טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentChechik Helena
SubjectMulticomponent Condensation Reactions as an Efficient
Route to Aldol Product
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

Construction of new chemical bonds is one of the main issues in Organic Chemistry.

Another important issue in synthetic organic chemistry is the improvement of reaction sequence efficiency.

The target of this research is to develop synthetic method for the construction of aldol product with quaternary stereogenic center. Since the classical approach of such synthesis is difficult, we have to overcome those difficulties by developing a new strategy, which is based on the combination of carbocupration reaction and multicomponent homologation-allylation reaction.

The synthetic sequence will include a carbocupration reaction of alkyne to form the α-isomer, followed by a homologation reaction using diiodomethane/diethylzinc. Diiodomethane reacts with diethylzinc to form a reactive zinc carbenoid species that are able to react with vinylmetal to form an allylmetal intermediates.  Addition of aldehydes to allylmetal species will lead to the formation of enamide. Hydrolysis of the enamide should lead to the formation of the aldol product.

First, the carbocupration reaction was studied. In order to perform all the synthetic sequence and to obtain the aldol product, only α-isomer of vinyl copper should be prepared during the carbocupration reaction. The carbocupration reaction was performed using alkynyl carbamate, alkynyl sulfonamide and alkynyl amide as starting materials, CuI and different Grignard reagents as a source of the organocopper reagents. In all cases, the reaction was found to be regioselective. The scope of the reaction was proved to be broad, since different organocopper reagents can be used. The vinyl copper intermediates can be further functionalized. To improve the reaction even further, a copper-catalyzed carbomagnesiation reaction was also developed.

When the carbocupration reaction was established, it was combined with the homologation - allylation reactions to construct the desired enamide with a stereogenic quaternary carbon centers. Mechanistically, the vinyl copper undergoes a homologation reaction in presence of zinc carbenoid. Such homologation reaction leads to the formation of reactive allylmetal intermediate that reacts with an aldehyde to form the desired enamide. A large verity of enamide products was prepared. In all cases, the reaction proceeded diastereoselectively.

Several preliminary attempts were performed to develop an access to non-racemic enamide. Chiral alkynyl oxazolidinones were used as starting materials. Application of the carbocupration-homologation-allylation sequence on chiral alkynyl oxazolidinones led to the non racemic formation of the desired enamide. Although the diastereomeric ratio is very modest, it indicates that the two possible enantiomers can be slightly differentiated by this reaction. The enantioselectivity still need to be improved.