Asymmetric Iminium Ion Catalysis with a Novel Bifunctional Primary Amine Thiourea: Controlling Adjacent Quaternary and Tertiary Stereocenters

Abstract

Dedicated to the Centenary of the Italian Chemical SocietyThe development of novel and highly enantioselective transformations is one of the most exciting goals for organic chemists involved in the competitive and stimulating field of asymmetric organocatalysis. [1] In this area, the remarkable advances in the application of chiral secondary amine catalysts (asymmetric aminocatalysis) [2a,b] are linked with the accessibility of divergent carbonyl activation modes, through either nucleophilic enamine [2c] or dienamine [2e] intermediates, electrophilic iminium ions [2d] or even radical [2f] intermediates. In particular, the incredibly high efficiency and generality demonstrated by some "privileged" organocatalysts such as proline [3a] (I) or the synthetic MacMillan imid-A C H T U N G T R E N N U N G azA C H T U N G T R E N N U N G olidinones [2d] (II) and the silyl-protected diarylprolinols catalysts [3b] (III) (Scheme 1) have consolidated asymmetric aminocatalysis as a reliable and powerful synthetic tool for the chemo-and enantioselective functionalization of carbonyl compounds.[2] These general and readily available catalysts represent an important starting point for the investigations of new asymmetric processes because they often avoid the need for multiple screening processes of catalysts to determine the optimal reaction conditions. However, because aminocatalysis may face problems of increasing complexity and diversity, the privileged catalysts might not always be the best candidates to solve some specific and challenging tasks (Scheme 1). In this context, the stereocontrolled conjugate addition of prochiral trisubstituted carbon nucleophiles to a,b-unsaturated aldehydes through iminium activation still represents a daunting synthetic challenge [4] because the privileged catalysts generally allow the formation of products with high enantioselectivity but with poor diastereocontrol. [5] Herein, we describe the development of a new bifunctional chiral primary amine thiourea catalyst and its application in the first asymmetric conjugate addition of oxindoles to enals. A bifunctional catalyst was chosen because it was thought that only concomitant and synergistic activation of both the reacting partners may enforce high diastereocontrol during CÀC bond formation. The high levels of both enantio-and diastereoselectivity achieved demonstrate the ability of the catalyst to provide a solution to the challenging problem of generating valuable chiral scaffolds with contiguous quaternary and tertiary stereocenters.[6] Moreover, we demonstrated for the first time that chiral primary amine thiourea catalysts, which during the last two years have been successfully applied in many enamine-based asymmetric transformations expanding the synthetic potential of aminocatalysis, [7] can also be effective for iminium ion activation of a,b-unsaturated aldehydes.For exploratory studies, we selected the reaction between 3-methyl oxindole (1 a) and cinnamaldehyde (2 a), a combination of simple and readily available starting ...

Asymmetric Michael Addition of Aromatic Ketones to Nitroolefins Catalyzed by Simple Chiral Bifunctional Primary Amine-Thioureas

“…(1), just prepared by simple reaction of chiral 1,2-Diphenylethylenediamine with isothiocyanate, as an efficient bifunctional catalyst for the direct asymmetric Michael addition of a broad spectrum of aromatic ketones with nitroolefins in good enantioselectivities (up to 86% ee) and excellent yields (up to 97%). To the best of our knowledge, this simple primary amine thiourea catalyst has not attracted enough attention except one case recently reported by Melchiorre [10]. During the preparation of this manuscript, Wu's group reported the same chiral primary amine-thiourea 2 as an efficient catalyst for the analogous addition of aromatic ketones to more conjugated nitrodienes [9i], and before this submission of our work, Xu's group reported the analogous results [9j].…”

“…To improve yield and enantioselectivity, a series of solvents were investigated ( Table 1). In general, the enantioselectivity was slightly higher in aprotic solvents (entries 4-8, 13, 14) than in protic solvents (entries 10,12). In i-PrOH, excellent yield (89%) and good enantioselectivity (74% ee) were obtained (entry 10).…”

Dioxindole in Asymmetric Catalytic Synthesis: Routes to Enantioenriched 3‐Substituted 3‐Hydroxyoxindoles and the Preparation of Maremycin A

“…[2,5,6] In contrast, dioxindole 1, which would directly install the valuable hydroxy moiety at C3, has never been used as a competent nucleophile in analogous reaction pathways. [7] This is rather surprising, because the electron induction of the hydroxy moiety could be expected to increase the acidity of the hydrogen atom at C3 and the propensity toward an alkylation pathway.…”

Highly efficient stereoconservative syntheses of new, bifunctional atropisomeric organocatalysts

“…in enantioselective Baylis-Hillman reactions and later on by Melchiorre and co-workers 20 for the enantioselective addition of 3-methyloxindole to cinnamaldehyde. The same atropisomeric skeleton was used by Barbas and co-workers, 21 who connected an additional chiral alkaloid moiety to the other side of the thiourea and applied this novel multifunctional organocatalyst for enantioselective cascade reactions.…”