Asymmetric Total Synthesis of Heronamides A–C: Stereochemical Confirmation and Impact of Long‐Range Stereochemical Communication on the Biological Activity

Abstract

Heronamides are biosynthetically related metabolites isolated from marine-derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as-yet-unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure-activity relationship of synthetic and natural heronamides revealed the importance of both long-range stereochemical communication and the 20-membered macrolactam ring for the biological activity of these compounds.

Marine natural products

“…63) along with the known and related rifamycin congeners salinisporamycin, 92 and salinketals A and B, 93 were reported. Other total syntheses of marine bacterial metabolites include (AE)-spiroindimicins B and C, 94 bacilosarcin C, 95 cyclomarins A 96 and D, 97 cyclomarazines A and B, 98 nitropyrrolins A, B and D, 99 actinophenanthroline A, 100,101 jiolide A, 102 heronamides A-C, 103 dermacozines A-C. 104 The proposed chemical structure of marineosin A was also successfully synthesised; the structure of the target compound was established following X-ray data analysis. 105 While the NMR data of the synthetic compound showed a high degree of similarity with the previously reported natural product, there were also noticeable differences.…”

Stereochemical Assignment and Biological Evaluation of BE-14106 Unveils the Importance of One Acetate Unit for the Antifungal Activity of Polyene Macrolactams

“…4,14 As expected, BE-14106 was converted to a tetracyclic compound 6 after 14 days' incubation in DMSO at 40°C, although the yield was moderate (37% brsm). The NMR spectra closely resembled those of heronamide A except for the absence of two olefinic proton and carbon signals.…”

“…This is not surprising since heronamides A and B ( Figure S1) also significantly decreased their activities (not active at 100 and 50 μM, respectively). 14 In this report, we unambiguously determined the absolute stereochemistry of BE-14106 (1) and unveiled the importance of the hydrocarbon chain for the potent activity. The absolute stereochemistry of BE-14106 (1) was the same as heronamides.…”

“…4, 14 We examined the activity of BE-14106 (1) to find that the MIC value was 0.50 μM (0.21 μg/mL), which was 4 times less potent than heronamide C (3) (Figure 3a). To investigate whether BE-14106 (1) and heronamide C (3) share their mode of action, we examined the morphological changes of yeast cells after compound treatment (Figure 3b).…”

Stereopermutation on the Putative Structure of the Marine Natural Product Mucosin

“…In this sense, arachidonic acid ( 3 ) provides a link between mucosin and the prostanoid scaffold, pointing towards a possible mechanism. Yet, for the majority of examples found, the annulation produces a trans -1,2-disubstituted cyclopentane ring [ 89 , 90 , 91 , 92 , 93 , 94 ].…”