Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(<i>sp</i><sup>3</sup>)–H Bonds

Yu, Kuo Long; Zou, Zhiyong; Igareta, Nico V.; Tachibana, Ryo; Bechter, Julia; Köhler, Valentin; Chen, Dongping; Ward, Thomas R.

doi:10.1021/jacs.3c03969

Cited by 15 publications

(2 citation statements)

References 68 publications

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“…In addition to diazoacetate substrates, we also tested diazoketone 1f and diazoamide 1g , which upon cyclization form nonlactone products. These substrates proceeded smoothly with P411-LAS-5247 to furnish cyclic ketone 2f and γ-lactam 2g , with excellent TTNs (up to 5500 TTN, Figure D). It is worth noting that the lactam product was obtained without any additional protection–deprotection steps on nitrogen, underscoring the ability of the enzyme to work with substrates having active functional groups.…”

Section: Resultsmentioning

confidence: 99%

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Wackelin,

Mao,

Sicinski

et al. 2024

J. Am. Chem. Soc.

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Lactones are cyclic esters with extensive applications in materials science, medicinal chemistry, and the food and perfume industries. Nature's strategy for the synthesis of many lactones found in natural products always relies on a single type of retrosynthetic strategy, a C−O bond disconnection. Here, we describe a set of laboratory-engineered enzymes that use a new-tonature C−C bond-forming strategy to assemble diverse lactone structures. These engineered "carbene transferases" catalyze intramolecular carbene insertions into benzylic or allylic C−H bonds, which allow for the synthesis of lactones with different ring sizes and ring scaffolds from simple starting materials. Starting from a serine-ligated cytochrome P450 variant previously engineered for other carbene-transfer activities, directed evolution generated a variant P411-LAS-5247, which exhibits a high activity for constructing a five-membered ε-lactone, lactam, and cyclic ketone products (up to 5600 total turnovers (TTN) and >99% enantiomeric excess (ee)). Further engineering led to variants P411-LAS-5249 and P411-LAS-5264, which deliver six-membered δ-lactones and seven-membered ε-lactones, respectively, overcoming the thermodynamically unfavorable ring strain associated with these products compared to the γ-lactones. This new carbene-transfer activity was further extended to the synthesis of complex lactone scaffolds based on fused, bridged, and spiro rings. The enzymatic platform developed here complements natural biosynthetic strategies for lactone assembly and expands the structural diversity of lactones accessible through C−H functionalization.

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Section: Resultsmentioning

confidence: 99%

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Wackelin,

Mao,

Sicinski

et al. 2024

J. Am. Chem. Soc.

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“…Carbonyl nitrenes are key intermediates in the stepwise decomposition of carbonyl azides (Scheme ), a reaction known as the Curtius rearrangement . Owing to their application in the formation of carbon–nitrogen bonds, a number of methods for the generation of carbonyl nitrenes have been developed, such as the metal-catalyzed decomposition of dioxazolones . The facile intramolecular 1,2-R shift of carbonyl nitrenes (R–C(O)N → R–NCO) and their extremely reactive nature make the characterization of these intermediates challenging, which has been the subject of numerous experimental and theoretical studies .…”

Section: Introductionmentioning

confidence: 99%

Carbamoylphosphinidene: A Phosphorus Analogue of Carbonyl Nitrene

Lu,

Jiang,

Wang

et al. 2024

J. Am. Chem. Soc.

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Carbonyl nitrenes are versatile intermediates that have been extensively characterized; however, their phosphorus analogues remain largely unknown. Herein, we report the observation of a rare example of carbonyl phosphinidene NH 2 C(O)P, which was generated through the photolytic (193 nm) dehydrogenation of phosphinecarboxamide (NH 2 C(O)PH 2 ) in a solid N 2 -matrix at 12 K. The characterization of NH 2 C(O)P in the triplet ground state with matrix-isolation IR and ultraviolet− visible (UV−vis) spectroscopy is supported by comprehensive isotope labeling experiments (D and 15 N) and quantum chemical calculations. Upon visible-light irradiation at 680 nm, NH 2 C(O)P inserts into dihydrogen by the reformation of NH 2 C(O)PH 2 with concomitant isomerization to the more stable aminophosphaketene (NH 2 PCO). Additionally, the photoisomerization of NH 2 C(O)PH 2 to NH 2 C(OH) = PH along with decomposition by yielding hydrogen-bonded complexes HNCO•••PH 3 and HPCO•••NH 3 has been observed in the matrix.

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Chiral Osmium(II)/Salox Species Enabled Enantioselective γ‐C(sp³)−H Amidation: Integrated Experimental and Computational Validation For the Ligand Design and Reaction Development

Chen,

Xu,

Liu

et al. 2024

Angewandte Chemie

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Herein, multiple types of chiral Os(II) complexes have been designed to address the appealing yet challenging asymmetric C(sp3)‐H functionalization, among which the Os(II)/Salox species is found to be the most efficient for precise stereocontrol in realizing the asymmetric C(sp3)‐H amidation. As exemplified by the enantioenriched pyrrolidinone synthesis, such tailored Os(II)/Salox catalyst efficiently enables an intramolecular site‐/enantioselective C(sp3)‐H amidation in the γ‐position of dioxazolone substrates, in which benzyl, propargyl and allyl groups bearing various substituted forms are well compatible, affording the corresponding chiral γ‐lactam products with good er values (up to 99:1) and diverse functionality (> 35 examples). The unique performance advantage of the developed chiral Os(II)/Salox system in terms of the catalytic energy profile and the chiral induction has been further clarified by integrated experimental and computational studies.

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Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(sp³)–H Bonds

Cited by 15 publications

References 68 publications

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Carbamoylphosphinidene: A Phosphorus Analogue of Carbonyl Nitrene

Chiral Osmium(II)/Salox Species Enabled Enantioselective γ‐C(sp³)−H Amidation: Integrated Experimental and Computational Validation For the Ligand Design and Reaction Development

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Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(sp3)–H Bonds

Cited by 15 publications

References 68 publications

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Carbamoylphosphinidene: A Phosphorus Analogue of Carbonyl Nitrene

Chiral Osmium(II)/Salox Species Enabled Enantioselective γ‐C(sp3)−H Amidation: Integrated Experimental and Computational Validation For the Ligand Design and Reaction Development

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Product

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Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(sp³)–H Bonds

Chiral Osmium(II)/Salox Species Enabled Enantioselective γ‐C(sp³)−H Amidation: Integrated Experimental and Computational Validation For the Ligand Design and Reaction Development