טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMinko Yury
SubjectQuaternary Stereocenters in Acyclic Systems: From
Alkynes via Stereodefined Trisubstltuted Enolates
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

The past several decades have witnessed an impressive progress in the field of stereoselective organic synthesis. However, the development of new strategies leading to the enantioselective creation of quaternary stereocenters, i.e. carbon atoms asymmetrically bonded to four different non-hydrogen substituents, is still among the remaining significant challenges in chemical synthesis.

In this manuscript, we describe the development of novel methodologies that allow for a great increase in molecular complexity through single-flask operations that string together many steps that collectively achieve the same high complexity increase. A challenging goal of step economy and efficiency can be reached by using such methods since the number of steps in a synthetic sequence is of paramount importance.

In the course of this study, we have successfully merged the regioselective carbocupration of simple alkynyl carbamates with electrophilic oxidation of the resulting intermediate vinylcopper (or cuprate) species in a single-flask synthetic sequence. We have shown that particularly promising is the chemistry of oxenoids as electrophilic oxidants leading to the formation of stereodefined trisubstituted enolates from simple precursors.

The one-flask protocol that was developed and published as a result of this research represents an interesting alternative to the existing methodologies since it is the first example of generation of acyclic stereodefined trisubstituted chiral metal enolates which does not depend on stereoselective enolization of carbonyl compound. Important outcomes of the developed method have been demonstrated in the synthesis of complex molecular structures possessing quaternary carbon stereogenic centers in acyclic scaffolds that are difficult to synthesize.

Thus, we have achieved highly diastereoselective protonation, aldol addition, Mannich-type reaction, and asymmetric allylation of the intermediate enolates generated by the originally developed methodology. The remarkable feature of the new method is that up to two new stereocenters (including challenging quaternary ones) and three new bonds (two new C-C and one carbonyl functionality) can be selectively and concomitantly formed in a single-flask synthetic protocol operating in relatively simple experimental manifolds. The key features in all developed reactions are the high levels of stereocontrol, the level of predictability, and the simplicity of experimental manifolds that ensure success in the application of such methods.

This study illustrates that even the most challenging problems can be efficiently addressed when new and powerful synthetic tools are provided.