Adriaan J. Minnaard

Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents

Catalytic asymmetric C-C bond-forming reactions using organometallic reagents are among the most important of organic transformations. Frequently, these transformations are key steps in the synthesis of complex biologically active molecules. The conjugate addition (CA) and allylic alkylation (AA) with organometallic compounds are especially versatile in asymmetric C-C bond-forming reactions. These transformations are complementary to the catalytic asymmetric allylic alkylation and the Michael addition, both based on soft carbon nucleophiles (Scheme 1A). For both CA and AA, the organic moiety of the organometallic reagent reacts with the sp carbon of an electron-deficient substrate, converting it to an sp carbon (Scheme 1B). In the case of CA, subsequent quenching of the enolate leads to the final product, whereas for the related AA an appropriate leaving group is expelled to form the chiral product. The organometallic compounds used most frequently for these transformations are organozinc, Grignard, organoaluminium, organolithium and cuprate reagents. Over the last three decades considerable effort has been directed toward the development of efficient catalytic systems for the asymmetric CA and AA reactions using organometallic reagents. Complexes derived from Cu salts and chiral ligands have provided the broadest scope in the catalyzed enantioselective CA and AA of organometallic reagents. Organozinc reagents have been the most successful of the organometallic reagents in this respect. Major contributions and progress in the field of asymmetric CA and AA based on organozinc reagents have been summarized in several reviews. Organomagnesium compounds were among the first organometallic compounds to be applied to synthetic organic chemistry and the use of Grignard reagents in Cu-catalyzed CA was first reported in 1941 by Kharash and Tawney. Achieving chemo-, regioand stereocontrol in both asymmetric conjugate addition (ACA) and asymmetric allylic alkylation (AAA), however, has proven to be challenging and has restricted the application of these transformations, in particular, to total synthesis. Typical selectivity issues pertain to 1,2versus 1,4-addition (Scheme 2A) and SN2versus SN2′-substitution (Scheme 2B). The challenge faced in the development of stereoselective C-C bond-forming reactions is apparent when one considers that, despite three decades of intensive research in this area, only recently has efficient Cu-catalyzed enantioselective CA of Grignard reagents been achieved. The earlier discovery of the highly enantioselective Cu-catalyzed CA of dialkylzinc reagents allowed for replacement of Grignard reagents in this asymmetric C-C bond-forming reaction. Dialkylzinc reagents offer distinct advantages over Grignard reagents in their low reactivity in noncatalyzed reactions and their high tolerance to functional groups both on the substrate and on the organozinc reagent itself. Nevertheless, there are several advantages to the use of common mono-alkylMg halide reagents, most importantly their widespread availability and the ability to transfer all of the alkyl groups of the organometallic compound. The synthetic potential of these asymmetric transformations has driven intensive research in this area, and over the past few years major breakthroughs have been realized in the enantioselective CA and AA of Grignard reagents. * Author for correspondence. E-mail: B.L.Feringa@rug.nl Chem. Rev. 2008, 108, 2824–2852 2824

Recent advances in the catalytic asymmetric synthesis of β-amino acids

In this critical review, the progress in catalytic asymmetric synthesis of beta-amino acids is discussed, covering the literature since 2002. The review treats transition metal catalysis, organocatalysis and biocatalysis and covers the most important synthetic methods, such as hydrogenation, the Mannich reaction and conjugate additions (160 references).

Recent advances in enantioselective copper-catalyzed 1,4-addition

A comprehensive overview of recent literature from 2003 concerning advances in enantioselective copper catalysed 1,4-addition of organometallic reagents to alpha,beta-unsaturated compounds is given in this critical review. About 200 ligands and catalysts are presented, with a focus on stereoselectivities, catalyst loading, ligand structure and substrate scope. A major part is devoted to trapping and tandem reactions and a variety of recent synthetic applications are used to illustrate the practicality and current state of the art of 1,4-addition of organometallic reagents. Finally several mechanistic studies are discussed (162 references).

Chiral separation by enantioselective liquid-liquid extraction

The literature on enantioselective liquid-liquid extraction (ELLE) spans more than half a century of research. Nonetheless, a comprehensive overview has not appeared during the past few decades. Enantioselective liquid-liquid extraction is a technology of interest for a wide range of chemists and chemical engineers in the fields of fine chemicals, pharmaceuticals, agrochemicals, fragrances and foods. In this review the principles and advances of resolution through enantioselective liquid-liquid extraction are discussed, starting with an introduction on the principles of enantioselective liquid-liquid extraction including host-guest chemistry, extraction and phase transfer mechanisms, and multistage liquid-liquid extraction processing. Then the literature on enantioselective liquid-liquid extraction systems is reviewed, structured on extractant classes. The following extractant classes are considered: crown ether based extractants, metal complexes and metalloids, extractants based on tartrates, and a final section with all other types of chiral extractants.

Improving conversion and enantioselectivity in hydrogenation by combining different monodentate phosphoramidites; a new combinatorial approach in asymmetric catalysisElectronic supplementary information (ESI) available: Experimental details. See http://www.rsc.org/suppdata/ob/b3/b302097e/

The combination of monodentate ligands in the rhodium-catalysed enantioselective hydrogenation enables a new approach when searching for the optimal activity and enantioselectivity in catalysis.

Iridium/Monodentate Phosphoramidite Catalyzed Asymmetric Hydrogenation of N-Aryl Imines

Asymmetric hydrogenation of N-aryl acetophenone imines using iridium/PipPhos leads to very high enantioselectivities up to >99% depending on the presence of electron-donating substituents in the 2-, 3-, and 5-position of the aryl ring. If the substituent is 2-methoxy, the resultant secondary amines are easily oxidatively deprotected using trichloroisocyanuric acid to give the primary amines in good yield with full retention of enantioselectivity.

A Comparative Lipidomics Platform for Chemotaxonomic Analysis of Mycobacterium tuberculosis

The lipidic envelope of Mycobacterium tuberculosis promotes virulence in many ways, so we developed a lipidomics platform for a broad survey of cell walls. Here we report two new databases (MycoMass, MycoMap), 30 lipid fine maps, and mass spectrometry datasets that comprise a static lipidome. Further, by rapidly regenerating lipidomic datasets during biological processes, comparative lipidomics provides statistically valid, organism-wide comparisons that broadly assess lipid changes during infection or among clinical strains of mycobacteria. Using stringent data filters, we tracked more than 5,000 molecular features in parallel with few or no false-positive molecular discoveries. The low error rates allowed chemotaxonomic analyses of mycobacteria, which describe the extent of chemical change in each strain and identified particular strain-specific molecules for use as biomarkers.

Dynamic Kinetic Resolution of Racemic β-Haloalcohols : Direct Access to Enantioenriched Epoxides

The direct chemo-enzymatic DKR of racemic beta-haloalcohols is reported, yielding the corresponding optically active epoxides in a single step. The mutant haloalcohol dehalogenase HheC Cys153Ser Trp249Phe is used for the asymmetric ring closure, whereas racemization of the remaining enantiomer of the haloalcohol is achieved using the new iridacycle 3, one of the most effective racemization catalysts to date for beta-haloalcohols.

Reduction of Carbon−Carbon Double Bonds Using Organocatalytically Generated Diimide

An efficient method has been developed for the reduction of carbon-carbon double bonds with diimide, catalytically generated in situ from hydrazine hydrate. The employed catalyst is prepared in one step from riboflavin (vitamin B(2)). Reactions are carried out in air and are a valuable alternative when metal-catalyzed hydrogenations are problematic.

Rhodium/MonoPhos-Catalysed Asymmetric Hydrogenation of Enamides

The monodentate phosphoramidite MonoPhos has been used in the rhodium-catalysed asymmetric hydrogenation of N-acetyl-α-arylenamides. This ligand is readily available via a one-step procedure and is air stable. Its Rh(I) complex, which is an effective catalyst precursor for the hydrogenation of dehydroamino acids, also gives high enantioselectivities for this class of substrates. Because of the facile synthesis and stability of MonoPhos, its complex provides a general solution in preparing chiral amine derivatives through asymmetric hydrogenation.