TEMPLATE DIRECTED C-H INSERTION REACTIONS FOR STEREOCONTROLLED SYNTHESIS OF HETEROCYCLES

Template Directed C-H Insertion Reactions for Stereocontrolled Synthesis of Heterocycles Orobosa Marvis Erhunmwunse, PhD. Non aromatic heterocycles and their analogues are abundant in a large variety of bioactive natural products and continue to play crucial roles in modern day chemotherapy. The bioactivities of these heterocycles are highly dependent on the stereochemistry of the substituents and therefore the development of elegant new methodologies for the selective construction of heterocycles remains attractive to the synthetic chemist. Described in this thesis, is a tandem methodology for the stereocontrolled synthesis of highly functionalised oxygen heterocycles. The strategy adopted resulted in the successful synthesis of 2,3,4,5-tetrasubstituted tetrahydrofurans and 2,3,4,5,6-pentasubstituted oxepanes. The key step involves catalytic C-H insertion of diazocarbonyl acetal templates. Diazocarbonyl substrates representing the three classes of carbenoids were synthesised. In the foremost route that led to the first class, the diazoacetoacetates were obtained from the oxidation of the diazoketols prepared by an aldol type condensation between the aldehyde acetals and ethyldiazoacetate. Good yields of the diazoketols and the required diazoacetoacetates were isolated. Importantly, the sequence led to the development of a general and efficient one-pot protocol for the synthesis of diazoacetoacetate derivatives. The synthesis of the vinyldiazoketones was equally achieved from the aldehyde acetals in 3 steps involving diazotransfer onto the vinylketones prepared by oxidation of the allylalcohols which resulted from treating the aldehyde acetals with allylmagnesium bromide. Good yields of products were achieved in all 3 steps. The aldehyde acetals were synthesised following a Swern oxidation protocol from the corresponding alcohols prepared from the ester acetals which were synthesised by ketalisation of 2-substitutedpropan-1,3-diols with pyruvate esters. Initial efforts in screening for catalyst suitable for the decomposition of the diazoacetoacetates resulted in the novel synthesis of the Barceloneic lactone derivatives in respectable yields. Further efforts led to the preparation of the achiral rhodium (II) heptafluorobutyramide which proved successful for the decomposition of the vinyldiazoketones to give the bicyclic acetals in moderate yields. An asymmetric synthesis of the bicyclic acetals was also achieved. Finally, the reductive cleavage of the bicyclic acetals in a regio- and stereoselective fashion resulted in the highly functionalised tetrahydrofurans and oxepanes.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

Durham University

Year dc:date.issued

2009

Author dc:creator

• Erhunmwunse, Orobosa Marvis