Synthesis ofent-Halimanolides froment-Halimic Acid

Abstract

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...

Halimane diterpenoids: sources, structures, nomenclature and biological activities

“…(1) ent-Halimanolides. 123,141,207,208 (2) Chettaphanin I and II. 109,209 (3) Bioactive sesterterpenolides.…”

“…ent-Halimanolides synthesis. The rst three known natural ent-halimanolides (85, 131 and 132) 122 were synthesized from ent-halimic acid methyl ester (39) using methyl ketone 285 as an intermediate 123,207 (Scheme 11).…”

The Methylene-Cycloalkylacetate (MCA) Scaffold in Terpenyl Compounds with Potential Pharmacological Activities

“…Recently, molecules containing methylene-cycloalkylacetate (MCA) fragments (Figure 1) have been reported to show very interesting neurotrophic properties [1]. The MCA scaffold can be observed in many easily available terpenes of natural origin and synthetic derivatives, many of which show interesting pharmacological activities [2,3,4,5,6].…”

“…Ent -halimic acid is very abundant in the Halimium viscosum extract, and its methyl ester 2 has been used as a starting material for the synthesis of a series of natural halimanes corroborating their structures, biologically active derivatives and the preparation of other interesting compounds. Figure 5 shows some of the diterpene or sesquiterpene derivatives synthesized from ent -halimic acid: 1. ent -halimanolides [2,56,57,58]; 2. chettaphanin I and II [4,5]; 3. sesterterpenolides [6,59,60]. Figure 6 shows other groups of compounds prepared from 2 , among which are as follows: 4. hybrid compounds: sesterterpenolide bioconjugates and glycerophospholipids [61]; 5. rearranged derivatives: ent -labdanes [62], abeopicrasanes [63], and a propellane [64]; 6. sequiterpene-quinone/hidroquinones [65]; 7. terpene alkaloids: sesqui- and diterpene-alkaloids [7,8,66,67,68,69].…”

“…The first three natural ent -halimanolides 90 , 91 and 92 were synthesized from ent -halimic acid using the methyl ketone 94 as intermediate [2,56] (Scheme 1). This methyl ketone 94 was obtained from ent -halimic acid methyl ester 2 by a six-step procedure that includes reduction of the methoxycarbonyl at C18.…”