Enantioselective Protonation: Hydrophosphinylation of 1,1-Vinyl Azaheterocycle N-Oxides Catalyzed by Chiral Bis(guanidino)iminophosphorane Organosuperbase.

Enantioselective protonation by hydrophosphinylation of diarylphosphine oxides with 2-vinyl azaheterocycle N-oxide derivatives was demonstrated using chiral bis(guanidino)iminophosphorane as the higher-order organosuperbase catalyst. It was confirmed by several control experiments that a chiral weak conjugate acid of the chiral bis(guanidino)iminophosphorane, instead of achiral diarylphosphine oxides, directly functioned as the proton source to afford the corresponding product in a highly enantioselective manner in most cases. Enantioselective protonation by a weak conjugate acid generated from the higher-order organosuperbase would broaden the scope of enantioselective reaction systems because of utilization of a range of less acidic pronucleophiles. This method is highlighted by the valuable synthesis of a series of chiral P,N-ligands for chiral metal complexes through the reduction of phosphine oxide and N-oxide units of the corresponding product without loss of enantiomeric purity.

Enantioselective direct Mannich-type reactions of 2-benzylpyridine N-oxides catalyzed by chiral bis(guanidino)iminophosphorane organosuperbase.

2-Benzylpyridine N-oxides possessing less acidic α-protons were utilized as pronucleophiles for the first time in enantioselective addition reactions under Brønsted base catalysis. A chiral bis(guanidino)iminophosphorane was able to overcome the inherent issue of low acidity of the pronucleophiles, establishing the diastereo- and enantioselective direct Mannich-type reaction with N-Boc imines. The control experiments indicated that the N-oxide moiety of the substrates played a critical role in achieving the high stereoselectivity.

Rh-Catalyzed Chemo- and Enantioselective Hydrogenation of Allylic Hydrazones.

A highly efficient P-stereogenic diphosphine-rhodium complex was applied to the chemo- and enantioselective hydrogenation of allylic hydrazones for the synthesis of chiral allylic hydrazines in 89-96 % yields and with 82-99 % ee values. This methodology was successfully applied to the preparation of versatile chiral allylic amine derivatives.

Rh-Catalyzed One-Pot Sequential Asymmetric Hydrogenation of α-Dehydroamino Ketones for the Synthesis of Chiral Cyclic trans-ß-Amino Alcohols.

Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand (R)-2-tert-butylmethylphosphino-3-(di-tert-butylphosphino)quinoxaline ((R)-3H-QuinoxP*), five-membered cyclic α-dehydroamino ketones bearing endocyclic vinyl and endocyclic keto-carbonyl groups were sequentially hydrogenated to give chiral cyclic trans-ß-amino alcohols with two contiguous stereocenters in quantitative conversions, excellent enantioselectivities and good diastereoselectivities.

Rh-Catalyzed Asymmetric Hydrogenation of Cyclic α-Dehydroamino Ketones.

Catalyzed by a rhodium complex of P-stereogenic diphosphine trichickenfootphos, five-membered cyclic α-dehydroamino ketones bearing endocyclic acyl and endocyclic vinyl groups were hydrogenated to give chiral α-amino ketones with quantitative conversions and excellent enantioselectivities.

ZnCl2 -promoted asymmetric hydrogenation of ß-secondary-amino ketones catalyzed by a P-chiral Rh-bisphosphine complex.

A new catalytic system has been developed for the asymmetric hydrogenation of ß-secondary-amino ketones using a highly efficient P-chiral bisphosphine-rhodium complex in combination with ZnCl2 as the activator of the catalyst. The chiral γ-secondary-amino alcohols were obtained in 90-94 % yields, 90-99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl2 on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high yields and with excellent enantioselectivities.