Asymmetric synthesis of trisubstituted isoindolines and tetrahydropalmatine via tandem 1,2-addition-cyclisation

A straightforward and highly diastereoselective access to 1,2,3-trisubstituted isoindolines via a tandem 1,2-addition/cyclisation process was developed. After condensation of SAMP with o-phthalic dicarboxaldehyde, the remaining aldehyde functionality was transformed into different alkenes by Horner-Wadsworth-Emmons reaction. Addition of a organolithium reagent/cerium chloride combination to a solution of the phenylsulfonyl vinyl SAMP-hydrazone yielded 32% of the methyl substituted and 47% of the n-butyl substituted 2,3-dihydro-1H-isoindole in excellent diastereoselectivity. However, until now, the cleavage of the auxiliary to synthesise the 1,3-disubstituted isoindolines could not be achieved. The first diastereo- and enantioselective synthesis of 3,4-disubstituted tetrahydro-2-benzazepines in a tandem 1,2-addition/ring closure sequence was attempted. The necessary tandem precursor was prepared in 59% yield with an excellent diastereomeric excess by a-alkylation of propanal-SAMP hydrazone with an ortho-ester substituted benzyl iodide. Two attempts for the tandem 1,2-addition/ring closure sequence were made, one with two equivalents of methyllithium, the other with two equivalents of the methyllithium/cerium chloride system but none of them led to the formation of the desired trisubstituted tetrahydro-2-benzazepine. The methodology developed in our laboratory for the asymmetric synthesis of 3-substituted tetrahydroisoquinolines via tandem 1,2-addition/ring closure was applied to the total synthesis of both enantiomers of tetrahydropalmatine. Reaction of 2,3-dimethoxy-6-methyl benzamide and 3,4-dimethoxybenzaldehyde SAMP- or RAMP-hydrazone gave the dihydroisoquinolones in high diastereomeric purity (de = 96%) and reasonable yield (54-55%) taking into account the complex functionalities established in one step. After cleavage of the the chiral auxiliary and reduction of the carbonyl group of the amide moiety in the same step, the resulting tetrahydroisoquinolines (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 the natural product with slight racemization (ee = 90%), whereas the Friedel-Crafts reaction proved to be unsuccessful. Finally, Pomeranz-Fritsch-type cyclization gave over 7 steps the desired (R)-(+)-enantiomer in excellent enantioselectivity in 9% overall yield and optimization of the last step produced (S)-(-)-tetrahydropalmatine in 17% overall yield.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2005

Author dc:creator

• Boudou, Marine

Contributors dc:contributor

• Enders, Dieter

• info:eu-repo/classification/ddc/540
• Isoindolinderivate
• Benzazepinderivate
• Tetrahydropalmatin
• Asymmetrische Synthese
• Additionsreaktion
• Cyclisation
• Chemie
• Organische Chemie
• Isoindoline

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123699%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62106