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

Abstract

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.

Iron catalysts with N-ligands for carbene transfer of diazo reagents

“…The aminoacidic replacement strategy (Scheme 30, pathway a), in which protein structure rearrangements and changes in the active site shape are responsible for non-natural activities, has been extensively studied [101][102][103][104][105][106][107] and reviewed 99,[108][109][110][111] and it will be not discussed herein. This review only discusses the catalytic activity of artificial biomolecules, which were obtained by inserting a synthetic catalyst into a bio-scaffold.…”

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…281 As asymmetric synthesis would, however, be the preferred synthetic strategy, Merck also investigated biocatalytic cyclopropanation towards this fragment. 282 The team envisioned recently discovered new-to-nature carbene transfer onto activated alkenes catalysed by haemoproteins to achieve cyclopropanation. Use of the non-activated 5-chloropentene (228), however, proved to be challenging, but a mutant of Hells' Gate globin I (HGG) from Methylacidophilium infernorum was found to catalyse the desired reaction.…”

“…286 An interesting small scale cascading approach was taken by co-expressing the latter enzyme with an epoxide hydrolase and two alcohol dehydrogenases (ADHs) to allow for the conversion of epoxides to amino alcohols (Scheme 49B). 287 Scheme 48 Synthesis of (1R,2R)-2-(pent-4-ynyl)cyclopropanol through enzymatic resolution (A) 281 or enzymatic asymmetric synthesis by carbene transfer (B) 282 followed by several chemical steps (I). 281 by the ADHs allowed for closed-loop recycling of co-factor NAD + .…”

Exploring and Adapting the Molecular Selectivity of Artificial Metalloenzymes

“…Examples include the synthesis of molecules like Levomilnacipran, 200 Ticagrelor (Figure 8A), 25,201 a TRPV1 inhibitor, 25 Tasimelteon (Figure 8B), 25 both (+) and (-) forms of Tranylcypromine, 25 a Merck antidiabetic drug, 69 and Grazoprevir ( Figure 8C). 202 Another recent example with much potential has been the use of P411s to carry out intermolecular alkylation via carbene C-H bond insertion. Through this highly enantioselective methodology, preparation of (+)-Lyngbic acid (Figure 8E), 47 and both (+) and (-) forms of Cuspareine ( Figure 8D) have been shown possible.…”