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The stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668) is described. The key step is the selective synthesis of intermediate threo-2(2,4-difluorophenyl)-2-(1-substituted ethyl)oxirane. threo-2-(2,4-Difluorophenyl)-2-(1-methylthioethyl)oxirane was synthesized threo-selectively by the reaction of 1-(2,4-difluorophenyl)-2-methylthio-1-propanone with dimethyloxosulfonium methylide in a heterogeneous media consisting of a hydrophobic solvent and aqueous alkaline solution.

An efficient synthesis of 1β-methylcarbapenem from the 1-(2-oxoazetidinyl)acetate 8 was developed by application of the Dieckmann reaction. Dieckmann-type cyclization of 8 and conversion to the enolphosphate 10 were achieved without epimerization to the 1α-methyl isomer in a one-pot procedure. Treatment with the mercaptan 22 after the phosphorylation resulted in a practical one-pot preparation of the 1β-methylcarbapenem derivative 23 from 8.

The stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668) is described. The key step is the selective synthesis of intermediate threo-2(2,4-difluorophenyl)-2-(1-substituted ethyl)oxirane. threo-2-(2,4-Difluorophenyl)-2-(1-methylthioethyl)oxirane was synthesized threo-selectively by the reaction of 1-(2,4-difluorophenyl)-2-methylthio-1-propanone with dimethyloxosulfonium methylide in a heterogeneous media consisting of a hydrophobic solvent and aqueous alkaline solution.

(±)-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.

In order to discriminate the possible racemization mechanisms shown in Chart 1 (for (S)-(-)-1a) for the α-hydroxy ketone moiety (C9-position of the optically active anthracyclinones ((S)-(+)-1a-c), some plausible intermediates ((±)-2 and -3) and their equivalent ((R)-(-)-12) were first synthesized. Thus, the tertiary alcohol ((R)-(-)-12) was prepared from the 1'(S), 2 (R)-diol ((-)-10) according to the reaction scheme shown in Chart 2. The isomeric seven-membered α-hydroxy ketones ((±)-2 and -3) were elaborated from the 1, 4-dihydronaphthalene (13), following the synthetic scheme shown in Charts 3 and 4 based on Dieckmann condensation, dihydroxylation, regioselective enol acetate formation, and oxidation as key steps. By subjecting the plausible intermediates ((±)-2 and -3, 5, and (R)-(-)-12) to the racemization conditions, the facile loss of optical integrity observed for (S)-(+)-1a-c was found to proceed through the ring-expanded seven-membered α-hydroxy ketones ((±)-2 and -3 for (S)-(+)-1a, which might be produced by equilibrium C (Chart 1).

Microbial reduction of the racemic α-hydroxy ketones ((±)-3a, b) with fermenting baker's yeast was found to afford diastereomeric mixtures of the vicinal-diols ((-)-4a, b) and ((+)-5a, b) in 90 and 91% yields, respectively. Separation of these diastereomers was readily accomplished by fractional recrystallization, giving pure (-)-4a, b and mixtures of (-)-4a, b and (+)-5a, b. Oxidation of these samples furnished optically pure anthracyclinone intermediates ((R)-(-)-3a, b) and their partially optically active antipodes ((S)-(+)-3a, b). The undesired enantiomers ((S)-(+)-3a, b) and vicinal-diols ((+)-5a, b) could be recycled to (±)-3a, b and the prochiral ketones (6a, c) by racemization with p-toluenesulfonic acid and oxidative cleavage with sodium metaperiodate, respectively. Another important optically pure anthracyclinone intermediate ((R)-(-)-3c) was prepared from (R)-(-)-3a, b according to the reported method.

Reduction of the racemic α-hydroxy ketones((±)-3a,b) with fermenting baker's 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.

(±)-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.

δ-Lycorane (IV), one of the four possible stereoisomers of the skeleton of the Amaryllidaceae alkaloids including lycorine and caranine, was synthesised from methyl 1,2,t-4a,t-9a-tetrahydro-6,7-methylenedioxy-9-oxofluorene-r-1-carboxylate (V). Treatment of its hydrogenation product with base gave the epimeric methyl 1,2,3,4,c-4a,c-9a-hexahydro-6,7-methylenedioxy-9-oxofluorene-r-carboxylate (VII), from which 1,2,3,4,c-4a,c-9a-hexahydro-r-1-hydroxymethyl-6,7-methylenedioxyfluoren-9-one (IX) was prepared. The Schmidt reaction with the fluorenone afforded 1,2,3,4,c-4a,5,6,c-10b-octahydro-r-4-hydroxymethyl-8,9-methylenedioxyphen-anthiridin-6-one (X), which was converted into 1,2,3,4,c-4a,5,6,c-10b-octahydro-8,9-methylenedioxy-6-oxophenanthiridin-r-4-ylacetonitrile (XIII). Hydrolysis of the nitrile followed by cyclisation gave 2,3,r-3a,t-11c-tetrahydro-9,10-methylenedioxy-7H-pyrrolo[3,2,1-de]phenanthiridine-5(4H),7(t-11bH)-dione (XV), furnishing δ-lycorane on reduction with lithium aluminium hydride.

In order to discriminate the possible racemization mechanisms shown in Chart 1 (for (S)-(-)-1a) for the α-hydroxy ketone moiety (C9-position of the optically active anthracyclinones ((S)-(+)-1a-c), some plausible intermediates ((±)-2 and -3) and their equivalent ((R)-(-)-12) were first synthesized. Thus, the tertiary alcohol ((R)-(-)-12) was prepared from the 1'(S), 2 (R)-diol ((-)-10) according to the reaction scheme shown in Chart 2. The isomeric seven-membered α-hydroxy ketones ((±)-2 and -3) were elaborated from the 1, 4-dihydronaphthalene (13), following the synthetic scheme shown in Charts 3 and 4 based on Dieckmann condensation, dihydroxylation, regioselective enol acetate formation, and oxidation as key steps. By subjecting the plausible intermediates ((±)-2 and -3, 5, and (R)-(-)-12) to the racemization conditions, the facile loss of optical integrity observed for (S)-(+)-1a-c was found to proceed through the ring-expanded seven-membered α-hydroxy ketones ((±)-2 and -3 for (S)-(+)-1a, which might be produced by equilibrium C (Chart 1).

Microbial reduction of the racemic α-hydroxy ketones ((±)-3a, b) with fermenting baker's yeast was found to afford diastereomeric mixtures of the vicinal-diols ((-)-4a, b) and ((+)-5a, b) in 90 and 91% yields, respectively. Separation of these diastereomers was readily accomplished by fractional recrystallization, giving pure (-)-4a, b and mixtures of (-)-4a, b and (+)-5a, b. Oxidation of these samples furnished optically pure anthracyclinone intermediates ((R)-(-)-3a, b) and their partially optically active antipodes ((S)-(+)-3a, b). The undesired enantiomers ((S)-(+)-3a, b) and vicinal-diols ((+)-5a, b) could be recycled to (±)-3a, b and the prochiral ketones (6a, c) by racemization with p-toluenesulfonic acid and oxidative cleavage with sodium metaperiodate, respectively. Another important optically pure anthracyclinone intermediate ((R)-(-)-3c) was prepared from (R)-(-)-3a, b according to the reported method.

(±)-Clivonine and (±)-clividine, lactonic alka-loids in Amaryllidaceae plants, have been synthesised.