Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes

Abstract

The formation of the stable form of 1-azabicyclo[4.1.0]heptane tosylate was successfully achieved from 2-[4-tolenesulfonyloxybutyl]aziridine, by stirring in MeCNa t room temperature. The ring strain in the three-membered ring could be released through the cleavageo fe ither CÀN bond, but ring opening with various nucleophilesproceeded in ah ighly regio-ands tereoselective manner.T wo possible pathways, in which the aziridine ringw as opened by nucleophilic attack at the bridge and the bridgehead, yielded piperidine and azepane rings, respectively.T his selective transformation starting from chiral aziridines constitutes an efficient route for the asymmetric synthesis of biologically importantn atural products, such as fagomines,f ebrifugine, sedamine, hydroxypipecolic acid, and balanol.

Alkylative Ring-Opening of Bicyclic Aziridinium Ion and Its Application for Alkaloid Synthesis

“…Optically active conine, the poisonous hemlock alkaloid is a very important among piperidines alkaloids (Hattori and Yamamoto, 1993; Hirai and Nagatsu, 1994; Munchhof and Meyers, 1995; Reding and Buchwald, 1998; Jo et al, 1999; Pachamuthu and Vankar, 2001; Chacko and Ramapanicker, 2015). Using our strategy, we were able to synthesized N -Boc-conine 5 in optically pure form in few steps from 1-azoniabicyclo[4.1.0]heptane tosylate 2 , which was easily access from commercially available chiral aziridine (Choi et al, 2017) (Scheme 2).…”

“…Synthesis of N -Boc-conine 5 was initiated by the preparation of bicyclic aziridinium ion 2 (Choi et al, 2017) followed by its ring expansion with EtMgBr and CuI in 1,4-dioxane as solvent to yield the compound 3b in 64% yield in two steps. One-pot debenzylation followed by Boc-protection furnished N -Boc-conine 5 in 70% yield whose Boc group would be removed by the known procedure yielding the natural product conine 6 .…”

“…The importance of this receptor encourages us to utilize our strategy for its synthesis. The formal synthesis of (+)-epiquinamide 7 began with our previously prepared hydroxybutyl aziridine 9 from aziridine carboxylate 8 (Scheme 3) (Choi et al, 2017).…”

“…However, no synthetic method is available to construct piperidine ring with concomitant introduction of the proper alkyl group at the alpha-position of the piperidine ring. Recently, 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 herein report the alkylative, regio-, and stereo-selective ring-opening of 1-azoniabicyclo[4.1.0]heptanes tosylate by various organocopper reagents to afford piperidines with carbon-chain extension at C2 position.…”

Synthetic Applications of Aziridinium Ions

“…Aziridinium ions can also be generated upon expulsion of the leaving group at the β-position of amine of the acyclic starting substrate (Equation (2i), in Scheme 2 ) [ 18 , 19 ]. The same strategy to expulse the leaving group from the pendant of aziridine or 2-leaving group substituted methyl aza-cycle yielded a bicyclic aziridinium ion (Equation (2ii), in Scheme 2 ) [ 22 , 23 ]. The same bicyclic aziridinium ion can also be derived from removal of the leaving group at the β-site of cyclic starting substrates through aza-ring contraction (Equation (2iii), in Scheme 2 ) [ 24 , 25 ].…”