Synthesis and Ring‐Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis‐ and trans‐Fused Perhydro‐indoles and ‐quinolines

• Published in: European journal of organic chemistry Vol. 27; no. 33
• Main Authors: Xing, Xingxing, He, Yu‐Tao, Song, Jian‐Guo, Lan, Ping, White, Lorenzo V., Tan, Shen, Pham, Le Nhan, Coote, Michelle L., Wu, Xin, Banwell, Martin G.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 02.09.2024
• Subjects: Acrylates; Chemical synthesis; conjugate addition; cyclization; decahydroquinolines; Indoles; Metathesis; octahydroindoles; Organic compounds; Quinoline; Stereoselectivity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202400455

Two epimeric pairs of N‐Ts‐protected cyclohexylamines that incorporate an unsaturated side‐chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically‐induced intramolecular hydroamination reactions to give the corresponding perhydro‐indole or ‐quinoline. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so‐formed engaged in base‐promoted and completely diastereoselective, intramolecular aza‐Michael addition (cyclization) reactions to give the isomeric and C2‐substituted perhydro‐indoles or ‐quinolines with the structures of these being confirmed by single‐crystal X‐ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n‐propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C. Two epimeric pairs of N‐protected cyclohexamines bearing acrylate residues attached at C2 have been investigated for their capacities to undergo base‐promoted intramolecular aza‐Michael addition reactions. Three of these substrates do so both efficiently and completely diastereoselectively. Simple manipulation of the product perhydroindoles and decahydroquinolines afford ready access to novel analogues of the potent neurotoxin pumiliotoxin C.