein, Kanemasa et al. have described a 1,2-diamine-Cu( 11) triflate complex derived from 18, which is applicable to the cyclopropanation of disubstituted alkenes as well;13 diastereoisomeric and enantiomeric excesses are only moderate however.Finally, Martin and co-workers have studied the intramolecular cyclopropanation reactions of secondary allylic diazoacetates 20 using the rhodium catalyst 19; good to excellent degrees of endo- selectivity were achieved.I4 17 18 P A R 3 20 endo 21 Me0& -b 19 1.2 Free radical methods ex0 22 4 Free radical methods are not commonly used for cyclopropane ring synthesis, since 3-exo-trig closures to give cyclopropylmethyl radicals are readily reversible, with the equilibrium favouring the open- chain form. However, if the product radical is either trapped out, or is sufficiently stable to allow reduction to be competitive with ring opening, cyclopropane products can be obtained. An example of the former has been reported by Gravel, where dienes such as 23 may be cyclised to give the intermediate 24, which immediately eliminates phenylthiyl radical to give the bicycl0[3.l.O]hexane 25.15 A more unusual example has been described by Malacria, where the enyne 26 undergoes sequential 5-exo-dig, 6-exo-trig and 3-exo-trig cyclisations to give an allylic radical, which proves to be more stable than the open chain form resulting from the first two cyclisations.'6 Final hydrogen abstraction from the tin hydride then leads to the tricycle 27.20 Contemporary Organic Synthesis1.4 Other routes to three-membered rings Fused cyclobutane ring systems such as 31 have been transformed cleanly and efficiently into the fused cyclopropanes 32.19 Two research groups have Me02C C02Me c y c ~ ~ ~ e o & c o w reported new approaches to various cyclopropyl amino acids.Cativiela et al. have followed the most straightforward of these, by treating a$-didehydro- amino acid derivatives such as 33 with either diazoalkanes or sulfonium ylides, to give the protected amino acids 34.*' In contrast, de Meijere and co-worker have reported the use of three carbon synthons such as 36 as Michael acceptors in a synthesis of the cyclopropyl-substituted protected amino acids 37.2' phsk sexetrig. (Bu$n)* then r% Sexetrig 23 24 l- Me02C '6 CO*e I EuSnH. AIEN. PhH, 80 'c. 16 h 25 Stwedig, Bexetrig, then Sexetrig. folkwed by hydrogen abstraction Me0& C02Me xq 0 0 U 26 27 1.3 Wide-based methods An unusual method for the synthesis of cyclo- propanes, based on organotellurium chemistry, has been described by Huang et al., wherein chalcones 28 are reacted with the reagent 29 in the presence of an inorganic base, giving the cyclopropanes 30.'7 Also, the familiar dimethylsulfoxonium methylide cyclopropanation of chalcone has now been carried out in the solid state." 6545% yield cs2c03 Ar.vinyl trans :cis 210:l Ar. PhCO always trans 1 31 32 CH2N2. 0 'c. 5 h 33 xn6 34 (=cp' I. BuLi. THF,-78 'c, 1 h ii. 36, -78 'c, 1-1 5 h 63-81s >959cde c02eu' 2 Four-membered rings 2.1 Photochemical methods The elaboration of cyclobutanes by photocyclo- additions between alkene bonds remains one of the most engaging and enduring reactions in modern synthesis. Houk et a1.22 have used ab initio theory to study the regioselectivity of intermolecular photo- cycloadditions of triplet cyclohexenones to alkenes; and Becker et a1.23724 have provided further results of their extensive studies of the regio- and stereo- chemical outcomes of intramolecular [2 + 21 photocycloadditions involving various alkene substituted cyclo-Zalkenones. A silicon-tethered variant of the intramolecular [2 + 21 photocyclo- addition process has been described.25 Meyers et al.,26 together with Koga et al. ,27 have demonstrated the power of intramolecular [2 + 21 photocyclo- additions involving chiral starting materials (38 and 40) in the target synthesis of natural products, viz lintenone A 39 and stoechospermol B 41 respectively. Boden and Pattenden: Saturated and partially unsaturated carbocycles 2138 95% 39 Qp - 0 OTBS 0 H H OTBS 40 41 2.2 Other routes to four-membered rings The procedure whereby cyclobutanones can be prepared through an intramolecular [2 + 21 cycloaddition between an in situ generated a$-unsaturated ketene and a C=C bond, has now been ~ t i l i s e d ~ ~ , ~ ~ in a stereoselective synthesis of the pheromone grandisol42 (Scheme l).30 iii I 42 Reagents: i.A@. CH,CQK. 4 S. NHfiH, then (EtOCH&3i2)20, then SOCIS v. LWHAtfl KOH, II. RUCI-104; iv. Me8K=H&lgCI, Scheme 1 43 Some interesting alkenylidene cyclobutanes have been synthesised by cyclisations of acetylenic alkyllithiums (formed by lithium-iodine exchange) bearing a prop-2-ynylic leaving group, viz 44-+45,32 and Ihara et a1.33 have described a neat synthesis of fused four-membered rings from cyclopropyl ketones on treatment with TMS-iodide, i.e.46-+47. Me0 Bu'Li,-78 "C 44 45 46 2.3 Cyclobutenes Cyclobutenes are useful intermediates in synthesis; for example, they undergo facile electrocyclic ring opening to functionalised 1,3-dienes. 3,3-Dimethoxycyclobutenes 49 are now easily prepared from the [2 + 21 cycloaddition of 1,l-dimethoxyalkenes 48 to electron-poor alkynes in anhydrous chloroform at low temperature, e.g. 18 0C.34 Other substituted cyclobutenes, e.g. 51 can be produced from Lewis acid catalysed reactions between allylsilanes and acetylenes, viz 50-+51.35 COPh CHCI,, 18 "C M . & ) y P h COPh MeoToMe + 111 98% In a demonstration of the scope for the reported selenium-directed, stereoselective [2 + 21 cyclo- addition of silyl vinyl selenides to enones, Yamazaki et aL3' have described a concise synthesis of fragenol COPh 43, which is a constituent of Artemisia fiagrans willd.40 49 22 Contemporay Oiganic Synthesis51 3 Five-membered rings 3.1 lkansition metal-based methods 3.1.1 Cobalt The familiar Pauson-Khand reaction (henceforth 'PKR') has once again been the subject of considerable interest. Perhaps the most notable achievement has been the discovery by Jeong, Chung and co-workers of the first reasonably general catalytic version of the reaction.36 The method is effective for both the intermolecular (52+53) and the intramolecular (54-55) reaction; the same authors have reported an alternative method for the latter based on the use of phosphite co-ligand~.~' R' H 19 (1 ,S-Ood)Co( ind), 1-5 md% CO (15 atrn), DME, 100 "C, 40 h 9x0 only 82%7% h R2 52 53 R', R2 = alkyl, Ph, H (1,s-cod)Co(ind), 2 mol% 92% 54 55 Another interesting development has been the observation by Schore et al.of reversed (endo) selectivity in the PKR of the dienyne 56;38 this clearly indicates that the normal ex0 preference of the intramolecular reaction can be reversed in certain situations. Progress has also been made in the field of chiral auxiliaries, with Greene and Pericas describing the use of a camphor-derived auxiliary to control diastereoselectivity in the PKR of 57; the conversion of the product 58 into the useful chiral cyclopentenone 59 is also described.39 De Meijere et al. have synthesised a range of spiro(cyclopropy1)cyclopentenones such as 61 by using met hylenecyclopropanes 60 as the alkene c o m p ~ n e n t ~ ~ ' ~ ' - a reasonable (6.5: 1) ratio of diastereoisomers was obtained by the use of the appropriate chiral dioxolane auxiliary. In a similar vein a-methylene cyclopentenones 63 have been prepared by carrying out the PKR with allene intermediates such as 62.42 In this case the substitution of molybdenum for cobalt was required in order to effect reaction.Finally, syntheses of ( + )-kainic acid,43 (+)-ta~lorione~~ and a model for xest~bergsterol~~ have been published using the PKR in key steps. One other novel use of cobalt catalysis is in the cycloisornerisation of &'-acetylenic P'-alkyl b-ketoesters such as 64 to methylenecyclopentanes 65.46 i. C02(C0)8 ii. TMANO, 0,25 "C. 16 h 1 76% 46Hll 61 MO(CO)~, DMSO, PhMe, 100 "C 68% 62 - wpo+wo I.C02(CO),, CH&12 ii. NMO, 02.25 'C, 3 h 55%, I : H ' : h I 1 1 1 I * 56 3: 1 (COh (COh & b where R*=& SMe co co 57 58 59 i. NMO, 25 "c, CH2CI2 R'O '*'flfH ii. norbornadiene, -20 OCd SiMe, 63 Boden and Pattenden: Saturated and partially unsaturated carbocycles 233.1.2 Palladium and nickel The use of methylenecyclopropanes in Pd-catalysed [3 + 21 cycloadditions to alkynes has been explored by Motherwell et aL4’ and by Lautens et aLa Lautens et al. have also shown that the process (e.g. 66+67) proceeds with overall retention of stereochemistry at the cyclopropane chiral centre. Mandai and co- workers have devised an interesting route from /I-alkynyl carbonates such as 68 to the cyclic products 69; the reaction is believed to proceed via a 1,l-dicarboethoxyallene intermediate, which undergoes an intramolecular ene reaction to give the observed HO 10 mol% Pd@ao 40 md% (P+O)3p, @o PhMe.reflux. 3 h. 85% H ( 5 6 h 1 i=6H 11 66 67 68 Pd(OAc)2 (5 m) I dppp (5 d 9 L ) PhM&hOH. 4 h, 799c I 6Q Liebeskind et al. have reported a convenient approach to cyclopentenones such as 71 by the Pd-Hg mediated ring expansion of alkynyl cyclo- butenols such as 70.50 The method can also be used to make cyclopent-4-ene-l,3-diones, as can the treatment of 1-hydroxy-1-alkynyl cyclobutenols with Fischer ~arbenes.~~ In another related use of ring expansion Fukumoto et al. have developed a novel approach to tetrahydro-indanones 73 by treating vinylcyclobutanols such as 72 with catalytic Pd(1r); the alkyl palladium species formed by ring expansion inserts in situ into the pendant alkene.52,53 The work of Trost et al. towards ‘atom economical’ cyclisations continues; a Pd catalyst for the cycloisomerisation of 1,6- or 1,7-enynes to di- alkylidene cyclopentanes or cyclohexanes (which can 70 y y Bu Me0 81% 71 qL TBSO 72 P ~ C I ~ ( M O C N ) ~ DME.reflux, 18 h 28% I TBSO 9 73 then be used as dienes in similarly economical Diels-Alder cycloadditions) has been De Meijere and co-workers have reported a similar method, whereby the cycloisomerisation step is replaced with a Heck rea~tion.~’ Finally, two interesting uses of nickel catalysis have been reported. In the first of these Ryu, Sonoda and others have described a relatively mild method for carrying out a vinylcyclopropyl ether to cyclopentanone enol ether rearrangement, viz 74475, based on the use of a Zn-Ni catalyst.56 In the second, Mori et al.have published details of a novel cyclisation of n-ally1 nickel complexes, derived from 1,3-dienes, onto pendant carbonyl groups; the method is also applicable to six- and seven- membered rings.57 TBSO TBSY (PPh,),NiCI, (5 moffi), zn (10 moffi) PhMe, refkm, 2 d 74 84% 75 3.1.3 Zirconium The Zr-mediated intramolecular cyclisation of 1,6-dienes or enynes 76 is a well-established method of forming cyclopentanes, and proceeds by way of intermediate zirconabicycles 77. Whitby et al. have shown that the conversion of 77 into amino bicyclo[3.3.0]octanes 78 is possible by treatment with 24 Contemporary Organic Synthesis76 isonitriles, followed by heating and then quenching, either with methanol or an alkyne (the latter giving a vinyl amine A number of researchers have published studies of regio- and stereo-control in the initial cyclisation step,"-" of which Negishi's is perhaps the most interesting.62 Finally, the method has been used as the key step in a formal total synthesis of ( -)-dendr~bine.~"~ 3.1.4 Other transition metals Normant and Marek have published a general study of intramolecular carbometallations of organozinc reagents derived from 6-halo-l-alkenes, and observed exclusively 5-exo-trig cyclisation in all cases studied.65 This is a potentially powerful method, in that it tolerates quite reactive functional groups (e.g.esters). The RZn species is also easily prepared and, unlike in radical reactions, the product can be trapped intermolecularly using a wide range of electrophiles.The same authors have also published a novel route to alkynyl exo-methylene cyclo- pentanes 80, based on the 3-metallation of 3-methoxy-l,7-diynes 79.66 In related work the MeO 79 -70 "C + 20 OC L -I I E+ + Me3Si ,, E &rSiMe3 80 equivalent metallo-ene reaction has also been performed, by carrying out the metallation- transmetallation procedure on a 1,6-en~ne.~~ Oppolzer et al. have described a similar reaction, using a Pd-Zn system to effect the conversion of 81 into 82, as predominantly the cis isomer.68 i. 5 m1Y0 Pd(PPh&, p m z s ~ , , Ph02S ii. E', where E = H, I 4 eq. ZnEt, Etfl, reflux -. ... 45-6046, >91 de 81 82 In another variation on metal-catalysed enyne cyclisation, Murai et al.have demonstrated that the isomerisation of 1,6-enynes 83 to vinyl cyclo- pentenes 84 (usually achieved using Pd catalysis - see Section 3.6 for examples) can be effected using a ruthenium catalyst.69 This approach has the advantage over Pd-based methods in that terminal alkynes can be used without formation of undesirable isomers; it can also be applied to 1,7-enynes. Finally, a new variant on the cyclisation of 1,6-diynes has been reported by Ojima et al., based on silylformylation.70 4 md% RuC12(CO&, PhMe, CO, 80 "C Kw. TBsb 83 lBsd 04 3.2 Free radical-based methods Work by Singleton and collaborators has shown that the synthesis of methylenecyclopentanes, starting from methylenecyclopropanes, can be carried out by using a radical-mediated [3 + 21 cyclisation ~trategy.~' The method is illustrated by the conversion of 85 into the diquinane 86,72 and can also be applied to intermolecular cycloaddition~.~~ SiMe3 I MenSi Me3SnSnMe3.hv. PhH 77% 85 86 COzEt Snider has utilised the Mn-based oxidative radical fragmentation of alkynyl cyclobutanols 87 (cf the Pd/Hg method in Section 3.1.2) in a total synthesis of ( -)-methyl cantabradienate 88.74 Shirahama and Matsuda have described a completely diastereo- selective route to 2-vinylcyclopentaols 90, based on the trapping of ketyl radicals formed by samarium( 11) iodide reduction of carbonyl compounds such as 89.75 Molander et al. have published a related study on the 5-exo and 6-ex0 cyclisations of similarly-obtained ketyl radical^,'^ and Fallis et al.have studied the intramolecular trapping of samarium-generated radicals with hydrazone acceptors.77 Boden and Pattenden: Saturated and partially unsaturated carbocycles 2587 Smi,. THF-HMPA. -78 "c 789'0 f , steps 89 90 The concurrent use of radical methods and Lewis acid chelation of chiral ester auxiliaries has been deployed by Nishida et al. for the asymmetric synthesis of 3-alkylcyclopentenes 92 starting from cu-haloalkenyl acrylates 91.78 The reaction gives good enantiomeric excesses and can also be used with dibromoolefins. 91 MAD. BuoSnH, EtoB, PhMe, -98 "c, 2 h 90% yield, 88% ee I wco2"' 92 Hydrogen atom transfer reactions are an increasingly important facet to radical cyclisation chemistry, and Malacria has reported an interesting example (Scheme 2).79 In a similar vein, Parsons and Caddick have described a synthesis of spiro-fused cyclopentanones based on 1,5-abstraction from an allylic centre.*' Finally, radical spirocyclisation has been used by Clive et al. in a total synthesis of (k)-fredericamycin A," and the same authors have described a route to the triquinane ( f )-cerato- picanol using a radical derived from an epoxide." 3.3 Cationic methods The conversion of ketones (or their ketals) into cyclopentane 1,3-diones (e.g.93 +94) by reaction with 1,2-bis(trimethylsilyloxy)cyclobutene is a well- established tactic in total synthesis. Burnell and co- workers have reported a method for carrying out this transformation in a single step, using an excess of boron trifluoride etherate,83 and have used the method in a new total synthesis of (&)-penta- 1enene.84 Furthermore, Curran et al.have extended the process to include a subsequent 5-exo cyclisation onto a pendant alkene or alkyne, giving a diquinane such as 95 (Scheme 3)."@ The use of Q4 -1 95 Scheme 3 96 164% 97 Scheme 2 26 Contemporary Organic Synthesis1,2-bis(trimethylsilyloxy)cyclopentenes instead gives a bicyclo[4.3.0]nonane product 97, by way of the 1,3-dione 96. for cationic cyclisations remains the ally1 or propargyl silane. Amberlyst-15 has been shown to be a simple and effective catalyst for such reactions.*' Weinreb et al. have reported a fascinating synthesis of the natural product papuamine, featuring as a key step a Lewis acid- catalysed imino-ene reaction onto an allenylsilane (98-+99).88 Such catalysis has also been used effectively in a more straightforward Alder-ene approach to vinyl cy~1opentanes.*~~~~ Nagao and co- workers have developed a new geminal spiro-endo mode of cyclisation of allenyl ketones, which is illustrated for dimethoxyaryl cases by loo+ 101.91-93 One of the most widely used terminating groups @ p S i M e 2 P h 98 SnCI,.PhH, 25 "C 281% 1 H H, A N C H 2 P h 'SiMe2Ph 99 OMe loo BF@Et2,-78 "C to-10 "C, CH2CIZ 8096 I YMe./,O 0 m 101 3.4 Anionic methods Cooke et al. have extended their work on halogen- metal exchange as an initiator of sequential Michael additions to the formation of bicyclic [4.3.0] and [3.3.0] In related work, Ovaska, Bailey and co-workers have devised a synthesis of 1,3-bis- exocyclic dienes 103, based on 5-exo-dig cyclisation of vinyllithiums onto alkynes such as 102.96 As with the Pd-catalysed work of T r o ~ t , ~ ~ the diene products can be reacted in situ with a suitable dienophile, making for a one-pot synthesis of bicyclo[4.3.0]- nonenes. 1 02 i.2.0 eq. Bu'Li, Et20, pentane. -100 "C ii. MeOH, 0 "C I 103 944b single isomer Padwa et al. have published a convenient route to bicyclo[3.3.0]octenes 104, based on an anionic [3 + 21 cycloaddition The same authors have published a route to arylcyclopentones from diazoacet~phenones,~~ and Asaoka et al. have described a convenient and enantioselective route to a capnellene fragment, based on silyl-directed cyclopentanone enolate alkylation." 2-sulfonyl cyclopentenones 106, via a tandem Michael addition-carbene insertion methodology starting from y-ketoethynyl phenyl iodonium triflates 105.1"03'01 Finally, Stang et al.have reported a novel route to 0 S02Ph 1 NaH S02Ph I 0 104 + 105 MePhSOfla, CH2CI2, 20 "C 75% I 0 106 3.5 Other routes to five-membered rings Thermal Wolff rearrangement of the 1,2-bis(diazo- ketone) 107 has been used by Nakatani and co-workers as the basis of a synthesis of trans- hydro-1H-2-inden-1-one 108. Io2 Boden and Pattenden: Saturated and partially unsaturated carbocycles 271 07 108 3.6 Polyquinanes and 'cascade' polycyclisations The methods of five-membered ring synthesis detailed so far have all dealt primarily with the formation of single ring. However, the trend in modern organic synthesis is increasingly towards the formation of two or more rings in the same step, whether by conventional means (e.g.rearrange- ments) or by the increasingly popular 'tandem' or 'cascade' processes, wherein the product from the first cyclisation initiates further ring closures. Five membered rings are well suited to the latter, as 5-ex0 cyclisations are usually preferred to 6-endo, and 5-endo to 4-ex0, especially in free radical processes, making polyquinane constructions a favourable option. One of the most useful and rapid rearrangement- based methods is the conversion of squarate esters 109 to diquinanes 112 by sequential treatment with suitable anions. Paquette and co-workers have shown that by using an acetylide as the second anionic component, the regiochemistry of the aldol reaction (110+111) can be c ~ n t r ~ l l e d ' ~ " " ~ ~ (Scheme 4; compare this with the work of Hirama et al.described in Section 7, i.e. 212-+213). Rawal et al. have developed a fragmentation route to diquinanes based on the photocycloadducts 113, which are readily obtainable by a photo- cyclisation of norbornene derivative^.'^^ The radical Proi pro&oo 109 i. "-0 ii. LiECMe Pro' prois 0 110 PSO @ PSO OH 112 Scheme 4 28 Contemporary Organic Synthesis 111 LDBB = Li+ 114 formed on the diquinane skeleton arising from the initial fragmentation can be trapped with a pendant alkene, allowing the triquinane skeleton 114 to be prepared. lo6 The Heck reaction is a well-established staple of carbocycle synthesis.lo7 Weinreb et al. have assessed the possibility of carrying out the reaction on a substrate such as 115 which gives rise to a 71-ally1 Pd complex 116, which can then be displaced with a soft carbanion.'os The results confirm that the reaction is possible, but is reduced somewhat in value by the usual problems of a:y selectivity, giving a mixture of 117 and 118.Palladium also features in a fascinating extension to Trost's work of enyne cycloisomerisation; Trost et al. have developed a catalyst which allows direct conversion of 1,6-enynes 119 into tricycles 121, by reaction with 1,3-dienes or 1,3-enynes such as 120 (Scheme 5).'09 The most common ways of effecting 'cascade' reactions involve either free radical intermediates or palladium catalysis. The single exception to appear recently is the use by Negishi et al. of an aluminium-titanium reagent to effect the tricyclisation of a triene; selectivity is lacking in this process, however.'" Of the Pd-catalysed methods 7 C 0 2 M e C02Me 115 Pd(OAc), P(eTd)a Bu,NCI, NaH, DMF I C0,Me 116 117 118r I cHFB 120 E"" H w2c>cf7H Meo2c 6 121 EHFB 1 L Scheme 5 KH.THF. 25 "C 5 m ~ l % Pd(0AC)z 10 mow dppe 0 - capnelkne # * Ql 5% + Scheme 6 the most notable work has been that of Balme and co-workers (Scheme 6) which has been used in a total synthesis of (+)-capnellene and, like the work of Weinreb et al. cited above, involves the trapping of a Heck reaction product.1"311Z Oppolzer has also made a recent contribution to this field.'I3 Of radical cascade methods the work of Pattenden and co-workers is notable. Thus, the 5,7,5-tricycle 123 has been assembled by a macrocyclisation- transannulation approach, starting from the triene 122 (Scheme 7)."4,115 Kilburn et al.have also made contributions to this 4 Six-membered rings 4.1 Diels-Alder reactions The scope for the intramolecular variant of the Diels-Alder reaction in difficult ring constructions has been further illustrated in Jackson and Shea's synthesis of the highly functionalised taxane intermediate 125 from 124,"' and in the elaboration of the steroid-taxane hybrid 126, described by Danishefsky et al. In another neat approach to the taxane ring system Winkler et al. have used a combination of inter- and intra-molecular Diels- Alder reactions, vis 127+128 and 1284129, from readily available precursors; this very direct two step synthesis produces 129 in 50% overall yield and with excellent stereocontrol.Spino et al. have published similar sequential inter- and intramolecular Diels-Alder reactions in their approaches to perhydrophenanthrenes, viz 130+132 via 131,'217122 and to the quassinoids."' De Clerq and his collaborators have extended their elegant studies on the scope of the intra- Bu3SnH, AIBN, PhH 55% H G 122 123 13-endo 1 [v - 0 Scheme 7 Boden and Pattenden: Saturated and partially unsaturated carbocycles 29&& 0 0 PhMe,A 124 125 M e G PhMe, 180 "C 126 130 Ideps 132 127 TQ3 H O 129 molecular Diels-Alder reaction with furan-dienes, and described a total synthesis of gibberellins Al and A3, based on the cycloaddition 1334134 as a key step.124 Lithium perchlorate in diethyl ether has been shown to have a profound effect on the reaction rates of many Diels-Alder reaction^.'^' Now Grieco et aZ.have shown that catalytic camphorsulfonic acid in 5.0 M lithium perchlorate-diethyl ether solution promotes Diels-Alder reactions of conformationally restricted substrates with concomitant migration of the diene moiety prior to cycloaddition, viz 135-+137 via 136.'26 In a detailed investigation Gorman and Gassman'*' have studied the influence of alkyl substitution on the ionic intermolecular Diels-Alder reactions of a wide range of methyl analogues of 3E,8E-1,3,8,10-undecatetraenes; this paper is well worth reading in detail. The transannular Diels-Alder reaction of the triene 138 produces the trans-anti-cis tricyclic COzMe 133 # bOzMe 134 135 136 e 137 0 lactone 139 as a single cycloadduct in 63% yield;'28 and Takahashi et have extended their investi- gation of this approach to polycycle constructions by carrying out detailed studies of the transannular Diels-Alder reactions of the trienones 140. 30 Contemporaly Organic Synthesis25 "C - CF,SO#I,A,,NS02CF, ArxA' I 138 139 98% yield, 93% ee H eR=H; bR=OH 140 Catalytic enantioselective Diels-Alder reactions are very much in vogue these days.Thus Corey et al. have described further aspects of their oxazaboro- lidine-catalysed reaction^,'^' and also the first example of an enantioselective catalytic Diels-Alder reaction of an achiral C2,-symmetric dienophile and an achiral diene, i.e. 141 + 142-+143.13' The applications of q4-diene iron tricarbonyl complexes132 and of a chiral scandium enantioselective Diels-Alder reactions have also been described.in MeO 1 + (Nb 0 141 142 143 4.2 Other cycloaddition routes Allenes have been used as new partners in intra- molecular cobalt-mediated [2 + 2 + 21 cycloaddition reactions for the first time, leading to facile syntheses of polycycles after decomplexation, e.g. 144+145.'34 Padwa et al. have shown that dipolar cycloaddition reactions using carbonyl ylides can be used as key steps in the construction of the illudin, ptaquilosin and pterosin families of sesquiterpenes, e.g. 146-+147.1353'36 A new sequential carbonyl ene cyclisation/cyclo- addition of trifluoromethyl ketones catalysed by Lewis acids has been applied to the synthesis of polycycles, viz 148-+ 149.'37 White and So~ners'~* have published full details of their approach to the 144 C~CO(CO)~, xylenes - A, hv, 5 h 145 SiOp 4 N2 146 HO-- 9$& \ opJ& 0 illudm M 147 EtAIC12,O "C C 3 1 ratio d I4Bepimer F3C 0 148 F3d q9 OH 149 + F3C VHJ OH stemodane nucleus based on a hydroxy-directed intramolecular ene reaction.4.3 Free radical cyclisations A number of interesting 6-endo cyclisations leading to six-membered annulated ring systems have been published in recent years. Thus Parker and F o k a ~ ' ~ ~ , ' ~ ' have used this tactic in their approach to the morphine ring system, e.g. 150+151, and Ghatak et al. 14' have synthesised a range of linearly condensed hydroaromatic carbocyclic systems, e.g. 153 from 152 through 6-endo-trig closures. Now Marco-Contelles and c011eagues'~~ have shown that cyclitols of constitution 155 containing a trans 1,3-dioxolane moiety can be produced from Boden and Pattenden: Saturated and partially unsaturated carbocycles 31Me0 BuSnH - 0 150 151 152 153 OAC OAc 154 155 5-hexenyl radicals derived from 154 by way of a facile 6-endo-dig cyclisat ion.hexenones containing pendant aldehyde functionality leads to a neat synthesis of directed aldols by way of allylic O-stannylketyl intermediates, e.g. 156+157.'43 Some novel cyclobutanone-based tandem free radical rearrangements,la and cyclisations involving methylenecyclopropane derivatives,'457146 have been used to access certain mono- and bi-cyclic cyclohexanes. The addition of Bu3SnH-AIBN to cyclo- 15s 1 H 157 Tandem radical-mediated cyclisations have also been used with silicon tethered precursors, e.g.158, to access intermediates 159 containing the steroid ske1et0n.l~' Treatment of appropriately substituted polyene phenylselenyl esters, e.g. 160 and 162, with Bu3SnH-AIBN has been shown to lead to linear and angular six-ring fused carbocycles (such as 163 and the steroidal ring system 161), via consecutive 6-endo-trig mode cyclisations starting from the corresponding polyolefin acyl radical intermediate^.'^^ 4.4 Electrophilic polyene cyclisations The elaboration of polycycles based on cyclisations of polyolefinic substrates in the presence of electro- &:. \ 158 L Bu&H Y. CH3MgBr 1 QpP Sie3 159 160 0 B@nH AlBN 1 0 1 62 Bu3SnH AlBN 1 163 philic reagents, pioneered by W. S. Johnson, has provided organic chemistry with one of its major and enduring synthetic methods.Now Fish and Johnson have described further ramifications of this strategy in synthesis, reporting the first examples of non-enzymatic biomimetic polyene pentacyclisa- tions, viz 164+165,149 and a total synthesis of sophoradiol 166 using the tetramethylallyl cation as a surrogate for the epoxide function as an initiator of the polyene cycli~ation.'~~ The same research group has also described the use of the allylsilane group as an internal terminator group in polyene 32 Contemporary Organic Synthesis1% CFSCO~H, CH&12 -78 "C, 31% I x t x HO q(j@ - . 1 66 cyclisations, 15* and studies towards the oleanes based on similar polyene cyclisations P-alkynyl involving silane precursors. 152 Finally, in the first demonstration of a carbo- cation-olefin cyclisation route to the lanasterol series, Corey et al.153 have described the silicon- assisted double cyclisation 167+168. 4.5 Other routes to six-membered rings Palladium-catalysed cyclisations remain popular in approaches to six-membered carbocycles. Thus Tietze and S ~ h i m p f ' ~ ~ and Terakado et al. 155 have . 167 i. MeAIC12, -78 "C ii. AcCI, pyr, DMAP I 168 both highlighted the control that can be exercised by the allylsilane moiety in intramolecular Heck reactions, e.g. 169-170, and Hatakeyama et al. (cf work by M ~ r i a r t y ) ' ~ ~ have outlined an efficient route to the A-ring synthon 173 for la,25-dihydroxy- vitamin D3 based on the same Heck reaction, viz 171 -172. Pd catalysis (S )-BINAP 169 170 171 172 POPh, TBSO'* &TBS 173 An unusual sequence of ring-closure metathesis reactions from acyclic dienynes, catalysed by the ruthenium carbene complex 174 has been used by Grubbs et al.'" to produce fused bicyclic rings, including the 6,6-fused system 175. The first examples of tandem Cope-Cope rearrangements have now been identified, e.g. 176-+178 via 177,'59 and a range of new tandem anion-induced reactions involving the Michael reaction and the Claisen condensation,'60 the aldol reaction16' and or-alkylation,'62 have been described. 175 I 176 - 177 cope-2 1 1 78 Boden and Pattenden: Saturated and partially unsaturated carbocycles 33Ally1 and vinyl silanes have featured prominently in a range of recently described cationic six-ring cycli~ations.'~"~" Perhaps one of the most impressive examples of a vinyl silane-mediated cationic cyclisation is the synthesis of the tricyclic inter- mediate 180 from 179 described by Burke et their approach to an enantioselective synthesis of nagilactone F 181.in 0 U CH&12, -78 "C 181 5 Seven-membered rings Perhaps the most common approaches to seven- membered ring constructions are those utilising ring expansions, which are typically carried out by fragmentation reactions. Thus, Dowd and co- workers have devised a neat synthesis of fused cycloheptanones such as 183 based on radical fragmentation of the alkoxyl radicals derived from cyclobutanones such as 182.'66 Several strategies for forming the substrates have been devised.'66-'68 The same research group has also reported an unusual rearrangement of cyclobutanones 184 to give tricycles 185. ' 69 183 184 185 Radical fragmentations of cyclobutanes have also been used by Lange and co-worker, as the basis for the synthesis of 7 5 , 7,6-, 8,s- and 8,6-fused bicyclic~.'~~ Either tin hydride- or samarium- mediated reductions can be used,'71 and the method has been used in a total synthesis of alismol 186.17* Ranu has examined similar radical fragmenta- t i o n ~ .' ~ ~ A thermal diradical fragmentation has been reported by Little and where the diradical formed from 187 is converted into 188, presumably via an hydrogen atom-transfer step. I. Me&O,H+ ii. MeMgBr, CeCl, H \\ 186 -OH I CO,Me PhMe, reflux. 73% slow additionc sMe 1 87 188 Lautens et al. have devised a new route to the 7,s-systems 190, based on intramolecular ring opening of adducts 189 derived from [4 + 31 cycloadditions to f~rans."~ A similar cycloaddition has been used by Harmata and colleagues in a model study for the synthesis of the ingenane carbon skeleton;'76 and an alternative approach to ingenanes has been described by Winkler, Blumberg and co-workers, based on intramolecular [2 + 21 cycloaddition of 191 to give 192, followed by ring opening under basic conditions to give the tricycle 193.'77 Similarly, Tochtermann et al.have reported a route to the tremulane carbon skeleton based on alkaline rearrangement of oxepine~.'~~ McMills et al. have described an approach to tigliane diterpenes, based on cyclisation of the oxonium ylide 195 derived from the diazocarbonyl 34 Contemporary Organic SynthesisSnBu, 0 (0% 189 0' Mdi.M F , -78 OC W 5 % / R = H. Me, f3n. TBS 190 191 Me6 1 92 C02H 193 0 195 196 precursor 194, to give the 5,7,6-tricycle 196.179 Finally, two research groups have published studies of cationic cyclisations leading to seven-membered rings: Angle et al. have utilised cations derived from p-quinonemethides,'" and Majetich et al. have further developed their work on the addition of electron rich aryl systems (in this case furans) to conjugated dienones.'" 6 Eight-membered rings Radical cyclisations are generally not used for eight- membered ring synthesis, owing to the slowness of the ring closure relative to common side reactions. However, Molander and co-worker have shown that ketyl radicals deriving from SmI, reduction of ketones can be rendered highly persistent by carry- ing out the formation under certain conditions.'82 Thus the radical 8-endo cyclisation of 197 to 198 is rendered feasible.O R Me 197 Sml,. Bu'OH. THF, HMPA 4943% 3-30:l de. R - Me. Ph. Pr' I W 198 Another unusual approach to eight-membered rings has been described by Grubbs et al., who use Ru-catalysed olefin metathesis to effect the conversion of 1,9-dienes into fused cyclo-octenes, e.g. 199+200, using complex 201 as the catalyst.'*' cyclooctanes is the use of Ni-catalysed [4+4] cycloaddition of butadienes. In a related process, Harmata et al. have shown that cationic [4+3] cycloadditions can be used in similar fashion, e.g. by conversion of furan-cyclopentanones 202 into the doubly bridged cyclo-octene 2O3.ls4 Several researchers have used more standard methods to make eight-ring containing natural products, and of these the most interesting is perhaps Schreiber's use of the Nicholas reaction in the synthesis of ( + )-epoxydi~tyrnene.'~~ Other examples include the use of the C1aisenlE6 and ~xy-Cope"~ rearrange- ments to effect ring expansion, and the use of sulfone-stabilised carbanion additions to esters.188 One of the most widely-used routes to 5 mol% 201.PhH. 25 "c. 4 h 75% 199 200 .Ph CI. FHPh crqu- PCY3 201 Boden and Pattenden: Saturated and partially unsaturated carbocycles 35203 [a] /55% Interest in the much-studied taxane 6,8,6-fused tricyclic carbon skeleton has remained high,lg9 culminating in two total syntheses of the valuable anticancer agent Taxol@ 204.'90-'95 Both of the synthetic approaches taken are interesting from the point of view of eight-membered ring synthesis, as is the work of Kuwajima et al.on the synthesis of taxinine derivatives such as 206.196 In the latter work intermediates such as 205 were cyclised in a facile and diastereoselective manner by the use of an appropriate Lewis acid catalyst. In similar work, Swindell et al. have reported a synthesis of the eight- membered ring in the taxanes by Ti-mediated pinacol closure,'97 and Romero et al. have utilised an intramolecular aldol c~ndensation.'~~ Paquette et al. have published more work based on the use of oxy-Cope rearrangements to give the eight-membered ring,'99 as have Martin et aL2" Finally Kanematsu and co-workers have devised a novel route to the taxane carbon skeleton, making use of a tandem [2 + 2]-cycloaddition-[3,3]-sigma- tropic shift process for the conversion of 207 into 209, via the allenyl intermediate 208.20' OAC Ph 204 OTIPS HO:@ CH(OMe)2 Me 4 5 SnC14'CHzC'2 7796, "C, single 330 min M& c H o g r e Me0 isomer o& L O 208 209 7 Nine-membered and larger rings Melikyan et al.have described an interesting variation on the well-known Nicholas reaction, which allows the cobalt-complexed 1,5alkadiynes 210 to be cyclised via P-alkynyl radical inter- mediates.202 Subsequent oxidative decomplexation then gives the cyclic alkadiynes 211. Hirama et al. have reported a remarkable synthesis of the highly strained nine-membered ring 213 (which rearranges on warming to give the diquinane 214) by intramolecular acetylide addition in the m-alkadiynal 212.*03 In related studies, the synthesis of enediyne antibiotics remains an active field, with several research groups reporting new result^.^^-^^^ investigated by a number of research groups.McMurry and Siemers have reported a total The synthesis of medium ring dienes has also been i. HBF, 21 0 ii. Zn co2(co)6 ?02(c0)6 p: / 21 1 205 206 36 Contemporary Organic Synthesis?% 21 3 26Y 21 4 synthesis of periplanone based on intramolecular low-valent titanium coupling of aldehyde and alkenone moieties;208 and Hodgson et al. have described a route into the germancranes, based on a Pd-catalysed vinyl halide-vinyl stannane coupling to the corresponding 1,3-diene.2w Allyl-ally1 cyclisation has also been reported by Takayanagi et al., as part of a total synthesis of the cembranoid sarcophytol A,210 and by Williams and Coleman as part of a synthesis of neodolabellenol.211 As with eight-membered rings, ring expansion remains a popular method for the formation of medium rings.The most notable innovation has been the use by Suarez et al. of a tandem alkoxyl radical fragmentation-cyclopropylcarbinyl A c o ' - w OH 21 5 I DIB+ (2.51.5). 40 'c Ar, 90 min, 50% I C8H17 ACOI I 4 0 21 6 DIE = (diacetoxyiodo)benzene rearrangement strategy to enable the conversion of decalins such as 215 into the corresponding eleven- membered cyclic ketones such as 216.212,213 The oxy- Cope rearrangement has also been used as the basis of a route to the dolabellane carbon 8 General carbocycle synthesis Although no reviews directly concerned exclusively with carbocycle synthesis have been published, a number of reviews offering partial coverage have appeared.These include reviews of the Heck reaction,lo7 particularly in its asymmetric and a review of synthetic routes to vitamin D.217 9 References 1 A. 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