Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

Abstract

The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8-endo-dig hydroarylation and a 6-exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided.

Buchwald‐Type Ligands on Gold(I) Catalysis

“…Recently, our group has demonstrated the potential of the gold-catalyzed intramolecular hydroarylation of indoles to construct the pyrroloazocine indole core in 17 [61] which was later applied in the total syntheses of Kopsia alkaloids [62] (À )lundurines A-C [63] and seven members of the lapidilectine/ grandilodine family. [64] Analogously, gold(I) complexes supported by Buchwaldtype phosphines are able to modulate the reactivity of 1,6enyne bearing propargylic alcohols, ethers or silyl ethers. In fact, enynes with a propargyl acetate such as 18 react in presence of gold(I) catalyst E via cyclopropyl gold(I) carbene 19 to form an intermediate that can be represented as an α,βunsaturated gold(I)-carbene (20) or a gold(I) stabilized allyl cation (21) via 1,5-migration of the OAc group (Scheme 6).…”

“…Recently, our group has demonstrated the potential of the gold‐catalyzed intramolecular hydroarylation of indoles to construct the pyrroloazocine indole core in 17 which was later applied in the total syntheses of Kopsia alkaloids (−)‐lundurines A‐C and seven members of the lapidilectine/grandilodine family …”

Total Synthesis of Lapidilectine B Enabled by Manganese(III)‐Mediated Oxidative Cyclization of Indoles

“…The unique structures and interesting biological activities of these Kopsia alkaloids have prompted their synthetic studies from a number of research groups . As a result, Nishida,– Qin, and Echavarren, groups have achieved the total synthesis of lundurine‐type alkaloids by using radical cyclization, an intramolecular Simmons–Smith reaction, and gold‐catalyzed cyclization as the key steps, respectively. Zu and co‐workers accomplished the first total synthesis of grandilodine B ( 6 ) via construction of the key spiro‐indoline intermediate with a Diels–Alder reaction.…”

Selectivity in Ring‐Closing Metathesis: Synthesis of Propellanes and Angular Aza‐tricycles

“…[5] For example, synthesis of cis-syn-cis triquinane [6] over the propellanes, [7] tandem ring-closing metathesis (RCM) [8] followed by aromatization, chemo-selective self-metathesis [9] and crossmetathesis (CM) reactions. The propellanes [11] and angular aza-tricycles are generally found as core structural units in biologically active natural products [12] (Figure 1) such as kopsia indole alkaloids (e. g., fruticosine and kopsanone) [13] and erythrina alkaloids [14] (e. g., isococculidine and b-erythrodine). Fischer indolization and Grignard reactions are used as key steps to prepare the substrates required for RCM.…”

“…Fischer indolization and Grignard reactions are used as key steps to prepare the substrates required for RCM. The propellanes [11] and angular aza-tricycles are generally found as core structural units in biologically active natural products [12] (Figure 1) such as kopsia indole alkaloids (e. g., fruticosine and kopsanone) [13] and erythrina alkaloids [14] (e. g., isococculidine and b-erythrodine). [15] More specifically, this method is applicable for the synthesis of compounds containing quaternary carbon centers, present in several naturally occurring alkaloids ( Figure 1).…”