Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine

Abstract

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site‐selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site‐selective intramolecular α‐amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

Formal Synthesis of Arboridinine Enabled by a Double-Mannich Reaction

“…The core skeleton was finally formed through an intramolecular dearomative alkylation by them. Recently, we finished the synthesis of arboridinine ( 1 ) and arborisidine ( 2 ) using a divergent synthetic strategy (Scheme b) . A site-selective intramolecular Mannich reaction was adopted to establish the tetracyclic skeleton.…”

“…Our approach to arboridinine ( 1 ) emanated from tricyclic compound 11 , which was given through the reaction of tryptamine derivative 9 and 4-hexen-3-one ( 10 ) as disclosed in our previous report (Scheme ). In line with the strategy aforementioned, an ester group needs to be installed to realize the decarboxylative acetoxylation at the late stages of synthesis. A highly regioselective α-carboethoxylation of 11 with NCCO 2 Et using NaHMDS as the base resulted in β-keto ester 7 as a single diastereomer in 78% yield at −78 °C .…”

“…Upon treatment of the resultant amine with paraformaldehyde or formalin in the presence of diverse acids, such as hydrochloric acid, trifluoroacetic acid, p -toluenesulfonic acid, or formic acid, , no desired product was detected (entries 1–6, Table ). Fortunately, the complex caged pentacyclic core skeleton 8 of arboridinine could be isolated in low yield when ammonium formate was used (entries 7 and 8) . Switching to ammonium acetate − resulted in a better result, giving 8 in 32% yield (entry 9).…”

“…Our experience in the previous synthesis of arboridinine also showed that olefination was not feasible with a similar substrate embedded with an acetate at the same position. We thus had to resort to a multistep silicon-tethered reaction in nucleophile delivery, an intramolecular Peterson olefination specifically, to solve the problem . Although these precedents indicate that olefination of the C15 carbonyl group is problematic, unexpectedly, olefination of 8 could be operated with a typical Peterson olefination process, a strategy that has been adopted by Zhai and Li in the olefination of their tetracyclic framework of arboridinine. , The desired β-silylcarbinol 12 could be obtained without event in 60% yield through intermolecular nucleophilic addition with TMSCH 2 Li at 60 °C.…”

“…Next, N -debenzylation of 13 was investigated. Exposure of 13 to the conventional conditions Li/NH 3 (l) resulted in reduction of the ester . Owing to the presence of the exocyclic double bond in 14 , hydrogenation would not be suitable.…”