Christophe Malan

Highly Efficient Asymmetric Synthesis of Sitagliptin

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.

Artificial Metalloenzymes for Asymmetric Allylic Alkylation on the Basis of the Biotin–Avidin Technology

Palladium in the active site: The incorporation of a biotinylated palladium diphosphine within streptavidin yielded an artificial metalloenzyme for the title reaction (see scheme). Chemogenetic optimization of the catalyst by the introduction of a spacer (red star) between biotin (green triangle) and palladium and saturation mutagenesis at position S112X afforded both R- and S-selective artificial asymmetric allylic alkylases.

The copper-catalyzed asymmetric allylic substitution

This mini-review discusses the rapidly growing field of asymmetric copper-catalyzed chemistry. Although the allylic substitution has been less studied than the conjugate addition, recent breakthroughs have made this methodology a very valuable synthetic tool. Thus, a primary allylic halide or phosphate reacts with Grignard or diorganozinc reagents to afford the SN product (or ?-product) in high regio- and enantioselectivities. Besides the results of the authors, we present also other, different approaches to this reaction, with emphasis on the organo-metallic and the type of chiral ligand used.

P-Stereogenic diphosphines in the ruthenium-catalysed asymmetric hydrogenation of CC and CO double bonds

Abstract Bis(acetato) and dichloro complexes of ruthenium(II) containing P -stereogenic ligands have been prepared and tested in the asymmetric catalytic hydrogenation of functionalised olefins and keto esters. The best performance (52.6% ee) has been obtained in the hydrogenation of ethyl acetoacetate with [RuCl(PPh 3 )(( S , S )-1,1′-bis(1-naphthylphenylphosphino)ferrocene)] 4 .

New Chiral Ligands with Nonstereogenic Chirotopic Centers for Asymmetric Synthesis

Pseudo-C2 -symmetrical ligands have been prepared efficiently: The attachment of the chiral alkyl group to the heteroatom (P or N) through a nonstereogenic, chirotopic carbon center facilitates their synthesis as the configuration at this carbon atom no longer needs to be controlled. Two such ligands were combined, for example, in the base 1, which is especially useful for asymmetric deprotonation of prochiral ketones [Eq. (a)].

Chemical optimization of artificial metalloenzymes based on the biotin-avidin technology: (S)-selective and solvent-tolerant hydrogenation catalysts via the introduction of chiral amino acid spacers

Incorporation of biotinylated-[rhodium(diphosphine)]+ complexes, with enantiopure amino acid spacers, in streptavidin affords solvent-tolerant and selective artificial metalloenzymes: up to 91% ee (S) in the hydrogenation of N-protected dehydroamino acids.

Neue chirale Liganden mit nichtstereogenen chirotopen Zentren für die asymmetrische Synthese

Pseudo-C2-symmetrische Liganden wurden in effizienter Weise synthetisiert: Die Verknupfung der chiralen Alkylgruppe mit dem Heteroatom (P oder N) uber ein nichtstereogenes, chirotopes Kohlenstoffzentrum fuhrt zu einer betrachtlichen Vereinfachung der Synthese, da sich die Kontrolle der Konfiguration dieses Zentrums erubrigt. Zwei solcher Liganden wurden z.u2009B. in der Base 1 verknupft, die besonders geeignet ist fur die asymmetrische Deprotonierung prochiraler Ketone [Gl. (a)].