Stereoselective synthesis of cyclopropane-containing molecules of pharmaceutical interest

This PhD thesis describe the development of novel methodologies for the synthesis of pharmaceutically relevant scaffolds containing a cyclopropyl moiety. In Chapter 1, a general overview on asymmetric catalytic cyclopropanation methods is reported. The chapter is divided into three paragraphs describing Simmons-Smith reaction, cyclopropanation using metal carbenes formed by reaction of metal complexes (Cu, Co, Rh) with diazocompounds, and Michael Initiated Ring Closure (MIRC). In Chapter 2, three different synthetic procedure for the synthesis of 1,2-disubstituted cyclopropane bearing ester or amine moiety are described. A novel diasteroselective method for the synthesis of a trans-protected cyclopropanol from commercially available and cheap L-malic acid has been discovered. The obtained product is a suitable substrate for further functionalization including nucleophilic substitution of the alcohol moiety. The second method exploit cyclopropylamine as an interesting starting material since its cheapness and the possibility to avoid the usually difficult cyclopropanation step. The functionalization of the ring in β-position in a cis manner was achieved by means of Ir catalysis introducing a boron moiety with excellent diasteroselectivity. The borylated product can benefit of a wide variety of post functionalization such as Sukuzi-Miyaura coupling, oxidation to install alcohol moiety, and fluorination. The third method consisted of a C-H functionalization of the β-carbon of the cyclopropyl moiety by means of a tandem reaction based on lithiation and subsequent electrophilic quenching to achieve the formation of new C-C, C-D, and C-Si bonds. In Chapter 3, the synthesis of syn-3-azabicyclo[3.1.0]hexane-6-carboxylic acid derivatives was explored. This class of compounds gained particular interest in the Pharma field for their use as functional groups in different drugs such as Trovafloxacin, Alatrofloxacin. The goal was focused on the synthesis of the less stable syn- isomer. A high diastereoselective catalytic protocol based on Co-salen catalysis was reported, being more selective than ones present in the literature. Co is cheaper and more abundant than common Rh catalysts and allow to avoid the use of stoichiometric reagent, such as ylides. The new synthetic procedure was scaled up in Lundbeck Pharmaceutical Italy laboratories. Attempts to obtain the final target product through selective reduction or by complete reduction and then selective re-oxidation were not successful. The optimization of the intermediate purification and selective reduction/re-oxidation will be further explored in Lundbeck Pharmaceutical Italy. In Chapter 4, CuH catalysis was applied to enable asymmetric access to chiral cyclopropanes, which is unprecedented. Specifically, prochiral bromocrotonates underwent enantioselective hydride conjugate addition using chiral Cu–H complex to give a chiral Cu-enolate. Intramolecular cyclization produced the desired chiral cyclopropane. Key to the success and to the reproducibility of this protocol was the identification of CsF as the base to activate the silane (hydride source) without promoting the vinylogous enolization of the substrate. Under these conditions various disubstituted cyclopropanes were accessed in high yield, complete trans-diasteroselectivity and enantioselectivity up to 99% ee. The hydroalkylation process proved to be general, allowing access to differently substituted derivatives, spanning aryl, heteroaryl, N-indolyl and alkyl substituents. A DFT mechanistic analysis was also performed to elucidate the mechanism of the reaction. In addition to confirming the mechanistic working hypothesis in which bromocrotonate, in presence of a chiral Cu-H complex, provide cyclopropane through formation of chiral Cu-enolate, this analysis in addition with a few mechanistic experiments, allowed to provide a full understanding of the factors affecting the reaction diastereo- and enantio-selectivity.