Shiro Terashima

Stereochemical studies—LVII: Synthesis of optically active compounds by the novel use of meso-compounds—1. Efficient synthesis of two structural types of optically pure prostaglandin intermediates

Abstract With an aim to overcome several inefficient aspects of ordinary methods of preparing optically active compounds, we have developed a new method which recommends utilization of symmetrically functionalized meso -compounds in place of racemic compounds. As shown in Scheme 1, when the mesa-compound ( I ) is monofunctionalized by an optically active functional group ( A ) and each of the formed diastereomers ( II and III ) is subjected to further chemical elaborations including protective group transposition, it is theoretically possible to convert the total amount of the starting material ( I ) into the requisite optically pure product ( VI or VII ) by selecting synthetic schemes. By employing this novel concept, two structural types of the prostaglandin intermediates ((−)- and ( + )- 2a , b ) have been prepared from the meso -diols ( 1a, b ) by way of the two diastereomeric monoesters ( 13a , b and 14a, b ) which are produced by the reactions of 1a, b with N-mesyl- and N-phthaloyl-(S)-phenylalanyl chloride ( 3a, b ).

Asymmetric halolactonisation reaction—1 : Asymmetric synthesis of optically active α,α-disubstituted-α-hydroxy acids from α,β-unsaturated acids by the novel use of halolactonisation r

Abstract 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.

Asymmetric halolactonisation reaction-2 : Elucidation of general applicability and mechanism of the asymmetric bromolactonisation reaction

Abstract 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.

Asymmetric synthesis of optically pure (R)(−)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol, a key intermediate for optically active anthracyclinone synthesis

Abstract Asymmetric reduction of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene(3) with lithium aluminum hydride partially decomposed with (−)-N-methylephedrine and N-ethylaniline was found to give the optically active allylic alcohol((−)-4) in 92% optical yield. Optically pure (−)-4 obtained in 87% yield based on 3 by recrystallization, was elaborated to the title compound((R)(−)-1) according to the reaction scheme exploited in the preceding paper.

Asymmetric halolactonisation reaction—4: Asymmetric synthesis of optically active α,β-epoxyaldehydes from α,β-unsaturated acids

Abstract 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).

Amino acids and peptides—IV: Novel peptide bond formation catalysed by metal ions—II Formation of optically active peptide esters

Abstract The novel peptide bond formation previously reported in the reaction of glycine ester with Cu(II) ion in an anhydrous solvent, was examined using several kinds of optically active amino acid esters. Various reaction conditions were studied in detail for Phe-OEt. From Phe-OEt, Ala-OMe, Leu-OMe, Trp-OMe, Ser-OMe, and Met-OMe, the expected dipeptide esters with the same amino acid components were obtained without racemization. Asp(OEt)-OEt, and Glu(OMe)-OMe gave only optically active α-dipeptide esters. No formation of dipeptide esters was observed with Ile-OMe, Cys-OMe, His-OMe, and Pro-OEt. However, Lys-OMe, and Orn-OMe afforded optically active lactam derivatives. Some explanations of these abnormal observations have been given. Attempts to prepare di- and tri-peptide esters carrying different kinds of amino acid units were also studied.

Novel resolution of the anthracyclinone intermediate by the use of (2r, 3r)-(+)- and (2s, 3s)-(-).1,4-bis(4-chlorobenzyloxy)butane-2,3-diol: a simple and efficient synthesis of optically pure 4-demethoxydaunomycinone and 4-demethoxyadriamycinone☆

Abstract (±)-7-Deoxy-4-demethoxydaunomycinone((±)-3) was found to be cleanly resolved by forming a mixture of the diastereomereic acetals((-)-9and(+)-10 or(+)-9 and(-)-10)with the title vicinal-diol(+)-or ( )-5), affording optically pure (R)-( )-3. The resolving agents (( + )- and ( )-5) were readily synthesized from unnatural(2S,3S)-(-)-tartaric acid((-)-6)or D-(-)-mannitol and natural (2R,3R)-(+)-tartaric acid((+)6), respectively. The undesired enantiomer ((S)-(+ )-3) obtained by the optical resolution could be racemized by heating with trifluoromethanesulfonic acid in aq acetic acid. Optically pure (R)-3 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-2b) and (+)-demethoxyadriamycinone ((+)-2a) by featuring highly stereoselective ( ⪢ 20:1) introduction of the OH group into the C7-position as a key step.

An efficient synthesis of optically pure anthracyclinone intermediates by the novel use of microbial reduction

Reduction of the racemic α-hydroxy ketones((±)-3a,b) with fermenting bakers yeast followed by fractional recrystallization and oxidation was found to readily afford optically pure anthracyclinone intermediates((R) (−)-3a,b and their partially optically active antipodes ((S)(+)-3a,b). The useless enantiomers ((S)(+)-3a,b and diastereomeric vicinal-diols((+)- 5a,b) could be recycled to (±)-3a,b and the achiral ketones(6a,b) by racemization and oxidative cleavage, respectively.

Asymmetric reduction of αβ-unsaturated ketones with lithium aluminium hydride partially decomposed by (–)-N-methylephedrine and N-ethylaniline

The title asymmetric reaction is found to convert open chain enones into the corresponding optically active allylic alcohols in high optical (78–98% enantiomeric excess) and chemical (92–100%) yields.

(+)- and (-)-1-0, 4-0-bis(p-chlorobenzyl)threitol as novel resolving agents for optically active anthracyclinone synthesis: an efficient synthesis of optically pure 4-demethoxydaunomycinone

(±)-7-Deoxy-4-demethoxydaunomycinone(±)-3) was cleanly resolved by forming a mixture of the diastereomeric acetals ((−)-9 and (+)-10 or (+)-9 and (−)-10 with the title vicinal-diol((+)- or (−)-5) to give optically pure (R)(−)-3. The method for racemizing the undesired enantiomer((S)(+)-3) was also explored. Optically pure (+)-4-demethoxydauno-mycinone ((+)-2b) was elaborated from (R)(-)-3 according to the reported reaction scheme.