Allenes and alkynes are among the most important building blocks in organic synthesis. We have been defining the reactivity of a new class of nitrogen-substituted allenes and alkynes, specifically allenamides and ynamides, in which the nitrogen atom contains an electron-withdrawing group. These allenamides and ynamides possess much needed stability compared to classical nitrogen-substituted allenes and alkynes. However, more significantly, their unique conformational rigidity and attractive coordination ability have allowed us to develop highly stereoselective synthetic methods. Therefore, it is the goal of this NIH proposal to explore applications of these stereoselective methodologies. For chemistry of ynamides in Aim-l, we propose en-ynamide ring-closing metathesis to construct complex nitrogen heterocycles. For chemistry of allenamides, we propose in Aim-2 a total synthesis of (+)-zincophorin, featuring the application of a hetero [4 + 2] cycloaddition.
In Aim -3 and Aim-4, we propose total syntheses of (-)-1-isothiocyanate-aromadendrane, (+)-parvineostemonine, and (+)-Iyconadin A, featuring applications of N-substituted oxyallyl cation intramolecular [4 + 3] cycloadditions. These synthetic applications can demonstrate the potential of allenamides and ynamides in constructing complex natural products. Investigations proposed here should continue to revitalize interest in the chemistry of allenamines and ynamines which show great promise in organic synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066055-04
Application #
7385887
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$229,820
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ma, Zhi-Xiong; Fang, Li-Chao; Hsung, Richard P (2017) Facile Synthesis of 3-Amido-Dienynes via a Tandem ?-Propargylation-Isomerization of Chiral Allenamides and their Applications in Diels-Alder Cycloadditions. Synlett 28:2906-2912
Wang, Xiao-Na; Ma, Zhi-Xiong; Deng, Jun et al. (2015) A Silver(I)-Catalyzed Intramolecular Ficini's [2 + 2] Cycloaddition Employing Ynamides. Tetrahedron Lett 56:3463-3467
Wang, Xiao-Na; Krenske, Elizabeth H; Johnston, Ryne C et al. (2015) AlCl?-Catalyzed Ring Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained Cis,Trans-Cycloheptadienone Intermediates. J Am Chem Soc 137:5596-601
Ma, Zhi-Xiong; Patel, Ashay; Houk, K N et al. (2015) Highly torquoselective electrocyclizations and competing 1,7-hydrogen shifts of 1-azatrienes with silyl substitution at the allylic carbon. Org Lett 17:2138-41
Patel, Ashay; Vella, Joseph R; Ma, Zhi-Xiong et al. (2015) Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes. J Org Chem 80:11888-94
Al-Rashid, Ziyad F; Hsung, Richard P (2015) A computational view on the significance of E-ring in binding of (+)-arisugacin A to acetylcholinesterase. Bioorg Med Chem Lett 25:4848-53
Xu, Yan-Shuang; Tang, Yu; Feng, He-Jing et al. (2015) A highly regio- and stereoselective synthesis of ?-fluorinated imides via fluorination of chiral enamides. Org Lett 17:572-5
Fang, Li-Chao; Hsung, Richard P (2014) Stereoselective synthesis of isoquinuclidines through an aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes. Org Lett 16:1826-9
Wang, Xiao-Na; Krenske, Elizabeth H; Johnston, Ryne C et al. (2014) Torquoselective ring opening of fused cyclobutenamides: evidence for a cis,trans-cyclooctadienone intermediate. J Am Chem Soc 136:9802-5
Lu, Ting; Hsung, Richard P (2014) Novel ynamide structural analogues and their synthetic transformations. ARKIVOC 2014:127-141

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