The Crucial Role of S ‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover. Enantiopure proline-cysteine analogs were obtained by 1,3-dipolar cycloaddition between homochiral thiazolines and azomethine ylides. The reactivity and regioselectivity are controlled by the oxidation state of the thiazoline sulfur atom. Sulfoxide and sulfone groups led to 2,3 addition whereas reactions starting from the thioether group resulted in 2,4 addition. Diastereofacial selectivity is controlled by the bulky tert-butyl group at the thiazoline ring.
The authors thankfully acknowledge MINECO (Ministerio de Economía y Competitividad, grant CTQ2013-40855-R) and Gobierno de Aragon-FEDER (Grupo Aminoácidos y Péptidos E19_20R; FEDER 2014–2020‘Construyendo Europa desde Aragón’), for the financial support provided to this work. J. G.-V. thanks the Gobierno de Aragón–FSE for a pre-doctoral Grant.