Kuwanol E (1) is a Diels-Alder adduct-type belonging to polyphenolic natural compound isolated from Morus alba1, Morus nigra2, and Sorocea ilicifolia3 plants. Previously, we showed as kuwanol E (1) is the most potent naturally occurring inhibitor of Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B reported so far (Ki = 1.6 ± 0.1 μM),4 a virulence factor secreted into the host cell by Mtb, and necessary for its survival. Thus, compound 1, is a good candidate as lead compound for the development of new antitubercular drugs. Herein we reported the convergent synthetical approach for the total synthesis of kuwanol E (1)5 via Diels-Alder reaction, a biomimetic intermolecular [4+2]-cycloaddition between stilbene-derived diene 3 and chalcone-derived dienophile 4. This key reaction permits the construction of a 6-membered monounsaturated ring, moreover, modulating the experimental conditions the regio- and stereochemical features of the products can be controlled. Compounds 3 and 4, required or the Diels-Alder reaction, have been synthesized in five and three steps, in 25% and 28% yield respectively. The cycloaddition between 3 and 4, promoted by Lewis acid catalysis, afforded the desired endo-kuwanol E heptamethyl ether (2), which has been deprotected to obtain kuwanol E (1) in 2% overall yield. Compounds 3 and 4, required or the Diels-Alder reaction, have been synthesized in five and three steps, in 25% and 28% yield respectively. The cycloaddition between 3 and 4, promoted by Lewis acid catalysis, afforded the desired endo-kuwanol E heptamethyl ether (2), which has been deprotected to obtain kuwanol E (1) in 2% overall yield.

Convergent total synthesis of (±)-kuwanol E

ACS Spring Meeting 2021

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