Biferrocene-Based Diphosphine Ligands: Synthesis and Application of Walphos Analogues in Asymmetric Hydrogenations.

A total of four biferrocene-based Walphos-type ligands have been synthesized, structurally characterized, and tested in the rhodium-, ruthenium- and iridium-catalyzed hydrogenation of alkenes and ketones. Negishi coupling conditions allowed the biferrocene backbone of these diphosphine ligands to be built up diastereoselectively from the two nonidentical and nonracemic ferrocene fragments ()-1-(,-dimethylamino)ethylferrocene and ()-2-bromoiodoferrocene. The molecular structures of ()-2-bromoiodoferrocene, the coupling product, two ligands, and the two complexes ([PdCl(L)] and [RuCl(-cymene)(L)]PF) were determined by X-ray diffraction.

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.

Synthesis, coordination behaviour, structural features and use in asymmetric hydrogenations of bifep-type biferrocenes.

A protocol for the synthesis of C2- and C1-symmetric 2,2''-diarylphosphino-substituted biferrocenes (bifep-type ligands) is presented and the preparation of four representatives is described [(Sp,Sp)-2-R1(2)P-2''- R2(2)P-1,1''-biferrocene; (bifep): R1=R2=Ph; : R1=Ph, R2=Cy; : R1=R2=3,5-Me2C6H3; : R1=3,5-Me(2-)4-OMe-C6H2, R2=3,5-(CF3)2C6H3]. In addition, the synthesis of three palladium(II) complexes ([PdX2(L)], : L=, X=Cl; : L=, X=Cl; : L=, X=C6F5 and of four bifep ruthenium complexes (: [RuCl(p-cymene)()]PF6; : [RuI(p-cymene)()]PF6; : [RuCl(benzene)()]PF(6); : [RuI(p-cymene)()]I) is reported. In the solid state the biferrocene unit of complexes , and adopt either a (P)-shaped () or an (M)-shaped (, ) conformation.

Solphos: a new family of efficient biaryl diphosphine ligands.

Solphos (7,7'-bis(diarylphosphino)-3,3',4,4'-tetrahydro-4,4'-dimethyl-8,8'-bis-2H-1,4-benzoxazine) is a new modular atropisomeric biaryl ligand with a very attractive activity profile. A technically feasible synthesis is described allowing the synthesis of various derivatives of enantiopure ligand on a technical scale. Very good catalytic performances have been demonstrated for the following transformations: Ru-catalyzed hydrogenation of various beta-keto esters (95-99 % ee, s/c up to 100,000), of acetyl acetone (>99 % ee, dl/meso>98:2), and of an exocyclic alpha,beta-unsaturated acid (98.

SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1.

Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.

From a chiral switch to a ligand portfolio for asymmetric catalysis.

This Account is divided into two sections. In the first section, the development of an enantioselective manufacturing process for ( S)-metolachlor, the active ingredient of the grass herbicide Dual Magnum, is described. This is today's largest application of asymmetric catalysis, and the Ir-Xyliphos hydrogenation catalyst achieves unprecedented 2 millions turnovers.

Asymmetric homogeneous hydrogenation of 2,5-disubstituted furans.

A homogeneous catalyst system for the asymmetric cis-hydrogenation of 2,5-disubstituted furans leading to 2',3'-dideoxynucleoside analogues is described. Best enantioselectivities (ee values of up to 72%) were obtained with cationic rhodium complexes ligated by diphospholanes of the butiphane family. The selectivity of the hydrogenation was reversed by the addition of a base or a polar protic solvent in certain cases.

Chiral iridium [corrected] xyliphos complexes for the catalytic imine hydrogenation leading to the metolachlor herbicide: isolation of catalyst-substrate adducts.

Iridium complexes relevant to the catalytic enantioselective hydrogenation of 2-methyl-6-ethylphenyl-1'-methyl-2'-methoxyethylimine (MEA-imine, 1) in the Syngenta Metolachlor (3) process were prepared and characterized. Reaction of the diphosphane (S)-1-[(R)-2-(diphenylphosphanyl)ferrocenyl]ethyldi(3,5-xylyl)phosphane ((S)-(R)-Xyliphos, (S)-(R)-4) with [Ir(2)(micro-Cl)(2)(cod)(2)] (cod=1,5-cyclooctadiene) afforded [Ir(Cl)(cod)[(S)-(R)-4]] (7), which reacted with AgBF(4) to form [Ir(cod)[(S)-(R)-4]]BF(4) (8). Complexes 7 and 8 reacted with iodide to yield [Ir(I)(cod)[(S)-(R)-4]] (9).

Exploring stereogenic phosphorus: synthetic strategies for diphosphines containing bulky, highly symmetric substituents.

Diphosphine ligands bearing highly symmetric, bulky substituents at a stereogenic P atom were prepared, exploiting established protocols, which include the use of chiral synthons such as 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (3a) and phenylmethylchlorophosphine borane (10) and the enantioselective deprotonation of dimethylarylphosphine boranes. However, only (Bu(t)())(Me)PCH(2)CH(2)P(Bu(t)Me (8a) could be prepared from 3a. The diphosphines (S,S)-1,2-bis(mesitylmethylphosphino)ethane, ((S,S)-8b) and (S,S)-1,2-bis(9-anthrylmethylphosphino)ethane ((S,S)-8c), which contain 2,6-disubstituted aryl P-substituents, were prepared by Evans' sparteine-assisted enantioselective deprotonation of P(Ar)(Me)(2)(BH(3)) (Ar = mesityl or 9-anthryl), but the enantioselectivity did not exceed 37% ee.