Three-Component Tandem Knoevenagel/Hetero Diels−Alder Reactions − Total Synthesis of (±)-Preethulia Coumarin

Abstract

Starting from 4-hydroxy-5-methylcoumarin (7), (±)-preethulia coumarin (3) was synthesized in six steps and in 4% overall yield. The key synthetic procedure was a new type of Lewis acid catalysed, three-component Knoevenagel/hetero Diels−Alder reaction, which employs α-dicarbonyl comOver the past few decades, an impressive variety of prenylated 5-methylcoumarins have been characterised, mainly from plants belonging to the Mutisieae tribus of the Compositae family. [1] These prenylated polyketides represent a significant addition to the shikimate-derived coumarins from umbelliferous and rutaceous plants, a class of compounds extensively investigated for their anticoagulant and phototoxic properties. [2] Interest in polyketide coumarins was sparked by the discovery of the powerful anthelmintic [3] and molluscicidal [4] properties of ethuliacoumarin A (1), a constituent of the Egyptian medicinal plant Ethulia conyzoides L. [5] The related analogues 2Ϫ4 were also isolated, [6] and some of them showed biological activity comparable to 1. [4] All these compounds share a 4,10-dimethyl-4-vinylpyrano[3,2-c]coumarin core, and only differ in the oxygenation of C-2 and the norprenyl residue. The powerful biological activity of these compounds suggests interaction with a host-specific target. This, however, remains unidentified, and the pharmacological potential of these compounds, though recognised, is still untapped. Ethuliacoumarins are [a] 3711 pounds to generate chromandiones, and vinyl ethers to trap them. Some unexpected rearrangements were observed during the manipulation of various acetalic Diels−Alder adducts, resulting in the serendipitous assembly of bridgehead and fused tetracyclic coumarin assemblies. available in sizeable amounts by isolation, [5b] but their plant source is not readily available, nor is the number of natural analogues sufficient to sustain a significant medicinal chemistry effort. These considerations prompted us to develop a straightforward route to the acetal 6. This compound features the 4,4,10-trisubstituted pyrano[3,2-c]coumarin core of ethuliacoumarins, and offers the potential to afford a library of analogues by modification of the oxygen function at C-2 and of the acetyl substituent at C-4, as outlined retrosynthetically in Scheme 1. We report here an expeditious route to the acetal 6, its remodelling to the vinyl-substituted lactol 5 and the eventual straightforward conversion of the latter into (Ϯ)-preethulia coumarin (3), [6b] the least oxygenated member of ethulia coumarins. Scheme 1. Retrosynthetic analysis of preethulia coumarin (3)Our plan to assemble the acetal 6 entailed the development of a three-component tandem Knoevenagel/hetero DielsϪAlder reaction [7] between 4-hydroxy-5-methylcoumarin (7), diacetyl (ϭ 2,3-butandione, 8a) and a vinyl ether, with diacetyl serving the dual purpose of generating the chromandione intermediate and providing a double bond equivalent in the form of an acetyl group. The assembly of a pyran ring by tandem Knoevenagel/hetero DielsϪAlder

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…This compound showed identical spectroscopic properties identical data except the optical rotation to those of natural preethulia coumarin (485). 529 (R)-Dihydroactinidiolide (494) has been found as one of the three components of the pheromone involved in queen recognition of the workers of the red re ant, namely Soleneopsis invicta. 530 Due to importance of pheromones in controlling insects its, total synthesis has attracted much attentions.…”

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…This compound showed identical spectroscopic properties identical data except the optical rotation to those of natural preethulia coumarin (485). 529 (R)-Dihydroactinidiolide (494) has been found as one of the three components of the pheromone involved in queen recognition of the workers of the red re ant, namely Soleneopsis invicta. 530 Due to importance of pheromones in controlling insects its, total synthesis has attracted much attentions.…”

Natural Product Synthesis Using Multicomponent Reaction Strategies

“…112 Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (()-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers 113…”

“…Scheme 39. Synthesis of Preethulia Using a Three-Component Knoevenagel/Hetero-[4 + 2]-Cycloaddition/Retro-[4 + 2]-Fragmentation, by Appendino et al113 …”

“…Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (±)-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers started with a variant of the three-component Knoevenagel/hetero Diels−Alder reaction developed by Tietze and co-workers. Thus, 4-hydroxycoumarin ( 260 ), 2,3-butadione ( 261 ), and vinyl t -butyl ether ( 262 ) were combined under established reaction conditions to afford the desired MCR adduct 264 in a satisfactory yield (Scheme ).…”

Recent Advances in Solution-PhaseMulticomponent Methodology for the Synthesis of HeterocyclicCompounds

“…Commercial 2,3-butandione 262 proved a succesfull starting material in this MCR as well. 125 However, initial attempts to react 261, 262, and 263 under the above conditions failed. Subsequent optimization studies revealed that the reaction was best carried out in dry dioxane in the presence of molecular sieves and catalytic amounts of Yb(OTf) 3 , which allowed pyranocoumarin 264 to be obtained in good yield (Scheme 60).…”

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…This compound showed identical spectroscopic properties identical data except the optical rotation to those of natural preethulia coumarin (485). 529 (R)-Dihydroactinidiolide (494) has been found as one of the three components of the pheromone involved in queen recognition of the workers of the red re ant, namely Soleneopsis invicta. 530 Due to importance of pheromones in controlling insects its, total synthesis has attracted much attentions.…”

Natural Product Synthesis Using Multicomponent Reaction Strategies

“…112 Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (()-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers 113…”

“…Scheme 39. Synthesis of Preethulia Using a Three-Component Knoevenagel/Hetero-[4 + 2]-Cycloaddition/Retro-[4 + 2]-Fragmentation, by Appendino et al113 …”

“…Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (±)-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers started with a variant of the three-component Knoevenagel/hetero Diels−Alder reaction developed by Tietze and co-workers. Thus, 4-hydroxycoumarin ( 260 ), 2,3-butadione ( 261 ), and vinyl t -butyl ether ( 262 ) were combined under established reaction conditions to afford the desired MCR adduct 264 in a satisfactory yield (Scheme ).…”

Recent Advances in Solution-PhaseMulticomponent Methodology for the Synthesis of HeterocyclicCompounds

“…Commercial 2,3-butandione 262 proved a succesfull starting material in this MCR as well. 125 However, initial attempts to react 261, 262, and 263 under the above conditions failed. Subsequent optimization studies revealed that the reaction was best carried out in dry dioxane in the presence of molecular sieves and catalytic amounts of Yb(OTf) 3 , which allowed pyranocoumarin 264 to be obtained in good yield (Scheme 60).…”

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…This compound showed identical spectroscopic properties identical data except the optical rotation to those of natural preethulia coumarin (485). 529 (R)-Dihydroactinidiolide (494) has been found as one of the three components of the pheromone involved in queen recognition of the workers of the red re ant, namely Soleneopsis invicta. 530 Due to importance of pheromones in controlling insects its, total synthesis has attracted much attentions.…”

Natural Product Synthesis Using Multicomponent Reaction Strategies

“…112 Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (()-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers 113…”

“…Scheme 39. Synthesis of Preethulia Using a Three-Component Knoevenagel/Hetero-[4 + 2]-Cycloaddition/Retro-[4 + 2]-Fragmentation, by Appendino et al113 …”

“…Some analogues have also shown a similar activity profile, which rendered their syntheses rather valuable. The synthesis of (±)-preethulia coumarin by the groups of Appendino, Cravotto, and co-workers started with a variant of the three-component Knoevenagel/hetero Diels−Alder reaction developed by Tietze and co-workers. Thus, 4-hydroxycoumarin ( 260 ), 2,3-butadione ( 261 ), and vinyl t -butyl ether ( 262 ) were combined under established reaction conditions to afford the desired MCR adduct 264 in a satisfactory yield (Scheme ).…”

Recent Advances in Solution-PhaseMulticomponent Methodology for the Synthesis of HeterocyclicCompounds

“…Commercial 2,3-butandione 262 proved a succesfull starting material in this MCR as well. 125 However, initial attempts to react 261, 262, and 263 under the above conditions failed. Subsequent optimization studies revealed that the reaction was best carried out in dry dioxane in the presence of molecular sieves and catalytic amounts of Yb(OTf) 3 , which allowed pyranocoumarin 264 to be obtained in good yield (Scheme 60).…”