Chang-Wu Zheng

Asymmetric [3+2] Cycloadditions of Allenoates and Dual Activated Olefins Catalyzed by Simple Bifunctional N‐Acyl Aminophosphines

Recently, phosphine-catalyzed [3+2] cycloadditions of allenoates with electron-deficient olefins and imines—a process which provides efficient access to a variety of synthetically useful carboand heterocycles from readily available starting materials—have received considerable research interest since the pioneering works of Lu and co-workers. As a result of continuing efforts from many research groups in this field, an array of new annulation reactions were disclosed, in which aor g-substituted allenoates, allylic compounds, and electron-deficient olefins were recognized as novel “three-carbon-atom units” and “two-carbon-atom units”. However, the development of enantioselective variants of these transformations has met with very limited success. Up to now, only a handful of chiral organocatalysts have been found to be effective for this kind of reaction, most of which are monodentate phosphines. Recently, two excellent research reports highlighted the great potential of phosphine-containing molecules bearing additional active sites as efficient catalysts in this kind of reaction. Miller and coworkers pioneered the use of multifunctional a-amino acid derived phosphines as efficient catalysts for allenoate–enone cycloadditions. In addition to the high ee values achieved, this system also provided regioselectivity opposite to those obtained with monodentate phosphine catalysts in similar reactions. Later, Jacobsen and co-workers demonstrated bifunctional phosphine-containing thioureas catalyzed allenoate–imine cycloadditions with excellent enantioselectivities. The problem of regioselectivity is common in [3+2] cycloadditions of allenoates with electron-deficient olefins. Such a problem could be circumvented by using dual activated olefins, which was recently disclosed by Lu and co-workers. Despite this advantage, to the best of our knowledge, no asymmetric example of this kind of reaction has been reported. Recently, our group has focused on the development of chiral organocatalysts from natural a-amino acids, a cheap and readily accessible chiral source, and their applications in various organic transformations. a-Amino acid derived aminophosphines and their N-protected counterparts have been used as efficient chiral ligands for numerous metal-based reactions. We envisaged that their modular, bifunctional structures would also make them excellent candidates for organocatalysts (Scheme 1). Herein, we describe highly regioand enantioselective [3+2] cycloadditions

The Enantioselective, Organocatalyzed Diels–Alder Reaction of 2‐Vinylindoles with α,β‐Unsaturated Aldehydes: An Efficient Route to Functionalized Tetrahydrocarbazoles

The asymmetric, catalytic Diels–Alder reaction is one of the most powerful methods to construct functionalized, enantioenriched six-membered cyclic compounds from relatively simple substrates. MacMillan and co-workers pioneered the use of organocatalysts for this reaction that features a LUMO-lowering strategy by using iminium formation. Since then considerable research effort has been devoted to the development, and application, of various organocatalysts for this reaction, which has provided many efficient, organocatalytic systems that achieve excellent stereoselectivities for both carbo-Diels–Alder and heteroDiels–Alder reactions. Among the various organocatalysts employed in this field, diaryl prolinol derivatives, which are capable of promoting the reaction through both iminium and enamine catalysis, have attracted considerable interest. Surprisingly, the more readily available diaryl prolinACHTUNGTRENNUNGols themselves have seldom been used for such Diels–Alder reactions. Chiral tetrahydrocarbazoles are an important structural motif present in many biologically active compounds. Retrosynthetic analysis of these compounds reveals that a Diels–Alder reaction between readily available 2-vinylindoles and a,b-unsaturated aldehydes would give direct access to this kind of compound. Methodologies by the L vy group and, very recently, the Macmillan group, who have investigated Diels–Alder reactions of vinyltryptamine, were ingeniously demonstrated in the concise syntheses of the Echitamine ring system and ( )-Minfiensine, respectively. In this paper, we present the results of our research into an efficient catalyst system for the Diels–Alder reaction by using simple prolinols as the catalysts and the application of this method in the synthesis of the core structure of the akuammiline alkaloid vincorine. One problem with the realization of a Diels–Alder reaction between 2-vinylindoles and a,b-unsaturated aldehydes through iminium catalysis is the well-documented, competitive alkylation reaction of indoles under similar reaction conditions. In the model reaction between (Z)-1-methyl2-styryl-1H-indole (1 a) and trans-cinnamaldehyde (2 a), which was catalyzed by the widely used a,a-diphenylprolinol trimethylsilyl ether (3 a) (20 mol %) and trifluoromethane

Enantioselective synthesis of functionalized fluorinated cyclohexenones via robinson annulation catalyzed by primary-secondary diamines.

Primary-secondary diamine catalysts were used to catalyze the asymmetric Robinson annulation to synthesize multiply substituted fluorinated chiral cyclohexenones with two contiguous stereogenic centers, one of which is a fluorinated quaternary chiral center, with excellent enantioselectivities and diastereoselectivities in moderate to good yields.

Asymmetric Dual‐Reagent Catalysis: Mannich‐type Reactions Catalyzed by Ion Pair

The combination of a new bifunctional phosphine and an acrylate generate a zwitterion in situ and it serves as an efficient catalyst for asymmetric reactions through a homogeneous ion-pairing mode. This new catalytic system has been successfully applied to Mannich-type reactions to give excellent results and it demonstrates a broad substrate scope. Such reactivity is not accessible with general organophosphine catalytic modes. Preliminary investigations into the mechanism are also presented.

Highly enantio- and diastereoselective synthesis of α-trifluoromethyldihydropyrans using a novel bifunctional piperazine-thiourea catalyst

The first enantioselective Michael addition of alpha-cyanoketones to alpha,beta-unsaturated trifluoromethyl ketones using a novel piperazine-thiourea catalyst was described. The resulting alpha-trifluoromethyldihydropyrans were obtained in high yields and with up to 95% ee within a short reaction time. A useful transformation of the chiral adduct was also illustrated.

Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis.

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.

Enantioselective direct Mannich reactions of cyclic β-ketoesters catalyzed by chiral phosphine via a novel dual-reagent catalysis.

A combination of an amino acid derived chiral phosphine catalyst and methyl acrylate efficiently catalyzed the direct Mannich reaction of cyclic β-ketoesters and N-Boc-aldimines. The dual-reagent catalysis was presumed to function through the formation of a zwitterion, which catalyzed the reaction with excellent stereocontrol via a hydrogen-bonding assisted chiral ion-pair pathway.

Organocatalyzed aza-Michael–Michael cascade reactions to construct spirooxindole tetrahydroquinolines with all-carbon chiral centers

An efficient organocatalytic aza-Michael-Michael cascade reaction for the asymmetric synthesis of highly functionalized spirooxindole tetrahydroquinolines has been reported through a formal [4+2] annulation strategy.

Facile stereoselective synthesis of fluorinated flavanone derivatives via a one-pot tandem reaction.

A series of fluorinated flavanones were synthesized in moderate to good yields with excellent diastereoselectivities under mild reaction conditions via a one-pot tandem procedure involving a proline-catalyzed Knoevenagel condensation, a Michael addition, and an electrophilic fluorination by NFSI.

Palladium(II)-Catalyzed Formal [3 + 2] Cycloaddition of Aziridines with 3-Substituted Indoles: Synthesis of Enantioenriched Pyrroloindolines

A Pd-catalyzed enantiospecific formal [3 + 2] cycloaddition between chiral aziridines and indoles has been developed. With this method, chiral pyrroloindolines in enantiomerically pure forms were constructed in high yields and diastereoselectivities under mild conditions.