Total Synthesis of the Diterpenoid Alkaloid Arcutinidine Using a Strategy Inspired by Chemical Network Analysis

Abstract

Arcutinidine and other arcutinidine-type diterpenoid alkaloids feature an intricate polycyclic, bridged framework with unusual connectivity. A chemical network analysis approach to the arcutane skeleton enabled the identification of highly simplifying retrosynthetic disconnections, which indicated that the caged structure could arise from a simpler fused ring system. On this basis, a total synthesis of arcutinidine is reported herein, featuring an unprecedented oxopyrrolium Diels− Alder cycloaddition which furnishes a key tetracyclic intermediate. In addition, the synthesis utilizes a diastereoselective oxidative dearomatization/cycloaddition sequence and a SmI 2 -mediated C−C coupling to forge the bridged framework of the natural products. This synthetic plan may also enable future investigations into the biosynthetic relationships between the arcutanes, the related diterpenoid atropurpuran, and other diterpenoid alkaloids.Communication pubs.acs.org/JACS

Fe‐Catalyzed Anaerobic Mukaiyama‐Type Hydration of Alkenes using Nitroarenes

“…The hydration of alkenes in the presence of a transition metal catalyst, oxygen and a reductant has been intensively investigated in the past with the first studies being published already in the 1980s (Scheme 1 a). [2–14] In these cascades, mainly first row transition metals (Fe/Co/Mn) have been applied [15] . Moreover, O 2 is generally used as the C‐radical oxygenation reagent in a reaction that proceeds either near the diffusion limit or diffusion‐controlled and accordingly is difficult to run with high stereoselectivity in non‐rigid systems [16–18] .…”

Fe‐Catalyzed Anaerobic Mukaiyama‐Type Hydration of Alkenes using Nitroarenes

“…[1] The hydration of alkenes in the presence of at ransition metal catalyst, oxygen and ar eductant has been intensively investigated in the past with the first studies being published already in the 1980s (Scheme 1a). [2][3][4][5][6][7][8][9][10][11][12][13][14] In these cascades, mainly first row transition metals (Fe/Co/Mn) have been applied. [15] Moreover,O 2 is generally used as the C-radical oxygenation reagent in ar eaction that proceeds either near the diffusion limit or diffusion-controlled and accordingly is difficult to run with high stereoselectivity in non-rigid systems.…”

Retrosynthetic strategies and their impact on synthesis of arcutane natural products

“…There are three reported syntheses of arcutane alkaloids to date-by the Qin, 32 Sarpong, 33 and Li 34 groups-all of which were published in close succession in 2019. Qin and Sarpong identied similar bond-network disconnections, but with very different outcomes.…”

“…Here, we discuss the Sarpong group's synthesis rst. 33 Similar to Qin's retrosynthetic strategy, the Sarpong synthesis took advantage of the bond-network derived disconnection set 2.2. The synthesis began by bringing together known starting materials 60 and 61 through a Wittig reaction.…”