Total Synthesis of Mersicarpine through a Cationic Cyclization Approach

Abstract

A concise total synthesis of mersicarpine is achieved by exploiting a cyclic carbamate for generation of a tertiary carbocation. The key step involves intramolecular Friedel-Crafts alkylation with this carbocation for the construction of a quaternary carbon center and a subsequent oxidation and cyclization cascade for the formation of a seven-membered cyclic imine. The chemistry allowed for a rapid one-pot synthesis of mersicarpine from a simple intermediate using straightforward chemical operations.

Total Synthesis of Leuconoxine, Melodinine E, and Mersicarpine through a Radical Translocation–Cyclization Cascade

“…A functionalization of the indole C2 carbon forms the valerolactam substructure producing 8 , followed by cyclization leading to the target alkaloids. This strategy has been used in a divergent synthesis of 2 , 3 , and 4 ; however, it is particularly common for mersicarpine ( 4 ) –…”

Pd-Catalyzed Aerobic Oxidative Heck Cross-Coupling for the Straightforward Construction of Indole δ-Lactams

“…The efficient construction of the δ-lactam-containing (Figure 1, highlighted in red) ring-fused system has been the key issue of intensive synthetic efforts. The reported methods include free radical-induced cyclization (Magolan and Kerr, 2006, Magolan et al., 2008, Biechy and Zard, 2009, Zhu et al., 2015, Yu et al., 2016a, Yu et al., 2016b), Heck cross-coupling (Umehara et al., 2014, Iwama et al., 2013), and Friedel-Crafts reactions (Feng et al., 2015, Lv et al., 2014, Zhong et al., 2012, Zhong et al., 2014, Zhong et al., 2015, Liang et al., 2016, Zheng et al., 2018) at C 20 −C 21 ; the amidation of ester (Xu et al., 2013, Xu et al., 2015, Nakajima et al., 2010, Higuchi et al., 2015, Li et al., 2015) or oxidative amidation of alcohol (Pfaffenbach and Gaich, 2015) at N 1 −C 2 ; and the transannular cyclization (Yang et al., 2014a, Yang et al., 2014b, Dagoneau et al., 2016) of an aryl amide with ketone functionality via N 1 −C 21 .

Figure 1Selected Structures of Leuconoxine Subfamily

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Indole, a Privileged Structural Core Motif

“…The total synthesis of the monoterpene alkaloid mersicarpine (10) was reported in 2014 by Liang's group. 10 The synthesis involves the nucleophilic attack of the NH of the indole 7 to the activated carboxylic acid 8, giving the corresponding amide intermediate 9.…”

“…The total synthesis of the monoterpene alkaloid mersicarpine (10) was reported in 2014 by Liang's group. 10 The synthesis involves the nucleophilic attack of the NH of the indole 7 to the activated carboxylic acid 8, giving the corresponding amide intermediate 9. This allows access to indole analogue 10, an unusual seven-membered cyclic imine fused with a δ-lactam with two stereogenic centers.…”