Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides

Athavale, Soumitra V.; Gao, Shilong; Liu, Zhen; Mallojjala, Sharath Chandra; Hirschi, Jennifer S.; Arnold, Frances H.

doi:10.1002/anie.202110873

Cited by 52 publications

(75 citation statements)

References 42 publications

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“…Finally, density functional theory (DFT) calculations with a truncated system were carried out to explore the nature of the nitrene insertion into propargylic C(sp 3 )–H bond using model substrate 1a (Figure , see the SI for computational details). DFT calculations describe the putative iron–nitrenoid active species as a triplet ground state, in line with similar reported iron–nitrenoid species . Calculations indicate that nitrene insertion proceeds through a hydrogen atom transfer (HAT) step (TS1 Δ G ‡ = 14.7 kcal·mol –1 , in the triplet state) to initially form a propargyl radical intermediate, which then undergoes a radical rebound step (TS2 Δ G ‡ = 8.2 kcal·mol –1 , in the triplet state) generating the final propargyl amine product (Figure , and Figure S3 in the SI).…”

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confidence: 81%

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes

et al. 2021

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Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp 3 )-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is

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confidence: 81%

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes

et al. 2021

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“…In 2021, Athavale et al reported a P411 variant developed through nine rounds of directed evolution which is capable of nitrene transfer of pivaloxyl-amides. 216 In contrast to the P411 enzymes designed for tosylazide as the substrate, the ratedetermining step (RDS) in this variant is not C-H activation but nitrene formation as shown by KIE studies. These variants extend the substrate scope of the benzylic amines while also increasing the TON compared to that of P411-BPA.…”

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confidence: 99%

Designing Artificial Metalloenzymes by Tuning of the Environment beyond the Primary Coordination Sphere

et al. 2022

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Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an important role in both conferring and tuning their phenomenal catalytic properties, enabling active sites with otherwise similar primary coordination environments to perform a diverse array of biological functions. However, since the interactions beyond the primary coordination sphere are numerous and weak, it has been difficult to pinpoint structural features responsible for the tuning of activities of native enzymes. Designing artificial metalloenzymes (ArMs) offers an excellent basis to elucidate the roles of these interactions and to further develop practical biological catalysts. In this review, we highlight how the secondary coordination spheres of ArMs influence metal binding and catalysis, with particular focus on the use of native protein scaffolds as templates for the design of ArMs by either rational design aided by computational modeling, directed evolution, or a combination of both approaches. In describing successes in designing heme, nonheme Fe, and Cu metalloenzymes, heteronuclear metalloenzymes containing heme, and those ArMs containing other metal centers (including those with non-native metal ions and metallocofactors), we have summarized insights gained on how careful controls of the interactions in the secondary coordination sphere, including hydrophobic and hydrogen bonding interactions, allow the generation and tuning of these respective systems to approach, rival, and, in a few cases, exceed those of native enzymes. We have also provided an outlook on the remaining challenges in the field and future directions that will allow for a deeper understanding of the secondary coordination sphere a deeper understanding of the secondary coordintion sphere to be gained, and in turn to guide the design of a broader and more efficient variety of ArMs.

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“…Enzymatic C–H bond functionalization is an effective strategy for building and diversifying organic molecules. − C–H hydroxylation, an important C–H functionalization reaction, is an attractive pathway for synthesizing hydroxy amino acids, which are widely used as chiral building blocks in the pharmaceutical and fine chemical industries. For example, trans -4-hydroxy- l -proline is the functional intermediate for the synthesis of N -alkylpyrrole and carbapenem antibiotics. , Moreover, a series of hydrophobic hydroxy amino acid natural products from legume seeds exhibit important physiological activities; for example, (2 S ,3 R ,4 S )-hydroxyisoleucine (4-HIL) is a natural nonproteinogenic amino acid derived from fenugreek seeds with potential insulinotropic biological activity …”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Regioselectivity of the Fe(II)/2-Ketoglutarate-Dependent Dioxygenase-Catalyzed C–H Hydroxylation of Amino Acids

Jing

et al. 2022

ACS Catal.

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l-Isoleucine dioxygenase (IDO) directly catalyzes the C–H bond hydroxylation of several hydrophobic aliphatic amino acids. However, the ambiguous selectivity of IDO prevents its application in chiral hydroxy amino acid production. The hydroxylation of l-norleucine by IDO, which produces 4-hydroxynorleucine and 5-hydroxynorleucine with obvious regioselectivity, was used to investigate the mechanism of IDO regioselectivity. Along with computational structural analysis and high-throughput screening, the IDO structure revealed single-site variants (T244A, T244G, and T244S) with enhanced regioselectivity; for example, the 4-hydroxynorleucine purity in regioisomeric products increased from 78.9% (by wild-type IDO) to 95.1%, 96.6%, and 95.3%, respectively. Molecular dynamics simulations showed that mutating T244 into smaller amino acids fine-tuned the substrate binding pose. For asymmetric catalysis requiring precise positioning, this change expanded the most frequent distances between the substrate C4 or C5 and Fe2+, giving a maximum 4-hydroxynorleucine purity of 96.6%. We improved the understanding of the regioselectivity of Fe(II)/2-ketoglutarate-dependent dioxygenases and provide a route for diversifying C–H hydroxylation-based active compounds.

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Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides

Abstract: Supporting information for this article is given via a link at the end of the document.

Cited by 52 publications

References 42 publications

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes

Designing Artificial Metalloenzymes by Tuning of the Environment beyond the Primary Coordination Sphere

Molecular Insights into the Regioselectivity of the Fe(II)/2-Ketoglutarate-Dependent Dioxygenase-Catalyzed C–H Hydroxylation of Amino Acids

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