In the previous proposal, we identified the formal [3 + 3] cycloaddition as a viable approach to arisugacin A, a potent inhibitor of acetylcholinesterase [AChE]. We also recognized the potential of the [3 + 3] reaction as a general methodology for constructing heterocycles including nitrogen heterocycles. We have accomplished those goals. ? ? To demonstrate the usefulness of this formal cycloaddition methodology, pursuing its applications in natural product syntheses has become an important focus. Thus, in this competitive renewal, in addition to furthering the medicinal knowledge of arisugacin A for dementias as originally proposed, we intend to pursue syntheses of natural products containing oxygen heterocycles, and to develop a visible program around alkaloid synthesis particularly using the formal aza-[3 + 3] cycloaddition. While we are pursuing several different endeavors, this renewal focuses on selected topics to best illustrate these efforts, and is organized in the following four aims. ? ? Specific Aim 1 [Aim 3 in the previous proposal] focuses on synthesis of analogs of arisugacin A using the formal oxa-[3 + 3] cycloaddition and in vitro assay of the analogs to explore binding of arisugacin A to AChE. ? ? Specific Aim 2 focuses on applications of formal oxa-[3 + 3] cycloadditions in total syntheses of the natural products hongoquercin A and phomactin A. ? ? Specific Aim 3 focuses on employing the oxa-[3 + 3] along with the carbo-[3 + 3] formal cycloaddition toward the synthesis of the hyperforin family of natural products. ? ? Specific Aim 4 focuses on applications of formal aza-[3 + 3] cycloadditions toward total syntheses of lepadins and cylindricines, and further development of the intramolecular formal aza-[3 + 3] cycloaddition including its asymmetric variants using chiral Lewis acids and amine salts. ? ?

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National Institute of Neurological Disorders and Stroke (NINDS)
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Medicinal Chemistry Study Section (MCHA)
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Murphy, Diane
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University of Minnesota Twin Cities
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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
Gerasyuto, Aleksey I; Ma, Zhi-Xiong; Buchanan, Grant S et al. (2013) Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis. Beilstein J Org Chem 9:1170-8
Buchanan, Grant S; Cole, Kevin P; Li, Gang et al. (2011) Constructing the Architecturally Distinctive ABD-Tricycle of Phomactin A through an Intramolecular Oxa-[3 + 3] Annulation Strategy. Tetrahedron 67:10105-10118
Al-Rashid, Ziyad F; Hsung, Richard P (2011) (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase. Bioorg Med Chem Lett 21:2687-91
Buchanan, Grant S; Cole, Kevin P; Tang, Yu et al. (2011) Total synthesis of (±)-phomactin A. Lessons learned from respecting a challenging structural topology. J Org Chem 76:7027-39
Buchanan, Grant S; Dai, Huifang; Hsung, Richard P et al. (2011) Asymmetric aza-[3+3] annulation in the synthesis of indolizidines: an unexpected reversal of regiochemistry. Org Lett 13:4402-5
Buchanan, Grant S; Feltenberger, John B; Hsung, Richard P (2010) Aza-[3 + 3] Annulations: A New Unified Strategy in Alkaloid Synthesis. Curr Org Synth 7:363-401
Li, Gang; Carlson, Lauren J; Sagamanova, Irina K et al. (2009) A Stereodivergent Approach for Accessing Both C2,8a-Syn and C2,8a-Anti Relative Stereochemical Manifolds in the Lepadin Family via a TiCL(4)-Promoted Aza-[3 + 3] Annulation. Synthesis (Stuttg) 2009:2905
Tang, Yu; Cole, Kevin P; Buchanan, Grant S et al. (2009) Total synthesis of phomactin A. Org Lett 11:1591-4
Li, Gang; Hsung, Richard P (2009) Assignment of the C5' relative stereochemistry in (+)-lepadin F and (+)-lepadin G and absolute configuration of (+)-lepadin G. Org Lett 11:4616-9

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