Synthetic studies on maoecrystal V and studies on the rhodium catalyzed 1,2-addition of alkynes to activated ketones and aldehydes
Date of Award
Doctor of Philosophy (PhD)
John D. Chisholm
Maoecrystal, Rhodium, Alkynes, Ketones, Aldehydes
The first section of this document discusses attempts at synthesizing a model system of the natural product maoecrystal V. Maoecrystal V was isolated from the leaves of a Chinese medicinal herb, Isodon eriocalyx, and displays selective growth inhibitory activity toward HeLa cells. The first generation synthetic plan involved the synthesis of an advanced intermediate through an intramolecular hetero Diels-Alder (IHDA) reaction between an aldehyde dienophile and a highly substituted cyclopentadiene. Several conditions were explored to facilitate the [4+2] cycloaddition, but none resulted in product formation.
The problem with this approach was unclear. The inability to induce a [4+2] cycloaddition may have been due to the dithiane present in the molecule, the strain caused by the bicyclic core, or the poor reactivity of the cyclopentadiene. Two model systems incorporating the IHDA reactions were studied to address these questions. In the first model system a pyran ring system could be formed under thermal and Lewis acid conditions; the dithiane was ruled out as the problematic issue. A second, more complex, model system was then synthesized to study the reactivity of the cyclopentadiene functionality in the IHDA reaction. All attempts to induce the IHDA reaction were unsuccessful and this appeared to be an insurmountable problem; a new synthetic strategy was required.
A second generation synthetic approach was initiated which will employ an intramolecular Aldol reaction as the key step. An advanced tricyclic intermediate and fully substituted dithiane have been successfully synthesized en route to complete the synthesis of the desired target molecule. This synthetic sequence would then be incorporated towards the total synthesis of maoecrystal V.
The second section of the dissertation discusses the activation of an alkyne to induce its nucleophilic addition to activated ketones and aldehydes with the use of Rh(acac)(CO) 2 in the presence of a phosphine ligand. Attempts were made to induce enantioselectivity with the use of chiral phosphine ligands. α-Chiral substituents were also explored to probe diastereoselectivity. As a prelude to the synthesis of chiral rhodium complexes, several rhodium complexes with substituted acac ligands were synthesized and tested. The reactions were found to be first order with respect to the alkyne, with bulky electron donating groups on the acac increasing the rate of reaction.
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Carberry, Patrick, "Synthetic studies on maoecrystal V and studies on the rhodium catalyzed 1,2-addition of alkynes to activated ketones and aldehydes" (2009). Chemistry - Dissertations. Paper 3.