Eine regio‐ und diastereoselektive anodische Aryl‐Aryl‐Kupplung in der biomimetischen Totalsynthese von (−)‐Thebain

Abstract

Die Biosynthese von Thebain basiert auf der regioselektiven intramolekularen oxidativen Kupplung von (R)-Reticulin. Seit Jahrzehnten versuchen Chemiker diese Kupplung mithilfe stçchiometrischer Oxidationsmittel zu imitieren. Allerdings wurden stets entweder niedrige Ausbeuten oder unerwünschte Regioisomere erhalten. Die Elektrochemie wäre zwar eine nachhaltige Alternative,j edochs ind bisher alle Versuche zur Verwirklichung einer elektrochemischen Thebain-Synthese gescheitert. Hier zeigen wir eine regio-und diastereoselektive anodische Kupplung 3',4',5'-trioxygenierter Laudanosin-Derivate,w elchee rstmals einen elektrochemi-schenZ ugang zu (À)-Thebain gestattet.

A Seven-Step Total Synthesis of (–)-Thebaine

“…Treatment of compound 18 with dimethyl sulfate in the presence of potassium tert -butoxide 18 then gave the enol ether 19 19 (76%) which was itself reduced with LiAlH­ 4 in refluxing THF for 2 hours to afford (–)-thebaine ( 1 ) in 73% yield. All the spectral data acquired on this material matched those reported previously, 4 20 but final confirmation of its structure followed from a single-crystal X-ray analysis (see experimental section and SI for details). 21 As noted above, (–)-thebaine is an important precursor to a range of opioids, including the readily derived oxycodone ( 4 ).…”

“…The ensuing oily residue was subjected to flash chromatography (silica gel, 1:19 v/v ammoniacal MeOH/CH 2 Cl 2 elution) and concentration of the relevant fractions ( R f = 0.3) afforded (–)-thebaine ( 1 ) as an off-white, crystalline solid; yield: 30 mg (73%); mp 188–189 °C (Lit. 4 mp 189.5–191.0 °C); [α] D 25 –182.5 ( c 0.2, EtOH) {[Lit. 4 [α] D 22 –186.8 ( c 0.18, EtOH)}.…”

“…1 2 For these reasons, and given the potential climatic, pathogenic, and geopolitical threats to the habitats of opium poppies, 3 developing concise chemical syntheses of (–)-thebaine remains an important task. 4,5 While many elegant total syntheses of the morphinans have been reported to date, a commercially viable process for their synthetic production will almost certainly require a reaction sequence that is no more than five or six steps in length and starts with readily available materials. 5 Our recently reported, 6 enantioselective, seven-step total synthesis of codeine is the shortest preparation of the alkaloid devised so far.…”

Electrochemical Dearomatization: Evolution from Chemicals to Traceless Electrons

“…Therefore, the long‐standing challenge of regioselectivity, i.e., the coupling of 4a–2′, was surmounted to deliver the desired skeleton (Scheme ). Most importantly, this procedure was applied for the diastereoselective biomimetic total synthesis of (−)‐thebaine …”

Electrochemically Enabled Total Syntheses of Natural Products

“…Electrochemical methodology and the community of researchers involved in this exciting area of chemistry expands on a daily basis. Investigators such as Opatz and Waldvogel, [13–18] Baran, [19–28] Shono, [29,124,125,138,140,224] Moeller, [77,79,108,143] Little, [30–44] Lin, [45–54] and Stahl [55–62] are just a few of the researchers that have been integral to growing the available electrochemical toolset, educating the broader synthesis community, and drawing these techniques into mainstream organic synthesis. Electrochemical toolsets have been extensively reviewed in various contexts including comprehensive monographs; [5–17] this brief review highlights the use of electrochemical bond formations in the arena of natural products total synthesis with particular focus on completed works.…”