New methodologies in organic synthesis using the Wolff rearrangement from unsaturated diazoketones

Author(s)

Barbara Bernardim de Souza

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT)
• Defense date: 2017-03-09

Examining board members

Antonio Carlos Bender Burtoloso; Timothy John Brocksom; Carlos Roque Duarte Correia; Kleber Thiago de Oliveira

• Advisor: Antonio Carlos Bender Burtoloso

Abstract

Among the various types of diazocarbonyl substrates found in the literature, α,β-unsaturated diazoketones have shown a number of promising applications as multifunctional intermediates. This thesis is divided into three chapters, aimed at expanding the reactivity of such α,β-unsaturated diazoketones for synthetic chemistry and chemical biology applications. In the first chapter, diazoketones are presented as platforms for the direct synthesis of β,γ-unsaturated amides and esters via a Wolff rearrangement reaction. When diazoketones derived from amino-aldehyde are substrates, peptidic isosters are obtained, as demonstrated in the efficient synthesis of the nitroxide drug, JP4-039. In the same chapter, a study demonstrating the efficiency of several commercial light sources (CFL and LED) to promote the Wolff rearrangement was described, representing a sustainable alternative to UV lamps for this interesting reaction. The second chapter sought to expand the chemistry of unsaturated diazoketones for the study of [2 + 2] and [4 + 2] cycloaddition reactions. The preparation of the precursor esters for cycloaddition reaction was demonstrated by the Wolff rearrangement of precursors in the presence of allylic alcohols, and the attempt then culminated in the synthesis of a Diels-Alder cycloadduct. Chapter 3 was devoted to the use of α,β-unsaturated diazoketones for the site-specific chemical modification of proteins. These have been successfully demonstrated for this purpose, as well as inspiring the development of a promising new method for selective bioconjugation of cysteines. (AU)

• FAPESP's process: 12/22274-2 - Study in the photochemical Wolff rearrangement from a,b-unsaturated diazoketones. Aplication in diversity synthesis of nitrogen and oxygen heterocycles
• Grantee: Barbara Bernardim de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate