In this overview, recent trends and developments for the selective hydrogenation of multifunctional molecules are discussed and assessed from the point of view of fine chemicals synthesis. In a first part, the design and preparation of catalysts and ligands with interesting properties are summarized, particularly meant for the catalysis specialist. The following topics are described in some detail: How enantioselective homogeneous catalysts are designed and tested; new effective chiral monodentate phosphines; successful bidentate phosphines ligand families (with axially chiral biaryl-and ferrocenyl-based backbones, new phospholanes and with stereogenic phosphorus); novel bidentate ligand families with P-O and P-N bonds; and oxazoline-based ligands. A short overview on immobilized chiral complexes and of the toolbox of heterogeneous catalysis (bimetallic, colloidal and modified catalysts) concludes this chapter. In a second part, progress for selected catalytic transformations and generic selectivity problems is described, intended mainly for the organic chemist who has to solve specific synthetic problems. Emphasis is on the following topics: The enantioselective hydrogenation of olefins with various substitution patterns; the chemo-and enantioselective hydrogenation of ketones; the diastereo-and enantioselective hydrogenation of C N functions; the stereoselective hydrogenation of aromatic rings; chemoselectivity and hydroxylamine accumulation in the reduction of functionalized nitroarenes; chemoselectivity and new protecting groups for catalytic debenzylation; the mild hydrogenation of carboxylic acid derivatives; and the chemoselective hydrogenation of nitriles. In the last parts of the review, transfer hydrogenation and mechanistic issues are discussed, followed by a short conclusions and outlook paragraph.

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives beta-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required.

PhanePhos-ruthenium-diamine complexes catalyze the asymmetric hydrogenation of a wide range of aromatic, heteroaromatic, and alpha, beta-unsaturated ketones with high activity and excellent enantioselectivity.

Organic chemistryOrganic chemistry Z 0200 Selective Hydrogenation for Fine Chemicals: Recent Trends and New Developments. -[about 100 refs.] -(BLASER*, H.-U.; MALAN, C.; PUGIN, B.; SPINDLER, F.; STEINER, H.; STUDER, M.; Adv. Synth. Catal. 345 (2003) 1-2, 103-151; Solvias AG, CH-4002 Basel, Switz.; Eng.) -Lindner 18-260

Dedicated to Professor Dieter Seebach on the occasion of his 70th birthdayPalladium-catalyzed CÀC bond-forming reactions play a prominent role in the construction of complex organic molecules. [1][2][3][4] As this versatile precious metal is absent in natural enzymes, nature has devised very different strategies to create C À C bonds for the construction of complex natural products. [5][6][7] The palladium-catalyzed asymmetric allylic alkylation (AAA) is a CÀC bond-forming reaction that has attracted much attention. [4,[8][9][10][11][12][13] In this transformation, the enantiodiscrimination event occurs through the external attack of a soft nucleophile on a palladium-bound h 3 -allyl moiety (Scheme 1 a). [4,12] The AAA thus bears resemblance to enzymatic reactions, in which the substrate(s) need not necessarily bind to the active site of the enzyme for the reaction to proceed with high stereoselectivity. [7] In recent years, there has been increasing interest in the creation of artificial metalloenzymes for enantioselective catalysis. For this purpose, an active-catalyst precursor is anchored in a biomolecule, which provides the chiral environment. [14][15][16][17][18][19][20][21][22][23] The enantioselective reactions implemented thus far include ester hydrolysis, [24] dihydroxylation, [25] epoxidation, [26,27] sulfoxidation, [28][29][30][31][32] hydrogenation, [33][34][35][36][37][38][39][40][41][42][43] transfer hydrogenation, [44,45] and Diels-Alder reactions. [46][47][48][49][50] Inspired by the early studies of Wilson and Whitesides, [33] several research groups [34,35,41] have exploited the biotinavidin technology to ensure the localization of a biotinylated catalytic moiety within (strept)avidin (either avidin or streptavidin). This methodology has allowed the creation of artificial metalloenzymes for enantioselective hydrogenation and transfer-hydrogenation reactions. [33][34][35][36][37][38][39][40][41][42][43][44][45] Herein we describe our efforts to create artificial metalloenzymes for the AAA. We show that a combination of chemical and genetic optimization allows the identification of [Pd(h 3 -allyl)(biotin-spacer-ligand)] + &(strept)avidin catalysts that afford both R and S alkylation products (in up to 90 and 82 % ee, respectively; Scheme 1).With the aim of identifying the most promising chelating ligand, we evaluated five different biotinylated scaffolds in the presence of (strept)avidin (Scheme 2). Little, if any, conversion was detected (Table 1, entry 1): Most of the starting 1,3-diphenylallylacetate was hydrolyzed to the corresponding 1,3-diphenylallyl alcohol. We therefore screened various surfactants that are commonly used in aqueous Scheme 1. The postulated enantiodiscrimination event in the AAA in a) a homogeneous catalytic system and b) an artificial metalloenzyme. The host protein (streptavidin, brown) displays high affinity for the anchor (biotin, green triangle). The introduction of an amino acid spacer (red star) combined with a chelating ligand (purple) allows the chemical optimizat...

Complexes prepared in situ from RuCl 2 (PPh 3 ) 3 and chiral phosphine-oxazoline ligands are effective catalysts for the hydrogenation of various aryl ketones with ees up to 99% and substrate to catalyst ratios of 10,000 -50,000; the reaction tolerates high substrate concentrations and a pilot process has been developed for the hydrogenation of 3,5-bistrifluoromethyl acetophenone.

Cinnamyl chlorides undergo selective S N 2' allylic substitution by Grignard reagents using catalytic amount (1 mol%) of CuCN and 1-2 mol% trivalent phosphorus ligand, in dichloromethane. With chiral phosphorus ligands derived from TADDOL ee's up to 73% could be obtained.