# name
Azapolycyclic Building Blocks for the Synthesis of Daphniphyllum Alkaloids: Approaches toward Himalensine A and 2-Deoxymacropodumine A

# metadata.dc.contributor.other[].value
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació

# metadata.dc.description.abstract[].value
[eng] Daphniphyllum alkaloids, isolated from various species of the Daphniphyllum genus, constitute a diverse family of natural products containing over 320 distinct members and featuring more than 20 unique polycyclic frameworks. Besides their fascinating architectonic structures, many of these compounds exhibit a wide range of biological activities, including anticancer, anti-HIV, antioxidant, antiviral, vasorelaxation, and nerve growth factor regulation properties. During the last decades, these synthetically challenging molecules have been subject to many studies resulting in the total synthesis of several members. Moreover, this scientific activity has enabled the development of new synthetic methods and strategies for the preparation of advanced intermediates toward their total synthesis.  
In the present work, we have investigated the synthesis of the ABC ring core of both himalensine A and 2-deoxymacropodumine A, two members of the Daphniphyllum family, establishing a solid groundwork for future endeavors in their total synthesis. 
After a brief introduction, where we report the last advances published to date in the total or partial synthesis of these alkaloids, our investigation work is then detailed in three consecutive chapters.
In the first chapter, we present a robust and readily scalable synthetic protocol for the preparation of 3a-methyl- and 3a-methoxycarbonyl octahydroindole moieties found in the calyciphylline A-type Daphniphyllum alkaloids. This method is based on the 5-endo-trig radical cyclization of N-benzyl-N-(2-methylcycloalkenyl)trichloroacetamides and their analogs using Bu3SnH and AIBN. Our research has also led to the diastereoselective alkylation and methoxycarbonylation of these bicyclic structures through their enelactams. Additionally, enelactam compounds embodying two consecutive stereogenic carbon atoms were also achieved by means of a radical cyclization involving carbo-substituted dichloroacetamides. Upon further reduction, a series of polyfunctionalized cis-octahydroindoles was obtained which could serve as valuable building blocks for the synthesis of more complex polycyclic structures en route to Daphniphyllum alkaloids.  
In the next chapter, a concise formal synthesis of himalensine A has been accomplished while providing access to the ABC ring of Calyciphylline A-type alkaloids. The key steps in this synthesis involve a radical cyclization, to form the hydroindole AB ring system, followed by a stereocontrolled aldol cyclization resulting in the closure of the piperidine ring.  Additionally, the cyclic alcohol derived from these processes is utilized to introduce the methyl group at C-18 in the bowl-shaped azatricyclic structure, the reaction taking place with configuration retention.
 Finally, in the last part of this PhD thesis, we have successfully constructed the azatricyclic ABC ring of 2-deoxymacropodumine A for which no total synthesis has been reported yet. In this part, we have investigated the access to the 7-membered ring through a ring expansion of the cyclohexanone moiety within two ring cores previously synthesized in this thesis. Initially, we have explored several ketone homologation methodologies using diazo derivatives from morphans to homomorphans. The optimized reaction conditions have been applied to the available ABC tricyclic and AC bicyclic scaffolds. From the latter, the reaction has provided regioselectively the corresponding homoindole 3a-methylperhydrocyclohepta[b]pyrrole with excellent yield. This outcome has facilitated a further synthesis of the desired azatricyclic [5-6-7] framework. With these promising results, we propose a strategy for achieving the total synthesis of this natural product and several reactions have been explored. These developments represent significant strides in our ongoing quest to comprehend and synthesize intricate natural compounds.

# metadata.dc.description.abstract[].value
[cat] Els alcaloides Daphniphyllum, són una família de productes naturals que conté més de 320 membres amb més de 20 estructures policícliques diferents. Més enllà de les seves fascinants estructures, molts d'aquests compostos mostren una àmplia varietat d'activitats biològiques. En aquesta tesi, s’ha investigat el nucli ABC present en dos d’aquests alcaloides, l’himalensina A i la 2-desoximacropodumina A, per tal d’obtenir intermedis avançats per a la seva síntesi. Després d’introduir els últims avenços en el camp de la síntesi total o parcial d’aquests productes naturals, el treball d’investigació s’ha dividit en tres capítols. En el primer capítol es descriu l’obtenció del nucli octahidroindòlic (AC) contingut en aquestes estructures. A partir de la metodologia radicalària desenvolupada pel grup per a la ciclació de tricloroacetamides, s’han preparat diverses enelactames les quals s’han alquilat i metoxicarbonilat diastereoselectivament a C-3. Addicionalment, s’ha realitzat una aproximació més directa a partir de la ciclació de cloroacetamides carbo-substituïdes. Després de processos de reducció, s’ha obtingut un conjunt de cis-octahidroindols polifuncionalitzats aplicables com a plataformes sintètiques per a l’obtenció d’alcaloides Daphniphyllum. En el segon capítol, s’ha construït el nucli tricíclic 3a,8-dimetil-1,6-etanohidroindol (ABC) present en els alcaloides de la subfamília tipus calicifilina A, com l'himalensina A. A partir del sistema octahidroindòlic prèviament obtingut, s’ha completat la formació de l'anell restant de piperidina a través d’una ciclació aldòlica diastereoselectiva. La crucial introducció del grup metil a C-8 ha permès l’obtenció del sistema ABC constituint una síntesi formal de l'himalensina A. Finalment, s'ha sintetitzat el fragment [5-6-7]-azatricíclic comprès en la 2-desoximacropodumina A. La instal·lació de l'anell principal de 7 membres s’ha dut a terme a través de l’expansió de la corresponent ciclohexanona emprant diazo derivats. Primerament, s’ha estudiat la metodologia utilitzant compostos morfànics per l’obtenció d’homomorfans. Aplicant les condicions de reacció sobre els azatricicles ABC i azabicicles AC prèviament sintetitzats, els millors resultats s’han obtingut en la formació regioselectiva del nucli 3a-metilperhidrociclohepta[b]pirrol que ha permès una síntesi eficient del azatricicle [5-6-7]. Amb aquest prometedors resultats, s’han explorat posteriors etapes basades en una proposta d’estratègia per a l’obtenció de la 2-desoximacropodumina A, per a la qual no hi ha cap precedent de síntesi.

# metadata.dc.source[].value
Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació

# metadata.dc.title[].value
Azapolycyclic Building Blocks for the Synthesis of Daphniphyllum Alkaloids: Approaches toward Himalensine A and 2-Deoxymacropodumine A