Collect. Czech. Chem. Commun. 1995, 60, 1196-1212

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

Antonín Holý and Milena Masojídková

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


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.