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Diastereoselective Synthesis of (Aryloxy)phosphoramidate Prodrugs
Author(s) -
Arbelo Román Cristina,
Wasserthal Philip,
Balzarini Jan,
Meier Chris
Publication year - 2011
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201100614
Subject(s) - phosphoramidate , chemistry , diastereomer , prodrug , stereochemistry , phenols , residue (chemistry) , enantioselective synthesis , combinatorial chemistry , organic chemistry , catalysis , biochemistry
The first diastereoselective synthesis of aryloxyphosphoramidate prodrugs of 3′‐deoxy‐2′,3′‐didehydrothymidinemonophosphate (d4TMP) was recently reported. The synthetic approach utilized the chiral auxiliary ( S )‐4‐isopropylthiazolidine‐2‐thione ( 2 ). For this strategy, a stereochemically pure phosphorodiamidate intermediate was needed. The diastereoselective formation of this key compound was investigated by using different phenols and L ‐alanine methyl or benzyl ester. Generally, the reaction with 3‐ or 4‐substituted phenols led to significantly better diastereoselectivities compared to their 2‐substituted counterparts. Moreover, variation of the ester group in the amino acid residue resulted in no significant differences with regard to the obtained diastereoselectivity. From the reported results, a model for the transition state was elaborated. Finally, eight new ( S P )‐arylphosphoramidates were synthesized with very high diastereoselectivities (up to ≥ 95 % de ) and tested for their anti‐HIV potency, showing a tendency for higher antiviral activity from the ( S P ) diastereomers.