Guofu Zhong

Amine-catalyzed direct asymmetric Mannich-type reactions

Three chiral cyclic secondary amines are shown to be catalysts for the direct asymmetric Mannich-type reaction of acetone with a variety of preformed aldimines derived from o-anisidine. A simple one-pot three-component reaction procedure consisting of aldehyde, acetone, p-anisidine and an amine catalyst provides the corresponding β-amino ketones with 50–89% ee under very mild conditions.

Chiral Brønsted Acid-Catalyzed Enantioselective α-Hydroxylation of β-Dicarbonyl Compounds

A novel, facile, and highly enantioselective Brønsted acid-catalyzed alpha-hydroxylation of beta-dicarbonyl compounds with up to 99:1 er using nitroso compounds as the oxygen source has been developed. The results disclosed herein considerably extend the substrate scope for the alpha-aminoxylation, allowing expeditious, straightforward, and efficient access to valuable alpha-hydroxy-beta-dicarbonyl compounds with the highest levels of enantiocontrol.

Organocatalytic asymmetric tandem Michael-Henry reactions: a highly stereoselective synthesis of multifunctionalized cyclohexanes with two quaternary stereocenters.

A novel organocatalytic asymmetric tandem Michael-Henry reaction catalyzed by 9-amino-9-deoxyepiquinine (VI) has been developed. The reaction was efficiently catalyzed by catalyst VI to give highly functionalized cyclohexanes with four stereogenic carbons including two quaternary stereocenters in excellent enantioselectivities (97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr). Thus, the first organocatalytic asymmetric Henry reaction of common ketones as acceptors is shown.

Rational design of organocatalyst: highly stereoselective Michael addition of cyclic ketones to nitroolefins.

A remarkable organocatalyst that facilitates the asymmetric Michael addition of cyclic ketones to nitroolefins in excellent stereoselectivities (98:2 to >99:1 dr, 92% to >99% ee) has been developed and afforded various types of optically active nitroalkane derivatives of synthetic and biological importance. The extremely simple and practical operational procedure at room temperature increases the attractiveness of this reaction.

Core Structure‐Based Design of Organocatalytic [3+2]‐Cycloaddition Reactions: Highly Efficient and Stereocontrolled Syntheses of 3,3′‐Pyrrolidonyl Spirooxindoles

A spirocyclic oxindole core is the structural centerpiece of a wide variety of natural and synthetic compounds that exhibit diverse biological activities. Consequently, approaches towards the efficient asymmetric synthesis of these molecules have received considerable attention. As part of a program to address this family of molecules with organocatalysis, we have recently reported strategies based on oxindoles that provide rapid access to bispirooxindoles, spirocyclopenteneoxindoles, and carbazolespirooxindoles. While these approaches have met with some success, these efforts do not address the 3,3’-pyrrolidonyl spirooxindole motif common to many bioactive molecules from this family of molecules (Scheme 1). Thus, an enantioselective catalytic approach for the direct construction of 3,3’-pyrrolidonyl spirooxindole skeletons is a significant unmet challenge. To address this challenge, we sought to design an organocatalytic domino reaction that would ideally involve the reaction of two simple and readily accessible starting materials. Given the recent success of a-isothiocyanato derivatives as nucleophiles in organocatalytic aldol and Mannich reactions, we envisioned that [3+2]-cycloaddition reactions between a-isothiocyanato imides and methyleneindolinones would yield the desired 3,3’-pyrrolidonyl spirooxindole skeletons in a highly stereoselective transformation (see Scheme 3). Given the pioneering studies of Deng and coworkers on cinchona alkaloid catalysis and our own findings that this class of catalysts works efficiently in oxindolebased reactions, we focused our attention on this class of organocatalysts (Scheme 2). Herein, we present organocatalytic asymmetric [3+2]-cycloaddition reactions between isothiocyanato imide and methyleneindolinones that provide 3,3’-pyrrolidonyl spirooxindoles in good yields with high diastereoand enantio-purity. We initiated our studies by evaluating the reaction between isothiocyanato imide 1 a and methyleneindolinone 2 a using quinine as the catalyst in dichloromethane at room temperature (Scheme 3). We found that the reaction proceeded smoothly and afforded the desired product in high yield, albeit with poor diastereoselectivity (3:2). Although high enantioselectivities (up to 97 % ee) were attained with the thiourea catalysts of Scheme 2, the diastereoselectivities were consistently poor despite optimization studies with re[a] Dr. B. Tan, Prof. Dr. C. F. Barbas, III The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) Fax: (+1) 858-784-2583 E-mail : carlos@scripps.edu [b] Dr. B. Tan, X. Zeng, W. W. Y. Leong, Z. Shi, Prof. Dr. G. Zhong College of Materials, Chemistry and Chemical Engineering Hangzhou Normal University, Hangzhou 310036 (P. R. China) E-mail : zgf@hznu.edu.cn [c] X. Zeng, W. W. Y. Leong, Z. Shi, Prof. Dr. G. Zhong Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University 21 Nanyang Link, Singapore 637371 (Singapore) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201103449. Scheme 1. Examples of natural and synthetic bioactive compounds containing a 3,3’-pyrrolidonyl spirooxindole structural motif.

Control of four stereocenters in an organocatalytic domino double Michael reaction: efficient synthesis of multisubstituted cyclopentanes.

A highly enantioselective and diastereoselective domino organocatalytic double Michael reaction which provides expedited access to multifunctionalized five-membered rings catalyzed by 9-amino-9-deoxyepiquinine (V) has been developed. Simple operational procedures, high yields (81-92%), excellent enantioselectivity (90-97% ee), diastereoselectivities (95:5->99:1 dr), and immense potential of synthetic versatility of the products render this new methodology highly appealing for asymmetric synthesis.

Facile Domino Access to Chiral Bicyclo[3.2.1]octanes and Discovery of a New Catalytic Activation Mode

A highly enantio- and diastereoselective organocatalytic domino Michael-Henry process for the preparation of synthetically unique and medicinally important bicyclo[3.2.1]octane derivatives with four stereogenic centers including two quaternary stereocenters has been developed. Theoretical DFT calculations on the transition states have been carried out to reveal origins of the excellent stereoselectivities. A novel dual model was thus proposed.

Broadening the Aldolase Catalytic Antibody Repertoire by Combining Reactive Immunization and Transition State Theory: New Enantio- and Diastereoselectivities.

Nine efficient aldolase antibodies were generated by using hapten 1. This hapten unites reactive immunization and the transition state analogue approach in a single molecule. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro-aldol reactions and exhibit enantio- and diastereoselectivities opposite to that of antibody 38C2.

A Highly Diastereo- and Enantioselective Synthesis of Multisubstituted Cyclopentanes with Four Chiral Carbons by the Organocatalytic Domino Michael−Henry Reaction

Highly functionalized cyclopentanes with four stereogenic carbons including two quaternary stereocenters have been synthesized in excellent yields (90-95%) with complete diastereoselectivities and excellent enantioselectivities (88-96% ee) by the organocatalyzed asymmetric domino Michael-Henry reaction.

Catalytic enantioselective retro-aldol reactions: Kinetic resolution of beta-hydroxyketones with aldolase antibodies

High enantiomeric enrichment after 50% conversion: Racemates of aldols can be resolved by the title reaction [Eq.(1)] by use of the aldolase antibody 38C2 or 33F12; the ee values of the unconverted aldols are greater than 95% in most cases. Since the antibodies also catalyze the aldol reaction-that is, the reverse reaction-it is possible to prepare both enantiomers using the same antibody catalysts.