865363-93-5Relevant articles and documents
Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose
Nawrat, Christopher C.,Whittaker, Aaron M.,Huffman, Mark A.,McLaughlin, Mark,Cohen, Ryan D.,Andreani, Teresa,Ding, Bangwei,Li, Hongming,Weisel, Mark,Tschaen, David M.
, p. 2167 - 2172 (2020)
A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.
Enantioselective Synthesis of 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) via Enzymatic Desymmetrization
McLaughlin, Mark,Kong, Jongrock,Belyk, Kevin M.,Chen, Billy,Gibson, Andrew W.,Keen, Stephen P.,Lieberman, David R.,Milczek, Erika M.,Moore, Jeffrey C.,Murray, David,Peng, Feng,Qi, Ji,Reamer, Robert A.,Song, Zhiguo J.,Tan, Lushi,Wang, Lin,Williams, Michael J.
, p. 926 - 929 (2017)
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.
Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication
Kamata, Mai,Takeuchi, Toshifumi,Hayashi, Ei,Nishioka, Kazane,Oshima, Mizuki,Iwamoto, Masashi,Nishiuchi, Kota,Kamo, Shogo,Tomoshige, Shusuke,Watashi, Koichi,Kamisuki, Shinji,Ohrui, Hiroshi,Sugawara, Fumio,Kuramochi, Kouji
, p. 217 - 227 (2020)
4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) and 4′-ethynyl-2′-deoxyadenosine (EdA) are nucleoside analogues which inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. EdAP, a cyclosaligenyl (cycloSal) phosphate derivative of EdA, inhibits the replication of the influenza A virus. The common structural feature of these compounds is the ethynyl group at the 4′-position. In this study, these nucleoside analogues were prepared by a common synthetic strategy starting from the known 1,2-di-O-acetyl-D-ribofuranose. Biological evaluation of EdAP revealed that this compound reduced hepatitis B virus (HBV) replication dose-dependently without cytotoxicity against host cells tested in this study.
Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone
Andreani, Teresa,Brunskill, Andrew,Fryszkowska, Anna,Huffman, Mark A.,Lévesque, Fran?ois,Li, Hongming,Maloney, Kevin M.,Mclaughlin, Mark,Nawrat, Christopher C.,Patel, Niki R.,Tschaen, David M.,Whittaker, Aaron M.,Xu, Yingju,Yang, Hao
, (2020/06/25)
The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition o