Part I. Geminal Fluorosulfonimidation of 1,2-Diketones via Formal N‒F Insertion Enabled by Dealkylation-Resistant Phosphoramidite Part II. Study on Chemoselective Esterification of Complex, Unprotected Natural Carboxylic Acids

Abstract

Part I. The simultaneous introduction of fluorine and other functional groups on the same carbon has been intensely studied because of its synthetic and pharmaceutical importance. However, only a few studies have been reported on the synthetic methods of α-fluoroamines. Most examples employ diazo compounds as substrates and require high temperatures and long reaction times. Moreover, either excess amounts of reagents or transition metal catalysts are needed. Thus, it is desirable to develop a synthetic approach to α-fluoroamines. In combination with the dealkylation-resistant neopentyl glycol-derived phosphorus(III) reagent, dioxaphospholene was employed as a carbene surrogate. Our P(III) reagent has convenient access to transition metal-free conditions and short reaction times. With the optimized conditions previously studied on geminal fluorosulfonimidation, α-fluoroamines were synthesized from 1,2-diketones with (PhSO2)2NF in up to 80% yield. Also, the unsymmetrical 1,2-diketones were investigated for their site selectivity. Furthermore, for the expansion of the substrate scopes, geminal difunctionalization was carried out on the external nitrogen nucleophiles as well as the halogen electrophile such as N-chlorosuccinimide which provided the α-chloramine in 14% yield. Additionally, a detailed reaction mechanism was established by a computational study. Part II. A simple addition of methyl group to unprotected phosphatidylserine (PS) that has several functional groups is challenging. Compared to the previous multi-step synthesis in our laboratory, direct methyl esterification would improve the efficiency. N-Carboxyanhydride (NCA) is a useful tool to manipulate the esterification methods of amino acids. However, when NCA is applied to PS, an unwanted phosphoric acid ester might be formed via an intramolecular reaction with NCA. It is proposed that the undesired reaction of the phosphoryl group could be prevented by lowering the electrophilicity of NCA. Therefore, selective methylation may be enabled by replacing the carbonyl oxygen with sulfur. We supposed that the N-thionocarboxyanhydride (NTCA) proceed with the methylation on PS. However, the formation of NTCA was unsuccessful. On the other hand, oxazaborolidinone could also selectively react with amino acids to give amino acid ester, and other esterification methods were investigated. After the preliminary studies on amino acids, the application to PS will be carried out. The amine group protection was investigated because of the reactive amine group which probably caused the side reaction. However, the amine protection did not provide the desired products. It is assumed that the amine group is too reactive. Therefore, the amine protection was also performed with the poorer leaving group.