Proposed are the total syntheses of the natural products Y W3548 and Y W3699, potent inhibitors of cellular glycophosphatidylinositol (GPI)-anchoring. GPI-anchoring is a biochemical process for covalently attaching proteins onto cell surfaces, whose species-specific inhibition is sought as a means for developing anti-parasitic drugs. We propose herein divergent syntheses of these natural products that highlight a novel application of the Ni(ll)/Cr(ll)-mediated coupling reaction with enolizable and highly electrophilic vicinal tricarbonyl substrates. This application will permit the concise assembly of the tetracyclic skeletons of YW3548 and YW3699, by the stereospecific intramolecular coupling of the respective vinyl iodide and vicinal tricarbonyl functionalities to form their central oxocene rings. The brevity of the proposed syntheses depends on the procurement of most stereocenters with the advantageous employment of thermodynamic and kinetic conditions. In this manner, all but one (Cl of YW3548) stereogenic center of natural products are derived from the amplification of one stereocenter present in (+)-carvone. The realization of the proposed syntheses would promote the elucidation of GPI-biosynthesis that is necessary for the design of new anti-parasitic drugs to combat the observed drug resistance among virulent parasites.
| Wan, Zhao-Kui; Choi, Hyeong-Wook; Kang, Fu-An et al. (2002) Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: stoichiometric process. Org Lett 4:4431-4 |
| Choi, Hyeong-Wook; Nakajima, Katsumasa; Demeke, Damtew et al. (2002) Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: catalytic process. Org Lett 4:4435-8 |
