Biosynthetic Interrelationships within Polycyclic Cembranoids Isolated from Corals: Conjecture, Biomimetic Synthesis and Reality

Abstract

Macrocyclic furanobutenolide-based cembranoids are precursors to a wide variety of complex ring-fused diterpene structures in corals, implicating a wide variety of oxidation and photochemical processes, cyclisation and transannulation reactions, and skeletal rearrangements from a variety of

Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin

“…The Fenical group was first to report a FBC-macrocycle artifact of isolation derived from lophotoxin bearing a dearomatized furan as an unusually stable exo- enol ether moiety . Since then, other exo- enol ethers have been genuinely isolated, leading to the hypothesis that exo- enol ethers (e.g., 15 ) might be plausible biosynthetic precursors to various transannular reactions . The seemingly straightforward conversion of the furanyl epoxide moiety present in macrocycles 8 into the corresponding dearomatized exo -enol ethers 15 was revealed to be the most challenging step of the synthesis.…”

“…The furanobutenolide-derived cembranoids (FBCs) from gorgonian corals constitute a large family of highly oxygenated and stereochemically complex polycyclic diterpenes possessing a broad range of biological activities . FBCs are unique in that they are built upon the functionalization of a parent 14-membered-ring macrocyclic skeleton.…”

“…As shown in Figure , some of the most complex cembranoid metabolites such as verrilin ( 5 ), plumarellide ( 6 ), and bielschowskysin ( 7 ) have been proposed to be derived from a series of relatively challenging transannular reactions such as a 1,4-conjugate addition or a Diels–Alder or a [2 + 2] cycloaddition. , Even if the common biosynthetic origin of these natural products 5 – 7 remains speculative, it is unlikely that a cyclase enzyme is involved in forming the various polycyclic scaffolds. Indeed, these complex natural products have been postulated to originate from lower-oxidation-state metabolic precursors (e.g.…”

“…Indeed, these complex natural products have been postulated to originate from lower-oxidation-state metabolic precursors (e.g. Z -bipinnatin J ( 1 ) or Z -rubifolide ( 2 )) . Strikingly, E -(Δ 7,8 )-configured FBC-macrocycles are rare in nature, while their corresponding trans (7 S ,8 R )-epoxides are prevalent (e.g.…”

Total Syntheses of Scabrolide A and Nominal Scabrolide B

“…These compounds are thought to derive from 5-episinuleptolide ( 5 ), which in turn descends from a furano-butenolide of type 4 (Scheme ). − Specifically, 5 is linked to nominal scabrolide B ( 1 ) as the purported key intermediate of the biosynthetic pathway by a sequence of transannular Michael addition and retro-oxa-Michael reactions. − , Subsequent isomerization of the vinylogous diketone of 1 into the presumably more stable tetrasubstituted enone gives rise to scabrolide A ( 2 ) ,, and its dehydrated sibling yonarolide ( 3 ). − In contrast to many other norcembranoids, the scabrolides exhibit only modest cytotoxicity; however, 2 was shown to inhibit IL-6 and IL-12 production in vitro and is hence of potential interest as an anti-inflammatory agent …”