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

Abstract

As promising antifungal agents, the eight stereoisomers of eushearilide, including the natural compound, were synthesized relying on an asymmetric Mukaiyama aldol reaction, Julia-Kocienski olefination, and Shiina macrolactonization. Moreover, their in vitro antimicrobial activities against some fungi and bacteria were evaluated by the disk-diffusion method, which revealed that not only natural eushearilide but also its stereoisomers exhibited significant antimicrobial activity against a variety of 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

“…A β-hydroxy carboxylic acid moiety of the ring-closure precursor 5 could be synthesized by the asymmetric Mukaiyama aldol reaction [16,17,18] of aldehyde 6 with enol silyl ether. The ( E )-alkene moiety at the C14 position of aldehyde 6 could be synthesized using the Julia–Kocienski olefination [19,20,21] between the known sulfone 7 and aldehyde 8 [9], both of which may be easily prepared through conventional transformations from commercially available products.…”

“…The above describes the synthesis of the novel eushearilide congener, (3 S ,16 E ,20 E )- 3 (I deriv ), and eight known stereoisomers of eushearilide [9], (16 Z ,20 E )- 1 ( B , G , C , H ) and (16 E ,20 E )- 2 ( D , A , E , F ), each of which has different configurations corresponding to two stereogenic centers (C3, C23) and the double bond geometry (C16–C17). This preparation is shown in Figure 2.…”

“…The antimicrobial activities of the eushearilide congeners A – H [9] and I deriv against fungi are shown in Figure 3. Although no breakpoint was determined, eushearilide congeners G and C exhibited relatively low minimum inhibitory concentration (MIC) against C. albicans .…”

“…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.…”

“…On the basis of synthetic methodology, a novel eushearilide derivative, 23-demethyleushearilide ( 3 ), was synthesized to investigate the effects on antimicrobial activity of the methyl substituent at the C23 carbon of eushearilide. We report herein the synthesis of compound 3 and the preparation of known structural congeners of eushearilide [9], whose antimicrobial activity against a wide spectrum of fungi and bacteria was also evaluated in detail.…”