Studies toward a total synthesis of the aplyronines

ORGN 639

L. Y. W. Lee,, S. J. Atkinson, S. J. Fink, S. B. Blakey, and Ian Paterson, University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
Aplyronine A (1), first isolated in 1993 from the Japanese sea hare Aplysia kurodai by Yamada and co-workers, is a 24-membered macrolide that displays potent cytotoxicities against a range of implanted cancer cell lines and impressive actin-binding properties. In addition to the medicinal potential that aplyronine A possesses, the challenging structural complexity of the natural product has inspired synthetic studies within our group. Herein, we detail our efforts towards a total synthesis of aplyronine A, of which our strategy is based on the introduction of the (E)-trisubstituted double bond with a highly selective Horner-Wadsworth-Emmons reaction, a Yamaguchi lactonisation followed by a late stage incorporation of the C28-C34 side chain via a boron-mediated aldol reaction. Having already accessed an advanced intermediate for the macrolide, the envisaged end game would involve the installation of the amino acid residues and global desilylation of the alcohol moieties. Together with the recent advancement of our understanding towards the pharmacological properties of aplyronine A, our strategy could be tailored to allow various target-specific analogues to be synthesised for further biological investigations.