Enantioselective Total Synthesis of (−)-Alstoscholarisine A

Abstract

We report a concise and highly enantioselective total synthesis of (-)-alstoscholarisine A (1), a recently isolated monoterpenoid indole alkaloid that has significant bioactivity in promoting adult neuronal stem cells proliferation. A highly enantioselective (99% ee), intramolecular Ir-catalyzed Friedel-Crafts alkylation of indole 9 with a secondary allylic alcohol was utilized to establish the first stereogenic center upon which the other three contiguous chiral centers were readily set by a highly stereoselective tandem 1,4-addition and aldol reaction. The key tetrahydropyran was constructed through a hemiacetal reduction, and the final aminal bridge was forged by a one-pot reductive amination/cyclization. The conciseness of this approach was highlighted by building core bonds in each step with a minimalist protecting group strategy.

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

…”

Total Syntheses of the Monoterpenoid Indole Alkaloids (±)‐Alstoscholarisine B and C

“…A total synthesis of racemic alstoscholarisine A ( 1 ) was described in 2016 by Bihelovic and Ferjancic . In the same year, a synthesis of the natural (−)‐enantiomer of 1 was reported by Yang, et al . Our interest has primarily focused on developing a divergent synthetic approach to the more complex members of the series which bear a carboxyl group at C‐16, and in this Communication, we describe the first total syntheses of racemic alstoscholarisine B ( 2 ) and C ( 3 ).…”

Synthesis of two novel C-19 analogues of (±)-alstoscholarisine A

“…As a result, very elegant syn-936 BIHELOVIC, FERJANCIC and JONCEV theses of this intriguing molecule have been published so far, two racemic and two enantioselective syntheses. [11][12][13][14]…”