β,γ-CHF- and β,γ-CHCl-dGTP diastereomers: synthesis, discrete 31P NMR signatures, and absolute configurations of new stereochemical probes for DNA polymerases.

ABSTRACT: Deoxynucleoside 5'-triphosphate analogues in which the β,γ-bridging oxygen has been replaced with a CXY group are useful chemical probes to investigate DNA polymerase catalytic and base-selection mechanisms. A limitation of such probes has been that conventional synthetic methods generate a mixture of diastereomers when the bridging carbon substitution is nonequivalent (X ≠ Y). We report here a general solution to this long-standing problem with four examples of β,γ-CXY dNTP diastereomers: (S)- and (R)-β,γ-CHCl-dGTP (12a-1/12a-2) and (S)- and (R)-β,γ-CHF-dGTP (12b-1/12b-2). Central to their preparation was conversion of the prochiral parent bisphosphonic acids to the P,C-dimorpholinamide derivatives 7 of their (R)-mandelic acid monoesters, which provided access to the individual diastereom

SUBMITTER: Wu Y 

PROVIDER: S-EPMC3595068 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature