Derek Tan: Diversity-Oriented Synthesis of Polyketides

diversity oriented synthesis, rational drug design, and chemical biology research Enlarge Image Polyketide Diversity in Biologically Active Natural Products

Polyketides exhibit an impressive range of biological activities. Examples from the anti-cancer arena include discodermolide, a microtubule stabilizer, and trichostatin, a histone deacetylase inhibitor. Despite being derived biosynthetically from reiterative couplings of just two primary building blocks, malonyl-CoA and methylmalonyl-CoA, polyketides undergo a variety of post-coupling modification reactions that generate enhanced structural diversity. The resulting combinations of stereochemical features, functional groups, and cyclic constraints then enforce diverse three-dimensional conformations.

Diversity-oriented synthesis of polyketides remains a major challenge. While the reiterative coupling/post-coupling modification approach is effective in the biosynthetic setting, this strategy is difficult to emulate in chemical synthesis, since the length of the resulting synthetic scheme quickly becomes intractable in the laboratory. Moreover, previous approaches have focused primarily on stereochemical aspects of the polypropionate subclass, with little attention to accessing other backbone modifications.

To address this challenge, we have developed a unified approach to the diversity-oriented synthesis of linear polyketides that provides efficient access to complex molecules with a wide range of polyketide motifs. This synthesis exploits both stereochemical and functional group diversity to provide conformationally diverse polyketide products.

Publications

  1. A unified synthetic approach to polyketides having both skeletal and stereochemical diversity.
    Shang, S.; Iwadare, H.; Macks, D. E.; Ambrosini, L. M.; Tan, D. S.* Org. Lett. 2007, 9, 1895–1898.
    Abstract | PubMed | PMC ]

  2. An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis.
    DiBlasi, C. M.; Macks, D. E.; Tan, D. S.* Org. Lett. 2005, 7, 1777–1780.
    Abstract | PubMed ]
    (Highlighted in Lett. Org. Chem. [PDF] )