Asymmetric Synthesis of Functionalizedtrans-Cyclopropoxy Building Block for Grazoprevir

Abstract

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular S2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH)NEt. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

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

“…Stereoselective cyclopropanol synthesis remains challenging, with catalytic asymmetric syntheses being particularly rare . We envisioned generating the desired chiral cyclopropanol from the corresponding cyclopropyl methyl ketone by Baeyer–Villiger oxidation . This allowed us to target the cyclopropyl ketone 4 , which could, in principle, be made by cyclopropanation of unactivated olefin 5 with diazoacetone 6 .…”

“…Our interest in enzymatic cyclopropanation catalysts stemmed from the presence of a trans ‐1,2‐disubstituted cyclopropanol moiety within grazoprevir 1 (Scheme ), a component of the two‐drug hepatitis C treatment Zepatier. Stereoselective cyclopropanol synthesis remains challenging, with catalytic asymmetric syntheses being particularly rare . We envisioned generating the desired chiral cyclopropanol from the corresponding cyclopropyl methyl ketone by Baeyer–Villiger oxidation .…”

“…With proof‐of‐concept for the enzyme‐catalyzed step in‐hand, we next looked to demonstrate conversion of cyclopropyl ketone 4 to the desired cyclopropanol. 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.…”

General Cyclopropane Assembly by Enantioselective Transfer of a Redox‐Active Carbene to Aliphatic Olefins

“…With these results in hand, we explored the valorization of simple feedstocks in the synthesis of relevant chiral cyclopropanes (Scheme b–d). As such, 5‐bromopentene ( 5 f ) can be transformed in a three‐step process into the enantioenriched cyclopropanol fragment 76 of the drug grazoprevir® . l ‐allylglycine ( 5 g ) can be utilized to produce (via 77 ) the cyclopropylamine fragment 78 of the bioactive natural product (+)‐belactosin A (Scheme c) .…”

General Cyclopropane Assembly via Enantioselective Redox-Active Carbene Transfer to Aliphatic Olefins

“…As such, 5-bromopentene (5f)can be transformed in at hree-step process into the enantioenriched cyclopropanol fragment 76 of the drug grazoprevir . [27] l-allylglycine (5g)c an be utilized to produce (via 77)t he cyclopropylamine fragment 78 of the bioactive natural product (+ +)-belactosin A(Scheme 4c). [28] Moreover,propene gas (5h), the simplest prochiral aliphatic olefin, leads efficiently on ag ram-scale to 79 en route to the enantiopure cyclopropylboronate building block 80,u sed in the total synthesis of (À)-spongidepsin (Scheme 4d).…”