Tetrahydrofurans and pyrrolidines are important structural motifs that are found in a variety of natural products that exhibit useful biological properties. Owing to their abundance in nature and both varied and potentially useful biological activity, numerous synthetic methods and strategies have been developed for the preparation of substituted tetrahydrofurans and pyrrolidines. The research work presented in this thesis describes the use of α-chloroaldehydes in the synthesis of the tetrahydrofuran-containing natural product pachastrissamine, as well as the development of new methods that provides rapid access to hydroxyalkyldihydropyrroles and iminosugars such as (-)-swainsonine.Pachastrissamine (also known as jaspine B), is a naturally-occurring anhydrophytosphingosine isolated in 2002 from two different marine sponges Pachatrissa sp. and Jaspis sp., and displays potent activity against numerous cancer cell lines. A total synthesis of this natural product was achieved in 8 steps that included an α-chloroaldehyde aldol reaction and novel thermal cyclization of the aldol adduct as the key steps. The second part of the thesis details the development of a concise and stereoselective strategy for the synthesis of hydroxyalkyldihydropyrroles. This study involves the nucleophilic addition of protected propargyl amines to α-chloroaldehydes, followed by Lindlar reduction of resultant chlorohydrin and an epoxide formation/cyclization sequence. This methodology was further demonstrated in the synthesis of unnatural iminosugars and in a formal synthesis of natural product (-)-swainsonine, a potent lysosomal α-mannosidase inhibitor.
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Thesis advisor: Britton, Robert
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