The synthesis and enzymatic reduction of several 6-substituted dioxohexanoates are presented. Two-step syntheses of tert-butyl 6-bromo-3,5-dioxohexanoate and the corresponding 6-hydroxy compound have been achieved in 89% and 59% yield, respectively. Regio- and enantioselective reduction of these diketones and of the 6-chloro derivative with alcohol dehydrogenase from Lactobacillus brevis (LBADH) gave the (5S)-5-hydroxy-3-oxo products with enantiomeric excesses of 91%, 98.4%, and >99.5%, respectively. Chain elongation of the reduction products by one carbon via cyanide addition, and by more than one carbon by Julia-Kocienski olefination, gave access to well-established statine side-chain building blocks. Application in the synthesis of the cholesterol-lowering natural compound solistatin is given.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The chemoenzymatic synthesis of the tert-butyl (S)-6-chloro-5-hydroxy-3-ketohexanoate is described. Our approach relies on a highly regio- and enantioselective reduction of a beta,delta-diketohexanoate ester catalysed by NADP(H)-dependent alcohol dehydrogenase of Lactobacillus brevis (LBADH). A detailed description of the scale-up of the enzymatic synthesis of the hydroxyketo ester is given which includes a scale-up of the substrate synthesis as well, i.e. the preparation of diketo ester on a 100 g scale. Furthermore, studies directed towards improving the co-catalyst [NADP(H)] consumption of the enzymatic key step by kinetic studies and application of a biphasic reaction medium were performed.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A new large-scale approach to the synthetically versatile chloromethyl-substituted, alpha,beta-unsaturated delta-lactone 3 is described. The synthesis is based oil a blocatalytic process performed oil an industrial scale. Conjugate addition of G, N-, O-, and S-nucleophiles to lactone 3 affords a variety of new pyranoid building blocks in a highly diastereoselective manner. The operational simplicity of the whole sequence allows for preparing these building blocks oil an attractive scale.

A synthetic route for the preparation of glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin and 5-(adamantan-1-yl-methoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive aniination sequence of 2,3,4,5-tetra-O-benzyl-D-glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzyl-protected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yield. Hydrogenolysis of the penultimate and crystallization of the end product as its methanesulfonic acid salt produced AMP-DNM in 76% yield with a purity of > 99.5%. The described route enables the production of multikilogram amounts of inhibitor AMP-DNM as a stable crystalline solid with high purity under cGMP control.

The applicability of the recent published bienzymatic protocol for the synthesis of (R)-2amino-1 -phenylethanol was tested using L-threonine aldolase from Pseudomonas putida and L-tyrosine decarboxylase from either Enterococcus faecalis (Efa) or two genes from Enterococcus faecium (Efi1, Efi2). In all 21 benzaldehyde derivatives were applied for an initial TLC screening. On a small scale, octopamine and noradrenaline were obtained as (S)-enantiomers using Efi1. Three protocols were up-scaled yielding enantioenriched (S)-octopamine (yield 99%, ee 81%), (R)-2-amino-1-phenylethanol (yield 61%, ee 62%) and (S)-noradrenaline (yield 76 %, ee 79 %).

Dynamisch zum Erfolg: Die asymmetrische Synthese von 2-Amino-1-phenylethanol gelang durch eine Zweistufen-Aminomethylierung von Benzaldehyd in Gegenwart der zwei Enzyme L-Threonin-Aldolase und L-Tyrosin-Decarboxylase in einem neuartigen Eintopf-Zweienzym-Verfahren (siehe Schema). Eine verfeinerte Methode mit sogar drei Enzymen lieferte den enantiomerenreinen Aminoalkohol in sehr guten Ausbeuten.

In a systematic study, 21 ring-substituted benzaldehydes were reacted with glycine under catalysis with a l-threonine aldolase (lTA) from Pseudomonas putida and a d-threonine aldolase (dTA) from Alcaligenes xylosoxidans to form the corresponding β-hydroxy-α-amino acids 1–18. dTA proved to be highly selective with ee's >99% (d) and de's up to 99% (syn). Two thiamphenicol precursors were synthesized utilizing dTA on a preparative scale. lTA-catalyzed reactions led to ee's >99% (l) but low to moderate de's (20–50%, syn).

Angewandte Chemie International EditionVolume 46, Issue 10 p. 1624-1626 Communication Overcoming Thermodynamic and Kinetic Limitations of Aldolase-Catalyzed Reactions by Applying Multienzymatic Dynamic Kinetic Asymmetric Transformations† Johannes Steinreiber Dr., Johannes Steinreiber Dr. Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this authorMartin Schürmann Dr., Martin Schürmann Dr. DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorMichael Wolberg Dr., Michael Wolberg Dr. DSM Pharma Chemicals, ResCom, Donaustaufer Strasse 378, 93055 Regensburg, GermanySearch for more papers by this authorFriso van Assema, Friso van Assema DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorChristoph Reisinger Dr., Christoph Reisinger Dr. Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this authorKateryna Fesko, Kateryna Fesko Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 16, 8010 Graz, AustriaSearch for more papers by this authorDaniel Mink Dr., Daniel Mink Dr. DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorHerfried Griengl Prof., Herfried Griengl Prof. [email protected] Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this author Johannes Steinreiber Dr., Johannes Steinreiber Dr. Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this authorMartin Schürmann Dr., Martin Schürmann Dr. DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorMichael Wolberg Dr., Michael Wolberg Dr. DSM Pharma Chemicals, ResCom, Donaustaufer Strasse 378, 93055 Regensburg, GermanySearch for more papers by this authorFriso van Assema, Friso van Assema DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorChristoph Reisinger Dr., Christoph Reisinger Dr. Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this authorKateryna Fesko, Kateryna Fesko Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 16, 8010 Graz, AustriaSearch for more papers by this authorDaniel Mink Dr., Daniel Mink Dr. DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, The NetherlandsSearch for more papers by this authorHerfried Griengl Prof., Herfried Griengl Prof. [email protected] Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria, Fax: (+43) 316-873-8740 http://www.a-b.atSearch for more papers by this author First published: 19 February 2007 https://doi.org/10.1002/anie.200604142Citations: 67 † The Österreichische Forschungsförderungsgesellschaft (FFG), the Province of Styria, the Styrian Business Promotion Agency (SFG), the City of Graz, the Fonds zur Förderung der wissenschaftlichen Forschung (FWF, project W901-B05 DK Molecular Enzymology), and the European Commission (within the framework of a Marie-Curie Industrial Host Fellowship to M.S. and M.W.) are acknowledged for financial support. We would like to thank Marcel Wubbolts, Theo Sonke, and Kurt Faber for stimulating discussions, as well as to Karl Gruber and Michael Uhl for the model of L-threonine aldolase in the Table of Contents graphic. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Dynamic and successful: The asymmetric synthesis of 2-amino-1-phenylethanol was achieved by aminomethylation of benzaldehyde in the presence of the two enzymes L-threonine aldolase and L-tyrosine decarboxylase in a novel one-pot, two-enzyme process (see scheme). A modified method with three enzymes led to the enantioenriched amino alcohol in very high yield. Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z604142_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1 1aM. G. Silvestri, G. Desantis, M. Mitchell, C.-H. Wong, Top. Stereochem. 2003, 23, 267–342; 1bW.-D. Fessner in Modern Aldol Reactions (Ed.: ), VCH, Weinheim, 2004, pp. 201–272. 2L. J. Whalen, C.-H. Wong, Aldrichimica Acta 2006, 39, 63–71. 3M. Braun in Modern Aldol Reactions (Ed.: ), VCH, Weinheim, 2004, pp. 1–62. 4Review on threonine aldolases: J. Q. Liu, T. Dairi, N. Itoh, M. Kataoka, S. Shimizu, H. Yamada, J. Mol. Catal. B 2000, 10, 107–115. 5 5aF. P. Seebeck, D. Hilvert, J. Am. Chem. Soc. 2003, 125, 10158–10159; 5bF. P. Seebeck, A. Guainazzi, C. Amoreira, K. K. Baldridge, D. Hilvert, Angew. Chem. 2006, 118, 6978–6980; Angew. Chem. Int. Ed. 2006, 45, 6824–6826. 6 6aB. T. Lotz, C. M. Gasparski, K. Peterson, M. J. Miller, J. Chem. Soc. Chem. Commun. 1990, 1107–1109; 6bV. P. Vassilev, T. Uchiyama, T. Kajimoto, C.-H. Wong, Tetrahedron Lett. 1995, 36, 4081–4084; 6cT. Kimura, V. P. Vassilev, G.-J. Shen, C.-H. Wong, J. Am. Chem. Soc. 1997, 119, 11734–11742. 7J. Steinreiber, K. Fesko, C. Reisinger, M. Schürmann, F. van Assema, M. Wolberg, D. Mink, H. Griengl, Tetrahderon 2007, 63, 918–926. 8M. Bechthold, S. Makart, M. Heinemann, S. Panke, J. Biotechnol. 2006, 124, 146–162. 9J. Q. Liu, M. Odani, T. Yasuoka, T. Dairi, N. Itoh, M. Kataoka, S. Shimizu, H. Yamada, Appl. Microbiol. Biotechnol. 2000, 54, 44–51. 10T. Nikaido, N. Kawada, T. Hamatani, Y. Ueda (Daicel Chemical Industries), WO 9523869, 1995; T. Nikaido, N. Kawada, T. Hamatani, Y. Ueda (Daicel Chemical Industries), US 5731175, 1998; T. Nikaido, N. Kawada, T. Hamatani, Y. 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Many polyketide-derived natural products contain a synor anti-1,3-diol unit. No general and simple approach exists for the flexible synthesis of polyols and other polyketide-derived structural units, therefore a multitude of methods for the stereoselective synthesis of 1,3-diols has been developed. Asymmetric homogeneous and heterogeneous hydrogenation and diastereoselective reduction, chain elongation, enzymatic and nonenzymatic desymmetrization, or dynamic kinetic resolution are some of these methods. The development of different methods to synthesize these 1,3-diols stereoselectively is important, as often small structural changes in a molecule result in low yields or low stereoselectivity with a known method. This review article highlights some of the recent developments in this field.

Aldolases are emerging as powerful and cost efficient tools for the industrial synthesis of chiral molecules. They catalyze enantioselective carbon-carbon bond formations, generating up to two chiral centers under mild reaction conditions. Despite their versatility, narrow substrate ranges and enzyme inactivation under synthesis conditions represented major obstacles for large-scale applications of aldolases. In this study we applied directed evolution to optimize Escherichia coli 2-deoxy-D-ribose 5-phosphate aldolase (DERA) as biocatalyst for the industrial synthesis of (3R,5S)-6-chloro-2,4,6-trideoxyhexapyranoside. This versatile chiral precursor for vastatin drugs like Lipitor (atorvastatin) is synthesized by DERA in a tandem-aldol reaction from chloroacetaldehyde and two acetaldehyde equivalents. However, E. coli DERA shows low affinity to chloroacetaldehyde and is rapidly inactivated at aldehyde concentrations useful for biocatalysis. Using high-throughput screenings for chloroacetaldehyde resistance and for higher productivity, several improved variants have been identified. By combination of the most beneficial mutations we obtained a tenfold improved variant compared to wild-type DERA with regard to (3R,5S)-6-chloro-2,4,6-trideoxyhexapyranoside synthesis, under industrially relevant conditions.

Whole baker’s yeast cells reduce t-butyl 6-chloro-3,5-dioxohexanoate regioselectively to the corresponding C5 hydroxy keto ester. While the (R)-alcohol was favored, the enantioselectivity was poor (41% ee). A variety of process conditions were evaluated in order to improve both the enantioselectivity and yield of this reduction. Including a nonpolar resin in the reaction mixture afforded the (R)-alcohol in 94% ee and 50% isolated yield. The enantioselectivity was further improved to >99% ee by substituting purified YGL157w in place of whole yeast cells. This reductase was identified by screening a collection of yeast enzymes uncovered by genome sequence analysis.