Approach to Dual Base and Sugar Modification of Adenosine, Cross-Dehydrogenative Coupling Reactions of Quinazolinones, and a Novel Entry to Carbazolones and Indolones

Author

Dellamol Sebastian, The Graduate Center, City University of New YorkFollow

Date of Degree

6-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Mahesh K. Lakshman

Committee Members

Barbara Zajc

Shengping Zheng

Subject Categories

Other Life Sciences

Abstract

Analogues of purine nucleosides are of interest due to their antiviral, antibacterial, and anticancer properties. Although there are large number of reports on C6-modification of 6-chloropurine nucleosides with alkyl amines via the S_NAr reaction pathway, there are fewer reports on comparable reactions with aryl amines. Notably, S_NAr reactions of 6-chloropurine nucleosides with electron-deficient aryl amines is a relatively understudied area. A simple method has been developed for the S_NAr reactions of 6-chloropurine ribonucleosides with electron-deficient-, electron-rich-, and electronically neutral aryl amines. Under the developed conditions, S_NAr reactions of 2’,3’,5’-O-(tert-butyldimethyl)silyl-protected 6-chloropurine ribonucleoside with the aryl amines result in a concomitant desilylation at the primary hydroxyl terminus of the sugar. In contrast, S_NAr reactions of 2’,3’,5’-O-(tert-butyldimethyl)silyl-protected 6-chloropurine ribonucleoside with alkyl amines did not lead to 5’-desilylated products. In those cases, the 5’-desilylation was achieved by employing conditions available in the literature. The ensuing 5’-desilylated product was then used for reactions with alkyl amines. Several N⁶-alkyl and N⁶-aryl adenosine derivatives were subjected to diverse conversions at the 5’-terminus. In the overall scheme, the work provides an approach for broadly modifying the exocyclic amino group and the C5’-terminus of adenosine. The results of this work are important because C5’, N6-doubly modified adenosine derivatives possess significant and diverse biological activities, and this work provide a convenient approach to such compounds.

Quinazolinones are important heterocycles from a biological standpoint, and their chemical modification can be challenging because of multiple potential reactive centers. Thus, selective modification of quinazolinones is interesting and challenging from a chemical standpoint. A new organo-catalytic method has been developed for the selective alkylation of quinazolinones at the amide nitrogen atom, with ethers and amides, through cross-dehydrogenative coupling. Mechanistic studies have been conducted to gain an insight into a plausible reaction mechanism. The studies revealed that a C–H cleavage in the ether/amide likely occurs in a rate-determining step. In this work, relative reactivities of ethers were also investigated.

The carbazolone and indolone moieties are present in many natural and pharmaceutically important compounds. The development of a new method for the synthesis of carbazolones and indolones will make the key intermediates required for the synthesis of these natural products easily accessible, and possibly in a modular manner. In a new approach, 2-aryl-1,3-cycloalkanediones (6- and 5-membered) were synthesized. Activation of one of the carbonyl groups, a step that can be done regioselectively with unsymmetrical diones, and azidation then yields a b-azido enone. A subsequent rhodium-catalyzed generation of a nitrene or metal-nitrenoid results in a C(_sp2)–N bond formation, and the formation of an indole unit. We have utilized this approach for the synthesis of a key intermediate that can be further elaborated to natural products such as kopsihainanine A, limaspermidine, aspidospermidine, and vincadifformine.

Recommended Citation

Sebastian, Dellamol, "Approach to Dual Base and Sugar Modification of Adenosine, Cross-Dehydrogenative Coupling Reactions of Quinazolinones, and a Novel Entry to Carbazolones and Indolones" (2022). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/4887