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.

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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 series of diphosphines of the novel Walphos ligand family all based on a phenylferrocenylethyl backbone were synthesised in a four-step sequence. In the rhodium-or ruthenium-catalysed asymmetric hydrogenation of olefins and ketones enantioselectivities of up to 95% and 97%, respectively, were obtained. A 2-isopropylcinnamic acid derivative of industrial interest was hydrogenated in 95% ee and with turnover numbers of > 5000.Keywords: alkene reduction; asymmetric catalysis; asymmetric hydrogenation; ketone reduction; Pligands; rhodium; ruthenium Over a period of more than three decades homogenous enantioselective hydrogenation has been investigated extensively by numerous researchers in academia and industry, and is now being considered as a mature methodology for the production of enantiopure, bioactive ingredients and fine chemicals on an industrial scale.[1] The most efficient catalysts for the asymmetric hydrogenation of olefins, ketones or imines [2] are rhodium, ruthenium and iridium complexes of chiral diphosphine ligands. However, even though innumerable chiral diphosphines have been designed and investigated in the past, only a few out of more than thousands have been found suitable for industrial processes. Representative examples are biaryl-, phospholaneand ferrocenyl-based ligands like binap, duphos or josiphos type ferrocenes. [3] In our search for novel classes of diphosphines, we focused on the design of ligands that fulfil all relevant prerequisites particularly with regard to industrial applications: shortness and modularity of ligand synthesis that should allow an efficient fine tuning of catalysts× properties. In addition, such ligands should be readily accessible from enantiopure key intermediates. In this context, we have examined the potential of a new family with a novel phenylferrocenylethyl backbone that we named Walphos (1; Figure 1). The synthesis concept for this ligand family is straightforward: (i) the enantiomerically pure ligand framework ± an orthobromophenylferrocenylethylamine (3) ± is constructed from Ugi×s amine [4] and (ii) the final functional groups are implemented stepwise.[5] (Scheme 1) In this preliminary contribution, we report the synthesis of six representatives of the Walphos family with varying phosphino substituents R 1 and R 2 , together with first applications in the enantioselective hydrogenation.Starting from amine 2, six derivatives with electronrich and electron-withdrawing phosphino substituents R 1 and R 2 were prepared in a four-step sequence. In a Negishi coupling reaction [6] of (R c )-N,N-dimethyl-1-ferrocenylethylamine, (R c )-2, with 2-bromoiodobenzene the enantiomerically pure key intermediate (R c ,R p )-3 was built up. A subsequent lithiation of this bromide followed by trapping with the appropriate electrophile ±either chlorodiphenylphosphine or chlorobis(3,5-dimethyl-4-methoxyphenyl)phosphine ±result-ed in the formation of the corresponding aminophosphines. In order to prevent a ring closure reaction in the next step, the aminophosphin...