Dataset Information

Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

ABSTRACT: Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid.

SUBMITTER: Storch G

PROVIDER: S-EPMC7108786 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

Storch Golo G van den Heuvel Naudin N Miller Scott J SJ

Advanced synthesis & catalysis 20200101 2

Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functi ...[more]

PMID: 32256275

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Project description:Despite the astonishing diversity of naturally occurring biocatalytic processes, enzymes do not catalyze many of the transformations favored by synthetic chemists. Either nature does not care about the specific products, or if she does, she has adopted a different synthetic strategy. In many cases, the appropriate reagents used by synthetic chemists are not readily accessible to biological systems. Here, we discuss our efforts to expand the catalytic repertoire of enzymes to encompass powerful reactions previously known only in small-molecule catalysis: formation and transfer of reactive carbene and nitrene intermediates leading to a broad range of products, including products with bonds not known in biology. In light of the structural similarity of iron carbene (Fe═C(R1)(R2)) and iron nitrene (Fe═NR) to the iron oxo (Fe═O) intermediate involved in cytochrome P450-catalyzed oxidation, we have used synthetic carbene and nitrene precursors that biological systems have not encountered and repurposed P450s to catalyze reactions that are not known in the natural world. The resulting protein catalysts are fully genetically encoded and function in intact microbial cells or cell-free lysates, where their performance can be improved and optimized by directed evolution. By leveraging the catalytic promiscuity of P450 enzymes, we evolved a range of carbene and nitrene transferases exhibiting excellent activity toward these new-to-nature reactions. Since our initial report in 2012, a number of other heme proteins including myoglobins, protoglobins, and cytochromes c have also been found and engineered to promote unnatural carbene and nitrene transfer. Due to the altered active-site environments, these heme proteins often displayed complementary activities and selectivities to P450s.Using wild-type and engineered heme proteins, we and others have described a range of selective carbene transfer reactions, including cyclopropanation, cyclopropenation, Si-H insertion, B-H insertion, and C-H insertion. Similarly, a variety of asymmetric nitrene transfer processes including aziridination, sulfide imidation, C-H amidation, and, most recently, C-H amination have been demonstrated. The scopes of these biocatalytic carbene and nitrene transfer reactions are often complementary to the state-of-the-art processes based on small-molecule transition-metal catalysts, making engineered biocatalysts a valuable addition to the synthetic chemist's toolbox. Moreover, enabled by the exquisite regio- and stereocontrol imposed by the enzyme catalyst, this biocatalytic platform provides an exciting opportunity to address challenging problems in modern synthetic chemistry and selective catalysis, including ones that have eluded synthetic chemists for decades.

Project description:Recent research has highlighted the key role played by the electron affinity of the active metal-nitrene/imido oxidant as the driving force in nitrene additions to olefins to afford valuable aziridines. The present work showcases a library of Co(II) reagents that, unlike the previously examined Mn(II) and Fe(II) analogues, demonstrate reactivity trends in olefin aziridinations that cannot be solely explained by the electron affinity criterion. A family of Co(II) catalysts (17 members) has been synthesized with the assistance of a trisphenylamido-amine scaffold decorated by various alkyl, aryl, and acyl groups attached to the equatorial amidos. Single-crystal X-ray diffraction analysis, cyclic voltammetry and EPR data reveal that the high-spin Co(II) sites (S = 3/2) feature a minimal [N3N] coordination and span a range of 1.4 V in redox potentials. Surprisingly, the Co(II)-mediated aziridination of styrene demonstrates reactivity patterns that deviate from those anticipated by the relevant electrophilicities of the putative metal nitrenes. The representative L4Co catalyst (-COCMe3 arm) is operating faster than the L8Co analogue (-COCF3 arm), in spite of diminished metal-nitrene electrophilicity. Mechanistic data (Hammett plots, KIE, stereocontrol studies) reveal that although both reagents follow a two-step reactivity path (turnover-limiting metal-nitrene addition to the C b atom of styrene, followed by product-determining ring-closure), the L4Co catalyst is associated with lower energy barriers in both steps. DFT calculations indicate that the putative [L4Co]NTs and [L8Co]NTs species are electronically distinct, inasmuch as the former exhibits a single-electron oxidized ligand arm. In addition, DFT calculations suggest that including London dispersion corrections for L4Co (due to the polarizability of the tert-Bu substituent) can provide significant stabilization of the turnover-limiting transition state. This study highlights how small ligand modifications can generate stereoelectronic variants that in certain cases are even capable of overriding the preponderance of the metal-nitrene electrophilicity as a driving force.

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Dataset Information

Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

Publications

Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

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