Structure Determination of a Chloroenyne from Laurencia majuscula Using Computational Methods and Total Synthesis.

Erin D Shepherd,William E Hak,Bryony S Dyson,Quynh Nhu N Nguyen,Te-Ik Sohn,Robert S Paton,Mi Jung Kim,Miseon Lee,Jonathan W Burton,Deukjoon Kim

doi:10.1021/acs.joc.8b02975

Abstract

Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.

Highlights

Elucidating the structures of natural products that are available only in very small quantities is often exceptionally difficult, highlighted by the high number of structure revisions reported every year in the chemical literature.[1]
We aimed to solve the complete stereostructure of this natural product using the combined approach which we had previously found successful, namely, biosynthetic postulates coupled with density functional theory (DFT) calculations of Nuclear magnetic resonance (NMR) chemical shifts and total synthesis
Merck Molecular Force Field (MMFF) geometries have been used in structure prediction,31c,33 DFT optimization allows for more confident structural assignment as there is a narrower distribution of errors with respect to experimental chemical shifts.16a,31c As an illustration, for 82 molecules with 709 experimentally assigned 13C chemical shifts, we verified that DFT optimizations led to a

Summary

Introduction

Elucidating the structures of natural products that are available only in very small quantities is often exceptionally difficult, highlighted by the high number of structure revisions reported every year in the chemical literature.[1]. NMR computations have been used to establish relative stereochemistry,[3] to confirm or reassign proposed natural product structures,[4] to characterize the identity of a side product,[5] and in conformational assignment of cyclic peptides.[6] this approach can become challenging for molecules containing multiple stereogenic centers and with a high degree of conformational flexibility. In such cases, weighted ensemble averages must be considered in comparison against experimentally observed NMR parameters. Flexible, halogenated natural products epitomize this challenge and have been variously misassigned.[9]

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