Asymmetric Synthesis using Redox-Active Diazocompounds as Chiral Carbon Atom Precursors

This thesis summarizes the development of general and efficient methods to synthesize enantiomerically enriched cyclopropane compounds. The works reported herein exploit the opportunity presented by redox-active esters to explore the orthogonality between asymmetric carbene-transfer and geminal radical generation. Together, these two processes enable the enantioselective manipulation of a carbon atom with multiple leaving groups, allowing sequential and systematic molecular assembly. This thesis discloses a unified approach to transform abundant alkene substrates into unrelated cyclopropane products, circumventing the need of specific methods, catalysts and carbene precursors for each individual case. The exploration of redox-active diazoacetate reagents in this strategy resulted in the discovery of the general enantioselective cyclopropanation method presented in Chapter 2. This method engages olefins, even aliphatic, to produce a variety of cyclopropane derivatives in high yields and selectivity. The late-stage diversification of the resulting products enables facile access to useful chiral building blocks and biologically important scaffolds in a more practical and sustainable way. The mechanism of this ruthenium-catalyzed cyclopropanation employing a novel redox-active carbene precursor is investigated in Chapter 3, disclosing the origin of the selectivity and performance of the system. Several techniques including gas evolution monitoring, benzhydrylium benchmarking, in situ high resolution mass spectroscopy and VTNA kinetic analysis are used to gain insight on this reaction. Chapter 4 describes the development of a key stereoselective photo-decarboxylation of cyclopropyl redox-active esters to obtain chiral cis-arylcyclopropanes. These are commonly used as conformationally restricted olefin isosteres in medicinal chemistry. The modular assembly of these challenging compounds is explored, along with the photophysical and photochemical features of the new efficient method. Finally, Chapter 5 describes the development of a robust protocol to transform cyclopropyl redox-active esters in versatile cyclopropylboronates by a new photo-organocatalyzed method, which is mediated by new non-symmetric diboronic acid monoesters. These findings originate from a detailed mechanistic investigation of a known borylation procedure by in situ NMR spectroscopy. The new method facilitates the synthesis of chiral cyclopropylboronates in a more sustainable and efficient way, and illustrates the opportunities bestowed by the new diboron species to enhance performance, robustness and stereoselectivity