Date of Award

5-2019

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Organic Chemistry

First Advisor

Wei Zhang

Second Advisor

Hannah Sevian

Third Advisor

Adan Colon-Carmona

Abstract

Multicomponent reactions (MCRs) are reactions that combine at least three reactants in the same pot to generate a product containing most or all atoms of the starting materials. The merits of MCRs include high atom- and step economy, efficiency, mild conditions, high convergence, diversity-oriented synthesis, and library generation. Presented in this dissertation is my effort to apply MCRs to synthesize compounds of biological interests. The MCRs were followed by various post condensation modifications such as Suzuki coupling reaction, (5+n) annulations, and radical trifluoromethylation. This thesis covers the following projects: 1) Structure-guided design and green synthesis of potent and selective CBP inhibitors; 2) Sequential (3+2) cycloadddition and (5+n) annulation for the synthesis of dihydrobenzoxazines, tetrahydrobenzoxazepines and tetrahydrobenzoxazocines; and 3) (3+2) Cycloaddition and cascade radical reaction for the synthesis of trifluoromethylated tetrahydrobenzodiazepin-3-ones. In the above mentioned projects, MCRs were used to synthesize the intermediates followed by various post-condensation modifications to assemble compounds of biological interests. For example, in the first project of this dissertation, Groebke−Blackburn−Bienayme (GBB) reaction was applied as a multicomponent reaction to synthesize UMB298. It has CBP and BRD4 inhibitory potencies of 72 nM and 5193 nM, respectively. This work has been published in the patent, WO 2019/014514 (Zhang, W.; Muthengi, A.; Yosief, H. PCT/US2018/041933). Additionally, we will be submitting the manuscript to Journal of Medicinal Chemistry (Muthengi, A. et al. Journal of Medicinal Chemistry 2019), we thank our collaborators for their contributions, including Dr. Jun Qi from Dana Farber Cancer Institute, and Dr. Zied Gaieb from Univ. of California San Diego for carrying out biological assay and computational study, respectively. The second and third project utilized one-pot (3+2) cycloaddition reactions followed by two post condensation reactions of (5+n) annulation or radical trifluoromethylation reactions. The synthetic projects presented in this thesis are benign, resource efficient, diastereoselective, and with excellent yields. The work from the second project has been published in the journal of Green Chemistry (Muthengi, A. et al. Green Chemistry 2018, 20, 3134–3139), while the work from the third project was been submitted to Journal of Organic Chemistry (Muthengi, A. et al. Journal of Organic Chemistry 2019).

Comments

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