Chemoenzymatic Stereoselective Synthesis of Substituted γ‐ or δ‐lactams with Two Chiral Centers via Transaminase‐catalysed Dynamic Kinetic Resolution

Dong, Wenyue; Yao, Peiyuan; Wang, Yingang; Wu, Qingping; Zhu, Dunming

doi:10.1002/cctc.202001142

Cited by 6 publications

(3 citation statements)

References 42 publications

(26 reference statements)

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“…In our previous work, a ( S )‐selective ω‐TA from Burkholderia vietnamiensis G4 (HBV) was identified which exhibited modest activity and excellent stereoselectivity toward β‐keto esters with small steric hindrance [16b,18] . Herein, we describe the identification of HBV variants for the asymmetric transamination of β‐keto esters with steric hindrance to prepare chiral β‐amino esters and β‐amino acids in good yields and ee values (Scheme 1).…”

Section: Methodsmentioning

confidence: 99%

Improving Catalytic Activity and Reversing Enantio‐Specificity of ω‐Transaminase by Semi‐Rational Engineering en Route to Chiral Bulky β‐Amino Esters

et al. 2021

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The application of wild‐type ω‐transaminase was limited by steric hindrance towards bulky substrates, therefore improvement of the catalytic efficiency and stereoselectivity toward substrates with two bulky substituent adjacent to the carbonyl is of general interest. In this study, according to the double substrate binding pocket theory, a (S)‐selective ω‐transaminase from the Burkholderia vietnamiensis G4, which showed puny catalytic activity toward the β‐keto esters with small steric hindrance, was engineered to accept bulky β‐keto esters, which were not accessible by any wild‐type enzyme. A few desired variants were obtained that exhibited activity toward bulky β‐keto esters. Furthermore, a substrate‐dependent shift in enantio‐preference of HBV variant towards β‐keto esters with linear or branched aliphatic substituents was observed. The best variant was applied to the asymmetric synthesis of aliphatic β‐amino acids at semi‐preparative scale with high yield and enantioselectivity. This study will improve the general understanding and inspire further engineering work for reversing enantio‐specificity of ω‐transaminases.

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Section: Methodsmentioning

confidence: 99%

Improving Catalytic Activity and Reversing Enantio‐Specificity of ω‐Transaminase by Semi‐Rational Engineering en Route to Chiral Bulky β‐Amino Esters

et al. 2021

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“…Recently, we represented a promising approach to asymmetric synthesis of chiral β,γ‐disubstituted pyrrolidinones from easily accessible keto esters via transaminase catalyzed dynamic kinetic resolution and intramolecular cyclization (Scheme 1, eq. 4) [14] . Despite these advances, highly efficient construction of chiral γ‐amino esters or γ‐lactams containing α,γ‐stereogenic centers is still underdeveloped.…”

Section: Introductionmentioning

confidence: 99%

“…4). [14] Despite these advances, highly efficient construction of chiral γ-amino esters or γ-lactams containing α,γ-stereogenic centers is still underdeveloped.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of N‐Substituted γ‐Amino Esters and γ‐Lactams Containing α,γ‐Stereogenic Centers via a Stereoselective Enzymatic Cascade

Cui

et al. 2021

Adv Synth Catal

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γ‐Amino esters and γ‐lactams containing α,γ‐stereogenic centers are widely used as chiral intermediates in various bioactive compounds, while their efficient synthesis remains a challenge. Herein, an enzymatic cascade reaction involving an ene reductase (ERED) and an imine reductase (IRED) for accessing to α,γ‐stereospecific γ‐amino esters and γ‐lactams from α,β‐unsaturated γ‐ketoesters has been developed. 21 EREDs and 13 IREDs have been identified with high activity and stereoselectivity toward various α,β‐unsaturated γ‐ketoesters and the corresponding chiral γ‐ketoesters, respectively. By employing suitable ERED and IRED, (1S,3S), (1S,3R), (1R,3S), and (1R,3R) stereoisomers of methyl 3‐(cyclopropyl amino) cyclohexane‐1‐carboxylate were obtained as a single stereoisomer in 63–72% yield, and (3R,5R)‐ and (3R,5S)‐1‐cyclopropyl‐3,5‐dimethylpyrrolidin‐2‐one and 1‐cyclopropyl‐3,5‐dipropylpyrrolidin‐2‐one were also prepared as a single stereoisomer in 60–65% yields. This study establishes an environmentally friendly enzymatic route for the synthesis of γ‐amino esters and γ‐lactams containing α,γ‐stereogenic centers.

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Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction

et al. 2023

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Substituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and 'chiral pool' strategies. Herein, we report multi-enzymatic and chemo-enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee > 99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N-heterocycles using either platinum(0)-catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one-pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr � 98:2) and isolated yields of up to 73%. Leadlikeness analysis of five representative products using an open-source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.

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Chemoenzymatic Stereoselective Synthesis of Substituted γ‐ or δ‐lactams with Two Chiral Centers via Transaminase‐catalysed Dynamic Kinetic Resolution

Cited by 6 publications

References 42 publications

Improving Catalytic Activity and Reversing Enantio‐Specificity of ω‐Transaminase by Semi‐Rational Engineering en Route to Chiral Bulky β‐Amino Esters

Improving Catalytic Activity and Reversing Enantio‐Specificity of ω‐Transaminase by Semi‐Rational Engineering en Route to Chiral Bulky β‐Amino Esters

Asymmetric Synthesis of N‐Substituted γ‐Amino Esters and γ‐Lactams Containing α,γ‐Stereogenic Centers via a Stereoselective Enzymatic Cascade

Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction

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