Felix Spindler

Solvias Josiphos ligands: from discovery to technical applications

The various stages from the invention of a ligand class to its technical application are described and illustrated by the case history of the Solvias Josiphos ligands. First, the prerequisites for a so-called “privileged ligand” are discussed, followed by a description of the Josiphos ligand family and their technical synthesis. Then, the catalytic performance of various Josiphos metal complexes in model reactions and in “real world” synthetic applications are summarized in the next two chapters. In the last part, three technical processes using Josiphos ligands are described: (i) The Ir-PPF-P(Xyl)2-catalyzed hydrogenation of MEA imine for the large scale production of the herbicide (S)-metolachlor; (ii) the application of a Rh-PPF-P(tBu)2 complex for the hydrogenation of a biotin intermediate; (iii) the Ru-PPF-P(Cy)2-catalyzed hydrogenation of a tetrasubstituted C=C bond for the production of cis-methyl dihydrojasmonate.

More than 100,000 Turnovers with Immobilized Ir‐Diphosphine Catalysts in an Enantioselective Imine Hydrogenation

A modular concept to prepare immobilized enantioselective catalysts is described, consisting of a functionalized xyliphos ligand covalently attached to a support via a linker. Immobilized xyliphos bound to silica and to polystyrene as well as soluble dimeric xyliphos and an extractable analogue were prepared and tested in the Ir-catalyzed hydrogenation of a hindered N-arylimine used for the production of (S)-metolachlor. The best heterogeneous catalyst 9b exhibited TONs >100,000 and TOFs up to 20,000 h−1, the best values so far for immobilized catalysts. The immobilized catalysts gave similar enantioselectivities but lower activities and higher deactivation rates than the homogeneous analogues. These negative effects were tentatively explained by the higher local catalyst concentration on the support surface leading to an increased tendency to deactivation by irreversible dimer formation. Separation of these catalysts by filtration and extraction is easy and efficient.

Tunable ferrocenyl diphosphine ligands for the Ir-catalyzed enantioselective hydrogenation of N-aryl imines

Abstract Ferrocenyl diphosphines R2PF-P(R′)2 are effective, tunable ligands for the iridium catalyzed enantioselective hydrogenation of N-aryl imines in the presence of iodide and acid promoters. Structure–activity/selectivity correlations were found for the hydrogenation of N-(2-ethyl-6-methylphenyl)-N-(1′-methoxymethyl)-ethylidene-amine (MEA-imine) and for 2,3,3-trimethylindolenine (TMI). Extremely high catalytic activity and moderate to good enantioselectivity were observed for the MEA imine using a catalyst generated in situ from [Ir(cod)Cl]2 and (R)-(S)-PPF–P(3,5-Xyl)2 (xyliphos). With the same type of catalysts, several other N-aryl imines can be hydrogenated with enantioselectivities between 31 and 96%, albeit with lower catalyst activities.

Enantioselective hydrogenation of α-ketoesters: comparison of homogeneous and heterogeneous catalysts

Abstract A case study concerning the development of enantioselective hydrogenation processes for aliphatic α-ketoesters, particularly ethyl 2-oxo-4-phenylbutyrate ( 1 ) and ethyl pyruvate ( 2 ), using homogeneous Rh-diphosphine and heterogeneous Pt/Al 2 O 3 -cinchona catalysts is presented. Important parameters to obtain high enantioselectivities using the homogeneous system were shown to be the ligand, the nature of the Rh complex and the solvent. Unfortunately, the best optical yields (ee 96%) were achieved only at a low substrate/catalyst ratio of s/c=50. For the heterogeneous system , the structure and concentration of the modifier, the nature and pretreatment of the Pt/Al 2 O 3 catalyst, the type of solvent and the hydrogen pressure were decisive for high enantioselectivity (ees up to 95%). A major problem was the effect of the substrate quality on rate and optical yield. A comparison of catalyst costs showed a significant advantage for the heterogeneous catalyst, mainly due to its very high activity and catalyst productivity.

Synthesis and structure of new chiral ferrocenylphosphines for asymmetric catalysis

Abstract The reaction of ( R )-1-[( S )-(diphenylphosphino)ferrocenyl]ethyl acetate ( 1 ) or N,N -dimethyl-( R )-1-[( S )-(diphenylphosphino)ferrocenyl]ethylamine ( 2a ) with secondary phosphines in acetic acid leads to the diphosphines 5 in moderate to good yields. Two of these ligands, ( R )=1[( S )-(diphenylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine ( 5a ) and ( R P , R )-1[( S )-(diphenylphosphino)ferrocenyl]ethyl-phenyl-(2-methoxyphenyl)phosphine ( 5g ), as well as the complexes [Rh( 5a )(NBD)]BF 4 ·2CH 2 Cl 2 ( 9 ), [Pd(η 3 -C 3 H 5 ) ( 5a )]OTf ( 10 ) and [PtCl 2 ( 5a )] ( 11 ), have been characterized by X-ray diffraction. Crystals of 5a, 9, 10 and 11 are orthorhombic, space group P 2 1 2 1 2 1 , with four molecules in the unit cell. 5a : a =10.772(1), b =15.278(1), c =21.069(2) A; 9 : a =18.166(2), b =17.540(2), c =14.564(1); 10 : a =10.995(4), b =14.021(8), c =25.410(11) A; 11 : a =15.077(14), b =15.122(16), c =16.188(11) A. The stereogenic-at-phosphorus derivative 5g crystallizes in the monoclinic system, space group P 2 1 , with two pairs of symmetry independent molecules per the unit cell with a =7.896(1), b =25.667(2), c =15.654(1) A and β=92.39(1)°. Very similar conformations of the chelate rings in the complexes 9–11 are observed, this being indicative of the relative rigidity of the ligand 5a .

A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate

We report a convergent synthesis of the potent orally active non-peptide renin inhibitor CGP60536B. The key reaction employs the coupling of the enantiopure Grignard species derived from chloride 13 with the diastereomerically pure γ-lactone 9b. The stereoselective reduction of the resulting ketone 14b has been thoroughly investigated.

Enantioselective catalysis for agrochemicals. The case histories of (S)–metolachlor, (R)–metalaxyl and clozylacon

The application of enantioselective catalytic methods for the technical preparation of chiral agrochemicals is illustrated for three active ingredients of the acylanilide type. The key step for the technical synthesis of the herbicide (S)–metolachlor (trade name DUAL MAGNUM®) is the enantioselective hydrogenation of an imine intermediate using a novel iridium ferrocenyl–diphosphine catalyst that exhibited an unprecedented high activity (average turnover frequency up to 350,000 h-1) with an enantioselectivity of 80%. (R)–metalaxyl and clozylacon were synthesized with > 95% and 99% enantiomeric purity, respectively. The enantioselective hydrogenation of the corresponding enamides with Rh or Ru/binap catalysts was the key step in both cases. Some conclusions regarding the development of the catalyst system are made and important prerequisites for the use of enantioselective catalysts for the production of agrochemicals are discussed.

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.

Enantioselective imine hydrogenation with Ir diphosphine catalysts: fighting deactivation

Abstract While Ir diphosphine complexes are very active catalysts for the enantioselective hydrogenation of imines with good to excellent enantioselectivity, their deactivation is often a serious problem, leading to low catalyst productivity. Our study describes attempts to stabilize Ir catalysts with diop, bdpp and bppm ligands for the hydrogenation of different imines. The best results were obtained with complexes immobilised on silica gel and with bimetallic W–Ir and Mo–Ir complexes. In most cases, enantiomeric excesses as well as initial rates were only slightly affected while the stability of the catalysts was enhanced significantly.

Two enantioselective syntheses of a precursor of the biologically most active isomer of CGA 80000 (clozylacon)

Abstract The unchlorinated precursor 4 of CGA 80000 ( 1 ) was synthesized enantioselectively by two conceptionally different routes: a) by a “chiral pool” approach starting from L-malic acid and b) by enantioselective hydrogenation of an enamide intermediate, catalyzed by chiral Rh- or Ru-phosphine-complexes.