New applications of the enantioselective Heck reaction: desymmetrizations and intramolecular reactions

Author(s)

Rafaela Costa Carmona

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2018-04-06

Examining board members

Carlos Roque Duarte Correia; Arlene Gonçalves Corrêa; Cristiano Raminelli; Igor Dias Jurberg; Júlio Cezar Pastre

• Advisor: Carlos Roque Duarte Correia

Abstract

The Heck reaction is considered a very efficient method for the formation of carbon-carbon bonds and one of the most used transformations in organic synthesis. The use of arenediazonium salts as electrophiles, known as the Heck-Matsuda reaction, is increasingly contributing to the synthesis of valuable compounds in a practical and efficient way. This doctoral thesis presents the development and evolution of the enantioselective Heck-Matsuda reaction for the synthesis of carbo- and heterocycles. First, the desymmetrization of cis-4-cyclopentene-1,3-diol was studied, leading to the formation of 3-hydroxy-4-arylcyclopentanones and 4-arylcyclopentenones in excellent yield and in a diastereo- and enantioselective manner. The products obtained are considered important synthetic building blocks for the synthesis of natural and unnatural bioactive compounds containing five membered rings. In the sequence, an enantioselective Heck desymmetrization reaction was developed for the synthesis of heterocyclic compounds containing two stereogenic centers, one at the heteroatom (S and P) and the other at the carbon. The selected prochiral symmetrical substrates were efficiently arylated using the PyraBOx chiral ligand and a variety of aryl sulfones, sulfoxides and five-membered phosphine oxides were obtained in excellent yields, good diastereoselectivities and enantiomeric ratios of up to 98:2. Furthermore, the developed methodology is extremely simple and based on an unprecedented non-covalent director effect of S=O and P=O functionalities. The development of the intramolecular Heck-Matsuda asymmetric reaction poses an extra challenge due to the instability of the arenediazonium salt and the rapid formation of styrenes and/or aromatization of the intermediate. However, this issue could be overcome by capturing the alkyl-palladium intermediate formed with nucleophiles. In this way, this methodology was developed and the first examples of the asymmetric Heck-Matsuda cascade reaction are being reported in this work. In addition, during an internship abroad, the development of the cascade aza-Heck reaction was carried out leading to the formation of functionalized heterocycles (AU)

• FAPESP's process: 13/10183-5 - Arylation of Cycloalkenes via asymmetric Heck-Matsuda reaction and synthetic applications
• Grantee: Rafaela Costa Carmona
• Support Opportunities: Scholarships in Brazil - Doctorate