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The Nazarov cyclization has been established as a powerful tool in constructing cyclopentenone skeletons. In sharp contrast, oxa-Nazarov cyclization that affords dihydrofuranones, a new type of product, has been less explored. In this work, we report the I

An N-heterocyclic carbene (NHC)-catalyzed enantioselective monoesterification of silicon-centered dialdehydes with alcohols or phenols is accomplished, providing optically active organosilanes bearing a stereogenic center at the silicon atom. This desymmetrization protocol is suitable for scale-up synthesis and late-stage modifications of complex molecules, and the products can be further transformed to other enantiopure functionalized silanes.

This work discloses an N-heterocyclic carbene (NHC) and base-mediated [3 + 3] annulation reaction of unsaturated carboxylic esters and sulfonium salts for rapid and direct access to enantioselective dihydropyrano[3,2-b]indoles.

An efficient protocol for the synthesis of 4,5,6-trisubstituted α-pyrones was developed via an NHC-catalyzed [3 + 3] annulation between α-bromo enals and 2-chloro-1,3-diketones under oxidant-free conditions.

Phthalidyl promoiety has been used in several drugs, but they were all marketed in racemic form. The pharmaceutical effects of each enantiomer have not been clearly demonstrated. In this project, an anticancer chemotherapy drug, chlorambucil, was modified as enantiopure phthalidyl prodrugs. The enantiomers, together with phthalidyl unit and their racemic mixture, were then subject to the in vivo bioactivity tests against B16F10 melanoma cells. It was found that proper chirality within the promoiety had noticeably better in vivo pharmacological effects than the parent drug, the enantiomer and racemic mixture. This merit perhaps could be extended from the phthalidyl prodrugs to other chirality containing prodrugs.

In this work, a selective chemosensor, (E)-N'-((4-oxo-4H-chromen-3-yl)methylene)isoquinoline-1-carbohydrazide (ENO), was rationally developed for colorimetric and fluorogenic detection of Zn

An N-heterocyclic carbene (NHC) catalyzed formal [3 + 3] cycloaddition reaction of β,β-disubstituted, α,β-unsaturated carboxylic esters with 3-aminobenzofurans is doucumented, furnishing benzofuran fused δ-lactams bearing an all-carbon quaternary stereocenter with moderate to excellent yields and excellent enantioselectivies. Further gram-scale preparation and synthetic transformation of the cycloadducts demonstrate good practicality and applicability of this β-carbon functionalization reaction.

An NHC-catalyzed α-carbon amination of chloroaldehydes was developed. Cyclohexadiene-1,2-diimines are used as amination reagents and four-atom synthons. Our reaction affords optically enriched dihydroquinoxalines that are core structures in natural products and synthetic bioactive molecules. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

N-Heterocyclic carbene (NHC) organocatalysis has been developed as an important approach in modern organic synthesis. Versatile activation modes within NHC organocatalysis have been established with countless transformations being realized in both efficient and selective fashion. We would like to provide an overview on the key progresses achieved within this field in the past two decades. Since numerous excellent reviews have been documented within this area, we will mainly focus on the scientific development of this research field based on the basic reaction modes and typical reaction intermediates. Accepted version We acknowledge financial support by the National Natural Science Foundation of China (No. 21772029), the National Key Technologies R&DProgram (No. 2014BAD23B01), The 10 Talent Plan (Shicengci) of Guizhou Province ([2016]5649), the Natural Science Foundation of Guizhou Province ([2018]2802),the Gui-zhou Province First-Class Disciplines Project (GNYL(2017)008), Jinan University (Guangzhou), Guizhou University of Traditional Chinese Medicine (China) and Guizhou University (China).

Fern-like In2O3/ZnO nanocomposite with mesoporous structure was derived from MIL-68/ZIF-8 via a simple template method. Abundant nanowires grew on the surface of microrods to form novel fern-like structure. The effect of MIL-68 concentration on component, structure, morphology and gas-sensing properties of In2O3/ZnO nanocomposite were studied. The results of gas tests exhibited that the sensor based on In2O3/ZnO (the mass of MIL-68 is 0.3 g) showed excellent sensing properties to TEA, which included superior response (44.6), ultralow work temperature (100 °C) and fast response-recovery time. The enhanced gas sensing properties of fern-like In2O3/ZnO nanocomposites were due to mesoporous structure, a large specific surface area, the specific structure of abundant nanowires growing on microrods and the n-n heterojunction formed at the interface of In2O3 and ZnO, which all accelerated the gas sensing reaction between TEA molecules and adsorbed oxygen on the surface of materials. The fern-like In2O3/ZnO composite with mesoporous structure was an ideal gas sensing material for the detection of TEA.

A highly enantioselective method for quick access to dihydrocoumarins is reported. The reaction involves a cooperative catalytic process with carbene and in situ generated Brønsted acid as the catalysts. α-Chloro aldehyde and readily available and stable o-hydroxybenzhydryl amine substrates were used to generate reactive azolium ester enolate and ortho-quinone methide (o-QM) intermediates, respectively, to form dihydrocoumarins with exceptionally high diastereo- and enantioselectivities. The catalytic reaction products can be easily transformed to valuable pharmaceuticals and bioactive molecules. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

The research in the field of asymmetric carbene organic catalysis has primarily focused on the activation of carbon atoms in non-aromatic scaffolds. Here we report a reaction mode of carbene catalysis that allows for aromatic aldehyde activation and remote oxygen atom functionalization. The addition of a carbene catalyst to the aldehyde moiety of 2-hydroxyl aryl aldehyde eventually enables dearomatization and remote OH activation. The catalytic process generates a type of carbene-derived intermediate with an oxygen atom as the reactive centre. Inexpensive achiral urea co-catalyst works cooperatively with the carbene catalyst, leading to consistent enhancement of the reaction enantioselectivity. Given the wide presence of aromatic moieties and heteroatoms in natural products and synthetic functional molecules, we expect our reaction mode to significantly expand the power of carbene catalysis in asymmetric chemical synthesis., Selective functionalization of aromatic compounds is important in synthetic chemistry. Here the authors report an N-heterocyclic carbene-catalysed approach for enantioselectively converting ortho-hydroxyaldehydes to cyclic products, via activation of both phenol and aldehyde groups.

A new class of chiral oxidants is developed. These readily accessible oxidants contain a nitro group for oxidation and a chiral sulfonamide moiety for stereoselectivity control. The chiral information from the oxidants can effectively transfer to the substrates in carbene-catalyzed β-hydroxylation of enals via single-electron-transfer radical processes. We expect these oxidants to find unique applications in other asymmetric oxidations and oxygen-atom-transferring reactions. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules., Phthalidyl esters, commonly used prodrug moieties, are mostly prepared as a racemate. Here, the authors report an N-heterocylcic carbene-catalysed enantioselective acetalization of carboxylic acids and dialdehydes to give phthalidyl esters in high yields with good enantioselectivity.

The porous Pd-loaded In2O3 hollow spheres were successfully prepared by simple one-step method with the template of carbon spheres. The effect of calcination temperatures on morphology, composition and gas sensing performance of the as-obtained products was discussed by a series of test methods. The sample calcined at 550∘C showed uniform porous hollow spheres with an average diameter of 100[Formula: see text]nm. Gas-sensing results exhibited that the Pd-In2O3 hollow spheres-based sensor possessed excellent sensing properties to formaldehyde, which include high response value (33), low working temperature (180∘C) and fast response and recovery time (12[Formula: see text]s and 22[Formula: see text]s). The enhanced HCHO-sensing properties of Pd-In2O3 composites were attributed to the special porous and hollow structure, abundant oxygen vacancies and the catalysis of palladium. Pd-loaded In2O3 hollow spheres had been proved to be an ideal material for detecting HCHO at a low working temperature.

Carbene-catalyzed reaction of carboxylic esters has the potential to offer effective synthetic solutions that cannot be readily achieved by using the more conventional aldehyde-type substrates. Here we report the first carbene-catalyzed dynamic kinetic resolution of α,α-disubstituted carboxylic esters with up to 99:1 er and 99% yield. The present study clearly illustrates the unique power of carbene-catalyzed reactions of readily available and easy to handle carboxylic esters. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) Accepted version

This thesis focuses on exploring new reaction modes and new synthetic methodologies that are enabled by N-heterocyclic carbenes (NHCs) catalysts. It contains five parts: Doctor of Philosophy (SPMS)

A scalable procedure for the title transformation of a broad range of α,α-disubstituted carboxylic esters is developed which delivers the products in often very high yields and with very high enantiomeric purity.

Aryl aldehyde activation: Oxidative activation of 2-methylindole-3-carboxaldehyde (I) through N-heterocyclic carbene (NHC) organocatalysis generates heterocyclic ortho-quinodimethane (II) as a key intermediate. This intermediate then undergoes formal [4+2] cycloaddition with trifluoromethyl ketones or isatins to form polycyclic lactones containing a quaternary carbon center.

The first N-Heterocyclic Carbene (NHC) mediated activation of stable carboxylate esters to generate enolate intermediates is disclosed. The catalytically generated arylacetic ester enolates undergo enantioselective reactions with α,β-unsaturated imines.

The direct oxidative cross-dehydrogenative coupling (CDC) of two C H bonds can be an efficient and relatively clean strategy in organic synthesis. Various sp C Hbonds, such as benzylic and allylic C H bonds, the a-C H bonds of amines and ethers, and the C H bonds of alkanes can be oxidized for direct reaction with carbon nucleophiles. Among these reactions, the oxidation of tertiary amines to generate iminium intermediates, as pioneered by Murahashi et al., Li et al. and others, has received considerable attention. Carbonyl compounds, such as 1,3-dicarbonyls, 10b,g] a,bunsaturated ketones, and simple ketones have been successfully coupled with tertiary amines by using metal catalysis, acid catalysis, metal/organic cooperative catalysis, or photoredox catalysis. In all of these reactions, the development of enantioselective catalysis remains a challenge. Very recently, Wang and co-workers used metals together with chiral bisoxazoline ligands to realize enantioselective reactions of activated carbonyl nucleophiles (such as 1,3dicarbonyls and acetyl phosphates) to oxidatively generate iminiums or their analogues. However, this approach with chiral ligands was found to be unsuccessful for reactions starting with simple ketone nucleophiles, as reported by Klussmann and co-workers as well as Xie and Huang. Approaches that use asymmetric enamine catalysis for the activation of carbonyl compounds have led to disappointing results (for example, less than 20% ee) as well . As part of a larger program for developing sustainable oxidation chemistry, we herein report an enantioselective oxidative coupling reaction of aldehydes and tertiary amines under cooperative amine and metal catalysis. The racemic version of this reaction was also realized by using metal catalysts alone (without amine catalysts), on account of its potential utility and the very different optimized conditions, relative to the enantioselective reactions. We examined metal-catalyzed oxidative coupling reactions between N-phenyltetrahydroisoquinoline (1a) and propionaldehyde (2a) in the presence of tBuOOH without an amine catalyst. An initial survey of solvents and catalysts indicated that DMF is a good solvent and CuBr2 is an effective metal catalyst (Table 1, entries 1–3, see also the Supporting Information). The amino aldehyde product 3a is unstable and, thus, was isolated as the corresponding amino alcohol product 4a in 72% yield after reduction with NaBH4 in situ, albeit with no diastereoselectivity (Table 1, entry 3). Under these conditions, various amines, such as N-aryl tetrahydroisoquinolines 1 and N,N-dialkyl anilines, and aldehydes 2 were used to obtain the corresponding racemic amino alcohols 4 in acceptable yields. Aldehydes with longer carbon chains required elevated reaction temperatures. N,Ndialkyl anilines gave the corresponding products in lower yields (Table S6 and Scheme S3 in the Supporting Information).

An electron-withdrawing group was introduced to the α-position of chalcones, and the resulting alkylidene diketones showed new reactivities with enals under the catalysis of N-heterocyclic carbenes (NHCs). Selective activation of enals affords enolate equivalents that undergo highly enantioselective intermolecular Diels-Alder reactions with the alkylidene diketones. No products that might have resulted from typical homoenolate pathways were observed.

A novel tandem cross-Rauhut–Currier/cyclization reaction between α,β-unsaturated ketones was developed. Using DABCO (20 mol %) as the catalyst, a series of densely functionalized 3,4-dihydropyrans were obtained in excellent yields and stereoselectivities (up to 98% yield, >99:1 dr). A tentative catalytic cycle was proposed with key intermediates confirmed by ESIMS studies.

Facile access to trisubstituted pyridines from α-chloro acetic ester and unsaturated imines is achieved. DMAP-catalyzed activation of ester to form an enolate intermediate constitutes a key reaction step. On the application side, the wide availability and low cost of the substrates and catalysts make this method very attractive.

A highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-keto esters catalyzed by amino acid-derived thiourea-tertiary-amine catalysts is presented. Using 5 mol% of a novel tyrosine-derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.

A diarylprolinol-derived organocatalyst is successfully applied in the highly stereoselective cycloaddition reaction of 2-vinylindoles towards α,β-unsaturated aldehydes.

A convergent, organocatalytic asymmetric aminomethylation of α,β-unsaturated aldehydes by N-heterocyclic carbene (NHC) and (in situ generated) Bronsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde-derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox-neutral strategy is suitable for the scalable synthesis of enantiomerically enriched β(2) -amino acids bearing various substituents.

A convergent, organocatalytic asymmetric aminomethylation of α,β-unsaturated aldehydes by N-heterocyclic carbene (NHC) and (in situ generated) Bronsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde-derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox-neutral strategy is suitable for the scalable synthesis of enantiomerically enriched β(2) -amino acids bearing various substituents.

Aryl aldehyde activation: Oxidative activation of 2-methylindole-3-carboxaldehyde (I) through N-heterocyclic carbene (NHC) organocatalysis generates heterocyclic ortho-quinodimethane (II) as a key intermediate. This intermediate then undergoes formal [4+2] cycloaddition with trifluoromethyl ketones or isatins to form polycyclic lactones containing a quaternary carbon center.

The synthesis of the cis-homoenolate equivalents can be realized from cis-enols in the presence of an NHC-catalyst.

The NHC-catalyzed reaction of enals (I) with chalcones (II) in water leads to trisubstituted cyclopentenes (III).

The protocol applies a stoichiometric amount of quinone as an oxidant and proceeds via oxidative enolate formation to afford γ-lactones with high yields and complete enantioselectivity.

Water is demonstrated as a suitable solvent for NHC-catalyzed reactions of enals. The use of D2O as a solvent allows for the effective incorporation of deuterium isotopes into organic molecules.

The first successful generation of cis-homoenolate equivalents from cis-enals under the catalysis of N-heterocyclic carbenes (NHCs) has been realized. The cis-homoenolate intermediates undergo effective reactions with α,β-unsaturated imines to afford chiral cyclic ketone products. Compared to the trans-enals, cis-enals show different stereoselectivities and new reactivity patterns.

For the first time Sc-based Lewis-acids have found to be effective in cooperative NHC catalysis for the enantioselective control in the title reaction.