A Concise Total Synthesis of (+)-Scholarisine A Empowered by a Unique C–H Arylation

Abstract

The structurally unique akuammiline alkaloid (+)-scholarisine A was synthesized in 14 steps from a known enone (15 steps from commercial materials) through a route empowered by a unique C-H arylation reaction to forge its polycyclic core. Additional key steps include a pyrone Diels-Alder reaction and a radical cyclization/Keck allylation to fashion the core cage polycycle and one of the molecule's quaternary centers, as well as the use of a carefully positioned pendant hydroxyl group to facilitate the chemoselective reduction of an extremely unreactive lactam in the presence of a readily reduced lactone.

Evolution of a Polyene Cyclization Cascade for the Total Synthesis of (−)‐Cyclosmenospongine

“…Traces of m ‐chlorobenzoic acid that are formed during the generation of the sulfoxide have a detrimental effect and inhibit the progress of the reaction. For the completion of the synthesis, we first unmasked the vicinal cis ‐dimethyl group with the aid of Raney nickel . The ketone function was then fully reduced upon exposure to lithium aluminum hydride (LiAlH 4 ) followed by treatment with triethylsilane (Et 3 SiH) in the presence of boron trifluoride etherate (BF 3 ⋅OEt 2 ) to give 37 .…”

Total Synthesis of Strychnine

“…Numerous Fischer‐indolization conditions were examined on aldehyde 18 but largely afforded complex mixtures, or a speculated 1,2‐migratory product 20 instead of the desired spirocyclic imine 19 . Inspired by the work of Smith and Snyder in their total synthesis of scholarisine A, conceptually related 1,5‐radical abstraction or transition‐metal based CH‐activation type processes also did not prevail. Recognizing the nucleophilicity of TBS enol ether 6 , a palladium‐catalyzed direct arylation reaction was also attempted but largely afforded intractable reaction mixtures.…”

Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)-Cathafoline, and (−)-Aspidophylline A

“…5 With regard to the skeletally rearranged akuammilines, breakthroughs include total syntheses of vincorine ( 4 ) by Qin, 6 Ma, 7 and MacMillan, 8 and total syntheses of scholarisine A ( 5 ) by Smith 9 and Snyder. 10 …”