Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Barbara Zajc

Committee Members

Mahesh Lakshman

Shengping Zheng

Subject Categories

Chemicals and Drugs

Keywords

Diastereoselectivity, Fluorination, Olefination, Flavone

Abstract

Diastereoselectivity of fluorination of a carbanion alpha to a sulfone in enantiomerically pure N-Boc protected (R)- and (S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines has been studied. Fluorination proceeded with good to excellent diastereoselectivity, which was base-dependent and was highest with lithium diisopropylamide (LDA). Diastereoselectivity also depended on the aryl moiety of the aryl sulfone and was highest with benzothiazole-derived sulfones. Under basic conditions, epimerization at the C–F stereogenic center alpha to the sulfone has been achieved for the first time and proceeded with good to excellent diastereoselectivity, which was highest in the case of a benzothiazole sulfone and with a lithium base. Enantiomeric purity was preserved in both, in the fluorination and in the epimerization reactions. Either of the two enantiomerically pure diastereomers of the fluorinated sulfones are accessible from a single chiral precursor. Synthetic utility of these chiral fluorinated building blocks was demonstrated by further conversions of diastereomeric benzothiazole sulfones to benzyl sulfones, via the sulfinate salts, and to enantiomerically and diastereomerically pure unnatural alpha amino acids, via amino alcohols. A plausible explanation for high diastereoselectivities observed in the fluorination and the epimerization reactions was proposed based on the computational modelling.

Utility of tert-butyl derivatives of (S)-4-((S)-(benzo[d]thiazol-2-ylsulfonyl)fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate and its (R,R)-enantiomer as Julia olefination reagents for synthesis of chiral a-fluorovinyl oxazolidines has been demonstrated. Olefinations were performed with aromatic and heteroaromatic aldehydes, and with alkanals, and fluoroalkenes were obtained in good to moderate yields. For most aldehydes, selectivity of olefinations could be modulated towards Z or E-selectivity. Olefinations using a combination of LHMDS, DMF/DMPU were Z-selective whereas the use of a combination of KHMDS, DME gave E-selective reactions. Stereoselectivity could not be reversed for o-methoxybenzaldehyde, p-cyanobenzaldehyde, and octanal. Fluoroalkene E/Z mixtures bearing an electron-rich aryl or heteroaryl substituent were isomerized to exclusive, or major (≥ 94) Z-isomer by catalytic iodine and blue LED. a-Fluorovinyl oxazolidine derivatives were converted to amino alcohols in good to moderate yields, and p-methoxyphenyl and p-cyanophenyl derivatives were further converted to amino acid methyl esters. This demonstrated that this approach can be used for the synthesis of fluorovinyl a-amino acids with fluorine installed at the proximate, alpha vinylic carbon. High enantiomeric purity was maintained through the synthetic sequence, with enantiomer ratio ³ 96:4.

A facile, straightforward approach to the synthesis of 3-fluoro substituted derivatives of flavone and chromone has been developed. Flavanone analogues and a 2-alkyl-chromanone were synthesized from chromone, followed by fluorine introduction alpha to keto functionality by Selectfluor. Resulting 3-fluoro-substituted derivatives were oxidized with IBX-Tos to give fluorinated flavone and chromone analogues in high yields.

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