Synthesis of Key Fragments Contained in the Framework of Amphidinol 3
Amphidinol 3 was isolated from the marine dinoflagellate Amphidinium Klebsii found off the shores of Kanagawa, Japan. Structurally, amphidinol 3 (AM3) features a skipped northern polyene chain, a highly oxygenated central THP core, and a southern polyol chain containing a series of 1,5 diols. The 67-carbon backbone houses a total of 25 stereogenic centers and 8 (E) olefins.
Biologically, AM3 has the highest activity of the known 15 isolated members of the amphidinol family and possesses antifungal and hemolytic activities. Comparison to two other potent polyene antiobiotics, amphotocerin B (AmB) and filipin III, proved that AM3 exhibited both channel-type and damage-type hemolytic properties. Furthermore, the pore size created by AM3 in a cell membrane resembles that of cationic amine natural products of which AM3 shares virtually no similar defining structural characteristics.
The synthesis of the C1-C30 irregular polyol domain of AM3 was accomplished using the pathway originally developed by Chang with strategic optimization and alteration of the route. The readily available D and L-malic acids were utilized to construct large portions of the polyol chain and highly stereoselective methods were used
to elaborate these fragments. The coupling of the polyol components took place using the highly efficient Julia-Kocienski olefination to form the fully protected backbone.
The highly oxygenated C31-C52 central core of AM3 was synthesized from two THP fragments that were coupled via the Nozaki-Hiyama-Kishi reaction. The construction of the THP fragments was realized through a central intermediate in order to take advantage of the partial symmetry of the molecule. The readily available D-ribose served as a means for assembling the common intermediate.
After synthesis of the C53-C67 skipped polyene chain, the three major fragments of AM3 were completed. The union of these fragments via the highly selective Julia- Kocienski olefination to form the fully protected version of AM3 was explored with ultimate assembly of the C31-C67 fragment. Progress toward the complete total synthesis of this unique marine polyketide will also be reported.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:amphidinol 3 julia kocienski olefination polyene marine polyketide
Date of Publication:01/01/2008