Iridium(III)-Catalyzed Asymmetric Site-Selective Carbene C–H Insertion during Late-Stage Transformation

Yamakawa, Yuki; Ikuta, Takashi; Hayashi, Hiroki; Hashimoto, Kazunobu; Fujii, Ryoma; Kawashima, Kyohei; Mori, Susumu; Uchida, Toshihiro; Katsuki, Tsutomu

doi:10.1021/acs.joc.2c00470

Cited by 7 publications

(2 citation statements)

References 89 publications

(34 reference statements)

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“…There are evidences of non-covalent interaction (e.g., π-π) playing a decisive role in the active configuration and reactivity of a Ir-carbene species in the free state as well as in the IPC intermediate inside an enzyme. (12, 24)While the C317G mutation accounts for accommodating the Ir(Me) moiety, T213G mutation envelope and help to orient the ester part of diazoester by hydrophobic interactions. These results are in excellent agreement with the reported Ir-ArM crystal structure.…”

Section: Resultsmentioning

confidence: 99%

Non-Electrostatic Basis for an Artificial Metalloenzyme Catalysis

Mukherjee,

Roy

2024

Preprint

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The artificial metalloenzyme (referred to asIr-Q) reported by Hartwig and coworkers presented an important milestone in merging the extraordinary efficiency of biocatalyst with the versatility of small molecule chemical catalyst in catalyzing a new-to-nature carbene insertion reaction. The artificial enzyme results from formal replacement of the Fe by an Ir(Me) moiety along with four C317G, T213G, L69V, V254L mutations in a natural Cytochrome enzyme CYP119 by directed evolution method. Importantly, this is a show-stopper enzyme as it exhibits a catalytic rate enhancement similar to that of natural enzymes. Despite this remarkable discovery, there is no mechanistic understanding as to why it displays extraordinary efficiency, so far been intractable to experimental methods. In this study, we have deciphered the ‘catalytically active conformation’ ofIr-Qusing large-scale molecular dynamics simulations and rigorous quantum chemical calculations. Our study reveals how directed evolution mutations precisely position the cofactor-substrate in an unusual orientation within a reshaped active site that emerged during evolution and fostered by C−H…π interactions from more ordered mutated L69V and V254L residues. This productive conformation correctly reproduces the experimental barrier height and the catalytic effect of 2.7 kcal/mol, in excellent agreement with observed rate enhancement. Moreover, the active conformation features an unprecedented bonding interaction in a metal-carbene species that preferentially stabilizes the rate determining formation of an Iridium-Porphyrin Carbene intermediate to render the observed high catalytic rate acceleration. While the electrostatic criteria are widely established, this study suggests a new design paradigm towards realization of fully programmable protein catalysis.

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Section: Resultsmentioning

confidence: 99%

Non-Electrostatic Basis for an Artificial Metalloenzyme Catalysis

Mukherjee,

Roy

2024

Preprint

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“…Given the widespread availability of alkyne derivatives, the enantioselective construction of a C–C or C–X (X = N, O, etc.) bond at the propargylic position is an especially attractive strategy for accessing versatile chiral building blocks en route to stereochemically and functionally complex targets. , However, in contrast to a variety of well-developed protocols that employ prefunctionalized alkyne derivatives for asymmetric propargylation − or metal acetylide precursors for enantioselective nucleophilic addition to synthesize α-chiral alkynes, , the use of simple alkynes for enantioselective propargylic C–H functionalization remains an underdeveloped approach (Scheme A). − …”

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confidence: 99%

Enantioselective and Diastereodivergent Allylation of Propargylic C–H Bonds

2022

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An iridium-catalyzed stereoselective coupling of allylic ethers and alkynes to generate 3,4-substituted 1,5-enynes is reported. Under optimized conditions, the coupling products are formed with excellent regio-, diastereo-, and enantioselectivities, and the protocol is functional group tolerant. Moreover, we report conditions that allow the reaction to proceed with complete reversal of diastereoselectivity. Mechanistic studies are consistent with an unprecedented dual role for the iridium catalyst, enabling the propargylic deprotonation of the alkyne through π-coordination, as well as the generation of a π-allyl species from the allylic ether starting material.

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Enantioselective and Regiodivergent Synthesis of Propargyl‐ and Allenylsilanes through Catalytic Propargylic C−H Deprotonation

Zhu,

Xiang,

Chang

et al. 2024

Angewandte Chemie

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We report a highly enantioselective intermolecular C−H bond silylation catalyzed by a phosphoramidite‐ligated iridium catalyst. Under reagent‐controlled protocols, propargylsilanes resulting from C(sp3)−H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less‐hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ‐generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3‐enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3‐propargyl/allenyl Ir intermediate is generated upon π‐complexation‐assisted deprotonation and undergoes outer‐sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step.

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Iridium(III)-Catalyzed Asymmetric Site-Selective Carbene C–H Insertion during Late-Stage Transformation

Cited by 7 publications

References 89 publications

Non-Electrostatic Basis for an Artificial Metalloenzyme Catalysis

Non-Electrostatic Basis for an Artificial Metalloenzyme Catalysis

Enantioselective and Diastereodivergent Allylation of Propargylic C–H Bonds

Enantioselective and Regiodivergent Synthesis of Propargyl‐ and Allenylsilanes through Catalytic Propargylic C−H Deprotonation

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