Studies on the total synthesis of gambierol via endo-selective epoxide-opening cascades
Massachusetts Institute of Technology. Department of Chemistry.
Timothy F. Jamison.
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Progress towards the total synthesis of gambierol inspired by the biosynthetic hypothesis for ladder polyethers is described. Syntheses of the ABCD and FGH fragments have been completed in 29 and 3 1 steps, respectively, using water-promoted endo-selective epoxide-opening cascades to construct the poly-THP motifs. The concentration and temperature effects in the waterpromoted cascades were examined, and an operationally simple protocol was developed for the synthesis of polycyclic cascade products on multigram scale. [diagram] A sulfone tether between the ABCD and FGH fragments was used to facilitate an intramolecular olefination via the Ramberg-Backlund reaction. The highly site-selective hydrogenation of the fragment coupling alkene in the presence of H-ring alkene was developed using Noyori's hydrogenation catalyst, and several ring E cyclization precursors were subsequently prepared from C21 ketone. Investigation of a variety of methods for the C21-0 bond construction revealed a remarkably general spiroketalization pathway, which was previously unprecedented in ladder polyether synthesis and invariably led to the isolation of undesired 6,6-spiroketal products under most conditions. We have hypothesized that the presence of the FG ring junction methyl group disfavors the desired cyclization by exerting destabilizing 1,3-diaxial strain onto the newly forming ring junction of the requisite oxepane. We have therefore proposed that future studies examine the reverse direction for the synthesis of ring E via C16-0 bond formation. This approach would require installation of the tertiary alcohol on ring F prior to cyclization and would thus avoid the undesired reactivity resulting from the steric effects of the FG ring junction methyl group. [diagram]
Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2016.Vita. Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry.
Massachusetts Institute of Technology