Stereodivergent Total Syntheses of (+)‐Mycaperoxides C, D, G Methyl Ester and (−)‐Mycaperoxide B**

Abstract

Mycaperoxides are natural endoperoxides isolated from different Mycale genus sponges, showing significant antiviral or antibacterial activities. We report herein the first total syntheses of representative congeners of this family from sclareol using a stereodivergent approach. Thus, an innovative oxidative ring expansion of cyclobutanol was used to bring the 1,2-dioxane subunit, and a Mukaiyama aldol reaction on peroxycarbenium species was utilized to install the propionic acid subunit. During the study toward (+)-mycaperoxide D methyl ester (2), the isolation of the eight possible diastereomers under their ethyl thioester form allowed to build a pertinent database for further NMR assignment studies. Thus, we completed the total syntheses of (+)-mycaperoxides D, C, G methyl ester, and (-)-mycaperoxide B in 11 to 15 steps, confirming their original assignment.

Mukaiyama aldol reaction: an effective asymmetric approach to access chiral natural products and their derivatives/analogues

“…Various researchers have attempted to describe the total synthesis of these naturally occurring endoperoxides, but a concise and efficient stereoselective route has not been developed yet. Thus, Kerim et al 103 in 2022 synthesized various members of the mycaperoxide class for the first time. The synthesis initiated with the generation of cyclopropylidene 187 by treating sclareol 186 over a number of steps.…”

Stereodivergent Total Synthesis of Ethyl Plakortide Z

“…We are currently involved in the development of methodologies to synthesize and functionalize endoperoxides and their application in the total synthesis of natural products. Recently, we have shown that 1,2-dioxanes are readily accessible through the ring-expansion of cyclobutanols and functionalized via a subsequent alkylation of the endoperoxyacetal. − We also demonstrated that this methodology was applicable in the total synthesis of 1,2-dioxane rings, such as mycaperoxides, enabling them to be accessed in a few steps . These successes interested us, and we set our sights on other subclasses of natural products such as plakortides.…”

“…15−17 We also demonstrated that this methodology was applicable in the total synthesis of 1,2-dioxane rings, such as mycaperoxides, enabling them to be accessed in a few steps. 18 These successes interested us, and we set our sights on other subclasses of natural products such as plakortides. One of the main challenges of this objective was introducing an ethyl group in the C 4 position.…”

“…Endoperoxyketal 2 could be obtained using our cyclobutanol ring-expansion technology. 15,18 The configuration of the ethyl group at the C 4 position of cyclobutanone 3 would be set up by the asymmetric alkylation of 4.…”

“…We also hoped that the C 6 diastereomers could be separated by chromatography to obtain a pure synthetic sample of 1 . Endoperoxyketal 2 could be obtained using our cyclobutanol ring-expansion technology. , The configuration of the ethyl group at the C 4 position of cyclobutanone 3 would be set up by the asymmetric alkylation of 4 .…”