The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.1,2 Among all asymmetric catalytic methods, asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines, have become one of the most efficient methods for constructing chiral compounds.3 The development of homogeneous asymmetric hydrogenation was initiated by Knowles4a and Horner4b in the late 1960s, after the discovery of Wilkinson’s homogeneous hydrogenation catalyst [RhCl(PPh3)3]. By replacing triphenylphosphine of the Wilkinson’s catalystwithresolvedchiralmonophosphines,6Knowles and Horner reported the earliest examples of enantioselective hydrogenation, albeit with poor enantioselectivity. Further exploration by Knowles with an improved monophosphine CAMP provided 88% ee in hydrogenation of dehydroamino acids.7 Later, two breakthroughs were made in asymmetric hydrogenation by Kagan and Knowles, respectively. Kagan reported the first bisphosphine ligand, DIOP, for Rhcatalyzed asymmetric hydrogenation.8 The successful application of DIOP resulted in several significant directions for ligand design in asymmetric hydrogenation. Chelating bisphosphorus ligands could lead to superior enantioselectivity compared to monodentate phosphines. Additionally, P-chiral phosphorus ligands were not necessary for achieving high enantioselectivity, and ligands with backbone chirality could also provide excellent ee’s in asymmetric hydrogenation. Furthermore, C2 symmetry was an important structural feature for developing new efficient chiral ligands. Kagan’s seminal work immediately led to the rapid development of chiral bisphosphorus ligands. Knowles made his significant discovery of a C2-symmetric chelating bisphosphine ligand, DIPAMP.9 Due to its high catalytic efficiency in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids, DIPAMP was quickly employed in the industrial production of L-DOPA.10 The success of practical synthesis of L-DOPA via asymmetric hydrogenation constituted a milestone work and for this work Knowles was awarded the Nobel Prize in 2001.3k This work has enlightened chemists to realize * Corresponding author. 3029 Chem. Rev. 2003, 103, 3029−3069

New Chiral Phosphorus Ligands for Enantioselective Hydrogenation

Over the past ten years, scientific and technological advances have established biocatalysis as a practical and environmentally friendly alternative to traditional metallo- and organocatalysis in chemical synthesis, both in the laboratory and on an industrial scale. Key advances in DNA sequencing and gene synthesis are at the base of tremendous progress in tailoring biocatalysts by protein engineering and design, and the ability to reorganize enzymes into new biosynthetic pathways. To highlight these achievements, here we discuss applications of protein-engineered biocatalysts ranging from commodity chemicals to advanced pharmaceutical intermediates that use enzyme catalysis as a key step.

Engineering the third wave of biocatalysis

The purpose of this perspective is to indicate the range of chemistries used in the manufacture of drug candidate molecules and to highlight certain gaps in current technologies. To do this a survey was carried out of chemical syntheses within the Process Chemistry R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer.

Analysis of the reactions used for the preparation of drug candidate molecules.

Stereoselective organic reactions in water.

Through the use of Pd2(dba)3/P(t-Bu)3 as a catalyst, a wide range of aryl and vinyl halides, including chlorides, undergo Suzuki cross-coupling with arylboronic acids in very good yield, typically at room temperature; through use of Pd(OAc)2/PCy3, a diverse array of aryl and vinyl triflates react cleanly at room temperature. Together, these two catalyst systems cover a broad spectrum of commonly encountered substrates for Suzuki couplings. Furthermore, they display novel reactivity patterns, such as the selective cross-coupling by Pd2(dba)3/P(t-Bu)3 of an aryl chloride in preference to an aryl triflate, and they can be used at low loading, even for reactions of aryl chlorides. Preliminary mechanistic work indicates that a palladium monophosphine complex is the active catalyst in the cross-coupling of aryl halides.

Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions

Enantiomerically pure amino acids, amino alcohols, amines, alcohols, and epoxides play an increasingly important role as intermediates in the pharmaceutical industry and agrochemistry, where both a high degree of purity and large quantities of the compounds are required. The chemical industry has primarily relied upon established chemical methods for the synthesis of these intermediates, but is now turning more and more to enzymatic and biotechnological fermentation processes. For the industrial implementation of many transformations alternative methods are available. The advantages of the individual methods will be discussed herein and exemplified by syntheses of relevant compounds.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200300599

Industrial Methods for the Production of Optically Active Intermediates

Enantiomerenreine Aminosauren, Aminoalkohole, Amine, Alkohole und Epoxide spielen heutzutage als Zwischenprodukte in pharmazeutischer Industrie und Agrochemie eine immer grosere Rolle. Dabei sind sowohl ein hoher Reinheitsgrad als auch grose Mengen der Verbindungen gefragt. Die chemische Industrie hat sich bei der Synthese dieser Zwischenstufen bislang auf bewahrte chemische Verfahren gestutzt, greift jedoch zunehmend auf enzymatische und fermentative Prozesse aus der Biotechnologie zuruck. Fur die industrielle Umsetzung vieler Transformationen stehen alternative Verfahren zur Verfugung. Die Vorteile der einzelnen Methoden werden in diesem Aufsatz anhand der Synthesen wichtiger Beispielverbindungen diskutiert.

Industrielle Verfahren zur Herstellung von optisch aktiven Zwischenprodukten

Unreactive chloroarenes have been outwitted: The key to successful C-C, C-N, and C-O bond formation on chloroarenes is the development and optimization of suitable catalysts. Electron-rich alkylphosphanes are mandatory as ligands in these palladium-catalyzed reactions.

Take the Right Catalyst: Palladium‐Catalyzed C−C, C−N, and C−O Bond Formation on Chloroarenes

Using 1,2-dicyclohexyl-1,2-ethanediol as chiral auxiliary, the enatiomerically pure Z-pentenylboronate 9c was obtained. Its addition to benzaldehyde proceeded with complete transfer of chirality to give the syn-E-homoallyl alcohol 11. The ability of the reagent 9c to create new stereocenters under reagent control of diastereoselectivity was tested in its addition to the chiral aldehydes 15 and 24. This resulted in a short and stereospecific synthesis of invictolide (18), as well as of a C-9/C-15-partial structure 25 of erythronolide A.



Stereoselektive Synthese von Alkoholen, XXXI. — Stereoselektive C-C-Bindungsbildung mit Hilfe chiraler Z-Pentenylboronsaureester



Unter Verwendung von 1,2-Dicyclohexyl-1,2-ethandiol als chiralem Auxiliar wurde der enantiomerenreine Z-Pentenylboronsaureester 9c erhalten. Dessen Addition an Benzaldehyd ergab den syn-E-Homoallylalkohol 11 unter vollstandiger Chiralitats-Ubertragung. Die Fahigkeit des Reagenz 9c zur Bildung neuer Stereozentren unter Reagenz-Kontrolle der Diastereoselektivitat wurde in der Addition an die chiralen Aldehyde 15 und 24 gepruft. Dies fuhrte zu einer kurzen stereospezifischen Synthese des Invictolids (18) wie der eines C-9/C-15-Bausteins 25 des Erythronolids A.

Rainer Stürmer

Papers

Industrial Methods for the Production of Optically Active Intermediates

Industrielle Verfahren zur Herstellung von optisch aktiven Zwischenprodukten

Take the Right Catalyst: Palladium‐Catalyzed C−C, C−N, and C−O Bond Formation on Chloroarenes

Stereoselective synthesis of alcohols, XXXI: Stereoselective CC bond formation using chiral Z‐pentenylboronates

Enzymes and Transition Metal Complexes in Tandem—A New Concept for Dynamic Kinetic Resolution