Triene Cyclizations. The Total Synthesis of Pallescensin A

Abstract

The total synthesis of pallescensin A has been achieved using a six x , thermal electrocyclization reaction as the key step.Pallescensin A, is a furanosesquiterpenoid marine natural product isolated from the sponge Disidea pallescens.l It is postulated to be involved in the chemical defense mechanism of the opisthobranch molluscs, which concentrate sponge metabolites in their skin glands and, when in danger, employ them in defensive secretions.2There have been a number of syntheses of pallescensin A reported at the time of this writing (vide infra). Three of these approaches make use of cationic cyclizations between a furan and one or more olefin units3 and generally suffer from the fact that both cis-and transring junctures are produced during the cyclizations. A second type of approach relies on a phenoVfuran interconversion whose key step is the ozonolysis of an extensively-modified derivative of dehydroabietic acid.4 Finally, the most 1655 1656 LIOTTA AND OTT recent approach involves the conversion of enantiomerically-pure Wieland-Miescher ketone to a decalone keto aldehyde, which is then transformed to 1 via a cyclization/dehydration sequence.5 Nasipun et al p 0In this communication we wish to report our approach to the total synthesis of pallescensin A which utilizes a thermal, six II: electrocyclization of furanodiene 6 as its key step (see Scheme I).Intermediate 6 was prepared in three steps from compounds j! and 3.6Addition of furylacetylide 3 to trimethylcyclohexanone, 2, resulted in the formation of acetylenic alcohol 4, which was isolated in a pure enough state to be used without further purification. Exposure of this material to boron trifluoride etherate resulted in clean dehydration to produce 5 in 77% overall yield from 2 and 3. Lindlar hydrogenation of 5 proved to be problematic. If the reaction was allowed to proceed until all the starting material was consumed (as monitored by TLC), then significant amounts of overreduction products were observed. This problem was circumvented by allowing the reduction to only proceed to 50%completion. The starting material and product could then be easily Downloaded by [University of Chicago Library] at 19:50 16 November 2014 1657 TRIENE CYCLIZATIONS separated by silica gel chromatography. Using this approach, no other side products were observed and the starting material could be recycled in subsequent runs. The thermolysis of 6 was carried out in a sealed tube with either benzene of toluene as a solvent. (Note: if deuterobenzene was used in place of benzene, the reaction could be carried out in a sealed NMR tube and monitored by NMR.) Thermolysis temperatures typically ranged from 1600 to 200OC. If the temperature of the thermolysis exceeded 21 OOC, then large amounts of unidentified by-products were obssnred. Scheme I 5 6 z Scheme II I F I Downloaded by [University of Chicago Library] at 19:50 16 November 2014 1658 LIOTTA AND OTTA number of features of the key cyclization step are noteworthy.First, according to the Woodward-Hoffman rules, 5 should undergo t...

Marine natural products

“…Both aaptamine (1 89) and demethyloxyaaptamine (1 9 1) have been synthesized in good overall yield^.'^^. '^^ Three metabolites of a Pacific species of Reniera,15' namely renierone (192), N-formyl-1,2-dihydrorenierone (193), and the isoquinolinequinone (194). were synthesized in good yields by using a method that enabled replacement of the angelate ester by many other ester groups.…”

Silica gel in organic synthesis

“…The use of silica gel in the synthesis of the sesquiterpene pallescensin A (12) has been described. 6 Trimethylcyclohexanone 13 and furylacetylenide 14 were used as the starting compounds. The addition of acetylenide 14 to cyclohexanone 13 and subsequent dehydration of the reaction product followed by hydrogenation over Lindlar's catalyst yield the derivative 15; its cyclisation on silica gel affords the trans-fused tricyclic product 16.…”