Expanding the Reactivity of Aza-Oxyallyl Cationic Intermediates
Authors
Acharya, Arjun
Issue Date
2016
Type
Dissertation
Language
Keywords
Aza-oxyallyl , Cycloadditions , Heterocycles , Macrocycles , Oxazolidinones , Pyrroloindolines
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Abstract
Cycloaddition reactions are powerful transformations for the construction of various cyclic organic molecules. Cycloaddition reactions of oxyallyl cations are widely studied and applied in the synthesis of various natural products. Our group's interest in generating electrophilic nitrogen species led us to generate aza-analog of such allylic cation intermediate to provide easy access to seven-membered lactams. Following our groups’ previous discovery, intramolecular aza-(4+3) cycloadditions of such transient intermediates generated by the dehydrohalogenation of corresponding α-halohydroxamates with furan and N-Boc pyrroles were developed. α-Halohydroxamates with two reacting termini separated by tether chains of three to six atoms underwent cycloaddition reactions successfully to provide unique tricyclic and polycyclic lactams in good yields. Those polycyclic lactams were further transformed into an array of functionalized molecules including polyhydroxylated azepane derivates.Macrocycles are an important class of compounds having conformational flexibility with potential bioactivity. Macrocyclic hydroxamates were comparatively less explored targets. Here we were able to demonstrate the extended scope of the intramolecular aza-(4+3) cycloaddition reactions of allylic cations to generate macrocyclic motifs. These macrocycles were further functionalized into wide varieties of interesting scaffolds with potential bioactivity. This method provides easy access to 12-18 membered hydroxamate macrocycles.Hexahydropyrrolo[2,3-b]indole compounds are important targets in the synthetic community. We have successfully developed the new method for pyrroloindolines synthesis utilizing (3+2) cycloaddition approach. The aza-oxyallyl cations generated by dehydrohalogenation form α-halohydroxamates underwent (3+2) cycloaddition reaction with substituted indoles. This method was found compatible with wide varieties of indoles substituted at 3-position. The synthetic utility of this method has been demonstrated in the concise synthesis of physostigmine and debromoflustramine.Natural products with 4-oxazolidinones units are rarely found and only a few synthesis methods have been reported for the construction of such structural motif. Getting inspired from the previous (3+2) cycloaddition reactions of indoles, we further expanded this reactivity in other carbonyl compounds. This method was found fairly general with different substrates including aldehydes, ketones, amides, and esters to provide a good yield of products. Aromatic aldehydes were found to be the best substrate, however, aliphatic aldehydes, ketones, esters, and amides also provided a good yield of desired cycloadducts.All the compounds were characterized using 1H-NMR, 13C-NMR, IR and high-resolution mass spectrometry. The relative stereochemistry of few compounds, if necessary, was assigned using NOESY spectrometry and X-ray crystallography.
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