Jiefeng Shen

Asymmetric domino reaction of cyclic N-sulfonylimines and simple aldehydes with trans-perhydroindolic acid as an organocatalyst.

An asymmetric domino reaction was developed utilizing readily available cyclic N-sulfonylimines and simple aldehydes to construct biologically important and synthetically challenging piperidine derivatives consisting of three contiguous stereocenters. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 89% yield, 80:20 dr, and 99% ee). The absolute configuration of the catalytic product was determined by X-ray crystallography studies. The product could be conveniently converted to synthetically useful intermediates, such as (3R,4S)-4-ethyl-3-methyl-6-phenylpiperidinyridin-2-one (8), via a simple transformation.

Highly efficient asymmetric Michael addition of aldehyde to nitroolefin using perhydroindolic acid as a chiral organocatalyst

Perhydroindolic acids, the by-products obtained in the industrial production of a trandolapril intermediate, were used as chiral organocatalysts in asymmetric Michael addition reactions of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with two H atoms attached to the bridgehead C atoms lying on the opposite side of the ring. They therefore showed high efficiency in asymmetric Michael additions of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 99/1 dr and 98% ee) were obtained with high chemical yields for a series of aldehydes and nitroolefins using only 5 mol% catalyst loading. The methodology features easily available catalysts, high catalytic efficiency and environmentally green procedures.

Asymmetric Hydrogenation of α-Substituted Acrylic Acids Catalyzed by a Ruthenocenyl Phosphino-oxazoline–Ruthenium Complex

Asymmetric hydrogenation of various α-substituted acrylic acids was carried out using RuPHOX-Ru as a chiral catalyst under 5 bar H2, affording the corresponding chiral α-substituted propanic acids in up to 99% yield and 99.9% ee. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 5000 S/C), and the resulting product (97%, 99.3% ee) can be used as a key intermediate to construct bioactive chiral molecules. The asymmetric protocol was successfully applied to an asymmetric synthesis of dihydroartemisinic acid, a key intermediate required for the industrial synthesis of the antimalarial drug artemisinin.

The synthesis of chiral β-aryl-α,β-unsaturated amino alcohols via a Pd-catalyzed asymmetric allylic amination

Chiral β-aryl-α,β-unsaturated amino alcohols were synthesized via a Pd-catalyzed asymmetric allylic amination of 4-aryl-1,3-dioxolan-2-one using planar chiral 1,2-disubstituted ferrocene-based phosphinooxazolines as ligands. Under the optimized reaction conditions, a series of substrates were examined and the products were obtained in good to excellent yields (up to 92%) and enantioselectivities (up to 98% ee) under mild reaction conditions. The desired products were determined to be of (R)-configuration and could subsequently be transformed into compounds with interesting biological activity using simple transformations.

Synthesis of Chiral α,β-Unsaturated γ-Amino Esters via Pd-Catalyzed Asymmetric Allylic Amination

A Pd-catalyzed asymmetric allylic amination of 4-substituted 2-acetoxybut-3-enoates with amines has been developed for the regiospecific synthesis of chiral α,β-unsaturated γ-amino esters. The desired chiral aminated products can be obtained in up to 98% yield, and 99% ee and can be conveniently transformed to chiral γ-amino acid/alcohol derivatives and chiral γ-lactams, which can then be subjected to the synthesis of several types of chiral drugs and drug candidates. The preferential formation of chiral γ-amino esters may be attributed to the bulky substituents on the right side of the allyl substrates. This work provides an efficient strategy for the synthesis of chiral α,β-unsaturated γ-amino esters and their derivatives.

The Construction of Chiral Fused Azabicycles Using a Pd-Catalyzed Allylic Substitution Cascade and Asymmetric Desymmetrization Strategy.

A highly enantioselective Pd-catalyzed asymmetric allylic substitution cascade of cyclic N-sulfonylimines with an accompanying asymmetric desymmetrization has been developed for the construction of fused tetrahydroindole derivatives bearing two chiral centers. Mechanistic studies confirmed that the cascade reaction proceeds by initial allylic alkylation and subsequent allylic amination. The first alkylation is a chirality-control step and represents an asymmetric desymmetrization of cis-cyclic allyl diacetates. The reaction has been performed on a gram scale, and the desired products can take part in several transformations.

Construction of Chiral-Fused Tricyclic γ-Lactams via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Domino Reaction

An asymmetric domino reaction was developed utilizing readily available cyclic α-dehydroamino ketones and aldehydes, which when subjected a 2-iodoxybenzoic acid (IBX)-mediated oxidation gives pyrrolidinone-containing tricyclic derivatives. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 94% yield, 99% ee, and >20:1 dr). The product could be conveniently converted to synthetically useful intermediates via simple transformations. A possible stereocontrolled process has been suggested according to X-ray crystallography studies.