Year: 2023
Type: article
Abstract: The hicksoane alkaloids contain an unusual propane-2,2-diamine unit embedded within a 1,3,6-triazocane, the only natural product known to possess this eight-membered heterocycle. Herein, we report the results examining a biosynthesis proposal that this heterocycle emerges from a late-stage reaction of a dipeptide with acetone. Ile-Trp-CONH2 and Trp-Ile-CONH2 dipeptides were trialled as substrates; in both cases, the intermediate iminium ion did not engage with the primary amide to form the triazocane, reacting instead to generate an imidazolidinone and a β-carboline, respectively. The results from this study infer the triazocane present in these alkaloids is unlikely to be biosynthesised by the late-stage reaction of a dipeptide with biogenic acetone. The isolation of the hicksoane alkaloids from the Gorgonian Subergorgia hicksoni was reported in 2004 [[1]Řezanka T. Hanuš L.O. Dembitsky V.M. Sigler K. Eur. J. Org. Chem. 2008; 7: 1265-1270Crossref Scopus (18) Google Scholar] (Fig. 1). These alkaloids are structurally intriguing for a number of reasons – the presence of a (di)iodinated tryptophan [[2]Wang L. Zhou X. Fredimoses M. Liao S. Liu Y. RSC Adv. 2014; 4: 57350-57376Crossref Google Scholar], an unusual propane-1,2-diamine unit embedded within a 1,3,6-triazocane (the only natural product known to possess this eight-membered heterocycle) [[3]Lee S. Sperry J. Bioorg. Med. Chem. 2022; 54116560Crossref Scopus (8) Google Scholar] and biogenesis from unnatural amino acids (d-tryptophan and D-allo-isoleucine). We recently disclosed our efforts to assemble the unique triazocane present in the hickosanes by lactamisation of the (tryptophanoamido)methylgycinate 1, which unexpectedly led to the formation of a (tryptophyl)imidazolidin-4-one 2, a rare imidazopyrido [3,4-b]indolone 3 and a β-carboline 4 [[4]Lee S. Söhnel T. Sperry J. Org. Biomol. Chem. 2023; https://doi.org/10.1039/D3OB01596CCrossref Google Scholar] (Scheme 1). Alongside this lactamisation study, an alternative approach was pursued, the details of which are described herein. The hicksoane triazocane contains a propane-2,2-diamine unit; this motif is rare in natural products, with some being known artefacts emanating upon reaction with acetone during isolation/purification [5Koshino S. Koshino H. Matsuura N. Kobinata K. Onose R. Isono K. Osada H. J. Antibiot. (Tokyo). 1995; 48: 185-187Crossref PubMed Scopus (15) Google Scholar, 6Abdel-Kader M. Berger J.M. Slebodnick C. Hoch J. Malone S. Wisse J.H. Werkhoven M.C.M. Mamber S. Kingston D.G.I. J. Nat. Prod. 2002; 65: 11-15Crossref PubMed Scopus (43) Google Scholar, 7Son S. Ko S.-K. Kim S.M. Kim E. Kim G.S. Lee B. Ryoo I.-J. Kim W.-G. Lee J.-S. Hong Y.-S. Jang J.-H. Ahn J.S. J. Nat. Prod. 2018; 81: 2462-2469Crossref PubMed Scopus (10) Google Scholar] while for others the biosynthetic origin is not understood [8Wang L. Wang S. Yang S. Guo X. Lou H. Ren D. Phytochemistry. 2012; 82: 166-171Crossref PubMed Scopus (23) Google Scholar, 9Liu S. Han X. Jiang Z. Wu G. Hu X. You X. Jiang J. Zhang Y. Sun C. J. Antibiot. (Tokyo). 2016; 69: 769-772Crossref PubMed Scopus (17) Google Scholar, 10Wu J. Zhang B.-J. Xiao W.-N. Bao M.-F. Cai X.-H. RSC Adv. 2017; 7: 51245-51251Crossref Google Scholar, 11Yan J.-X. Chevrette M.G. Braun D.R. Harper M.K. Currie C.R. Bugni T.S. Org. Lett. 2019; 21: 6275-6279Crossref PubMed Scopus (14) Google Scholar]. In principle, the propane-2,2-diamine motif could emerge from acetone that is unnatural (derived from solvent) or biogenic (derived from decarboxylation of acetoacetate) [[12]Nemecek-Marshall M. Wojciechowski C. Kuzma J. Silver G.M. Fall R. Appl. Environ. Microbiol. 1995; 61: 44-47Crossref PubMed Scopus (40) Google Scholar,[13]Beale R. Dixon J. Arnold S. Liss P. Nightingale P. J. Geophys. Res. 2013; 118 (5412–5225)Crossref Scopus (54) Google Scholar]. No acetone was used during the isolation of the hickosanes [[1]Řezanka T. Hanuš L.O. Dembitsky V.M. Sigler K. Eur. J. Org. Chem. 2008; 7: 1265-1270Crossref Scopus (18) Google Scholar] and as a result, a plausible biosynthesis of the triazocane heterocycle invokes biogenic acetone reacting with a dipeptide in a late-stage cyclocondensation reaction (Scheme 2). Our initial results seeking to validate this biosynthesis hypothesis are shown in Scheme 3 (D)-Tryptophan methyl ester 5 underwent smooth coupling with N-Boc D-allo-isoleucine (6) to give the dipeptide 7, which was readily converted into the primary amide 8. Carbamate cleavage gave 9 that upon desalting gave the 1,5-aminoamide 10, which did not react with acetone under several different conditions. However, subjecting 10 to an acetone equivalent (2,2-dimethoxypropane) led to the imidazolidinone 11, a result of the secondary amide undergoing preferential cyclisation over the primary amide. The aliphatic region in the 1H and 13C NMR spectra for imidazolidinone 11 did not align with that reported for the natural products, so the presence of a triazocane was not in doubt at this stage. Although a considerable distance from the reaction site, an iodinated dipeptide was trialled in this reaction (Scheme 4). (±)-6-Iodotryptophan [[14]Yamada Y. Akiba A. Arima S. Okada C. Yoshida K. Itou F. Kai T. Satou T. Takeda K. Harigaya Y. Chem. Pharm. Bull. (Tokyo). 2005; 53: 1277-1290Crossref PubMed Scopus (24) Google Scholar] (12) underwent esterification and coupling with N-Boc D-allo-isoleucine (6) to give the dipeptide 13 which was converted to the primary amide 14, deprotected and desalted as described previously. Upon exposure of 15 to 2,2-dimethoxypropane, imidazolidinone 16 was formed, the structure of which was confirmed by X-ray crystallographic analysis (Fig. 2). The imidazolidinone 16 is a regioisomer of hicksoane A, but the NMR spectroscopic data for 16 does not align with that of the natural product [[1]Řezanka T. Hanuš L.O. Dembitsky V.M. Sigler K. Eur. J. Org. Chem. 2008; 7: 1265-1270Crossref Scopus (18) Google Scholar]. The results in Scheme 3, Scheme 4 demonstrate that the while the dipeptides 10 and 15 do react with 2,2-dimethoxypropane, this only occurs under harsh conditions and in low yield, preferentially forming a 5-membered imidazolidinone over the eight-membered triazocane. This casts doubt on the proposed biosynthesis hypothesis outlined in Scheme 2.Fig. 2Molecular structure of imidazolidinone 16 (CCDC 2281803) Co-crystallised acetone and water omitted for clarity. Atomic displacement parameters are drawn at the 50 % probability level.View Large Image Figure ViewerDownload (PPT) At this stage, we considered that the natural product may have misassigned, with the triazocane 17 being the true structure which in turn could emerge from the regioisomeric dipeptide Trp-Ile-CONH2 18 reacting with acetone (Scheme 5). This results from this alternative biosynthesis proposal are shown in Scheme 6. Boc-(d)-tryptophan 19 [[15]Khopade T.M. Ajayan K. Vincent D.M. Lane A.L. Viswanathan R. J. Org. Chem. 2022; 87: 11519-11533Crossref PubMed Scopus (3) Google Scholar] underwent coupling with (D)-allo-isoleucine methyl ester (20) to give the dipeptide 21, which was readily converted into the primary amide 22. Carbamate cleavage gave 1,5-aminoamide 18; subjecting this compound to 2,2-dimethoxypropane led to the β-carboline 23, a result of the indole preferentially attacking the incipient iminium ion over the primary amide. The structure of β-carboline 23 was confirmed by X-ray crystallographic analysis (Fig. 3). The aliphatic region in the 1H and 13C NMR spectra for β-carboline 23 does not align with that reported for the natural products.Fig. 3Molecular structure of β-carboline 23 (CCDC 2281804). Co-crystallised water omitted for clarity. Atomic displacement parameters are drawn at the 50 % probability level.View Large Image Figure ViewerDownload (PPT) In summary, attempts were made to assemble the 1,3,6-triazocane heterocycle present in the hicksoanes by late stage-installation of the propane-2,2-diamine unit by reaction of Ile-Trp-CONH2 (10), Ile-6-I-Trp-CONH2 (15) and Trp-Ile-CONH2 (18) with 2,2-dimethoxypropane. In all three cases, the intermediate iminium ion did not engage with the primary amide to install the propane-2,2-diamine unit and hence forge the triazocane, reacting instead at alternative sites to form imidazolidinone 11 and 16 [from Ile-Trp-CONH2 (10) and Ile-6-I-Trp-CONH2 (15), respectively] and a β-carboline 23 [from Trp-Ile-CONH2 (18)]. The study reported here suggests that the triazocane unit of these alkaloids is not assembled in Nature upon late-stage reaction of a dipeptide with biogenic acetone. CCDC 2281803 (for 16) and CCDC 2281804 (for 23) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +441223336033. Stephanie Lee: Data curation, Formal analysis, Investigation, Methodology, Resources, Writing – original draft, Writing – review & editing. Tilo Söhnel: Data curation, Formal analysis, Resources, Software, Writing – review & editing. Jonathan Sperry: Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft, Writing – review & editing. No data was used for the research described in the article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jonathan Sperry reports financial support was provided by University of Auckland. Stephanie Lee reports financial support was provided by University of Auckland. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We thank the University of Auckland for the award of a Doctoral Scholarship (S. L.) and Dr Timothy Christopher for collecting the single crystal X-ray diffraction data. The following is/are the supplementary data to this article: Download .pdf (1.34 MB) Help with pdf files Multimedia component 1
Source: Tetrahedron Chem
Authors: Stephanie Lee, Tilo Söhnel, Jonathan Sperry
Institution: University of Auckland
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funder: University of Auckland
OpenAlex ID: W4389956310