Total Synthesis of the Nagelamides – Synthetic Studies toward the Reported Structure of Nagelamide D and Nagelamide E Framework

Abstract

The nagelamides are a small subset of the oroidin family of marine sponge-derived alkaloids and are, for the most part, dimeric in nature. As part of our efforts to develop synthetic access to this family, a Stille cross-coupling strategy is used to construct the bis-imidazolyl core skeleton. Reduction of the bis-vinylimidazole delivered the core framework of nagelamide D. Introduction of the 2-amino groups via the corresponding azides and introduction of the pyrrolecarboxamides through a double Mitsunobu reaction using a pyrrole hydantoin provided the putative structure of nagelamide D. The spectroscopic data for the synthetic and sponge-derived materials did not match well, whereas the spectroscopic data were a good match for closely related oroidin alkaloids, supporting the structure of the synthetic material. The structure of the synthetic material was further corroborated by obtaining an X-ray crystal structure of a derivative. Electrocyclization of an advanced precursor affords a dihydrobenzimidazole, which is expected to serve as a key intermediate en route to nagelamide E and ageliferin.

Marine Pyrrole Alkaloids

“…However, no final evidence was given at this point. A recently published synthetical approach [ 277 ] of the same laboratory towards alkaloids belonging to the nagelamide class then corroborated the correctly proposed but incorrectly assigned structure by Kobayashi. In this case, crystallographic measurements [ 277 ] unequivocally demonstrated that the assignments for C9, C9′, C10′ as well as H9′a and H9′b were inadvertently switched in the original literature [ 275 ].…”

“…A reaction sequence involving several protection and deprotection reactions as well as the installation of the azide group via TsN 3 furnished diol 310. Replacing the alcohol functional groups by a pyrrole hydantoin 311, hydrolysis, and deprotection of the corresponding urea followed by azide hydrogenation finally furnished nagelamide D (304) in 32% over four steps (Scheme 19) [277]. Scheme 19.…”

Marine natural products

“…It is likely the difference relates to the relative configuration of the NP. 490 A similar state of affairs exists following the total synthesis of the reported structure of nagelamide D. 491 The first total syntheses of several other alkaloids have also been achieved. 492–496 Preparation of two semi-synthetic alkaloid libraries were reported in 2020; the first utilised 290 mg of psammaplysin F from only 46 g of freeze-dried Hyattella to probe prostate cancer cells using multiparametric quantitative single-cell imaging, 497 while the other exploited 780 mg of renieramycin M from 18 kg of Xestospongia to synthesise two series of compounds, many of which exhibit potent (low nM) activity against H292 cells.…”

Feature-Based Molecular Networking Discovery of Bromopyrrole Alkaloids from the Marine Sponge Agelas dispar

“…Several bromopyrrole alkaloids display antibacterial activity. ,− Synthesis of bromopyrrole alkaloid analogues has been explored toward the development of new antibiotics as well . Moreover, several syntheses have been described for ageliferins, alkaloids that can be, therefore, considered as potential lead scaffolds for the development of new antibiotics.…”