Description of Funded Grant (Project Summary for R01 GM071779): The overarching goal of this project is to develop new catalysts and reactions to empower the chemical synthesis of biologically active natural product targets and pharmaceuticals. In particular, we formulate a rationale for designing strained and bridged bicyclic phosphine oxides that can be readily reduced back to phosphines after the phosphine oxides are formed in situ. A new bridged [2.2.1] bicyclic phosphine oxide has already displayed reactivity, in both catalytic Wittig and Staudinger reactions, superior to that of the best alternatives known today. Experimental and theoretical investigations have predicted that the proposed [2.1.1] bicyclic phosphine oxides would be even more reactive. Considering the ubiquity of reactions driven by the formation of phosphine oxides (e.g., Staudinger, Wittig, Mitsunobu, and Appel reactions), and their environmental consequences, our proposed research should have significant impact on organic synthesis. Our inspiration for the bridged [2.2.1] bicyclic phosphine oxide originated from the trans-4-hydroxy-L-proline (Hyp)?derived chiral phosphines we developed during the last funding period. Building on the greater faculty of the [2.2.1] bicyclic phosphine oxide, we will apply the Hyp-derived 2-aza-5-phosphabicyclo[2.2.1]heptanes to catalytic asymmetric Staudinger, Wittig, Mitsunobu, and Appel reactions. These chiral phosphines have already exhibited tremendous potential in facilitating enantioselective Mitsunobu and Appel reactions and the first successful example of a catalytic asymmetric Staudinger/aza-Wittig reaction. We will also create new bridged [2.2.1] bicyclic chiral phosphines from carvone. Carvone-derived P-chiral phosphines should be versatile catalysts because both enantiomers of carvone are naturally abundant and, therefore, inexpensive. Capitalizing on the capacity of phosphines to serve as both organic catalysts and ligands on homogeneous transition metal catalysts, we propose to develop a tandem Michael?Heck reaction of alkenyl halides and activated acetylenes for the assembly of 5- and 6-membered carbo- and heterocycles. One particular Michael?Heck process employing iodoalcohols is a powerful tool for assembling furans of almost any substitution pattern and provides access to several structurally disparate furanosesquiterpenoid natural products. We have already made 10 different Hyp-derived chiral phosphines commercially available through Sigma?Aldrich and will collaborate with them again to make our phosphine oxides and chiral phosphines available to the scientific community. Many research groups have already used Hyp-derived phosphines in a variety of catalysis reactions. We anticipate that the proposed research will have a similar significant impact on chemical synthesis. Collectively, the catalysts and reactions developed in this application will allow the enantioselective preparation of medicinally significant pharmaceuticals and natural product targets.
Supplement for Quintana, Jason ? Narrative Description of Funded Grant (Project Narrative for R01 GM071779): The natural products and pharmacologically relevant compounds stemming from this project have significant biomedical ramifications, specifically in anesthesia, cancer, diabetes, immunology, inflammation, anti-HSV, anti-adenoviral, depression, and Alzheimer?s and Parkinson?s diseases.
|Guo, Hongchao; Fan, Yi Chiao; Sun, Zhanhu et al. (2018) Phosphine Organocatalysis. Chem Rev 118:10049-10293|
|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|
|Fernández-Del-Río, Lucía; Nag, Anish; Gutiérrez Casado, Elena et al. (2017) Kaempferol increases levels of coenzyme Q in kidney cells and serves as a biosynthetic ring precursor. Free Radic Biol Med 110:176-187|
|Schweitzer, Maria K; Wilting, Fabiola; Sedej, Simon et al. (2017) Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models. JACC Basic Transl Sci 2:737-747|
|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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