4 Aliphatic and alicyclic chemistry By PETER QUAYLE Department of Chemistry University of Manchester Manchester M13 9PL UK 1 Introduction This year saw the passing of an icon of contemporary organic chemistry. It is fitting therefore that a short personal account of the development of the Birch reduction should have appeared.1 As pointed out by the author application of the Birch reduction to heterocyclic systems has received scant attention but has been the subject of a timely review.2 World-wide interest in the chemistry of fullerenes,3 buckybowls4 and enediynes5 continues unabated. Applications of combinatorial6 and solid-phase techniques7 are now well established and find uses in many diverse areas of synthesis ranging from medicinal chemistry to catalyst design.8 A resurgence in interest in carbohydrate chemistry is manifested in the appearance of seminal articles by Danishefsky9a and Fraser-Reid9b on the chemistry of unsaturated sugars.An extensive review by Boons10a on oligosaccharide assembly and articles concerned with the synthesis of inhibitors of carbohydrate-processing enzymes10b and glycosphingolipid biosynthesis11a all attest to a growing awareness in the synthetic community of this much neglected area of natural product chemistry.11b Multifarious aspects of bioorganic chemistry continue to be the focus of much attention.12 From the parochial viewpoint of the synthetic chemist the practical use of catalytic antibodies for the catalysis of a variety of synthetic transformations is now a real possibility.12a Enzymemediated transformations,13 amino acid chemistry,14 reactions in aqueous media15 and higher order cycloaddition reactions16 have again come under scrutiny.The synthesis and chemistry of organofluorine compounds have enjoyed something of a renaissance of late,17a certain aspects of which may have dramatic consequences on the ecosystem as a whole.17b The literature concerned with organometallic-based18 transformations including controlled methods for the polymerisation of olefins,18 continues to expand exponentially pride of place in this area continues to be the burgeoning use of palladium-mediated19 transformations whilst organo-titanium,20 - zirconium,21 -samarium,22 -ruthenium23 and -zinc24 reagents continue to gain importance. The realisation that these can be used in ‘tandem’ or cascade25 reactions can greatly simplify approaches to a variety of structurally complex molecules and presumably these reagents will be the focus of further attention in the future.The development of tandem reactions in general is currently much in vogue a definitive appraisal of much of this chemistry can be found in a compilation of articles edited by Wender.26 The use of free radicals in organic synthesis27 has been extensively re- Royal Society of Chemistry–Annual Reports–Book B 69 appraised this year including a compilation par excellence by Giese et al.28 which is a gold-mine of information. The underlying chemical principles associated with ‘molecular recognition’,29 self replication30 and self assembly31 phenomena continue to attract academic interest and practical applications of functionalised supramolecular assemblies32 are now on the horizon.It should not be forgotten that many of the advances in these areas are themselves associated with the continued development of advanced analytical tools e.g. electrospray mass spectrometry33 and X-ray crystallography.34 O O O N S O R OH HO 1a epothilone A (R = H) 1b epothilone B (R = CH3) OMe H N S H H 2 OBz H OAc O O AcO OH HO O BzNH Ph O OH 3 The subtlety of molecular recognition in vivo is highlighted this year by the isolation35 a of epothilones A 1a and B 1b which exhibit cytotoxic activity towards mouse fibroblasts and in vitro activity against breast and colon cell lines. It is indeed ironic that relatively uncomplex natural products such as 1 and curacin35b 2 have the same biological activity and mode of action as more complex structures such as Taxol 3 whilst there is no apparent structural homology between the two compounds.Furthermore it is rather poignant that Danishefsky36 reported the total synthesis of 1 within six months of the report of its structure! Some would question the merits of funding research programmes directed towards the synthesis of newly isolated natural products such as prymnesin-237 4 or maitotoxin38 5. However it is only by attempting such synthetic endeavours that we realise the inadequacies of the synthetic methodology to 70 Peter Quayle O O O O O O O O O Cl Me HO NHR HO OH O O OH Cl O O O HO OH HO OH OH OH OH OH OH OH OH O O OH OH OH Cl OH OH Me O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O Me Me OH HO H H H H H H Me Me Me H H Me H Me H Me H H OH H H OH HO H OH H H H H HO NaO3SO H H OH H H H H HO Me OH Me OSO3Na HO Me OH H OH OH H Me H Me H HO HO OH H H H H HO H H H HO H OH HO H H OH H Me OH H Me H H H HO Me Me H H H H H Me Me Me OH OH OH A B C D E F G H I J K L M N 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 91 5¢ 1¢ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z A¢ B¢ C¢ D¢ E¢ F¢ 142 140 164 135 130 125 120 115 110 105 100 155 95 90 85 80 150 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 1 143 144 5 4 145 71 Aliphatic and alicyclic chemistry O O O O O HO OH HO OH HO OH HO NHAc O HO O O O O O OH OH HO HO HO (CH2)12CH3 N H (CH2)14CH3 O OH H3C HO OH OH 6 O O HO HO OH 7 HN CO2H N NH O Me O Me O HN HN HN NH Me O HO2C O O Me Me OMe Me O 8 O Me Me O OH OH O Me OH O O OH OH Me O Me OH O OR Me Me O Me OMe HO Me Me OH MeO R OR1 9 swinholide A R = R1 = Me O O Me Me HN N O Me Me Me N O (+)-paraherquamide B 10 H Me 72 Peter Quayle O N O O O R O N O O O R Ph i–iii I N RAM H O iv v H2N O [ref.45( a)] [ref. 47( a)] [ref. 47( b)] O O Br + ZnBr vi vii O O R cat. R + [ref. 48] PCy3 Ru PCy3 Cl Cl cat. = Ph S OSiMe3 R1 R + R3CHO + R2NH2 viii ix HO R3 NHR2 R1 [ref. 50] Scheme 1 Reagents and conditions i LDA (2 equiv.) THF 0 °C; ii PhCH 2 Br (2 equiv.); iii NH 4 Cl (aq.); iv Bu 3 SnPh ultrasound 40 W Pd0; v trifluoroacetic acid (TFA); vi PdII THF room temp. 18 h; vii MeONa MeOH 70 °C; viii Sc(OTf) 3 (10 mol%); ix LiBH 4 . 73 Aliphatic and alicyclic chemistry O OTBS S S O O HO H CH3 H OH H H H HO H [ref. 51] steps N OH HO H HO (–)-rosmarinecine O RO O O2N O OG* + [ref. 52] Et H OH H 55% (1:1 mixture of isomers) [ref.54] [ref. 56] i ii I N X Y Ac Pd0 X N Ac Y Et (continued) 74 Peter Quayle O RO A O Br O OR O H A 70–80% A = NTs C(CO2Me)2 O O O SePh O Pd0 iii 65% O O O H H H H H [ref. 57] [ref. 58] [ref. 62] X Cr(CO)3 X R R1 32–87% iv v Scheme 2 Reagents and conditions i 0.6 equiv. Et 2 AlCl 3% Ti(OPr*) 4 ; ii O 2 ; iii Bu 3 SnH AIBN heat; iv RC–– – CH; v R@C–– – CH. 75 Aliphatic and alicyclic chemistry S C7H15 OBn OMe OMe + SiMe3 C7H15 OBn OMe –e– (ref. 64) 53% (ref. 65) OMe OMe OH OBn OAc H OAc O MeO OBn O –e– 68% Scheme 3 hand and this realisation provides the impetus for the development of more selective and economic synthetic transformations.23b In terms of total synthesis a number of elegant reports have appeared this year including the synthesis of the Mbr-1 antigen 6,39 macrolactin A 7,40 microcystin-LA 8,41 swinholide A 9,42 Taxol 143 and paraherquamide B 10.44 2 Aliphatic chemistry General A major growth area in recent years has been the interest in solid-phase organic synthesis.There are a myriad examples this year dealing with applications of this technique a timely review7 provides a comprehensive guide to those reactions which have succumbed to this methodological onslaught and perhaps more importantly an indication of those reactions which have not been attempted on solid support. Examples of the more recent and potentially general applications include aldol,45 iterative aldol,46 Suzuki47a and palladium-mediated coupling reactions of organozincs 47b ring-closure metathesis reactions,48 combinatorial approaches to chiral phosphine ligand synthesis49 and Mannich-type reactions,50 Scheme 1.The current interest in developing ‘cleaner’ more e¶cient processes has resulted in the report of a number of tandem or cascade reaction sequences. The basic notion behind such reactions of course is not new and dates back to Robinson’s tropinone synthesis of 1917. However what is astonishing is the degree of sophistication which can now be brought to bear in terms of the timing of individual bond-forming reactions and the complexity of the intermediates which can now be incorporated into such sequences. A number of representative examples including a classical polyene cyclisation51 [using optically pure starting materials via Sharpless asymmetric di- 76 Peter Quayle Scheme 4 Reagents and conditions i Tf 2 O pyridine; ii AgOTf; iii HNBn 2 LiBF 4 CH 3 CN 62%; iv Et 2 NSF 3 THF room temp.94%; v LIP–MCPBA. hydroxylation (AD) chemistry] tandem [4]3]–[3]2] cycloadditions of nitroalkenes 52 alkylation–homoaldol reactions,53 titanium-catalysed cascades of unsaturated alanes,54 enzyme-initiated oxidation–Diels–Alder reactions,55 palladiumcatalysed cascade reactions,56,57 radical cascades58–60 and Michael–Dieckmann sequences 61 and multiple metal-mediated cycloaddition reactions,62 Scheme 2. In a similar vein preparative electrochemical reactions have been regarded by most syn- 77 Aliphatic and alicyclic chemistry O OTBS OTf H H + O Li PhSO2 OBn O OTBS SO2Ph O OBn H H 98% RO H SiPh3 O i (ref. 71) [ref. 71( a )] RO SiPh3 O Li CHO RO O SiPh3 OH steps O N O O S 52% W-lamp (500 W) H O H H SPyr (ref.72) O OH O 75% overall yield Scheme 5 Reagents and conditions i BunLi THF. thetic chemists with a fair degree of scepticism. The recent report of a very simple electrochemical reactor63 should engender further investigations into this technique as such processes can be high yielding easy to perform and again can a§ord rapid access to quite complex structures,64,65 Scheme 3. Oxidation Epoxides are well recognised as being valuable synthetic intermediates,66–68 Scheme 4 a situation which has been enhanced considerably since the development of the Sharpless–Katsuki reaction. In related areas Katsuki69a has reported that Mn–salen complexes e§ect highly enantioselective epoxidation of enol derivatives whilst Bhakuni69b has demonstrated that liposomised m-chloroperbenzoic acid (MCPBA) e§ects highly enantioselective epoxidation of functionalised olefins Scheme 4.The synthetic utility of oxiranyl anions is becoming more widespread70,71 as is the chemistry of oxiranyl radicals,72 Scheme 5. The synthetic chemistry of endo-peroxides derived from cyclic dienes is not well developed in areas other than the reduction of the O–O 78 Peter Quayle O O i 74% OBu OH + OH OBu (ref. 73) ascaridole 9 1 11 Scheme 6 Reagents and conditions i BunLi THF,[78 °C. bond. In an interesting development Little73 has demonstrated that peroxides such as 11 undergo facile reactions with reactive organometallics to a§ord synthetically versatile mono-alkylated allylic diols Scheme 6. Dimethyl dioxirane (DMDO) and its derivatives continue to find application as selective oxidising agents,74,75 as does methylrhenium trioxide (MTO),76 Scheme 7.Of note is Yang’s77 report of the first enantioselective epoxidation of trans-olefins which utilises the C 2 -symmetric reagent 12 Scheme 7. The use of a silicon residue as a masked hydroxy group continues to find applications78 and has been reviewed,79 whilst recent methodological improvements by Fleming80 will further expand the scope of this procedure Scheme 8. The finer mechanistic subtleties81 of the Sharpless asymmetric dihydroxylation reaction continue to be unravelled. Irrespective of these controversies synthetic applications82 continue to be reported as illustrated in Scheme 9. In contrast to the accepted paradigm for dihydroxylation reactions it was reported that the hindered olefin 13 underwent dihydroxylation (in the presence of toluene-p-sulfonamide) to a§ord the diol 14 with p-facial selectivity opposite to that expected for such reactions,83 Scheme 9.Further reports from the Sharpless group have demonstrated the viability of catalytic aminohydroxylation84a and diamination84b reactions Scheme 9. Other useful oxidation reactions reported this year include the conversion of allenes into a-hydroxy ketones,85 the formation of quinols from phenols,86 and the aerobic oxidation of alkanes in the presence of copper salts.87 Functional group preparations The preparation of bis- and tris-ketenes,88 the use of Weinreb’s amide on solid support for the synthesis of ketones,89 and radical carbonylation reactions have been described this year.90 The direct acylation of olefins with carbon monoxide at ambient temperature in the presence of ‘waterless’ zeolites such as H-ZSM-5 has been observed spectroscopically and has many industrial applications if its e¶ciency can be optimised 91 Scheme 10.Novel ketone amination,92 lanthanide-catalysed Mannich reactions 93 radical-promoted oximations94 and alkene aziridination95 sequences have also appeared. The use of the Mitsunobu96 reaction for the synthesis of amines from alcohols under mild conditions will doubtless find many synthetic applications as will direct allylic amination97 and azidonation,98 Scheme 11. The Wittig reaction has been reviewed:99 new synthetic applications include the olefination of lactones100 and control of double bond stereochemistry by remote polar functional groups.101 Functionalised alkenes are available from the reaction of electron deficient alkenes with nucleophilic carbenes102a,b or by novel radical-mediated 79 Aliphatic and alicyclic chemistry O O O OH i 99% AcO H ii 62% H O O O AcO O N Cr(CO)5 SPh O N Cr(CO)5 S+ iii 64% O– Ph Ph Ph Ph Ph O 92% (75% ee) iv O O O O O Br Br 12 catalyst = [ref.74( a)] [ref. 74( b)] [ref. 76] H Scheme 7 Reagents and conditions i dimethyldioxirane (DMDO) CH 2 Cl 2 0 °C; ii DMDO acetone,CH 2 Cl 2 0 °C; iii MTO,CH 2 Cl 2 MeOH,H 2 O 2 ; iv Oxone catalyst NaHCO 3 CH 3 CN H 2 O. 80 Peter Quayle Et SiPh2 OH OH OH Et 87% (ref. 78) i–iii O Ph2Si iv v HO (ref. 80) (I)-lavendulol 2 steps Scheme 8 Reagents and conditions i I`(collidine) PF 6 ~ CH 2 Cl 2 ; ii Bu 3 SnH–Et 3 B hexane; iii H 2 O 2 KF KHCO 3 ; iv HCl KF MeOH; v H 2 O 2 KHCO 3 KF.13 Scheme 9 Reagents and conditions i AD-mix-b MeSO 2 NH 2 H 2 O 2 ButOH; ii (DHQD) 2 PYR K 2 OsO 2 (OH) 4 Fe3` p-TolSO 2 NH 2 K 2 CO 3 ; iii (DHQD) 2 ·PHAL TsNClNa; iv ArN––Se––NAr. 81 Aliphatic and alicyclic chemistry Scheme 10 Reagents and conditions i MeSiCl 3 ; ii 180 °C; iii dicyclohexylcarbodiimide hydroxybenzotriazole; iv base E`; v R@M; vi Bu 3 SnH CO (95–100 atm) AIBN 80 °C; vii CO zeolite H-ZSM-5. reactions which do not rely upon organotin hydrides for initiation,103 Scheme 12. Yamamoto has developed a ‘catalytic’ Shapiro reaction which requires substoichiometric quantities (0.3 equiv.) of bases such as LDA or LiTMP. A formal synthesis of (])-a-cuparenone nicely demonstrates the utility of this improved procedure 104 Scheme 13. In a new development Fuchs has reported that ethynyl and vinyl trifluoromethyl sulfones undergo direct (regioselective) C–H insertion reactions under thermal or photolytic conditions generating the corresponding alkenes or acetylenes in good overall yields.105a,b Mechanistic investigations showed that these reactions proceeded via free radical pathways,105c Scheme 14.Bromoalkenes are versatile intermediates whose preparation is sometimes problematical. Reports this year provide simple solutions to the synthesis of a-haloenones106 and the (Z)-1- bromoalk-1-enes,107 Scheme 15. The synthesis of ethers and oxygen heterocycles has been addressed by a number of workers. Again the mild conditions associated with the Mitsunobu reaction have been used to good e§ect in the synthesis of a number of oxygen heterocycles.108 Cationic palladium complexes have been found to be e§ective for the promotion of hetero-Diels–Alder reactions between relatively unactivated dienes with aldehydes.109 The stereoselective introduction of glycosidic linkages continues to challenge the synthetic chemist.10a Two novel approaches to this problem110,111 are outlined in Scheme 16.Organometallic-based transformations are again much in evidence this year. As suggested last year,112 olefin metathesis reactions could have almost universal application now that well characterised readily accessible and functionally tolerant catalysts have been described.113 A few representative examples which hopefully indicate the potential scope of this reaction are shown in Scheme 17.114–123 Future developments in this area may well include a kinetic resolution strategy for asymmetric ring closure metathesis a theme which at present is at an embryonic stage of development.124 82 Peter Quayle O OBn BnO OBn Br OBn OSiMe3 i O NH CF3 O 55% (ref.92) O OBn BnO OBn OBn ii N H3C OBn (ref. 94) OH NC PBu3 + NTs 2 iii iv NH 2 76% (ref. 96) ArNO2 + CO + cat. NHAr + CO2 (ref. 97) N N R R cat. = Ru3(CO)12 + (R = H Me OMe Cl) Scheme 11 Reagents and conditions i (salen)Mn(N) (CF 3 CO) 2 O pyridine CH 2 Cl 2 [78 °C; ii PhSO 2 (CH 3 )C––NOBu Me 3 SnSnMe 3 hv; iii TsNH 2 PhH room temp. 24 h; iv Na` Naphth~ THF,[30 °C; v (PhIO)n TMSN 3 CH 2 Cl 2 ,[30 °C. O O O O O O H O O O O O H CO2Me 90% i (ref. 100) O OTBDPS HN SO2 Cl OTHP ii iii OTBDPS HN SO2 Cl OTHP CO2Me (ref. 101) 'single isomer' O O CO2Me OTHP O O 65% iv–vi O O N MeO OMe OMe OMe THPO O O O [ref.102( b)] Scheme 12 Reagents and conditions i Ph 3 P–– CHCO 2 Me PhMe 140 °C; ii LiN(SiMe 3 ) 2 HO 2 C(CH 2 ) 4 P`Ph 3 Br~; iii CH 2 N 2 Et 2 O; iv LiOH H 2 O; v DPPA Et 3 N; vi 2,2-dimethoxy-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazole heat; vii AIBN. PhMe heat. 84 Peter Quayle p-Tol CH3 O N Ph H H2N + p-Tol CH3 N N Ph + CH3 p-Tol N N Ph i 86% i 84% p-Tol CH3 CH3 p-Tol O CH3 CH3 CH3 p-Tol (ref. 104) (+)-a-cuparenone Scheme 13 Reagents and conditions i LDA (0.1 equiv.) Et 2 O. R SO2 CF3 + O CH3 O CH3 R i (major) ~ 90% [ref. 105( a)] SO2CF3 Ph + O Ph O 65% ii [ref. 105( b)] Scheme 14 Reagents and conditions i heat; ii AIBN heat. Palladium-catalysed coupling reactions continue to be used extensively,125–138 Scheme 18. Significant advances this year include the synthesis of oxygen heterocycles via sp2–X insertion reactions,139,140 and definitive mechanistic studies into Heck,141,142 amination143 and cine substitution144 reactions Scheme 19.The use of trifluoromethanesulfonates (triflates) in transition metal-catalysed coupling reactions is now well established,145 but problems may arise in the preparation of the triflates themselves. Netscher has presented a detailed study of such reactions and has shown 85 Aliphatic and alicyclic chemistry Scheme 15 Reagents and conditions i Oxone NaBr H 2 O CCl 4 ; ii Bu 3 SnH Pd(PPh 3 ) 4 . OH OH OBn OBn BnO BnO O OBn OBn BnO BnO i (ref. 108) 91% O OR RO RO O S O O CH3 H + O S O O O BnO OBn (ref. 110) O O O O BnO OBn ii BnO BnO O OBn O Si Osugar BnO BnO S Ph O O OBn OH BnO BnO Osugar iii (ref.111) 42–82% overall Scheme 16 Reagents and conditions i NCCH––PBu 3 (1.5 equiv.) PhH 100 °C; ii Raney Ni PhH heat; iii 2,6-di-tert-butylpyridine Tf 2 O Et 2 O–CH 2 Cl 2 . 86 Peter Quayle N BnO BnO O OMe O OBn N BnO BnO O OBn i 70% Ru Ph Ph PCy3 Cl Cl PCy3 catalyst A OMe MeO O O i OMe O O 94% MeO (ref. 114) (ref. 115) O H OTBS CH3 O O O H H O O O H H CH3 OTBS H 36% i (ref. 119) Scheme 17 Reagents and conditions i catalyst A (5% w/w) PhMe 110 °C; ii catalyst A (6 mol%) CH 2 Cl 2 room temp.; iii Cp 2 Ti––CH 2 THF 25 °C. that when the alcohol or phenol is hindered high yields of alternative products such as sulfinate esters can be obtained hindered bases such as 2,6-lutidine and DIPPA are preferred in these problem cases,146 Scheme 20. The beneficial e§ect of adding catalytic quantities of copper salts to Stille coupling reactions has been utilised by Nicolaou147 in the synthesis of bisglycals.The use of stoichiometric148 amounts of copper salts as a replacement for palladium in Stille couplings and copper-mediated intramolecular coupling of bis-stannanes are useful variations on this chemistry and fuel the mechanistic debate concerning these reactions,149 Scheme 21. Cuprates150 and highly coordinated zincates151 have been found to act as very selective metallating agents. Copper-catalysed enantioselective conjugate addition reactions of dialkyl zincs152 have also been reported albeit with moderates ees. These reports are of particular interest as the organozinc reagents themselves can be prepared in the presence of electrophilic functional groups which is not necessarily the case with other nucleophilic metal systems.The development of new ligands for asymmetric conjugate reactions of cuprates has again been the focus of much inter- 87 Aliphatic and alicyclic chemistry OMe OMe OTf O TBS O OMe OMe O TBS i 82% Bu3Sn n-C6H13 SO2CF3 H Ph n-C6H13 SO2CF3 H ii Ph I + 91% (ref. 125) (ref. 127) O HO NH SnBu3 O O O HO HN O O HN O OH O (±)-alisamycin OH O NH Br + O iii 64% (ref. 128) O Scheme 18 Reagents and conditions i Pd0; ii Pd0 80 °C PhH; iii Pd0 DMF–THF. est.153 The mechanism of cuprate additions to ynoates154 and the role of TMS iodide155 in the conjugate addition of alkylcopper reagents to enones have again been the subject of some scrutiny the intermediacy of Cu–p-complexes was proposed in both cases. In a definitive study Bertz156 has developed a new class of organocuprates which incorporate b-silicon substituents in the non-transferable ligand.These reagents have greater thermal stability than conventional cuprates yet exhibit enhanced reactivity towards enones in conjugate addition reactions Scheme 22. The Nozaki–Hiyama–Kishi reaction has found extensive application in organic synthesis a position which will doubtless be further maintained by the development of a cycle which is catalytic in chromium,157 Scheme 23. A variety of cobalt- and iron-catalysed coupling reactions have appeared this year which are also of interest due to their chemoselectivity158 or ability to couple with unreactive functionalities such as vinyl chlorides,159 Scheme 24. 88 Peter Quayle Br CH3 HO O H Me 73% i (ref.139) Me3Sn Ph + ArPd X Ph Ar (ref. 144) [Pd] Ph Ar ? Scheme 19 Reagents and conditions i Pd(OAc) 2 Tol-BINAP K 2 CO 3 PhMe 100 °C. N + (F3CSO2)2O + ROH ROSO2CF3 ROSOCF3 (ref. 146) competing process for hindered alcohols Scheme 20 Asymmetric transformations A striking example of an ‘absolute’ asymmetric reaction was reported by Sakamoto et al.160 in which photolysis of the crystalline thioamide 15 which exists in a chiral space group a§orded the b-thiolactam 16 with 94% ee at 58% completion. Feringa’s and Kellogg’s groups have reported that the versatile synthetic intermediate 17 can be obtained in essentially optically pure form ([99% ee) using second-order asymmetric transformations,161 Scheme 25. New catalyst systems for asymmetric cyclopropanations 162 Michael reactions,163 aldol,164 Mukaiyama-type reactions165,166 and Diels–Alder reactions167 represent useful additions to present methodology as does the first example of an enantioselective catalytic protonation of a silyl enol ether,168 Scheme 26.Desymmetrisation of polyols169 and epoxides170 is a potentially powerful strategy for asymmetric synthesis and has been further refined this year Scheme 27. The application of asymmetric reductions171–177 and aldol-type178–182 reactions continues to be explored for the synthesis of stereochemically complex intermediates as illustrated in Scheme 28. Asymmetric 1,3-dipolar cycloadditions have enormous synthetic potential a prospect which has been realised by a number of workers,183,184 Scheme 29. 89 Aliphatic and alicyclic chemistry Scheme 21 Reagents and conditions i Pd(PPh 3 ) 4 CuCl,K 2 CO 3 THF 25 °C 0.5 h; ii copper thiophene-2-carboxylate (1.5 equiv.) NMP 0 °C 15 min; iii CuCl (5 equiv.) DMF 60 °C.O O Bu 98% O O Bu 64% (ref. 156) Scheme 22 Reagents and conditions i,Bun (TMSCH 2 ) CuLi Et 2 O,[78 °C ca. 5 s; ii BuCu(thexyl) Li·LiCN Et 2 O,[78 °C ca. 5 s. 90 Peter Quayle Scheme 23 Reagents and conditions i CrCl 2 (15 mol%) Mn TMSCl THF room temp.; ii CrCl 2 (7 mol%) Mn TMSCl THF room temp.; iii p-TsOH cat. H 2 O. Ph Br + AcO Zn 2 Ph AcO i (ref. 158) 88% O Cl + BuMnCl O Bu i 74% (ref. 159) Scheme 24 Reagents and conditions i 3%Fe(acac) 3 THF NMP room temp. Scheme 25 Reagents and conditions i hv solid state; ii Candida antarctica n-hexane BunOH. 91 Aliphatic and alicyclic chemistry OSiMe3 Ph O Ph 89% (90%ee) (ref.168) Scheme 26 Reagents and conditions i (R)-BINOL-Me SnCl 4 2,6-dimethylphenol [80 °C. Scheme 27 Reagents and conditions i 2mol% catalyst B Et 2 O. 3 Alicyclic chemistry Cyclopropanes The Simmons–Smith cyclopropanation is undoubtedly one of the most synthetically useful methods for the preparation of cyclopropanes. Charette has published the results of in-depth spectroscopic185 and structural186 studies of the reactive intermediates generated during the course of these reactions. Synthetic applications by this187,188 and other groups189 have centred upon the use of asymmetric variations of this reaction in synthesis of U-106305 and FR-900848. Falck’s synthesis of FR-900848 utilised a diastereoselective coupling of lithiocyclopropanes,190a whereas the approach adopted by Zercher relied upon ylide chemistry for the installation of contiguous cyclopropanes,190b Scheme 30.The transition metal-catalysed decomposition of a- diazocarbonyl compounds has been exploited in both an intermolecular191 and intramolecular192–194 sense to provide a variety of functionalised cyclopropanes Scheme 31. The synthetic potential of the Kulinkovich195 reaction has been investigated by a number of workers who report that mono- and poly-cyclic cyclopropanes are readily accessible by this methodology Scheme 32. Hanessian196 and Warren197 have utilised intramolecular displacement reactions for the synthesis of optically active cyclopropanes. Wege198 has developed a highly convergent strategy to (^)-favelanone based upon a Diels–Alder reaction of the highly reactive cyclopropene 18 Scheme 33.92 Peter Quayle Scheme 28 Reagents and conditions i TiCl 4 [78 °C; ii (allyl)SnBu 3 ; iii (ipc) 2 BCH 2 CH––CHMe,[78 °C; iv H 2 O 2 NaOH. Cyclobutanes Cyclobutyl ketones are useful synthetic intermediates199 which are now readily available200 from substituted 1,4-dihalobutanes by treatment with lithium naphthalenide. Cycloaddition201 of ketones with cyclopentadiene at low temperatures (\ [30 °C) a§ords unstable [4]2] cycloadducts 19 which undergo [3,3] sigmatropic rearrangements to cyclobutanones 20 the formal products of [2]2] cycloaddition in good 93 Aliphatic and alicyclic chemistry CH3 N O O O + Ph N O– Ph + O PhN Ph CH3 N O O endo > 95 5 (93% ee) (ref 184) i O O Ph Ph Ph Ph O O Ti OTs OTs Me Me Catalyst C O Scheme 29 Reagents and conditions i catalyst C room temp.24 h. overall yields. Photocycloaddition reactions provide access to diversely functionalised cyclobutanes,202 as does the copper triflate203 variant of this procedure. Sequential cycloadditions of functionalised cyclobutadienes prepared in situ from cyclobutadiene –Fe(CO) 3 complexes provide a novel approach to the synthesis of oligomeric cyclobutanes–‘ladderanes’.204 The pKa of protons in the cubane 21 has been estimated as lying between 20.5 and 22.5 deprotonation of 21 can be e§ected using NaN(SiMe 3 ) 2 to form a stable anion which can be trapped with a variety of electrophiles,205 Scheme 34. Cyclopentanes Application of the Trost metal-catalysed Alder–ene reaction to natural product synthesis has gained momentum as exemplified in approaches to the picrotoxanes206 and pumiliotoxins,207 Scheme 35.Cobalt208 and samarium209 analogues of the Trost palladium reaction have also appeared. Tandem ketyl–olefin coupling reactions,210 nickel catalysed alkynyl enone cyclisations,211 and cyclisation of organozinc212,213 reagents provide valuable new strategies for the synthesis of fused cyclopentanes Scheme 36. Bicyclo[3.3.0]octanes and bicyclo[4.3.0]nonanes are readily accessible using Piers’s bifunctional organocopper chemistry,214 whilst spiro[cyclopentane-1,1@- indane]diones a structural feature of fredericamycin A may be obtained215 in optically pure form from readily available epoxy alcohol derivatives Scheme 37. The synthesis of cyclopentane derivatives via C–H insertion reactions is now well established Taber216 has developed semi-empirical rules which allow prediction of the stereochemical outcome of these reactions Scheme 38.The Pauson–Khand reaction has seen many developments advances this year including its application to solidsupported synthesis,217 photochemical activation218 and its application to the synthesis of cyclopentanes fused to carbohydrate219 and b-lactam220 templates Scheme 39. Analogous titanium221 and iron222 [2]2]1] cycloadditions further expand the potential scope of this general strategy whose synthetic utility will doubtless be the subject of future studies. Cyclohexanes The synthesis of functionalised cyclohexanes from aromatic compounds has seen 94 Peter Quayle Scheme 30 Reagents and conditions i N,N-dimethyl-2-butyl-1,3,2-dioxaboralane-2- carboxamide Zn(CH 2 I) 1,2-dimethoxyethane CH 2 Cl 2 0 °C; ii BusLi; iii [ICu(PBu 3 )]; iv O 2 ; v (CH 3 ) 3 S(O)CH 2 DMSO.something of a revival as highlighted in an overview of the area,223 Scheme 40. The Diels–Alder reaction has again been the subject of much scrutiny both from a theoretical224 and synthetic standpoint. The use of copper,225 niobium and tantalum226 complexes and boron-containing Brønsted–Lewis acids227,228 enable Diels–Alder reactions to be performed at low temperatures and with good to excellent levels of asymmetric induction. Some examples of interesting Diels–Alder reactions are given in Fig. 1 (see refs. 229–237). The total synthesis of (])-digitoxigenin238 and 95 Aliphatic and alicyclic chemistry O RO R1O OR2 O R1O OR2 CO2Et OR (ref 191) i OMOM C O N2 OMOM CO2Me H OMOM O H CO2Me 58% ii (ref 192) O O CHN2 O O CH3 O O O CH3 O 61%(90% ee) iii O O But But catalyst D Scheme 31 Reagents and conditions i EtO 2 CCHN 2 Rh(OAc) 4 CH 2 Cl 2 room temp.; ii Cu(acac) 2 ClCH 2 CH 2 Cl heat; iii [Cu(MeCN) 4 ]PF 6 catalyst D.(])-andrenosterone239 both utilise intramolecular Diels–Alder (IMDA) reactions as key steps albeit of di§ering types Scheme 41. Organometallic240–245 and free-radical cyclisations246,247 and conjugate addition reactions248–251 all provide ready access to functionalised cyclohexanes Scheme 42. Finally a general route to the synthesis of (more potent) analogues of the acetylcholinesterase inhibitor huperzine A 22 and their interaction with AChE has been reported.252 It is hoped that such studies will result in the development of new agents for the management of Alzheimer’s disease.96 Peter Quayle CO2Me Ph ( ) n OH Ph ( ) n n = 1 77% n = 2 89% [ref. 195( b)] R1 NR2 O LnTi R3 + R1 NR2 R3 50–75% [ref. 195( c)] i Scheme 32 Reagents and conditions i Ti(OPr*) 4 Pr*MgCl. Scheme 33 Reagents and conditions i LiEt 3 BH THF [78 °C; ii TFA CH 2 Cl 2 0 °C; iii ButOK ButOH. 97 Aliphatic and alicyclic chemistry OMe O O R I I R O i ii 45% overall for R = CH3 (ref 200) + O • R1 R2 O R2 R1 19 (ref 201) O R1 R2 H H 20 Claisen T > –30 °C Ha OMe Hb Hc + MeO MeO iii [ref. 202( a)] [4 + 2] (continued) 98 Peter Quayle Scheme 34 Reagents and conditions i Li cat. naphthalene THF 0 °C; ii H 3 O`; iii hv Pyrex filter PhH; iv naphthalene-2-methanol THF pyridine; v ceric ammonium nitrate dry acetone,[46 to 0 °C; vi NaN(SiMe 3 ) 2 .99 Aliphatic and alicyclic chemistry O Br TBDMSO TBDMSO CH3 O Br RO CH3 RO 70% i P P ( )3 (ref. 206) OBn OH H NH H H ii 61% (+)-pumiliotoxin C Scheme 35 Reagents and conditions i Pd(OAc) 2 (cat.) 2-diphenylphosphinobenzoic acid (cat.); ii (dba) 3 Pd 2 ·CHCl 3 (2.5 mol%) N,N@-bis(benzylidene)ethylene diamine (BEEDA) (5 mol%) polymethylhydrosiloxane (PMHS) (10 equiv.) AcOH (1 equiv.) dichloroethane. Medium large and polycyclic ring systems The use of [4]3] cycloadditions has been e§ectively utilised for the stereoselective synthesis of functionalised 8-oxabicyclo[3.2.1]octenes,253–255 which are themselves versatile synthetic intermediates. A related strategy has also been applied to the synthesis (])-5-epitreulenolide,255a Scheme 43. An intramolecular palladium-TMM cycloaddition reaction has been applied to the synthesis of ([)-isoclavukerin A256 whilst metal-promoted higher-order cycloaddition reactions have also been utilised to good e§ect for the synthesis of a variety of cycloheptane derivatives,257 Scheme 44.The synthesis of cyclooctanes is still dominated by the global preoccupation with the taxane diterpenoids. Representative approaches to the central core of this ring system include pinacol-type couplings,258 IMDA259 and intramolecular alkylation reactions as depicted in Scheme 45.260 Radical261 and metal-promoted262 ring enlargement reactions have general applicability to the synthesis of medium-sized rings. The synthesis of enediyne-containing macrocycles has again been the subject of much interest resulting in the synthesis of the basic core of C-1027263 and a functionalised model system of the neocarzinostatin chromophore.264 Most syntheses of this compound rely upon now well-established palladium-catalysed coupling reactions for the installation of the enediyne moiety.However in a novel departure Nicolaou has reported that macrocyclic enediynes can be prepared via a retro-Diels–Alder sequence 265 Scheme 46. The syntheses of a number of carbocycles of theoretical interest e.g. 23 24 and 25 Fig. 2 have appeared this year (see refs. 266–268). 100 Peter Quayle Scheme 36 Reagents and conditions i SmI 2 (1 equiv.) THF HMPA 0 °C; ii Bu 2 Zn BuZnCl Ni(COD) 2 (5 mol%) PPh 3 (25 mol%); iii R 2 Zn or RZnCl Ni(COD) 2 (5 mol%); iv Et 2 Zn (2 equiv.) MnBr 2 (5 mol%) CuCl (3 mol%) DMPU 60 °C 0.5–3h. 101 Aliphatic and alicyclic chemistry Scheme 37 Reagents and conditions i TMSBr,[78 °C; ii BF 3 ·OEt 2 0 °C.N2 O O MeO2C MeO2C O O 89% i (ref. 216) O O CO2Me O O 85% i N2 CO2Me Scheme 38 Reagents and conditions i Rh 2 (C 7 H 15 CO 2 ) 4 CH 2 Cl 2 . 102 Peter Quayle OMBn NTs O O NTs O H CO2H 'good yield' i,ii EtO2C EtO2C O EtO2C EtO2C iii 95% O MBnO OMe O O OMe H 30% iv (ref. 219) (ref. 218) (ref. 217) N BnO O N BnO O H 95% v,vi (ref. 220) O Scheme 39 Reagents and conditions i Co 2 (CO) 8 NMO CH 2 Cl 2 ; ii TFA CH 2 Cl 2 ; iii Co 2 (CO) 8 (1 atm) hv DME; iv Co 2 (CO) 8 CO(1 atm) 110 °C; v Co 2 (CO) 8 PhMe room temp.; vi heat. 103 Aliphatic and alicyclic chemistry OH MeO OH OH MeO O i 61% (ref. 223) HO (NH3)5Os2+ O (NH3)5O5 O 86% ii (ref. 223) O N But Cr(CO)3 O N But iii,iv (ref. 223) Scheme 40 Reagents and conditions i NaIO 4 ; ii but-3-en-2-one Pr 2 *NEt; iii MeLi; iv allyl bromide.R OSO2 O SO2 R (ref. 229) B F O O – N H H B O O O O Ph – F (ref. 230) OR (continued) 104 Peter Quayle OBn OR BnO OBn OBn BnO OR O O H CO2Me H OBn (ref. 232) N O OSiR3 MeO N MeO O CO2Me OH (ref. 233) O O O (ref. 234) O P(OEt)2 O OAc O PPh2 O (ref. 235) N O SOTol Boc N O Boc (ref. 236) Fig. 1 105 Aliphatic and alicyclic chemistry (continued) Scheme 41 Reagents and conditions i PhMe 200 °C 3 h; ii PhMe 200 °C 18 h; iii Nu~; iv CeIV; v Bun 3 SnH AIBN heat. 106 Peter Quayle OMOM MeO Li Fe(CO)3 OMe MeO + + BF4 – OMOM MeO OMe Fe(CO)3 OMe MeO O O H CN MeO O H steps NMe (ref. 244) O I CO2Me TBSO O CO2Me H TBSO (ref. 247) 85% v OH lycoramine Scheme 41 107 Aliphatic and alicyclic chemistry Scheme 42 Reagents and conditions i (dba) 3 Pd 2 ·CHCl 3 HCO 2 H dichloroethane room temp.; ii (CH 3 ) 2 C~CN (2 equiv.) [78 °C; iii H 3 O`; iv Pd0 CuI; v Bu 3 SnH NiII; vi heat; vii base; viii BusLi THF,[78 °C 5 min; ix MeOTf Et 2 O 0 °C 3 h.108 Peter Quayle Scheme 43 Reagents and conditions i EtMgCl (1 equiv.); ii Zn–Ag; iii 2,4-dibromopentan- 3-one; iv Rh 2 L 4 ; v catalyst,[78 °C CH 2 Cl 2 ; vi 140 °C. 109 Aliphatic and alicyclic chemistry Scheme 44 Reagents and conditions i Pd(OAc) 2 ) (Pr*O) 3 P Me 3 SnOAc; ii DBU. 110 Peter Quayle O CHO O O O O OH OH i 74% (ref. 258) O OTIPS OMe TBSO TBSO H O H H OMe OTIPS (ref. 259) ii 95% CHO O O SO2Ph O O O O O O SO2Ph O iii iv 95% (ref. 260) O CO2Et O N S N CH3 O CO2Et CH3 v 76% (ref.261) O Br ButO H MeO2C ButO CO2Me H O ButO CO2Me H O vi vii 63% (2.5 1) + Scheme 45 Reagents and conditions i SmI 2 25 °C; i PhMe 140 °C 110 h; iii LiN(SiMe 3 ) 2 . 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