Organocatalytic Asymmetric Synthesis of Versatile γ‐Lactams

Optically pure lactams have a wide diversity of applications, one of which is serving as important intermediates in the synthesis of agricultural bioactive compounds or pharmaceuticals. Efficient stereoselective synthesis of chiral lactams with low‐cost amine donors under mild conditions is desired for manufacturing of these important chemicals. Herein, a two‐step chemo‐enzymatic strategy has been designed to produce (S)‐lactams by engineering a natural amine dehydrogenase from Thermoanaerobacter thermohydrosulfuricus (TtherAmDH). TtherAmDH was subjected to eight cycles of directed evolution to enhance its reductive amination activity toward keto acid substrates. The variants showed improved specific activity toward 6 tested substrates and gave high stereoselectivities of up to 99% in the asymmetric synthesis of γ‐ and δ‐ lactams. In particular, TtherAmDHV8 showed a 237‐fold higher specific activity toward the model substrate levulinic acid and gave (S)‐5‐methyl‐2‐pyrrolidone in 99% ee with a space‐time yield of 75.3 g L−1 d−1. These results indicate that the engineered amine dehydrogenase TtherAmDH can serve as an efficient biocatalyst for the manufacture of highly valued chiral lactams.

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Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

Qian

Chu

Zhang

et al. 2022

Adv Synth Catal

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Silver‐Catalyzed Stereoselective trans Addition of 4‐Hydroxycoumarins to Haloalkynes and Late‐Stage Nitration

Hong

Zha

et al. 2018

Asian J Org Chem

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An efficient silver-catalyzed stereoselective transaddition of 4-hydroxycoumarins to haloalkynes under ambient air is described, allowing the straightforward synthesis of vinyl halides. The late-stage nitration of the resulting products with silver nitrate proceeded with retention of configuration, affording a series of nitroalkenes in good yields. Additionally, DFT calculations were employed for mechanistic studies, and a possible mechanism for the Ag(I)catalyzed addition was proposed.

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Asymmetric Organocatalytic Electrophilic Phosphination

2011

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The asymmetric incorporation of phosphorus-containing groups into target molecules is an important goal in diverse areas of synthetic chemistry. Organophosphorus compounds are used in various fields such as the synthesis of natural products [1] and their analogues, [2] ligands in organometallic catalysis, [3] organocatalysis, [4] and in general synthetic chemistry. [5] Hence, the development of asymmetric organocatalytic approaches towards optically active organophosphorus molecules is highly important. [6] A synthetic limitation is that previously the asymmetric catalytic formation of stereogenic carbon centers bonded to phosphorus (C*ÀP) has only been performed using nucleophilic phosphorus compounds. [7] Herein we present the first asymmetric catalytic C*ÀP bond formation employing a phosphine electrophile. By reacting asubstituted cyanoacetates (1) [8] with diaryl phosphine chlorides (2) under organocatalytic conditions, [9] optically active a-phosphinated cyanoacetates (3), which contain a stereogenic quaternary carbon center, are obtained (Scheme 1).

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Organocatalytic Asymmetric Synthesis of Versatile γ‐Lactams

Cited by 9 publications

References 46 publications

Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

Silver‐Catalyzed Stereoselective trans Addition of 4‐Hydroxycoumarins to Haloalkynes and Late‐Stage Nitration

Asymmetric Organocatalytic Electrophilic Phosphination

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