Mechanistic Investigation of Biocatalytic Heme Carbenoid Si−H Insertions

Abstract

Recent studies reported the development of biocatalytic heme carbenoid Si−H insertions for the selective formation of carbon‐silicon bonds, but many mechanistic questions remain unaddressed. To this end, a DFT mechanistic investigation was performed which reveals an FeII‐based concerted hydride transfer mechanism with early transition state feature. The results from these computational analyses are consistent with experimental data of radical trapping, kinetic isotope effects, and structure‐reactivity data using engineered variants of hemoproteins. Detailed geometric and electronic profiles along the heme catalyzed Si−H insertion pathways were provided to help understand the origin of experimental reactivity trends. Quantitative relationships between reaction barriers and some properties such as charge transfer from substrate to heme carbene and Si−H bond length change from reactant to transition state were found. Results suggest catalyst modifications to facilitate the charge transfer from the silane substrate to the carbene, which was determined to be a major electronic driving force of this reaction, should enable the development of improved biocatalysts for Si−H carbene insertion reactions.

Computational Investigations of Heme Carbenes and Heme Carbene Transfer Reactions

“…Another significant bonding feature is that, compared with the two Fe d π and O p π interactions in the Fe IV complex, there is only one Fe d π and C p π interaction in IPC (Figure A). More recent calculations of other heme carbene systems also showed only one Fe d π and C p π interaction . Notably, the studied Fe IV complex has an effective Fe III coupled with O .− radical electronic structure based on spin densities; a pattern seen in typical ferryl heme systems .…”

“…Calculations have elucidated the origins of numerous qualitative experimental reactivity and selectivity trends due to different structural factors of reaction systems and protein environments –. Moreover, quantitative experimental stereoselectivities and KIE data have also been accurately reproduced in certain heme carbene transfer reactions . These results clearly indicate the importance of computational studies in this area.…”

“…A more recent study provides detailed comparisons to establish the basic reaction mechanism and reveals the origin of experimental reactivity trends of different substrates, carbenes, and axial ligands from the catalytic center …”

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.…”