An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

Transition‐metal‐mediated metalation of an aromatic C−H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four‐membered chelate ring was first discovered in 1968. Herein, we overcome a long‐standing problem with the ortho‐C−H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium‐catalyzed ortho‐selective C−H borylation of various commercially available arylphosphines with B2pin2 through PIII‐chelation‐assisted C−H activation. This discovery is suggestive of a generic platform that could enable the late‐stage modification of readily accessible arylphosphines.

Background: Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored. Methods: Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments. Results: Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration. Conclusions: Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC.

Cisplatin (cDDP) remains one of the first-line chemotherapeutic agents for gastric cancer (GC) treatment, and resistance to cDDP is the major limitation in its clinical application. Mechanisms of cDDP resistance have been shown to be varied and complicated. Aquaporin 3 (AQP3) has been demonstrated to be overexpressed in GC tissues and is thought to be involved in GC carcinogenesis and progression. However, the role of AQP3 in chemosensitivity of GC to cytotoxic agents remains unknown. In this study, we show that AQP3 overexpression induced resistance to cDDP in AGS cells (P<0.05), and AQP3 knockdown increased the chemosensitivity in MGC803 and SGC7901 cells (P<0.05). Moreover, cDDP treatment enhanced AQP3 expression in MGC803, SGC7901 and AGS cells. AQP3 overexpression promoted the conversion of LC3-I to LC3-II in AGS cells, whereas AQP3 knockdown inhibited this conversion in MGC803 and SGC7901 cells. AQP3 upregulation increased Atg5 and Beclin-1 expression, and inhibited P62 expression in AGS cells, whereas AQP3 knockdown showed the opposite results in MGC803 and SGC7901 cells. Chloroquine (CQ), an autophagy inhibitor, enhanced the cytotoxicity of cDDP in GC cells, and CQ reversed the chemoresistance to cDDP caused by AQP3 overexpression in GC cells. Together, our data demonstrate that AQP3 facilitates cisplatin resistance in gastric cancer cells via autophagy, and suggest that the development of AQP3-based tumor therapeutics could play a key role in future GC treatment strategies.

Conspectus The widespread presence of hydrocarbons makes C–H functionalization an attractive alternative to traditional cross-coupling methods. As indole is an important heteroarene in a plethora of natural products and pharmaceuticals, C–H functionalization of indole moieties has emerged as one of the most important topics in this field. Due to the presence of multiple C–H bonds in indoles, site selectivity is a long-standing challenge. Much effort has been devoted to the C–H functionalization of indoles at the C3 or C2 position, while accessing the benzene core (from C4 to C7) is considerably more challenging. This Account summarizes our recent efforts toward site-selective C–H functionalization of indoles at the benzene core based on innovative strategies. A common method to solve the issue involves the development of directing groups (DGs). Our early studies establish that the installation of the N-P­(O) t Bu2 group at the N position can produce C7 and C6 arylation products using palladium and copper catalysts, respectively. The developed system can also be extended to direct arylation of indoles at the C5 and C4 positions by installing a pivaloyl group at the C3 position. Further investigation of indoles bearing N-P t Bu2 groups shows a more diverse reactivity for C–H functionalizations at the C7 position, including arylation, olefination, acylation, alkylation, silylation, and carbonylation with different coupling partners. Compared to the P­(V) DG, the P­(III) group can be easily attached to the indole substrates and detached from the products. However, these attractive reactions rely mostly on precious metal catalysts with ligands; this requirement can be a significant limitation, particularly for large-scale syntheses and the necessity of removal of toxic trace metals in pharmaceutical products. We have also uncovered a general strategy for chelation-assisted aromatic C–H borylation just using simple BBr3 under mild conditions, in which the installation of pivaloyl groups at the N1 or C3 position of indoles can selectively deliver the boron species to the unfavorable C7 or C4 positions and allow subsequent C–H borylation without any metal. This transition-metal-free strategy can be extended to synthesize C7 and C4 hydroxylated indoles by boron-mediated directed C–H hydroxylation under mild reaction conditions and with broad functional group compatibility. In this Account, we describe our contributions to this topic since 2015. These studies provide efficient and attractive methods for the divergent synthesis of valuable substituted indoles and insights into the exploration of new strategies for the site-selective C–H functionalization and directives for other important heteroarenes.