Aryl H-Phosphonates. 6. Synthetic Studies on the Preparation of Nucleoside N-Alkyl-H-phosphonamidates

Abstract

Various approaches to the synthesis of nucleoside H-phosphonamidates have been investigated. Direct couplings of nucleoside H-phosphonates with amines have been hampered by extensive reactions of the condensing agents with amines. Preactivation of nucleoside H-phosphonates with pivaloyl chloride or chlorophosphates, followed by the addition of amines, notably diminished these side reactions. The most efficient and versatile route to nucleoside N-alkyl H-phosphonates was found to be aminolysis of the in situ-produced aryl nucleoside H-phosphonates with appropriate amines.

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

“…Nucleoside aryl H-phosphonate can be prepared ei ther by phosphonylation of a suit able pro tected nucleoside with an ap pro pri ate phosphonylating re agent bear ing an aryl moiety [10], or by re act ing a nucleoside H-phosphonate with an ap pro pri ate phe nol in the pres ence of a con dens ing agent [8,11]. The lat ter ap proach (Scheme 1) al le vi ates prob lems con nected with prep a ra tion of sep arate phosphonylating re agents for each kind of aryl H-phosphonate de riv a tive and, in light of the eas ily ac ces si ble H-phosphonate monoesters, ap pears to be also the most con -ve nient and ver sa tile route to these compounds.…”

“…The H-phosphonate meth od ol ogy, due to its ef fi ciency, re li abil ity and ex per i men tal simplic ity, has emerged in the last de cade as a ver sa tile and pow er ful ap proach to the syn thesis of bi o log i cally ac tive phos phate an a logues [2,3]. As part of our stud ies in this field, we have re cently de vel oped aryl H-phosphonates as a new type of ac tive H-phosphonate de riv atives [4][5][6][7][8][9]. Their ad van tages as syn thetic inter me di ates stem from the fact that these com pounds pos sess, in prin ci ple, only one electrophilic cen ter lo cated on the phos pho rus atom, and in con tra dis tinc tion to other re active H-phosphonate spe cies (e.g.…”

“…These features sig nif i cantly broaden syn thetic ap pli cations of H-phosphonate meth od ol ogy by enabling the syn the ses of oth er wise dif fi cultly ac ces si ble com pounds, e.g. nucleoside H-phosphonamidates [8].…”

Georgetown Institute for Cognitive and Computational Sciences, 2001

“…Compound 1 was prepared using a literature method Conjugate addition of Sodium hypophosphite to a-methylene dibenzyl glutarate 1 afforded the phosphonite 2, which was converted to benzyl group protected compound 3a in presence of trimethylacetyl chloride. 10 Deprotonation of compound 3a with NaH followed by conjugate addition to compound 1 provided the all protected pentaester 4a, which was finally transformed to compound FN6 after hydrogenolysis (Scheme 2). Reagents and conditions: (a) NaH 2 P0 2 , TMSC1, Et 3 N, then compound 1, rt, 24 h; (b) PivCl, BnOH, CH 2 Cl 2 /py(10 : 1), rt, 2 h; (c) NaH, THF, 0° C, then compound 1, rt, 2 h; (d) 20% Pd(OH) 2 /C, 70 psi H 2 , rt, 24h, (e) PivCl, R-(+)-l-phenyl-l-butanol, CH 2 Cl 2 /py(10 : 1), rt, 2 h.…”

Facile Substituent Exchange at H‐Phosphonate Diesters Limiting an Effective Synthesis of D‐Phosphonate Diesters

“…Similarly, alcoholysis (also reported as transesterification) is possible under high concentrations of alcohol (Scheme b) . Less well‐known for H ‐phosphonate diesters, but potentially useful (or problematic depending on the application), is aminolysis of H ‐phosphonate diesters (Scheme c) where the RO substituent is replaced by NHR′ from an amine (NH 2 R′) . The mechanism of these processes has been postulated to occur via pentacoordinate P(V) intermediates formed by nucleophilic attack on the tetracoordinated phosphorus (Scheme , pictured at the bottom).…”