I. The Asymmetric Total Synthesis of Apratoxin D II. Studies in the Gold(I)-Catalyzed Cycloisomerization of 7-Aryl-1,6-Enynes. III. Synthesis and Application of Multidentate Ligands Toward the Realization of Fluxional Mechanocatalysis

Abstract

Apratoxin D, recently isolated from two species of cyanobacteria, L. majuscula and L. sordida, exhibits highly potent in vitro cytotoxicity against H-­‐‑460 human lung cancer cells with an IC50 value of 2.6 nM. The potent biological activity exhibited by apratoxin D combined with its intriguing molecular architecture has led to the pursuit of its asymmetric total synthesis. Studies toward and completion of the first asymmetric total synthesis of apratoxin D are reported. Key transformations include a Kelly thiazoline formation, Paterson anti-­‐‑aldol and an Evans syn-­‐‑aldol. The synthesis was completed in 2.1% total yield over 31 steps from (R)-­‐‑citronellic acid.Cationic gold (I) complexes are highly efficient catalysts for the cycloisomerization of 1,6-­‐‑enynes, a transformation capable of providing a great amount of structural complexity from simple starting materials. The in situ spectroscopic analysis of the catalytic cycloisomerization of a 7-­‐‑phenyl-­‐‑1,6-­‐‑enyne, as well as the tandem gold/silver-­‐‑catalyzed cycloaddition/hydroarylation of 7-­‐‑aryl-­‐‑1,6-­‐‑enynes is described. The cycloaddition/hydroarylation reaction provides 6,6-­‐‑ diarylbicyclo[3.2.0]heptanes in good yield under mild conditions. Experimental observations point to a mechanism involving gold-­‐‑catalyzed cycloaddition followed by silver-­‐‑catalyzed hydroarylation of a bicyclo[3.2.0]hept-­‐‑1(7)-­‐‑ene intermediate.The control of bond scission and formation by mechanocatalysis has potential in a variety of applications, including biomedical devices, mechanical sensors and self-­‐‑6healing materials. The synthesis and study of C2-­‐‑symmetric bis(phosphine) ligands with applications toward mechanocatalysis is described. Additionally, the synthesis and study of a tetradentate ligand designed toward mechanochemical activation of a latent catalytic complex is reported. These studies have allowed further development in the design of transition metal complexes capable of activation by mechanical force.