Accessing Natural Product Scaffolds; A Top-Down and Bottom-Up Approach
Natural products, and natural product derivatives, have applications in both total synthesis and synthetic methodology, as well as having medical applications. Whilst many natural products possess suitable activity against therapeutically relevant targets, they often do not have the physiochemical properties which are essential for a clinically useful drug. Two ways to employ synthetic methods to make natural product analogues, and identify potential pharmaceuticals include: a “top-down” approach where a natural product is truncated to retain moieties necessary for biological activity; or, working towards a privileged natural product scaffold from the “bottom-up”, in the hopes of obtaining or increasing biological activity. The top-down approach involved the truncation of brefeldin A, a natural product with anti-cancer and antimicrobial activity. This was achieved through a transesterification and subsequent dihydroxylation/periodate cleavage. Unfortunately, due to the lability of the protecting groups, we were unable to reach our final synthetic target for biological testing. However, we are hopeful the utilisation of a different protecting group will alleviate this problem in the future.The bottom-up approach involved exploration of a new intramolecular Tsuji-Trost reaction, and applying this methodology to the synthesis of the chromone scaffold along with the scaffold of xyloketal H, a natural product which exhibits antioxidant and neuroprotective properties. Exploring the scope of the reaction revealed electron-withdrawing substituents produced the corresponding chromone faster than electron- neutral/donating substrates, presumably due to the increased electrophilicity of the carbonyl group. 15 new 2-allyl-1,3-diketones were produced, along with 8 new chromone species. Of note was a lactol formation and subsequent oxa-Michael addition to afford the xyloketal H scaffold in good yields.
Advisor: Hawkins, Bill
Degree Name: Master of Science
Degree Discipline: Chemistry
Publisher: University of Otago
Keywords: Natural Products; Synthesis; Organic; Chemistry; Scaffolds
Research Type: Thesis