Synthesis of Ent-16-hydroxycleroda-4(18),13-dien-15,16-olide and Ent-cleroda-4(18),13-dien-15,16-olide from (+)-hardwickiic acid

Abstract

As configurações absolutas de dois diterpenos butenolidos naturais foram confirmadas através da síntese do ent- 16-hidroxicleroda-4(18), 13-dien-15,16-olida (2) e ent-cleroda-4(18),13-dien-15,16-olida (3), enantiômeros de produtos naturais, a partir do ácido (+)-hardwickiico (1).The absolute configurations of two natural diterpene butenolides were confirmed through the synthesis of ent- 16-hydroxycleroda-4(18), 13-dien-15,16-olide (2) and ent-cleroda-4(18), 13-dien-15,16-olide (3), enantiomers of the natural products, starting from (+)-hardwickiic acid (1). Keywords: (+)-hardwickiic acid, clerodane, butenolide, absolute configuration IntroductionThe occurrence of natural clerodane diterpene butenolides and hydroxybutenolides has been reported in plants of the genera Polyalthia, 1-10 Acritopappus, 11 Premna, 12 and Cyathocalyx, 13 as well as their biological properties as antifeedants, 1 cytotoxicity to tumor cell cultures, 2,9 toxicity against Artemia salina 2,13 and Aedes aegypti, 13 febrifuges, 3 antimicrobials, 5,12 chewing sticks for sterilizing milk container, 12 and diuretics. 14 Syntheses of some biologically active clerodanolides and ent-halimanolides were recently published 15,16 showing the importance of this new class of terpenoids. In connection with a previous study on the synthesis of some biological active hydroxybutenolide derivatives and regarding the use of the readily available methyl (+)-hardwickiate (1b) for the synthesis of natural products, 14,17,18 the clerodanes 2 and 3, enantiomers of two natural products, 4,10 have been synthesized (Figure 1). Since only the relative stereochemistry was reported in the literature, the syntheses of 2 and 3 allowed to elucidate the absolute stereochemistry of the compounds isolated from Polyalthia longifolia Thw. 4 Results and DiscussionThe reduction of carbomethoxy group of 1b to the corresponding methyl group and isomerization of endocyclic double bond to exocyclic double bond in order to obtain a desired A ring functionality of the structures 2 and 3, a dehydration reaction of the known alcohol 4 18 was considered. Although the alcohol 4 was prepared previously in a reasonable yield through the reduction of (+)-methyl hardwickiate (1b) using an excess of sodium in propan-1-ol, a mixture with corresponding carboxylic acid was always obtained. 18 Thus, the crude product was first treated with diazomethane and then submitted to the reduction with lithium aluminum hydride to furnish the desired alcohol 4 in 59% overall yield. (Scheme 1)In a previous study 19 it was observed that the elimination reaction of the corresponding sulfonic ester (-OTs or -OMs) using basic conditions (DBU, t BuO -K + ) led to the desired olefin in a low yield and recovering the starting material. To detour this problem the dehydroiodination reaction was considered. Mesylation of alcohol 4 with methanesulfonyl chloride followed by treatment with sodium iodide gave the corresponding iodide 6 in 50% yield. Next, the dehydroiodination reaction of 6 was performed using silver fluori...

The Kornblum DeLaMare rearrangement in natural product synthesis: 25 years of innovation

“…The authors were able to assign the absolute conguration through a successful semi-synthesis from methyl (+)-hardwickiate; again, they utilised the KDM rearrangement to reveal the key butenolide. 131,132 Dysiodiolide (191) is a natural product isolated form the marine sponge Dysidera etheris and is a potent inhibitor of the human cdc25A protein phosphatase. 133 This natural product has received considerable attention since is identication in 1996.…”