A total of 165 new terpenes (1–165, Table 1) were isolated and identified from 10 marine-derived Trichoderma species, including T. asperelloides (18 compounds), T. asperellum (47), T. atroviride (2), T. brevicompactum (20), T. citrinoviride (4), T. erinaceum (5), T. hamatum (3), T. harzianum (27), T. longibrachiatum (4), and T. virens (19), and five unidentified strains (16) [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65]. These terpenes can be classified to monoterpenes with a menthane skeleton, sesquiterpenes with cyclonerane, bisabolane, trichothecane, carotane, cadinane, acorane, cuparane, farnesane, synderane, pupukeanane, and harzianoic acid skeletons, and diterpenes with harziane, proharziane, wickerane, citrinovirin, fusicoccane, cleistanthane, and sordaricin skeletons. The above 19 basic scaffolds along with the degraded and substituted ones demonstrate the high structural diversity of terpenes from marine-derived Trichoderma.

Monoterpenes have seldom been discovered from Trichoderma species, including marine-derived ones. Monoterpenes 1 and 2 (Fig. 6) were obtained from the alga-endophytic T. asperellum and represent the only two menthane derivatives from this genus [25]. These two compounds with only two chiral centers were identified as mutual epimers by the similar but different NMR data, because those of enantiomers are the same as each other. Their absolute configurations at C-7 were assigned to be S and R, respectively, by quantum chemical calculations of electronic circular dichroism (ECD) spectra. Based on the epimeric relationship between 1 and 2, these two metabolites were proposed to have the same absolute configuration at C-1, but it was not determined spectroscopically. As a chlorinated analog of them, 3-chloromenthan-1,2,7-triol had also been isolated from a fungus, Tryblidiopycnis sp. of mangrove origin [131]. Based on previous reports, monoterpenes were rarely encountered not only in Trichoderma species but also in other marine and even terrestrial-derived fungi [132].

Monoterpenes from marine-derived Trichoderma

Sesquiterpenes with 126 new members (3–128, Table 1) make up the largest group of terpenes from marine-derived Trichoderma, and they comprise 11 basic carbon skeletons [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. A common cyclonerane skeleton is present in 23 isolates (3–25, Fig. 7), obtained from T. asperellum [26,27,28], T. harzianum [29, 30], T. hamatum [31], T. erinaceum [32], T. citrinoviride [33], and T. asperelloides [34]. This scaffold is characterized by the dimethylated cyclopentane ring attached by a 1,6-dimthylhexanyl side chain. Oxidation, reduction, cyclization, and substitution construct their diverse structures. All of them feature an oxygen atom bonded to C-7. The hydroxy group at C-3 of 22–24 possesses an opposite orientation, and the double bond in the five-membered ring of 25 also renders this molecule unique [33, 34]. Two isolates (26 and 27, Fig. 7) from T. asperellum and T. asperelloides, respectively, have degraded cyclonerane frameworks, with the degradation happening at the side chain or the ring unit [28, 34]. In addition, 10 nitrogenous cyclonerane derivatives (28–37, Fig. 8) were obtained from T. asperellum [27, 35]. Each of them contains a nitrogen-bearing substitute, and the highlight is the presence of an isoxazole ring in 35 [27]. Cyclonerins A (28) and B (29) harbor a hydroxamic acid unit, that can chelate ferric ion, and represent the first two fungal hydroxamic acids with a terpene-derived scaffold [27]. The identification of these compounds was performed through various spectroscopic methods. Quantum chemical calculations were used to aid the assignments of relative configurations for 22 and 26 and absolute configurations for 22, 28–32, and 34, and X-ray diffraction was employed to determine the absolute configuration of 6 [27, 28, 33]. Although the relative configuration at C-7 of 7–9 and 12 was not given in literature [28], it should be the same as that 26 based on biogenetic considerations. Cyclonerane sesquiterpenes, especially the known cyclonerodiol, can be produced by many species of Trichoderma and other fungal genera, such as Trichothesium, Fusarium, and Epichloe [33], but they have rarely been detected in plants and animals. It is worth mentioning that marine-derived Trichoderma strains have contributed more diverse cycloneranes than terrestrial-derived ones so far [20, 22].

Cyclonerane sesquiterpenes and catabolites from marine-derived Trichoderma

Nitrogenous cyclonerane sesquiterpenes from marine-derived Trichoderm

Bisabolane sesquiterpenes have been known as metabolites of plants, animals, and microbes for a long time, but the first discovery from Trichoderma just happened in 2011 [133, 134]. Bisabolane derivatives from marine-derived Trichoderma also exhibit high structural diversity. 14 members (38–51, Fig. 9) with an untouched bisabolane skeleton were isolated from four Trichoderma species, including T. asperellum [25, 26, 36], T. brevicompactum [37], T. asperelloides [34], and T. erinaceum [32]. Among them, trichaspside A (38) represents the first natural bisabolane aminoglycoside, and all the others possess oxygenated side chain termini. Meanwhile, 21 norbisabolane sesquiterpenes (52–72, Fig. 10), with four (53–56) containing an aminoglycoside moiety, were discovered from T. asperellum [25, 26, 36, 38], T. atroviride [39], and T. asperelloides [34]. All the norbisabolanes are possibly produced by elimination of a terminal methyl group from the side chain moieties of their precursors, and the majority of them bear an oxygen atom at C-11. It is regretted that absolute configurations for most of the bisabolane and norbisabolane derivatives remain unsolved because of lacking ECD signals and perfect crystals. However, trichobisabolin Z (72) has a Cotton effect at 328 nm due to the presence of an α,β-unsaturated carbonyl group, which enabled the assignment of the absolute configuration at C-6 by quantum chemical calculations [34]. An acidic hydrolysis reaction was performed during the absolute configuration establishment of 38 [26]. Trichodermaerin A (51) with no optical activity was deduced to be a racemic mixture, but the separation failed via various chiral HPLC columns [32]. In general, the high populations of norbisabolane sesquiterpenes and aminoglycosides may be characteristic of marine-derived Trichoderma.

Bisabolane sesquiterpenes from marine-derived Trichoderma

Norbisabolane sesquiterpenes from marine-derived Trichoderma

As secondary metabolites of some Trichoderma and Fusarium species, trichothecane sesquiterpenes have been regarded as a class of mycotoxins for animals and humans [20]. Besides the known trichodermin, 18 trichothecane derivatives (73–90, Fig. 11) were isolated from marine-derived Trichoderma species, including T. brevicompactum and T. hamatum as well as an unidentified strain [31, 40,41,42,43]. Similar to the known trichothecane sesquiterpenes [135], the majority of these new isolates possess a 2,11-epoxy unit. However, trichodermol chlorohydrin (82) and trichodermarin N (90) are exceptions, with the former being the first natural halogenated trichothecane derivative. Both 2,11-epoxy and 11,12-epoxy units are present in trichodermarin H (84), of which the absolute configuration along with that of trichodermarin G (83) was assigned by X-ray crystallography. The absolute configurations of 77–80 were ascertained by analysis of their ECD data aided by quantum chemical calculations, while that of 81 was determined by agreement of its specific optical rotation with the hydrolysate of 77. It is interesting that glycosides are also not absent in this class of metabolites. Three members (88–90) were identified to possess sugar moieties, with 90 being the first glucosamine-coupled trichothecane. It is worth noting that the production of trichothecane toxins may decrease the application of their producers, though some strains display excellent antifungal effects [136].

Trichothecane sesquiterpenes from marine-derived Trichoderma

Carotane, also designated d