https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Asymmetric enamine catalysis.

Most enzymatic transformations have a synthetic counterpart. Often though, the mechanisms by which natural and synthetic catalysts operate differ markedly. The catalytic asymmetric aldol reaction as a fundamental C-C bond forming reaction in chemistry and biology is an interesting case in this respect. Chemically, this reaction is dominated by approaches that utilize preformed enolate equivalents in combination with a chiral catalyst.1 Typically, a metal is involved in the reaction mechanism.1d Most enzymes, however, use a fundamentally different strategy and catalyze the direct aldolization of two unmodified carbonyl compounds. Class I aldolases utilize an enamine based mechanism,2 while Class II aldolases mediate this process by using a zinc cofactor.3 The development of aldolase antibodies that use an enamine mechanism and accept hydrophobic organic substrates has demonstrated the potential inherent in amine-catalyzed asymmetric aldol reactions.4 Recently, the first small-molecule asymmetric class II aldolase mimics have been described in the form of zinc, lanthanum, and barium complexes.5,6 However, amine-based asymmetric class I aldolase mimics have not been described in the literature.7 Here we report our finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes. Recently we developed broad scope aldolase antibodies that show very high enantioselectivities, have enzymatic rate accelerations, and use the enamine mechanism of class I aldolases.4 During the course of these studies, we found that one of our aldolase catalytic antibodies (Aldolase Antibody 38C2, Aldrich) is an efficient catalyst for enantiogroup-differentiating aldol cyclodehydrations of 2,6-heptanediones to give cyclohexenones, including the Wieland-Miescher ketone.8,9 These intramolecular reactions are also catalyzed by proline (Hajos-Eder-Sauer-Wiechert reaction)10 and it has been postulated that they proceed via an enamine mechanism.11 However, the proline-catalyzed direct intermolecular asymmetric aldol reaction has not been described. Further, there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism.7 Based on our own results and Shibasaki’s work on lanthanum-based small-molecule aldol catalysts,4,6 we realized the great potential of catalysts for the direct asymmetric aldol reaction. We initially studied the reaction of acetone with 4-nitrobenzaldehyde. Reacting proline (30 mol %) in DMSO/acetone (4:1) with 4-nitrobenzaldehyde at room temperature for 4 h furnished aldol product (R)-1 in 68% yield and 76% ee (eq 1). This result

https://www.scripps.edu/barbas/pdf/List00JACS.pdf

Proline-Catalyzed Direct Asymmetric Aldol Reactions

The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Bronsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.

Lewis Base Catalysis in Organic Synthesis

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts Structure-based catalyst screening identified l-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99% The reactions are assumed to proceed via a metal-free Zimmerman−Traxler-type transition state and involve an enamine intermediate The observed stereochemistry of the products is in accordance with the proposed transition state Further supporting evidence is provided by the lack of nonlinear effects The reactions tolerate a small amount o

https://www.scripps.edu/barbas/pdf/Sakthivel01JACS.pdf

Amino Acid Catalyzed Direct Asymmetric Aldol Reactions: A Bioorganic Approach to Catalytic Asymmetric Carbon-Carbon Bond-Forming Reactions

Stereochemistry-60 : Kinetic control of asymmetric induction during oxazolidine formation from (-)-ephedrine and aromatic aldehydes

Is the mechanism of the proline-catalyzed enantioselective aldol reaction related to biochemical processes?

Stereochemistry-59: New insights into the mechanism of the proline-catalyzed asymmetric robinson cyclization; structure of two intermediates. asymmetric dehydration

Claude Agami

Papers

Stereochemistry-60 : Kinetic control of asymmetric induction during oxazolidine formation from (-)-ephedrine and aromatic aldehydes

Is the mechanism of the proline-catalyzed enantioselective aldol reaction related to biochemical processes?

Stereochemistry-59: New insights into the mechanism of the proline-catalyzed asymmetric robinson cyclization; structure of two intermediates. asymmetric dehydration

Total synthesis of (−)-desoxoprosopinine via the diastereoselective reduction of homochiral2-Acyl-N-Boc-oxazolidines

Enantioselective Synthesis of Clavepictine Analogues and Evaluation of Their Cytotoxic Activity