NMR revision: Compound all at sea

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  • Published: Apr 15, 2017
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: NMR revision: Compound all at sea

Time for revision

Photo of the marine Anomoianthella rubra from Garson paper in J Nat Prod, courtesy of American Chemical Society

Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool and throws up chemical structure insights for even the most complex of natural products. Sometimes, however, those spectral lines can lead chemists to the wrong stereocentres and skeletons. An international team has now revised the structure of an important marine metabolite.

The Acremonium genus of fungi are found on land and in the sea, they produce a wide range of metabolites and other natural products all of which increase the molecular diversity of known organic compounds, and include meroterpenoids, alkaloids, peptides, and oxygenated metabolites. Such substances have proven useful in drug discovery in the search for novel antibiotics, anticancer agents and other medicinal targets.

Mary Garson and Gregory Pierens of the University of Queensland, in Brisbane, Australia, Warren Hehre of Wavefunction Inc., in Irvine, California, USA, and Suciati of Airlangga University, in Surabaya, East Java, Indonesia, have taken a second look at one of these compounds. Recently, the team reported a stereochemical structural elucidation of the meroterpenoid acremine P from a particular strain of the fungus Acremonium persicinum which was found in the marine sponge Anomoianthella rubra, collected offshore of Mooloolaba in southeast Queensland.

Chemical shifts shifted

In their original paper, the team correlated the structure of acremine P with its co-metabolite acremine A using catalytic hydrogenation under mild conditions to help them construct the molecular skeleton and glean a partial relative configuration for acremine P. They were then able to obtain an absolute configuration at the potentially ambiguous C-6 carbon by NMR analysis of O-methylmandelate (MPA) ester derivatives of the compound. The use of NOESY (Nuclear Overhauser effect spectroscopy) then allowed them to pin down the other stereochemical elements with the help of molecular modelling and determination of pertinent heteronuclear coupling constant values.

Now, the team reports that a comparison of calculated and experimental NMR chemical shift data suggested a necessary revision to the structure, of which they provide details in the journal Molecules. They point out that, "The predictions of chemical shift values by quantum chemical methods have provided valuable insights into natural product structures, including guiding the choice of diastereomer for structure confirmation by total synthesis." It was thus the modelling work that informed their re-interpretation of the original NMR spectra and suggested that the original structure was not quite right. Indeed, their preliminary computational hunt for conformers of the compound showed a single dominant conformer existed and that the nearest alternative was much higher in energy. Not only that, the discrepancies between the calculated and experimental carbon-13 NMR chemical shifts were enormous; delta values deviating by between 20 and 24 ppm from predicted values for some carbon atoms in the structure. Deviations of 3 ppm in the shifts would perhaps be acceptable and reconcilable but not such large deviations.

Definitive structure

"The structural revision of acremine A likewise necessitated a review of its overall relative stereochemistry, and this was informed by nOe data as well as molecular modelling [density functional theory (DFT) calculations]," the team explains. With the revised structure in hand the team was also able to reconcile a putative biosynthetic pathway, namely an oxidative cleavage of a didehydro analogue of acremine Q with the actual chemistry.

The team alludes to an invaluable lesson or two having been learned in the process of revising this structure: "Our revision of the structure of acremine P illustrates the valuable role of computational studies in evaluating the structures and stereochemistry of stereochemically complex natural products," they say. "At the same time, a single piece of data in the original study, i.e., the suggested conversion of acremine P into acremine A by hydrogenation, compromised the structural study and thereby incorrectly informed the structure determination," the team concludes.

Related Links

Molecules 2017, 22, 521: "Revision of the Structure of Acremine P from a Marine-Derived Strain of Acremonium persicinum"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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