SYNTHESIS OF PHOSPHONIC ACIDS RELATED TO THE ANTIBIOTIC FOSMIDOMYCIN FROM ALLYLIC α- AND γ-HYDROXYPHOSPHONATES

Abstract

Pd(O) catalyzed amination of dialkyl (1-methoxycarbonyloxy-2-alkenyl)phosphonates 4 (R³ = H) with the N,O-alkoxycarbonyl protected hydroxylamines BocNHOBoc (3a) and MocNHOMoc (3b) proceeds regiospecifically and with high (E)-stereoselectivity to give the protected (3-N-hydroxyamino-1-alkenyl)-phosphonates 5 and 6, respectively, with very good yields. Alternatively compounds 5 and 6 are obtained in excellent yields from the (3-hydroxy-l-alkenyl)phosphonates 2 under Mitsunobu conditions using 3a and 3b, respectively, as nucleophiles. Much less satisfactory yields of compounds 7 and 8 have been obtained in both pathways using the hydroxylamine derivatives BocNHOBn (3c), and AcNHOAc (3d), respectively, as nucleophiles. Compounds 5–8 have been further transformed to various precursors and analogues of the natural phosphonic acid antibiotics FR 32863 and FR 31564 (fosmidomycin).

Key Words:

• (3-N-hydroxyamino-1-alkenyl)phosphonic acids
• phosphonate substituted allylic carbonates
• N-hydroxyamination
• N-hydroxyureas
• tert-butyl (tert-butoxycarbonyloxy)carbamate
• rotational restriction