Search

An ene-reductase (ERED 36) with broad substrate specificity was identified, and optimization studies led to the development of an enzymatic protocol for the reduction of α,β-unsaturated acids under mild, aqueous conditions. The substrate scope includes aromatic- and aliphatic-substituted acrylic acids, as well as cyclic α,β-substituted acrylic acids, yielding chiral α-substituted acids with exquisite levels of enantioselectivity (>99% ee).

Prochiral hydrazones undergo efficient and highly selective hydrogenation in the presence of a chiral diphosphine ruthenium catalyst, yielding enantioenriched hydrazine products (up to 99% ee). The mild reaction conditions and broad functional group tolerance of this method allow access to versatile chiral hydrazine building blocks containing aryl bromide, heteroaryl, alkyl, cycloalkyl, and ester substituents. This method was also demonstrated on >150 g scale, providing a valuable hydrazine intermediate en route to an active pharmaceutical ingredient.

The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement–ring closure, followed by a Baeyer–Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.

[reaction: see text] A rapid, highly efficient and general dynamic kinetic resolution (DKR) of racemic alpha-aryl UNCAs with the dual-function catalysis of modified cinchona alkaloid was accomplished at room temperature. This DKR led to the development of a highly enantioselective catalytic method for the practical synthesis of a wide range of alpha-aryl and alpha-heteroaryl amino acids in 89-92% ee and 86-95% yield from racemic UNCAs.

In this communication, we report an efficient asymmetric Friedel-Crafts reaction that, unprecedently, is applicable to a wide range of both indoles and carbonyls. The use of a readily accessible catalyst in combination with a high enantioselectivity that is insensitive to reaction concentration, temperature, air, and moisture should allow this reaction to provide useful enantioselective access to new chiral indole derivatives. [reaction: see text]

[Reaction: see text] The catalytic construction of nitrogen-substituted quaternary stereocenters is an important and challenging task in asymmetric synthesis. In this paper, we describe the use of 6'-OH-modified cinchona alkaloids that are accessible from either quinine or quinidine for the development of a highly enantioselective amination of alpha,alpha-disubstituted carbonyl compounds that is suitable for the creation of nitrogen-substituted quaternary stereocenters in either the R or S configuration.