Mathematisch-Naturwissenschaftliche Fakultät

Institut für Chemie

Fachgebiet: Organic Chemistry and Catalysis

Betreuer: Prof. Dr. Johannes Gerardus de Vries

MSc. Soumyadeep Chakrabortty
(e-mail: )

Development and Application of Chiral Phosphorus Ligands for Enantioselective Hydrogenation

A new P-chiral synthon has been developed in an operationally simple and efficient way bearing electronically different P-atoms as compared to literature ones. The new P-chiral synthon (depicted as P*-2 in Figure 26) can easily be synthesized in two steps starting from the commercially available rac-chlorophosphine and chiral primary amines in two steps. Optically pure P*-2 can be easily isolated via a simple recrystallization of the diastereomeric mixture from pentane/heptane. Further derivatization of the P-chiral synthon with different chlorophosphites (atropisomeric, axially chiral or backbone chiral) resulted a library of narrow-bite angle mixed donor P-P ligands.First, a set of chiral P-P ligands bearing achiral, bulky bisphenol and 1,1′-bi-2-naphthol substituents was synthesized and applied to Rh-catalyzed asymmetric hydrogenation of functionalized olefins. A strong match/mismatch effect was also noticed comparing the diastereomeric and enantiomeric pairs of the ligands. Moderate enantioselectivity (upto 32%) was observed in the rhodium-catalyzed hydrogenation of itaconates, whereas excellent ee’s (up to 96%) were observed employing dehydroamino acids as substrates. Details are described in Section 5.1.

A small set of narrow bite angle P-P ligand has been developed using a cheap amino alcohol with backbone chirality (called Betti base). For the first time we have incorporated two electronically different P-stereogenic synthons into one ligand via a stereospecific reaction. The ligand contains five stereocenters in the backbone including two P-stereogenic centers. A match-mismatch effect was also observed in Rh-catalyzed asymmetric hydrogenation and Pd-catalyzed asymmetric allylic substitution. Several α-amino acid derivatives were synthesized with excellent ee’s (>99%) in quantitative yields. Moderate ee (74%) was observed in the allylic substitution of diphenyl allyl acetate using dimethyl malonate as nucleophile. Details are described in section 5.2.

The newly developed ligand library (JoSoPhos) was also applied in the synthesis of an active pharmaceutical (Rasagiline, anti-Parkinson’s therapeutic). Interestingly, a difference in coordination behavior (which had a direct influence on the catalytic behavior) was found between ligands, depending on the steric bulk on one of the phosphorus atoms. This could be proven by the aid of 1D and 2D NMR spectroscopy. The asymmetric synthesis of Rasagiline was performed via enantioselective hydrogenation (using Rh/JoSoPhos catalyst) as key step, followed by hydrolysis of the amide and propargylation in 79% isolated yield and >99% ee. Several other α-alkyl or α-aryl amines/amine derivatives were also prepared via asymmetric enamide hydrogenation employing the JoSoPhos ligand upto >99% ee. A number of chiral cyclic amides was prepared in excellent ee’s. Isotope labelling experiments showed that Rh/JoSoPhos catalyzed asymmetric hydrogenation is an isomerization (imide-enamide tautomerization) free asymmetric direct hydrogenation (ADH) process with molecular hydrogen. A number of chiral primary amines were also prepared via asymmetric hydrogenation of the enamides followed by deacylation. The detailed work is described in section 5.3.

A cobalt-based catalyst was developed for the enantioselective hydrogenation of tri-substituted carbocyclic olefins using commercially available bisphosphines. Excellent ee’s have been obtained (upto 99%) for the preparation of chiral amides. Preliminary mechanistic studies based on EPR and mass spectroscopy, showed the presence of a high spin (S=3/2) cobalt species throughout the catalytic cycle. It is proposed that the hydrogenation of the carbon-carbon double bond proceeds through a sigma bond metathesis pathway. The detailed work is described in section 5.4.

Direct asymmetric reductive amination of bio-based levulinic acid (LA) was achieved using a readily available chiral Ru-bisphosphine catalyst. In this way, chiral 5-methyl-pyrrolidinone was synthesized in 89% isolated yield with up to 96% ee in trifluoroethanol. Methyl levulinate (ML), a byproduct from the industrial synthesis of 2,5-furandicarboxylic acid (FDCA), could also be converted to the chiral pyrrolidinone in a similar way. Based on isotope labelling and mass spectroscopy experiments, we propose that the chiral lactam is formed via imine-enamine tautomerization/cyclization followed by asymmetric hydrogenation of the cyclic enamide. The detailed work is described in section 5.5.