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Title: Synthesis of IR-analogue of cyclopamine and enzymatic enantioselective synthesis of (S)-norcoclaurine
Tutor: Botta, Bruno
Keywords: cyclopamine; norcoclaurine; natural compounds analogues; green chemistry; enantioselective reaction; Pictet Spengler reaction
Issue Date: 4-Feb-2011
Abstract: The huge biosynthetic potential of plants as a renewable source of fine chemicals and pharmaceuticals has long been recognized. Identification of biologically active compounds from plants and improvement of the isolation methods are of great interest for their therapeutic applications. Moreover, they are a huge source of inspiration for the design of new active compounds, not only for their structure, carrying the features responsible for drug’s biological activity, but also for the biosynthetic pathways that Nature has established for them, often a suggestion for an easier synthetic access to the targeted molecule. Therefore, the future demands for pharmaceuticals is dependent on a detailed understanding of the biologically active compounds, of their biosynthetic pathways as well as the complex mechanisms regulating the development of diseases. Thus in both sections of this work two biologically active compounds and their therapeutic properties are discussed in relation to their methods of synthesis. The first part of this work deals with the synthesis of a potential inhibitor of the hedgehog signaling pathway, a key regulator of multiple developmental processes of embryogenesis as well as in adult tissue maintenance and repair. Since its aberrant activation has been linked to the development of severe malignancies, the hedgehog signaling inhibitors has emerged as a valuable tool for cancer treatment. Several modulators have been reported so far, including cyclopamine, the first known inhibitor identified in 1968. Since its discovery, only in 2009 the first synthetic route to cyclopamine was established by Giannis et al. using a biomimetic and diastereoselective approach. This flexible synthetic strategy provides access to several structural modifications leading to multiple potential analogues of cyclopamine that do not exist in nature. Exploiting this route, in order to have new insights into the biological activity of the natural compound, the first synthetic analogue of cyclopamine was designed and partially synthesized. In the second part of this work the catalytic activity of (S)-norcoclaurine synthase was investigated and used to set up a method for an easy access to (S)-norcoclaurine, the first common intermediate of all benzylisoquinoline alkaloids. Recently (S)-norcoclaurine gained a widespread interest in both organic and medicinal chemistry for its well recognized rich pharmacological potential in the treatment of several diseases. So far, several synthetic strategies have been employed based on asymmetric catalytic approaches involving the use of a chiral metal catalyst. Even though these synthetic routes are highly efficient and guarantee a very good enantioselectivity, they entail extensive use of organic solvents and metal catalysts. In order to develop a clean and green synthetic process towards (S)-norcoclaurine without using organic solvents and metal catalysts, an efficient one pot-two steps synthesis was set up, starting from tyrosine and dopamine in the presence of (S)-norcoclaurine synthase providing the first attempt to exploit the potential of a “Pictet-Spengler” enzyme in the direct synthesis of chiral benzylisoquinolines.
Research interests: Organic chemistry, bioanalytical methods development, immunochemistry, biocatalysis, green chemistry
Skills short description: Smart, communicative and patient person
Personal skills keywords: team-work
personal initiative

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