Synthesis and opioid receptor activity of indolopropellanes

Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction

“…Opioids without the 4, 5-ether bridge (referred to as morphinones, Figure 1) are of particular interest due to their novel biological and pharmacological properties 7–11. The only reported method used today to remove the 4,5-ether bridge7–13 was originally described by Sawa and coworkers in the 1960’s and uses ammonia gas and solid sodium metal 14,15.…”

“…The only reported method used today to remove the 4,5-ether bridge7–13 was originally described by Sawa and coworkers in the 1960’s and uses ammonia gas and solid sodium metal 14,15. This synthetic route involves multiple steps, including protection and deprotection of the ketone moiety, resulting in a low overall yield of the final morphinone product 7–15. A shorter, higher yielding alternative route to these intriguing compounds would be quite valuable and necessary to access the morphinone scaffold efficiently making them readily available for pharmacological and biological evaluation.…”

“…The phenol moiety of naltrexone ( 5 ) and naloxone ( 6 ) was methylated using iodomethane and potassium carbonate to yield derivatives 7 29 and 8 , respectively. Hydrocodone ( 3 ), oxycodone ( 4 ), 7 and 8 were then reduced to their phenol derivatives ( 9–12 ) using zinc under acidic conditions 7,11,30. Finally, the triflates ( 13–16 ) were obtained after treating phenols ( 9–12 ) with N-phenylbis(trifluoromethanesulfonate)amide and cesium carbonate or sodium hydride (see supplemental information for details).…”

“…As shown, the alternate route for the synthesis of morphinones 17–19 is accomplished in two steps (from intermediates 9, 11 and 12 ) compared to the four steps needed for the synthesis of 18 and 19 and six steps for 17 via the traditional route 7,8,11,12,15. The new method offers a faster, more efficient alternative and utilizes less harsh reaction conditions/reagents than that required for the traditional process.…”

Design and synthesis of quinolinopropellane derivatives with selective δ opioid receptor agonism

“…However, indolopropellane 2 ( Fig. 3) was reported to show almost no affinity for opioid receptors 14 although 2 has not only a propellane skeleton as a message structure but also an indole moiety as a possible DOR address part like the selective DOR antagonist NTI. 1,2 To explain these observations, we developed the working hypothesis that 2 could adopt two different conformations, bent and extended (Fig.…”