Ruthenium Hydride/Brønsted Acid-Catalyzed Tandem Isomerization/N‑Acyliminium Cyclization Sequence for the Synthesis of Tetrahydro-β-carbolines

• Published in: Journal of organic chemistry 2013-12, Vol.78 (24), p.12545-12565
• Main Authors: Hansen, Casper L, Clausen, Janie W, Ohm, Ragnhild G, Ascic, Erhad, Le Quement, Sebastian T, Tanner, David, Nielsen, Thomas E
• Format: Article
• Language: English
• Subjects: Acids - chemistry; Carbolines - chemical synthesis; Carbolines - chemistry; Catalysis; Cyclization; Hydrogen - chemistry; Molecular Structure; Organometallic Compounds - chemistry; Ruthenium - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo402192s

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-β-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to N-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient “aldehyde-free” alternative to the classical Pictet–Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/N-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively.