Wanxiang Zhao

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.

A New Strategy for Efficient Synthesis of Medium and Large Ring Lactones without High Dilution or Slow Addition

We have developed an efficient method for medium and large ring lactone synthesis by a conceptually different ring-expansion strategy. The design of an unprecedented ring conjunction mode of oxetene, combined with the appropriate choice of a Lewis acid promoter and an additive, constitutes the key components of the new process. Enabled by this new approach, the reaction does not require high dilution or slow addition.

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).

Cascade Copper-Catalyzed 1,2,3-Trifunctionalization of Terminal Allenes

A cascade cyanation/diborylation of terminal allenes proceeds efficiently with copper catalysis using bis(pinacolato)diboron (B2Pin2) and N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as reagents. Mechanistic studies suggest that the process proceeds through cyanoborylation of the substituted π-system of the allene followed by hydroboration of the remaining π-component. A wide array of product derivatives may be accessed through site-selective cross-couplings and N-bromosuccinimide-promoted heteroarylations as well as standard oxidative and reductive conversions of the initially obtained adducts.

Highly Active Nickel Catalysts for C-H Functionalization Identified through Analysis of Off-Cycle Intermediates.

An inhibitory role of 1,5-cyclooctadiene (COD) in nickel-catalyzed C-H functionalization processes was identified and studied. The bound COD participates in C-H activation by capturing the hydride, leading to a stable off-cycle π-allyl complex that greatly diminished overall catalytic efficiency. Computational studies elucidated the origin of the effect and enabled identification of a 1,5-hexadiene-derived pre-catalyst that avoids the off-cycle intermediate and provides catalytic efficiencies that are superior to those of catalysts derived from Ni(COD)2.

Enzymatic hydroxylation of an unactivated methylene C–H bond guided by molecular dynamics simulations

The hallmark of enzymes from secondary metabolic pathways is the pairing of powerful reactivity with exquisite site selectivity. The application of these biocatalytic tools in organic synthesis, however, remains under-utilized due to limitations in substrate scope and scalability. Here, we report how the reactivity of a monooxygenase (PikC) from the pikromycin pathway is modified through computationally guided protein and substrate engineering, and applied to the oxidation of unactivated methylene C–H bonds. Molecular dynamics and quantum mechanical calculations were used to develop a predictive model for substrate scope, site selectivity and stereoselectivity of PikC-mediated C–H oxidation. A suite of menthol derivatives was screened computationally and evaluated through in vitro reactions, where each substrate adhered to the predicted models for selectivity and conversion to product. This platform was also expanded beyond menthol-based substrates to the selective hydroxylation of a variety of substrate cores ranging from cyclic to fused bicyclic and bridged bicyclic compounds. The reactivity of a monooxygenase (P450 PikC) has been modified through protein and substrate engineering, and applied to the oxidation of unactivated methylene C–H bonds. The protein engineering was guided by using molecular dynamics and quantum mechanical calculations to develop a predictive model for substrate scope, site selectivity and stereoselectivity of the C–H hydroxylation.

Functionalization of Styrenes by Copper‐Catalyzed Borylation/ ortho‐Cyanation and Silver‐Catalyzed Annulation Processes

An efficient two-step method for the assembly of indanone derivatives starting from a simple vinyl arene has been developed. The sequence first involves addition of bis(pinacolato)diboron (B2 pin2 ) and N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) to a broad range of styrenes by utilizing IMesCuCl as catalyst. This step simultaneously accomplishes hydroboration of the alkene and ortho cyanation of the benzene unit. The products thus obtained are further functionalized by a AgNO3 /Selectfluor-mediated coupling of the BPin and cyano functionalities to annulate a new five-membered ring. This combined two-step sequence provides a versatile method for the site-selective derivatization of a broad range of vinyl arene substrates.

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.

Catalytic Ring Expansion of Cyclic Hemiaminals for the Synthesis of Medium‐Ring Lactams

A mild and efficient intermolecular ring-expansion approach was developed for the synthesis of medium-ring lactams by using siloxy alkynes. Key to success is the suitable combination of a superior catalyst and an exceptional nitrogen-protecting group. Control experiments indicated that the reaction is remarkably selective toward the desired lactam formation, even with many possible non-productive pathways.