Manoalide

Ketones can be prepared by trapping (transmetallation) the acyl palladium intermediate 402 with organometallic reagents. The allylic chloride 400 is car-bonylated to give the mixed diallylic ketone 403 in the presence of allyltri-butylstannane (401) in moderate yields[256]. Alkenyl- and arylstannanes are also used for ketone synthesis from allylic chlorides[257,258]. Total syntheses of dendrolasin (404)f258] and manoalide[259] have been carried out employing this reaction. Similarly, formation of the ketone 406 takes place with the alkylzinc reagent 405[260],... 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

A 1,2-metalate rearrangement of a higher order cuprate, known as a Kodenski rearrangement [64], was used as a key step in the synthesis of the marine antiinflammatory sesterterpenoid manoalide 95 (Scheme 9.20) [65]. Treatment of the alkenyl lithium 89 (prepared from the alkenylstannane 88 with s-BuLi in a diethyl ether-pentane mixture) with the homocuprate 91 (produced from iodoalkane 90) gave the iodoalkene 94 in 72% overall yield from 88. The reaction proceeds as fol-... 

Manoalide (164), a marine natural product which inhibits the release of arachidonic acid from phospholipids by phospholipase A2 [397,398], showed topical anti-inflammatory activity in mouse ear models [399]. Activity in ISN and cRBL (< 1 M) have also been reported [400]. A series of analogues consisting of the furanone ring of manoalide bearing simple unsaturated 16-20 carbon chains showed similar activity in rabbit neutrophils and isolated guinea-pig neutrophil 5-LO [401] interestingly, however, topical anti-inflammatory activity was seen in phorbol ester ear oedema but not in AAE [399]. The importance of 5-LO inhibition to the anti-inflammatory activity of manoalide is unknown effects on phospholipase C and calcium channels have also been shown [402, 403]. 

Sponge-derived sesterterpenoids are potent anti-inflammatory metabolites which inhibit phospholipase A2 (Sipkema et ah, 2005a). In arachi-donic acid pathway of inflammatory response (Fig. 8.3), phospholipase A2 catalyzes the release of membrane-bound phospholipids to produce inflammatory mediators once stimulated by tissue injury. Manoalide (Fig. 8.4) is a best known sponge-derived anti-inflammatory sesterterpe-noid. Dysidotronic acid (Fig. 8.5), non-complex manoalide analogue, has been identified as an anti-inflammatory metabolite of the sponge Dysidea sp. The mechanism by which dysidotronic acid inhibit inflammation is much more selective and potent than manoalide. This sesquiterpenoid... 

Manoalide, a marine anti-inflammatory sesterterpenoid, has been synthesized555 using a 1,2-metallate rearrangement of a higher order cuprate and a Pd(0)-catalysed carbonylation of an iodoalkene to generate the central dihydropyranone ring. 

Syntheses and uses of isotopically labelled compounds 3. Synthesis of carbon-14 and tritium labelled analogues of manoalide... 

D. Two syntheses of manoalide via heteroatom-assisted alkyne carbometalation. Tetrahedron 1994, 50, 8793-8808. 

PLA2 inhibitors were the subjects of two recent review articles [4,42]. Nonspecific irreversible sPLA2 inhibitors, -bromophenacyl bromide (covalently modifying the active histidine residue) [43,44] and a natural product manoalide (covalently modifying lysine residue) [45,46], are often used to study physiologi-... 

KB Glaser, RS Jacobs. Inactivation of bee venom phospholipase A2 by manoalide. A model based on the reactivity of manoalide with amino acids and peptide sequences. Biochem Pharmacol 36 2079-2086, 1987. 

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