Abstract
Alkylative ring-opening of bicyclic aziridinium ion generated from 4-hydroxybutylaziridine with organocopper reagent was achieved successfully to afford 2-alkylsubstituted piperidine in high or moderate yield. This method allowed carbon-carbon bond formation of “non-activated” aziridine via aziridinium ion ring-opening in regio- and stereo-selective manner for the first time. This newly developed reaction was applied for an efficient synthesis of alkaloid with the representative example of conine and epiquinamide.
Highlights
Aziridine as a nitrogen-containing three membered ring has high ring-strain described as a “spring-loaded” compound by Yudin in his book (Yudin, 2006)
For the successful reactions with these heteroatom nucleophiles, the aziridine ring should be activated as aziridinium ion in the presence of acids (Kim et al, 2006; Stankovicet al., 2012)
The bioavailability and importance of 2-alkyl piperidines as key intermediate for synthesis of various bioactive compounds encourage us to develop an efficient method for these systems from chiral aziridines
Summary
Aziridine as a nitrogen-containing three membered ring has high ring-strain described as a “spring-loaded” compound by Yudin in his book (Yudin, 2006). We succeeded in regio- and stereoselective ring opening reaction of stable bicyclic aziridinium ion by diverse heteroatom nucleophiles to get various pipiridines and azepane in good to excellent yields (Ji et al, 2014; Eum et al, 2015; Dolfen et al, 2016; Choi et al, 2017; Yadav and Ha, 2018; Macha et al, 2019) In continuation of this chemistry, we report the alkylative, regio-, and stereo-selective ring-opening of 1azoniabicyclo[4.1.0]heptanes tosylate by various organocopper reagents to afford piperidines with carbon-chain extension at C2 position. This selective transformation allow us to access various biologically important natural products with representative examples including (+)-conine (Hattori and Yamamoto, 1993; Hirai and Nagatsu, 1994; Munchhof and Meyers, 1995; Reding and Buchwald, 1998), and (+)-epiquinamide (Suyama and Gerwick, 2006; Tong and Barker, 2006; Srivastava et al, 2009; Airiau et al, 2010) in highly efficient manner
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