Total syntheses and synthesis-based structure elucidation of macrosphelides

ORGN 784

Jaebong Jang,, Hwayoung Yun,, Dong-Jo Chang,, Nam-Jung Kim,, Young Taek Han,, and Young-Ger Suh, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea
Ever since the first isolation and structural elucidation of macrosphelides in 1990s, these marine polyketides have attracted much interest from biologists because of their potent tumor-metastasis-suppressant and immunomodulating activities. In addition, their unique macrocyclic tri-ester skeleton with five stereogenic centers has also attracted interest from synthetic chemists.

In this connection, we have achieved highly efficient and convergent syntheses of macrosphelide A and B. The key feature of the syntheses includes efficient preparation of γ-keto-α,β-unsaturated acid fragment via a direct addition of trans-vinylogous ester anion equivalent to the readily available Weinreb amide. In particular, the facile construction of the 16-membered marcrolide core of the macrosphelide B was achieved by an intramolecular nitrile oxide-olefin cycloaddition (INOC), which provided excellent regio and streoselectivity.

We have also accomplished the first total syntheses of macrosphelides J and K from ethyl (S)-(-)-lactate in 15 steps using chiral sultam auxiliary. Thus, we extended our work to elucidate their structures, particularly the stereochemistries of five stereocenters.