anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

Abstract

In the last decade, remarkable progress has been made toward direct catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and environmentally friendly conditions. [1] In enamine catalysis, significant effort has focused on understanding the origin of diastereo-and enantioselectivity in organocatalysis. These studies have facilitated the design of syn-selective aldol and anti-selective Mannich reactions not originally addressed by organocatalytic methods. [2][3][4][5] The organocatalytic Michael reaction is often regarded as one of the most efficient and broadly applicable carbon-carbon bond-forming reactions known because a wide variety of acceptors can be employed and high stereoselectivity has been realized. [6] Although a large number of reports on the organocatalytic Michael reaction of aldehydes have been published, to the best of our knowledge, all of these reactions are syn selective.[7] Several studies, however, have reported success in the anti-selective organocatalytic Michael reaction of ketones.[8] Herein, we report the first highly anti-selective asymmetric Michael reactions of aldehydes and nitroolefins using a strategy designed to control the configuration of the reacting enamine.The predominant stereochemical outcome of the enamine-based Michael reaction was first explained in the classic studies of Seebach and co-workers.[9] Seebach deduced that high syn selectivity can be explained by an acyclic synclinal transition-state model (Scheme 1 a).[9a] In this transition state, the thermodynamically stable E enamine reacts with E nitroolefins in a synclinal arrangement, in which the actual donor and acceptor atoms are situated close to each other (see NO 2 and NR'R'' in Scheme 1 a).We have explored two routes for control of the overall diastereoselectivity of organocatalytic enamine reactions: 1) controlling the face selectivity of the reactive enamine to affect anti-Mannich reactions [2] and 2) controlling the E/Z configuration of the reactive enamine to affect anti-Mannich and syn-aldol reactions (Scheme 1 b). [3] For the anti-Michael reactions described herein, we have taken the latter approach.The classic organocatalytic Michael reaction of aldehydes and ketones utilizes pyrrolidine-based catalysts which react via E-enamine intermediates with nitroolefins and other Michael acceptors in synclinal transition states to provide predominately syn-configured Michael products. The Z-enamine intermediate formed using secondary amine catalysts are significantly less favored. Movement from a secondary amine catalyst to a primary amine catalyst provides steric latitude which enables Z-enamine formation with ketones. A caveat, however, is that Z-enamine formation from aldehydes is likely to be more difficult than that from ketones since the E-configured enamine derived from an aldehyde minimizes steric conflicts between the catalyst and Scheme 1. a) Synclinal transition-state model, b) anti-Mannich and synaldol...

Carboxylate Salt Bridge‐Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)‐Pristiq

“…Carboxylate salt‐based enamine catalysis is known but not widely employed,, and we speculated that its application could overcome the non‐compatibility of acidic spectator functional groups during enantioselective catalysis, in particular for the Michael reaction. Here we show that threonine or serine potassium salt catalysis (i) far surpasses the lone catalysis examples employing 3‐ or 4‐hydroxy‐β‐nitrostyrenes, (ii) is applicable to unreported and more acidic spectator groups, e.g., 3,4‐catechols, 3‐ or 4‐positioned acetamide or carboxylic acid moieties, and (iii) allows both the Michael electrophile and nucleophile to simultaneously contain an acidic spectator group.…”

“…Ignoring, temporarily, the challenge of coexisting acidic spectator groups, it is noteworthy that a smaller number of reports show the addition of α‐branched aldehydes, as opposed to linear aldehydes, to β‐nitrostyrenes . We have consequently focused on α‐branched aldehyde additions here, which lead to the more difficult to form quaternary carbon‐based Michael products.…”

Construction of Quaternary Stereocenters: Asymmetric α‐Amination of Branched Aldehydes Catalyzed by Monoimide Substituted Cyclohexane‐1,2‐Diamines

“…Chiral amines have emerged as powerful tools in asymmetric catalysis. [19][20][21][22][23][24] Among them, 1,2-diphenylethane-1,2-diamine and cyclohexane-1,2-diamine are widely used as starting materials for the preparation of chiral reagents, ligands, and catalysts, such as Jacobsen's salen ligands, [25][26][27] Trost's ligand, [28][29][30][31][32] and chiral thioureas. [33][34][35] Imide monosubstituted-1,2-diamines, the key intermediates in the preparation of those chiral molecules, have drawn our attention and were successfully applied to asymmetric double Michael reaction 36 and enantioselective Diels-Alder reaction of anthrone with maleimide.…”

Catalyst‐Controlled, Enantioselective, and Diastereodivergent Conjugate Addition of Aldehydes to Electron‐Deficient Olefins

“…The selectivity of this process is governed by an acyclic synclinal transition state, wherein minimal steric strain and close proximity between the enamine nitrogen and the electron‐withdrawing group of the Michael acceptor are favored ( TS1 , Scheme A) . To reverse the stereochemical preference of this reaction to favor the anti adduct, substrate control has previously been exploited, by using either specific Z olefins as acceptors ( TS2 ), or siloxyacetaldehydes as nucleophiles, which form Z enamines in the presence of a primary amine catalyst ( TS3 ) . On the other hand, examples of catalyst‐controlled anti ‐selective conjugate addition between simple aldehydes and E alkenes are scarce and limited in scope .…”