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4‐(Acetylthio)‐2,2‐dimethyl‐3‐oxobutyl and 4‐( tert ‐Butyldisulfanyl)‐2,2‐dimethyl‐3‐oxobutyl as Protecting Groups for Nucleoside 5′‐Phosphoramidates Derived from L ‐Alanine Methyl Ester
Author(s) -
Sontakke Vyankat A.,
Lönnberg Harri,
Ora Mikko
Publication year - 2015
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.201500531
Subject(s) - chemistry , phosphoramidate , reductive amination , glutathione , nucleoside , amination , hydrolysis , dimer , medicinal chemistry , phosphonate , protecting group , stereochemistry , organic chemistry , enzyme , catalysis , alkyl
Phosphoramidates 1 and 2 were synthesized by H ‐phosphonate methodology and subsequent oxidative amination with L ‐alanine methyl ester. The removal of the protecting groups at pH = 7.5 and 37 °C in the absence and presence of porcine liver esterase (PLE) or glutathione (GSH) was monitored by HPLC. The stability of phosphoramidate 1 was additionally studied at pH = 9 and 10. The reduction of the disulfide bond with glutathione from 2 triggers the removal of the protecting group by cyclization releasing quantitatively nucleoside 5′‐{ N ‐[(1 S )‐2‐oxo‐2‐methoxy‐1‐methylethyl]phosphoramidate} ( 7 ) as the desired product. With 1 , enzymatic deacetylation or acetyl migration from the sulfur atom to the adjacent hydrated oxo group followed by chemical cyclization produces 7 . The S–S‐bond‐mediated dimerization ( 8 ) competes as a side reaction. Prolonged treatment, however, resulted in the conversion of the S–S dimer 8 into 7 that undergoes slow alanine methyl ester hydrolysis to form 10 .