Towards the total synthesis of Mycapolyol E Sheenagh G. Aiken, Dylan Rigby, Daniele Fiorito, Joseph M. Bateman, Adam Noble, Varinder K. Aggarwal* School of Chemistry, University of Bristol, UK
Polyketides are arguably the most important class of natural products, given their extensive application as small-molecule drugs. Due to their assembly-line like biosynthesis from small repeating building blocks, these compounds often possess repeating motifs. This is true for polyacetates, a sub-class of polyketides, which display repeating 1,3-hydroxyl stereocentres. Our research group recently reported a two-step iterative strategy for the rapid synthesis of stereodefined 1,3-polyol motifs. This strategy harnesses platinum catalysed, asymmetric diboration of terminal alkenes, furnishing an enantioenriched 1,2- bis boronic ester 1 . This is then followed by a regioselective homologation of the primary boronic ester with an enantiopure butenyl metallated carbenoid 2 , yielding an enantioenriched 1,3- bis boronic ester 3 which bears a terminal alkene primed for subsequent iterations. A final stereospecific oxidation of the enantioenriched polyboronic ester provides the desired stereodefined 1,3-polyol motif. We now aim to apply this methodology towards the first total synthesis of Mycapolyol E, a member of a family of linear polyketide metabolites that display cytotoxicity towards HeLa cells. Notably, these compounds bear 9-14 contiguous, stereodefined, skipped hydroxyl groups. Other key structural characteristics are the formamide and tetramic acid derived head groups that flank these molecules. Our retrosynthetic analysis of Mycapolyol E disconnects to three fragments of near equal complexity, of which two would utilise our iterative strategy to set 8 of the 10 1,3-hydroxylstereocentres. Fragment unification by regioselective homologation of primary boronic esters would then set the remaining 2 hydroxyl stereocentres. The synthesis of these fragments, and their unification, has now been optimised. Current work focuses on the remaining downstream manipulations to install the tetramic acid derived head-group. Following this, global deprotection would complete the first total synthesis of any member of the Mycapolyol family. References 1. Phuwapraisirisan, P., Matsunaga, S., and Fusetani, N.*, Org. Lett. 2005 , 7 , 2233. 2. Kliman, L. T., Mlynarski, S. N., and Morken, J. P.*, J. Am. Chem. Soc. 2009 , 131 , 37 , 13210. 3. Aiken, S. G., Bateman, J. M., Liao, H. H., Fawcett, A., Bootwicha, T., Vincetti, P., Myers, E. L., Noble, A., Aggarwal, V. K.*, Nat. Chem. 2023 , 15 , 248.
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