Macrocyclic and polycyclic ‘cembranoid’ diterpenes are one of the most widespread groups of natural products that are found in the marine milieu. The macrocyclic cembranoids are linked to each other by a network of oxygenation processes, which often climax with the formation of furano- and furanobutenolide-based macrocyclic cembranoids commonly found in gorgonian and soft corals. These macrocycles are then prone to oxidative rearrangements, photochemical ring contraction, and transannular cyclisations amongst others, leading to a plethora of novel and architecturally attractive marine metabolites. Although there is a dearth of knowledge about the enzymes that trigger some of the steps in their biosynthesis, speculations are rife. In this personal perspective we have examined many of the structural relationships within oxycembranoids and their relatives isolated from corals. This has allowed us to speculate on the likely biosynthetic interrelationships between structurally similar metabolites, and then propose some likely key carbon-to-carbon bond forming reactions that are followed in vivo in linking macrocyclic cembranoids to their polycyclic congeners. Biomimetic synthesis studies, which vindicate some of the biosynthetic speculations, are interweaved in the discussion.
The marine environment is a seemingly inexhaustible treasury of organisms whose secondary metabolites bear witness to the lavishness and inventiveness with which nature is able to manipulate molecular architecture. But to what purpose are these diverse and often grotesque compounds produced? This review is founded on the premise that some of them may be involved in the uptake and transport of metal ions present in the aquatic milieu. Many metabolites produced by terrestrial organisms are known to act as ionophores, but the case for similar behavior by their marine counterparts is far hazier. Notwithstanding the relative abundance of certain metal ions in the oceans, and of metabolite structures possessing features that should facilitate the chelation of metal ions, few attempts to establish a connection between these two phenomena have been reported. We have whittled down the voluminous literature of natural products derived from marine sources to expose a core of observations and speculations germane to our premise. These facts and fantasies are evaluated in this review. A mere handful of metal-containing complexes has actually been isolated; furthermore, attempts to prepare such complexes in vitro are rare, and spectroscopic evidence for metal-metabolite interactions, whether in vivo or in vitro, is not common. Only with the vanadium-sequestering tunichromes does a logical (but by no means complete) picture begin to emerge. In several other cases, the plausibility of metal chelation, though mooted by authors, remains unsupported by experimental evidence. However, continuing efforts to obtain structural, and particularly conformational, information on the metabolites by means of X-ray crystallography, nuclear magnetic resonance spectroscopy, and molecular mechanics calculations would seem to provide the key to a rational approach to this neglected topic. On the basis of recent studies dealing with such structural aspects, we present a selection of candidate compounds, some of which are the targets of our own synthetic attentions, whose potential for binding to metal cations merits further research.
Azole-based cyclic peptides found in ascidians ("sea squirts") of the genus Lissoclinum have a high propensity to chelate metal ions. This Highlight summarises the current evidence for marine cyclic peptide-metal congruence, and the structural and stereochemical features in cyclic peptides which seem necessary to facilitate metal complexation. The biological relevance of the metal ions in these associations, including their possible role in the assembly of cyclic peptides in the marine milieu, is also briefly considered. Finally, the synthesis of natural, and some novel non-natural, azole-based cyclic peptides from the cyclooligomerisation and assembly of azole-based amino acids, including in the presence of metal ions, is presented.
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