An Unconventional trans - exo -Selective Cyclization of Alkyne-Tethered Cyclohexadienones Initiated by Rhodium(III)-Catalyzed C–H Activation via Insertion Relay

Abstract

Different from the established trans-endo-selective cyclization of alkyne-tethered electrophiles that involve an E/Z isomerization process, herein, the authors present a novel strategy to allow trans-exo -selective arylative cyclization of 1,6-enynes. Through initiation of rhodium(III)-catalyzed C-H activation, a diverse range of N-heterocyclic directing groups, including pyridine, pyrazole, imidazo[1,2-a] pyridine, benzoxazole, benzothiazole, and purine, was feasible for the cascade transformation, exhibiting high efficiency (up to 92% yield), broad substrate scope, and excellent functional group compatibility. Moreover, the modification of natural products and pharmaceutical compounds was also demonstrated to showcase its synthetic utility. Based on density functional theory (DFT) calculations, a key three-membered ring intermediate through the insertion relay, rather than the direct E/Z isomerization of alkenyl rhodium species, controlled the stereochemical outcome for this trans-exo -selective cyclization. The subsequent ring-opening protonation of the more favored rotamer led to exclusive trans-exo-selectivity.

Recent Advances in Cyclization Reactions of 1,6‐Enynes

“…In 2020, the Lin and co-workers presented a transexo-selective arylative cyclization reaction for the assembly of 4-alkynylcyclohexanediones (Scheme 84). [66] This Rh-catalyzed protocol, which employed NDG heterocycles as the substrates and 1,6enynes as coupling partners, provided the valuable and complex nitrogen-containing polycyclic compounds in high yields, featuring wide functional group compatibility. In addition, the synthetic practicability of the reaction has been confirmed in the further application In 2020, the Tanaka group reported an enantioselective [2 + 2 + 2] cycloaddition of 1,6-enynes with allylic alcohols, which enabled preparation of optically active bicyclic cyclohexenes bearing three stereogenic centers with excellent enantioselectivity (Scheme 86).…”

Mechanistic insight into anti-carbometalation of an alkyne via η2-vinyl-nickel type Z/E isomerization

“…The carbon–carbon double bond character is decreased by resonance with the formation of a metal carbene, which facilitates rotation via the carbon–carbon single bond. This reaction mode has been well studied in Pd, 7 Rh 8 and Co 9 catalyzed alkyne functionalizations. In another case, the Z / E isomerization of syn -alkenylmetal occurs via the η 2 -vinyl metal transition state to afford the anti -isomer (mode B).…”