A Chemoenzymatic Route to Chiral Intermediates Used in the Multikilogram Synthesis of a Gamma Secretase Inhibitor

Burns, Michael P.; Martínez, Carlos A.; Vanderplas, Brian C.; Wisdom, Richard; Yu, Shu; Singer, Robert A.

doi:10.1021/acs.oprd.7b00096

Cited by 31 publications

(28 citation statements)

References 12 publications

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“…One such example is the preparation of a gamma secretase inhibitor designed by Pfizer scientists using a transaminase for the synthesis of the key chiral amine building block 13 and a KRED for the reduction of an α‐ketoester, delivering both fragments with high stereopurity (Scheme 3). [29] The Pfizer team took advantage of commercially available enzymes for screening which provided confidence that the most successful hit would be available in suitable quantities for the multi‐kg scale and with sufficient stability to be immediately applied. More applications of transaminases and their synthetic readiness are discussed in Chapter 3.1.…”

Section: Alcoholsmentioning

confidence: 99%

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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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Section: Alcoholsmentioning

confidence: 99%

“… A route to the chiral intermediate 13 of a gamma‐secretase inhibitor using a KRED and a transaminase [29] …”

Section: Alcoholsmentioning

confidence: 99%

Biocatalysis: Enzymatic Synthesis for Industrial Applications

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“…Methods have been developed for the determination of the position of equilibrium that can allow for a very rapid assessment as to whether this type of reaction is suitable for introducing the amine functionality . From an industrial perspective, an expedient solution to shifting the equilibrium position is often achieved using an excess of the amine donor, and in cases where isopropylamine is used as the donor, the reaction by‐product, acetone, can be removed from the reaction mixture by sparging . However, as this approach does not remove all acetone, an excess of isopropylamine is still required to drive the reaction to high conversions.…”

Section: Mature Reaction Classesmentioning

confidence: 99%

Biocatalysis: A Pharma Perspective

et al. 2019

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Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufacturing. While some reaction classes are well established, and may even be the option of first intent, other more recently discovered enzyme classes are being rapidly developed both in academia and industry. Notwithstanding this, there are further promising enzymes that require further investment and investigation to allow their future industrial use. We here outline GSK's perspective on the current status of biocatalysis for pharmaceutical manufacturing and provide our views on areas of significant potential.

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“…[14] Parameter [18a,19a, 20] eines Gamma-Sekretasehemmers,d ie von Wissenschaftlern bei Pfizer entworfen wurde und fürdie Synthese des chiralen Amin-Schlüsselbausteins 13 eine Tr ansaminase und eine KRED zur Reduktion eines a-Ketoesters einsetzt und so beide Fragmente mit hoher Stereoreinheit liefert (Schema 3). [29] Das Te am von Pfizer nutzte den Vorteil kommerziell erhältlicher Enzyme fürd as Screening, um sicherzustellen, dass der beste Hit auch in ausreichenden Mengen fürd en Multi-kg-Maßstab zur Verfügung steht und ausreichend stabil füreinen umgehenden Einsatz ist. Weitere Anwendungen von Tr ansaminasen und ihre präparative Verfügbarkeit werden in Abschnitt 3.1 diskutiert.…”

Section: Produktion Chiraler Alkohole Durch Kredsunclassified

Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

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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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A Chemoenzymatic Route to Chiral Intermediates Used in the Multikilogram Synthesis of a Gamma Secretase Inhibitor

Cited by 31 publications

References 12 publications

Biocatalysis: Enzymatic Synthesis for Industrial Applications

Biocatalysis: Enzymatic Synthesis for Industrial Applications

Biocatalysis: A Pharma Perspective

Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

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