European Journal of Organic Chemistry
Volume 26, Issue 9 e202201316
Correspondence
Open Access

Structural Reassignment of Two Polyenol Natural Products

Prof. Andrei G. Kutateladze, 

Corresponding Author

Prof. Andrei G. Kutateladze

Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208 USA

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Prof. Roderick W. Bates, 

Corresponding Author

Prof. Roderick W. Bates

School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371 Singapore

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Prof. Mikhail Elyashberg, 

Corresponding Author

Prof. Mikhail Elyashberg

Advanced Chemistry Development Inc. (ACD/Labs), Toronto, ON, M5 C 1B5 Canada

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Prof. Craig M. Williams, 

Corresponding Author

Prof. Craig M. Williams

School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia

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First published: 03 February 2023
https://doi.org/10.1002/ejoc.202201316
Citations: 1

Graphical Abstract

Chemical principles together with CASE and DFT methods were used to reassign unusual polyenols as nucleosides.

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Abstract

Unusual polyenols that defied chemical principles were reassigned as the nucleosides, adenosine and uridine, using a combination of chemical intuition underpinned by Computer Assisted Structure Elucidation (CASE) and DFT methods.

Introduction

In 2016 Ma et al. reported the isolation of (5S,6R,7S,8R)-5-amino-(2Z,4Z)-1,2,3-trihydroxybuta-2,4-dienyloxy-pentane-6,7,8,9-tetraol (1) from the southeast Asian spice Murraya koenigii (L.) (Scheme 1).1 More recently, Siebatcheu et al. isolated 1, together with a related isomer, (Z)-5-amino-5-(1,1,2-trihydroxybuta-1,3-dienyloxy)pentane-6,7,8,9-tetraol (2), from an endophytic fungus, Trichoderma erinaceum (Scheme 1).2 These purported natural products were elucidated based on extensive spectroscopic methods (e.g., NMR, MS, UV, IR and CD), and were isolated as stable solid substances (i.e., colourless and white powders, respectively). From a structural perspective, however, both 1 and 2 contain multiple enol moieties, which would under normal chemical circumstances be expected to exist in the respective keto (carbonyl) tautomeric forms (Scheme 1). For example, 1 would be better represented as either 3 or 4 (and 2 as 7), and in both cases the hemiaminal ether moiety would also be considered quite sensitive to even mild acid (Scheme 1). The latter undergoing hydrolysis to give degradation products 5 and 6 (Scheme 1). Furthermore, stable enols are rare and exist only when stabilised in some form, while stable ene-diols are even rarer with ascorbic acid (vitamin C) being one of a very few. Therefore, based on these chemical principles it was suspected that a potential structure misassignment had occurred in both cases (i.e., 1 and 2).

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Scheme 1
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A) and B) Suspected misassigned natural products 1 and 2 highlighted in red, and associated keto tautomers (3, 4 and 7); hemiaminal ether (highlighted in green) degradation products 5 and 6.

Throughout the history of natural product elucidation misassigned (incorrectly assigned) chemical structure has been well noted and reviewed.3-7 In most occurrences these errors are understandable given the complexity associated with determining the chemical identity of natural products, and the extensive demands on interpreting spectroscopic information involved in modern elucidation.8 However, with the advent of computing, practitioners soon developed computer-assisted structural elucidation (CASE)9 to assist in combating potential errors that can eventuate with subjective interpretation using classical elucidation methods.10 A subsequent evolution occurred when CASE was combined with DFT which substantially improved structural resolving power.11

We have previously witnessed success in reassigning a range of natural products,12 using the combination of ACD/Structure Elucidator (ACD/SE)13 and a hybrid DFT-parametric computational method, DU8+,14, 15 and herein apply a mixture of these methods and chemical principles to address the proposed structures 1 and 2.

The reassessment of 1 was initially approached by inspecting the non-controversial moiety of the molecule, which in this case was the carbohydrate fragment (righthand fragment) concerning carbons C6-C9. All four carbon chemical shift values were in the range (δc 75.5, 72.7, 88.2, 63.5 ppm) matching that expected for hydroxylated sp3 carbon atoms. The hemiaminal ether at C5 would also be expected to resonate in the recorded region (i.e., δc 91.3 ppm) and was reinforced by the observed HSQC correlations. However, closer inspection of the 13C NMR spectra revealed an additional resonance at ∼121 ppm. Therefore, attention was then focussed on the reported molecular formula i.e., C9H17NO8 (m/z 290.0853 [M+Na]+, calcd. for 290.0846), which contained an unusually high number of hydrogen atoms. Conversely, the observed value of m/z 290.0853 was also in agreement with a molecular formula consistent with C10H13N5O4 (calcd. for m/z 290.0860[M+Na]+), which caters for an additional carbon atom. Considering that the new molecular formula also indicated the presence of four additional nitrogen atoms, and that purine bases are often associated with carbohydrate moieties, it was conceivable that a nucleoside had been isolated. Consequently, the 1D and 2D NMR data, along with the molecular formula, was entered into ACDLabs Structure Elucidator (ACD/SE), which suggested adenosine (8) or a stereochemical isomer thereof (Figure 1). DU8ML,15 the DFT empowered NMR chemical shift and coupling constant prediction tool enabled with machine learning capability, confirmed the suspicion of adenosine (8), which was subsequently proven beyond doubt through direct 1H and 13C NMR comparison to commercial material (see Supporting Information).

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Figure 1
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The atom numbered structures of adenosine (8) and uridine (9).

Having deduced the presence of nucleosides, focus was then turned to assessment of 2. Evaluation of the HRMS-ESI spectrum for 2 revealed two peaks.2 The major closely matched the molecular formula previously seen for adenosine (8) [i.e. C10H13N5O4 (m/z 268.1041 [M+H]+, calcd. for 268.1046)], and the minor was observed at m/z 245.0769. Therefore, assuming the minor ion was also a [M+1] peak, a molecular formula of C9H13N2O6 (calcd. for 245.0774) could be generated. With these developments in hand, the combined functions of ACDLabs Structure Elucidator (ACD/SE) and DU8ML were deployed, which afforded uridine (9) as a potential candidate. Subsequent comparison to literature NMR data16 confirmed the identity of uridine (9) (Figure 1).

Conclusion

In conclusion, the reassignment of compound 1 as adenosine (8), and compound 2 as uridine (9), was achieved and proven unequivocally. Concerns with the reported structures of 1 and 2 were raised through chemical principle analysis, and subsequent structural revisions were undertaken using a combination of chemical intuition supported by CASE and DFT methods.

Acknowledgments

We thank the University of Denver, the University of Queensland, and Nanyang Technological University for financial support, along with Advanced Chemistry Development, Inc. (ACDLabs). The Australian Research Council for funding to C.M.W. (FT110100851). A.G.K. thanks the US National Science Foundation (CHE-1955892) for support. Open Access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians.

    Conflict of interest

    The authors declare no conflict of interest.

    Data Availability Statement

    Supporting data containing ACD Elucidator structure generations, DU8ML Cartesian co-ordinates and NMR spectra are available in the Supporting Information of this article.