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The proposed structures of cladocoran A and B, sesterterpenoid g-hydroxybutenolides, were synthesized from ent-halimic acid.The proposed structures of cladocoran A and B, sesterterpenoid g-hydroxybutenolides, were synthesized from enthalimic acid (Figure 1), the major component of Halimium viscosum (Villarino de los Aires). Interestingly, since our synthetic compounds 1 and 2 are not identical to cladocoran A or B, the structures of these marine sesterterpenoids must be revised. Figure 1 Cladocoran A and B, isolated from the mediterranean coral Cladocora cespitosa by Fontana et al. 1 in 1998, are novel sesterterpenoids possessing an unprecedented skeleton. Both of them occur in the organic extract as a mixture of a-and b-epimers at C 20 .Cladocoran A and B share more than one analogy with dysidiolide, 2 a natural inhibitor of protein phosphatase cdc 25A (IC 50 = 9.4 mM), which is essential for cell proliferation. Dysidiolide inhibits the growth of A-549 human lung carcinoma and P388 murine leukemia cell lines at low micromolar concentrations. 3Because of its atypical structure and its potentially important physiological activity, dysidiolide has attracted considerable attention as a target for total synthesis, ten total syntheses having been reported to date. [3][4][5][6][7][8][9][10][11] Cladocoran A and B have a g-hydroxybutenolide group previously associated with phospolipase A 2 inhibition, 12-15 but no total synthesis has yet been reported.In this work we describe the synthesis of the supposed structure for cladocoran A and B, compounds 1 and 2. Physical properties of the compounds synthesized by us do not correspond with those reported for cladocoran A and B. Compounds 1 and 2 are sesterterpenes structurally considered as "isopropenyl-ent-halimanes" with the stereogenic centers that match the decalin fragment plus an additional isopropenyl group. The synthesis for compounds 1 and 2 was planned starting from ent-halimic acid 16 methyl ester 3, of known absolute configuration, due to its structural analogy. At present, ent-halimic acid is being employed in the synthesis of natural ent-halimanolides. 17The synthesis of 1 and 2 from ent-halimic acid methyl ester 3 presented two main problems: manipulation of side chains on C 18 (south chain) and on C 9 (north chain) to achieve the introduction of the g-hydroxybutenolide group, and control of stereochemistry for the hydroxyl group to be placed at C 12 of ent-halimic acid methyl ester 3.The retrosynthetic route for 1 and 2 from ent-halimic acid methyl ester 3 is presented in Scheme 1.The g-hydroxybutenolide moiety of 1 and 2 was to be obtained from A following Faulkner 18 methodology. A could be obtained by addition of furyllithium to an aldehyde such as B. The elongation of the south chain of 3 by an isoprene unit was to be done in two steps: adding one carbon by Wittig condensation to give an intermediate such as B and then the four remaining carbons by S N 2 substitution, due to the difficulty of achieving substitution at a neopentyl carbon.Degradation of the ...

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Three natural ent-halimanolides have been synthesized from ent-halimic acid. Their structures have been confirmed as well as their absolute configurations established. Bestmann methodology has been used for the synthesis of butenolides and for the synthesis of g-hydroxybutenolides the Boukouvalas method has been employed.Annonaceae plants are a rich source of bioactive substances such as acetogenins. 1-4 The occurrence of natural diterpenes possessing hydroxybutenolide units has been reported frequently in plants of the genera Polyalthia, Acritopappus, Premna, and Cyathocalux (Annonaceae). [5][6][7] It is interesting to note that many species of these genera are widely used in folk medicine. 8 Genus Polyalthia has been widely studied, 9 in particular several alkaloids 11 and a large number of clerodane and ent-halimane diterpenes were isolated from Polyalthia longifolia. 10 In 1995 Hara et al. reported the isolation of three ent-halimanolides 1, 2, and 3. These compounds are the first ent-halimane diterpenes which have been isolated from Annonaceae plants. Their structures were elucidated by spectroscopic methods. Recently, the synthesis of the enantiomer 12 of 3 from (+)-hardwickiic acid (clerodane diterpene) was reported. In the present work, we report the synthesis of 1, 2, and 3, starting from ent-halimic acid, confirming the structure and establishing the absolute configuration of these natural products. ent-Halimic acid is the main component of Halimium viscosum (Villarino de los Aires) and has been used as the starting material in the synthesis of ent-halimanolides 13 and sesterterpenolides 14 similar to dysidiolide, 15 that show high anti-tumor activity, and chettaphanin I and II. 16 The synthesis of 1-3 is carried out in three parts:1. Reduction of C-18 and side chain degradation; 2. Functionalization of C-16; and 3. Synthesis of the butenolides and g-hydroxybutenolides.In the first part (reduction of C-18 and degradation of the side chain), the objective is the synthesis of methylketone 20. Several conditions and even strategies were developed in order to achieve this objective, first reduction and then degradation (Scheme 1) or vice versa (Scheme 2).For the transformation of the ester at C-18 several routes were attempted. The first employed a Huang-Minlon 17 reduction as the key step (Scheme 1). The hydroxyl group at C-15 was protected satisfactorily as methyl ether 5 or as the OTHP derivative 6; the subsequent reduction of C-18 with LiAlH 4 gave 7 and 8, respectively. tetra-n-Propylammonium perruthenate (TPAP) oxidation of these alcohols gave unstable aldehydes 9 and 10, respectively. These aldehydes were treated under Huang-Minlon conditions to produce 11 and 12 in 85% and 81%, respectively.The hydroxy derivatives 7 and 8 were subjected to other reduction procedures. The hydroxy derivative 8 was transformed into the xantogenate 13 by treatment with CS 2 and MeI. Reduction of 13 with n-Bu 3 SnH 18 gave 12 in a low 31% yield (Scheme 1). Reaction of 7 with N,N-dimethylphosphoramidic chloride and n-BuLi...