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

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.

Gilman reagent toward the synthesis of natural products

“…45 Owing to this fact, Yadav et al in 2019 disclosed an efficient methodology for the synthesis of (+)-epiquinamide 7 by employing Gilman reagent-induced aziridinium ion ring opening reaction as the key step (Scheme 8). 46,47 In their methodology, compound 73 (modied from aziridine carboxylate 72) was treated with methyl cyanide to provide aziridinium intermediate 74, which underwent ring opening reaction via treatment with reagent 75 in the presence of copper iodide and 1,4-dioxane as a solvent (for the in situ generation of Gilman reagent). The temperature was adjusted to 0 °C and the synthesis of compound 76 was achieved in 57% yield.…”

Synthetic Applications of Aziridinium Ions

“…This convenient approach renders the construction of various types of aza-rings with substituents from nucleophilic attacks either at the bridgehead or at bridge positions of bicyclic aziridinium ions without loss of the substrate's stereochemistry [65]. This synthetic strategy can be used to obtain many biologically active alkaloids and their analogues including fagomine, febrifugine, balanol, conine, and epiquinamide, as shown in Figure 4 [22,23,31,66]. This convenient approach renders the construction of various types of aza-rings with substituents from nucleophilic attacks either at the bridgehead or at bridge positions of bicyclic aziridinium ions without loss of the substrate's stereochemistry [65].…”

A short and efficient formal synthesis of (R)-pipecolic acid from the ring expansion of chiral aziridine

“…1). Activated aziridines are quite reactive towards ring opening reaction without further activation [13,14], while non-activated aziridine is quite stable and inert to the nucleophiles, unless it is activated as an aziridinium ion (Scheme 1) [15][16][17][18][19][20][21]. Activation of aziridine nitrogen with external electrophile (3a) followed by ring opening reaction results in the formation of acyclic compound 4.…”

“…Activation of aziridine nitrogen with external electrophile (3a) followed by ring opening reaction results in the formation of acyclic compound 4. In-situ formation and characterization of an bicyclic aziridinium ion were observed spectroscopically with non-reactive counting anion [18,19,21]. Proper selection of activating agents i.e.…”

“…Proper selection of activating agents i.e. electrophylic reagent and the nucleophile may afford pyrrolidine (6) and piperidines (7) via the regio-and stereoselective ring-opening reaction [15][16][17][18][19][20][21].…”