Abstract
SummaryA highly efficient phosphine-catalyzed enantioselective [4 + 2] annulation of allenoates with 3-nitroindoles or 3-nitrobenzothiophenes has been developed. The protocol represents a unique dearomatization–aromatization process to access functionalized dihydrocarbazoles or dihydrodibenzothiophenes with high optical purity (up to 97% ee) under mild reaction conditions. The synthetic utility of the highly enantioselective [4 + 2] annulation enables a concise synthesis of analgesic agent.
Highlights
Fused polycyclic indoles are common structural motifs found in a vast array of natural and biologically active molecules (Saxton, 1996; Knolker and Reddy, 2002; Schmidt et al, 2012; Tan and Cheng, 2019), such as kopsihainanine A, isoelliptitoxin, and analgesic agents (Scheme 1A) (Madalengoitia and Macdonald, 1993; Carmosin et al, 2000; Chen et al, 2011)
The synthetic utility of the highly enantioselective [4 + 2] annulation enables a concise synthesis of analgesic agent
We hypothesized that the development of new methods through the enantioselective phosphine-catalyzed [4 + 2] dearomatization would provide practical and efficient approach to this class of enantioenriched heterocycles (Scheme 1B)
Summary
Fused polycyclic indoles are common structural motifs found in a vast array of natural and biologically active molecules (Saxton, 1996; Knolker and Reddy, 2002; Schmidt et al, 2012; Tan and Cheng, 2019), such as kopsihainanine A, isoelliptitoxin, and analgesic agents (Scheme 1A) (Madalengoitia and Macdonald, 1993; Carmosin et al, 2000; Chen et al, 2011). The group of Jørgensen disclosed a novel [4 + 2] annulation by trienamine catalysis, obtaining dihydrocarbazoles in good yields and enantioselectivities (Li et al, 2016b) In this context, we hypothesized that the development of new methods through the enantioselective phosphine-catalyzed [4 + 2] dearomatization would provide practical and efficient approach to this class of enantioenriched heterocycles (Scheme 1B). We envisaged that heteroaromatic systems bearing an electron-withdrawing group could react with phosphine-mediated zwitterionic intermediate in a process involving the [4 + 2] reaction to achieve the chiral dihydrocarbazole scaffold (Scheme 1C) With this objective in mind, a readily available 3-nitroindole derivative was selected as a model substrate to investigate the optimum reaction condition for the enantioselective [4 + 2] dearomatization reaction using a phosphine catalyst
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