Completing the β,γ-CXY-dNTP Stereochemical Probe Toolkit: Synthetic Access to the dCTP Diastereomers and 31 P and 19 F NMR Correlations with Absolute Configurations

Nucleoside 5'-triphosphate (dNTP) analogues in which the β,γ-oxygen is mimicked by a CXY group (β,γ-CXY-dNTPs) have provided information about DNA polymerase catalysis and fidelity. Definition of CXY stereochemistry is important to elucidate precise binding modes. We previously reported the ( )...

Full description

Saved in:
Bibliographic Details
Published in:Journal of organic chemistry 2020-11, Vol.85 (22), p.14592-14609
Main Authors: Haratipour, Pouya, Minard, Corinne, Nakhjiri, Maryam, Negahbani, Amirsoheil, Chamberlain, Brian T, Osuna, Jorge, Upton, Thomas G, Zhao, Michelle, Kashemirov, Boris A, McKenna, Charles E
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nucleoside 5'-triphosphate (dNTP) analogues in which the β,γ-oxygen is mimicked by a CXY group (β,γ-CXY-dNTPs) have provided information about DNA polymerase catalysis and fidelity. Definition of CXY stereochemistry is important to elucidate precise binding modes. We previously reported the ( )- and ( )-β,γ-CHX-dGTP diastereomers (X = F, Cl), prepared via P,C-dimorpholinamide CHCl ( , ) and CHF ( , ) bisphosphonates (BPs) equipped with an ( )-mandelic acid as a chiral auxiliary, with final deprotection using H /Pd. This method also affords the β,γ-CHCl-dTTP ( , ), β,γ-CHF ( , ), and β,γ-CHCl ( , ) dATP diastereomers as documented here, but the reductive deprotection step is not compatible with dCTP or the bromo substituent in β,γ-CHBr-dNTP analogues. To complete assembly of the toolkit, we describe an alternative synthetic strategy featuring ethylbenzylamine or phenylglycine-derived chiral BP synthons incorporating a photolabile protecting group. After acid-catalyzed removal of the ( )-(+)-α-ethylbenzylamine auxiliary, coupling with activated dCMP and photochemical deprotection, the individual diastereomers of β,γ-CHBr- ( , ), β,γ-CHCl- ( , 3 ), β,γ-CHF-dCTP ( , ) were obtained. The β,γ-CH(CH )-dATPs ( , ) were obtained using a methyl ( )-(-)-phenylglycinate auxiliary. P and F NMR Δδ values are correlated with CXY stereochemistry and p values for 13 CXY-bisphosphonic acids and imidodiphosphonic acid are tabulated.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.0c01204