A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug.

Four enantiomerically pure stereoisomers of rosaprostol (1), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone (3) as chiral substrates. The latter were obtained by resolution of racemic 3 with (+)-(R)-1-(1-naphthyl)ethylamine. The conversion of (+)-3 into rosaprostol stereoisomer (-)-1a was accomplished in four steps in 56% overall yield. According to the same protocol, the second stereoisomer (+)-1c was obtained from (-)-3 in 55% overall yield. A slightly improved procedure of the last two steps of the transformation of (+)-3 into (-)-1a allowed an increase in the overall yield to 64%. The remaining two stereoisomers, (-)-1b and (+)-1d, were obtained from (-)-1a and (+)-1c in 71 and 68% yield, respectively, by a two-reaction sequence, in which a Mitsunobu inversion of configuration at C-5 was the key step.

Synthesis of Enantiomerically Pure Stereomers of Rosaprostol.

Enantiopure stereomers of rosaprostol 1, an antiulcer drug, were synthesized from diastereomeric building blocks (-)-5a and (+)-5b. Conversion of (-)-5a into rosaprostol stereomer (-)-(1S,2R,5R)-1a was accomplished in nine steps in 18% overall yield. In this sequence, fully diastereoselective hydrogeneration of the endocyclic carbon double bond in the cyclopentenone ring was key, generating a new stereogenic center (C-2 in 1a). C-5 epimeric rosaprostol (-)-(1S,2R,5S)-1b was obtained from (-)-1a in 72% yield by a two-reaction sequence involving methylation and one-pot Mitsunobu esterification-hydrolysis.

Diphosphine sulfides derived from 2,2'-biphosphole: novel chiral S,S ligands for palladium-catalyzed asymmetric allylic substitution.

Diphosphine sulfides derived from 2,2'-biphosphole have been efficiently synthesized in an enantiomerically pure form by a four step synthetic sequence. These S,S-ligands were used for the first time in Pd-catalyzed asymmetric allylic alkylation. Good yields and enantiomeric excess up to 73% were obtained.