Zhuo Chai

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

Pd(II)/Brønsted acid catalyzed enantioselective allylic C-H activation for the synthesis of spirocyclic rings.

A Pd(II)/Brønsted acid catalyzed migratory ring expansion for the synthesis of indene derivatives possessing a stereogenic spirocyclic carbon center was developed. This transformation is believed to mechanistically proceed via enantioselective allylic C-H activation with concomitant semipinacol ring expansion to the nascent π-allylpalladium species. Enantioselectivities as high as 98% ee were attainable.

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

Bifunctional N-acyl-aminophosphine-catalyzed asymmetric [4+2] cycloadditions of allenoates and imines.

Tetrahydropyridines are important structural motifs present in a huge number of pharmaceutically interesting substances and bioactive natural products. For example, the ergot alkaloid derivative lysergic acid diethylamide (LSD, 1), a strongly psychedelic agent; tadalafil (2), a drug which has been marketed for the treatment of erectile dysfunction and pulmonary hypertension, and the cytotoxic bisindole alkaloid Leucoridine B (3) all share the chiral tetrahydropyridine structure. Although many powerful synthetic methods for accessing these nitrogen-containing six-membered heterocycles have been established, the development of catalytic asymmetric approaches allowing for the construction of these structures in optically active forms remains an attractive goal in organic synthesis.

Efficient organocatalysts derived from simple chiral acyclic amino acids in asymmetric catalysis

Chiral amino acids have played a key role in the development of organocatalysis from a biomimetic concept to an independent methodology, together with metal catalysis and enzyme catalysis, comprising the three major catalytic methodologies in modern organic synthesis. As an excellent pool for the design of organocatalysts, chiral amino acids have two obvious advantages: ready availability with usually affordable costs and modular structures allowing facile tuning of the catalytic efficiency. Recently, bifunctional/multifunctional primary–secondary amines, tertiary amine–thioureas, aminophosphines easily prepared from simple acyclic amino acids have been developed as efficient organocatalysts for various asymmetric reactions leading to a variety of useful chiral compounds. In this perspective, we present a personal overview of some of these recent advances in this field based on our own research experience.

Copper(I)-Catalyzed Kinetic Resolution of N-Sulfonylaziridines with Indoles: Efficient Construction of Pyrroloindolines.

The first Lewis acid catalyzed [3 + 2] annulation of indoles and 2-aryl-N-tosylaziridines was realized by using copper(I)/chiral diphosphine complexes as a catalyst. With this method, a variety of uniquely substituted chiral pyrroloindolines bearing multiple contiguous stereogenic centers were facilely accessed in a straightforward, high-yielding, and highly stereoselective way under mild conditions.

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.

cis-2,3-Disubstituted Cyclopropane 1,1-Diesters in [3 + 2] Annulations with Aldehydes: Highly Diastereoselective Construction of Densely Substituted Tetrahydrofurans

A series of cis-2,3-disubstituted cyclopropane 1,1-diesters were examined in the AlCl3-promoted [3 + 2]-annulations with aldehydes. In this reaction, these cis-cyclopropanes displayed reactivities starkly different from their trans counterparts in terms of the high chemical yields (up to 98%) and provided the desired annulation products with excellent diastereomeric purity. This protocol provides a facile and highly stereoselective way to construct synthetically useful pentasubstituted tetrahydrofurans not easily accessible using other methods.