Diastereoselective Construction of Fused Carbocyclic Pyrrolidines via a Copper-Catalyzed [3 + 2] Cycloaddition: Total Syntheses of Pancratinines B–C

Abstract

A Cu-catalyzed diastereoselective [3 + 2] cycloaddition of 2-arylaziridines and cyclic silyl dienol ethers was developed to efficiently construct fused-[5,n] carbocyclic pyrrolidines, which are widespread in bioactive natural products. Mechanistic studies revealed that the high diastereoselectivity of this transformation arose from a sequential retro aza-Michael/epimerization/aza-Michael process. Taking advantage of this newly developed method, the first total syntheses of pancratinines B and C were concisely realized.

Asymmetric total synthesis of montanine-type amaryllidaceae alkaloids

“…Recently, our group reported a copper-catalyzed [3 + 2] annulation reaction to synthesize fused-[5, n ] carbocyclic pyrrolidine from readily accessible cyclic silyl dienol ether and aziridine, and using this method, we achieved the first racemic total synthesis of pancratinines B and C (Scheme 1A). 30 This inspired us to explore the application of the copper-catalyzed [3 + 2] annulation reaction to construct chiral 5,6 carbocyclic pyrrolidines using chiral diene as a starting material and then to accomplish the asymmetric total syntheses of five montanine-type alkaloids ( 1–5 ) in a divergent manner.…”

“…Starting from the piperonyl-substituted [5,6]-carbocyclic pyrrolidine 10 , oxidizing the ketone to the alkene 9 followed by a Pictet–Spengler cyclization would give rise to intermediate 6 . As to the key compound 10 , we expected to construct it from the known 2-arylaziridine 11 and enantiomerically pure carbocyclic alkene ( S )- 12 30,32 via a copper-catalyzed [3 + 2] annulation reaction.…”

“…Using (−)- 17 as the starting material, we completed the asymmetric total synthesis of (+)-pancratinines B and C ( 4 and 5 ) through the same route as the racemic synthesis reported earlier. 30 Next, the syntheses of (−)-montanine ( 1 ), (−)-pancracine ( 2 ) and (−)-brunsvigine ( 3 ) were performed (Scheme 3). According to Zhou's procedure, 39,40 epoxidation of 17 was performed with peroxymidic acid generated in situ from CCl 3 CN/H 2 O 2 in the presence of trifluoroacetic acid to avoid oxidation of the nitrogen atom.…”

“…Due to their extensive pharmacological activity and novel framework, these molecules have been highly sought-after as synthetic goals for decades, which has led to a number of successful total syntheses. 20–30 Using an aza-Cope rearrangement/Mannich cyclization strategy, Overman achieved the first synthesis of pancracine ( 2 ). 20,22 Other representative synthetic approaches for these molecules involve reductive cyclization, 21 intramolecular [3 + 2] cycloaddition, 29 chemoenzymatic method/intramolecular radical cyclization, 26 and intramolecular allenylsilane imino ene reaction.…”

“…31 Despite extensive synthesis work on nearly all members of the montanine-type amaryllidaceae alkaloids, there is no total synthesis of pancratinine B ( 4 ) and pancratinine C ( 5 ), which possess an intriguing C-11a tertiary alcohol, except for our latest racemic syntheses. 30 Herein, we report the first asymmetric total syntheses of (+)-pancratinine B ( 4 ) and (+)-pancratinine C ( 5 ), and the asymmetric total syntheses of (−)-montanine ( 1 ), (−)-pancracine ( 2 ) and (−)-brunsvigine ( 3 ) in a divergent fashion.…”