Proline-catalyzed Mannich Reaction Research Articles

Enantioselective Approach for Expanding the Three-Dimensional Space of Tetrahydroquinoline to Develop BET Bromodomain Inhibitors.

The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF3 ⋅ OEt2 , which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect.

Preparation of β2-Homologous Amino Acids Bearing Polar Side Chains via a Collective Synthesis Strategy.

β-Homologous amino acids (βhAAs) are a valuable class of building blocks for novel analogues of bioactive peptides. Thus, practical methods to synthesize enantiopure βhAAs are desirable. We report the application of a collective synthesis strategy to prepare protected β2-homologous amino acids with polar side chains. In this approach, a core structure is constructed via proline-catalyzed Mannich reaction and subsequently derivatized to furnish more than one protected β2-homologous amino acid with a proteinogenic side chain.

Enantiomeric O,O-dimenthyl α-iminotrifluoroethylphosphonates: Novel chiral building blocks in asymmetric synthesis of α-trifluoromethylated α-aminophosphonic acid derivatives

Based on reaction of (+)- or (-)-dimenthyl phosphite with trifluoroacetonitrile the synthesis of optically active O,O-dimenthyl α-iminotrifluoroethylphosphonates was developed. The synthetic potential of these novel chiral synthons was demonstrated by their easy diastereoselective functionalization (hydrogenation, proline-catalyzed Mannich reaction with acetone, aza-Henry reaction, aminoalkylation of electron-rich heterocycles) to afford optically active compounds bearing biorelevant (α-trifluoromethyl-α-amino)methylphosphonic residue.

Transition-Metal Acetate-Promoted Intramolecular Nitrene Insertion to Vinylogous Carbonates for Divergent Synthesis of Azirinobenzoxazoles and Benzoxazines.

Synthesis and isolation of highly unstable azirinobenzoxazole and benzoxazines in a chemodivergent fashion from aryl azido vinylogous carbonates by simple change in transition metal acetate is described. Thermal or rhodium(II) acetate-mediated decomposition of these azides gave dihydroazirino benzoxazole. Their nickel(II) acetate-promoted reaction gave 4-dihydro-2H-benzoxazines, whereas copper(II) acetate led to the corresponding oxidized imine derivatives. Benzaoxazine derivative could be kinetically resolved using a proline-catalyzed Mannich reaction. The benzoxazines were rapidly elaborated to angularly fused tetracyclic systems and coumarin-fused derivatives in a "one pot" fashion.

Benjamin List

Benjamin List

A Concise Enantioselective Synthesis of (+)-L-733,060 and (+)-T-2328 via Sequential Proline Catalysis

A new, sequential proline-catalyzed approach to the synthesis of (+)-L-733,060 and (+)-T-2328 in high optical purity (93% ee) is described starting from phenyl <i>N</i>-Boc imine. The strategy involves proline-catalyzed Mannich reaction of an arylimine with acetaldehyde followed by α-aminoxylation/Wittig olefination in a sequential fashion as the key steps.

Transformations and Tautomeric Equilibrium among Different Intermediates in Proline-Catalyzed Reactions of Aldehydes or Ketones

The enamines, iminium ions, and oxazolidinones are thought to be the key intermediates in the proline-catalyzed reactions of aldehydes or ketones, but there is an extensive controversy about their roles. Here, the corresponding transition states connecting any two of the three kinds of species are located at the ωB97XD/6-311++G** level of theory. The calculations demonstrate that the oxazolidinones are the predominant species in both the gas phase and solvents; there exists tautomeric equilibrium among these species and the equilibriums are controlled by the employed solvents and temperature in the reaction. These results demonstrate that the concentration and role of the mentioned species are controlled by the employed solvent and temperature. A new reaction pathway is presented herein for the transformation between iminium ions and oxazolidinones through iminium ion-water complex and oxazolidinone-water complex. The calculations demonstrate that the rate-limiting step in proline-catalyzed Mannich reaction between acetaldehyde/keteones and N-Boc imines is the formation of the C—C bond rather than the intermediates tautomerization. These calculations rationalize the available experimental observations and can be valuable in optimizing the experimental conditions of asymmetric organic-catalyzed reactions of aldehydes or ketones.

Role of stereoelectronic features of imine and enamine in (S)-proline catalyzed mannich reaction of acetaldehyde: An in silico study

A detailed mechanistic investigation of sixteen possible diastereomeric pathways for the C-C bond formation step in (S)-proline catalyzed Mannich reaction of acetaldehyde with N-acetyl protected benzaldimine in acetonitrile solvent has been carried out to understand how stereoelectronic features invoke enantioselectivity of the final product. Both kinetic and thermodynamic factors of the reaction obtained using various density functional theory methods point out that si-enantiofacial nucleophilic attack of anti-enamine on the iminium carbon of the E, s-cis N-acetyl protected imine is the stereoselective pathway. Structural features of the transition states predicted that enamine in anti conformation attacks the imine through a Burgi-Dunitz trajectory to yield the stereocenter. Computations at B3LYP-PCM/6-311++G(3df,2p)//B3LYP-PCM/6-31G(d,p) level showed a strong linear correlation between Burgi-Dunitz angle and activation energy when anti-enamine is used as nucleophile to react with all the configurations of the imine. Further, energy decomposition analysis has been carried out at B3LYP/TZ2P+ level for all the transition states, which revealed that the most dominant factor that control the enantioselectivity of the (S)-proline catalyzed Mannich reaction is steric effect. Though the less favored transition states showed high amount of stabilizing orbital interaction, the destabilizing steric effects from both Pauli repulsion and preparation energy for the reactant molecules are very high and overshadowed the stabilizing effects. However, in the most favored transition state, a balanced outcome of electronic and steric effects was observed. Solvation effect was nearly same for all the transition states and electrostatic effects showed no correlation to the rank order of the energy of the transition states.

Theoretical Investigations on the Stereoselectivity of the Proline Catalyzed Mannich Reaction in DMSO

The stereocontrol steps of the (S)-proline catalyzed Mannich reaction of cyclohexanone, formaldehyde, and aniline were theoretically investigated. The geometries of reactants, products, and transition states were optimized using density functional theory using the B3LYP functional with the 6-31++G(d,p) basis set. The energies of these compounds were then more accurately determined at the MP2 level, and the effect of DMSO as the solvent was included using a polarizable continuum model (PCM). The reaction was modeled from the previously proposed mechanism that cyclohexanone reacts with (S)-proline to generate an enamine, while formaldehyde reacts with aniline to produce an imine, and that the conformation around the C-N bond of the enamine 1 is crucial for the further enantioselective step. The formation of two conformations of the enamine via a proton transfer process was examined, revealing activation barriers for syn- and anti-enamine proton transfer of 10.2 and 17.9 kcal/mol, respectively. The transformation of syn- to anti-enamine through C-N bond rotation, however, was predicted to require only 4.2 kcal/mol, while the (S)- and (R)-intermediates could be obtained from subsequent reactions between enamine and imine with energy barriers of 8.5 and 12.4 kcal/mol, respectively. The difference between these barriers, but not the C-N rotation energy, becomes larger at the MP2 level and when DMSO as a solvent is included. This predicted enantioselective reaction, through the kinetic and thermodynamic favoring of the (S)-pathway, is in agreement with experimental results, which have reported the (S)-configuration as the major product.

Asymmetric Mannich Reaction of Acetaldehyde

A proline-catalyzed Mannich reaction of acetaldehyde with N-Boc imines has been reported. The authors have suppressed some potential side reactions by using 5-10 equivalents of acetaldehyde. Acetonitrile was found to be the best solvent for this reaction. With 20 mol% of proline catalyst, moderate to good yields (23-58%) and excellent enantioselectivities (er = 98:2 to >99:1) are obtained for different aromatic and aliphatic aldehyde derived N-Boc imines.

Proline‐Catalyzed Mannich Reaction of Aldehydes with N‐Boc‐Imines

A curious cat.: The proline-catalyzed Mannich reaction between aldehydes and N-Boc-imines (Boc=tert-butoxycarbonyl) gives crystalline β-amino aldehydes with exceptionally high diastereoselectivities and enantioselectivities (see scheme). The products of this reaction typically precipitate from the reaction mixture and are useful intermediates in the synthesis of α- and β-substituted β-amino acids.

Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric ­Addition as a Key Step

A total synthesis of ent-sedridine is described. The development of a new method for the construction of the C-2 chiral center of the piperidine ring was achieved using a proline-catalyzed Mannich reaction. Reaction of 4-hydroxybutanal and p-anisidine to form an imine and subsequent addition of acetone gave the key chiral aliphatic precursor with high enantioselectivity.

Direct Organocatalytic Enantioselective α‐Aminomethylation of Ketones.

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DPP-IV Inhibitor by Proline-Catalyzed Mannich Reaction

A novel lead structure (1) for DPP-IV inhibitors, which are important for type 2 diabetes treatment, was identified (S. D. Edmondson et al. Bioorg. Med. Chem. Lett. 2005, 3048-3052). The authors describe a (S)-proline-catalyzed Mannich reaction as the key step in the synthesis of β-phenyl aspartic acid derivative 6. Starting from PMP-protected imine 2 and phenylacetaldehyde 3, (S)-proline-catalyzed Mannich reaction and reduction gave alcohol 4 in 92:8 syn/anti-rate and >90% ee. Four more steps were required to yield the diamide aspartic acid derivative 6 in >99% optical purity after recrystallization and an overall yield of 24%.

(L)-Proline catalysed efficient synthesis of 3-substituted 2,6-diarylpiperidin-4-ones

L)-Proline catalyzed Mannich reaction of ketones, aromatic aldehydes and ammonia furnishes 3-substituted 2,6-diarylpiperidin-4-ones in enhanced yields (upto five times) compared to the reaction involving ketone, aldehyde and ammonium acetate. The catalytic efficiency of proline is ascribable to the involvement of an enamine intermediate that could result from the reaction of ketones with proline and the absence of the formation of bicyclic side product in this reaction.

Direct Catalytic Enantioselective α‐Aminomethylation of Ketones

A proline-catalyzed Mannich reaction produces α-aminomethylated ketones in high yield and with excellent ee values (see scheme). The Mannich bases resulting from this highly practical one-pot three-component asymmetric reaction are of particular interest, for example, as synthetic building blocks and precursors of pharmaceutically valuable 1,3-amino alcohols.

Asymmetric synthesis of quaternary alpha- and beta-amino acids and beta-lactams via proline-catalyzed mannich reactions with branched aldehyde donors.

[reaction: see text] L-Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected alpha-imino ethyl glyoxylate with various alpha,alpha-disubstituted aldehydes affords quaternary beta-formyl alpha-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted to the corresponding quaternary alpha- and beta-amino acids and beta-lactams.

Highly Enantioselective Synthesis of 1,2-Amino Alcohol Derivatives via Proline-Catalyzed Mannich Reaction

Here we report a new catalytic asymmetric synthesis of oxazolidin-2-ones 4 and Cbz-protected 1,2-amino alcohols 5. Our sequence is based on the chemistry of previously unknown 5-acyloxy-oxazolidin-2-ones, which are obtained via proline-catalyzed direct asymmetric three-component Mannich reaction and Baeyer-Villiger oxidation.