Enantioselective synthesis of natural products

Identificador:  TDX:2062

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

Autors:  Azzouz, Mariam

Resum:
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