Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. I. The Stepwise Approach

Abstract

The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses. This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates. The key intermediates, N-(2-hydroxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) and acid hydrolysis of the resulting N-[2-(2-tetrahydropyranyloxy)propyl] derivatives VIII and XXII. The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethoxy)aluminum hydride. This approach was used for the synthesis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates. Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.