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Synthesis of 1S-ethyl-4-substituted quinolizidines and other potentially bioactive compounds

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Universitat de Barcelona. Departament de Farmacologia i Química Terapèutica

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[spa] Esta Tesis Doctoral se presenta como Compendio de publicaciones. Los capítulos en los que se ha dividido la presente Tesis son los siguientes:

Capítulo 1 – parte A: Enantioselective, Protecting Group-Free Synthesis of 1S-Ethyl-4-Substituted Quinolizidines 
Se ha descrito una síntesis enantioselectiva que no implica grupos protectores para acceder a la quinolizidina clave 6 a partir de la lactama bicíclica derivada de fenilglicinol 1. La adición de un reactivo organometálico a 6 ocurre de manera estereoselectiva para conducir a las quinolizidinas 1S-etil-4-sustituidas 4-epi-207I y 7-9. Siguiendo una secuencia sintética análoga, se preparó el compuesto 9a-epi-6. Sin embargo, la adición de reactivos de Grignard al compuesto 9a-epi-6 no ocurre de manera estereoselectiva.

Capítulo 1 – parte B: A practical procedure for the removal of the phenylethanol moiety from phenylglycinol-derived lactams 
Las lactamas bicíclicas no racémicas derivadas de fenilglicinol se han relevado como intermedios clave en la preparación de compuestos nitrogenados enantiopuros. En este capítulo se describe la eliminación del inductor quiral de piperidonas sustituidas utilizando aire u oxígeno en medio básico.

Capítulo 2: Synthesis of triheptanoin and formulation as a solid diet for rodents 
En el presente estudio se describe la síntesis eficaz de triheptanoina de elevada pureza a partir de glicerol y ácido heptanoico, en presencia de carbono sulfonado como catalizador. La triheptanoina se formula como un sólido estable para que constituya la base de una dieta cetogénica mediante la combinación de custro gentes de formulación comerciales; dos tipos de sílica, celulosa microcristalina y talco. La adecuación de la dieta se prueba en ratones C57BI/6 en un periodo de 15 días, comparando el estado general y el cambio de peso corporal.

Capítulo 3: Toluene dioxygenase (TDO) mediated oxidation of halogen-substituted benzoate esters 
Una serie de esteres benzoicos metílicos sustituidos en o-, m- y p- se han sometido a hidroxilación enzimática via fermetación con E. coli JM109 8pDTG601A). Solo se metabolizaron los benzoatos sustituidos en orto. El 2-fluorobenzoato de metilo produjo regioselectivamente solo un diol mientras que el 2-cloro, 2-bromo y 2-iodobenzoato de metilo proporciona una mezcla de regioisómeros. 

Capítulo 4: Dauben–Michno oxidative transposition of allylic cyanohydrins
Enantiomeric switch of (–)-carvone to (+)-carvone
Cuando cianohidrinas alílicas se someten a la reacción de oxidación de Dauben-Michno a bajas temperaturas se accede a β-cianoenonas en buenos a excelentes rendimientos. El potencial de esta trasposición oxidativa se pone de manifiesto en enonas que contienen un plano latente de simetría como por ejemplo la conversión de la (-)-carvona en su enantiomero.

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[eng] A dissertation submitted by Vladislav SEMAK to obtain a doctoral degree from University of Barcelona. This thesis was developed under the supervision of Dr. Carmen Escolano Mirón from Faculty of Pharmacy, University of Barcelona. This doctoral thesis is presented as a compendium of publications. The thesis is divided in four chapters: 

CHAPTER 1 – PART A: Enantioselective, Protecting Group-Free Synthesis of 
1S-Ethyl-4-Substituted Quinolizidines (Amat, M.; Semak, V.; Escolano, C.; Molins, E.; Bosch, J. Org. Biomol. Chem. 2012, 10, 6866-6875.)

A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The organometallic addition reaction upon 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7-9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents upon 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. 

CHAPTER 1 – PART B: A practical procedure for the removal of the phenylethanol moiety
 from phenylglycinol-derived lactams (V. Semak; C, Escolano; C. Arróniz; J. Bosch; M. Amat Tetrahedron: Asymmetry 2010, 21, 2542-2549.)

Chiral non-racemic bicyclic lactams derived from phenylglycinol have been appointed as key building blocks for the preparation of enantiopure nitrogen compounds. The removal of the chiral inductor leading to substituted piperidones by using air or oxygen in basic media is presented in this chapter.

CHAPTER 2: Synthesis of triheptanoin and formulation as a solid diet for rodents (Semak, V.; Semakova, J.; Halbaut, L.; Asó, E.; Ferrer, I.; Calpena, A.; Escolano, C.; Perales, J. C. Eur. J. Lipid Sci. Technol. 2012, 114, 889-895.)

In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change.

CHAPTER 3: Toluene dioxygenase mediated oxidation of halogen-substituted benzoate esters (Semak, V.; Metcalf, T. A.; Endoma-Arias, M. A. A.; Mach, P.; Hudlicky, T. Org. Biomol. Chem. 2012, 10, 4407-4416.)

A series of ortho-, meta-, and para-halogen-substituted methyl benzoate esters was subjected to enzymatic dihydroxylation via the whole-cell fermentation with E. coli JM109 (pDTG601A). Only ortho-substituted benzoates were metabolized. Methyl 2-fluorobenzoate yielded one diol regioselectively whereas methyl 2-chloro-, methyl 2-bromo- and methyl 2-iodobenzoates each yielded a mixture of regioisomers. Absolute stereochemistry was determined for all new metabolites. Computational analysis of these results and a possible rationale for the regioselectivity of the enzymatic dihydroxylation is advanced. 

CHAPTER 4: Dauben–Michno oxidative transposition of allylic cyanohydrins. Enantiomeric switch of (–)-carvone to (+)-carvone. (Hudlicky, J. R.; Werner, L.; Semak, V.; Simionescu, R.; Hudlicky, T. Can. J. Chem. 2011, 89, 535-543.)

Allylic cyanohydrins were subjected to Dauben–Michno oxidation at low temperatures to provide β-cyanoenones in good to excellent yields. The potential of this oxidative transposition as a means of an enantiomeric switch of enones containing a latent plane of symmetry was tested by conversion of (–)-carvone to its enantiomer.

# metadata.dc.source[].value
Tesis Doctorals - Departament - Farmacologia i Química Terapèutica

# metadata.dc.title[].value
Synthesis of 1S-ethyl-4-substituted quinolizidines and other potentially bioactive compounds