Dissertations / Theses on the topic 'Natural products – Synthesis'

El objetivo general del trabajo presentado es investigar nuevas metodologías para la síntesis de: a) nectrisina, un inhibidor de α-glucosidasas y α-mannosidasas, b) del fragmento oligosacarídico del antibiótico AT2433-A1, un antibiótico utilizado en el tratamiento de numerosos tipos de cánceres y, c) de análogos del cidofovir o HPMPC, nucleósido acíclico que incorpora una unidad de fosfonato, y que se utiliza en el tratamiento del citomegalovirus (CMV) en pacientes con SIDA. Síntesis enantioselectiva de nectrisina Retrosintéticamente la síntesis de la nectrisina puede llevarse a cabo por ciclación del aminoaldehído 2 (R4=CHO), el cual puede proceder del alqueno trans 3 mediante una reacción de dihidroxilación estereoselectiva. La síntesis de 3 puede llevarse a cabo a partir de 4 mediante elongación de la cadena utilizando la reacción de metatesis cruzada catalizada por rutenio. Finalmente, el intermedio clave 4 procede de una aminación alílica asimétrica catalizada por Pd del monepóxido de butadieno racémico 5, reacción ya descrita por Trost. La aminación alílica asimétrica del monepóxido de butadieno racémico catalizada por Pd (η3-C3H5)PdCl/DACH-naftilo transcurrió con elevado rendimiento y enantioselectividad para dar el compuesto 4. La elongación de la cadena de 4 se realizó mediante una metatesis cruzada catalizada por el catalizador de Grubbs-Hoveyda con diferentes alquenos como acroleína, 2-vinil-1,3-dioxolano, y con acrilato de etilo. Sólo en este último caso se obtuvieron resultados relevantes del compuesto 3 (R4=COOEt) como para continuar la síntesis. La reacción de dihidroxilación estereoselectiva del alqueno trans 3 (R4=COOEt) condujo al diol deseado 2 (R4=COOEt) con buena selectividad utilizando OsO4/TMEDA. La hidrólisis del benzoato con LiOH y la ciclación in situ condujo a la lactama, a partir de la cual se siguió una secuencia sintética descrita en la bibliografía, consistente en la sililación de los grupos hidroxilo, protección del grupo amino en forma de terc-butil carbamato, reducción del carbonilo y eliminación con desprotección concomitante de los grupo sililo para dar la imina, que en nuestras manos no logró llevarse a fin debido a problemas en la última etapa de eliminación para dar la imina. Síntesis enantioselectiva de análogos de Cidofovir HPMPC La síntesis de los análogos del cidofovir se planteó siguiendo un esquema sintético similar al de la nectrisina, en el que la síntesis del intermedio 7 se llevó a cabo mediante la aminación alílica asimétrica del monoepóxido del butadieno y posterior reacción de metátesis cruzada como pasos clave. En primer lugar se realizó la aminación alílica asimétrica catalizada por Pd (η3-C3H5)PdCl/DACH-naftil del monepóxido de butadieno racémico, con adenina y citosina la cual se optimizó hasta conseguir rendimientos y excesos enantioméricos superiores al 90%. Seguidamente se optimizó la reacción de metátesis cruzada de los compuestos obtenidos (6) con un alil fosfonato convenientemente protegido, obteniendo 7 con buen rendimiento. La síntesis de los análogos de cidofovir insaturados 8 y 9 se completó tras la desprotección de todos los grupos protectores con TMSBr. La síntesis del derivado saturado 10 se realizó mediante la hydrogenación (3 bares de hidrógeno, Pd/C durante 5h) y la eliminación de los grupos protectores. Síntesis enantioselectiva del fragmento oligosacarídico del antibiótico AT2433-A1 La retrosíntesis de 18 se planteó por ciclación electrófila inducida por yodo de 15, donde X debiera ser un grupo activador del doble enlace que a su vez se pudiera comportar como grupo saliente en la subsiguiente reacción de glicosilación a partir de 15. La síntesis del intermedio 15 se planteó por diferentes procedimientos y en particular a partir del sulfato 14, el cual provendría del diol 13, que a su vez provendría de la dihidroxilación de 12. El compuesto 12 debería poder obtenerse a partir de 5 por la secuencia clásica de DYKAT y metatesis cruzada. Así, a partir del compuesto 11 (R=Boc) se realizó la metatesis cruzada con diferentes alquenos y en particular con el alil fenil tioéter. Las limitaciones se encontraron en la reacción de dihidroxilación, ya que en casi todos los casos ensayados se produjo la oxidación del azufre, lo que conduciría al cambio de la selectividad en posteriores etapas como la ciclación. Se consiguió evitar la oxidación utilizando ligandos quirales en la dihidroxilación, pero con rendimientos muy bajos no compatibles con un esquema de síntesis por etapas.<br>The present thesis deals with the development of methodology for the syntheses of several organic molecules that were selected by their interesting biological properties: the antibiotic AT2433-A1, the glycosidase inhibidor nectrisine and analogs of the anti-viral Cidofovir (Figure 1.1) . Although apparently structurally unrelated, they were envisaged to be synthesized through common high-efficient key steps that involve metal-catalyzed process. Enantioselective Synthesis of nectrisine We explore an enantioselective synthesis of nectrisine based on Pd-catalyzed asymmetric allylic amination, cross-metathesis and dihydroxylation as key steps. Scheme 1 shows the retrosynthesis proposed, where the key synthon is the allylamine 4 which is obtained in high enantiomeric purity by a deracemization process using Pd/DACH as a catalytic system. Cross-metathesis will allow increasing the chain length, and at the same time would provide the aldehyde functionality necessary for formation of the cyclic imine moiety in the final nectrisine. Besides, configuration of double bond resulting from cross-metathesis must be E in order to provide the correct configuration of hydroxyl groups in 2 after the dihydroxylation reaction. The stereoselectivity of this reaction will be controlled by the stereocenter in the molecule, which could be also be enhanced by chiral ligands in a matched double stereodifferentiation process. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and t-Butyl-benzoyl-imido carboxylate as a N-nucleophile proceeded with excellent yield (98%) and enantioselectivity (97%) to obtain the chiral allylic amine synthon 4. Elongation of the chain of the key chiral allylic imide with ethyl acrylate through cross metathesis using Hoveyda-Grubbs catalyst (5 mol %), proceeded quatitatively to obtain the trans alkene intermediates 3. The installation of the syn diol moiety via dihydroxylation of the alkene proceeded with high yield and good diastereoselectivity with OsO4/TMEDA. Hydrolysis of benzoate group in 2 with LiOH and in situ cyclization led to the lactam. Whose hydroxyl functionalities were fully protected by treatment with TBSCl. Subsequent protection with di-t-butyl dicarbonate (Boc) 2O and Et3N in CH2Cl2 gave desired product in 50% yield. The increased carbonyl electrophilicity resulting from NBoc protection should facilitate the smooth reduction of the lactam, which proceeded by reaction with Super Hydride® at −78°C to give lactol. Enantioselective Synthesis of Cidofovir Analogues In this context, the retrosynthetic proposal is shown in Scheme 2. Cidofovir (HPMPC) analogues could be obtained by double bond reduction of product 7 followed by protecting group cleavage on compound 11. Compound 7 in turn can be synthesized from compound 6 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral synthon 6 could be obtained by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from racemic butadiene monoepoxide (5). The asymmetric allylic amination of racemic butadiene monoepoxide with cytosine as N-nucleophile was carried out with (η3-C3H5)PdCl/DACH-naphtyl system to obtain chiral allylic cytosine in 85% yield and 72% ee. The reaction was successfully expanded to other pyrimidine and purine bases, among which adenine afforded chiral allyl adenine in 90% yield and 92% ee. Chain elongation via Ru-cross metathesis of key allylic nucleobases and diethyl allylphosphonate with second generation Grubbs catalyst (5 mol%), produced desired compounds in 92% and 90% yield, respectively. Deprotection of all protecting groups with TMSBr afforded the desired unsaturated acyclic nucleosides 8 and 9 in good yields. Hydrogenation with (H2, /Pd/C) at 3 bar rendered the saturated Cidifovir analogues 10. Approaches to the Enantioselective Synthesis of AT2433-A1 The objective of this work was to explore a new enantioselective method to obtain AT2433-A1 with special focus on the synthesis of the 2, 4-dideoxy-4-amino-xyloside moiety. The retrosynthetic proposal is shown in Scheme 5.6. The aminodeoxysugar (19) could be obtained from 16 by eletrophile-induced cyclization. A key point is the selection of group X, since it must control the regioselectivity of the cyclization to an endo-mode and eventually must behave as a leaving group in a future glycosylation reaction. Amino alcohol 16 could be prepared from allylic amine 13 by dihydroxylation, sulphate formation and elimination. Compound 13 can be synthesized from allyl amine 12 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral allyl amine 12 could be obtained, similarly to the previous chapters, by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from the racemic butadiene monoepoxide 5. On the other hand, the intermediate 15 could be also obtained by addition to the Garner aldehyde (18) followed by deprotection of the protecting groups in 17. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and imide as a nitrogen nucleophile proceeded with good yield (96%) and enantioselectivity (90%). Chain elongation of key chiral allylic amine 12 was carried out by cross metathesis with allyl phenyl sulphide with Hoveyda-Grubbs catalyst (5 mol%) to obtain the corresponding trans alkene 13 in 80% yield. The installation of the diol moiety with OsO4 was unsuccesful, due to the competitive oxidation of sulfur, preventing the completion of the synthesis.

Crude extracts of the rare macrofungus Serpula sp. collected from a wooded area in Sri Lanka showed antimicrobial activity. The novel fungal metabolite serpulanine (2.1) was isolated from the crude extract in very small amounts along with a number of additional secondary metabolites. In order to obtain sufficient quantities of serpulanine (2.1) for biological evaluation, a synthetic route was developed to the natural product and a small library of analogs that have been evaluated in a panel of bioassays. Serpulanine (2.1) inhibits the histone deacetylase I/II with a clear dose response curve. Halitoxins (3.1) that are frequently isolated from marine sponges have a complex macrocyclic chemical structure made of different numbers of monomeric alkylpyridinium units. An unknown halitoxin-related natural product named alotau potently inhibited the dephosphorylation activity of calcineurin. With the goal to elucidate the structure of alotau, compounds of one, two and three pyridinium rings (3.10, 3.7 and 3.8) were synthesized. Though these compounds have NMR spectra similar to the natural alotau, according to bioassay results, none of them recapitulates the activity of the unknown natural product alotau. (+)-Makassaric acid 4.1 was isolated in the Andersen Lab from the marine sponge Acanthodendrilla sp. It showed promising activity in a zebrafish screen for new drugs to treat stroke patients. The convergent synthetic scheme shown below was undertaken to conduct structure activity relationship (SAR) studies. The key intermediate 4.17 has been obtained, and further synthetic efforts will be needed to produce 4.1.<br>Science, Faculty of<br>Chemistry, Department of<br>Graduate