title: Asymmetric synthesis of tetrahydropalmatine via tandem 1,2-addition/cyclization.
abstract: [Reaction: see text]. The enantioselective synthesis of both enantiomers of tetrahydropalmatine (2) (ee = 98%), a natural alkaloid belonging to the tetrahydroprotoberberine family, is described. The key step of this total synthesis is based on our tandem 1,2-addition/ring-closure methodology employing lithiated methylbenzamide and benzaldehyde SAMP or RAMP hydrazones as substrates. An initial route was investigated for the formation of N- and 3-substituted dihydroisoquinolones starting from 2-substituted benzaldehyde SAMP hydrazones, but although high diastereoselectivity was achieved, only disappointing yields were obtained. In our subsequent synthetic strategy, 2,3-dimethoxy-6-methylbenzamide 6 and 3,4-dimethoxybenzaldehyde SAMP or RAMP hydrazone 19 gave the dihydroisoquinolones 20 in high diastereomeric purity (de > or = 96%) and reasonable yield (54-55%), taking into account the complex functionalities established in one step. Cleavage of the N-N bond of the chiral auxiliary and reduction of the carbonyl group of the amide moiety were performed in the same step, and the resulting tetrahydroisoquinolines 22 (ee = 99%) were N-functionalized by treatment with various electrophiles to investigate the ring closure by Pummerer, Friedel-Crafts, and Pomeranz-Fritsch reactions. The Pummerer cyclization led to the formation of (S)-(-)-2 with slight racemization (ee = 89%), whereas the Friedel-Crafts reaction proved to be unsuccessful. Finally, Pomeranz-Fritsch-type cyclization afforded the desired title compound (R)-(+)-2 in excellent enantioselectivity in 9% overall yield over seven steps and after optimization of the last step (S)-(-)-2 in 17% overall yield.
authors.affiliation: Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany.
authors.forename: Marine
authors.initials: M
authors.lastname: Boudou
authors.forename: Dieter
authors.initials: D
authors.lastname: Enders
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D001600:Berberine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D015394:Molecular Structure
chemical_list: D000470:Alkaloids; D001600:Berberine Alkaloids; C014215:tetrahydropalmatine