The aims of the proposed research are to develop asymmetric organocatalytic methods for use in synthesis. Recent advances in this area highlight the utility of small organic molecules for promoting synthetic transformations in an efficient and selective manner. Continued progress in the field of organocatalysis will provide access to novel, highly functionalized chiral building blocks in enantioenriched form that have been previously unavailable. The projects in this proposal will concentrate on identifying and exploring chiral Bronsted acid catalysis and chiral base catalysis in order to develop new organocatalytic methods applicable to the synthesis of novel chiral building blocks. We have developed the first highly enantioselective Morita-Baylis-Hillman (MBH) reaction involving enones and aldehydes catalyzed by a small chiral molecule. The reaction achieves high levels of enantioselectivity from an organic catalyst through hydrogen bonding. Mechanistic investigations allow us to apply what we have learned about the MBH reaction to expand the scope and utility of the reaction. Projects in this grant will develop the reaction for use in the synthesis of complex natural products such as the asmarine class of clerodane natural products, potent antiproliferative agents with unknown modes of action which inhibit small cell lung carcinoma growth in nanomolar concentrations. We will also continue to develop the asymmetric MBH reaction for the synthesis of the pycnanthuquinones, orally bioavailable natural products with a unique mode of overcoming the symptoms of type 2 diabetes mellitus. These natural products are unlike other known treatments of type 2 diabetes and will be used to identify the molecular target. We have also successfully developed the asymmetric Mannich reaction of ?-keto esters to acyl imines catalyzed by the cinchona alkaloid class of natural product organocatalysts. Through further investigations, we will expand the scope of the reaction to produce highly functionalized building blocks that can be used for Pharmaceuticals such as the melanin concentrating hormone receptor antagonist SNAP-7941 and the batzellidine natural products. We have also developed the first asymmetric allylboration of carbonyl containing compounds catalyzed by a simple organic compound. The asymmetric reaction will be highlighted in the synthesis of the natural product manzacidin A.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078240-04
Application #
7779425
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2007-04-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$302,371
Indirect Cost
Name
Boston University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Jiang, Yao; Thomson, Regan J; Schaus, Scott E (2017) Asymmetric Traceless Petasis Borono-Mannich Reactions of Enals: Reductive Transposition of Allylic Diazenes. Angew Chem Int Ed Engl 56:16631-16635
Jiang, Yao; Diagne, Abdallah B; Thomson, Regan J et al. (2017) Enantioselective Synthesis of Allenes by Catalytic Traceless Petasis Reactions. J Am Chem Soc 139:1998-2005
Jiang, Yao; Schaus, Scott E (2017) Asymmetric Petasis Borono-Mannich Allylation Reactions Catalyzed by Chiral Biphenols. Angew Chem Int Ed Engl 56:1544-1548
Allen, Emily E; Zhu, Calvin; Panek, James S et al. (2017) Multicomponent Condensation Reactions via ortho-Quinone Methides. Org Lett 19:1878-1881
Barbato, Keith S; Luan, Yi; Ramella, Daniele et al. (2015) Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols. Org Lett 17:5812-5
Rajasekaran, Devaraja; Siddiq, Ayesha; Willoughby, Jennifer L S et al. (2015) Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model. Oncotarget 6:26266-77
Luan, Yi; Barbato, Keith S; Moquist, Philip N et al. (2015) Enantioselective synthesis of 1,2-dihydronaphthalene-1-carbaldehydes by addition of boronates to isochromene acetals catalyzed by tartaric acid. J Am Chem Soc 137:3233-6
Luan, Yi; Yu, Jie; Zhang, Xiaowei et al. (2014) Diastereoselective three-component synthesis of ?-amino carbonyl compounds using diazo compounds, boranes, and acyl imines under catalyst-free conditions. J Org Chem 79:4694-8
Luan, Yi; Qi, Yue; Gao, Hongyi et al. (2014) Brønsted Acid/Lewis Acid Cooperatively Catalyzed Addition of Diazoester to 2H-chromene Acetals. European J Org Chem 2014:6868-6872
Luan, Yi; Qi, Yue; Yu, Jie et al. (2014) The development of a novel HAuCl4@MOF catalyst and its catalytic application in the formation of dihydrochalcones. RSC Adv 4:34199-34203

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