Synthesis and Methodology Development Involving Strained Heterocycles and Preparation of Immunodulatory Glycosphingolipids

Date of Completion

January 2012


Chemistry, Organic




Strained heterocycles serve as important synthetic intermediates in organic chemistry, as well as motifs for natural products. In this thesis, we report a short, straightforward synthesis of the first psico-oxetanocin analogue of the powerful antiviral natural product, oxetanocin A, from 2-methyleneoxetanes. This unusual class of strained heterocycles was derived from β-lactones prepared by the carbonylation of epoxides. F+- mediatednucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. The exploitation of anchimeric assistance to increase the selectivity was attempted but not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepared to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable. ^ We have also studied the olefin cross metathesis reactions involving another class of strained heterocycles, a-methylene-13-lactams. This methodology showed good tolerance of a variety of functionalities, providing α-alkylidene-β-lactams in good to excellent yields with either Grubbs or Hoveyda-Grubbs 2 nd catalysts. Electron-poor α-methylene-β-lactams undergo cross-metathesis more rapidly and efficiently than more electron-rich analogues. Significantly, tetrasubstituted alkenes have for the first time been accessed by CM reactions. ^ Glycolipids, particularly α-galactosylceramides (α-GalCers), can stimulate NKT cells, which play a central role in regulating immune responses. Tremendous efforts have been devoted to the understanding of the activating process and the fine tuning of the cytokine release (Thl vs. Th2) by altering either the sugar or lipid portions of KRN7000, a principle α-GalCer for the study of NKT cell stimulation. One theory suggested that glycolipids which elicit high Thl bias require antigen presenting cells (APCs), which were shown to be essential to truncate (α1-2) digalactosylceramides to KRN7000. We synthesized the direct disaccharide analogue of a Thl-biasing α-GalCer, hypothesizing that the Thl bias may be enhanced by adding a monosaccharide in a position known to be subject to glycosidase cleavage. The "armed-disarmed" concept in sugar chemistry has been used for the key glycosylation steps to achieve better reactivity and high α-selectivity. ^