The primary significance of the proposed research is that potentially- powerful new synthetic methods will be developed.
The specific aims i nclude the development of several new nickel-catalyzed procedures involving cyclizations and multicomponent couplings. Considerable attention will be devoted to the development of asymmetric and solid- phase procedures. The efforts in reaction discovery are designed to develop processes that rapidly construct complex organic substructures from simple, readily-available precursors in a predictable and efficient manner. The research will focus exclusively on the development of catalytic processes that should be amenable to scaleup in an environmentally-benign fashion. A new approach to alpha-amino acid synthesis will be pursued which is unique that the amino acid side chain is derived from up to four components in a simple three-step operation. The rapid and flexible preparation of amino acids in the solid phase should provide a powerful combinatorial tool for small molecule drug discovery and polypeptide synthesis employing nonproteinogenic amino acids. A general synthetic approach to the allopumiliotoxin alkaloids will be developed, and a formal total synthesis of a representative member, allopumiliotoxin 339B, will be pursued. The pharmacological activity of the pumiliotoxins in linked to mechanisms involving facilitation of calcium influx into the muscle fiber and/or a facilitation of calcium release from the sarcoplasmic reticulum. The proposed synthetic route to the allopumiliotoxins should allow rapid construction of the central bicyclic skeleton with complete stereocontrol. A general approach to the kainoid amino acids will be developed, and an enantioselective total synthesis of (-)-kainic acid, the simplest member, will be pursued. Their potent neuroexcitatory activity has allowed the kainoids to serve as effective models for neuronal diseases such as epilepsy and Huntington's chorea and for neuronal cell loss in senile dementia. The proposed synthetic route to the kainoids will allow facile introduction of various C-4 side chains, which is the position at which all kainoids differ structurally. The concise and flexible routes proposed for the synthesis of allopumiliotoxin alkaloids and kainoid amino acids should allow the facile preparation of preparative quantities of the natural products as well as new derivatives for further pharmacological investigations.

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National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Wayne State University
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Walk, Jordan T; Buchan, Zachary A; Montgomery, John (2015) Sugar Silanes: Versatile Reagents for Stereocontrolled Glycosylation via Intramolecular Aglycone Delivery. Chem Sci 6:3448-3453
Wang, Hengbin; Negretti, Solymar; Knauff, Allison R et al. (2015) Exo-selective reductive macrocyclization of ynals. Org Lett 17:1493-6
Jackson, Evan P; Montgomery, John (2015) Regiocontrol in catalytic reductive couplings through alterations of silane rate dependence. J Am Chem Soc 137:958-63
Jackson, Evan P; Malik, Hasnain A; Sormunen, Grant J et al. (2015) Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings. Acc Chem Res 48:1736-45
Haynes 2nd, M Taylor; Liu, Peng; Baxter, Ryan D et al. (2014) Dimer involvement and origin of crossover in nickel-catalyzed aldehyde-alkyne reductive couplings. J Am Chem Soc 136:17495-504
Miller, Zachary D; Montgomery, John (2014) Regioselective allene hydroarylation via one-pot allene hydrosilylation/Pd-catalyzed cross-coupling. Org Lett 16:5486-9
Miller, Zachary D; Li, Wei; Belderrain, Tomás R et al. (2013) Regioselective allene hydrosilylation catalyzed by N-heterocyclic carbene complexes of nickel and palladium. J Am Chem Soc 135:15282-5
Partridge, Katherine M; Bader, Scott J; Buchan, Zachary A et al. (2013) A streamlined strategy for aglycone assembly and glycosylation. Angew Chem Int Ed Engl 52:13647-50
Lage, Marta L; Bader, Scott J; Sa-Ei, Kanicha et al. (2013) Chemoselective hydrosilylation of hydroxyketones. Tetrahedron 69:5609-5613
Shareef, Abdur-Rafay; Sherman, David H; Montgomery, John (2012) Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs. Chem Sci 3:892-895

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