Organocatalytic α-functionalization of carbonyl compounds: chemo-, regio- and stereoselectivity.

Abstract

The aim of this thesis has been the development of new synthetic procedures for the asymmetric formation of carbonyl componenets bearing a stereocenter at C¿. Covered topics include (i) the particular case of the use of ¿-unsaturated aldehydes as donors in the aldol reaction with propargylic aldehydes and the subsequent Pauson-Khand reaction of the resulting 1,¿-enynes (Scheme 1), (i) the behaviour of alkynyl ketones (ynones) as acceptors in such aldol reactions. Main results on these topics have been published in Chem. Eur. J. 2014, 20, 15543¿15554.Scheme 1A second chapter deals with the use of ¿¿-oxy enones as acrylate equivalents in Brønsted base-catalyzed enantioselective conjugate addition of oxazolones for the stereoselective generation of new tetrasubstituted carbon stereocenters (results published in JACS 2014, 136, 17869¿17881; Scheme 2). Three situations have been addressed: a) addition to the unsubstituted enone (acrylate equivalent), b) addition to ß-substituted enones, and c) addition to ¿-substituted enones (metacrylate equivalent). Scheme 2As a complement, the behaviour of the homologue ¿¿-hydroxy dienones have been studied with the aim to ascertain to which extent both the stereoselectivity, and the regioselectivity of the process (1,4- vs 1,6-addition) could be controlled. For this purpose, new chiral guanidine and phosphanimines were synthetized and tested(Scheme 3). Scheme 3Chapter 3 deals with the Brønsted base-catalyzed addition of ¿-substituted cycloalkanones to suitable acceptors to produce the corresponding ¿,¿-disubstituted (quaternary) ketones in good yield and overall high selectivity. The method was demonstrated to be robust, admitting cycloalkanones with different ring-sizes (n = 0, 1, 2, 3; Scheme 4a). In the same context, the completely regio- and stereoselective functionalization of ¿-substituted ß-tetralones through the bifunctional Brønsted base-catalyzed Michael reaction with nitroalkenes (ACIE 2017, 56, 2059¿2063) and addition to azodicarboxylates have been achieved (Scheme 4b). Scheme 4The last part of this Thesis was carried out in the laboratory of Prof. Jonathan Clayden in the School of Chemistry of the University of Bristol. Studies there were focused on routes to the synthesis of the aromatic amino acid precursor arogenate from the natural amino acid L-tyrosine (Scheme 5). Scheme 5