Selective Functionalization of Aliphatic Amines via Myoglobin-Catalyzed Carbene N–H Insertion

Abstract

Engineered myoglobins have recently gained attention for their ability to catalyze a variety of abiological carbene transfer reactions including the functionalization of amines via carbene insertion into N–H bonds. However, the scope of myoglobin and other hemoprotein-based biocatalysts in the context of this transformation has been largely limited to aniline derivatives as the amine substrates and ethyl diazoacetate as the carbene donor reagent. In this report, we describe the development of an engineered myoglobin-based catalyst that is useful for promoting carbene N–H insertion reactions across a broad range of substituted benzylamines and α-diazo acetates with high efficiency (82–99% conversion), elevated catalytic turnovers (up to 7,000), and excellent chemoselectivity for the desired single insertion product (up to 99%). The scope of this transformation could be extended to cyclic aliphatic amines. These studies expand the biocatalytic toolbox available for the selective formation of C–N bonds, which are ubiquitous in many natural and synthetic bioactive compounds.

Organic solvent stability and long‐term storage of myoglobin‐based carbene transfer biocatalysts

“…Although a number of natural enzyme classes represent key components of the biocatalytic toolbox for organic synthesis (e.g., hydrolases, ketoreductases, transaminases) [1,4,18,19], we and others have reported that heme-containing enzymes and proteins are functional biocatalysts for "abiological" carbene transfer reactions, including olefin cyclopropanation [20][21][22][23][24][25][26][27][28][29], Y-H carbene insertion (where Y = N, S, B, or Si) [30][31][32][33][34][35][36], C-H functionalization [37][38][39][40][41], aldehyde olefination [42,43], and others [44,45]. In particular, engineered myoglobins (Mbs) have emerged as particularly selective and versatile scaffolds for promoting a variety of carbene-mediated transformations useful for the selective construction of new carbon-carbon and carbon-heteroatom bonds [23][24][25][26][27][28][29]31,32,35,36,38,39,42,…”

Exploring and Adapting the Molecular Selectivity of Artificial Metalloenzymes

“…Summarized in Figure 2, a plethora of research in literature has focused on expanding heme-containing proteins for carbene transfer reactions. With the number of literature examples growing constantly, these new-to-nature reactions have included aldehyde olefination, [14][15] alkyne cyclopropenation, [16][17] alkene cyclopropanation, [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] the Doyle-Kirmse reaction, 37 N−H bond insertion, [38][39][40] S−H bond insertion, 27,41 Si−H bond insertion, [42][43] B−H bond insertion, [44][45][46] and C-H insertion. [47][48][49] Other works have also shown high enantioselectivity with C(sp 3 )−H bond aminations that can proceed either intramolecularly, 36,[50][51][52][53][54][55][56]…”

“…One more protein scaffold that has received considerable attention is myoglobin from Physeter macrocephalus ( Figure 2E). Extensively applied in asymmetric catalysis, this protein scaffold has displayed the capacity to improve a plethora of reactions that include N−H bond insertion, 38,40 S−H bond insertion, 41 Si−H bond insertion, 43 aldehyde olefination, 15 alkene cyclopropanation, 21,[23][24][25][26][34][35][36] intramolecular alkene cyclopropanation, [32][33] C−H bond amination, 36,52 azide-to-aldehyde conversion, 65 and the Doyle-Kirmse reaction. 37 One potentially significant reaction for industrial biocatalysis applications is the work done on C(sp 2 )−H functionalization.…”

Enantioselective Synthesis of Chiral Amines via Biocatalytic Carbene N–H Insertion

“…30,31 More recently, the substrate scope of the myoglobin-based biocatalysts was extended toward the functionalization of benzylic and aliphatic amines. 32 In addition, artificial metalloenzymes have been also reported to be able to promote this reaction. [33][34][35] Despite this progress, biocatalytic strategies for asymmetric carbene N-H insertion have thus far remained elusive.…”