Assembling the prenylneoflavone system through a Pechmann condensation/Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis sequence

Abstract

The multistep synthesis of a prenylneoflavone through a sequence of the Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis reaction has been accomplished in 5% yield over six steps starting from commercially available 3-methoxyacetophenone. The sequence is shown to be compatible with a Pechmann condensation which proved to be a robust and cost-effective method for the assembling of the α-pyrone core. The results open doors to a general approach to the prenylneoflavone system starting from phenol and acetophenone derivatives. Graphic abstract

Scope and Applications of 2,3-Oxidative Aryl Rearrangements for the Synthesis of Isoflavone Natural Products

“…Isobutene, which has also been used for this cross metathesis reaction, has the disadvantage of being a gas at ambient temperature but gives the prenylated products in comparable yields and selectivity . Originally introduced by Grubbs and co-workers, CM reactions with 2-methyl-2-butene have been used for the synthesis of prenylated flavanones, flavones, isoflavones, , coumarins, ,− and other natural products. − The cross metathesis reactions of allyl isoflavones 32g – i and their flavone isomers 33g – i with 2-methyl-2-butene in the presence of 5 mol % second generation Grubbs’ catalyst A at ambient temperature furnished the respective prenyl isoflavones 12 , 35h , i , and prenyl flavones 36g – i in high yields and selectivity. The MOM-ethers 35h and 36h could be deprotected in methanol in the presence of aqueous HCl without concomitant acid catalyzed addition of methanol to the prenyl substituent (Scheme ).…”

Total Syntheses of Prenylated Isoflavones from Erythrina sacleuxii and Their Antibacterial Activity: 5-Deoxy-3′-prenylbiochanin A and Erysubin F

“…This has also been observed with phenols, but was not expected to be a problem in this case because the phenolic group is not in proximity to the allyl substituent. 2-Methyl-2-butene has emerged as a valuable and convenient-to-handle cross-metathesis partner for the regioselective construction of prenyl substituents and was also used in this study. − The 3′-allylisoflavone 16a was converted into 5-deoxy-3′-prenylbiochanin A ( 7a ) in the presence of 5 mol % of second-generation Grubbs catalyst ( A ) in high yield and 100% regioselectivity. THF was used as a solvent because 16a is sparingly soluble in CH 2 Cl 2 , which would normally be the solvent of choice for metathesis reactions.…”

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

“…Prenylneoflavones are derivatives of neoflavones whose synthesis has been reported by Lozinski et al in 2020. They employed a Mitsunobu reaction, olefin cross-metathesis reaction, and Claisen rearrangement as key steps to obtain a 5% overall yield in six steps [ 58 ]. The first step involved the conversion of 3-methoxyacetophenone 182 to neoflavone 183 in a 52% yield via Claisen rearrangement in the presence of diethyl carbonate, and Pechmann condensation in the presence of resorcinol in sulfuric acid.…”