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

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Title:Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach
Creators:
Holý, Antonín
Dvořáková, Hana
Masojídková, Milena
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 60, 8, pp. 1390-1409

Abstract

<p>Another approach to (<i>R</i>)- and (<i>S</i>)-<i>N</i>-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) <i>I</i> and <i>II</i> is described, consisting in alkylation of the heterocyclic base with (<i>R</i>)- and (<i>S</i>)-2-[bis(2-propyl)phosphonylmethoxy]propyl <i>p</i>-toluenesulfonates (<i>X </i>and <i>XVIII</i>) followed by transsilylation of the intermediary <i>N</i>-[2-bis(2-propyl)phosphonylmethoxypropyl] derivatives <i>XI </i>and <i>XIX</i>. The key intermediates <i>X </i>and <i>XVIII </i>were obtained from 1-benzyloxypropanols <i>VI </i>and <i>XIV </i>by two routes: (i) condensation with bis(2-propyl) <i>p</i>-toluenesulfonyloxymethylphosphonate (<i>XIII</i>), hydrogenolysis of the obtained 1-benzyloxy-2-bis(2-propyl)phosphonylmethoxypropanes <i>VIII </i>and <i>XVI </i>over Pd/C to 2-bis(2-propyl)phosphonylmethoxypropanols <i>IX </i>and <i>XVII </i>and tosylation of the latter or (ii) chloromethylation of compounds <i>VI </i>and <i>XIV </i>and subsequent reaction of the chloromethyl ethers <i>VII </i>and <i>XV </i>with tris(2-propyl) phosphite and further processing of the benzyl ethers <i>VIII </i>and <i>XVI </i>analogous to the enantiomeric propanols <i>IX </i>and <i>XVII</i>. This approach was used for the synthesis of derivatives of adenine (<i>Ia</i>, <i>IIa</i>), 2,6-diaminopurine (<i>Ib</i>, <i>IIb</i>) and 3-deazaadenine (<i>Ic</i>, <i>IIc</i>). Their guanine counterparts <i>Ie </i>and <i>IIe </i>were prepared by hydrolysis of 2-amino-6-chloropurine intermediates <i>XId </i>and <i>XIXd</i>. 6-Chloropurine was converted into diester <i>XIi </i>by reaction with tosylate <i>X</i>, which on reaction with thiourea and subsequent ester cleavage afforded the 6-thiopurine derivative <i>Ij</i>. Analogously, 2-amino-6-chloropurine derivative <i>XId </i>reacted with thiourea to give 9-(<i>R</i>)-(2-phosphonomethoxypropyl)-2-thioguanine (<i>If</i>), or with dimethylamine under formation of (2-phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine (<i>Ig</i>). Hydrogenolysis of compound <i>XId </i>gave 9-(<i>R</i>)-(2-phosphonomethoxypropyl)-2-aminopurine (<i>Ik</i>). Hydrolytic deamination of adenine derivatives <i>Ia </i>and <i>IIa </i>led to enantiomeric (2-phosphonomethoxypropyl)hypoxanthines <i>Ih </i>and <i>IIh</i>.

Title:Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach
Creators:
Holý, Antonín
Dvořáková, Hana
Masojídková, Milena
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:60
Number:8
Page Range:pp. 1390-1409
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc19951390UNSPECIFIED
ID Code:836
Item Type:Article
Deposited On:06 Feb 2009 17:04
Last Modified:06 Feb 2009 16:04

Citation

Holý, Antonín; Dvořáková, Hana; Masojídková, Milena (1995) Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach. Collection of Czechoslovak Chemical Communications, 60 (8). pp. 1390-1409. ISSN 0010-0765

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