Studies on the total synthesis of gambierol via endo-selective epoxide-opening cascades

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]

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2016

Author dc:creator

• Halkina, Tamara

Advisor dc:contributor.advisor

• Timothy F. Jamison.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/103508

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/103508