The overall objective of this application is to design and develop enantioselective phosphine-catalyzed annulations and to apply them in the chemical syntheses of natural products, their analogs, and unnatural small organic molecules of medicinal significance. Building on our successful studies of phosphine catalysis reactions and their applications in the total syntheses of medicinally useful natural products [(+)-ibophyllidine (?)-alstonerine, (?)-macroline, (?)-hirsutine, 3-deoxyisoochracinic acid, isoochracinic acid, isoochracinol], here we propose the development of new phosphine catalysis reactions and novel chiral phosphines. Specifically, we will prepare three families of new [2.2.1] bicyclic chira phosphines from a naturally occurring amino acid (trans-4-hydroxy-L-proline) and a terpenoid (carvone). These new phosphines have already displayed tremendous potential in facilitating enantioselective [3+2] and [4+2] annulations between allenes and imines. To build on these exciting preliminary observations, we propose to synthesize (-)-actinophyllic acid and (+) - ajmaline through enantioselective allene-imine [3+2] and [4+2] annulations, respectively, and another indole alkaloid, (+)-hirsutine, through the catalytic asymmetric allene-imine [4+2] annulation. In addition, we wish to develop new phosphine-catalyzed and -mediated reactions. We will examine and expand upon two hypotheses in the area of new reaction development: (i) tandem umpolung addition/Wittig olefination and (ii) sequential phosphine/transition metal catalysis. The proposed research could significantly expand the principles of organic reactions and provide new methods and reagents for the synthetic organic chemist's toolbox. Many innovations will be necessary to successfully implement our three specific aims. Our preliminary results have been strong in all three specific areas, supporting the likelihood of further successes. The small molecules described in this proposal are medicinally important, possessing activities related to diseases such as thrombosis [(-)-actinophyllic acid], hypertension and arrhythmia [(+)-ajmaline], influenzas [(+)-hirsutine], neurological disorders (glutamate receptor antagonist), and cardiac diseases and cancer (shihunidine). Successful completion of this proposed study would significantly impact the synthetic organic chemistry community by introducing a series of new chiral phosphines readily accessible from inexpensive natural products;in fact, we are collaborating with Sigma-Aldrich to make these chiral phosphines available to the scientific community. In addition to using these chiral phosphines in the proposed organocatalysis reactions, they should also serve as ligands for transition metal-catalyzed processes. Therefore, the proposed research could significantly increase the efficiencies of various synthetic organic processes.

Public Health Relevance

The natural products and pharmacologically relevant compounds stemming from this project have significant biomedical ramifications, specifically in thrombosis, hypertension, influenzas, cardiac diseases, cancer and several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson's disease, Alzheimer's disease and pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM071779-06A1
Application #
8786854
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2006-05-01
Project End
2018-06-30
Budget Start
2014-07-15
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lee, Craig J; Swain, Manisha; Kwon, Ohyun (2018) Synthesis of Cyclic ?-Silylalkenyl Triflates via an Alkenyl Cation Intermediate. Org Lett 20:5474-5477
Smaligo, Andrew J; Vardhineedi, Sriramurthy; Kwon, Ohyun (2018) Carvone-Derived P-Stereogenic Phosphines: Design, Synthesis, and Use in Allene-Imine [3 + 2] Annulation. ACS Catal 8:5188-5192
Xu, Qihai; Dupper, Nathan J; Smaligo, Andrew J et al. (2018) Catalytic Enantioselective Synthesis of Guvacine Derivatives through [4 + 2] Annulations of Imines with ?-Methylallenoates. Org Lett 20:6089-6093
Zhang, Kui; Cai, Lingchao; Yang, Zhongyue et al. (2018) Bridged [2.2.1] bicyclic phosphine oxide facilitates catalytic ?-umpolung addition-Wittig olefination. Chem Sci 9:1867-1872
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Xiao, Yumei; Guo, Hongchao; Kwon, Ohyun (2016) Nucleophilic Chiral Phosphines: Powerful and Versatile Catalysts for Asymmetric Annulations. Aldrichimica Acta 49:3-13
Cai, Lingchao; Zhang, Kui; Kwon, Ohyun (2016) Catalytic Asymmetric Total Synthesis of (-)-Actinophyllic Acid. J Am Chem Soc 138:3298-301
Wang, Zhiming; Xu, Xingzhu; Gu, Zhanshou et al. (2016) Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s. Chem Commun (Camb) 52:2811-4

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