Development of a Practical, Asymmetric Synthesis of the Hepatitis C Virus Protease Inhibitor MK-5172

Kuethe, Jeffrey T.; Zhong, Yong‐Li; Yasuda, Nobuyoshi; Beutner, Gregory L.; Linn, Katherine; Kim, Mary; Marcune, Benjamin; Dreher, Spencer D.; Humphrey, Guy R.; Pei, Tao

doi:10.1021/ol401864t

Cited by 53 publications

(33 citation statements)

References 10 publications

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“…[13,37] Theoriginal scale-up ( Figure 5a)was carried out at dilutions of 0.01m ;consequent challenges were [31] Also instructive are examples in which metathesis routes were ultimatelye xcluded on the basis of poor RCM yields, and scale-up was not undertaken( e.g. [33] Figure 4. [33] Figure 4.…”

Section: Ciluprevir (1 02 M)mentioning

confidence: 99%

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

2016

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Section: Ciluprevir (1 02 M)mentioning

confidence: 99%

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

2016

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“…Adapting conditions developed on a different substrate, we demonstrated small‐scale conversion of the cyclopropyl ketone to the cyclopropanol and its corresponding acetate and trifluoromethylacetate esters via Baeyer–Villiger oxidation in excellent yield (Scheme ). The hydrolysis of cyclopropanol esters, as well as the subsequent conversion of chlorocyclopropanol 3 to alkyne 2 , and its subsequent elaboration to grazoprevir has been demonstrated elsewhere, thus completing a formal synthesis of grazoprevir.…”

Section: Methodsmentioning

confidence: 99%

Hemoprotein‐Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir

et al. 2019

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Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti‐hepatitis C drug grazoprevir.

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“…Interestingly, by changing the position for RCM macrocyclisation the yield improved to 71 % using the Zhan 1 b catalyst . In addition, lactam macrocyclisation also proceeded in good yield (65 %) . Just as for vaniprevir ( 133 ) and grazoprevir ( 135 ), Zhan's 1 b catalyst proved to be efficient for the macrocyclisation in the synthesis of voxilaprevir ( 136 ).…”

Section: Major Classes Of Bro5 Drugs—background and Synthesismentioning

confidence: 97%

“…[141] In addition, lactam macrocyclisationa lso proceeded in good yield (65 %). [142] Just as for vaniprevir (133)a nd grazoprevir (135), Zhan's 1b catalystp roved to be efficient for the macrocyclisation in the synthesis of voxilaprevir (136).…”

Section: Hcv Ns3/4aprotease Inhibitorsmentioning

confidence: 99%

Drug Syntheses Beyond the Rule of 5

Tyagi

Begnini

Poongavanam

et al. 2019

Chemistry A European J

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Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi‐synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring‐closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.

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Development of a Practical, Asymmetric Synthesis of the Hepatitis C Virus Protease Inhibitor MK-5172

Abstract: The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.

Cited by 53 publications

References 10 publications

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

Hemoprotein‐Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir

Drug Syntheses Beyond the Rule of 5

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