Enantioselective total synthesis of naturally occurring eushearilide and evaluation of its antifungal activity

Abstract

The asymmetric total synthesis of a newly proposed structure of (3S,16E,20E,23S)-(+)-eushearilide was achieved primarily through an asymmetric Mukaiyama aldol reaction, Schlosser-modified Wittig reaction and 2-methyl-6-nitrobenzoic anhydride-mediated macrolactonization. Based on detailed spectroscopic analyses, the obtained synthetic compound was found to be identical to natural eushearilide. Therefore, we were able to determine the true structure of eushearilide. Moreover, the synthetic compound was found to exhibit significant in vitro antifungal activity against various fungi and bacteria.

Total Synthesis and Antimicrobial Evaluation of 23-Demethyleushearilide and Extensive Antimicrobial Evaluation of All Synthetic Stereoisomers of (16Z,20E)-Eushearilide and (16E,20E)-Eushearilide

“…From the results of detailed NMR analyses of these compounds, it was found that natural eushearilide comprises a (16 E ,20 E ) configuration (as shown in eushearilide ( 2 )) and not a (16 Z ,20 E ) configuration of the nonconjugated diene moiety at the C16 and C20 carbons. Thus, we addressed and first accomplished the total synthesis of naturally occurring eushearilide, (3 S ,16 E ,20 E ,23 S )-(+)- 2 [8]. Moreover, in order to improve the yield and reduce the number of steps in the synthetic process, we thoroughly revised our previous method of synthesis, as shown in Scheme 1 [9], enabling us to obtain a sufficient amount of eushearilide derivatives for structure–activity relationship (SAR) studies.…”

Total Synthesis and Antimicrobial Activities of All Stereoisomers of (16Z,20E)-Eushearilide and (16E,20E)-Eushearilide

“…First, the synthetic route to the desired seco acid is depicted in Scheme . When aldehyde 3 , which was prepared by conventional oxidation of primary alkenyl alcohol 2 , was subjected to Julia–Kocienski olefination with 5-methanesulfonyl-1-phenyl-1 H -tetrazole 4 and potassium hexamethyldisilazide at −78 °C, the desired diene 5 was obtained in a high yield with a very high stereoselectivity (90%, E / Z = 93/7). The geometry of the C8–C9 alkene in 5 was determined to be E on the basis of the downfield shifts of the allylic carbons (δ C 32.6 [C7] and δ C 32.6 [C10]), while the Z -configured alkene of the C8–C9 double bond was determined from the upfield shifts of the allylic carbons (δ C 27.3 [C7] and δ C 27.2 [C10]) .…”

“…On the other hand, the relative and absolute configuration at the C3 and C23 chiral centers of eushearilide was not known before our synthesis. Therefore, we initiated a project aimed at the total synthesis of eushearilide so as to clarify the absolute stereochemistry of the natural product and to promote studies of its structure–activity relationship (SAR). , Thus, we have recently achieved enantioselective total synthesis of (3 S ,16 E ,20 E ,23 S )-(+)- 1 , the naturally occurring eushearilide, as shown in Figure , which is found to exhibit significant antimicrobial activity against a variety of fungi and bacteria …”

Enhancing the Discovery of Bioactive Secondary Metabolites From Fungal Endophytes Using Chemical Elicitation and Variation of Fermentation Media

“…In summary, none of the six isolated compounds exhibited better antimicrobial activities than the commercial compounds used as standards in the study. Since the discovery of eushearilide some years back from the E. shearii , only total synthesis of the compound and its various stereoisomers and/or related compounds have been reported ( Tonoi et al, 2016 , 2019 ). This, therefore, is the second time that this class of compounds is being reported from nature.…”