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Catalytic asymmetric alkylation of achiral lithium enolates of 1-tetralone and cyclohexanone with reactive alkyl halides was realized by using a combination of a chiral tetradentate amine (∼0.05 equiv.) and an achiral bidentate amine (2 equiv.).

The 1,4-addition reaction of organolithium reagents with 2,6-bis( tert -butyl)-4-methoxyphenyl naphthalenecarboxylates gave regioselectively substituted dihydronaphthalenecarboxylates in high yields. Successive treatment of the esters with organolithiums in THF, lithium triethylborohydride, methyl iodide, and finally sodium borohydride in methanol, provided regio- and stereoselectively the corresponding 1,1,2- and 1,2,2-trisubstituted dihydronaphthalenylmethanols in good yields. This one-flask process is constituted from a sequence of five reactions involving a reductive generation of an aldehyde metal enolate from a ketene as the key step.

An efficient enantioselective alkylation of the lithium enolates of cyclohexanone and I-tetralone with reactive alkyl halides was realized using a stoichiometric amount of a tetradentate chiral amine as a ligand for the lithium in the presence of lithium bromide in toluene.

1H-NMR spectral studies have shown that lithium-hydrogen interchange between a chiral bidentate amine ( (R)- 3b ) and an achiral tridentate lithium amide (5a) occurs rapidly in THF, favoring the exclusive formation of a chiral bidentate lithium amide ( (R)- 2b ) at equilibrium. This finding was applied to catalytic asymmetric deprotonation of prochiral 4-substituted cyclohexanones (1) using 0.3 equivalent of (R)- 3b in the presence of 2.4 equivalents of 5a in THF in the presence of DABCO and HMPA.

Enantioselective deprotonation of 4-substituted cyclohexanones ( 1a∼d ) by chiral bidentate lithium amides ( (R)- 2a∼j ) having an alkyl- or a fluoroalkyl substituent at the amide nitrogen was examined. (R)- 2i having a 2,2,2-trifluoroethyl group at the amide nitrogen was found to be an excellent chiral base for the present deprotonation reaction. Structures of (R)- 2i in solution and solid state are discussed.

6 Li- and 15 N-NMR spectroscopic analyses of a labeled chiral bidentate lithium amide ( [ 6 Li , 15 N 2 ]-(R)- 1 ) have shown that it exists as a chelated monomer ( 5 ) in THF and in DME, as a chelated dimer ( 6 ) in toluene and in ether, while as a chelated monomer ( 5 ) in any of these solvents in the presence of 2 equivalents of HMPA. Solvent-dependent enantioselectivities in deprotonation of 4- tert -butylcyclohexanone ( 2 ) by (R)- 1 appear to be correlated to these solution structures.

Enantioselective deprotonation of prochiral 4-substituted cyclohexanones (4a∼d) by chiral chelated lithium amides (8a≈k) in the presence of excess trimethylsilyl chloride was realized to give the corresponding chiral silyl enol ethers (6a∼d) in up to 89% ee. It is shown that enantioselectivity of the reaction is dependent on the solvent used, but becomes almost independent on the solvent in the presence of HMPA. The sense of asymmetric induction can be correlated to the configuration at the chiral carbon bearing amide nitrogen of the lithium amide. © 1997 Elsevier Science Ltd.

An asymmetric 1,2-addition reaction of organolithiums with imines 3, 7 was catalysed by a 0.05–1.3 equivalent of a chiral amino ether 2 to provide the corresponding optically active amines 4, 8 .

Enantioselective total synthesis of (+)-stoechospermol 2, a representative of spatane diterpenes having a cis,anti,cis-tricyclo[5.3.0.02,6]decane skeleton, was achieved by employing a stereo- and regioselective intramolecular (2+2) photocycloaddition of (S)-γ-hydroxymethyl-γ-butenolide-derived ester 10.

Chlorotrimethylsilane promoted asymmetric Michael reaction of the chiral lithioenamines derived from α-alkyl β-keto esters and ( S )-valine tert -butyl ester is described. Complementary asymmetric syntheses producing either enantiomers from the same starting material have been realized by changing the solvent system. That is, the lithioenamines react with methyl vinyl ketone or ethyl acrylate in THF in the presence of chlorotrimethylsilane to give, after hydrolysis, the Michael adducts in 57–90% ee. On the other hand, the reaction using toluene-HMPA as a solvent system, instead of THF, affords the corresponding antipodes with enantiomeric purities of 41–77% ee.

Optically active and racemic azaisopicrostegane ( 3 ), azapicrostegane ( 4 ), and all of four stereoisomers of racemic azaisopicrosteganols and azapicrosteganols ( 5, 6, 8, 9 ) were successfully synthesized by oxidative coupling of dibenzylurethanes ( 12, 18, 19 ).

Enantioselective 1,2-addition of Grignard reagents to aldehydes using chiral diamine 1, 2 was examined. High ee (up to 75 %) of carbinol was achieved by the reaction of arylmagnesium bromide and benzaldehyde with chiral diamine. Utilizing 2,4,6-trimethylphenoxyaluminum dichloride 6 as a coordinating agent to benzaldehyde, enantioselectivity of the addition of alkylmagnesium bromide was dramatically increased (up to 70 %).

Asymmetric alkylation reaction of chiral enamines prepared from α-alkyl β-keto esters and ( S )-valine tert -butyl ester leading to either enantiomer is described. Lithiated chiral enamines can be alkylated with alkyl halides in a toluene solvent in the presence of HMPA to give, after hydrolysis, α,α-dialkyl β-keto esters in 70–99%ee. The reactions in the presence of THF, dioxolane, or trimethylamine, instead of HMPA, afford the corresponding antipodes with enantiomeric purities of 44–92%ee. The present method provides a procedure for the synthesis of both enantiomers of α,α-dialkyl β-keto esters in high enantiomeric purities starting from the same chiral enamines.

Novel chiral pyrrolidine-based diamines with C2-symmetry 2, 3 and their related compounds 4 – 8 were designed and synthesized in optically pure forms. Both (+)- and (−)-2 were prepared from optical active ditosylane 9. 3 was prepared from 3,5-dimethylbenzaldehyde through optical resolution and its absolute stereochemistry was correlated with 2,3-dimethylsuccinate 27. 4 was prepared from (−)-diol 28. 5 – 8 were prepared from 9 and 11.

Short-step asymmetric syntheses of (+)-7-dehydroxy-4-demethoxydaunomycinone 4 and (−)-9-deacetyl-7-dehydroxy-4-demethoxy-9-hydroxymethyldaunomycinone 5 were accomplished via enantioselective dihydroxylation by osmium tetroxide with chiral diamine 13.

Detailed studies on the asymmetric bromolactonisation were carried out by employing several structural types of α,β-unsaturated acids (2) as reaction substrates and various (S)-α-amino acids as chiral sources. Following several novel aspects of the asymmetric bromolactonisation were uncovered by combining the results obtained in this study with those of the previous report. Thus, the bromolactonisation of (S)-N-(cis(E)-α,β-disubstituted-α,β-unsaturat acylproline((S)-3a,b) proceeds more stereoselectively than that of the trans(Z)-α,β-disubstituted analogue ((S)-3c), to give the 6-membered bromolactone(4A) via the symmetrical and/or the carbocationic bromonium ions (5AB and/or 5AC). While (S)-N-(trans(E)-β-monosubstituted-α,β-unsaturated)acyl-proline((S)-3d) undergoes no bromolactonisation, (S)-N-(β,β-disubstituted-α,β-unsaturated)acylproline((S)-3e) regiospecifically gives the 7-membered bromolactone(11e) via the carbocationic bromonium ion(5AA) when submitted to the bromolactonisation. (S)-Proline((S)-8) is found to the superior chiral source for the asymmetric bromolactonisation among those examined.

Treatment of 16 α-amino acid esters with isoamyl nitrite in the presence of a small amount of organic acid in chloroform or benzene, followed by chromatographic purification on alumina was found to afford the corresponding α-substituted-α-diazo esters ( 1 ) in fairly good yields.

Considering the usefulness of optically active α,α-disubstituted -α -hydroxy acids (1) andα,α- disubstituted-α-hydroxy ketones (2) readily accessible from 1 exploitation of a new asymmetric synthesis of 1 from α,β-unsaturated acids (3) which utilised halolactonisation reaction as its key step, was studied. The asymmetric bromolactonisation of (S) N-(α, β-unsaturated)acylproline((S) 5) derivable from 3 such as tiglic acid (3a) and trans-α methylcinnamic acid (3b), with N-bromosuccinimide in N,N dimethylformamide was found to proceed in a highly stereoselective and regiospecific manner giving a mixture of the two diastereomeric bromolactones (8) in which one diastereomer (8A) was highly predominant. Debromination of 8 followed by acidic hydrolysis readily afforded (R)-1 being 89-98% optically pure.

An alkaloid sesbanine (1) was synthesized starting from 1-malic acid as a chiral four-carbon unit. The key step was a highly stereoselective cycloannelation reaction to form a chiral quaternary carbon center. By this synthesis, the absolute configuration of natural sesbanine was established to 1. Furthermore, sesbanine, in both optically active and racemic forms, was found to be marginaly cytotoxic, contrary to remarkable cytotoxicity reported.

A highly useful method for diastereoselective and enantioselective synthesis of trans- and cis-1,2-disubstituted cycloalkanecarboxaldehydes (trans- and cis-10), useful chiral synthons having asymmetric tertiary and quaternary carbon atoms in vicinal positions in their rings, is devised starting from cycloalkenecarboxal-dehydes (5) t-Leucine t-butyl ester (2, R=But), a highly effective chiral auxiliary reagent in the present method, can be recovered for recycling without any loss of optical purity Some mechanistic explanations on the stereochemical courses of the reactions are presented

An asymmetric total synthesis of (+)-ivalin ( 4 ), a representative of antileukemic eudesmane sesquiterpenes, is described. The ene-aldehyde ( 6 ) was converted to the nearly optically pure alcohol ( 20 ) through the asymmetric double a1ky1ation reaction of the chiral ene-enamine ( 14 ). The ene-carbonyl cyclization of ( 25 ) with tin(IV) chloride afforded the core skeleton ( 26 ). The stereoinversion of hydroxyl group and further transformation furnished (+)-ivalin ( 4 ).

The bromolactones (5) stereoselectively produced by the asymmetric bromolactonisation of (S)-N-(α,β-unsaturated) acylprolines(3), were elaborated to highly optically active 2(R),3(S)-epoxyaldehydes(8)(84–98% ee) by successive epoxide formation and reductive cleavage of the proline moiety. The overall process constitutes a highly efficient asymmetric synthesis of 8 from α,β-unsaturated acids(1).