Total Synthesis of Isosilybin B

Abstract

In memory of Toshiyuki KanWe report the first total synthesis of isosilybin B (4). Our synthetic strategy features the modified Julia-Kocienski olefination reaction developed in our laboratory between m-NPT sulfone 19 and aldehyde 27, the construction of benzodihy-dropyran 34 via formation of a quinomethide intermediate under acidic conditions and the oxidation of benzodihydropyran to flavanonol 37.

Total Synthesis of (+)-Silybin A

“…With the requisite aldehyde 21 in hand, we next examined olefination reaction to obtain alkene 22. Based on our previous finding that the modified Julia-Kocienski reaction with m-nitrophenyltetrazole sulfone m-NPT sulfone proceeded smoothly to afford the corresponding alkene in good yield with excellent geometric control, 21,26,27) we expected that this reaction would also be applicable to the present case. To our delight, upon treatment of a mixture of m-NPT sulfone 10 and aldehyde 21 with lithium bis(trimethylsilyl) amide (LiHMDS) in tetrahydrofuran (THF), the desired alkene 22 was formed in 83% yield with an E/Z ratio of >30 : 1.…”

“…The required diol precursor 7 could be obtained through a reaction sequence consisting of modified Julia-Kocienski olefination reaction between aldehyde 9 and m-nitrophenyltetrazole sulfone (m-NPT sulfone, 10) 26,27) and Sharpless dihydroxylation of alkene 8. 28) The (7′R,8′R)-1,4-benzodioxane 9 22) and m-NPT sulfone 10 21) would be synthesized according to our reported procedures.…”

“…20) In 2022, we reported a total synthesis of (−)-isosilybin B (4), in which the key step was the construction of the flavanol skeleton through the formation of a quinomethide intermediate under acidic conditions. 21) To our knowledge, however, total syntheses of silybin A (1) and B (2) have not yet been reported (Fig. 1).…”

Total synthesis of (−)-domoic acid, a potent ionotropic glutamate receptor agonist and the key compound in oceanic harmful algal blooms

“…We planned to introduce the side chain fragment at a late stage into the aldehyde intermediate 4 having the C1′–C2′ Z -double bond using the modified Julia–Kocieński reaction developed by our group. 11 The efficient stereo-control of the C1′–C2′ Z -configuration can be achieved by selective reduction and opening of the unsaturated lactam intermediate 6 . With the nitrogen functionality thus obtained, the pyrrolidine core can be formed through five-membered iminium formation, followed by the Strecker-type reaction to afford the C2 functionality.…”

“…Treatment of 22 with Dess–Martin periodinane resulted in the formation of α,β-unsaturated aldehyde 4 , the precursor for the side-chain formation. Using the m -nitrophenyltetrazolyl sulfone reagent 23 prepared from methyl ( R )-3-hydroxyisobutyrate and LHMDS as a base, the Julia–Kocieński-type reaction 11,25 efficiently proceeded to furnish 24 having the complete carbon framework of 2 with the appropriate stereochemistry. 26 We chose the allyl ester for protection at the C5′ position because this carbon was prone to epimerization due to the allylic position with ester functionality; the allyl group deprotection under neutral conditions and palladium catalysis 27 allowed stereochemical control at the sensitive position.…”