Development of New Strategies Towards Accessing Chiral Nitrogen Heterocycles
Groso, Emilia
2019
Abstract
The olefin-olefin metathesis reaction is a revolutionary industrial process that utilizes precious metal complexes to enable direct carbon-carbon bond formation from simple olefin starting materials. This powerful tool has been utilized in a wide range of applications including natural product synthesis, materials and polymers, medicines, and fine chemical synthesis. While this approach has been employed for the construction of new carbon-carbon bonds in a wide range of systems through the use of metal alkylidene catalysts, recent advances have led to the development of the direct metathesis between carbonyls and olefins that relies on Lewis acids catalysts. This method is not only marked by the use of inexpensive sustainable catalysts, but it also eliminates the need for the prerequisite synthesis of the olefin substrates. The Schindler lab recently identified an inexpensive iron catalyst capable of promoting exclusively carbonyl-olefin metathesis reactions with catalyst loadings as low as 1 mol percent. This design principle fundamentally differs from stoichiometric carbonyl-olefin metathesis protocols proceeding via intermediate oxametallacycles. It is instead based on the in situ formation of oxetanes as reactive intermediates via initial cycloaddition of a carbonyl and an olefin. While this method has been successfully applied to a wide range of carbocyclic systems, we envisioned that this could be a valuable method towards the synthesis of nitrogen heterocycles, which are ubiquitous in both natural products and pharmaceuticals. This thesis details the application of the carbonyl-olefin metathesis reaction towards the synthesis of chiral nitrogen heterocycles. While nitrogen containing systems have previously represented challenging substrates for metathesis reactions due to their ability to coordinate to the active catalyst, Chapter 2 describes the development and application of electron-deficient protecting groups enable the successful progression of the reaction as well as a general synthetic strategy from chiral amino acids that provides access to a diverse array of chiral substrates that can be utilized to access both chiral 3-pyrrolines. Chapter 3 further describes the application of both the synthetic strategy and carbonyl-olefin metathesis towards the preparation of tetrahydropyridines and other diverse nitrogen heterocycles in a unified approach. In order to gain insight into the principals governing this reaction, conducted a series of experimental and computational studies to model that provided a variety of mechanistic insights into the reaction pathway of both 3-pyrrolines and tetrahydropyridines. These studies have not only provided further insights into the electronics of the sulfonamide and its role as a competitive binding sight, but they have also provided key insights into substrate design. The details of these efforts are provided in Chapter 4.Subjects
carbonyl-olefin metathesis
Types
Thesis
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