Date of Degree

9-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Mahesh K. Lakshman

Committee Members

Barbara Zajc

Shengping Zheng

Subject Categories

Organic Chemistry

Keywords

nucleoside, aroylation, coumarin, diaryliodonium salt

Abstract

Nucleosides, and their analogs, are important biological molecules that are integral to cell signaling, metabolism, and DNA and RNA synthesis. Because of their presence in all living systems, they are ideal candidates for drug development. Although extensive literature exists on the alkylation and alkenylation at N1 of inosine and 2’-deoxyinosine, few reports have been published on arylation at this position. Using diaryliodonium salts, a copper-catalyzed method has been developed for the efficient N1-arylation of silyl group-protected inosine and 2’-deoxyinosine. Diaryliodonium salts are easily synthesized and allow for the use of mild conditions to promote transfer of aryl groups to the desired nitrogen atom under various conditions. Notably, in the copper-catalyzed reactions described herein, arylation occurred at the nitrogen atom of the amide functionality that is part of purine base and not the oxygen atom, although ring aromatization is achievable by the latter. That N- and not O-arylation occurred was chemically proven. The ring arylations were generally very successful with both symmetrical and unsymmetrical diaryliodonium salts, including those containing a sterically bulky, electron-rich dummy ligand. The products were desilylated and will undergo testing for anticancer and antiviral properties in the future.

Coumarin and its derivatives have long been known to exhibit biological activity making them popular drug development candidates. In this study, the coumarin moiety was linked to the N1 atom of silyl group-protected inosine and 2’-deoxyinosine through an uncatalyzed C–N bond-forming reaction. For this, a series of 4-hydroxycoumarins were converted to the 4-(benzotriazol-1-yl)-coumarin derivatives using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). These compounds, upon reaction with the amide functionalities in the nucleosides led to reactions at N1 position of the protected inosine and 2’-deoxyinosine. In all cases, two rotamers were observed in the 1H and 13C NMR spectra of the products. One case is discussed in detail and assignments were made using 2D NMR spectra. The products were desilylated and will undergo testing for potential anticancer and antiviral activities in the future.

Using the metal-coordinating abilities of the ring nitrogen atoms in purine bases, remote C–H bond activation and aroylation of 6-aryl purine nucleosides with aryl aldehydes under in mild conditions is described. The identified conditions were applied to both 6-aryl purine ribonucleosides and the more labile 2’-deoxyribonucleoside analogs. Both electron-deficient and electron-rich aryl aldehydes were successfully reacted, although higher yields were generally achieved with the former. Studies were also conducted in order to understand a likely mechanism for these reactions.

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