13 Synthetic Methods By W. CARRUTHERS Department of Chemistry The University Exeter EX4 400 1 Introduction The pace of advance in organic synthesis makes it impossible to include more than a selection of recent methods in this Report. A number of important topics for example oxidation and reduction have been omitted (but not forgotten) and it is hoped that it may be possible to include some of these in next year's Report. 2 Alcohols An extremely simple convenient and selective method for acetylating primary alcohols in the presence of secondary ones has been reported,' and has been applied in the carbohydrate series.* Primary hydroxyalkylphenols are thus converted into acetoxyalkylphenols and primary aromatic amines into the corresponding acetamides.t-Butyldimethylsilyl tri-isopropylsilyl and octadecyldimethylsilyl triflates are useful reagents for silylation of hindered alcohols which react sluggishly with the usual silylating agent^.^ 1,2- and 1,3-diols are conveniently protected by conversion into their di-t-butylsilylene derivatives by reaction with di-t-butyldi- chlorosilane. The protecting group is easily removed by treatment with pyridinium hydr~fluoride.~ The de-oxygenation of secondary alcohols by radical reduction of thiocarbonyl esters has been shown to be a general reaction of value in the synthesis and modification of natural products.' By appropriate modification of experimental conditions the reaction has now been extended to primary alcohols.6 A modified Barton procedure was used to convert ribonucleosides into 2'-deoxyn~cleosides.~ Methods for the inversion of secondary alcohols are valuable in synthesis.Caesium carboxylates in dimethyl formamide are good nucleophiles and are useful for the introduction of hydroxy-substituents by SN2 nucleophilic substitution. In practice the best results were obtained with the propionate. Mesylates of several secondary alcohols were cleanly converted into the propionates of the inverted alcohol in high yield in warm dimethyl formamide. The inversion of (S)-2-octanol ' G. H. Posner and M. Oda Tetrahedron Lett. 1981,22 5003. S. S. Rana J. J. Barlow and K. L. Matta Tetrahedron Lett. 1981 22 5007. E. J. Corey H. Cho C. Rucker and D. H. Hua Tetrahedron Lett. 1981,22,3455. B. M. Trost and C. G. Caldwell Tetrahedron Lett.1981 22,4999. D. H. R. Barton and W. B. Motherwell Pure Appl. Chem.. 1981,53,1081. D. H. R. Barton W. B. Motherwell and A. Stange Synthesis 1981.743. 'M. J. Robins and J. S. Wilson J. Am. Chem. SOC.,1981 103,932. 299 300 W.Carruthers for example to the enantiomerically pure (R)-isomer proceeded in 86 percent yield without detectable elimination a considerable improvement on published procedures.* Kinetic resolution of racemic allylic alcohols by enantioselective epoxi- dation provides a very effective route to optically pure allylic alcohols. (S)-Allylic alcohols are epoxidized by t-butylhydroperoxide much faster than the (R)-isomers in the presence of (+)-L-di-isopropyl tartrate-titanium alkoxide catalyst leaving the (R)-alcohol of high enantiomeric purity.' Methods for the stereoselective and regiospecific synthesis of allylic alcohols continue to be explored.Reaction of alkyl-lithium reagents with isoprene epoxide in the presence of a base such as a tertiary amine or lithium alkoxide gives fly-disubstituted allylic alcohols of predominantly (2)-configuration." A promising method for the specific conversion of propargylic alcohols into (2)-yy-disubstituted allylic alcohols which complements the well known Corey route to the (E)-isomers has been described (Scheme 1). Hydromagnesiation of propargylic alcohols (e.g. 1) by isobutylmagnesium halides in the presence of catalytic amounts of (q5-C5H5)2TiC12 affords the corresponding (E)-alkenylmagnesium halide (as 2) exclus-ively in almost quantitative yield; (2) is readily converted into the iodide (3) or the (2)-3-methyl-2-heptenol (4).Bu CH20H \/ /I/c=c\H Bu CH2OMgCl (3) \/ i c=c ClMg'\H CH20H (2) Me (4) Reagents i 2 Bu'MgCl-(q5-C,H,),TiCl,; ii I, -70 "C;iii MeI-THF 0 "C Scheme 1 A novel route to stereochemically defined 1,3-enynols and 1,2,4-trienols through reaction of the organoboranes (7) and (8) with aldehydes is reported (Scheme 2),12 Reaction of the thexylalkenylchloroborane(5) with two equivalents of lithium chloropropargylide at -78 "C furnished the alkenylallenic boranes via the 'ate' complex (6). Treatment of the reaction mixture containing (7) with an aldehyde afforded the 1,3-enynol (9). However if the organoborane (7) formed initially was brought to room temperature it rearranged in a recognised fashion to (8).Reaction of this with an aldehyde produced the 1,2,4-trienol (10).Reaction of the allenic * W. H. Kruizinga B. Strijtveen and R. M. Kellogg J. Org. Chem. 1981,46,4321. V. S. Martin S. S. Woodard T. Katsuki Y. Yamada M. Ikeda and K. B. Sharpless,J. Am. Chem. SOC. 1981,103,6237. lo M. Tamura and G. Suzukamo Tetrahedron Lett. 1981 22 577. F. Sato H. Ishikawa H. Watanabe T. Miyake andM. Sato J. Chem. SOC.,Chem. Commun. 1981,718. G. Zweifel and N. R. Pearson J. Org. Chem. 1981,46 829. Synthetic Methods R' 1iii,iv 1iii,iv R' R' R& OH (9) (10) Reagents i R-G-R' ii 2 equivs. ClCH,C=CLi-THF -78 "C; iii R'CHO -78 "C; iv H20,-NaOH Scheme 2 and propargylic carbon-boron bonds of (7) and (8)with the carbonyl groups of the aldehydes must proceed with bond transposition.Much recent work has been concerned with the enantioselective synthesis of alcohols and an account of some of this can be found in the section dealing with the aldol condensation. Organoboranes have proved useful in this regard. Monoalkyl and dialkylboranes exhibit high stereo- and regio-selectivity in the hydroboration of alkenes and this property coupled with the capability for asym- metric creation of chiral centres with chiral hydroborating agents makes this reaction a valuable one for asymmetric organic ~ynthesis.'~ A new crystalline chiral hydroborating agent dilongifolylborane readily prepared from (+)-longi- folene and borane-methyl sulphide complex is highly effective for asymmetric hydroboration of alkenes providing alcohols after oxidation of the intermediate organoboranes with high optical purities corresponding to 60-78 percent excess of the (R)-enantiomer in the cases ~tudied.'~ Optically active hydroxycarboxylic acids of the general formula RCHOH(CH2),C02H have been prepared from optically active propargylic alcohols themselves obtained by reduction of propargyl ketones with B-3-pinanyl-9-borabicyclo[3,3,1]nonane'5 (Scheme 3).l3 H. C. Brown P. K. Jadhav and A. K. Mandal Tetrahedron 1981,37,3541. '* P. K. Jadhav and H. C. Brown J. Am. Chem. Soc. 1981,46 2988. M. M. Midland and P. E. Lee J. Org. Chem. 1981 46 3933. 302 W. Carruthers Reagents i BuLi; ii Me,SiCl; iii HCI; iv (C6Hll)$H; v H20,-NaOH; vi Ac@; vii KMnO Scheme 3 It has been shown previously16 that intramolecular cyclic hydroboration of acyclic dienes provides an effective method for the stereoselective synthesis of acyclic molecules having widely separated asymmetric centres.The usefulness of this procedure has now been illustrated by the synthesis of the Prelog-Djerassi lactonic acid (12) from enantiomerically pure (11); (Scheme 4).17 The key hydroboration ButMe2SiO% Me i ii ButMe2sioTHYe + Me" Me' Me (1 1) H liii Reagents i BH,-THF; ii H,O,-NaOH; iii several steps Scheme 4 of (11)proceeded with the desired stereoselection for the p-face of the C-5-C-6 double bond to the extent of >20 :1.The chiral centre in (11)induces all the other chiral centres in a relatively efficient way except that at C-2 which results from the initial stereorandom hydroboration.A novel sequence that may be used to prepare erythru-1,2- or -1,3-diols from allylic or homoallylic alcohols involves initial stereoselective formation of the cyclic iodocarbonates followed by reductive removal of iodine and liberation of the diol with base (Scheme 9.'' A potential route to stereo-enriched 1,2- or 1,3-diols or 1,2,3-triols is provided by the iodolactonization of 3-hydroxy-4-alkenoic acids which leads predominantly to the thermodynamically less stable 3-hydroxy-4-alkyl- y-lactones (13). l6 W. C. Still and K. P. Darst J. Am. Chem. Soc. 1980,102,7385. l7 W. C. Still and K.R.Shaw Tetrahedron Lerr. 1981 22 3725. G. Cardillo M. Orena G. Porzi and S.Sandri,J. Chem. Soc. Chem. Commun. 1981,465. Synthetic Methods R' lv OH OH Reagents i BuLi; ii CO,; iii I,; iv Bu,SnH; v NaOH Scheme 5 Methanolysis of these affords mainly the threo- epoxy-alcohols (14) usefully with the opposite relative configuration of the hydroxy- and epoxy-groups from that obtained by direct epoxidation of the hydroxy-ester by the Sharpless procedure (Scheme 6)." A highly stereoselective synthesis of erythro-a@- epoxy-alcohols by reduction of a@-epoxy-ketones with zinc borohydride is reported.20 High preference for the erythro-isomer remains whatever the substitution pattern of the epoxide in contrast to reduction with sodium borohydride.Reagents i I,-CH,CN; ii -0Me; iii Bu'OOH-VO(acac),-CH,C12 Scheme 6 3 Alkenes Organoboranes continue to find new applications in synthesis. B-(Cycloalkyl-methyl)-9-BBN derivatives which are readily available from cycloalkenesY2' are readily converted into exocyclic methylene compounds by reaction with benzal- dehyde. The method appears to be general and since the synthesis proceeds from a cycloalkene it provides a valuable alternative to the well known methylenation of cyclic ketones by the Wittig and related procedures. 1-Methylcyclopentene for example is converted into 2-methylmethylenecyclopentane in 65% yield.22 The method is readily adapted to the preparation of methylene-d2- cycloalkanes but l9 A.R. Chamberlin M. Dezube and P. Dussault Tetrahedron Lea 1981 22,4611.2o T. Nakata T. Tanaka and T. Onishi Tetrahedron Lett. 1981,22,4723. H. C. Brown T. M.Ford and J. L. Hubbard J. Org. Chem. 1980,45.4067. 22 H. C. Brown and T. M.Ford J. Org. Chem. 1981,46,647. 304 W. Carruthers of course is limited to substrates which hydroborate regioselectively or which are symmetrical. Addition of copper(1) reagents to alkynes has been widely used in the synthesis of alkenes. In a new procedure it is shown that cis-dialkenylcuprates generated by addition of dialkylcuprates to acetylene add to ag-unsaturated sulphones with retention of double-bond geometry to give ?&unsaturated sulphones; these are readily desulphonylated to the corresponding alkene. The overall yields were in the range 70-80% .23 A versatile and selective route to difunctional trisubstituted (E)-alkenes by zirconium-catalysed carboalumination of alkynes has been In contrast to other known carbometallation reactions the zirconium-catalysed carboalumina- tion of alkynes shows high regioselectivity when applied to propargyl and homopropargyl derivatives containing OH OSiMe2Bu' SPh or I substituents.Coupled with known carbon-carbon and carbon-heteroatom bond-forming reac- tions this provides a route for the selective synthesis of difunctional trisubstituted olefins. Thus the iodoalkene (15) was obtained from 3-butynol in 87% yield with >98% stereoselectivity (Scheme 7). Stereochemically pure (E)-and (2)-1,2-disubstituted ethylenes are conveniently obtained by application of the Wittig- Horner modification of the Wittig reaction using diphenylphosphinoyl (Ph2PO) as Z(CH2)n H \/ Z(CH,),C=CH Me /C=C\AIMe2 Z = OH OSiMe2Bu' SPh or I; n = 1,2.Reagents i Me,Al-CI,ZrCp,; ii I,-THF -30 "C; iii Bu'Me,SiCI-Et,N Scheme 7 the anion-stabilizing group and this method has clear advantages over the conven- tional Wittig procedure for the preparation of stereochemically pure alkene~.~~ Pure (2)-alkenes are obtained from the erythro-alcohols (16) formed on addition of anions stabilized by PhzPO to aldehydes (Scheme 8). Acylation of the same anions with esters or lactones and reduction of the ketones (17) with sodium borohydride gives predominantly the threo- alcohols (18) readily purified by flash chromatography. Elimination then affords pure (E)-alkenes.The readily available [(trimethylsilyl)acetyl]trimethylsilane (19) can be used to prepare various trisubstituted olefins of defined stereochemistry by sequential deprotonation-alkylationdeprotonation-aldolizationreactions exemplified in the synthesis of the a@-unsaturated acid (21) and aldehyde (22) (Scheme 9).26A 23 G. De Chirico V. Fiandanese G. Marchese F. Naso and 0. Sciacovelli J. Chem. SOC. Chem. Commun. 1981,523 24 C. L. Rand D. E. Van Horn M. W. Moore and E. Negishi J. Org. Chem. 1981,46,4093. 25 A. D. Buss and S. Warren J. Chem. SOC.,Chem. Commun. 1981 100. " J. A. Miller and G. Zweifel J. Am. Chem. SOC.,1981,103,6217. 305 Synthetic Methods R' R ! (17) (18) Reagents i BuLi-THF -78 "C ii R'CHO; iii NaH-DMF; iv R'C0,Et or CH,(CH,),OC=O; v NaBH Scheme 8 Me$ /OLi Me,SiCH,COSiMe A \c=c 5 Me,SiCHCOSiMe3 (19) H SiMe Me (20) li IF;/\ I k-d>Me \ :osiMe] iii Me,Si /c=c\/OLI LiO SiMe Me SiMe 1 H COSiMe 9-Fco2* \I \xc=c\Me (21) +cHo(22) Reagents i LiN(Pr'),; ii MeI; iii CHO ;iv H20,-NaOH; v Bu,NF-HCO,H 75 "C Scheme 9 limitation is presented by the sluggish reaction of enolate (20) with halides other than methyl or ethyl iodides and ally1 and benzyl bromides.Higher alkyl halides react only slowly. A great deal of work continues on the synthesis of dienes and enynes. A new convenient and highly selective route to 1,4-dienes by palladium-catalysed cross-coupling of alkenylmetals containing aluminium or zirconium with allylic halides 306 W.Carruthers or acetates proceeds with essentially complete retention of the stereo- and regio- chemistry of both alkenyl and allyl groups.27 The corresponding reaction of aryl- metals such as those containing zinc is also markedly promoted by palladium catalysts but that of alkylmetals containing aluminium or zinc does not seem to be. Thus (E)-(2-methyl-1-octeny1)dimethylalane(23) prepared by the zirconium- catalysed carboalumination of 1-octyne with trimethylaluminium reacts with allyl bromide in presence of (Ph3P)4Pd to produce the cross-coupled product (24) in greater than 90% yield (Scheme 10). In the absence of the palladium catalyst the yield of coupled product was negligible. Reagents i e B r ;ii 5mol.% Pd(PPh,),-THF 0"C Scheme 10 A new route to 2-substituted butadi-1,3-enes makes use of the radical reduction of a-(hydroxymethy1)allyl sulphones with tri-n-butyltin hydride.The sulphones themselves are conveniently obtained by alkylation of the anion of allyl tolyl sulphone with alkyl halides followed by hydroxymethylation with paraformal- dehyde*' (Scheme 11). Reagents i BuLi; ii (CH,O) ;iii Bu,SnH-azobisisobutyronitriie-benzene,reflux Scheme 11 (E,Z)- and (2,Z)-1,3-dienes have been obtained stereospecifically by reaction of (2)-1-alkenyldisiamylboranes with (2)-or (E)-1-alkenyl bromides in the presence of a catalytic amount of (Ph,P),Pd and sodium eth~xide.~' The correspond- ing (E,E)-and (2,E)-dienes were obtained equally well by reaction of (E)-1-alkenyl-1,3,2-benzodioxaboroleswith the appropriate (E)-and (2)-1-alkenyl bromides.A similar sequence of reactions was employed in the synthesis of insect sex pheromones containing conjugated diene Several insect pheromones with an (E,E)-1,3-diene system have been synthesized by a novel general stereospecific procedure using a preformed simple 1,3-diene locked in the (E)-configuration by an iron tricarbonyl protecting group. Friedel- 27 H. Matsushita and E. Negishi J. Am. Chem. Soc. 1981,103,2882;see also Y.Hayasi M. Riediker J. S. Temple and J. S. Schwartz Tetrahedron Lett. 1981 22 2629. Y.Ueno H.-Sano S. Aoki and M. Okawara Tetrahedron Lett. 1981 22,2675. 29 N. Miyaura and H. Suginome Tetrahedron Lett. 1981.22 127. 30 R. Rossi A.Carpita and M. G. Quirici Tetrahedron 1981,37 2617. Synthetic Methods 307 Reagents i AIC1,-CICO(CH,),CO,Et; ii LiAIH,-AlCl,; iii Ac,O; iv Me,N +0 Scheme 12 Crafts acylation and further manipulation gave the long-chain diene as in Scheme lT31 Conjugated dienes can also be obtained with high isomeric purity by coupling of alkenyl cuprates and alkenyl halides in the presence of zinc bromide and a catalytic amount of PdoL4.32 The pinacol (E)-1-trilnethylsilyl-l-propene-3-boronate (25) in line with other 2-alkene-1-boronic esters reacts with aldehydes to yield (k)-(R,S) -3-trimethylsilyl-4-hydroxy-1-alkenes which are readily deoxy- silylated to give either (2)-or (E)-terminal dienes of >98% isomeric purity (Scheme 13).33 Reagents i RCHO; ii (HOCH,CH,),N; iii KH-THF; iv H,SO,-THF Scheme 13 The anion derived from bis(t-butyldimethylsily1)propyne reacts regioselectively with carbonyl compounds to give enynes with a preponderance of the (2)-isomers as shown in Scheme 14.Very high yields of the (Z)-isomer are obtained when the lithium counter ion is replaced by magne~iurn.~~ Thus hexanal gave a 65% yield of enyne (26) containing about 98% of the (2)-compound. Enynes of high stereoisomeric purity are obtained in excellent yields by reaction of alkenylcopper Bu'Me2SiCH2CGCSiMezBu' i* ii + Bu'Me2SiCH=C=C-SiMezBu' I 1iii Mg Y Ill I SiMe,Bu' (26) Reagents Bu'Li-THF -78 "C; ii MgBr,-ether; iii wCHO Scheme 14 31 G. R. Know and I. G. Thorn J. Chem. SOC.,Chem. Commun.1981,373. 32 N. Jabri A. Alexakis and J. F.Normant Tetrahedron Lett. 1981,22 959. j3 D.J. S.Tsai and D. S. Matteson Tetrahedron Lett. 1981,22 2751. 34 Y. Yamakado M. Ishiguro N. Ikeda and H. Yamamoto. J. Am. Chem. SOC.,1981,103,5568. 308 W. Carruthers intermediates generated in situ from ‘ate’ complexes of 9-borabicyclo[3,3,1]nonane and cuprous iodide or cuprous bromide-dimethyl sulphide complex with 1-halo-1-alkynes. The stereochemistry of the double bond in the enyne is defined by that of the starting alkenylb~rane.~’ The highly hindered olefin (29)was obtained in 65% yield by reaction of (27) with (28) at 185°C (Scheme 15). The related (30) was prepared by a similar method.36 4 Aldol condensation Work continues apace on stereoselective aldol condensations stimulated by wide- spread interest in using the aldol reaction in the synthesis of naturally occurring \ + Ph3PN-Na/ -* / (27) (28) (29) (30) Scheme 15 macrolide and ionophore antibiotics.There appears to be some uncertainty about the stereochemical nomenclature of aldol products. In the convention used by Heathcock3’ if the main aldol chain is written in an extended zig-zag conformation that diastereomer which has the C substituent and the CBhydroxy-group both extending toward the viewer or away from the view is called the erythro- diastereomer (31) and the other the threo (32) although this is not in agreement with the Fischer convention as it is customarily interpreted. The same system is used by Bartlett38 and Evans3’ Masam~ne,~’ however would apparently call (31) the syn-isomer and Kishi4’ would regard (31) as the threo-isomer.R R’ R’ R’ (31 erythro) (32 threo) Scheme 16 ” H. C. Brown and G. A. Molander J. Org. Chem. 1981,46,645. 36 E.R.Cullen F. S. Guziec M. I. Hollander and C. J. Murphy Tetrahedron Lett. 1981,22 4563. 37 C. H. Heathcock C. T. White J. J. Morrison and D. Van Derveer J. Org. Chem. 1981,46,1296. ’* P. A.Bartlett Tetrahedron 1980 36 2 Tables 7 and 9. 39 D. A.Evans J. Bartroli and T. L. Shih J. Am. Chem. Soc. 1981 103 2127; D. A. Evans J. V. Nelson E. Vogel andT. R. Taber J. Am. Chem. Soc. 1981,103 3099. *O S. Masarnune Sk. A. Ali D. L. Snitrnan and D. S. Garvey. Angew. Chem. Inr. Ed. Engl. 1980 19 557. 41 cf.N. Nagaoka and Y.Kishi Tetrahedron 1981,37 3873. Synthetic Methods 309 Earlier work has led to an understanding of the factors responsible for stereocon- trol in aldol condensations (s~mmarized~~). When carried out in aprotic solvents in the presence of a co-ordinating counter ion the reactions proceed by way of chelated six-centred cyclic transition states. For kinetically controlled reactions the erythro- product (Heathcock sense) is favoured from (Z)-enolates whereas the threo- product usually predominates from (E)-enolates. Under thermodynamic control the threo- product is favoured regardless of the geometry of the starting enolate. Much recent work has been concerned with increasing the selectivity of the reactions even further. Evans and his co-workers have now published4* a full account of their study of the generation of stereochemically homogeneous boron enolates from ketones and carboxylic acid derivatives and their stereoselective aldol reaction with a range of aldehydes.For a range of acyclic ketones consistently good correlation was observed between the geometry of the enolate and the stereochemistry of the aldol products regardless of the structure of the ketone or the boron ligands. For the reaction of the cis-enolate of 3-pentanone with isobutyraldehyde for example the erythro-aldol formed at least 97%of the product the same within experimental error as the proportion of cis-isomer in the enolate (Scheme 17). LL Me Me Scheme 17 Carboxylic acids could also be converted into the dialkylboryl enediolates.The enediolate from propionic acid on condensation with benzaldehyde afforded mainly the threo-2-methyl-3-hydroxycarboxylicacid; with benzyloxyacetic acid the threo-isomer was the exclusive product. The reaction of chiral boron enolates with aldehydes was also studied. Enolates derived from methyl ketones gave only moderate levels of chirality transfer but with the cis-enolate derived from the ethyl ketone (33)the stereochemically homogeneous erythro-aldol (34) was obtained in 57% yield by direct crystallization from the reaction mixture (Scheme 18). 42 D. A. Evans J. V. Nelson E. Vogel and T. R. Taber J. Am.Chem. Soc. 1981,103,3099. 310 W.Carruthers Tos Tos (33) (34) Reagents i LiN(Pr') or L,BOSO,CF,-EtN(Pr'),+ther -78 "C; ii >CHO Scheme 18 Chiral boron enolates have been used in a highly effective enantioselective synthesis of erythro-P- hydroxy-a-methylcarboxylic acids (38) and (41); (Scheme 19).43Reaction of the chiral enol boronates (36)and (40) prepared from the chiral Me OSiMe,Bu' Bu'Me,SiO H HO 1iii iv (38) ".c ii-iv ,R '-OH Me Bu'Me,SiO HO 0 (39) (40) (41) Reagents i R2BOS0,CF,-EtN(Pr'),-CH~Clz -78 "C; ii R'CHO; iii HF-CH,CN; iv NaI0,-MeOH-H,O,r.t.Scheme 19 a-trimethylsilylketones (35) and (39) with a range of aldehydes followed by desilylation and oxidative cleavage with sodium metaperiodate gave the a-alkyl-P- hydroxycarboxylic acid with a high degree of erythro- selectivity. Both pure enan- tiomers of the erythro-products could be obtained by starting with the appropriate dialkylboron enolate derived from (1s)-or (1R)- t-butyldimethylsiloxy-l-cyclo-hexylbutan-2-one.The diastereoselectivity of the new reagents (36) and (40) is greatly superior to that of any reported previously for this sequence. (R)-and 43 S. Masamune W. Choy F. A. J. Kerdesky and B. Imperiali J. Am. Chem. Soc.,1981,103,1566; W. Choy P. Ma and S. Masamune Tetrahedron Lett. 1981,22 3555. (/+ Synthetic Methods (S)-methyl p-hydroxyisobutyrate for example were obtained in greater than 98% optical purity and the control possible in complex cases has been vividly demon- strated in a synthesis of 6-deoxyerythronolide B.44 Another procedure for the enantioselective synthesis of p-hydroxy-cr-alkylcar-boxylic acids of both the erythro-and threo-series makes use of chiral boron azaen~lates,~~ although the enantioselectivity is not as high as that achieved in Masamune's method outlined above.By changing the location and nature of the chiral auxiliary unit the stereochemical course of the aldol process was altered from predominantly threo (77-85% enantiomeric excess) to erythro (40-60% enan- tiomeric excess). Chiral erythro p-hydroxy-a-methylcarboxylic acid derivatives can also be obtained through boron enolates derived from N-propionylimides (42b) and (43b) of the recyclable chiral auxiliaries (42a) and (43a).46 The imides (42b) and (43b) undergo highly stereoselective enolization with either lithium di-isopropylamide (THF -78 "C) or di-n-butylboryl trifluoromethanesulphonate to form the corres- ponding (2)-enolates almost exclusively.Condensation of the boron enolates with several aldehydes and oxidative work-up led to the stereoisomeric aldol adducts (44) and (45); (Scheme 20). For the boron enolate reactions the combined threo-adducts never amounted to more than 0.9% of the product and in all cases the imide (42b) afforded erythro-isomer (44) whereas (43b) gave (45) with the y O\'O (43) a; R = H b; R =1COCHzMe i-iii (44) (45) Reagents i Bu2BOS0,CF,-(P~),NEt-THF,-78 OC; ii R'CHO; iii 30% H202; iv KOH-MeOH Scheme 20 44 S. Masamune M. Hirama S. Mori Sk. A. Ali and D. S. GaNey J. Am. Chem. SOC.,1981,103 1568. 45 A. I. Meyers and Y. Yamamoto J. Am. Chem. SOC.,1981,103,4278.46 D.A.Evans J. Bartroli andT. L. Shih J. Am. Chem. SOC.,1981,103 2127. 312 W. Carruthers opposite sense of asymmetric induction. In contrast condensations using the lithium enolates showed low levels of stereoselectivity. Excellent results have also been obtained with the zirconium enolates (46) and (49) shown in Scheme 2 1. Condensation with aldehydes afforded the erythro- aldols (47) and (50) with high selectivity (96-989'0) and after hydrolysis the erythro-8- hydroxy-a- methylcarboxylic acids (48) and (5 1) of opposite absolute (47) R' = methoxymethylene (48) (49) Reagents i RCHO; ii H30+ Scheme 21 stere~chemistry.~' For reaction of isobutyraldehyde with the enolate (46) the product was 96% the erythro-aldol (47; R = i-C3H7) whereas with enolate (49) 97.5% of (50) was obtained.In contrast the lithium enolates showed low levels of both erythro-threo diastereoselection and enolate diastereoface selection under kinetic conditions in all the cases studied. The aldol condensation of the enolates (46) and (49) with chiral a-substituted aldehydes also showed excellent results. Thus reaction of zirconium enolate (49) with both (S)-(52) and (R)-(52) again gave very high levels of erythro-selection (Scheme 22). Similar results were obtained Me (52) (S,R,S)-erythro :(R,S,R)-erythro :threo 98.7 10.9 0.4 ii Reagents i py bMe ' ;ii H,O+ 0- Scheme 22 " D. A. Evans and L. R. McGee. J. Am. Chem. SOC.,1981,103,2876. Synthetic Methods in condensations of (46) with aldehydes (S)-(52) and (R)-(52).The erythro- specificity of the zirconium enolates is attributed to steric interactions in the transition state between the substituents on the enolate and the bulky cyclopen- tadienyl ligands on the metal. Other metal enolates besides the lithium zirconium and boron derivatives have been employed in the aldol reaction. Previous work has shown that the Lewis-acid mediated addition of both cis-and trans-crotyltrialkyltin to aldehydes leads prefer- entially to erythro- products. It is now found4' that triphenyltin enolates prepared from lithium enolates and triphenyltin chloride in tetrahydrofuran at -78 "C undergo rapid aldol condensation with aldehydes without assistance from Lewis acids to give predominantly the erythro-products regardless of the geometry of the enolate.Erythro-compounds are also the main products from the reaction of silyl enol ethers with aldehydes in the presence of a catalytic amount of tris(diethy1- amino)sulphonium difluorotrimethylsiliconate again irrespective of the configur- ations of the en01ates.~~ Titanium enolates also give rise to erythro- aldols preferen- tially. They provide a means of obtaining erythro- products from cyclic ketones; these have hitherto not been readily available because their formation has required the geometrically inaccessible (Z)-en~lates.'~ The diastereoselection with the titanium enolates is reported to be higher than that available using zirconium or tin enolates. Hitherto threo-aldolization products have not been easy to come by but it has now been found that preformed lithium enolates of certain hindered aryl esters condense with aldehydes to give predominantly threo- aldols thus providing a good preparative route to threo-a-alkyl-P- hydroxycarboxylic acids (Scheme 23)." The propionate (53) for example prepared from 2,6-dimethylphenol reacts with ben- zaldehyde and a-unbranched aliphatic aldehydes to give threo :erythro ratios of about 6.5 1.With aldehydes branched at the a-position the threo-aldols were the (53) >98% threo (54) R' = Me (55) R' = OMe Reagents i LiN(Pr'),-THF -78."C; ii >CHO ; iii KOH-H,O-MeOH 25 "C Scheme 23 '* Y. Yamamoto H. Yatagai and K. Maruyama J. Chem. SOC.,Chem. Commun. 1981 162. '' R.Noyori I. Nishida and J. Sakata J. Am. Chem. SOC.,1981 103 2106. M. T. Reetz and R. Peter Tetrahedron Lett. 1981,22,4691. C. H. Heathcock M. C. Pirrung S. H. Montgomery and J. Lampe Tetrahedron 1981,37,4087. 314 W. Carruthers only products detected. Hydrolysis .afforded the corresponding threo-a-alkyl-P-hydroxycarboxylic acids. The esters (54) and (55) gave only threo-aldols with all aldehydes studied but they could not be hydrolysed without retroaldolization. Aldols from (54) can be reduced with lithium aluminium hydride to the correspond- ing threo-diol and aldols from (55) are converted into the P-hydroxy-acid by oxidation with ceric ammonium nitrate. A general synthesis of erythro-a-alkyl-P- hydroxyketones has been reported. It is well known that ketones having one bulky group attached to the carbonyl group give homogeneous (2)-enolates on treatment with lithium di-isopropylamide which condense with aldehydes to give erythro-aldols.But other ketones give mixtures of (2)-and (E)-enolates which take part in the aldol condensation with varying degrees of kinetic stereoselectivity. The general method (Scheme 24) now Reagents i LiN(Pr’),; ii RCHO; iii H,IO,-MeOH; iv I -H+; v BuLi 0 Scheme 24 put forward is based on a route from the same laboratory to erythro-a- hydroxy-acids [for example (58)]from the ketone (56) by reaction with aldehydes followed by reduction of the carbonyl group of (57) and oxidation with periodic acid.52 It is now showns3 that protection of the hydroxy-group in the aldol (57) reaction with an alkyl-lithium reagent (Grignard reagents are unsuitable) and oxidation affords the erythro-P-hydroxy ketone (59)in high yield.It is to be noted that this sequence not only accomplishes the stereospecific synthesis of aldols derived from a wide range of simple ketones but also allows the preparation of regiospecific aldols. Thus (59) is the aldol from specific attack on 3-heptanone at (2-2. Remarkable examples of mutual kinetic resolution in reactions of racemic chiral a-(trimethylsily1oxy)ketonessuch as (60)with racemic chiral aldehydes have been recorded.54Thus reaction of (60) with isobutyraldehyde gave a mixture of two 52 C. H. Heathcock C. T. Buse W. A. Kleschick M. C. Pirrung J. E. Sohn and J. Lampe J. Org. Chem.1980,45,1066. ” C. T. White and C. H. Heathcock J. Ore. Chem. 1981,46 191. 54 C. H. Heathcock M. C. Pirrung J. Lampe C. T. Buse and S. D. Young J. Org. Chem. 1981 46 2290; see also C. H. Heathcock C. T. White J. J. Morrison and D. Van Derveer J. Org. Chem. 1981,46,1296. Synthetic Methods 7+Me OSiMe (60) (61) erythro-aldols in the ratio 3 :1 the main component of which is believed to be (61); higher ratios were obtained with some other aldehydes. With racemic a-phenylpropionaldehyde a single racemic aldol (62) was formed and on oxidation with periodic acid afforded the racemic acid (63) which was at least 98% diastereomerically pure; the other erythro-diastereomer (64) was not detected (Scheme 25). The diastereoface selection shown by phenylpropionaldehyde in this reaction is >40 :1.Several other chiral aldehydes showed similar high diastereoface selectivity in reactions with (60) and related ketones. OSiMe Me Me OSiMe Ph CHO OH Me PhbC Me 0 H (62)liphJgc02H OH OH (64) (63) Reagent i H,IO,-MeOH Scheme 25 It has previously been shown that reaction of crotyl bromide with aldehydes in the presence of chromous ion provides the threo- condensation products very selec- tively. The threo-acids are then available by cleavage of the double bond (Scheme 26).55But the reaction seemed to be less attractive for control of the stereochemistry of three adjacent positions by reaction with a chiral aldehyde. Nevertheless it has now been found4' in work on the synthesis of rifamycin S' that reaction of either cis- or trans-crotyl iodide with the aldehyde (65) gave the threo-product (66)with a selectivity of >20 1.Manipulation of the functional groups of (66) led to (67) which again reacted with crotyl iodide in the presence of chromous chloride to give the threo-product (68) with high selectivity. threo-cis- Products are also formed predominantly by reaction of a-silyl- or a-stannyl-crotyl-9-borabicyclo[3,3,l]nonanewith aldehydes in the presence of certain bases (pyridine n-butyl-lithium or s-butyl-lithi~m).~~ Further elaboration 55 Y. Okude S. Hirano T. Hiyama and H. Nozaki J. Am. Chem. Soc. 1977,99,3179;T.Hiyama K. Kimura and H. Nozaki Tetrahedron Lett. 1981,22,1037; C.T.Buse and C. H. Heathcock Tetrahedron Lett.1978 1685. 56 Y. Yamamoto H. Yatagi and K. Maruyama J. Am. Chem. SOC., 1981,103 3229. 316 W.Carruthers OH RCHO + BrL R& Me Me Me Hfn Ox0 Me ButPh,SiO $ -vi Bu'Ph,SiO H t OH OX0 (68) (67) Reagents i CrC1,-THF 25 "C; ii 0,;iii H,O,-NaHCO,; iv V B r -CrC12-THF 25 "C; v several steps; vi -1 -CrC12-THF 25 "C Scheme 26 of the cis-alkenyl-silanes or -stannanes thus obtained offers the possibility of stereoselective formation of four contiguous chiral centres (Scheme 27). Me R Me //11-1v WH20H OH M HO -.LRw Y4 Me M = SiMe3or SnMe3 Rwe OH Reagents i RCHO-pyridine; ii BuLi; iii CH,O; iv m-ClC,H,CO,H; v Me1 Scheme 27 Fluoride ion-catalysed reaFtion of silylated aci-nitro derivatives (69) with aldehydes also leads almost exclusively to the threo-diastereomer (70) [Heathcock's nomenclature is used here for consistency; the authors call (70)the erythro-is~mer].~' Catalytic reduction with hydrogen and Raney nickel and desilyla- tion affords the corresponding p-amino-alcohols (Scheme 28).The preferential '' D. Seebach A. K. Beck F. Lehr T. Weller and E. Colvin Angew. Chem. In?.Ed. Engf. 1981,20 397. Synthetic Methods Reagents i R'CHO; ii Bu,NF-THF; iii H,-Ni Scheme 28 formation of one diastereomer here is consistent with the mechanism suggested for the normal aldol reaction. 5 Alkylation Ally1 chlorides are readily converted into their anions with lithium di-isopropyl- amide. These anions are alkylated exclusively at the a-position affording syntheti- cally useful secondary ally1 chlorides in high yield." The enantioselective alkylation of carboxylic acids and ketones has been extensively studied by Meyers and his co-workers and a full account has now been published of their work on the alkylation of cyclic ketones with the aid of chiral metalloenamines.s9 Chiral imines (S)-(72) are readily prepared from cyclic ketones and the chiral methoxyamine (S)-(71).Metalation and alkylation followed by hydrolysis of the imine leads to the 2-alkylcycloalkanones (74)with enantiomeric purities in the range 87-100% (Scheme 29). The chelating effect of the methoxy-group in the intermediate lithio-derivative (73) is crucial to the stereoselectivity achieved. Reagents i cyclohexanone;ii LiN(Pri)2-THF,-20 "C;iii RHal -78 "C;iv H,O' Scheme 29 T.L. MacDonald. B. A. Narayanan and D. E. O'Dell J. Org. Chem. 1981,46,1504. 59 A. I. Meyers D. R. Williams G. W. Erickson S. White and M. Druelinger J. Am. Chem. Soc. 1981,103,3081. 318 W.Carruthers The reaction has been extended to the enantioselective synthesis of a-alkyl macrocyclic and acyclic ketones. Here complications arise because of the possibility of (E)-(2)isomerism in the intermediate lithio-derivatives related to (73). (E)-(Z)-Isomerism does indeed occur but can be exploited to prepare the two enantiomers of the alkylated ketones at will with moderate to excellent isomeric purity.60 Thus metallation and alkylation of chiral imines derived from Cl0 CI2,and C, cyclic ketones gave under kinetic metalation conditions 2-alkylcycloalkanones of absolute configuration opposite to that obtained from thermodynamic metalation.(S)-2-Methylcyclododecanone for example is obtained from cyclododecanone in 60% enantiomeric excess under kinetic conditions whereas the (R)-isomer is reached in 80% enantiomeric excess under thermodynamic control. In a similar fashion acyclic ketones are alkylated enantioselectively via chiral imines such as (79 under both kinetic and thermodynamic conditions. Kinetic metalation of (75) gives exclusively the (2)-lithioenamine (76) converted exclusively into the (E)-isomer on refluxing the solution. Chiral a-alkylated derivatives were obtained in 18-97% enantiomeric excess from a selection of open-chain ketones (Scheme 30).Chiral a-alkylation of carboxylic acids can be effected by way of enolates (E -76) (75) (Z-76) \ iii iv /iii iv Reagents i LiN(Pr'),-THF -30 "C; ii reflux; iii MeI-THF -78 "C; iv H20 Scheme 30 derived from chiral amides.61 In another procedure esters derived from the asym- metric alcohols [(77)-(79)] are used.62 a-Alkylation of the lithium enolates pro- ceeds in very good yields with excellent diastereoselection. The sulphonamides (77b)-(79b) show particularly remarkable properties. Products with inverse configuration are obtained with almost complete asymmetric induction using either tetrahydrofuran or tetrahydrofuran-hexamethylphosphoramide(4 :1) as solvent. Purification of the alkylated esters by chromatography and reduction with lithium aluminium hydride then gives the enantiomerically pure alcohols R'R2CHCH20H in excellent yield.6o A. I. Meyers D. R. Williams S. White and G. W. Erickson J.'Arn.Chern. Soc. 1981 103 3088. D. A. Evans J. M. Takas L. R. McGee M. D. Ennis D. J. Mathre and J. Bartroli Pure Appl. Chem. 1981,53,1109. 62 R. Schmierer G. Grotemeier G. Helmchen and A. Selim Angew. Chem. Int. Ed. Engl. 1981,20,207. Synthetic Methods OR (77) (79) Ph (a) X = -0CON / 'Me Me Scheme 31 ap-Unsaturated acids are alkylated at the y-position by reaction of the copper enolates with ally1 halides but alkyl halides react only sluggishly with little prefer- ence for the y-carbon. Best results are obtained with vinylic epoxides.They undergo allylic transposition and react at the y-carbon of the dienolate with high selectivity to form 1,Sdienes with an oxygenated functional group at each end (Scheme 32).63 Mel + " O Me n COzH Me COZH HO) 86% of product 14%of product Reagents i LiN(Pr'),-THF -78 OC -P 0OC; ii CuJ, -78 "C; iii -0 Scheme 32 Further work has been reported on the specific alkylation of @-unsaturated ketones. Earlier studies had shown that 0-silylated dienolates are useful intermedi- ates for the y-substitution of cup-unsaturated carbonyl although the ya-ratio of alkylation was sensitive to both substrate substitution pattern and the nature of the electrophile. It is now found that a suitably chosen silyl group makes it possible to obtain a high degree of y-alkylation of any enone that can be converted into a linearly conjugated silyl dienol ether.65 1,3-Dithienium fluoroborate gave a high degree of y-alkylation in reaction with a range of 0-trimethylsilylated dieno- lates.66a 0-Trimethylsilyl enolates of aldehydes ketones esters and lactones also can be regiospecifically alkylated by 1,3-dithienium fluoroborate to give a selectively protected P-dicarbonyl compound.The 1,3-dithiane substituent may be hydrolysed to a formyl group or desulphurized to a methyl group.66b " P. M. Savu and J. A. Katzenellenbogen,J. Org. Chem. 1981,46 239. 64 I. Fleming J. Goldhill and I. Paterson Tetrahedron Letr. 1979 3205,3209. " I. Fleming and T. V. Lee Tetrahedron Lett. 1981,22 705. " (a)I. Paterson and L. G. Price Tetrahedron Lett.1981,22 2833;(b)I. Paterson and L. G. Grice ibid. 1981,22 2829. 320 W. Carruthers 0 OSiMe 8. . .. 5oo RQ Reagents i LiN(Pr'),-THF -78 "C; ii Me3SiC1; iii RLi or RMgBr; iv H30'; v R,CuLi Scheme 33 Particular interest attaches to methods for the specific alkylation of cyclo- hexenones. 2-and 6-alkylcyclohexenones and cyclopentenones can be obtained from the corresponding ap-epoxycycloalkanone by reaction of the derived trimethylsilyl enol ethers with an organolithium or Grignard reagent or by allylic attack on the epoxide by a cuprate reagent (Scheme 33).67 A new route to 3- substituted cyclohexenones proceeds from cyclohexane-1,3-diones by reaction of the derived 3-mesyloxy-cyclohex-2-enonewith a nucleophile.68 They are also conveniently obtained from 3-bromocyclohexenones by lithiation of the corre- sponding ethylene ketals with two equivalents of butyl-lithium and reaction of the bis-lithio-derivative with alkylating agent.69 The synthetically awkward 5-substituted cyclohexenones can be prepared from tricarbonyl(3-methoxycyclohexa-2,4-dien-l-yl)iron(l') (80) which in these reactions is equivalent to the 5-cyclohex-2-enone cation (81)." It reacts with various nucleophiles to give 5-substituted cyclohex-2-enones in good yield after removal of the iron tricarbonyl (Scheme 34).OMe OMe OMe 6. (81) Reagents i Nu e.g. WSiMe ;ii Jones reagent or pyridinium chlorochromate Scheme 34 " P.A. Wendler J. M.Erhardt and L. J. Letendre J. Am. Chem. SOC.,1981,103,2114.68 C. J. Kowalski and K. W. Fields J. Org. Chem. 1981,46 197. 69 C. Shih and J. S. Swenton Tetrahedron Lett. 1981,22,4217. 70 L. F. Kelly P.Dahler A. S.Narula and A. J. Birch Tetrahedron Lett. 1981 22 1433. Synthetic Methods The palladium(0)-catalysed alkylation of allylic substrates by nucleophiles has been widely developed (review7') and frequently provides complementary selec- tivity to standard methods (see below). A mechanism which invokes the functional equivalent of a .rr-allylpalladium cationic complex has been put forward71 and questioned,'* but further evidence in support has now been adduced.73 Palladium- catalysed alkylation of allylic substrates by carbon nucleophiles has usually been considered to be restricted to anions derived from carbon acids of pK < 20.Among the conjugate bases of acids of pK > 20 the enolate of acetophenone was the only one reported to alkylate ally1 acetate. Conditions have now been found under which ketone enolates are efficient nucleophiles in this reaction (Scheme 35).74 Lithium enolates of 2-pentanone cyclohexanone acetophenone and mesityl oxide reacted with representative allylic acetates in the presence of a Pd(0) catalyst to form the allylic displacement products in good yield and with retention of configuration. qoAc qH2C0Me ~ Ph Ph OLi I Reagent i CH,-C=CH,-Pd(dba),dppe-THF -78 "C +20 "C Scheme 35 Continuing his earlier extensive work Trost now that 1,3-diesters P-keto esters P-keto sulphides and P-sulphonyl esters are readily converted into allylic alcohols under neutral conditions by alkylation with ap-unsaturated epoxides (vinyl epoxides) in the presence of palladium(0) catalysts.The reactions proceed with attack from the same face as the oxygen of the epoxide group so that epoxide (83) for example gives cleanly the cyclohexenol (84) whereas direct substitution under standard base-catalysed conditions leads with inversion to (82); (Scheme 36). (84) Reagents i 5 mol % Pd(PPh,),-THF; ii NaCH(CO,Et),-EtOH; iii CH2(C02Et),-Pd(PPhJ4-THF Scheme 36 71 B. M. Trost Acc. Chem. Res. 1980,13 385. 'I2 J. C. Fiaud and J.-L. Malleron TerruhedronLett.,1981 22 1399. " B. M. Trost and N. R.Schmuff Tetrahedron Lett. 1981,22,2999. 'I4 J. C. Fiaud and J.-L. Malleron J. Chem.SOC.,Chem. Commun.,1981 1159. 75 B. M. Trost and G. A. Molander J. Am. Chem. SOC.,1981,103,5969. 322 W. Carruthers 6 Annelation There is considerable interest in the development of methods for the construction and annelation of five-membered rings. A novel method for the stereoselective synthesis of cyclopentenols from 1,3-dienes which may also be used for annelation exploits the rearrangement of 2-vinylcyclopropanols.76Formation of cyclopentene derivatives by rearrangement of vinylcyclopropanes although frequently used suffers from some disadvantages occasioned by the high temperatures required. It has recently been however that the lithium salts of 2-vinylcyclopropanols undergo greatly accelerated rearrangements in high yield at only 25 "C.It is now found that the alkoxy-accelerated rearrangements generally proceed with high stereoselectivity thus providing a stereoselective method for conversion of 1,3-dienes into cyclopentene derivatives as shown in Scheme 37.Stereospecific syn-addition of (2-ch1oroethoxy)carbene to 1,3-dienes produces mixtures of vinyl- cyclopropanes (85a) and (85b). Exposure of these to butyl-lithium then effects the (85) a; X' = H X2 = OCH2CH2Cl b; X' = OCHZCH2C1 X2 = H [74%] [73%] Reagents i [:CHOCH,CH,Cl]; ii Bu"Li Scheme 37 cleavage and rearrangement of the resulting salts in one step. The intermediate syn-and anti-2- vinylcyclopropanol salts rearrange by topologically different path- ways to afford in most cases a single cyclopentenol. A conceptually related approach leads to bicyclo[4,3,0]-5-nonenonesby pyrolytic rearrangement of vinyl- cyclopropane derivatives obtained by intramolecular addition of an a-ketocarbene to a 1,3-diene Another route to cyclopentenones and cyclohexenones proceeds by rearrangement of 2-vinylcyclobutanones.79In the presence of acid 2-alkyl-2-vinylcyclobutanonesrearrange mainly by a 1,2-acyl migration to give cyclopentenones.2-Vinylcyclobutanones lacking a 2-alkyl substituent how'ever undergo a 1,3-acyl migration to give cyclohexenones (Scheme 38). The rearrange- '' R. L. Danheiser C. Martinez-Davila R. J. Auchus and J. T. Kadonaga J. Am. Chem. SOC.,1981 103,2443. '' R. L. Danheiser C. Martinez-Davila and J. M. Morin J. Org. Chem. 1980 45 1340. '* T. Hudlicky F. J.Koszyk D. M. Dochwat and G. L. Cantrell J. Org. Chem. 1981,46,2911. 79 J. R. Matz and T. Cohen Tetrahedron Letr. 1981 22 2459. Synthetic Methods 0 (J+ OTI Q-u OH O-H + 0 0 [65%] Reagent i MeS0,H-P,O Scheme 38 ments are not completely exclusive except in the case of spirocyclobutanones where 1,3-migration would violate Bredt's rule; here fused cyclopentenone derivatives are formed exclusively. The required vinylcyclobutanones are conveniently obtained from ketones.80 A novel [3 + 21 approach to cyclopentane derivatives by addition of trimethyl- silylallenes to a@-unsaturated ketones in the presence oftitanium tetrachloride seems useful provided the required allenes are readily accessible (Scheme 39).81The reaction involves initial complexation of the a@-unsaturated ketone and titanium \ R' (86) (87) Reagent i TiC1,-CH,Cl, -78 "C Scheme 39 tetrachloride to generate an alkoxyallylic carbocation.Regiospecific electrophilic substitution of this cation at C-3 of the allene provides a vinyl cation stabilized by interaction with the adjacent C-Si bond. A 1,2-shift of the trimethylsilyl group then affords an isomeric vinyl cation which is intercepted by the titanium enolate to produce a five-membered ring. Cyclic acylic and a@-unsaturated ketones all T. Cohen and J. R. Matz Tetrahedron Lett. 1981 22 2455. R. L. Danheiser D. J. Carini and A. Basak J. Am. Chem. Soc. 1981 103,1604. 324 W. Carruthers participate in the reaction and a-methylene ketones form spiro-compounds.Only some heavily substituted enones failed to react. Annelation of trans-3-penten-2-one and carvone afforded stereoselectively the derivatives (87) and (88). 4aSi,, S0,Ph (90) S02Ph (89) 1 ii Cb S02Ph Reagents i KH-DME; ii Bu,NF-THF Scheme 40 The allylsilane (90) is an excellent alkylating agent towards anions of P-keto sulphones and sulphides but gives only poor yields of alkylated products with thermally unstable enolates. With thermally stable nucleophiles such as the anion from (89) excellent yields of the desired alkylation products are obtained and can be cyclized to cyclopentane derivatives (Scheme 40).82In continuation of earlier work on the cycloaddition reactions of trimethylenemethanepalladium complexes it is now shown in studies on the regiochemistry of the addition that the two derivatives (91)and (92) both react with cyclopentenone to form the same annelated product (93).82a 1-Phenylthio- 1-methylthio- and l-isopropylthio-cyclopropyl-phosphonium fluoroborates (94) have been used as synthetic equivalents of the cyclopropanone zwitterion (95).They react with anions of p-keto esters to form vinyl In sulphides which can be hydrolysed to cyclopentanone deri~atives.~~ a OH xe3 & ‘ I ’ PdL Me3sz H MePdL2 ns$3BF4 rP (91) (92) (93) (94) (95) Scheme 41 different approach cyclopentanone annelation has been effected by reaction of [a-(carbethoxy)vinyl]cuprates with a& unsaturated acid chlorides followed by Nazarov cyclization of the a,a’-dienones produced (Scheme 42).84 m2 B.M.Trost and D. P. Curran Tetrahedron Lett. 1981.22 5023. B.M. Trost and D. M. T. Chan J. Am. Chem.,Soc.,1981,103,5972. R3 J. P.Marino and M.P. Ferro J. Org. Chem. 1981,46,1828. “ J. f.Marino and R.L. Linderman J. Org. Chem. 1981,46 3696. Synthetic Methods li 0 R Reagent i SnC1,-CH,CI, 25 "C Scheme 42 7 Cyclization Reactions Although many known methods of spirocyclization involve intramolecular alkyla- tion there has been need for an operationally simple procedure which avoids the use of a strong base. Such a procedure has now been found in the regiospecific intramolecular alkylation of enolates generated in situ by halide-induced non- hydrolytic decarbalkoxylation of w-halogeno-& keto esters (Scheme 43).The reac- tion has been applied in new syntheses of P-vetivone and P-veti~pirene.~~ A novel 0 n = 1 m = l,64%; n = 3; m = 3,70y0 Reagent LiCI-HMPA 125-140 "C Scheme 43 route to macrocyclic ketones by intramolecular alkylation of protected cyanohydrins has been reported.86 The necessary carbanion is generated with sodium hexamethyl- disilazane and under the conditions employed cyclization is rapid and irreversible so that high dilution conditions are unnecessary. Subsequent mild treatment of the cyclized product with acid and base affords the macrocyclic ketones in good yield. The sequence has been applied to the synthesis of 2-cyclopentadecenone (96) a precursor of muscone and exaltone and the macrolides (f)-zearalenone8' and dihydroxy-trans- resorcylide.88 A synthetically useful alternative to base-catalysed intramolecular t-alkylation of ketones is provided by the stannic chloride-catalysed intramolecular reaction of a double bond with the appropriate p-keto ester or P-diket~ne.'~ Reaction plausibly 13' R.G. Eilerman and B. J. Willis J. Chem. SOC.,Chem. Commun. 1981 30. 86 T.Takahashi T. Nagashima and J. Tsuji Tetrahedron Lett. 1981 22 1359. " T. Takahashi; H. Ikeda and J. Tsuji Tetrahedron Lett. 1981,22 1363. T. Takahashi I. Minami and J. Tsuji Tetrahedron Lett. 1981 22 2651. I. Chatzuosifidis and K. Schwellnus,Angew. Chem. Int. Ed. En& 1981,20,687. 326 W.Carruthers I ii iii + __* R = a-ethoxyethyl Reagents i Hexamethyldisilazane-THF 40 "C;ii 3 N-HCl; iii 5% NaOH Scheme 44 takes place by 0-stannylation of the enolized form of the carbonyl compound; protonation of the olefinic bond is then followed by cyclization of the cation (Scheme 45).1 Reagents i SnC1,-CH,Cl, 0 "C; ii LiI-collidine Scheme 45 To date the carbonyl anion equivalence of the 1,3-dithian function has not been realised in intramolecular additions to carbonyl compounds (aldol or Michael reactions). Any base strong enough to deprotonate a dithian can also react with the carbonyl group either as a base or as a nucleophile. A way round this difficulty has now been found by liberation of the required dithianyl carbanion from the corresponding 2-trimethylsilyl dithian by treatment with fluoride The intramolecular aldol(97) -+ (98) and Michael (99) -+ (100)reactions were effected thus in good yield (Scheme 46).Cationic olefin cyclizations continue to provide access to various ring systems. The high synthetic potential of the cyclization of a-acyliminium ions is again shown in the quantitative conversion of the hydroxylactam (101) into a single stereoisomer of (102) on treatment with hydrogen chloride in methanol. The usual reagent formic acid gave only poor yields in this case. Dehydrochlorination of (102) and reduction of the carbonyl group gave the elaeocarpus alkaloid elaeokanine B 9" D. B. Grotjahn and N. H. Andersen J. Chem. Soc. Chem. Commun. 1981,306. Synthetic Methods OH to ( 100) Reagent i Bu,NF-THF Scheme 46 ( 103).91The vinylogous N-acyliminium ion cyclization (104) -B (105) formed the key step in a synthesis of depentylperhydrogephyr~toxin.~~ The occurrence of an aza-Cope rearrangement accompanying the cyclization of the acyliminium ion (106) was detected by using triethylsilane as an acyliminium ion trap.93 Reagents i HCI-MeOH; ii HC0,H-CH,CI, 0 "C Scheme 47 A promising new method of cyclization involving addition of a vinyl anion generated from a vinylsilane to an iminium ion was used in an elegant chiral synthesis (Scheme 48) of the poison-arrow dendrobatid toxin 251D (107).94 91 B.P.Wijnberg and W. N. Speckamp Tetrahedron Lett. 1981,22 5079. 92 D.J. Hart J. Urg. Chem. 1981,46 367. 93 D.J. Hart and Y.-M. Tsai Tetrahedron Lett. 1981,22 1567. 94 L.E.Overman and K.L. Bell. J. Am. Chem. SOC.,1981,103 1851. 328 W.Carruthers :OH L OH Me (107) Reagents i HCHO-EtOH; ii d-10-camphorsulphonic acid Scheme 48 Intramolecular nucleophilic termination during mercuric ion-initiated diene cyc- lizations has been st~died.~' Carboxylic acids ketones and alcohols are effective trapping nucleophiles leading to lactones cyclic enol ethers and saturated ethers respectively. Intramolecular capture by nitrogen was exploited in a synthesis of trans-2,5-dimethylpyrr01idine~~ (Scheme 49). TFAHg Reagents i Hg(OCOCF,),-MeNO,; ii NaBH,; iii Hg(OAc),-THF; iv HCI-HOAc Scheme 49 Unsaturated substrates carrying internal nucleophiles (NuX = C02H OH SH SAC NHCO,Et or CH2SnMe2) also react smoothly with certain organoselenium reagents to afford cyclic systems according to Scheme 50.These reactions have been re~iewed.~' Selenium can be removed from the initial cyclization products by oxidation and elimination of selenoxide or by reduction to give respectively an unsaturated product or a saturated one and the sequence can be used to prepare 95 T. R. Hoye A. J. Caruso and M. J. Kurth J. Org. Chem. 1981,46,3550. 96 K. E. Harding and S.R. Burks J. Org. Chem. 1981,46,3920. 97 K. C. Nicolaou Tetrahedron 1981 37 4097. Synthetic Methods Reagent i PhSe' Scheme 50 lactones ethers thioethers nitrogen heterocycles and carbocycles (Scheme 5 1). N-Phenylselenophthalimide and N-phenylselenosuccinimide are excellent new reagents for the oxyselenation of olefins and a unique feature is their ability to SePh Reagents i PhSeCl-CH,Cl, -78 "C;ii H,-Raney Ni or Bu,SnH; iii H20z-THF Scheme 51 induce macrolide formation from long-chain unsaturated acids9' at room tem- perature.It is known that alkenyl-substituted p-dicarbonyl compounds can be cyclized by certain selenating agents to give cyclic p-keto esters or cyclic enol ethers the products of the reactions depending on the reaction conditions. It is now found that it is possible to effect similar cyclizations via a rearrangement of alkenyl-substituted a-phenylseleno-p- keto esters in the presence of acidic catalysts.98 In general cyclization to the enol ether is effected by reaction under kinetic conditions with toluenesulphonic acid; cyclization to the p-keto ester is favoured by strong Lewis acids (e.g.SnC14) and longer reaction times. At least one other example of the migration of the phenylseleno-group during a cyclization reaction has been recorded.99 A particularly challenging problem in the synthesis of polyether antibiotics is presented by the need for stereocontrolled construction of the tetrahydrofuran units found in many of these natural products particularly those units in which there is a cis-relationship between substituents at C-2 and C-5. An attractive method for the formation of substituted tetrahydrofurans is electrophilic cyclization of yS-unsaturated alcohols but trans- isomers are usually favoured in this reaction. This difficulty has now been cleverly circumvented by exploiting the two transient trans- 1,2-relationships in the cyclization of olefinic ethers (Scheme 52).loo In 9a W.P. Jackson S. V. Ley and J. A. Morton Tetrahedron Lett. 1981 22 2601. 99 T. Kametani H. Kurobe and H. Nemoto J. Chem. SOC.,Perkin Trans. 1,1981 756. loo S. D. Rychnovsky and P. A. Bartlett J. Am. Chem. SOC.,1981 103,3963. 330 W. Carruthers /-{ Rt/yERIQJs I E Rl minor 0 R'&E R1oE I major R Scheme 52 practice cyclization of y6-olefinic ethers with iodine was found to provide a general highly stereoselective route to cis-2,s-disubstituted tetrahydrofurans. Best results were obtained with the 2,6-dichlorobenzyl ethers. 2,2,5-Trisubstituted tetrahy- drofurans which also appear as subunits in many polyether ionophores are also accessible by this route.cis-Linalyl oxide (109) for example was obtained as the main product on cyclization of the benzyl ether acetate (108) followed by elimination and ester hydrolysis. The corresponding diol gave the trans-isomer on cyclization. \4 21 1 CI Reagents i I,-CH,CN; ii KOBu'; iii -OH Scheme 53 The acid-catalysed decomposition of a-diazoketones with subsequent intramolecular cyclization of the electrophilic species produced has come into prominence recently in the synthesis of polycyclic natural products. A review has been published"' covering the formation of cyclic ketones by acid-promoted decomposition of a-diazoketones in the presence of suitably placed heteroatoms benzene rings or olefinic double bonds.Thus a cyclization of the type (110) -+ (111) was the cornerstone of Mander's elegant synthesis of (*)-gibberellin A1 and gibberellic acid"* and more recently acid-catalysed cyclization of the diazoketone (112) to the tricyclic (113)was used in an approach to the ring A. B. Smith 111and R. K.Dieter Tetrahedron 1981 37,2407. lo* L. Lombardo L. N. Mander and J. V. Turner J. Am.Chem. SOC.,1980,102,6626. Synthetic Methods Reagent i CF,CO,H-CH,Cl, -20 "C Scheme 54 system of aphidicolin and related natural products (Scheme 54).'03 Spiro-compounds have also been made as exemplified in a synthesis of (f)-solavetivone.104 In the presence of suitably placed double bonds intramolecular cationic cyclizations may take place (Scheme 55). With Py-unsaturated diazoketones cyclopentenones [44%] [18°/o] (118) Reagents i BF,.Et20-CH2CI,; ii BF,.Et,O-MeNO, 0-5 "C Scheme 55 K.C. Nicolaou and R. E. Zipkin Angew. Chem. Inf.Ed. Eng. 1981,20,785. lo' C. Iwata T. Fusaka T. Fujiwara K. Tomita and M. Yamada J. Chem. Soc. Chem. Commun.. 1981 463. 332 W.Carruthers are formed'05 and with highly nucleophilic double bonds the initial cyclization may be followed by attack on another suitably placed olefinic bond or benzene ring. Compound (114; R = Me) for example was converted into (115) stereoselec-tively in 31% yield but (114; R = H) did not afford a tricyclic product; instead the benzocycloheptanone (116) was obtained.lo6 With the diazoketone (117) and some analogues Lewis acid-catalysed decomposition gave tricyclic products [for example (118)] with cis-ring junctions exclusively attributed to a stepwise cyclization involving initial complexation of the Lewis acid with the oxygen of the diazoketone.lo' Electrocyclic ring-opening of bromocyclopropane derivatives containing internal nucleophilic hydroxy- and carboxy-groups provides a new route to vinyl lactones tetrahydropyrans and tetrahydrofuranslo8 (Scheme 56). Reaction is brought about by warming the substrate in a non-nucleophilic polar solvent such as trifluoroethanol for the more substituted systems or in other cases by treatment with silver(1) or mercury (11) salts. Various methods are available for the stereoselective synthesis of the required cyclopropanes. CO,H HO 0 Reagents i AgOCOCF,-CF,CH20H 25 OC; ii AgOAc-CF,CH,OH Scheme 56 Dreiding has applied his a-alkynone cyclization reaction as the key step (119) + (121) in a synthesis of the sesquiterpene (*)-modhephene (Scheme 57).lo9The preferred formation of the propellane (121) in this reaction shows that the insertion of the postulated alkylidene carbene intermediate (120) into the tertiary ring C-H bond takes preference over insertion into the secondary C-H bonds.Me (1 19) Reagent i 620 "C [95'/0] Scheme 57 H. C. Brown's 'stitching and rivetting with boron' has not so far been widely used in the synthesis of cyclic compounds but recent examples (Scheme 58) lo' A. B. Smith 111 B. H. Toder S. J. Branca and R. K. Dieter J. Am. Chem. Soc. 1981,103,1996. A.B. Smith 111and R. K.Dieter J. Am. Chem. SOC.,1981,103,2009. lo' A. B. Smith I11 and R. K.Dieter .I. Am. Chem. Soc. 1981,103,2017. lo' R. L. Danheiser J. M. Morin M. Yu,and A. Basak Tetrahedron Lett. 1981 22,4205. log M. Karpf and A. S. Dreiding Helv. Chim. Acta 1981.64 1123. Synthetic Methods 0 i-iii iv-vi;iii ~~3 d p-p Cbz Cbz Reagents i BH,-THF; ii CO;iii H,O,-NaOH; iv H-BH ;v KCN; vi (CF,CO),O Scheme 58 underline its potentialities. Thus hydroboration of the triene (122) followed by carbonylation with carbon monoxide under pressure and oxidation with alkaline hydrogen peroxide afforded the carbinol(l23) as a mixture of isomers.11o A better example is provided by the formation of the ketone (125) from the N-allyl-N-(3- buteny1)amine (124) in 33% yield using the Pelter carbonylation technique."' An interesting synthesis of spermidine alkaloids by boron-templated cyclization of appropriate open-chain precursors has been reported."* In a model sequence the amino-ester (126) was converted into the thirteen-membered lactam (128) in 77% yield by treatment with tris(dimethy1amino)boranein boiling xylene presum- ably by way of the intermediates (127) and (129).Reagent i B(NMe,),-xylene reflux Scheme 59 8 The Diels-Alder Reaction The Diels-Alder reaction remains one of the most widely used reactions in organic synthesis and there have been many examples of its application during the past year but other aspects of the reaction have not been overlooked. 'lo C. F.Reichert W. E. Pye. andT. A. Bryson Tetrahedron 1981,37,2441. 'I' M. E. Garst and J. N. Bonfiglio Tetreedron Lett. 1981 22 2075. '12 H. Yamamoto and K. Maruoka J. Am. Chem. Soc. 1981,103,6133. 334 W. Canuthers Addition of unsymmetrical electron-rich dienes to methoxybenzoquinones or naphthoquinones gives adducts in which the more nucleophilic diene terminus becomes bonded to the non-methoxylated carbon and this observation has led to the generalization that electron-donating substituents deactivate alkenes toward attack by nucleophilic cycloaddends and direct attack to the carbon remote from the sub~tituent."~ This generalization is contrary to predictions based purely on alkene LUMO coefficients and the results are not what would be expected from arguments based on classical resonance theory.A rationale has been ~ffered."~ It is well known that Lewis acids can enhance the reactivity of some dienophiles containing oxygen-bearing functional groups. It is now shown usefully that Diels- Alder reactions involving neutral or electron-rich dienophiles may be catalysed by the stable radical cation salt tris( p-bromopheny1)aminium hexachlorostibnate. Thus the Diels-Alder dimerization of cyclohexa- 1,3-diene has been effected in 30% yield after 20 hours at 200°C. In the presence of the radical cation the dimerization occurs in 70% yield within fifteen minutes at 0 OC.ll' Asymmetric induction during Diels-Alder additions to chiral acrylates has been reinvesti- gated."6 Chiral induction in the conversion (130) -P (131) varied between 47- 93% in favour of the 2-(R)-adducts depending on the auxiliary chiral group and the Lewis acid catalyst (Scheme 60).Stannic chloride and titanium tetrachloride gave the highest enantiomeric excess of the (R)-isomer. In all cases the phenylmen- thy1 group (130; R = C6H5) induced chirality more efficiently than the menthyl group itself although the differences were not so great as in an earlier study of an ene cyclization catalysed by Me2A1C1."' Apparently the first example of control of the orientation of addition in a Diels-Alder reaction by a Lewis acid catalyst was encountered in a step in a synthesis of a-and P-himachelene."* Reagent i cyclopentadiene-Lewis acid Scheme 60 2-(Pheny1thio)cyclopentenone is the synthetic equivalent of cyclopentynone in the Diels-Alder reaction.It reacts readily with substituted butadienes to give adducts which are readily converted into dihydro- 1-indanones by elimination from '13 I.-M. Tegmo-Larsson. M.D. Rozeboom and K. N. Houk. Tetrahedron Lert.. 1981,22,2043. IM I.-M. Tegmo-Larsson M. D. Rozeboom N. G. Rondan and K. N. Houk Tetrahedron Lett. 1981 22,2047. '15 D.J. Belleville D. D. Wirth and N. L. Bauld J. Am. Chem. Soc. 1981,103,718. '16 W.Oppolzer M. Kurth D. Reichlin and F. Moffatt Tetrahedron Lett. 1981 22 2545; G.Helmchen and R. Schmierer Angew. Chem. Int. Ed. Engl. 1981,20,205. 11' W. Oppolzer C. Robbiani and K. Battig Helu. Chim. Acta 1980,63 2015. H.-J. Liu and E. N. C. Browne Can. J. Chem. 1981,59,601. Synthetic Methods 335 the sulphoxide.'19 In Diels-Alder reactions with 3-nitrocycloalkenones the direction of addition is controlled by the nitro-group. Removal of the nitro-group from the adduct gives an ap-unsaturated ketone formed in effect by Diels-Alder addition of an alkynone to the diene (Scheme 61).l2' trans- l-Benzenesulphonyl-2- (trimethylsilyl)ethyleneis another useful acetylene equivalent in the Diels-Alder 0 0 YOsiMe3 + ii iii 1,,,+ i rnSiMe3 -Reagents i toluene 110"C 20h; ii 0.05 N-HCl; iii 1,5-diazabicyclo[4,3,0] non-5-ene-THF. 0 "C. Scheme 61 reaction since treatment of the initial adducts with tetrabutylammonium fluoride leads to elimination of the trimethylsilyl and benzenesulphonyl residues.12' Alkyla- tion of the a-sulphonyl carbanion can be effected before elimination so that the reagent can also be considered as the equivalent of a monosubstituted alkyne dienophile.Again the allenic dienophile (132) has been used as the equivalent of the carbalkoxyketene (134). With furan it gives the adduct (133) used in a synthesis of the antibiotic C-nucleoside dl-showdomycin (135).'22 C0,Et EtO,C-CH=C=CH-CO,Et -h bo2Et 0 Reagent i furan-benzene-AlC13 room temperature Scheme 62 The synthetic value of Diels-Alder reactions involving 1-acylaminobutadienes has been demonstrated recently in the synthesis of several complex nitrogenous natural products including dl-perhydrogephyr~toxin'~~ and dZ-isogabaculine.'24 '19 S.Knapp R. Lis and P. Michna J. Org. Chem. 1981,46,624.E. J. Corey and H. Estreicher Tetrahedron Lett. 1981 22 603. 12' L.A.Paquette and R. V. Williams Tetrahedron Lett. 1981,22,4643. lZ2 A.P.Kozikowsky and A. Ames J. Am. Chem. Soc. 1981,103,3923. lZ3 L.E.Overman and C. Fukaya J. Am. Chem. Soc. 1980,102,1454. lZ4 S.Danishefsky and F. M. Hershenson J. Org. Chem. 1979,44 1180. 336 W. Carruthers Overman and his co-workers have now given details of their pioneering work on this reaction and give a survey of the reactions of eight l-(acylamino)-1,3-dienes with thirteen varied dien0phi1es.l~~ The reactions provide convenient access to diversely substituted amino-cyclohexanes and -octalones. An important feature of value in synthesis is the high regio- and stereo-selectivities shown in reactions of the aminodienes with unsymmetrical dienophiles.The acylamino-group is a power- ful directing group and in many reactions only one regioisomer is detected; formed generally through the endo-transition state. Diels-Alder reaction of 1-trimethylsilylbutadienes with dienophiles provides a good route to cyclic allylsilanes especially if the diene is symmetrical or has other substituents to control the regioselectivity of the addition. The trimethylsilyl group itself reduces the rate of Diels-Alder reactions and has if anything only a weak 'ortho-directing' effect. The allylsilanes thus obtained undergo the expected range of reactions including clean protodesilylation with acid and epoxidation to give ally1 Continuing their work on Diels-Alder reactions with 1,3-bis-oxygenated-buta-1,3-dienes Danishefsky and his co-workers have now prepared optically active arogenate (pretyrosine) (138) from the precursor (137) itself obtained from 1-methoxy-3-trimethylsilyloxybutadieneand the optically active glutamic acid derived dienophile (136) ; (Scheme 63).127 l-Methoxy-2-acetoxy-3-trimethylsilyl-oxybuta-l,3-diene is available by enol silylation of l-methoxy-2-acetoxybut-l-ene-3-one.It reacts readily with various dienophiles addition to acetylenes specifically giving convenient access to catechol derivatives. Heterocyclic com- pounds have been obtained by addition of alkoxy- and trimethylsilyloxy-substituted butadienes to heterodienophiles. A series of C-4-branched pseudoglycals was Cbz Cbz H OMe ow C02CH,Ph ... + 0s) +> OSiMe OV0 -(138) Reagents i benzene reflux; ii AcOH Scheme 63 125 L. E. Overman R. L. Freerks C. B. Petty L. A. Clibe R. K. Ono G. F. Taylor and P. J. Jessup J. Am. Chem. SOC.,1981,103,2816. 126 M. J. Carter I. Fleming and A. Percival J. Chem. Soc. Perkin Trans. 1 1981,2415. S. Danishefsky J. Morris and L. A. Clizbe J. Am. Chem. SOC.,1981,103. 1602. 12* S.Danishefsky and T. A. Craig Tetrahedron 1981 37,4081. 12' Synthetic Methods 337 obtained by reaction of (2,E)-1-methoxybutadienes with diethyl mes~xalate~*~ and reaction of di- and tri-acylimines prepared from aza-Wittig reagents and glyoxalates or keto-malonates with methoxy- and trimethylsilyloxy-butadienes gave tetrahydropiperidine derivatives in synthetically useful ~ie1d.l~' Intermolecular Diels-Alder reactions have also been used in synthetic approaches to anthracycline~'~~ and hydroxyanthraquinones including some naturally occurring examples13* and a reaction involving a 1,2-dihydropyridine derivative as the diene component formed a key step in a synthesis of de~ethy1catharanthine.l~~ However many of the most interesting syntheses of natural products have involved the intramolecular Diels-Alder reaction rather than the intermolecular reaction and although employed in the synthesis of natural products only compara- tively recently it is now finding widespread use in the synthesis of steroids alkaloids and terpenoids.Work on the total synthesis of steroids by intramolecular cycloaddi- tion reactions has been reviewed134 but some more recent advances are summarized here.In a commonly used approach a new six-membered ring is formed by intramolecular cycloaddition to an ortho-quinodimethane generated in one of a number of ways. In a synthesis of (+)-chenodeoxycholic acid for example,'35 the ortho- quinodimethane was formed by thermolysis of a benzocyclobutene (Scheme 64). The cis,anfi,trans-D-aromatic steroid (140) was obtained stereoselectively OAc (139) several steps & I 'OH HO' H OAc (140) Scheme 64 129 W. Abele and R. R. Schmidt Tetrahedron Lett. 1981,22 4807. 130 M.E.Jung K.Shishido L. Light and L. Davis Tetrahedron Lett. 1981 22,4607. 131 J.-P. Gesson J.-C. Jaquesy and M. Mondon Tetrahedron Lett.1981 22 1337; F.A. J. Kerdesky R. J. Ardecky M. V. Lakshmikantham and M. P. Cava J. Am. Chem. SOC., 1981,103,1992. 132 C. Brisson and P. Brassard J. Org. Chem. 1981,46 1810;G.Roberge and P. Brassard J. Org. Chem. 1981,46,4161. 133 C.Marazano J.-L. Fourrey and B. C. Das J. Chem. SOC.,Chem. Commun. 1981,37. lJ4 T. Kametani and H. Nemoto Tetrahedron 1981 37 3. 13' T.Kametani H. Suzuki and H. Nemoto J. Am. Chem. Soc. 1981,103,2890. 338 W.Carruthers through the intermediate (139). A more convenient route to ortho-quinodimeth- anes which requires much milder conditions than that from benzocyclobutenes is by elimination from suitable ortho- silylmethylbenzylammonium salts induced by fluoride ion. The quinodimethane (141) for example generated in the presence of dimethyl fumarate gave the adduct (142) in quantitative yield (Scheme 65).'36 (141) Reagents i Bu,NF-CH,CN 25 "e;ii Me0 C (142) *C02Me Scheme 65 Similarly the precursor (143) gave oestrone methyl ether (144) in 86% yield in a stereoselective reaction (see also ref.137) and in a novel route to 11-oxygenated steroids the 11-ketotestosterone derivative (147) was obtained by ozonization of the tetracyclic precursor (146) itself formed stereoselectively by intramolecular Diels-Alder cycli~ation'~~ of (145). A different route to 11-oxygenated steroids which proceeds through ortho- quinodimethanes has been exemplified in a synthesis of 1la-hydroxyoestrone methyl ether.'39 OH ,Me OSiMe2Bu' (145) (146) (147) Reagents i CsF-CH,CN reflux; ii CF,CO,H -78 "C; iii 0,; iv KOH-MeOH 40"C Scheme 66 136 Y.Ito M.Nakatsuka and T. Saegusa J. Am. Chem. SOC.,1981,103,476. 13' Y.Ito S. Mujata M. Nakatsuka and T. Saegusa J. Am. Chem. SOC.,1981,103,5250. G.Stork G. Clark and C. S. Shiner J. Am. Ch m. SOC.,1981,103,4948. 13' S.Djuric T. Sarkar and P. Magnus J. Am. Chem. SQC.,1980,102,6885. Synthetic Methods 339 In the alkaloid field the indolizidine alkaloid 6-coniceine (150)was synthe~ized'~' by cyclization of the imino-diene (149) followed by reduction of the double bond and the carbonyl group and intramolecular cyclization of an imine was also a feature of a new synthesis of (&)-lysergic acid. 14' An intramolecular Diels-Alder reaction (Scheme 68) using for the first time a trimethylsilyloxydienamidewas the key step in a synthesis.of cis-dihydrolycoricidine triacetate (153)14* and a related sequence involving cyclization of an enamide was employed in a synthesis of racemic 1yc0rine.l~~ In the synthesis of cis-dihydrolycoricidine reaction of (15 1) with chlorotrimethylsilane and triethylamine in refluxing dimethylformamide resulted in spontaneous cyclization of the intermediate trimethylsilyloxydienamide.Removal of the trimethylsilyloxy-group with aqueous acid gave the cyclized alcohol (152) in 6045% yield as a mixture of two isomers. The ortho-quinodimethane route has also been employed in a new approach to the synthesis of indole alka10ids.l~~ (148) (149) Reagents i toluene 370-390 "C; ii H,-Pd; iii BH3-THF Scheme 67 OSiMe CHO 0 N-Ph 0 0 1 OH (153) (152) Reagents i Et,N-Me,SiCl-DMF 160"C; ii H,O' Scheme 68 140 N.A. Khatri H. F. Schmitthenner J. Shringarpure and S.M. Weinreb J Am. Chem. Soc. 1981 103,6387. 141 W. Oppolzer E.Franwtte and K. Battig Helu. Chim. Actu 1981,64,478. 14' G. E.Keck E. Boden and U.Sonnewald Tetrahedron Lett. 1981,22,2615. 143 S.F.Martin and Chih-Yun Tu J. Org. Chem. 1981,46 3763. 144 T.Gallagher and P. Magnus Tetrahedron 1981 37,3889. 340 W. Carruthers Intramolecular cyclization of N-acyl-1 -aza-1,3-dienes although not yet employed in alkaloid synthesis provides another route to nitrogen heterocyclic The aza-dienes may be obtained by gas-phase pyrolysis of N-acyl-0-acetyl-N- allylhydroxylamines.Intramolecular Diels-Alder cyclizations have also been used for the stereospecific synthesis of substituted indane and octalin deriva- tives. For example in experiments aimed at the synthesis of the ionophore antibiotic X-14547A146 the trans- hexahydroindene (155) was obtained specifically in 70% yield from the triene (154) via the sterically favoured endo-transition state and in a closely related sequence (156) was obtained in 7 1'/o yield in a catalysed reaction at room temperature (Scheme 69).147 Similarly the cis-octalone (157) was ~btained'~' by way of the correspond- from 3,ll -dimethyl-l,3,9-dodecatrien-8-one ing endo- transition state. Nevertheless a growing body of evidence supports the view that the Alder endo- rule which governs many intermolecular Diels-Alder reactions is not universally valid for the intramolecular reaction and several cases have been reported in which cyclization has clearly proceeded by way of an em- transition Reagent i toluene 130 "C Scheme 69 Many other cycloadditions that have proved useful in synthesis although strictly speaking not Diels-Alder reactions nevertheless are conceptually related and may conveniently be considered here.The first synthesis of the antitumour neolignan megaphone (160) has been achieved15' using as the key step the elegant Lewis acid-catalysed cycloaddition of the propenylbenzene (158)to the p-benzoquinone monoketal (159); (Scheme 70). In a continuation of earlier work on the synthetic Yea-Shun Cheng F. W. Fowler and A.T. Lupo J. Am. Chem. Soc. 1981,103,2090. K. C. Nicolaou and R.L. Magolda,J. Org. Chem.,1981,46,1506,1509;see also M. P. Edwards,S.V. Ley and S. G. Lister Tetrahedron Lett. 1981 22 361. W. R. Roush and A. G. Myers J. Org. Chem. 1981,46 1509. J.-L. Gras J. Org. Chem. 1981,46 3738. 149 J. D. White and B. G. Sheldon J. Org. Chem. 1981 46 2273; W. R. Roush and S. E. Hall J. Am. Chem. SOC.,1981,103 5200. Is' G. Buchi and Ping-Sun Chu J. Am. Chem. Soc. 1981,103 2718. 14' Synthetic Methods 341 OMe OMe Me0 OMe Reagents i SnC1,-CH,CI, -30 “C; ii several steps Scheme 70 uses of oxyallyls,’” the a-multistriatin analogue (163) has been prepared from the adduct (162) of 2,s-dimethylfuran and the oxyallyl(l61); (Scheme 71). The oxyallyl was obtained by a convenient new route from 2-bromopentan-3-one and silver tetrafluoroborate.The muscarine analogue (165) was obtained in a similar way from the adduct (164) through reduction of the double bond and Beckmann 0 0 Me,&Me & (MeAMe Me -% Me Me Br (161) (162) (163) H ‘ Me02cYYkMe3 Reagents i AgBF,-Et3N-CH3CN; ii MeOMe ;iii several steps 0 Scheme 71 rearrangement of the derived o~irne.~’~ A novel route to the cis,anti,cis-linearly- fused tricyclopentanoid ring system found in several sesquiterpenoids of current interest employs in the key step a regiospecific and highly stereoselective *” J. Mann and A. A. Usmani J. Chem. SOC.,Chem. Commun. 1980,1119. lS2 A.P.Cowling J. Mann and A. A. Usmani J. Chem. SOC.,Perkin Trans.I 1981 2116. 342 W. Carruthers intramolecular addition of a diyl to a carbon-carbon double bond. It has previously been shown that cyclopenta- 1,3-diyls can be trapped by alkenes carrying electron- withdrawing substituents to afford preferentially fused rather than bridged ring cycloadduct~.'~~ An intramolecular version of this reaction was used to construct the hirsutene ring On refluxing the azo-compound (166) in acetonitrile a highly stereoselective cyclization ensued from the intermediate diyl to give the tricyclopentanoid (167) in 85'/o yield subsequently converted into dl-hirsutene (168). The marine sesquiterpene A9"*'-capnellene (169) was synthesized by a similar method (Scheme 72).155 Reagent i CH,CN reflux Scheme 72 9 1,3-Dipolar Cycloaddition Reactions 1,3-Dipolar cycloaddition reactions particularly of nitrones are being employed increasingly in synthesis as in a recent approach to quinolizidine alkaloids'56 and perhydroquin~lizinones.'~~ A good illustration is provided by a chiral synthesis of L-daunosamine (175a) and its C-4 epimer L-acosamine (175b) shown in Scheme 73.'58 The chiral nitrone (172) was prepared from the masked aldehyde (170) and the oxalate salt of (S)-(-)-N-hydroxy-a-methylbenzenemethanamine(171) in a refluxing xylene and under the reaction conditions cyclized to give a mixture of the diastereomers (173) and (174) by a reversal of the normal addition of the nitrone oxygen to the oxygen-bearing carbon of an enol ether or ester.Further manipulation of (174) led to (175a) and (175b).The 1,3-dipolar cycloaddition of azomethine ylides (176) to activated alkenes is a good synthetic route to certain pyrrolidine derivatives but is limited in scope because R and R' have to be aryl or electron-withdrawing substituents as a consequence of the methods needed to generate the ylides (Scheme 74). It is now J. A. Berson Acc. Chem. Res. 1978 11 446. 154 R. D. Little and G.W. Muller J. Am. Chem. SOC.,1981 103 2744. R. D. Little and G. L. Carroll Tetrahedron Left. 1981 22,4389. ''' S. Takano and K.Shishido J. Chem. SOC. Chem. Commun. 1981 940. 157 R. Brambilla R. Friary A. Ganguly M S. Puar B. R. Sunday J. J. Wright K. D. Onan and A. T. McPhail Tetrahedron 1981 37 3615. ''' P. M. Wovkulich and M. R.UskokoviC J. Am. Chem. SOC., 1981,103,3956. Synthetic Methods ' (172) 1 (175) a; R = OH R' = H (175) b; R = H R' = OH (174) 82 12 (173) Reagents i xylene reflux; ii several steps Scheme 73 A = electron-withdrawing group Reagents i 0-25 "C;ii Raney Ni; iii AgNO,; iv NaBH Scheme 14 344 W. Carruthers reported"' that the readily available ylides (177a) and (177b) afford adducts (178) on reaction with activated double bonds; these can be desulphurized and hydrolysed to form the pyrrolidines (179). The ylides (177a) and (177b) here act as synthetic equivalents of the inaccessible azomethine ylides (180). 10 Ene Reaction A review of his recent work on the synthesis of (+)-oestradiol (A)-chanoclavine (*)-isochanoclavine (+)-longifolene '(+)-sativene and the neurophysiologically interesting cyclic amino-diacid (+)-a-allokainic acid (181) has been given by Oppol- zer.l6' The synthesis of (181) included the first example of an ene reaction proceed- ing with high asymmetric induction (Scheme 75).161 -L -I= Reagents i.Et,AlCI -35 "C; ii several steps Scheme 75 Recent examples in synthesis have illustrated the 'hetero-ene' reaction in which a double bond to a hetero-atom is involved. Thus cyclopentenols are obtained from y-allenic aldehydes and with the optically active allene (182) the (S)-cyclopentenol (183) was obtained preferentially (Scheme 76) although it was only 36% optically (182) (183) Reagent i 200 "C Scheme 76 G. A. Kraus and J. 0.Nagy Tetrahedron Lett.1981,22 2727. W.Oppolzer Pure Appl. Chem. 1981.53 1181. W.Oppolzer C.Robbiani and K. Battig Helo. Chim. Actu 1980,63 2015. Synthetic Methods pure indicating reaction through both endo-and exo-transition states.16* In the nitrogen series thermal (120 "C) and catalytic (SnCL BF, AlCl,) ene addition reactions of butyl N-(p-tolylsulphony1)iminoacetate with alkenes gave adducts which could be readily converted into 78-unsaturated a-amino-acid~'~~ (Scheme -(COzBu pC0,Bu 1 NHS0,C6H4Me-p fi' /N Me Me S0,C,H4Me-p Reagents i benzene 120 "C sealed tube or SnCl,-CH2Cl, 0 "C Scheme 77 77). Both inter- and intra-molecular ene reactions of acylnitroso compounds also take place readily affording N-alkyl hydroxamic acids which are smoothly conver- ted into amides by reduction of the corresponding ally1 ethers with sodium amalgam (Scheme 78).164The intramolecular reactions are highly regioselective providing entry into either spiro or fused bicyclic nitrogen ring systems in appropriate cases.Reagents i benzene reflux; ii ABr-K2C03 ;iii Na-Hg-EtOH-Na,HPO Scheme 78 162 M. Bertrand M. L. Roumestant and P.Sylvestre-Panthet Tetrahedron Lett. 1981 22 3589. 163 0.Achmatowia and M. Pietraszkiewin J. Chem.SOC.,Perkin Trans. I 1981 2680. lo4 G. E. Keck R. R. Webb and J. B. Yates Tetrahedron 1981,37,4007.