Enantioselective Synthesis of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) via Enzymatic Desymmetrization.
An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Mark
0000-0003-0595-4754
M
McLaughlin
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Jongrock
J
Kong
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Kevin M
KM
Belyk
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Billy
B
Chen
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Andrew W
AW
Gibson
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Stephen P
SP
Keen
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
David R
DR
Lieberman
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Erika M
0000-0003-3123-2923
EM
Milczek
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Jeffrey C
JC
Moore
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
David
D
Murray
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Feng
F
Peng
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Ji
0000-0003-4585-6534
J
Qi
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Robert A
RA
Reamer
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Zhiguo J
ZJ
Song
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Lushi
L
Tan
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Lin
L
Wang
Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Michael J
MJ
Williams
D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D002384:Catalysis; D003839:Deoxyadenosines / Q000138:chemical synthesis*; D006027:Glycosides / Q000737:chemistry; D006031:Glycosylation; D006865:Hydrogenation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis*; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D003839:Deoxyadenosines; D006027:Glycosides; D018894:Reverse Transcriptase Inhibitors; C558823:islatravir