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Title: Asymmetric Synthesis of Decahydroquinolines via Organocatalysis: Total Synthesis of (+)-Lycoposerramine Z and (-)-Cermizine B
Author: Luque Corredera, Carlos
Director: Bonjoch i Sesé, Josep
Bradshaw, Ben
Keywords: Catàlisi
Compostos heterocíclics
Anàlisi conformacional
Heterocyclic compounds
Conformational analysis
Issue Date: 27-Jun-2014
Publisher: Universitat de Barcelona
Abstract: [cat] 1) En primer lloc s’ha desenvolupat una metodologia general per a la síntesi diastereoselectiva de 5-oxodecahidroquinolines mitjançant una reacció one-pot d’anel·lació de Robinson / reacció aza-Michael intramolecular, que permet obtenir el nucli de decahidroquinolina en un sol pas des d’un beta-cetoèster aquiral i acíclic. Aquesta metodologia, no només permet la formació de cis-decahidroquinolines (tipus A i B), sinó que també dóna accés als corresponents isòmers trans-decahidroquinolínics (tipus C i D) . 2) S’ha dissenyat una versió asimètrica de la metodologia desenvolupada per així tenir accés als diferents nuclis decahidroquinolínics enantiopurs per mitjà de organocatàlisis. El mètode ha estat optimitzat després de realitzar estudis de dissolvents, temperatures i catalitzadors. Aquest building block ha estat aplicat a la síntesis total de l’alcaloide licoposerramina Z, el qual s’ha sintetitzat de forma ràpida i eficient (10 etapes, 20% rendiment global). 3) L’aplicació de l’estratègia coneguda com “pot economy” a una síntesis formada per una sèrie de reaccions tàndem pot ser una solució en quant eficiència dels processos i economització de recursos i temps. S’ha realitzat la primera síntesi de l’alcaloide cermizina B de manera eficient i obtenint un gram de producte natural emprant un total de 8 hores treballades en el transcurs de 10 dies naturals. 4) La metodologia descrita no només és aplicable als nuclis decahidroquinolínics conduents a la síntesi d’alcaloides flegmarina, sinó que també pot conduir als altres alcaloides de la familia Lycopodium, completant així una síntesi biomimètica de tots aquests compostos de forma anàloga de com ho fa la natura. A més, la metodologia es pot extrapol·lar a altres tipus de nuclis (morfans o octahidroindols) emprant petites variacions en els materials de partida (així com variacions de número de carbonis en els materials de partida, o l’ instal·lació del nitrògen en el donador o acceptor de Michael)
[eng] 1) The treatment of a tert-butyl beta-keto ester tethered to an omega-amino monoprotected group with crotonaldehyde using LiOH as the base, furnishes domino reactions involving the consecutive formation of two C-C bonds and one C-N bond in a sequence that comprises an intermolecular Michael process, followed by intramolecular aldol and aza-Michael reactions. This general methodology for the diastereoselective synthesis of 5-oxodecahydroquinolines implies a biscyclization and the formation of three stereocontrolled stereogenic centres in a single operational step. The resulting cis-decahydroquinoline of type A (arising from the dealkoxycarbonylation reaction) allows, through thermodynamic controlled processes, access to all other relative stereochemistries, providing a set of valuable building blocks (decahydroquinolines of Type B, C, and D). 2) The asymmetric Robinson annulation / intramolecular aza-Michael reaction leading to decahydroquinolines in a single step, from an achiral and acyclic simple beta-keto ester, is not feasible using the classical reaction conditions developed by Jørgensen to synthesize cyclohexenones. After the initial organocatalyzed Michael addition, treatment with acid to promote the dealkoxycarbonylation and intramolecular aldol reaction failed, probably due to the presence of the nucleophilic nitrogen atom in the structure. In contrast, if LiOH is added after the organocatalysis step, the Robinson annulation and the following azacyclization take place in very good yield. The method has been optimized after screenings for the solvent, temperature, additives and catalysts. The resulting decahydroquinoline building block has been used in the total synthesis of the phlegmarine alkaloid lycoposerramine Z, which has been efficiently synthesized: 10 steps and 20% overall yield. 3) A potent solution for the problematic stop-and-go procedure, in which it is necessary to stop the synthesis after each operational step to carry out the work-up and purification of intermediates, is the combination of pot economy strategy and tandem reactions. Following this alternative strategy, we have developed an efficient synthesis of the alkaloid cermizine B via an uninterrupted sequence of 7 reactions, which allowed 1 gram of the natural product to be synthesized, employing 8-12 h of operational time over 10 days. 4) The scope of the strategy developed in the experimental studies carried out in the present PhD Thesis has been extended and applied to other research projects. Thus, the described methodology is not only applicable to the decahydroquinoline nucleus for the total synthesis of phlegmarine alkaloids, but can also be potentially applied to the synthesis of other members of the Lycopodium family. Furthermore, the method can also provide access to other nitrogen-containing heterocycles such as morphans or octahydroindoles with some structural changes in the starting materials (such as the number of carbon atoms in the initial beta-keto ester or the installation of the nitrogen atom in the Michael acceptor or in the donor).
Appears in Collections:Tesis Doctorals - Departament - Farmacologia i Química Terapèutica

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