טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMejuch Tom
SubjectNew and Efficient Methods for the Preparation of Quaternary
Stereocenters
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

The development of new and highly diastereoselective processes for the creation of carbon-carbon and carbon-heteroatom bonds is one of the major targets in chemical synthesis. The construction of quaternary stereocenters, that are carbon centers bearing four different non-hydrogen substituents, represents one of the most challenging and dynamic areas in organic synthesis. The state-of-the-art is the asymmetric construction of such quaternary stereocenters in non-cyclic systems (more complicated due to the number of degrees of freedom associated with these structures). Most of the current methods produce only one carbon-carbon bond per chemical step and, therefore, may suffer from low efficiency.


In this work, we have developed a highly diastereoselective and efficient process for the construction of 1,2-alkenyl diol moiety, bearing quaternary stereocenters, from simple alkynyl ethers through the formation of several carbon-carbon bonds in one chemical step. Our method consists of consecutive carbometalation-zinc homologation-allylation tandem reactions.


The stereochemistry was rationalized through a Zimmerman-Traxler transition state, in which the bulky group R3 of aldehydes occupies a less sterically-demanding pseudo-axial position to avoid gauche interactions with other substituents.


The allylation reaction was successfully established with ketones as well. The expected 1,2-alkenyl diols containing two adjacent quaternary stereocenters in good diastereomeric ratios and yields were obtained using our method. The stereochemistry of the major diastereoisomer can be rationalized through a Zimmerman-Traxler transition state, in which the alkyl group of the ketones occupies a less sterically-demanding pseudo-axial position.


The scope of the reaction was further extended to propargyl ether substrates. Like in the previouis case, the bulky group of the ketones occupies a pseudo-axial position.

We have initiated the studies towards the diastereoselective preparation of Fostriecin substructures, and specifically the C6-C12 fragment, using our combined carbometalation-zinc homologation-allylation reactions tandem. The emphasis was put on the diastereoselective construction of the C8 quaternary stereocenter.


Initial studies towards the development of the enantioselective allylation reaction were also attempted. The initial attempt to perform the reaction in the presence of chiral ligand on zinc atom (e.g. chiral carbenoid) was unsuccessful. The possible explanation could be the presence of multiple metal salts in the reaction mixture that interfere with the chiral induction. Attempts to minimize the amount of salts present in the reaction were only partially successful.