APPLICATION OF FLUOROUS MIXTURE SYNTHESIS (FMS) FOR THE SYNTHESIS OF NATURAL PRODUCT STEREOISOMER LIBRARIES: TOTAL SYNTHESIS OF EIGHT DIASTEREOMERS OF PASSIFLORICIN A AND STUDIES ON A CONVERGENT SYNTHESIS OF 6-EPI-DICTYOSTATIN
Passifloricin A, a natural product isolated from the tree Passiflora foetida is a polyol ?-lactone containing four stereocenters. The Fluorous Mixture Synthesis (FMS) of all eight diastereomers of passifloricin A is reported herein. FMS is a technique that exploits the simplicity and velocity of working with mixtures of compounds, yet still permits for a systematic separation of the mixtures to provide individual pure stereoisomers or analogs. Utilizing a multiple-tag FMS strategy we successfully obtained two mixtures of four double tagged quasiisomers that were separated (demixed) by fluorous HPLC to provide the eight quasiisomers in a systematic fashion. The eight quasiisomers were individually deprotected to provide the eight diastereomers of passifloricin A. Diastereomer (SRRR)-3 spectroscopic data matched the spectroscopic data for natural and synthetic passifloricin A.
Dictyostatin, a marine sponge-derived macrolactone has been extensively studied in our group because of its high potency as a microtubule-stabilizing agent. Our group, based on SAR studies, synthesized the four times more potent 6-epimer (6-epi-dictyostatin 36). We hypothesized a more convergent approach for the synthesis of 36 by introducing dienyl ester bottom fragment 41, easily synthesized by the ene-diene metathesis. We successfully coupled the fragments via ring closing metathesis of silaketal 89 to provide key advanced intermediate 94 after deprotection. The final steps led to the synthesis of 30 mg of 6-epi-dictyostatin.
Advisor:Dennis P. Curran; Peter Wipf; Paul Floreancig; Billy Day
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:06/16/2008