Ynolate anions Mitsuru Shindo Institute for Medicinal Resources University of Tokushima Sho-machi 1 Tokushima 770-8505 Japan Ynolates are carbanions having a triple bond in place of the double bond in enolate anions. For the past 20 years several methods for the generation of ynolates have been developed. Ynolates are ketene anion equivalents thus ynolates introduce a ketene unit into substrates and the resulting products possess high reactivity. This allows ynolates to undergo unique reaction sequences. This review provides an overview of the syntheses and the reactions of ynolates including recent progress in the area. 1 Introduction Carbanions are fundamental reactive species that are widely used for carbon–carbon and carbon–heteroatom bond formation in synthetic organic chemistry.Carbanions stabilized by the conjugation of p-electrons on a double bond such as enolate anions imine anions (metaloenamins) hydrazone anions oxime anions etc. are especially well known and their chemistry has been thoroughly studied and established. However carbanions stabilized by a triple bond have not been well studied. Ynolate anions have a triple bond in place of the double bond in enolate anions. The latter are one of the most important carbanions in synthetic organic chemistry. In contrast to enolate anions ynolate anions have attracted much less attention and only a few reports are scattered in even comprehensive reviews this has been due to a lack of general and convenient methods for their synthesis.Their chemistry should be no less interesting than that of enolates because they are not only carbanions forming a carbon–carbon bond but also ketene anion equivalents acting as a ketene precursor (Fig. 1). Recently several R – O R O – Ynolate anion Ketene anion Fig. 1 groups including our group have reported on ynolate chemistry concerning their generation and their reactivity. An indication of the great advances in ynolate chemistry is recognized. This recent progress in ynolate chemistry has prompted us to compile a review on this topic. This review will describe Mitsuru Shindo was born in Tokyo in 1963. He obtained his BSc MSc and PhD degrees on asymmetric synthesis at the University of Tokyo (Professor Kenji Koga). From 1991 till 1996 he was an assistant professor at the same laboratory.He joined Professor R. A. Holton’s group (Florida State University USA) as a postdoctoral fellow from 1992 until 1994. In 1996 he moved to the University of Tokushima as an associate professor (working with Professor Kozo Shishido). OLi R OEt Li ester dianion (31) 0 °C EtOLi OLi R R M B l h l B t methods for the preparation of ynolates their reactions and their synthetic utility. 2 Synthesis of ynolates 2.1 Fragmentation of 3,4-diphenyl-5-isoxazolyllithium In 1975 Schöllkopf and Hoppe reported the first synthesis of ynolates.1 3,4-Diphenylisoxazole 1a was lithiated by BuLi and the resulting 5-lithio-3,4-diphenylisoxazole 2a spontaneously fragmented into ynolate 3a and benzonitrile (Scheme 1).They PhCN Ph Ph N N BuLi OLi R O O R R Li H 3a R = Ph 3b R = Li 1a R = Ph 1b R = H Ph Ph N NLi O R R O Li 5 4 Fig. 2 R O Li R'Li R O ? H 6 OLi R R' H dimerization 2 Scheme 1 also reported the preparation of an ynolate dianion (dilithio ketene) from 3-phenylisoxazole 1b by the same protocol.2 It is not clear whether the fragmentation mechanism is a concerted [2p + 4p] (Fig. 2 4) or a stepwise one through a-lithioiminobenzylphenylketene (Fig. 2 5). The procedure is simple and the side product would theoretically only be benzonitrile. The yield is up to 79% (as a b-lactone prepared by the reaction with benzaldehyde see Section 3.1). However it is limited to the preparation of aromatic or unsubstituted ynolates.2.2 Lithiation of silylketenes Ynolates are ketene anion equivalents. Therefore deprotonation of mono-substituted ketenes 6 is expected to afford ketene anions that is ynolate anions. However the synthesis of ynolates by deprotonation of ketene itself or alkylketenes has never been reported to the best of our knowledge. This is probably due to the instability of these ketenes the low acidity of the vinylic proton and the strong electrophilicity of the carbonyl carbon (Scheme 2). In contrast to alkylketenes Scheme 2 Chemical Society Reviews 1998 volume 27 367 silylketenes are stable and easy to handle moreover the acidity of their vinylic proton would be higher than that of alkylketenes.Rathke reported that trimethylsilylketene 7a when treated with BuLi at 2100 °C afforded b-silyl ynolates 8 in good yield (as disilylketenes prepared by the reaction with trialkylsilylchlorides) (Scheme 3).3 tert-Butyldimethylsilylketene 7b can also be BuLi RMe2Si O H 7a R = Me 7b R = Bu t Scheme 3 employed.4 The reaction conditions seem to be critical since when other bases are used or BuLi is added at 278 °C the yield of the corresponding disilylketenes decreases to less than 30%. 2.3 Rearrangement of a-keto dianions Kowalski reported synthesis of ynolates via rearrangement of a-keto dianions (carbenoids).5 While simple a-halo enolate monoanions such as 10 are stable a-keto a-dianions 11 prepared by lithium–halogen exchange of 10 with ButLi [route (a) Scheme 4] or by addition of dibromomethyllithium to esters 12 [route (b)] followed by base induced elimination (see Section 3.3) rapidly rearrange with loss of lithium bromide to afford ynolates.An experiment using 13C-labeled dibromo ketone enolate 13 indicates that the alkyl group of dianion 14 not the oxygen migrates to afford ynolate anion 15 (Scheme 5). route (a) O CHBr R 2 9 LHMDS Br LiO ButLi Br R 10 LiO R OLi R CHBr2 OEt LTMP route (b) R CO2Et + CH2Br2 12 11 LHMDS; BusLi; BuLi Scheme 4 Therefore from a mechanistic viewpoint this rearrangement can be regarded as a carbon analogue of the Hofmann rearrangement. Although the rearrangement is a high-yielding process an excess amount of strong base is needed to prepare the precursor dianions 11 especially in route (b).When the Chemical Society Reviews 1998 volume 27 368 OLi RMe2Si 8 LiBr Li OLi R Br LiO LiO Li Br 13 13C C C C Br R R Br 13 O S R CO2Me + Ph Cl 16 R TsOH•H2O 14 Scheme 5 Li OK Scheme 6 OH Ph I 2.4 From ynol tosylates with MeLi Enol acetates and silyl enol ethers can be cleaved with MeLi to afford enolates. If this method is applied to the synthesis of ynolates ynol acetates or silyl ynol ether could be prepared efficiently. Stang7 and Kowalski8 independently reported the syntheses of tert-butyldimethylsilyl ynol ether and triisopropylsilyl ynol ether (see Section 3.6).Kowalski also reported an efficient generation of lithium ynolates from these silyl ynol ethers with methyllithium. However as silyl ynol ethers are prepared from ynolates it remains an unsettled question how to synthesize the desired ynolates. No efficient method for the preparation of silyl ynol ethers or ynol acetates without using ynolates has been reported so far. Stang found that ynol tosylates can be converted to ynolate anions by methyllithium (Scheme 7).7 It is worth noting that the 17 KH -OTs Ph I+ PhI(OAc)2 OTs 18 MeLi (2 equiv.) ynolate prepared by this rearrangement method is used as a nucleophile the electrophiles added for the ynolate to react with would have to be inert towards such bases. Satoh et al. reported that a-chloro-a-sulfinyl ketone 17 prepared by the reaction of an ester and 16 can be applied in place of dibromoketone 9 (Scheme 6).6 Sequential treatment of 17 with KH and ButLi affords ynolates via a similar rearrangement.15 13C O Cl R 19 R OLi R R = But Bus 23 Scheme 7 ynol tosylates are synthesized by a unique method which does not involve the generation of ynolate anions:9 commercial LiO 13C C R R'OH O R R' O O S Ph R SOPh KO ButLi Cl R R 20 R OTs 21 CuOTf (cat) – C OTs I+Ph MLn 22 iodosobenzene diacetate 18 is treated with toluene-p-sulfonic acid monohydrate to afford phenylhydroxy(tosyloxy)iodine 19. This hypervalent organoiodine reacts with terminal alkynes 20 to give iodonium tosylates 21 in 20–60% yields.These tosylates are then treated with 10 mol% CuOTf or AgOTf to afford ynol tosylates 23 in 50–60% yields.10 A metal assisted nucleophilic acetyleic displacement via an addition-elimination process is suggested as the mechanism for this ligand–ligand coupling process. Most of the pure ynol tosylates seem to be stable. As terminal alkynes 20 are the starting molecules this method can be regarded as overall oxidation of an alkyne. 2.5 Oxidation of acetylides A synthesis of ynolates via direct oxidation of a terminal C–H bond on a terminal alkyne has been studied. Since acetylides are easily prepared from terminal alkynes they are expected to afford ynolate anions via reaction with electrophilic oxygen donors.Julia reported that lithium acetylides 24 react with lithium tert-butyl peroxide to give the corresponding ynolates in up to 85% yield (isolated as ethyl esters) (Scheme 8).11 The + + O OLi Li R OLi OLi R 30–85% 24 R = Ph Hexyl But etc. electrophilic Scheme 8 acetylides do not react with molecular oxygen as would be expected for a radical process. With trimethylsilyl peroxides they do not attack oxygen but instead attack silicon. In contrast to these oxygen donors lithium peroxides having a-heterosubstituted oxyanions i.e. oxenoids have electrophilic character despite the fact that lithium alkoxides are not good leaving groups. This type of oxidation is considered to proceed by an ionic process not by a radical one.12 2.6 Silyl ynolates from a-diazoacyllithiums Murai developed the alternative method for the preparation of silyl ynolates in the course of his research on acyllithiums (Scheme 9).13 A lithiated silyldiazomethane 26 prepared from Me3Si Me3Si BuLi CO Me3Si N+ N– N2 N2 O Li H Li 25 27 Me3Si N 26 OLi Me3Si N Li O N2 28 8a Scheme 9 commercially available trimethylsilyldiazomethane 25 and BuLi is exposed to an atmospheric pressure of carbon monoxide at 278 °C to afford trimethylsilyl ynolate in good yield.The mechanism is elucidated by the following scheme the lithiated silyldiazomethane reacts with carbon monoxides to give a labile acyllithium 27 which is rapidly converted to a ketene intermediate 28. This extrudes dinitrogen to provide the desired silyl ynolate.This procedure provides an efficient and operationally simple access to trimethylsilyl ynolates. 2.7 Cleavage of ester dianions As described repeatedly ynolates are equivalent to ketene anions and thus lithium ynolates could be formed via lithiation of ketenes at the vinylic position. However direct lithiation of ketenes is troublesome. Lithiation of the precursors of ketenes followed by transformation into lithiated ketenes would be a better route to ynolates. On the basis of this concept our group has developed the efficient and convenient method for ynolate synthesis.14 Ester enolates are regarded as a precursor of ketenes because they are known to be converted into ketenes and alkoxides via thermally induced cleavage (Scheme 10).15 OR' OR' R + R'OLi O R R OLi O ketene enolate Scheme 10 a-Bromocarboxylic acid esters 29 are converted by LDA into a-bromoenolates 30 which are treated with tert-butyllithium to give the novel ester dianions 31 via lithium–halogen exchange at 278 °C.The dianions 31 are thermally cleaved at 0 °C into ynolates in good yields ( ~ 90%) (Scheme 11). Based on the OLi R LDA R CO2Et OEt Br Br 30 29 –78 °C ButLi OLi R ButLi R CO2Et Br Br OEt Li –78 °C 32 ester dianion (31) 0 °C EtOLi OLi R R = Me Bu cyclohexyl But Scheme 11 same concept a,a-dibromocarboxylic acid esters 32 prepared by a-bromocarboxylic acid esters and LDA with dibromotetrafluoroethane also afford ynolates in a simple fashion.16 The a,a-dibromocarboxylic acid esters are treated with tert-butyllithium at 278 °C and then the reaction mixture is warmed to 0 °C to give ynolates in good yields.These extremely simple procedures give primary secondary and tertiary-alkyl substituted ynolates. It is noteworthy that the latter procedure gives lithium amide (and amine) free ynolates. The starting esters are stable and easily available. From these results it is clear that this method is one of the most facile methods available and has high generality. 2.8 Ynolate dianions Unsubstituted ynolate anions have a terminal alkyne which is expected to deprotonate to give ynolate dianions. This is a ketene dianion equivalent therefore it should have great synthetic utility. As described in Section 2.1 an ynolate dianion has been prepared from 3-phenylisoxazole (Schöllkopf’s method).Another approach to an ynolate dianion was reported by Barton.17 Sequential lithiation of 2,3-dihydrofurans 33 with 2 equiv. of BuLi affords an ynolate dianion in up to 65% yield [isolated as bis(trimethylsilylketene) by quenching with chlorotrimethylsilane] (Scheme 12). In this process elimination from a dilithiated dihydrofuran cannot be ruled out. Application of ynolate dianions to organic synthesis has never been reported. 369 Chemical Society Reviews 1998 volume 27 R BuLi OLi H Li O O R R 3b BuLi 33a R = H 33b R = Ph OLi Li 38% from 33a 65% from 33b Scheme 12 3 Reactions of ynolates Ynolate anions are regarded as ketene anions ‘ketenylation’ reagents or masked ketenes.Ketenes have been used as important and highly reactive species in organic chemistry. However they are generally not easy to handle due to their instability so that they have usually been synthesized and utilized in situ. Ynolate anions give ketenes which are difficult to generate in simpler ways if they react with electrophiles at the b-position (Scheme 13a). Additionally ynolates are also considered as ynol ether (or ester) precursors when reactions occur at oxygen (Scheme 13b). Ynol ethers are also important reactive species. Thus ynolates should have great potential in organic chemistry. In this section a variety of reactions of ynolates studied so far are summarized. (a) (b) O O– R O O R ketene chemistry alkyne chemistry Scheme 13 3Si) are stable at low 3.1 Reactions with aldehydes and ketones synthesis of b-lactone enolates Ynolates react with aldehydes and ketones 38 to afford b-lactone enolates 34 (Scheme 14).It is not clear whether it is a stepwise mechanism (A) or a concerted mechanism (B) (Fig. 3). Ynolates bearing a phenyl1 or silyl substituent4 give b-lactones after protonation. However ynolates bearing an alkyl (primary secondary or tertiary) substituent react with aldehydes to afford 2 1 adducts 36 in good to moderate yields14,16 since the corresponding b-lactone enolates are more reactive than the ynolates themselves. The b-lactone enolates (34 R = Ph Me temperature but above 0 °C they are converted into a,bunsaturated carboxylates 37 in good to excellent E-selectivity.The mechanism is considered to be an electrocyclic thermal ring-opening. The 2 1 adduct 36 also gives unsaturated carboxylates at room temperature. These results suggest that the 2 1 adducts 36 which do not seem to be useful by themselves are converted into b-lactone enolates 34 via a retro-aldol reaction. Using our synthetic method for the generation of ynolates (Section 2.7) we have established an efficient method Chemical Society Reviews 1998 volume 27 370 R1 O– R O + R2 -78 °C O R R O– H+ O O R1 R1 R2 R2 35 34 R = Ph Me3Si R1 = Ph R2 = H R1 O R2 > 0 °C O– R CO2 – O 2:1 adduct R2 R1 O 37 R2 36 E-major R O– OLi O R1 R2 A B Fig.3 R CO2Et X Br 29 X = H 32 X = Br R1 38 O O R2 R CO2H H+ 38 45–73% R O– rt R2 R1 39 38 R1 R2 R R1 R = alkyl R1 = alkyl aryl R2 = H Scheme 14 R R1 R2 for the highly E-selective one-pot synthesis of a,b-unsaturated carboxylic acids 39 starting from a-bromoesters (Scheme 15).18 This method would be a useful alternative to the classical Horner–Wadsworth–Emmons reaction. E/ Z = >99:1 – 5:1 (R1 = alkyl aryl R2 = H) E/ Z = 7:1 (R1R2 = a-tetralone) Scheme 15 3.2 Reactions with imines Ynolate anions are expected to react with imines to give b-lactams. Phenyl ynolate 3a reacts with imines bearing electron withdrawing groups (e.g.40) to afford the 2 1 adducts 42 in good yields (Scheme 16).19 The b-lactam enolates 41 are more nucleophilic than the ‘stabilized’ ynolate. Silyl ynolate 8a reacts with an imine 43 bearing a toluene-p-sulfonyl group at O2N Ph –78 °C– –50 °C + OLi Ph N N 3a O2N NO2 41 O2N NH Ph N O2N 42 OLi Me3Si 8a + Ph OLi Me3Si N rt Me S N O O S O O 43 O Me3Si NH Ph S O O 45 OLi Bu 46 Bu O + Ph N N Me S O S O O O 47 43 40 Scheme 16 Scheme 17 room temperature to give (E)-a,b-unsaturated amide 45 (Scheme 17). However these stabilized ynolates do not afford b-lactams efficiently. Recently we have found that an alkyl ynolate 46 reacts with a tosyl imine to give a 3,4-disubstituted b-lactam 47 efficiently (Scheme 18).20 These results indicate that the fine tuning of the nucleophilicity of ynolates and the electrophilicity of imines is critical for the synthesis of b-lactams.–78 °C H+ Scheme 18 OLi 3.3 Ester homologation Ynolates are quenched with alcohols to give the corresponding esters. Kowalski extended this reaction to an ester homologation. 21 Esters are treated with dibromomethyllithium prepared from dibromomethane with LTMP to give tetrahedral intermediates 48. These are then converted into a-keto dianions 11 via two routes as shown in Scheme 19. As described in Section O NO2 OEt R 12 LiCHBr2 NO2 OLi CHBr R 2 OEt O 89% 48 NO2 LiO Br R Br 50 Me 68% RCO2Et + Me CH2Br2 68% Me R = primary secondary tertiary aryl alkynyl 2.3 the dianions rearrange to afford ynolates which are treated with acidic ethanol to give homologated esters 51 in 50–75% yields.By detailed analysis of by-products the reaction conditions have been optimized as shown in Scheme 20.22 The yields were improved in 67–90% although an excess amount of strong bases is still needed in the reaction vessel. This procedure provides an alternative to the Arndt–Eistert reaction. LTMP (2.2); LHMDS (2); Bu sLi (4); BuLi (2) 3.4 Reduction of ynolates Kowalski found that the triple bond of ynolates is reduced by reactive LiH suspended in THF on refluxing under N2 to afford the E-enolates 52 of aldehydes which should be important carbanions but can not be otherwise obtained easily (Scheme 21).23 This LiH is formed in situ from cyclohexa-1,3-diene with LTMP or from cyclohexa-1,4-diene with BuLi.24 On exposure to air this LiH loses the ability to reduce ynolate anions.Commercial LiH would also be ineffective due to oxidation of the surface. For mechanistic considerations the following experiments were carried out. In the presence of N-deuterated TMP 57 the b-position of the product 58 had 50% incorporation of deuterium and using LiD a-deuterated product 59 was generated (Scheme 22). These experiments suggest that the hydride adds to the a-position of ynolates to give the dianion 56 Chemical Society Reviews 1998 volume 27 11 Scheme 19 Scheme 20 BuLi LiO Br R H 49 LTMP Br LiO BuLi R Li OLi R HCl EtOH R CH2CO2Et 51 OLi R EtOH HCl RCH2CO2Et 67–90% 371 OLi R (Kowalski's method) H R OTMS H H+ RCH2CHO 55 50–68% OLi R LiH H R LiD OLi Li 56 D R Li OLi which is C-protonated by TMP in the reaction with retention of configuration.It is noteworthy that while the reduction of simple triple bonds under this condition was not observed the electron-rich ynolate anions are reduced completely. The E-enolates are converted to E-enol acetates 53 by acetic anhydride in 48–77% yields from the starting esters. It also is applicable to the synthesis of 1,3-dienes which should be important for Diels–Alder chemistry.25 This reductive homologation process can be applied to the synthesis of alcohols 54 via reduction and aldehydes 55 via protonation as shown in Scheme 21.3.5 Miscellaneous reactions Murai reported the reactions of silyl ynolates with several carbon electrophiles (Scheme 23). Lithium silyl ynolate 8a reacts with oxirane 60 to afford g-lactone 61 in the presence of Me3Al although it did not without the Lewis acid. Me3Al might form an ate complex with lithium ynolate. The reaction of lithium silyl ynolate with aziridine 62 activated by a toluenep-sulfonyl group affords g-lactam 63 without Me3Al. These reactions involve nucleophilic ring opening and recyclization by the resulting anions and ketenes. Like b-lactam and b-lactone formation they are kinds of tandem reactions.Among a,b-unsaturated carbonyl compounds as electrophiles acrylates and enones are inactive towards ynolates but a doubly activated olefin benzylideneacetoacetate 64 affords d-lactone 65 via a Michael-type reaction with the ynolate. Chemical Society Reviews 1998 volume 27 57 NH Scheme 22 372 R H reactive LiH OLi H E-enolate (52) NH Ac2O TMSCl 4 H R NaBH MeOH H OAc 53 RCH2CH2OH 54 48–78% 44–74% Scheme 21 H R Ac2O ND OAc D 58 D R Ac2O OAc H 59 O Me3Al OLi Me3Si –78 °C ® 20 °C 8a 62 Me3Al CO2Et Ph COMe 64 Me3Si O– Me3Si H+ Ph O Ph Me EtO2C EtO2C R OLi R unstable ynol ether 65 Scheme 23 3.6 Silyl ynol ethers Like enolates ynolates are expected to form silyl ynol ethers via O-silylation (Scheme 24).Ynolates are treated with chloro- Me3SiCl -78 °C ButMe2SiCl MeLi MeLi Pri 3SiCl 60 N SO2Tol –78 °C®64 °C O O Me OSiMe R 2But R OSiPri 3 69 68 Scheme 24 trimethylsilane at 278 °C to form a mixture of silyl ynol ethers 66 and silyl ketenes 67.8 Since this mixture is converted into the silyl ketene 67 it is suggested that silylation by chlorotrimethylsilane occurs kinetically on oxygen to afford silyl ynol ether 66 and upon warming the mixture isomerization to the more stable ketene 67 occurs. However with either chlorotriisopropylsilane and chloro-tert-butyldimethylsilane the silylation occurs on oxygen and the resulting silyl ynol ethers are thermally stable and isolable.7,8,26 Ynolate dianion 3b prepared by Barton’s method (Section 2.8) was treated with chloro-tertbutyldimethylsilane to afford firstly disilyl ynol ether 70 which was then isomerized into disilyl ketene 71 in the reaction mixture (Scheme 25).17 Interestingly under salt free conditions that is after isolation of the disilyl ynol ether the ynol ether 70 SiMe3 O– O H+ SiMe3 O O 93% 61 O– Me3Si N SO2Tol H+ O Me3Si N SO2Tol 63 65% OSiMe3 66 rt R C O Me3Si 67 ketene was not isomerized.This result suggests that the ketene products arise from a salt-promoted isomerization rather than from a purely thermal rearrangement. ButMe2SiCl OLi Li OSiMe2But ButMe2SiO 70 3b salt ButMe2Si C O ButMe2Si 40% 71 Scheme 25 The reaction of lithium ynolates with diethyl chlorophosphate gives phosphate esters 72 in moderate yields (Scheme 26) whereas the reaction with benzoyl chloride affords both products of O- and C-acylation.27 O ClPO(OEt)2 R OLi R O P(OEt)2 72 30–56% Scheme 26 Silyl ynol ethers are treated with MeLi to give ynolates efficiently (Scheme 24).Silyl ynol ethers are also useful substituents for alkoxy acetylenes in [2 + 2] cycloaddition reactions with ketenes and vinylketenes affording cyclobutenones 73 and resorcinol derivatives 74 respectively (Scheme 27).28 These reactions have been applied to the total syntheses of natural products (Scheme 28).29 O R R OSiPri 3 H2C C O MeLi R OSiPri 3 O Me 69 73 R O 62–92% Me OSiPri 3 R Me HO 4 Conclusion 74 77–88% Scheme 27 Silyl ynol ethers prepared by Kowalski’s method react with aldehydes mediated by TiCl4 to give a,b-unsaturated esters in 60–65% yield with high E/Z-stereoselectivity after a methanol quench.30 A proposed mechanism for this reaction is shown in Scheme 29.The intermediate 75 generated via a Mukaiyamatype aldol reaction is cleaved by conrotatory thermal opening and then the resulting silyl ester 76 is converted into the methyl ester 77 via transesterification. Ynolates have great potential in synthetic organic chemistry. Ynolates introduce a ketene unit into substrates and the resulting products have strong electrophilicity due to their ketene unit and sometimes nucleophilicity too.This means that a well designed reaction using ynolates should make one-pot OSiButMe2 + Pri 3SiO Me Me OSiPri 3 OH OSiButMe2 Scheme 28 R OSi(Pri)3 R O R1 75 R R1 alkyl aryl Scheme 29 R1CHO TiCl4 OSi( i-Pr)3 5 Acknowledgments 6 References multi-step syntheses possible. Ynolate chemistry will contribute not only to ketene chemistry but also to acetylene chemistry. Ynolate chemistry has just begun and much remains to be discovered. This review will hopefully stimulate further work on the use of ynolates and the development of new reactions. I am deeply grateful to Professor K. Shishido (Institute for Medicinal Resources University of Tokushima) for his kind discussions and to co-workers for their efforts.Our own work was supported by Grants-in-Aid for Scientific Research on Priority Areas (No. 283 ‘Innovative Synthetic Reactions’) from the Ministry of Education Science Sports and Culture Government of Japan and the Eisai Award in Synthetic Organic Chemistry Japan. 1 U. Schölkopf and I. Hoppe Angew. Chem. Int. Ed. Engl. 1975 14 765. 2 I. Hoppe and U. Schölkopf Liebigs Ann. Chem. 1979 219. 3 R. P. Woodbury N. R. Long and M. W. Rathke J. Org. Chem. 1978 43 376. 4 A. Akai S. Kitagaki T. Naka K. Yamamoto Y. Tsuzuki K. Matsumoto and Y. Kita J. Chem. Soc. Perkin Trans. 1 1996 1705. 5 C. J. Kowalski and K. W. Fields J. Am. Chem. Soc. 1982 104 7321. Chemical Society Reviews 1998 volume 27 E-selective O Me N2 [2+2] OSiPri 3 OSiButMe2 O Me O O O aegyptione A R H R1 76 MeOH R CO2Me 60–65% H R1 77 CO2Si(Pri)3 373 6 T.Satoh Y. Mizu Y. Hayashi and K. Yamakawa Tetrahedron Lett. 1994 35 133 7 P. J. Stang and K. A. Roberts J. Am. Chem. Soc. 1986 108 7125. 8 C. J. Kowalski G. S. Lal and M. S. Haque J. Am. Chem. Soc. 1986 108 7127. 9 P. J. Stang and B. W. Surber J. Am. Chem. Soc. 1985 107 1452. 10 P. J. Stang B. W. Surber Z.-C. Chen K. A. Roberts and A. G. Anderson J. Am. Chem. Soc. 1987 109 228. 11 M. Julia V. P. Saint-Jalmes and J. M. Verpeaux Synlett 1993 233. 12 E. J. Panek L. R. Kaiser and G. M. Whitesides J. Am. Chem. Soc. 1977 99 3708. 13 H. Kai K. Iwamoto N. Chatani and S. Murai J. Am. Chem. Soc. 1996 118 7634. 14 M. Shindo Tetrahedron Lett. 1997 38 4433. 15 K. Tomioka M. Shindo and K. Koga J. Org. Chem. 1990 50 2276. 16 M. Shindo Y. Sato and K. Shishido Tetrahedron 1998 54 2411. 17 B. L. Groh G. R. Magrum and T. J. Barton J. Am. Chem. Soc. 1987 109 7568. 18 M. Shindo Y. Sato and K. Shishido Tetrahedron Lett. 1998 39 4857. Chemical Society Reviews 1998 volume 27 374 19 R. M. Adlington A. G. M. Barrett P. Quayle and A. Walker J. Chem. Soc. Chem. Commun. 1981 404. 20 M. Shindo S. Oya Y Sato and K. Shishido to be submitted. 21 C. J. Kowalski M. S. Haque and K. W. Fields J. Am. Chem. Soc. 1985 107 1429. 22 C. J. Kowalski and R. E. Reddy J. Org. Chem. 1992 57 7194. 23 C. J. Kowalski and M. S. Haque J. Am. Chem. Soc. 1986 108 1325. 24 C. J. Kowalski and G. S. Lal J. Am. Chem. Soc. 1986 108 5356. 25 C. J. Kowalski and G. S. Lal Tetrahedron Lett. 1987 28 2463. 26 G. Maas and R. Brückmann J. Org. Chem. 1985 50 2802. 27 V. V. Zhdankin and P. J. Stang Tetrahedron Lett. 1993 34 1461. 28 C. J. Kowalski and G. S. Lal J. Am. Chem. Soc. 1988 110 3693. 29 For examples see R. L. Danheiser D. S. Casebier and A. H. Huboux J. Org. Chem. 1994 59 4844. 30 C. J. Kowalski and S. Sakdarat J. Org. Chem. 1990 55 1977. Received 5th May 1998 Accepted 22nd May 1998