Zhaobin Wang

Enantioselective formation of all-carbon quaternary stereocenters from indoles and tertiary alcohols bearing a directing group.

Described is an efficient catalytic asymmetric intermolecular C-C bond-formation process to generate acyclic all-carbon quaternary stereocenters. The reactions overcome the unfavorable steric hindrance around reactive centers, and the competitive elimination (E1), to form a range of useful indole products with excellent efficiency and enantioselectivity.

Organocatalytic Asymmetric Synthesis of 1,1-Diarylethanes by Transfer Hydrogenation

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

Catalytic Asymmetric 1,6‐Conjugate Addition of para‐Quinone Methides: Formation of All‐Carbon Quaternary Stereocenters

Described herein is a general and mild catalytic asymmetric 1,6-conjugate addition of para-quinone methides (p-QMs), a class of challenging reactions with previous limited success. Benefiting from chiral Brønsted acid catalysis, which allows in situ formation of p-QMs, our reaction expands the scope to general p-QMs with various substitution patterns. It also enables efficient intermolecular formation of all-carbon quaternary stereocenters with high enantioselectivity.

Organocatalytic Asymmetric Nucleophilic Addition to o-Quinone Methides by Alcohols

The first catalytic asymmetric intermolecular alcohol conjugate addition to o-quinone methides (o-QMs) is disclosed. Due to reversible C-O bond formation and low nucleophilicity of alcohols, catalytic asymmetric oxa-Michael additions with simple alcohol nucleophiles to establish acyclic oxygenated carbon stereocenters remain scarce. The present reaction represents a rare example of this type. With a suitable chiral acid catalyst, the in situ formation of o-QMs and subsequent conjugate addition proceeded with high efficiency and enantioselectivity. The chiral ether products are versatile precursors to other chiral molecules.

Synthesis of Eight‐Membered Lactones: Intermolecular [6+2] Cyclization of Amphoteric Molecules with Siloxy Alkynes

Medium-sized lactones (8to 11-membered rings) are important structural motifs that occur in a wide range of biologically active natural products. The efficient synthesis of these medium-sized lactones has attracted considerable attention in organic synthesis. Nevertheless, there are only a limited number of methods available, with lactonization and ringclosing metathesis (RCM) being the most popular choices. Owing to ring strain and transannular interactions, the formation of medium-sized lactones have proven difficult. Although the yields can sometimes be improved under high dilution or slow addition conditions, the results are unpredictable and highly dependent upon the substrates. Thus, there remains a great need for the development of new strategies for the synthesis of medium-sized lactones. Herein we report our design of a new type of amphoteric molecule for the synthesis of eight-membered ring lactones through [6+2] cyclization. Amphoteric molecules, which bear both nucleophilic and electrophilic moieties, have been demonstrated as a versatile platform for the development of new processes with high bond-forming efficiency and atom economy. 9] For example, isocyanides are well-known (1,1)-amphoteric molecules because the terminal carbon atom can be both nucleophilic and electrophilic sites for bond formation. Recently, Yudin and co-workers demonstrated that aziridine aldehydes (1; Scheme 1A) can serve as three-atom “connectors”, thus representing a (1,3)-amphoteric system. With this system, they have developed a range of efficient and chemoselective transformations which circumvent using protecting groups. We envisaged that the design of (1,n)-amphoteric molecules (where n> 5) may provide new opportunities for the formation of mediumand large-sized rings upon cyclization with dipolarophiles. However, the nucleophilic and electrophilic sites in such systems may react in the more favored intramolecular fashion, for example, the formation of a sixmembered ring in a (1,6)-amphoteric system (Scheme 1B, path a), thereby invoking difficulty in designing such systems for intermolecular cyclizations. Oxetanes represent a useful structural unit that is less reactive than epoxides and aldehydes, but still prone to ringopening upon activation. We decided to take advantage of such a combination of stability and reactivity to design a new (1,6)-amphoteric system. Our initial design is exemplified in structure 2 (Scheme 1B), in which an oxetane moiety is connected to an aldehyde group through a two-atom linker. The aldehyde carbon atom (C1) serves as the electrophilic center. Upon attack by a nucleophile, the resulting nucleophilic oxygen atom is expected to initiate an intramolecular ring-opening process and concomitantly generate another nucleophilic oxygen center at the 6-position. Thus, the system is (1,6)-amphoteric overall. Next, we began to test our designed system for the synthesis of mediumand large-sized rings. We initially aimed at developing new [6+2] cyclization processes for the formation of eight-membered rings. After some trials, we were pleased to identify siloxy alkynes as excellent reaction partners for our (1,6)-amphoteric system to form eightmembered lactones. Specifically, the reaction between 2(oxetan-3-yl)benzaldehyde (3) and siloxy alkyne 4, in the presence of triflimide (HNTf2, 10 mol %) as the catalyst and CH2Cl2 as the solvent, proceeds efficiently at room temperature to form the eight-membered lactone 5 in 71 % yield upon isolation (Table 1, entry 1). The structure assignment of 5 was based on the X-ray crystallography of its crystalline derivative (see the Supporting Information). Unlike the conventional formation of medium-sized lactones using Scheme 1. Examples of amphoteric molecules and their reaction topology. A) (1,3)-Amphoteric system (e.g., Yudin’s aziridine aldehyde 1). B) (1,6)-Amphoteric system (our design).

Chiral Phosphoric Acid Catalyzed Enantioselective Desymmetrization of meso-Epoxides by Thiols

The first chiral Brønsted acid catalyzed asymmetric nucleophilic ring-opening reaction of meso-epoxides is described. In the presence of TRIP, a range of meso-epoxides could undergo smooth ring-opening reactions by aryl thiols with good efficiency and enantioselectivity.

Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of (+)‐(8S,13R)‐Cyclocelabenzine

A one-pot wonder: 1,2,3,4-Tetrahydroisoquinolines with a C4 stereocenter can be formed by using a one-pot multicomponent chiral phosphoric acid catalyzed transformation of a mixture of oxetane-tethered benzaldehydes, amines, and the dimethyl ester derivative of the Hantzsch ester (see scheme). This transformation can be used to prepare the spermidine alkaloid (+)-(8S,13R)-cyclocelabenzine.

Enantioselective [4 + 2] Cycloaddition of o-Quinone Methides and Vinyl Sulfides: Indirect Access to Generally Substituted Chiral Chromanes

A catalytic asymmetric [4 + 2] cycloaddition of ortho-quinone methides (o-QMs) is described. With the readily available vinyl sulfides as the key 2π partner and a properly chosen chiral phosphoric acid catalyst, the reaction proceeded under mild conditions to form the corresponding adduct with high enantio- and diastereoselectivity. Owning to the easy removal and conversion of the sulfenyl group in the product, the present process provides indirect access to generally substituted chromanes previously lacking easy access. Mechanistically, the reaction is also a new demonstration of the rarely achieved sole activation of o-QM for asymmetric control.

Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines

The first catalytic asymmetric desymmetrization of azetidines is disclosed. Despite the low propensity of azetidine ring opening and challenging stereocontrol, smooth intermolecular reactions were realized with excellent efficiency and enantioselectivity. These were enabled by the suitable combination of catalyst, nucleophile, protective group, and reaction conditions. The highly enantioenriched densely functionalized products are versatile precursors to other useful chiral molecules. Mechanistic studies, including DFT calculations, revealed that only one catalyst molecule is involved in the key transition state, though both reactants can be activated. Also, the Curtin-Hammett principle dictates the reaction proceeds via amide nitrogen activation.

Organocatalytic Enantio- and Diastereoselective Synthesis of 1,2-Dihydronaphthalenes from Isobenzopyrylium Ions

A highly efficient asymmetric synthesis of dihydronaphthalenes is disclosed. The process represents a new addition to the limited asymmetric reactions of isobenzopyryliums, a family of versatile 10π-electron aromatic species. Excellent asymmetric induction is achieved for the first time without an anchoring group in the 4-position or a metal catalyst, both of which were required previously in these reactions. The success is attributed to the unusual chiral counteranion (meanwhile also the nucleophile) generated in situ from the chiral phosphate and the boronic acid as well as the leaving group. Preliminary control experiments provided important insight into the reaction mechanism.