Total Synthesis of the Ortho-Hydroxylated Protoberberines (S)-Govaniadine, (S)-Caseamine, and (S)-Clarkeanidine via a Solvent-Directed Pictet–Spengler Reaction

Abstract

The common para regioselectivity in Pictet–Spengler reactions with dopamine derivatives is redirected to the ortho position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen, this ortho-selective Pictet–Spengler produced the 1-benzyltetrahydroisoquinoline alkaloids (S)-crassifoline and (S)-norcrassifoline and the bioactive 1,2-dioxygenated tetrahydroprotoberberine alkaloids (S)-govaniadine, (S)-caseamine, and (S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed regioselectivity was demonstrated with a second Pictet–Spengler reaction as required for C-ring formation of caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene).

Synthetic Evidence of the Amadori-Type Alkylation of Biogenic Amines by the Neurotoxic Metabolite Dopegal

“…In the early stages of protein alkylation, Schiff’s bases 3 are readily formed in the reaction between the aldehyde of dopal and the lysine side chain amine residues (Scheme ). The imines thus obtained equilibrate to conjugated enamines 4 , a type of intermediate that is frequently observed during Pictet–Spengler reactions . In general, under aqueous conditions, imine/enamine adducts are not stable and swiftly hydrolyze to the starting compounds.…”

Total synthesis of haploscleridamine, villagorgin A and an approach towards lissoclin C

“…Some scouting experiments with formalin and acid catalysts were unsuccessful, but conditions reported by the van Maarseveen group using formalin and trifluorethanol (TFE) were more encouraging. 42 Reaction of haploscleridamine with 3.2 equivalents of formalin for 3 h delivered a single new product in 85% yield. However, it was clear that this material was not villagorgin A ( 7 ) but a constitutional isomer 53 (Scheme 7).…”

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020)

“…Alternatively, Hiemstra and van Maarseveen and co-workers demonstrated a regioselective ortho - or para- directed Pictet–Spengler reaction to construct the THIQ core. First, a chiral phosphoric acid-catalyzed Pictet–Spengler condensation of protected amine 207 with aldehyde 208 afforded THIQ 209 in 85% yield with 90% ee (Scheme A).…”

“…In 2010, Georghiou and coworkers harnessed a chiral auxiliary-assisted Bischler−Napieralski cyclization and reduction of amide 204 to achieve THIQ 205, upon which addition of formaldehyde followed by NaBH 3 CN reduction delivered (−)-corytenchine 206 (Scheme 27). 69 Alternatively, Hiemstra 70 and van Maarseveen 71 and coworkers demonstrated a regioselective ortho-or para-directed Pictet−Spengler reaction to construct the THIQ core. First, a chiral phosphoric acid-catalyzed Pictet−Spengler condensation of protected amine 207 with aldehyde 208 afforded THIQ 209 in 85% yield with 90% ee (Scheme 28A).…”