A Ternary Complex Reagent for an Asymmetric Reaction of Lithium Ester Enolates with Imines

Fujieda, Hiroki; Kanai, Motomu; Kambara, Takeshi; Iida, A.; Tomioka, Kiyoshi

doi:10.1021/ja963581u

Cited by 181 publications

(51 citation statements)

References 18 publications

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“…The similar and relatively high enantioselectivity was observed regardless to lithiation reagents. Butyllithium and LDA treatment of 6, and ternary complex with LDA 13) in the presence of 3 gave ent-17 in the almost similar level of selectivity 63-69% ee (Entries 6, 7, 9). Presence of lithium bromide affected on chemical yield and enantioselectivity (Entry 8).…”

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confidence: 89%

“…[5][6][7][8] Particularly, the reaction of a lithium ester enolate with an imine represents a successful entry to a carbon-carbon bond forming asymmetric reaction, which is mediated by a chiral diether 1 and a chiral aminoether affording the corresponding b-lactam in a satisfactorily high enantioselectivity and high chemical yield. [9][10][11][12][13] Straightforward extension of the imine condensation to an aldol-type reaction with an aldehyde as a reaction partner provides a formidable challenge, because the reactivity of an aldehyde itself is high enough to an extent that does not need any activation for the reaction with a lithium enolate (Fig. 1).…”

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A Chiral Ligand-Mediated Asymmetric Addition of a Lithium BHA Ester Enolate to an Aldehyde

Nomura

Iguchi

Doi

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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An asymmetric addition reaction of an ester enolate with a carbonyl compound is one of the important and fundamental carbon-carbon bond forming reactions. [2][3][4] We have been involved in the chiral ligand-mediated asymmetric reactions of highly reactive metalated nucleophiles. [5][6][7][8] Particularly, the reaction of a lithium ester enolate with an imine represents a successful entry to a carbon-carbon bond forming asymmetric reaction, which is mediated by a chiral diether 1 and a chiral aminoether affording the corresponding b-lactam in a satisfactorily high enantioselectivity and high chemical yield.9-13) Straightforward extension of the imine condensation to an aldol-type reaction with an aldehyde as a reaction partner provides a formidable challenge, because the reactivity of an aldehyde itself is high enough to an extent that does not need any activation for the reaction with a lithium enolate (Fig. 1). 14,15) We describe herein that the reaction of a lithium BHA ester enolate with an aldehyde is mediated by a chiral ligand giving a moderate enantioselectivity. 16)Asymmetric Reaction of Propanoate We began our studies with the reaction of tert-butyl propanoate 4 with benzaldehyde 7 (Fig. 2). Treatment of 4 with LDA in the presence of a chiral diether ligand 1 in toluene and then with 7 gave the target 10 as a 27 : 73 mixture of syn-and anti-aldol products (Table 1, Entry 1). However, the enantioselectivity of the acetate 11 was poor. It has been reported by Heathcock that a lithium enolate generated from BHA (2,6-di-tert-buty-4-methoxyphenyl) propanoate 5 in THF reacted with 7 to give stereoselectively anti-aldol product 12.17) Since a BHA ester methodology has been our favourite, 18) we applied the Heathcock procedure in our asymmetric aldol-type reaction in toluene, instead of a THF solvent.Generation of a lithium enolate from BHA ester 5 was possible by butyllithium treatment at Ϫ78°C for 1 h in the presence of 1.3 eq of 1 in toluene, and following treatment with 7 at Ϫ78°C for 5 min to give an almost diastereomerically pure anti-12. The aldol product was immediately subjected to acetylation with acetic anhydride-triethylamine-DMAP in methylene chloride to afford the corresponding acetate anti-13 as a major product of a 7 : 93 mixture (Entry 2). Enantioselectivity of anti-13 was determined to be 32% by a chiral stationary phase HPLC analysis. Improvement of the enantioselectivity was possible by using LDA as a base affording anti-13 in 80% yield and 50% ee (Entry 3). A ternary complex reagent 12) was proved not to be beneficial providing anti-13 in 40% yield and 15% ee (Entry 4). The ether ligand 2 having an ethoxy group was not a choice, giving poorer selectivity of 9% (Entry 5). The best ligand among examined was a tetradentate 3, which mediated the reaction to afford anti-13 in 61% ee. However, the syn/anti selectivity was lost to afford syn-13 as a major product in 35% ee (Entry 6). The present procedure was applicable in the reaction with pivalaldehyde 8 giving the corresponding aldol product a...

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confidence: 89%

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confidence: 99%

A Chiral Ligand-Mediated Asymmetric Addition of a Lithium BHA Ester Enolate to an Aldehyde

Nomura

Iguchi

Doi

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…We have been involved in reactivity enhancement of carbonucleophiles such as organolithium, [1][2][3][4][5][6][7][8] Grignard reagent, [9][10][11] organozinc, [12][13][14] lithium phosphonate, [15][16][17][18][19] and lithium enolate [20][21][22] by forming a chelate with a ligand. [23][24][25][26][27] The successful above technology was extended to heteronucleophiles, nitrogen, oxygen, 28) and sulfur atoms which were activated by lithiation.…”

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confidence: 99%

Asymmetric Conjugate Addition of Arylthiols to Enoates and Its Application to Organic Synthesis of Biologically Potent Compounds

Nishimura

Tomioka

2003

YAKUGAKU ZASSHI

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As a part of our studies aimed at asymmetric catalytic reactions by using an external chiral ligand, we have developed a catalytic asymmetric addition reaction of an arylthiol to a,b-unsaturated esters under the control of an external chiral ligand. The characteristic of our technology is a double activation of a thiol by lithiation and chelate formation with a chiral tridentate amino diether ligand, which simultaneously and eŠectively controls a stereochemistry of the reaction. One signiˆcant feature of an arylthiol is a bulky 2-substitution on aryl group, which enables the formation of a really reactive monomeric thiolate species. s-Cis conformation and capability of electron lone pair-diŠerentiating coordination of a carbonyl oxygen to lithium are structural requirements of the substrates for high enantioselectivity. The enantioselectivity came up to 97％ under the cited conditions. Asymmetric protonation of a transient enolate, generated by conjugate addition of a lithium thiolate to an enoate, was also realized. The stereochemistry of the protonation was controlled by the conformation of initially formed transient enolate in a 1,2-asymmetric induction manner. This technology enabled the asymmetric synthesis of (S)-naproxene. Stereoselective tandem C S and C C bond-forming reaction was developed as a logical extension by trapping the transient enolate intermediate with an aldehyde as a carbo-electrophile in the presence of phenylthiotrimethylsilane as an equilibrium-shift reagent. This tandem reaction was extended to a stereoselective cyclization of v-oxo-a,b-unsaturated esters initiated by a lithium thiolate. Stereoselectivity of both tandem inter-and intramolecular reaction is predictable by an allylic strain-controlled conformation model of the enolate, in which an approach of aldehyde takes place anti to C S bond through coordination of an aldehyde oxygen to lithium. Total synthesis of (-)-neplanocin A was achieved by using the tandem cyclization as a key tool for the direct construction of aˆve-membered carbocycle where every carbon is functionalized.

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“…The three-component reagent [49][50][51][52] of a lithium enolate, 2-18-LDA, in toluene was found to give 11 in the highest 54% enantioselectivity but in 24% yield together with 16 in 32% yield. Screening of lithium amide components, lithium cyclohexylisopropylamide (LICA), lithium dicyclohexylamide (LDCA), lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium hexamethyldisilazide (LiHMDS), lithium trimethylsilyltritylamide (LiNTrTMS), 53) and lithium tert-butyltritylamide (LTBTA), 54) gave 11 in 13-31% enantioselectivities and 35-50% yields (entries [8][9][10][11][12][13][14].…”

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Chiral Ligand-Controlled Asymmetric Conjugate Addition of .ALPHA.-Trimethylsilanylacetate to Acyclic and Cyclic Enones

Iguchi

Doi

Hata

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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We describe herein our approach to the chiral ligand-controlled asymmetric conjugate addition of a-trimethylsilanylacetate via its lithium enolate to acyclic and cyclic enones, giving the corresponding b,b-disubstituted ketones in a good chemo-and enantioselectivity. Since the conjugate addition reaction is one of the powerful methodologies in forming a carbon-carbon bond, 1) the mediator-controlled asymmetric conjugate addition of carbonucleophiles to a,b-unsaturated carbonyl compounds has been an area of active investigations.2-9) However, albeit of its versatility a lithium enolate of an acetate itself has been one of the scarcely investigated nucleophiles in an asymmetric conjugate addition reaction with enones and enoates probably because of its difficulty in the achievement of the chemo-selective reaction. In fact, the reported approach to the conjugate addition of an acetate via its lithium enolate to even enoates has been limited only to the reaction studied by Yamaguchi. 10,11) This situation is very contrasted to the many brilliant successes in the Lewis acidmediated addition reaction of the silylketene acetal of an acetate.12-15) It is also interesting to note that lithium enolates of ketones have been reported as nucleophiles in asymmetric conjugate addition reactions, 16,17) while little effort has been devoted to lithium ester enolates. 18,19) We have been engaged in the chiral ligand-controlled 20) asymmetric conjugate addition reactions of various types of carbon-, nitrogen-, oxygen-, and sulfur-nucleophiles such as organolithiums, [21][22][23] organocoppers, 24,25) organoboranes, 26) lithium amides 27) lithium peroxides 28,29) and arylthiols. [30][31][32][33] We turned our project to a lithium ester-enolate as the next carbonucleophile in the conjugate addition to enones. Combined with the characteristic nature of the Michael donor [34][35][36] and high ability in enantiofacial differentiation in an enantioselective Peterson reaction under control of a chiral aminodiether (Chart 1), 37) we selected a-trimethylsilanylacetate 1 37) as a precursor for a lithium enolate. The challenge is the methodology extension from discrimination of the either face of the enolate 2 to the enantiofacial differentiation of the carbon-carbon double bond of an enone as well as the chemoselective reaction at the olefin double bond not at the carbonyl carbon.We began our studies with the addition of 1 via 2, generated by treatment with lithium diisopropylamide (LDA) in THF, to chalcone 7 in THF at Ϫ78°C and found the formation of the expected adduct 9 in 37% yield together with Peterson product 13 in 49% yield and reduction product 15 38) in 8% yield (Chart 2; The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of a a-trimethylsilanylacetate to acyclic and cyclic a a,b b-unsaturated ketones was mediated by an external chiral ligand to give the correspondin...

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A Ternary Complex Reagent for an Asymmetric Reaction of Lithium Ester Enolates with Imines

Cited by 181 publications

References 18 publications

A Chiral Ligand-Mediated Asymmetric Addition of a Lithium BHA Ester Enolate to an Aldehyde

A Chiral Ligand-Mediated Asymmetric Addition of a Lithium BHA Ester Enolate to an Aldehyde

Asymmetric Conjugate Addition of Arylthiols to Enoates and Its Application to Organic Synthesis of Biologically Potent Compounds

Chiral Ligand-Controlled Asymmetric Conjugate Addition of .ALPHA.-Trimethylsilanylacetate to Acyclic and Cyclic Enones

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