- Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose
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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.
- 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.
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- Synthesis of Isotopically Labeled Anti-HIV Nucleoside Islatravir through a One-Pot Biocatalytic Cascade Reaction
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We report the synthesis of the carbon-14-labeled unnatural nucleoside islatravir, an investigational HIV drug, through a one-pot biocatalytic cascade starting from acetaldehyde-2-14C. Combining enzymatic reactions into multistep biocatalytic cascades accelerates delivery and increases the yield, and in this synthesis it has the added benefits of eliminating handling of radioactive intermediates and minimizing radioactive waste.
- Ren, Sumei,Huffman, Mark A.,Whittaker, Aaron M.,Yang, Hao,Nawrat, Christopher C.,Waterhouse, David J.,Maloney, Kevin M.,Strotman, Neil A.
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- Enantioselective Synthesis of 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) via Enzymatic Desymmetrization
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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.
- 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.
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- Biocatalytic oxidation of alcohols using galactose oxidase and a manganese(iii) activator for the synthesis of islatravir
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Galactose oxidase (GOase) is a Cu-dependent metalloenzyme that catalyzes the oxidation of alcohols to aldehydes. An evolved GOase variant was recently shown to catalyze a desymmetrizing oxidation as the first enzymatic step in the biocatalytic synthesis of islatravir. Horseradish peroxidase (HRP) is required to activate the GOase, introducing cost and protein burden to the process. Herein we describe that complexes of earth-abundant Mn(iii) (e.g.Mn(OAc)3) can be used at low loadings (2 mol%) as small molecule alternatives to HRP, providing similar yields and purity profiles. While an induction period is observed when using Mn(OAc)3as the activator, employment of alternative Mn(iii) sources, such as Mn(acac)3and K3[Mn(C2O4)3], eliminates the induction period and provides higher conversions to product. We demonstrate that use of the Mn(OAc)3additive is also compatible with subsequent biocatalytic steps in the islatravir-forming cascade. Finally, to exhibit the wider utility of Mn(OAc)3, we show that Mn(OAc)3functions as a suitable activator for several commercially available variants of GOase with a series of alcohol substrates.
- Johnson, Heather C.,Zhang, Shaoguang,Fryszkowska, Anna,Ruccolo, Serge,Robaire, Sandra A.,Klapars, Artis,Patel, Niki R.,Whittaker, Aaron M.,Huffman, Mark A.,Strotman, Neil A.
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- Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication
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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.
- 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
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- ADENOSINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed here is an adenosine derivative prodrug that can have reverse transcriptase inhibitor activity in vivo. This disclosure is also directed to a pharmaceutical composition comprising the adenosine derivative that can be used for the treatment of HIV infection or RNA virus infection.
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- Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone
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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
- 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
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- Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade
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A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water,
- Patel, Niki R.,Huffman, Mark A.,Wang, Xiao,Ding, Bangwei,McLaughlin, Mark,Newman, Justin A.,Andreani, Teresa,Maloney, Kevin M.,Johnson, Heather C.,Whittaker, Aaron M.
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supporting information
p. 14118 - 14123
(2020/10/06)
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- ENZYMATIC SYNTHESIS OF 4'-ETHYNYL NUCLEOSIDE ANALOGS
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The present invention relates to an enzymatic synthesis of 4'-ethynyl-2'-deoxy nucleosides and analogs thereof, for example EFdA, that eliminates the use of protecting groups on the intermediates, improves the stereoselectivity of glycosylation and reduces the number of process steps needed to make said compounds. It also relates to the novel intermediates employed in the process.
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(2020/02/06)
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- ENGINEERED PURINE NUCLEOSIDE PHOSPHORYLASE VARIANT ENZYMES
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The present invention provides engineered purine nucleoside phosphorylase (PNP) enzymes, polypeptides having PNP activity, and polynucleotides encoding these enzymes, as well as vectors and host cells comprising these polynucleotides and polypeptides. Methods for producing PNP enzymes are also provided. The present invention further provides compositions comprising the PNP enzymes and methods of using the engineered PNP enzymes. The present invention finds particular use in the production of pharmaceutical compounds.
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Paragraph 0192-0194; 0200-0208
(2020/02/06)
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- Design of an in vitro biocatalytic cascade for the manufacture of islatravir
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Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.
- Huffman, Mark A.,Fryszkowska, Anna,Alvizo, Oscar,Borra-Garske, Margie,Campos, Kevin R.,Canada, Keith A.,Devine, Paul N.,Duan, Da,Forstater, Jacob H.,Grosser, Shane T.,Halsey, Holst M.,Hughes, Gregory J.,Jo, Junyong,Joyce, Leo A.,Kolev, Joshua N.,Liang, Jack,Maloney, Kevin M.,Mann, Benjamin,Marshall, Nicholas M.,McLaughlin, Mark,Moore, Jeffrey C.,Murphy, Grant S.,Nawrat, Christopher C.,Nazor, Jovana,Novick, Scott,Patel, Niki R.,Rodriguez-Granillo, Agustina,Robaire, Sandra A.,Sherer, Edward C.,Truppo, Matthew D.,Whittaker, Aaron M.,Verma, Deeptak,Xiao, Li,Xu, Yingju,Yang, Hao
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p. 1255 - 1259
(2019/12/24)
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- 4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS AND PREPARATIONS THEREOF
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The present invention is directed to 4'-substituted nucleoside derivatives of Formula (I) and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment,
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Page/Page column 52; 55-56
(2017/04/11)
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- Synthesis of EFdA via a diastereoselective aldol reaction of a protected 3-keto furanose
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An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-d-glucose by a 14-step sequence that features a
- Fukuyama, Kei,Ohrui, Hiroshi,Kuwahara, Shigefumi
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supporting information
p. 828 - 831
(2015/03/31)
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- Concise synthesis of the anti-HIV nucleoside EFdA
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EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), a nucleoside reverse transcriptase inhibitor with extremely potent anti-HIV activity, was concisely synthesized from (R)-glyceraldehyde acetonide in an 18% overall yield by a 12-step sequence involving highly diastereoselective ethynylation of an α-alkoxy ketone intermediate. The present synthesis is superior, both in overall yield and in the number of steps, to the previous one which required 18 steps from an expensive starting material and resulted in a modest overall yield of 2.5%.
- Kageyama, Masayuki,Miyagi, Takuho,Yoshida, Mayumi,Nagasawa, Tomohiro,Ohrui, Hiroshi,Kuwahara, Shigefumi
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p. 1219 - 1225
(2012/10/18)
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- Enantioselective total synthesis of the potent Anti-HIV nucleoside EFdA
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A concise enantioselective total synthesis of 4′-ethynyl-2-fluoro- 2′-deoxyadenosine (EFdA), an extremely potent anti-HIV agent, has been accomplished from (R)-glyceraldehyde acetonide in 18% overall yield by a 12-step sequence involving a highly diastere
- Kageyama, Masayuki,Nagasawa, Tomohiro,Yoshida, Mayumi,Ohrui, Hiroshi,Kuwahara, Shigefumi
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p. 5264 - 5266
(2011/12/04)
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- 4' -C-substituted-2-haloadenosine derivative
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The present invention provides a 4′-C-substituted-2-haloadenosine derivative represented by the following formula (wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a ph
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(2008/06/13)
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