Deracemization By Simultaneous Bio-oxidative Kinetic Resolution and Stereoinversion**

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Abstract

Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100 % conversion and 100 % ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure ( S)-berbines. The racemic substrates were transformed to optically pure products ( ee>97 %) with up to 98 % conversion and up to 88 % yield of isolated product.

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Probing the Lewis acidity and catalytic activity of the metal-organic framework [Cu3(btc)2] (BTC=benzene-1,3,5-tricarboxylate).

Helga E. de Vries, Etienne Séguin, Luc Alaerts … (2006)

An optimized procedure was designed for the preparation of the microporous metal-organic framework (MOF) [Cu3(btc)2] (BTC=benzene-1,3,5-tricarboxylate). The crystalline material was characterized by X-ray diffraction, optical microscopy, SEM, X-ray photoelectron spectroscopy, N2 sorption, thermogravimetry, and IR spectroscopy of adsorbed CO. CO adsorbs on a small number of Cu2O impurities, and particularly on the free CuII coordination sites in the framework. [Cu3(btc)2] is a highly selective Lewis acid catalyst for the isomerization of terpene derivatives, such as the rearrangement of alpha-pinene oxide to campholenic aldehyde and the cyclization of citronellal to isopulegol. By using the ethylene ketal of 2-bromopropiophenone as a test substrate, it was demonstrated that the active sites in [Cu3(btc)2] are hard Lewis acids. Catalyst stability, re-usability, and heterogeneity are critically assessed.

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Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C–H Functionalization Sequences

Tehetena Mesganaw, Jonathan Ellman (2014)

A Rh-catalyzed C–H bond activation/alkenylation/electrocyclization cascade reaction provides diverse 1,2-dihydropyridines from simple and readily available precursors. The reaction can be carried out at low (<1%) Rh-catalyst loadings, and the use of the robust, air-stable Rh precatalyst, [RhCl(cod)]2, enables the cascade reaction to be easily performed on the benchtop. The 1,2-dihydropyridine products serve as extremely versatile synthetic intermediates for further elaboration often without isolation. The addition of electrophiles under kinetic or thermodynamic conditions provides a wide range of iminiums. Subsequent addition of a nucleophile then generates a diverse array of differently substituted piperidine products. Additionally, [3 + 2] and [4 + 2] cycloadditions of the 1,2-dihydropyridine intermediate provides access to bridged bicyclic structures such as tropanes and isoquinuclidines. These concise reaction sequences enable the formation of highly substituted piperidines in synthetically useful yields with excellent diastereoselectivity.

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Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products.

Diego Ghislieri, Anthony Green, Marta Pontini … (2013)

The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.

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Author and article information

Journal

Journal ID (nlm-ta): Angew Chem Int Ed Engl

Journal ID (iso-abbrev): Angew. Chem. Int. Ed. Engl

Journal ID (publisher-id): anie

Title: Angewandte Chemie (International Ed. in English)

Publisher: WILEY-VCH Verlag (Weinheim )

ISSN (Print): 1433-7851

ISSN (Electronic): 1521-3773

Publication date (Print): 01 April 2014

Publication date (Electronic): 24 February 2014

Volume: 53

Issue: 14

Pages: 3731-3734

Affiliations

Institut für Chemie, Organische und Bioorganische Chemie, Karl-Franzens-Universität Graz Heinrichstrasse 28, A-8010 Graz (Austria)

School of Chemistry, University of Manchester, Manchester Institute of Biotechnology 131 Princess Street, Manchester, M1 7DN (UK)

Institut für Biochemie, Technische Universität Graz Petersgasse 12, 8010 Graz (Austria)

Author notes

* E-mail: wolfgang.kroutil@ 123456uni-graz.at E-mail: nicholas.turner@ 123456manchester.ac.uk

[**]

This study was financed by the Austrian Science Fund (FWF Project P20903-N17 and P22115-N17). E.-M.F. received funding from the European Union’s seventh framework program FP7/2007–2013 under grant agreement no. 289646 (KyroBio). B.G. and D.G. were supported by a Marie Curie ITN (Biotrains FP7-ITN-238531), and we also acknowledge a Royal Society Wolfson Merit Award to N.J.T.

Article

DOI: 10.1002/anie.201400027

PMC ID: 4499246

PubMed ID: 24615790

SO-VID: 86183127-e1dd-42e3-99bf-09c9906219fb

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Deracemization By Simultaneous Bio-oxidative Kinetic Resolution and Stereoinversion**

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Most cited references 93

Probing the Lewis acidity and catalytic activity of the metal-organic framework [Cu3(btc)2] (BTC=benzene-1,3,5-tricarboxylate).

Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C–H Functionalization Sequences

Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products.

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