One-pot, Catalytic Asymmetric Reductive Bischler-Napieralski-Type Reaction of Amides: An Enantioselective Entrance to Biologically Active 1-Substituted Tetrahydroisoquinolines

doi:10.6023/A25120419

Abstract

Herein, we report the one-pot, catalytic asymmetric reductive Bischler-Napieralski-type reaction of amides as the first demonstration of a new strategy for the asymmetric reductive transformation of amides, which allowed for the one-pot, enantioselective entrance to tetrahydroisoquinoline (THIQ). The method features a tandem sequence involving the Tf₂O/2-F-Pyr.-promoted Bischler-Napieralski dehydracyclization and an aqueous Noyori-type catalytic asymmetric transfer hydrogenation (CATH). By this one-pot method, a variety of THIQ derivatives were synthesized in high yields and in excellent enantioselectivities. This protocol accommodates N-arylethyl aromatic amides bearing either electron-rich or electron-deficient group on the acyl moiety, and N-arylethyl aliphatic amides. The synthetic utility of this methodology was demonstrated via the efficient, catalytic enantioselective synthesis of four alkaloids: (S)-salsolidine, (S)-laudanosine, (S)-xylopinine, and (S)-N-norlaudanidine, and medicinal agent ACT-335827. Additionally, formal synthesis of alkaloid (S)-cryptostyline III and medicinal agents such as almorexant was achieved.

Key words: amide, amide activation, tetrahydroisoquinoline, Bischler-Napieralski-type cyclization, catalytic asymmetric transfer hydrogenation, alkaloid

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Lu Guang-Sheng, Han Zeng, Ye Jian-Liang, Huang Pei-Qiang. One-pot, Catalytic Asymmetric Reductive Bischler-Napieralski-Type Reaction of Amides: An Enantioselective Entrance to Biologically Active 1-Substituted Tetrahydroisoquinolines[J]. Acta Chimica Sinica, doi: 10.6023/A25120419.

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