Okilactomycin and chrolactomycin are antitumor antibiotics isolated in 1987 and 2001, respectively. These tetracyclic natural products possess a unique 6-5 fused tetrahydropyrone-butyrolactone. The spirocenter is part of a highly functionalized cyclohexene ring, which together with the aforementioned 6-5 system compose the core of these molecules. A six carbon, 1,3-dialkyl-substituted carbon chain tethers the tetrahydropyrone and cyclohexene ring giving rise to a rigid macrocycle. Both okilactomycin and chrolactomycin possess antiproliferative activity against a spectrum of human tumor cell lines as well as activity against Gram-positive bacteria. The biological profile in conjunction with the unprecedented molecular architecture renders these molecules important synthetic targets. To date, no total synthesis of these natural products has been reported This dissertation describes various approaches towards the synthesis of these interesting molecules. During the course of these studies, a novel Lewis acid catalyzed cyclization methodology was developed, which provides rapid access to highly substituted pyanones. The salient features of this synthesis include a streoselective anti-aldol reaction, a stereoselective Diels-Alder reaction and a novel cascade reaction that serves to join the principal fragments of the synthesis. Following the fragment coupling reaction, a silicate-mediated conjugate addition was used to form the pyranone ring. Following the presumed completion of the synthesis, it was determined that a diastereomer of the okilactomycin was actually prepared. We found through extensive experimentation that the silicate-mediated conjugate addition step was under thermodynamic control, which resulted in the formation of undesired diastereomers. Based on these data, we report preliminary studies on a third generation synthesis, which seeks to carry out the key conjugate addition under kinetic control.

Last modified

• 08/13/2018

Creator

• William Joseph Morris

DOI

• https://doi.org/10.21985/N2FB1C

Subject

• Chemistry

Keyword

• natural products
• total synthesis

Date created

• 2007-06-26

Resource type

• Dissertation

Rights statement

• In Copyright