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 .