Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

Bhuwan Khatri Chhetri,Kerstin Gagaring,Anne Marie Sweeney-Jones,Katy Soapi,Nazia Mojib,Vijay Raghavan,Cassandra L Quave,Julia Kubanek,Brandon Dale,Case W Mcnamara,Prasad L Polavarapu,Serge Lavoie

doi:10.1021/acs.joc.9b00884

Abstract

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A–B (1–2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.

Highlights

Diterpene glycosides and natural products with cyclopropane rings are each reported frequently, molecules with highly substituted cyclopropanes embedded in a complex polycyclic system are rare.[3,4]
We turned to rotating frame Overhauser effect spectroscopy (ROESY) NMR spectroscopy again, envisioning that the multiple ROESY cross-peaks observed between the sugar and diterpene could, if quantified as interproton distances, be compared with calculated interproton distances obtained from a Boltzmann population of conformers for the two diastereomers, which could reveal the absolute configuration
Molecular mechanics force fields (MMFF)-based conformational search[15,16] and final structural optimization with density functional theory (DFT) calculations at the B3LYP/6-311++G(2d,2p) level[17] using a polarizable continuum model (PCM)[18] to represent DMSO as the solvent, gave five conformations for each of the two possible diastereomers of 1.19 overlaid conformations of each diastereomer were very similar, with differences primarily observed in the orientation of glycosidic hydroxyls

Summary

■ INTRODUCTION

Diterpenoids including diterpene glycosides are one of the most widely distributed and structurally diverse groups of compounds.[1,2] diterpene glycosides and natural products with cyclopropane rings are each reported frequently, molecules with highly substituted cyclopropanes embedded in a complex polycyclic system are rare.[3,4] Their structural novelty and bioactivity is valuable for medicinal chemistry, biosynthetic studies, computational studies, and encourage the development of new synthetic methods.[5]. The structural elucidation of natural products is an inverse problem, where all solutions besides the most logical one must be carefully ruled out based on observations made from empirical data.[11] it is imperative that conclusions derived in each step of the process be supported with multiple analytical or computational tools. Along these lines, we have undertaken a systematic multifaceted approach, wherein the planar structure, relative and absolute configuration, as determined with extensive NMR-based methods, were sequentially supported with computer-assisted structure elucidation (CASE), density functional theory (DFT)-based prediction of 13C chemical shifts, and simulation of experimental ORD data (Figure 1)

■ RESULT AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES