Heterocyclic prostaglandins. V. Synthesis of (12R, 15S)-(-)-11-deoxy-8-azaprostaglandin e1 and related compounds.

Abstract

The synthesis of (12R, 15S)-(-)-11-deoxy-8-azaprostaglandin E1 ((R)-1a) and three diastereomers ((R)-2a, (S)-1a, and (S)-2a) starting from optically active pyroglutamic acid ((R)-3 and (S)-3) is reported. Esterification of (R)-3 and NaBH4 reduction gave (R)-(-)-5-hydroxymethyl-2-pyrrolidinone ((R)-5). Ethoxyethylation of (R)-5 and Nalkylation with methyl 7-bromoheptanoate, followed by acid treatment, provided (R)-hydroxymethyl pyrrolidinone ((R)-8). The Collins oxidation of (R)-8 gave (R)-(-)-methyl 7-(5-formyl-2-oxo-1-pyrrolidine) heptanoate ((R)-9), which served as a key intermediate. The Wittig reaction of (R)-9 and dimethyl 2-oxoheptylphosphonate gave the (R)-enone ((R)-10a) which was converted to the (12R, 15S)-enol ((R)-11a) and (12R, 15R)-enol ((R)-12a) by NaBH4 reduction. Alkaline hydrolysis of (R)-11a and (R)-12a gave (R)-1a and (R)-2a in high yields. Similarly, the (S)-aldehyde ((S)-9) was prepared from (S)-3 and converted to the (12S, 15S)-acid ((S)-1a) and (12S, 15R)-acid ((S)-2a) by the same sequence of reactions used for the (R)-series. Some (12R, 15S)-acid derivatives ((R)-1b-g) with a modified ω-chain were also synthesized. These analogs ((R)-1b-g) were also prepared from (R)-9 via synthetic sequences similar to that described above.