Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship

Abstract

The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.

Figure 1.

(a) Originally reported structures of representative members of the sesquiterpene-tropolones belonging to the pycnidione and eupenifeldin series. (b) Biosynthetic proposal for pycnidione series. (c) Prior key synthetic studies. (d) Biosynthetic studies of epolone B (4′).

Figure 2.

Retrosynthetic analysis of pycnidione (1′), dehydroxypycnidione (2′), and epolone B (4′).

Figure 3.

Preparation of HDA cycloaddition partners. (a) Synthesis of tropolones 19 and 20. (b) Synthesis of 10-hydroxy-α-humulene (11).

Figure 4.

(a) HDA cycloaddition studies involving α-humulene (12) and synthesis of dehydroxypycnidione (2′). (b) Optimized geometry of 2′ and (c and d) scatter plots of predicted ¹³C NMR shifts of 2′ as compared to both observed diastereoisomers. Insets correspond to error distributions. Diagonal dashed line: y = x.

Figure 5.

(a) HDA cycloaddition studies involving (−)-10-hydroxyhumulene (11) and synthesis of (+)-isoepolone B (ent-16) and (−)-epolone B (ent-4). (b) Computed transition state (TS) energies for the reaction of 11 and 20 to form 46 and 47. (c) Computed TS energies for the reaction of 20 and 46. (d) Computed TS energies for the reaction of 20 and 47. Calculations with ωB97X-D-CPCM(Mesitylene)/def2-QZVPP//ωB97X-D/6–31G(d).

Figure 6.

(a) Structural reinvestigation of authentic sample of (+)-pycnidione (1). (b) TD-DFT/ωB97X/def2-TZVP electronic transitions, plotted with UV/vis intensities (green lines). (c) TD-DFT transitions plotted with ECD intensities.

Figure 7.

Updated (bio)synthetic pathways of pycnidione series.