ASYMMETRIC SYNTHESIS OF (R_p)- AND (S_p)-2-ETHYL-, (R_p)-2-PENTYLOXY-, (S_p)-2-PENTYLTHIO- AND (S_p)-2-PENTYLAMINO-4H-1,3,2-BENZODIOXAPHOSPHORIN 2-OXIDES

Abstract

2-Substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides (2-substituted-BDPOs) are potent and stereoselective inhibitors of neuropathy target esterase (NTE) when the 2-substituent is n-alkyl, n-alkyloxy, n-alkylthio or n-alkylamino with maximum potency for the C₇ to C₉ analogs. Asymmetric syntheses were developed to assign the absolute configurations of each type of 2-substituted-BDPO. (S_p )-O-Methyl ethylphosphonothioic acid, the chiral starting material for (R_p )- and (S_p )-2-ethyl-BDPOs, was obtained by resolution of the racemate with quinine. It was ≤ 82% e.e. based on its stereospecific conversion to (R_p )-O-methyl ethylphosphonochloridothionate which was coupled with (S_c )-(−)-α-methylbenzylamine for analysis of the diastereomeric derivative by ¹H and ³¹P NMR and HPLC. The final (R_p )- and (S_p )-2-ethyl compounds were 80 and 82% e.e., respectively. The starting material for the chiral O-, S- and N-pentyl-BDPOs was (S_cR_p )-2-[1-(2-methoxycarbonylpyrrolidyl)]-4H-1,3,2-benzodioxaphosphorin 2-sulfide which was recrystallized to 100% d.e. (R_p )-2-Pentyloxy-BDPO (94% e.e.) was obtained by two reaction sequences involving two or four steps. (S_p )-2-Pentylthio-BDPO (100% e.e.) and (S_p )-2-pentylamino-BDPO (58% e.e.) were prepared in three- and five-step reactions, respectively. Optical purities were determined by HPLC with a CHIRALCEL OC column. In each asymmetric synthesis, the stereochemical orientation assigned for the substituents on phosphorus was consistent with the chromatographic characteristics on the chiral column.

Key Words:

• Asymmetric synthesis
• 1,3,2-benzodioxaphosphorin 2-oxide
• NTE inhibitors
• stereochemistry.