Clavulonate

Clavulones I and II are members of an unusual family of marine prostanoids from the coral Clavularia viridis which are biosynthesiied by a cationic (i.e. non-radical, non-endoperoxide) pathway. The total synthesis of clavulones I and II was accomplished from cyclopentadiene as SM goal. 

The 20-acetoxy derivatives of clavulones I, II and III (92-94) were reported shortly afterward with their structures being determined by spectroscopic methods [120]. A 4R and 12S (again, the incorrect 12R stereodescriptor was applied) stereochemistry in these three new compounds was deduced by the close comparability of their CD spectra with those obtained for clavulones I, II, and III (88-90). 

Soon afterwards [123] the bromo- (105) and iodo- (106) analogs of chlorovulone I (100) were also isolated from C. viridis in exceptionally low yield (ca. 0.01% of lipid extract). Their structures were established principally by spectroscopic means in comparison with chlorovulone I. Both of the new compounds possess the same olefin geometries as found in clavulone I and chlorovulone I. R Stereochemistry at Cl 2 was established in 105 by comparisons of CD spectra with those of chlorovulone I (100). These new halogenated clavulones showed levels of antiproliferative activity and cytotoxicity comparable to those of chlorovulone I (100). 

Scheme 10. Proposed biosynthesis of clavulone I (88) in Clavularia viridis [85]...

The antiproliferative properties of clavulone I (88) were studied in greater detail using the HL60 leukemia cell line [128]. Application of the natural product at 0.4 pM (0.2 pg ml 1) irreversibly decreased the growth rate of these cells to half that of controls. Complete growth inhibition was observed at about 1.0 pM and cytotoxicity was observed at higher concentrations. 

At about the same time, however, observation of strong antiproliferative activity in the CIO--11 epoxy analog of clavulone I (88) showed that the C10-11... 

More recently, the clavulones (not specified which ones) [134] were described to have potent effects on the spontaneous beating rate of cultured myocardial cells from fetal mouse hearts. At a concentration of 0.45 pM, clavulone had positive chronotropic action on these cells however, the character of this effect clearly differed from the positive ionotropic and negative chronotropic effects of the steroid glycoside ouabain or the drug Bay K 8644. Hence, these results suggest that the clavulones may possess a new mechanism of action in this assay system. 

Grechkin AN (1995) Clavulones and Related tert-Hydroxycyclopentenone Fatty Acids Occurrence, Physiological Activity and Problem of Biogenetic Origin. J Lipid Mediators Cell Signal 11 205... 

Watanabe K, Sekine M, Iguchi K (2003) Isolation of Three Marine Prostanoids, Possible Biosynthetic Intermediates for Clavulones, from the Okinawan Soft Coral Clavularia viridis. Chem Pharm Bull 51 909... 

Pd(OAc)2 to give the cyclohexenone 256. In clavulone synthesis, only the silyl enol ether in 257 reacts with Pd(OAc)2 to give the enone 258 [153]. The dehydrogenation can be carried out with a catalytic amount of Pd(OAc)2 using benzoquinone as the reoxidant. Cyclopentenone (260) is prepared from cyclopentanone (259) by using a supported Pd catalyst under 02 atmosphere [154], The enone 261 is converted to the dienone 263 via the dienol silyl ether 262 [155],... 

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