Highly Enantioselective Synthesis of N-Unprotected Unnatural α-Amino Acid Derivatives by Ruthenium-Catalyzed Direct Asymmetric Reductive Amination.

An unprecedented highly enantioselective Ru-catalyzed direct asymmetric reductive amination of α-keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N-unprotected unnatural α-amino acid derivatives bearing a broad range of aryl or alkyl α-substituents. This protocol features easily accessible substrates, good functional-group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N-unprotected unnatural α-amino acid derivatives containing an additional stereogenic center at the ß-position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N-unprotected unnatural α-amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method.

Design, Synthesis and Anti-Platelet Aggregation Activity Study of Ginkgolide-1,2,3-triazole Derivatives.

Ginkgolides are the major active component of Ginkgo biloba for inhibition of platelet activating factor receptor. An azide-alkyne Huisgen cycloaddition reaction was used to introduce a triazole nucleus into the target ginkgolide molecules. A series of ginkgolide-1,2,3-triazole conjugates with varied functional groups including benzyl, phenyl and heterocycle moieties was thus synthesized. Many of the designed derivatives showed potent antiplatelet aggregation activities with IC50 values of 5~21 nM.

Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts.

A Ru-catalyzed direct CH activation/meta-bromination of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups has been developed. A series of bromo aryl pyridines and pyrimidines have been synthesized, and further coupling reactions have also been demonstrated for a number of representative functionalized arenes. Preliminary mechanistic studies have revealed that this reaction may proceed through radical-mediated bromination when NBS is utilized as the bromine source. This type of transformation has opened up a new direction for the radical non-ipso functionalization of metal with regard to future CH activation development that would allow the remote functionalization of aromatic systems.

Ru-Catalyzed Asymmetric Reductive Amination of Aryl-Trifluoromethyl Ketones for Synthesis of Primary α-(Trifluoromethyl)arylmethylamines.

The ruthenium-catalyzed asymmetric reductive amination of aryl-trifluoromethyl ketones affording high value primary α-(trifluoromethyl)arylmethylamines using cheap NH4OAc as the nitrogen source and H2 as the reductant is reported. This user-friendly and simple catalytic method tolerates various aromatic functions with electron-withdrawing or -donating substituents at the para- or meta-positions and as well challenging heteroaromatic functions, yielding primary α-(trifluoromethyl)arylmethylamines with excellent chemoselectivities, enantioselectivities, and useful yields (80-97% ee, 51-92% isolated yields). Finally, scalable and concise synthesis of key drug intermediates using this methodology is presented.

Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia.

Cephalotaxine-type alkaloids (CTAs), represented by homoharringtonine (HHT, 1), display potent efficacy against different types of leukemia cells. In this study, a method for hydrogenation of ß-substituted itaconic acid monoesters with chiral Ru[DTBM-SegPhos](OAc)2 was developed. This metal-catalyzed asymmetric hydrogenation enabled the convenient semisynthesis of novel cephalotaxine derivatives with chiral 2'-substituted-succinic acid 4-mono-methyl esters as side chains. The preliminary structure-activity relationship (SAR) of the compounds' antineoplastic activities was studied. Eventually, we discovered compound 10b with potent antineoplastic activities against leukemia and broadly anticancer activities against a panel of cancer cells. Our study provided a highly enantioselective process enabling the semisynthesis of cephalotaxine derivatives, which are interesting for further study on a scientific basis.

Asymmetric Reductive Amination/Ring-Closing Cascade: Direct Synthesis of Enantioenriched Biaryl-Bridged NH Lactams.

We report here a Ru-catalyzed enantioselective synthesis of biaryl-bridged NH lactams through asymmetric reductive amination and a spontaneous ring-closing cascade from keto esters and NH4OAc with H2 as reductant. The reaction features broad substrate generality and high enantioselectivities (up to >99% ee). To showcase the practical utility, a highly enantioselective synthesis of 5-ethylindolobenzazepinone C, a promising antimitotic agent, has been rapidly completed. Furthermore, the amide group in the products enables versatile elaborations through directed C-H functionalization.

CuH-Catalyzed Atropoenantioselective Reduction of Bringmann's Lactones via Dynamic Kinetic Resolution.

A CuH-catalyzed atropoenantioselective reduction of Bringmann's lactones via dynamic kinetic resolution has been disclosed. This protocol features a broad substrate scope and good functional group tolerance and allows the rapid assembly of various valuable axially chiral biaryls in good to high yields (up to 92% yield) with high to excellent enantioselectivities (up to 96% ee). Moreover, this report represents a rare example that a carbonyl group of esters is reduced under homogeneous asymmetric CuH catalysis.

Selective mono-alkylation of N-methoxybenzamides.

We report our latest discovery of norbornene derivative modulated highly mono-selective ortho-C-H activation alkylation reactions on arenes bearing simple mono-dentate coordinating groups. The reaction features the use of readily available benzamides and alkyl halides. During the study, we prepared 30 mono-alkylated aryl amides in good yields with good mono-selectivity. We have also demonstrated that structurally rigid alkenes such as norbornene and its derivatives are a good class of ligand and could be used for future direct C-H functionalizations. The utilization of norbornene type ligands for assistance in C-H activation processes has opened a new window for future molecular design using direct C-H functionalization strategies.

Modular synthesis of dihydro-isoquinolines: palladium-catalyzed sequential C(sp2)-H and C(sp3)-H bond activation.

An efficient synthesis of dihydro-isoquinolines via a Pd-catalyzed double C-H bond [a C(sp2)-H and a C(sp3)-H bond] activation/annulation (CHAA) reaction is presented. This methodology features a short reaction time, high atom economy (loss of H2O only) and the formation of a sterically less favoured tertiary C-N bond. This fast (30 min) and environmentally benign radical C-H activation approach has demonstrated the potential direction for the future design/development of fast and efficient C-H direct functionalization processes.