Engineered C–N Lyase: Enantioselective Synthesis of Chiral Synthons for Artificial Dipeptide Sweeteners

Zhang, Jielin; Grandi, Eleonora; Fu, Haigen; Saravanan, T.; Bothof, Laura; Tepper, Pieter G.; Thunnissen, A.M.W.H.; Poelarends, Gerrit J.

doi:10.1002/ange.201910704

Cited by 5 publications

(1 citation statement)

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“…1B). More recently, a rapid increase in C-N lyase applications in biocatalytic and therapeutic elds has bene ted from the advancement of discovery and engineering technologies to improve these enzymes' functional properties and offer expanded synthetic scopes [19][20][21][22][23][24][25] (Fig. 1C and 1D).…”

Section: Introductionmentioning

confidence: 99%

Development of a versatile and efficient C-N lyase platform for asymmetric hydroamination via computational enzyme redesign

Cui¹,

Wang²,

Bu³

et al. 2020

Preprint

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Although C-N bonds are ubiquitous in natural products, pharmaceuticals, and agrochemicals, biocatalysts that forge these bonds with high atom efficiency and enantioselectivity have primarily been limited to a few select enzymes. In particular, the use of ammonia lyases has emerged as a powerful strategy to access C-N bond formation through hydroamination reactions, which has no counterpart in traditional synthetic chemistry. However, the broad utility of ammonia lyases is rather restricted due to their narrow synthetic scope, and the conjugate addition of a matrix of nucleophilic donors to electrophilic acceptors remains a longstanding challenge. Herein, we report the computational redesign of aspartase, a highly specific ammonia lyase, to yield C-N lyases with unprecedented cross-compatibility of nonnative nucleophiles and electrophiles. A wide range of noncanonical amino acids (ncAAs) are afforded with excellent conversion (up to 99%), regioselectivity > 99%, and product enantiomeric excess > 99%, and the process is scalable under industrially relevant protocols (demonstrated in kilogram-scale synthesis). Furthermore, the redesigned enzymes can be facilely integrated in cascade reactions, as we demonstrated the synthesis of β-lactams with different substitution patterns at the N-1 and C-4 positions in a one-pot reaction. This versatile and efficient C-N lyase platform supports the preparation of diverse libraries of ncAAs and their derivatives and will present opportunities in medicinal chemistry and synthetic biology.

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Section: Introductionmentioning

confidence: 99%

Development of a versatile and efficient C-N lyase platform for asymmetric hydroamination via computational enzyme redesign

Cui¹,

Wang²,

Bu³

et al. 2020

Preprint

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Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

et al. 2020

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www.angewandte.de 2020 Die Autoren. Verçffentlicht von Wiley-VCH GmbH. Dieser Open Access Beitrag steht unter den Bedingungend er Creative Commons AttributionN on-CommercialN oDerivs License, die eine Nutzung und Verbreitung in allen Medien gestattet, sofern der ursprüngliche Beitrag ordnungsgemäßzitiert und nicht fürkommerzielle Zwecke genutzt wird und keine ¾nderungen und Anpassungen vorgenommen werden.

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Biocatalysis: Enzymatic Synthesis for Industrial Applications

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in 2007, followed by postdoctoral studies at York University (UK) and Greifswald University (Germany). In 2010, she transitionedto industry applying and developing biocatalytic technologies at Novacta in the UK, prior to joining Chemical Process Development at GSK, with responsibility for the development and implementation of new biocatalytic technologyi nboth pre-and post-commercialization routes. Since Dec. 2016, Radka is leading the Bioreactions group in GDC at the Novartis Institute for Biomedical Research in Basel, Switzerland. Jeffrey Moore obtained his PhD in Chemical Engineeringf rom the California Institute of Technology in 1996 as Frances Arnold's first Directed Evolution graduate student. His foundational work led to an evolved p-nitrobenzyl esterase and the Lonza Centenary Prize (1997). In 1996, he joined the Biocatalysis Group of Merck & Co.in Rahway NJ, spending two decades inventing new enzymes and new enzymatic processes. In 2018, he transitionedtothe Merck Protein EngineeringG roup responsible for evolving enzymes for the discovery,d evelopmenta nd commercials cale manufacture of medicines. He has been awarded aUS Presidential Green Chemistry Award (2010), the BioCat2012 Award (2012) and the Thomas Edison Inventorship Award (2014). Kai Baldenius studied chemistry in Hamburg and Southampton. He received his PhD for research in asymmetric organometallic catalysis, supervised by H. tom Dieck and H. B. Kagan. After his postdoc on natural product synthesis with K. C. Nicolaou at the Scripps Research Institute he joined BASF in 1993. Kai served BASF in various functions (R&D, production, marketing, sales) before he took the lead of BASF'sbiocatalysis research for almost ad efcade. He left BASF to become afree-lancing consultanti n2019 and in 2020 he has founded Baldenius Biotech Consulting. Uwe T. Bornscheuer studied chemistry and received his PhD in 1993 at Hannover University followed by apostdoc at Nagoya University (Japan). In 1998, he completed his Habilitation at Stuttgart University about the use of lipases and esterasesi n organic synthesis. He has been Professor at the Institute of Biochemistry at Greifswald University since 1999. Beside other awards, he received in 2008 the BioCat2008 Award. He was just recognized as "Chemistry Europe Fellow". His current research interest focuses on the discovery and engineering of enzymes from various classes for applications in organic synthesis, lipid modification, degradation of plastics or complex marine polysaccharides.

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Engineered C–N Lyase: Enantioselective Synthesis of Chiral Synthons for Artificial Dipeptide Sweeteners

Cited by 5 publications

References 22 publications

Development of a versatile and efficient C-N lyase platform for asymmetric hydroamination via computational enzyme redesign

Development of a versatile and efficient C-N lyase platform for asymmetric hydroamination via computational enzyme redesign

Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

Biocatalysis: Enzymatic Synthesis for Industrial Applications

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