Yonggui Robin Chi

Oxidative γ-Addition of Enals to Trifluoromethyl Ketones: Enantioselectivity Control via Lewis Acid/N-Heterocyclic Carbene Cooperative Catalysis

An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)(3) or combined Sc(OTf)(3)/Mg(OTf)(2)] and NHC cooperative catalysis.

A Family of Metal‐Organic Frameworks Exhibiting Size‐Selective Catalysis with Encapsulated Noble‐Metal Nanoparticles

The encapsulation of noble-metal nanoparticles (NPs) in metal-organic frameworks (MOFs) with carboxylic acid ligands, the most extensive branch of the MOF family, gives NP/MOF composites that exhibit excellent shape-selective catalytic performance in olefin hydrogenation, aqueous reaction in the reduction of 4-nitrophenol, and faster molecular diffusion in CO oxidation. The strategy of using functionalized cavities of MOFs as hosts for different metal NPs looks promising for the development of high-performance heterogeneous catalysts.

β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies. Direct β-carbon activation of saturated carbonyl compounds represents a significant fundamental challenge in organic chemistry. Here, the catalytic activation of saturated ester β-sp3 carbon as nucleophile via N-heterocyclic carbene organocatalysis is reported. The catalytically generated nucleophilic β-carbon undergoes enantioselective reactions with various electrophiles.

Highly Enantioselective Addition of Enals to Isatin-Derived Ketimines Catalyzed by N-Heterocyclic Carbenes: Synthesis of Spirocyclic γ-Lactams

An N-heterocyclic carbene (NHC)-catalyzed annulation reaction of isatin N-Boc ketimines and enals is developed for the synthesis of spirocyclic oxindole-γ-lactams bearing one quaternary chiral center in good yields and excellent stereoselectivities (up to >20:1 dr and 99% ee).

Enantioselective Activation of Stable Carboxylate Esters as Enolate Equivalents via N-Heterocyclic Carbene Catalysts

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.

NHC organocatalytic formal LUMO activation of α,β-unsaturated esters for reaction with enamides.

a,b-Unsaturated carbonyl compounds are basic building blocks in organic synthesis. Lewis acid catalysts bearing chiral ligands have traditionally been used for the asymmetric catalytic activation of this class of molecules as Michael acceptors. 2] Indeed, Lewis acid catalysis continues to be a powerful approach in which innovative solutions are still emerging. Representative examples of chiral Lewis acid catalysts include the metal–bisoxazoline complexes introduced by the research groups of Evans and Corey, the multimetallic bifunctional catalysts developed by Shibasaki and co-workers, the bifunctional Lewis acid/base catalysts described by Lectka and co-workers, and the metal–N,N’dioxide catalysts developed by Feng and co-workers. In another direction, organocatalytic methods have received intense attention in the last decade or so. By iminium catalysis, pioneered by MacMillan and co-workers, a,bunsaturated aldehydes and ketones can be activated as electrophiles for a set of highly enantioselective reactions (Scheme 1a). The related equally useful ester substrates, on the other hand, are outside the scope of iminium/enamine catalysis, which has proved to be versatile for aldehyde and ketone substrates. We are interested in the organocatalytic activation of readily available esters for asymmetric synthesis. N-Heterocyclic carbenes (NHCs, typically imidazolium-based NHCs) have been studied previously for the catalysis of transesterification reactions (Scheme 1b). Two mechanisms were proposed for NHC-catalyzed transesterification; one involves ester activation, and the other involves alcohol activation, in which NHC behaves as a base catalyst. Recently, we disclosed the HOMO activation of saturated a-aryl acetic esters through catalysis with NHCs to generate enolate intermediates for enantioselective reactions. Herein we report the formal LUMO activation of a,b-unsaturated esters by NHC catalysis for highly enantioselective reactions with enamides (Scheme 1c). The key step involves the addition of the NHC catalyst to the ester substrate I to form an a,b-unsaturated acyl azolium intermediate II. Unsaturated acyl azolium intermediates of this type were previously generated from enals, a-hydroxyenones, a-bromoenals, ynals, and a,b-unsaturated acid fluorides by (oxidative) NHC catalysis. Lupton and co-workers reported an NHC-catalyzed enol ester rearrangement, which was proposed to proceed by addition of the NHC to the carbonyl group of the ester, followed by Claisen rearrangement. They suggested that an a,b-unsaturated acyl azolium intermediate (such as II) was unlikely to be involved as a key intermediate (Scheme 1b). In a related approach, Smith and co-workers recently reported the use of anhydrides as a,b-unsaturated acyl ammonium precursors with isothiourea catalysts. Each of these elegant methods has its own merits and limitations. For example, with a,b-unsaturated aldehyde substrates, relatively expensive organic oxidants 19] need to be used in the asymmetric oxidative NHC catalysis. The use of ynals as substrates is constrained by the limited substitution patterns (e.g. disubstitution at the a and b carbon atoms is not possible) and somewhat high cost of the ynal compounds. In our approach, the ester substrates are readily available, inexpensive, and stable (easy to handle). Various Scheme 1. a,b) Previously reported related approaches for the activation of carbonyl substrates with organocatalysts. c) LUMO activation of a,b-unsaturated carbonyl compounds by NHC catalysis. Ts = p-toluenesulfonyl.

N-heterocyclic carbene-catalyzed [3+4] cycloaddition and kinetic resolution of azomethine imines.

The first N-heterocyclic carbene (NHC)-catalyzed [3+4] cycloaddition of azomethine imines and enals is disclosed. Oxidative catalytic remote activation of enals affords 1,4-dipolarophile intermediates that react with 1,3-dipolar azomethine imines to generate dinitrogen-fused seven-membered heterocyclic products with high optical purities. Our approach also provides effective kinetic resolution of azomethine imines, in which the substrate chiral center that is remote from the NHC catalyst can be well resolved.

Enantioselective Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines to Aldehydes**

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).

Organocatalytic Enantioselective γ-Aminoalkylation of Unsaturated Ester: Access to Pipecolic Acid Derivatives

The direct γ-carbon functionalization of α,β-unsaturated esters via N-Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically generated nucleophilic γ-carbon undergoes highly enantioselective additions to hydrazones. The resulting δ-lactam products can be readily transformed to optically enriched pipecolic acid derivatives.

Enantioselective Diels–Alder Reactions of Enals and Alkylidene Diketones Catalyzed by N-Heterocyclic Carbenes

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.