Studies towards the total synthesis of mycapolyol e using iterative homologation of boronic esters Dylan Rigby, Sheenagh G. Aiken, 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 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 enantiopure metal carbenoid 2 , yielding an enantioenriched 1,3-bis boronic ester 3 , which bears a terminal alkene primed for subsequent iterations. Finally, stereospecific oxidation of the enantioenriched polyboronic ester provides the desired 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 polyketide metabolites that display cytotoxicity towards HeLa cells. These compounds bear 9-14 contiguous, stereodefined, skipped hydroxyl groups and are flanked by tetramic acid derived and formamide head-groups. Our retrosynthetic analysis of Mycapolyol E disconnects to three fragments of equal complexity, of which two would utilise our iterative strategy to set the 1,3-polyol stereocentres. The synthesis of these fragments, and their unification by regioselective homologation of primary boronic esters, has now been optimised. All that remains to complete the first synthesis of any member of the Mycapolyol family is downstream manipulations to install the tetramic acid derived head-group, where our efforts are currently focused. References 1. Fusetani, N. et al., Org. Lett. , 2005 , 7 , 2233. 2. Morken J. P. et al, J. Am. Chem. Soc. , 2009 , 131 , 13210. 3. Aggarwal, V. K. et al, Nat. Chem., 2023 , 15 , 248.
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