UC San Diego
Total Synthesis of Lagunamide A via Remote Vinylogous Mukaiyama Aldol Reactions, Chemical Studies Toward the Total Synthesis of Micromide and Preliminary Studies Toward the Total Synthesis of Azaspirene
- Author(s): Banasik, Brent
- Advisor(s): Bergdahl, Mikael
- Molinski, Tadeusz
- et al.
Lagunamide A represents a class of novel cyclic depsipeptide obtained from the marine cyanobacterium Lyngbya majuscula. With an array of biological activity and impressive IC50 values including anti-malarial properties (IC50 0.19-0.91 μM), significant cytotoxic properties against P388 murine leukemia cell lines (IC50 6.4-20.5 nM) and ileocecal colon cancer (1.6 nM), lagunamide A shows promise as an extremely powerful therapeutic agent. Unexpectedly, in a recent total synthesis of lagunamide A an incorrectly assigned configuration of stereochemistry was reported. Moreover, natural lagunamide A was isolated in 0.00012% yield from 15 L (~169 g isolated dry, powdered weight) of the cyanobacterium laden sea grass via arduous processes, reaffirming the need for an economically robust total synthesis to further encourage biological study. In light of this information an efficient alternative total synthesis was proposed. Through this optimized approach the target molecule was synthesized in significantly higher overall yield and greater selectivity. Specifically, remote stereocontrol via two iterative vinylogous Mukaiyama aldol reactions (VMAR) lead to a formal total synthesis of the C27-C45 fragment in record yield. Solution and solid phase peptide coupling methodology to construct the C5-C26 fragment of lagunamide A was explored. An optimized convergent strategy lead to the synthesis of lagunamide A and unveiled interesting chemical studies on Kobayashi’s protocol for VMAR, specifically a detailed account of relative rate of reaction for (R) vs. (S)-α-substituted aldehyde additions, including an enantiomeric resolution of a small panel of α-substituted aldehydes and proposed transition states.
Micromide is a cytotoxic alkaloid anti-tumor agent (IC50: 260 nM against KB cells) isolated from Symploca cyanobateria. The focus of this research was to develop an efficient and convergent strategy for the total synthesis of micromide. Key synthetic manipulation involved N-methylation protocol, solution phase peptide coupling and asymmetric acetate aldol reactions. The reported configuration of micromide was not equivalent to that of synthetic micromide, even though LC-MS data demonstrated the correct molecular weight. Epi-micromide was synthesized in ~1% overall yield (103 mg) via solution phase methodology and 7.5% overall yield (50 mg) via solid support methodology. Computational analysis of the 13C NMR data hypothesized that inversion of C35 would reveal the corrected structure for micromide. Preliminary chemical studies towards an expedient synthesis of azaspirene, an effective angiogenesis inhibitor isolated from the soil fungus Neosartorya sp., are proposed from (+)-tartaric acid. An efficient synthetic pathway for theses bioactive molecules could ultimately lead to structural analogs for structure-activity relationship (SAR) studies against various cancer cell lines.