Synthesis of the Sponge-Derived Plakortone Series of Bioactive Compounds

Abstract

The Caribbean sponges of the genus Plakortis, P. halichondrioides, and P. simplex have provided a series of biologically active furanolactones-the plakortones A-D (1-4) from the former sponge and B-F (2-6) from the latter. The defining motif of the plakortones is a sterically congested 2,6-dioxabicyclo[3.3.0]octan-3-one moiety, the emblematic furanolactone core. This core is efficiently accessed by a palladium(II) mediated hydroxycyclization-carbonylation-lactonization cascade with an appropriate ene-1,3-diol. Total syntheses of plakortones C (3) and F (6) are now described which settle constitutional and stereochemical features in this group of secondary metabolites. Acquisition of plakortone D (4), the most effective activator of SR-Ca(2+)-pumping ATPase, utilized stereodefined lactone cores that resulted from asymmetric dihydroxylation of protected homoallylic alcohol 29. A derived lactone aldehyde was then coupled with an independently generated, sulfone-activated side chain unit, 57. The 11,12-E-double bond, carried through the sequence as a protected, stereodefined diol, was released therefrom by stereospecific syn-elimination via an orthoester derivative. In this way, plakortone D (4) was demonstrated to possess the (3S,4S,6S,10R,11E) configuration. Racemic plakortone E (5) was also acquired by using the Pd(II) induced sequence, but in this case, the required, complete acyclic system 52 was assembled first. Plakortone C (3) resulted from a sequence commencing with (R)-(+)-3-hydroxy-2-methylpropionate, with a derived iodide 76 alkylating the enolate of the butyramide 77 generated from (1S,2S)-(+)-pseudoephedrine. The liberated primary alcohol 79 was converted by standard procedures to key enediol 89 which, with the Pd(II) protocol, afforded the major separable plakortones 90 and 91, with the former being identical with natural plakortone C (3). Very mild hydrogenation of 90 afforded a saturated plakortone, identical with natural plakortone F (6), thus establishing its structure and absolute stereochemistry. Available information on the stereoselective routes to plakortones E (5) and B (2) are also outlined, so that the constitution and absolute stereochemistry of plakortones B-F are now established.

PPAR Modulating Polyketides from a Chinese Plakortis simplex and Clues on the Origin of Their Chemodiversity

“…Plakortones have been the object of intense synthetic efforts 21,22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 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 In principle, plakortone Q (12) could be the product of a direct hydroxylation reaction; alternatively, it could derive from an epoxylactone epimeric to plakortoxide A through nucleophilic epoxide opening by water and subsequent oxa-Michael addition to the α,β-unsaturated γ-lactone ring (the mechanism has been reported in Scheme 1 in a concerted fashion). Of course, using hydride as nucleophile, the non-hydroxylated plakortones could be obtained.…”

Kinetic resolution of (E)-4-(2′,5′-dimethylphenyl)-but-3-en-2-ol and (E)-4-(benzo[d][1′,3′]dioxol-5′-yl)-but-3-en-2-ol through lipase-catalyzed transesterification

“…Some of them possess valuable odoriferous properties useful in the food or cosmetic industry. 1-3 They are also important building blocks in the synthesis of optically active odorants, 4-6 molecules with various pharmacological activity [7][8][9] or compounds with antifungal, 10 antibacterial, 11 insecticidal, 12 or antifeedant properties. 13 An interesting group of allyl alcohols used as chiral synthons in the synthesis of biologically active molecules are compounds with a 4-arylbut-3-en-2-ol system.…”

Anti-dermatophytic activity of marine sponge, Sigmadocia carnosa (Dendy) on clinically isolated fungi

“…This anti dermatophytic effect of the sponge might be the presence of several bioactive compounds [22][23][24] . Previous reports has showed initial inhibitory bioactivities of a marine sponge and isolated two new bioactive alkaloids such as N-methyl-epi-manzamine D1 and epi-manzamine D2 [25] .…”