Total Synthesis of seco-Plakortolide E and (−)-ent-Plakortolide I: Absolute Configurational Revision of Natural Plakortolide I

Abstract

A first total synthesis of (-)-ent-plakortolide I and seco-plakortolide E was accomplished from (S)-2-methylglycidol. The relevant key reactions involve a diastereoselective Mukaiyama aldol reaction, a regioselective hydroperoxysilylation, and elaboration of the 1,2-dioxane ring by intramolecular Michael addition of a hydroperoxide group to a butenolide. This synthesis allowed the revision of the absolute configuration of plakortolide I and structural revision of plakortolide E.

Peroxy natural products

“…7 The first total synthesis of seco-plakortolide E also supported the structural revision of plakortolide E. 8 Continuing investigation of the same sponge, P. clathrata, afforded an additional set of 16 plakortolide metabolites 10-25. 9 A Jamaican collection of Plakinastrella onkodes yielded two cyclic peroxides, plakortolide F 26 and plakortolide G 27.…”

“…11 Two 1,2-dioxane peroxylactones, plakortolides H and I 29 and 30, have been isolated from a Madagascar specimen of Plakortis aff simplex, both of which were cytotoxic against a range of human tumour cell lines. 12 Several years later, the relative and absolute configurations of plakortolide I were revised on the basis of synthetic studies and reassignment of the NMR data, 8,13 thereby establishing that the metabolite isolated was ent-plakortolide I 31. Whilst the trivial name plakortolide I has been proposed for an unnamed plakortolide metabolite 32 from the Philippine Sponge Plakinastrella sp., whose absolute stereochemistry was determined by application of Mosher's method to a derivative.…”

Advances in the synthesis of acyclic peroxides

“…Subsequent DIBAL-mediated reduction of the lactone, followed by addition of excess trimethylsilyl triate resulted in simultaneous deprotection of the peroxide group and cyclisation to the target cycloperoxides. Similar synthetic strategies have been employed by Vatèle in the rst total synthesis of seco-plakortolide E and (À)-ent-plakortide I 18 and for the total synthesis of andavadoic acid, a naturally occurring ve-membered ring peroxide. 19 Isayama demonstrated that the combination of Co(acac) 2 and TBHP efficiently promoted the peroxidation of a,b-unsaturated carboxylic acids and esters (Table 5).…”

“…This included Baylis-Hillman products bearing O-protected groups (entries 8-10). A range of aldehyde substrates were also tolerated including aromatic (entries 11-15), heteroaromatic (entries [16][17][18] and aliphatic aldehydes (entry 19). The transformation of formamides (entry 20) was similarly successful.…”

“…While cyclopentane was tolerated in place of cyclohexane (entry 12), the use of cyclooctane resulted in the formation of an unwanted cycloalkylated a-hydroxy product. This methodology was further expanded to include ester-substituted coumarins (entries [13][14][15][16][17][18][19][20].…”