High-yielding total synthesis of embelin, rapanone, and irisoquin A, D, F†

Abstract

Simple and sustainable three- and four-step sequences of di-OH-protection/mono-OMe-deprotection/OrgRC and di-OH-protection/mono-OMe-deprotection/OrgRC/OMe-deprotection protocols were developed to construct biologically active natural products of irisoquin, irisoquin A, irisoquin D, irisoquin F, sorgoleone-364, embelin, rapanone, 5-O-methylembelin, 5-O-methylrapanone and their analogues from the commercially available 2,5-dihydroxy-1,4-benzoquinone, aliphatic aldehydes and Hantzsch ester (1,4-DHP) in very good to excellent yields by using organocatalytic reductive coupling (OrgRC) as key reaction. Many of these natural compounds exhibited a broad spectrum of biological activities including antioxidant, anti-inflammatory, anticonvulsant, anxiolytic, analgesic, anthelmintic, antitumor, antibacterial, and antifertility properties. At the same time, simple and readily available 2,5-dihydroxy-1,4-benzoquinone was transformed into a functionally rich library of 2,5-dihydroxy-3,6-dialkyl-1,4-benzoquinones in very good yields by using sequential OrgRC followed by deprotection reactions and resulting natural/unnatural products would be excellent targets for investigation to show their biological activities compared to known natural products. Further, we tried to synthesize another mero-sesquiterpenoid of (+)-cyclospongiaquinone-1 from a chiral bicyclic aldehyde and hydroxy-1,4-benzoquinone by using OrgRC followed by etherification reactions, but we ended up with the synthesis of their ring-open analogues in good yields. The high-yielding gram-scale chemoselective synthesis of natural products irisoquin and demethylated-irisoquin demonstrated the potential to conduct these processes on larger scales.