Total Synthesis of the Caged Indole Alkaloid Arboridinine Enabled by aza-Prins and Metal-Mediated Cyclizations

Abstract

Although alkaloid natural products possess incredible diversity when considered broadly, certain domains are sometimes shared by several members, even from different sub-collections. Such homology can point to potential synthetic strategies. Herein, we highlight how such an analysis of the natural product arboridinine pinpointed two key elements of structural similarity that suggested the value of a metal-mediated 6-endo-dig cyclization to fashion its tetracyclic indolenine core, as well as the need to develop what could be considered a reversed polarity aza-Prins cyclization to deliver its tertiary allylic alcohol and final cage structure. The power of the latter design element is highlighted by several failures in achieving similar functional group patterning through more traditional aza-Prins and Mannich cyclization strategies. Overall, these operations fueled an inaugural 13-step racemic synthesis of the target; exploration of varied solutions for the enantioselective preparation of a key 7-membered indole-containing piece afforded a 16-step formal asymmetric solution.

Synthesis of Natural Products by C−H Functionalization of Heterocycless

“…In 2018, Synder and co‐workers reported the total synthesis of arboridinine, a cage‐containing indole alkaloid featuring a complex tetracyclic indolenine core (Scheme 11). [36] One of the early steps involved Ir‐catalyzed intermolecular C−H functionalization at the C2 position of indole using 3° alkyl halides. In this method, photoredox catalysis enables the formation of the reactive tertiary radical intermediate, which undergoes addition to the Boc‐protected tryptamine at the electron‐rich C2 position to afford substituted malonate esters.…”

Heteroarene‐tethered Functionalized Alkyne Metamorphosis

“…Af our-step transformationo fi ndolenine derivative 630 followed by aza-Prins cyclization furnishes the arboridinine 633 (Scheme 161). [183] In the first total synthesis of photo-protecting dipyrrolobenzoquinone natural product (+ +)-terreusinone 636,W ang and Sperryu tilized gold-catalyzed intramolecular hydroamination of indole-tethered propargyl alcohol derivative 634 as one of the key steps (Scheme 162). [184] Recently Ohno et al achieved af ormal synthesis of (AE)-Strictamine 644,a na kuammiline alkaloid havingacage like Scheme158.…”

“…A four‐step transformation of indolenine derivative 630 followed by aza ‐Prins cyclization furnishes the arboridinine 633 (Scheme 161). [183] …”

Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine

“…In 2018, the Snyder group reported the first racemic synthesis of arboridinine ( 1 ) and a 16‐step formal asymmetric synthesis involving a silver‐mediated 6‐ endo ‐dig cyclization (Scheme 1 a). [8] The Zhai and Li group disclosed an asymmetric total synthesis of (+)‐arboridinine ( 1 ) featuring a highly stereoselective double‐Mannich reaction and a cobalt‐catalyzed decarboxylative acetoxylation [9] . Qin and Song succeeded in adopting an aza‐Michael reaction to construct the tetracyclic skeleton of arborisidine ( 2 ) [10] .…”

“…While each disclosed strategy mainly focused on a single natural product, arboridinine or arborisidine (Scheme 1 a, b), [8–13] a unified synthetic strategy to access both skeletally distinct alkaloids would be highly desirable. In contrast to target‐oriented synthesis, diversity‐oriented synthesis aims to access a collection of natural products with appendage, functional group, stereochemical, or scaffold diversity [14] .…”