Zhigang Yang

Asymmetric Direct Aldol Reaction of Functionalized Ketones Catalyzed by Amine Organocatalysts Based on Bispidine

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including alpha-keto phosphonates, alpha-keto esters, as well as alpha,alpha-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction.

Organocatalyzed highly stereoselective Michael addition of ketones to alkylidene malonates and nitroolefins using chiral primary-secondary diamine catalysts based on bispidine

Organocatalysts containing primary-secondary diamines based on bispidine have been developed to catalyze the asymmetric Michael addition of ketones to alkylidene malonates and nitroalkenes. The corresponding products were obtained in high yields (up to 99%) with high diastereoselectivities (up to 99:1) and high enantioselectivities (up to 97% ee) under mild conditions using either environmentally benign water as the solvent or no solvent.

Palladium-catalyzed, asymmetric Mizoroki-Heck reaction of benzylic electrophiles using phosphoramidites as chiral ligands.

We report herein the first examples of asymmetric Mizoroki-Heck reactions using benzyl electrophiles. A new phosphoramidite was identified to be an effective chiral ligand in the palladium-catalyzed reaction. The reaction is compatible with polar functional groups and can be readily scaled up. Several cyclic olefins worked well as olefin components. Thirty-one examples are included.

Highly Enantioselective Michael Addition of Malonate Derivatives to Enones Catalyzed by an N,N′-Dioxide–Scandium(III) Complex

The catalytic asymmetric conjugate addition reaction is one of the most powerful methods for the carbon carbon bond formation because various chiral functionalized adducts can be obtained from numerous Michael acceptors and donors. Among them, the asymmetric Michael addition of 1,3-dicarbonyl compounds to enones provides a simple way for the preparation of synthetically useful 1,5-dicarbonyl compounds and attracts more and more chemists interests. There have been several catalysts developed for this reaction, such as chiral metal complexes, chiral ammonium salts, chiral amine catalysts and thiourea catalysts, but only few reports appeared successfully when chalcone derivatives were used as Michael acceptors. 6b] Despite excellent enantioselectivity have been achieved by Maruoka, Wang and Kobayashi et al., developing new and efficient chiral catalyst systems is still in great need. Recently, N,N’-dioxide–metal complexes have been successfully applied to promote many kinds of asymmetric transformations, herein we wish to report a highly enantioselective Michael addition of malonate derivatives to chalcone derivatives catalyzed by l-Ramipril acid derived N,N’-dioxide– scandiumACHTUNGTRENNUNG(III) complex. A wide range of substrates can be tolerated, affording the desired products with up to 99 % yield and 99 % ee. Inspired by our previous studies, we initiated the experiment by using l-Ramipril acid derived N,N’-dioxide L1– nickel(II) complex to catalyze the asymmetric Michael addition of diethyl malonate 1 a to chalcone 2 a in EtOH at 35 8C. However, only racemic product 3 a was obtained. Then serveral other Lewis acids, such as Cu, Zn, La, Y, Sc salts were investigated, which were known to be chelated well with dicarbonyl compounds. As summarized in Table 1, scandium triflate was found to be superior to all the other metals tested, producing 3 a in good yield with 91 % ee (Table 1, entries 1–6). Encouraged by the results, scandium triflate was selected as the central metal for further research. Then a series of N,N’-dioxides was synthesized and combined with scandium triflate to promote the conju-

Copper-Catalyzed Intermolecular Chloro- and Bromotrifluoromethylation of Alkenes.

A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br-containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes.

Design and Synthesis of Fluorinated Dendrimers for Sensitive F-19 MRI

To achieve high sensitivity for (19)F MRI, a class of novel dendritic molecules with multiple pseudosymmetrical fluorines was designed and efficiently synthesized. Through iterative bromination and Williamson ether synthesis under mild conditions, a fluorinated dendrimer with 540 pseudosymmetrical fluorines was conveniently prepared without performing the group protection in a convergent way. The dendrimer is characterized by a strong (19)F NMR peak and short relaxation times. Eventually, an appreciably enhanced (19)F MRI at an extremely low concentration (18.5 μM) was achieved, which demonstrated the potential utility of such dendritic molecules in highly sensitive (19)F MRI.

Highly Efficient Synthesis of Monodisperse Poly(ethylene glycols) and Derivatives through Macrocyclization of Oligo(ethylene glycols)

A macrocyclic sulfate (MCS)-based approach to monodisperse poly(ethylene glycols) (M-PEGs) and their monofunctionalized derivatives has been developed. Macrocyclization of oligo(ethylene glycols) (OEGs) provides MCS (up to a 62-membered macrocycle) as versatile precursors for a range of monofunctionalized M-PEGs. Through iterative nucleophilic ring-opening reactions of MCS without performing group protection and activation, a series of M-PEGs, including the unprecedented 64-mer (2850 Da), can be readily prepared. Synthetic simplicity coupled with versatility of this new strategy may pave the way for broader applications of M-PEGs.

Discovery of a 19F MRI sensitive salinomycin derivative with high cytotoxicity towards cancer cells

Salinomycin is a promising anti-cancer agent which selectively targets cancer stem cells. To improve its potency and selectivity, an analog library of salinomycin was generated by site-specific modification and CuAAc derivatization. Through a cytotoxicity analysis of the library, a fluorinated analog with high potency, selectivity, and (19)F MRI sensitivity was discovered as a novel theranostic agent.

Design, synthesis and evaluation of novel 19F magnetic resonance sensitive protein tyrosine phosphatase inhibitors

Fluorine is a highly attractive element for both medicinal chemistry and imaging technologies. To facilitate protein tyrosine phosphatases (PTPs)-targeted drug discovery and imaging-guided PTP research with fluorine, several highly potent and 19F MR sensitive PTP inhibitors were discovered through a structure-based focused library strategy.

Synthesis and biological evaluation of 20-epi-amino-20-deoxysalinomycin derivatives

To improve the druggability of salinomycin, a 20-epi-amino-20-deoxysalinomycin derivatives library was synthesized with high efficacy from which a few salinomycin derivatives with high potency and selectivity were identified through comprehensive cytotoxicity assay, including a fluorine-19 magnetic resonance sensitive tool molecule. Using a K-ras cellular model, salinomycin and its derivatives showed different molecular mode of action from literature reports. These results would be valuable for developing salinomycin-based cancer therapy.