Enantioselective synthesis of natural products

Identifier:  TDX:2062

Handle: https://hdl.handle.net/20.500.11797/TDX2062

Authors:  Azzouz, Mariam

Abstract:
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.