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Resistance of pathogenic microorganisms against antimicrobials is a major threat to contemporary human society. It necessitates a perpetual influx of novel antimicrobial compounds. More specifically, Gram− pathogens emerged as the most exigent danger. In our continuing quest to search for novel antimicrobial molecules, alkaloids from marine fungi show great promise. However, current reports of such newly discovered alkaloids are often limited to cytotoxicity studies and, moreover, neglect to discuss the enigma of their biosynthesis. Yet, the latter is often a prerequisite to make them available through sufficiently efficient processes. This review aims to summarize novel alkaloids with promising antimicrobial properties discovered in the past five years and produced by marine fungi. Several discovery strategies are summarized, and knowledge gaps in biochemical production routes are identified. Finally, links between the structure of the newly discovered molecules and their activity are proposed. Since 2015, a total of 35 new antimicrobial alkaloids from marine fungi were identified, of which 22 showed an antibacterial activity against Gram− microorganisms. Eight of them can be classified as narrow-spectrum Gram− antibiotics. Despite this promising ratio of novel alkaloids active against Gram− microorganisms, the number of newly discovered antimicrobial alkaloids is low, due to the narrow spectrum of discovery protocols that are used and the fact that antimicrobial properties of newly discovered alkaloids are barely characterized. Alternatives are proposed in this review. In conclusion, this review summarizes novel findings on antimicrobial alkaloids from marine fungi, shows their potential as promising therapeutic candidates, and hints on how to further improve this potential.

In this paper, the pentacyclic skeleton of hirsutellone B including the paracyclophane was constructed via a tandem IMDA/ketene-trapping scenario with the proper stereochemistry. Alternatively, from the common intermediate 4, we completed a formal synthesis of hirsutellone B.

Total synthesis of Hirsutellone B has been achieved by a convergent synthetic strategy. This synthesis features direct construction of the highly strained 13-membered macrocycle of Hirsutellone B utilizing the Ullmann-type reaction. To the best of our knowledge, this is the first application of macrocyclization utilizing an intramolecular Ullmann-type reaction between an aliphatic alcohol and aryl halide.

The amphilectane diterpenes, exemplified by 7-isocyanoamphilecta-11(20),15-diene 3, have been little investigated. In the course of a synthesis of 3, Hiroaki Miyaoka of the Tokyo University of Pharmacy and Life Sciences took advantage (Synlett 2011, 547) of the kinetic enolization and silylation of 1 to convert it into a trienone that spontaneously cyclized to 2. Scabronine G 6, isolated from the mushroom Sarcodon scabrosus, was found to enhance the secretion of neurotrophic factors from 1321N1 astrocytoma cells. To set the absolute configuration of the two quaternary centers that are 1, 4 on the cyclohexane ring of 6, Naoki Kanoh and Yoshiharu Iwabuchi of Tohoku University cyclized (Org. Lett. 2011, 13, 2864) 4 to 5. Although described by the authors as a double Michael addition, this transformation has the same connectivity as an intramolecular Diels-Alder cycloaddition. The diterpenes isolated from the genus Thapsia, represented by basiliolide B 9, induce rapid mobilization of intracellular Ca2+ stores. Brian M. Stoltz of Caltech effected (Angew. Chem. Int. Ed. 2011, 50, 3688) Claisen rearrangement of 7 to give an intermediate that cyclized to 8 as a mixture of diastereomers. A significant challenge in the synthesis was the assembly of the delicate enol ether/lactone of 9. Hirsutellone B 12, isolated from Hirsutella nivea, shows significant antituberculosis activity. Hiromi Uchiro of the Tokyo University of Science found it useful (Org. Lett. 2011, 13, 6268) to protect the intermediate unsaturated keto ester by intermolecular cycloaddition with pentamethylcyclopentadiene before constructing the triene of 10. Simple thermolysis reversed the intermolecular addition, opening the way to intramolecular cycloaddition to give 11. The tetracyclic ring system of the diterpene echinopine A 15 represents a substantial synthetic challenge. David Y.-K. Chen of Seoul National University approached this problem (Org. Lett. 2011, 13, 5724) by Pd-mediated cyclization of 13 to the diene, which then underwent intramolecular Diels-Alder cycloaddition to give 14, with control of the relative configuration of two of the three ternary centers of 15. Double bond migration followed by oxidative cleavage of the resulting cyclohexenone then set the stage for the intramolecular cyclopropanation that completed the synthesis of 15.

A stereoselective synthesis of the decahydrofluorene core of the hirsutellones was accomplished in eight steps and in 43% overall yield. The key step of the synthesis is the highly stereoselective intramolecular Diels–Alder cyclization of the siloxacyclopentene-constrained tetraene 1.