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An asymmetric Claisen rearrangement using Oppolzer’s camphorsultam was developed. Under thermal conditions, a geraniol-derived substrate underwent the rearrangement with good stereoselectivity. The absolute configuration of the newly formed all-carbon quaternary stereocenter was confirmed by the total synthesis of (+)-bakuchiol from the rearrangement product.

Asymmetric conjugate additions of branched aldehydes to vinyl sulfones promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile synthesis of the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee.

The design of novel 4′-thionucleoside analogues bearing a C2′ stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2′ center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1′,2′-anti thioaminal furnished the desired β-D-4′-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1′,4′-trans isomers, causing a significant decrease in their reaction rate relative to 1′,4′-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4′-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.

The development of efficient methodologies for the controlled manufacture of specific stereoisomers bearing quaternary stereocenters has prompted advances in a variety of scientific disciplines including pharmaceutical chemistry, materials science, and chemical biology. However, complete control of the absolute and relative stereochemical configurations of alkyne derivatives remains an unmet synthetic challenge. Herein, a Ni/Cu dual‐catalyzed asymmetric propargylic substitution reaction is presented to produce propargylated products with all‐carbon quaternary stereocenters in high yields with significant diastereo‐ and enantioselectivities (up to >20:1 dr, >99% ee). The synthesis of all stereochemical variants of methohexital, a widely used sedative‐hypnotic drug, exemplifies the efficacy of dual‐catalyzed stereodivergent propargylation. A highly efficient Ni/Cu dual‐catalyzed stereodivergent propargylation reaction is successfully devised, offering a novel approach for the asymmetric synthesis with significant diastereo‐ and enantioselectivities (up to >20:1 dr, >99% ee). This efficient process offers a novel pathway for the stereodivergent total synthesis of Methohexital.

The use of stereoselective phase-transfer catalysis as a reliable method for the enantioselective synthesis of optically active α-amino acid derivatives using achiral Schiff base esters has been well-developed in batch in the last 40 years. Recently, continuous flow technology has become of great interest in the academy and industry, since it offers safer process operating conditions and higher efficiency compared to a traditional batch processing. Herein, we wish to report the first example of enantioselective phase transfer benzylation of alanine Schiff base ester, under continuous flow conditions. Two different methodologies were investigated: a liquid-solid phase transfer catalytic benzylation using a packed-bed reactor and a liquid-liquid phase transfer catalytic benzylation in continuous stirred-tank reactors. Liquid-liquid phase transfer process in flow showed slightly better productivity than the batch process, while solid-liquid phase transfer benzylation proved much more advantageous in terms of productivity and space-time yield. Furthermore, continuous flow system allowed the isolation of benzylated product without any work up, with a significant simplification of the process. In both cases, phase transfer asymmetric benzylation promoted by Maruoka catalyst demonstrated high enantioselectivity of target quaternary amino ester in flow, up to 93% ee.

A practical four-step sequence for the synthesis of α,δ-dioxoesters with high enantiomeric excess was developed. It makes use of a regio- and stereoselective Michael addition of a chiral ketimine to ethyl 2-(phenylthio)-2-propenoate as a key transformation. The synthetic elaboration of the Michael adduct provides the new ethyl 3-(1-methyl-2-oxo-cyclohexyl)-2-oxopropanoate, bearing a quaternary stereocenter with 95% ee and high yield.

The efficient synthesis of chiral 2,2‐disubstituted indolin‐3‐ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one‐step construction of enantioenriched 2,2‐disubstituted indolin‐3‐ones is presented. The reaction proceeds through a self‐sorted [3+2] heteroannulation/regioselective dehydration/1,2‐ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3‐binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine‐directed regio‐ and enantioselective ortho‐Csp2‐H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well. Anilines are successfully applied to a catalytic asymmetric cyclizative rearrangement (CACR) sequence, which enables straightforward access to 2,2‐disubstituted indolin‐3‐ones in high yield and enantiopurity with adequate structural diversity. A high regio‐ and stereoselective ortho‐carbon addition of anilines to ketones is the key to the success of this overall sequence.

The oxygenated sesquiterpenoid (‐)‐integrifolian‐1,5‐dione, which originates from a plant that finds widespread use in South American traditional medicine, is distinguished by a rigid bicyclic framework consisting of a cyclopropane that is cis‐annulated to a cyclodecane ring. The first total synthesis of this demanding target is described, which relies on a highly selective cyclopropanation reaction of an α‐stannylated‐α‐diazoester catalyzed by a heteroleptic dirhodium paddlewheel complex, followed by an unprecedented Stille‐type cross coupling of the resulting stannylated cyclopropane with methyl iodide as the electrophilic partner to form the all‐carbon quaternary stereocenter at one of the bridgehead positions. Equally decisive was the bicyclization strategy based on lactonization/ring expansion that ultimately allowed the strained ten‐membered carbocycle to be forged. The intricate carbon framework of integrifolian‐1,5‐dione, derived from a plant that is widely used in traditional medicine, combines two formidable challenges: a stiff medium‐sized ring annulated to a cyclopropane at an all‐carbon quaternary chiral bridgehead center. These issues were successfully addressed by an unprecedented strategy based on rhodium catalyzed cyclopropanation/Stille coupling and a bicyclization/ring expansion sequence.

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quatemary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.