Highly Diastereo‐ and Enantioselective Synthesis of Nitrile‐Substituted Cyclopropanes by Myoglobin‐Mediated Carbene Transfer Catalysis

Abstract

Ac hemobiocatalytic strategy for the highly stereoselective synthesis of nitrile-substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction catalyzedb ya ne ngineered myoglobin in the presence of ex situ generated diazoacetonitrile within acompartmentalized reaction system. This method enabled the efficient transformation of abroad range of olefin substrates at ap reparative scale with up to 99.9 %d ea nd ee and up to 5600 turnovers.T he enzymatic product could be further elaborated to affordavariety of functionalized chiral cyclopropanes.T his work expands the range of synthetically valuable,a biotic transformations accessible through biocatalysis and paves the waytothe practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.The catalytic asymmetric cyclopropanation of alkenes with diazo compounds constitutes aconvenient and direct strategy for the construction of optically active cyclopropanes, [1] which are key structural motifs in numerous natural products and pharmaceuticals. [2] Within this structural class,c yano-substituted cyclopropanes represent particularly attractive building blocks owing to the versatility of the cyano group toward its interconversion to avariety of functional groups. [3] Moreover, cyano-functionalized cyclopropanes have been incorporated into pharmacologically active molecules,including the potent cathepsin Ki nhibitor Odanacatib. [4] Notable contributions from the Davies,C harette,a nd Zhang groups have recently introduced chemocatalytic protocols for the asymmetric synthesis of cyano-substituted cyclopropanes starting from donor-acceptor or acceptor-acceptor diazo compounds. [5] In stark contrast, methods for the asymmetric synthesis of cyano-substituted cyclopropanes using the acceptor-only diazo reagent diazoacetonitrile (N 2 CHCN) have remained elusive.A sa ni solated effort in this direction, chiral Ruporphyrins were reported to catalyze the cyclopropanation of styrene derivatives in the presence of pre-formed diazoacetonitrile (1a), but only with moderate diastereoselectivity (20-50 % de)a nd enantioselectivity (41-71 % ee) (Scheme 1). [6] More recently,the Koenigs group has reported the iron-catalyzed cyclopropanation of vinylarenes in the presence of in situ generated [7] diazoacetonitrile. [8] While offering good yields and scalability,t his method provides only moderate diastereoselectivity (2:1 to 7:1d .r.)a nd no enantioselectivity in the cyclopropanation reaction (Scheme 1). [8] Motivated by the shortcomings of current methodologies for this transformation, we have pursued and report herein the development of ab iocatalytic strategy for the highly stereoselective synthesis of nitrile-substituted cyclopropanes by myoglobin-catalyzed olefin functionalization with diazoacetonitrile.T his method provides ar ather general, efficient, and scalable route to enantiopure cyclopropanes incorporating ac yano group,w hich can be readily elaborated to afford variously functionalized ...

Stereodivergent Intramolecular Cyclopropanation Enabled by Engineered Carbene Transferases

“…19 Engineered hemoproteins have recently emerged as promising biocatalytic platforms for carbene transfer reactions. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Recently, our group have demonstrated that engineered myoglobins (Mb) are capable of catalyzing the stereoselective intermolecular cyclopropanation of vinylarenes in the presence of diazo compounds with varied α-electron withdrawing groups (-COOR, -CF 3 , -CN), thus providing access to enantioenriched cyclopropanes (Scheme 1). 21,22,24,25,38 Engineered P450s 20,23,26,27 as well as artificial metalloenzymes 32,[39][40][41][42][43][44][45][46] have also proven useful for promoting intermolecular cyclopropanation reactions.…”

Designer metalloenzymes for synthetic biology: Enzyme hybrids for catalysis

“…The majority of work has focused on using directed evolution to expand the chemistry of heme enzymes including P450s, cytochrome cs, and myoglobins (Mb) to utilise metal carbene and nitrene intermediates, making a whole range of molecules from bicyclobutanes to organosilanes [1,5]. Recent work has pushed this further adding borylation [6][7][8] to S-H, N-H and Si-H insertions, as well as broadening the scope of carbene [9][10][11] and nitrene insertions [12,13]. Following the success of engineered heme enzymes in abiotic reactions, non-heme enzymes have been investigated as a starting platform.…”

“…This has enabled them to be optimised quickly using methods such as directed evolution leading to highly active catalysts. Additionally, whole cells can act as compartments which isolate metalloenzymes from starting materials, providing opportunities for the synthesis of reactive reagents in situ [9]. For these reasons, and to enable the use of ArMs in biosynthetic pathways, it is desirable to design ArMs that can be used in vivo.…”

Combining enzymes and organometallic complexes: novel artificial metalloenzymes and hybrid systems for C–H activation chemistry

“…24 C-H alkylation represents a very interesting chemical reaction. In this term, recently, the Fasan group has developed different evolved myoglobin variants for site-specific C-H cyclopropanation [25][26][27] or functionalization of unprotected indoles. 28 Functionalized indoles are very interesting molecules which have received significant attention.…”