Proline-catalyzed Reaction Research Articles

5-Substituted N-Aminoimidazolone Peptide Mimic Synthesis by Organocatalyzed Reactions of Azopeptides and Use in the Analysis of Biologically Active Backbone and Side-Chain Topology.

Fifteen N-aminoimidazolone (Nai) dipeptides having a variety of 5-position side-chain groups were synthesized by regioselective proline-catalyzed reactions of azopeptide and aldehyde components followed by acid-mediated dehydration of an aza-aspartate semialdehyde intermediate. The introduction of 5-aryl-Nai dipeptides into cluster of differentiation 36 receptor (CD36) peptide ligands has provided insight into the conformation responsible for binding affinity and anti-inflammatory activity.

NH-Polyfluoroalkyl іminophosphonates in the synthesis of α-amino-α-polyfluoroalkyl- γ-oxobutylphosphonic acids

Aim. To develop the preparative method for the synthesis of optically active α-amino-α-polyfluoroalkyl-γ-oxobutylphosphonic acids as new promising chiral building blocks.Results and discussion. It has been shown that the reaction of NH-polyfluoroalkyl aminophosphonates with acetone in the presence of a catalytic amount of L- or D-proline occurs stereoselectively to give enantiomerically enriched (R)- or (S)-α-amino-γ-oxophosphonates, respectively. The resulting optically active phosphonates were converted into water-soluble α-amino-γ-oxophosphonic acids isolated in the individual form as hydrochlorides.Experimental part. By the reaction of рolyfluoroacetonitriles with diethyl phosphite in the presence of triethylamine the series of NH-рolyfluoroalkyl іminophosphonates were synthesized. They undergo the prolinecatalysed reaction with acetone to form optically active α-amino-α-polyfluoroalkyl-γ-oxobutyl phosphonates. The latter were converted into the corresponding phosphonic acids by the reaction with hydrogen chloride. The structures of the compounds synthesized were confirmed by analytical and spectral NMR (1Н, 13С, 19F, 31Р) methods.Conclusions. Based on the proline-catalyzed reaction of NH-рolyfluoroalkyl іminophosphonates with acetone the preparativesynthesis method for new chiral building blocks – α-amino-α-polyfluoroalkyl-γ-oxobuthylphosphonates and phosphonic acids has been developed.

Proline autocatalysis in the origin of biological enantioenriched chirality.

Biological enantioenriched chirality is a phenomenon that in living organisms, amino acids and carbohydrates typically have the same absolute configuration. Perhaps one of the earliest attempts to delineate the origins of this phenomenon was a theory known as asymmetric autocatalysis, a reaction in which the structures of the chiral catalyst and the product are the same, and in which the chiral product acts as a chiral catalyst for its own production. In theory, this would mean that small asymmetries in the product will propagate rapidly. However, autocatalysis also relies on the cross-inhibition of chiral states, something that would not likely be possible on primordial Earth. But recently, theories on asymmetric autocatalysis have begun to resurface as more recent findings indicate that other mechanisms exist to stabilize the homochiral states. In this study, I propose an autocatalytic cycle, and using density functional theory, prove that (1) it is plausible on primordial Earth, and (2) it propagates arbitrary asymmetries in proline. Thus, facilitating asymmetry in proline and allowing access to a wide variety of asymmetric proline-catalyzed reactions, including those involved in the synthesis of amino acids and carbohydrates from achiral precursors.

Stereochemical assignment of the unique electron acceptor 5'-hydroxyphylloquinone, a polar analog of vitamin K1 in photosystem I.

A unique electron-accepting analog of vitamin K1 found in photosystem I in several species of oxygenic photosynthetic microorganisms was confirmed to be 5'-hydroxyphylloquinone (1) through stereo-uncontrolled synthesis. Furthermore, the stereochemistry of 1 obtained from Synechococcus sp. PCC 7942 was assigned to be 5'S using proline-catalyzed stereocontrolled reactions.

Further insights into the organocatalytic reaction of 2,2-dimethyl-1,3-dioxan-5-one with α-silyloxy aldehydes

Proline-catalysed reactions of dihydroxyacetone isopropylidene acetal, 1, with enantiopure α-silyloxy aldehydes 2/4/6/8 afford 90–95% yields of cross-aldol products (only one stereoisomer in each case), provided that 15±10equiv of H2O are present in the medium. Individual reaction steps have been monitored by NMR spectroscopy to gain insight into the cause of these remarkable results. It is confirmed that proline ‘protects’ 2 as oxazolidinone 2-ox, but it means that proline—the catalyst—is trapped by 2; several equiv of H2O are required to avoid it. Moreover, H2O mediates prolyl group exchanges and goes against the dehydration of aldols. For the first time, we detected by NMR one ‘wanted’ intermediate (an enamine of the adduct).

Accessing the free energy profile of a ring closure in a proline-catalyzed reaction using a reactive force field

The free energy profile of a ring closure involving a carboxylate and an iminium functional group in a proline-derived compound is determined by applying the adaptive biasing force scheme along molecular dynamics simulations. As the reaction considered implies the formation of a covalent bond, the system is modeled with a reactive force field (FF), namely ReaxFF. The impact of the surrounding water molecules on the reaction mechanism is investigated in detail using three FF models for the water molecules. In particular, a hybrid reactive/non-reactive FF is used to assess explicit solvent effects while avoiding solute–solvent reactions. Combined with existing experimental observations, our results provide an explanation for the role of water molecules in the proline-catalyzed aldol reaction, which is one of the hallmark reactions in organocatalysis.

ChemInform Abstract: Tandem Organocatalyzed Knoevenagel Condensation/1,3‐Dipolar Cycloaddition Towards Highly Functionalized Fused 1,2,3‐Triazoles.

Facile synthesis of fused 1,2,3-triazoles by a proline-catalyzed reaction of an azido aldehyde and a nitroalkane is elaborated. The present tandem protocol proceeds via an organocatalytic Knoevenagel condensation of the azido aldehyde and nitroalkane followed by intramolecular azide–nitroalkene cycloaddition. The functionalized bicyclic triazole is obtained by elimination of HNO2 from the cycloadduct. Application of this strategy enabled us to synthesize a range of functionalised 5–7 membered ring fused triazoles. The reaction calls for mild conditions, affords high yields, and results in good regiospecificity while displaying excellent substrate scope.

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry.

A new 4-hydroxy-L-proline derivative with a charged 1-ethylpyridinium-4-phenoxy substituent has been synthesized with the aim of facilitating mechanistic studies of proline-catalyzed reactions by ESI mass spectrometry. The charged residue ensures a strongly enhanced ESI response compared to neutral unmodified proline. The connection by a rigid linker fixes the position of the charge tag far away from the catalytic center in order to avoid unwanted interactions. The use of a charged catalyst leads to significantly enhanced ESI signal abundances for every catalyst-derived species which are the ones of highest interest present in a reacting solution. The new charged proline catalyst has been tested in the direct asymmetric inverse aldol reaction between aldehydes and diethyl ketomalonate. Two intermediates in accordance with the List–Houk mechanism for enamine catalysis have been detected and characterized by gas-phase fragmentation. In addition, their temporal evolution has been followed using a microreactor continuous-flow technique.

Asymmetric synthesis of phosphonotrifluoroalanine derivatives via proline-catalyzed direct enantioselective C[sbnd]C bond formation reactions of N[sbnd]H trifluoroacetimidoyl phosphonate

Based on enantioselective proline-catalyzed reactions between NH-iminotrifluoroethylphosphonate and acetone, an effective synthetic approach to both enantiomers of α-amino-α-trifluoromethyl-γ-oxobutylphosphonate was developed. The synthetic potential of these novel chiral synthons was illustrated by their cyclocondensation reactions with 4-chlorophenylisocyanate or 2,5-dimethoxytetrahydrofuran to afford the first representatives of phosphorylated 3,4-dihydropyrimidin-2-ones or 3H-pyrrolizines, incorporating pharmacophoric optically active fragments of phosphonotrifluoroalanine.

Theoretical Investigation on the Role of Amine Bases in Stabilizing the Key Intermediate of Proline Enamine Carboxylate in Proline-Catalyzed Asymmetric Reactions

Quantum mechanical calculations have been performed to study the equilibrium among the key intermediates (iminium ion, oxazolidione, and enamine) in the proline-catalyzed reactions under base-free and base-present conditions. The results confirmed that the tautomeric equilibrium among these species can be tuned by the basic additives. The computations satisfactorily rationalized the experimental observations and provide a clue on how to stabilize the enamine intermediates.

Investigation of cis- and trans-4-Fluoroprolines as Enantioselective Catalysts in a Variety of Organic Transformations

Stereoselective fluorination is known to rigidify the ring structure of l-proline, as a result of a combination of electrostatic and hyperconjugative effects associated with the C–F bond. This is a potential strategy for enhancing the enantioselectivity of proline-catalysed reactions. In this study, cis- and trans-4-fluoroprolines were investigated as catalysts in five different organic transformations, including examples of both enamine and iminium ion catalysis. Some significant differences in enantioselectivity were observed between the cis- and trans-isomers of the fluorinated catalysts, confirming that the ring pucker is important. However, no substantial improvements were observed relative to the parent catalyst, l-proline.

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.

Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium–enamine conversion in a proline-catalyzed reaction

Among all strategies used by organic chemists to control the stereoselectivity of reactions, organocatalysis, which consists in using the chirality of a small organic molecule, is an increasingly popular method. The proline-catalyzed aldol reaction was one of the first reported cases that demonstrated the power of organocatalysis in the field of asymmetric synthesis. Previous theoretical contributions focused on the reaction mechanism using quantum mechanics (QM) methods. We here present a theoretical study about one specific step of the proline-catalyzed aldol reaction, namely, the conversion of the iminium intermediate into the corresponding enamine. It consists of an intramolecular rearrangement that involves the transfer of a hydrogen atom. First, we investigate this transfer using modern QM models, that is, density functional theory calculations with the M06-2X functional. On the basis of these QM results, we then assess the performance of a reactive force field, ReaxFF, used in combination with molecular dynamics simulations in order to provide a complementary light on this reaction.

Amino Acid Catalysed Aldol Reactions in Cyclic Carbonate Solvents

Ethylene and propylene carbonates are shown to be alternative polar aprotic solvents for cross-aldol reactions catalysed by the primary amino acids (S)-phenylalanine and (S)-tryptophan. In contrast to the corresponding proline-catalysed reactions, both enantiomers of these naturally occurring, primary amino acids are available at low cost. The optimal catalyst and solvent combination needs to be determined on a substrate by substrate basis.

( l)-Proline-catalysed novel tandem reactions of 1-substituted piperidin-4-ones with ( E)-4-arylbut-3-en-2-ones: N-substituent mediated product selectivity and synthesis of novel nitrogen heterocycles

( l)-Proline-catalysed reaction of 1-alkyl/aralkylpiperidin-4-ones with ( E)-4-arylbut-3-en-2-ones furnishes novel isoquinoline derivatives, with two or three rings, in good yields via tandem Robinson annulation–Michael addition(s) sequences, while the reaction of 1-arylpiperidin-4-ones with ( E)-4-arylbut-3-en-2-ones affords 3-azabicyclo[3.3.1]nonan-9-ones via a tandem Michael addition–aldol reaction sequence.

Synthesis of Azasugars through a Proline-Catalyzed Reaction

We report an efficient route to obtain azasugars from the enantiomerically pure L- and D-diethyltartrate. The key step is a proline-catalyzed aldol condensation, in which both enantiomers of proline have been used as catalyst, affording complementary anti-aldol products.

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β2-Amino Acids

Organocatalytic Mannich addition of aldehydes to a formaldehyde-derived iminium species catalyzed by proline-derived chiral pyrrolidines provides beta-amino aldehydes with >/=90% ee. Mechanistic analysis of the proline-catalyzed reactions suggests that non-hydrogen-bonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome. The beta-amino aldehydes from our process bear a substituent adjacent to the carbonyl and can be efficiently converted to protected beta2-amino acids, which are important building blocks for beta-peptide foldamers that display useful biological activities.

Pipecolic acid-catalyzed direct asymmetric mannich reactions.

Mannich reactions between aldehydes and N-p-methoxyphenyl-protected alpha-imino ethyl glyoxylate have been performed using (S)-pipecolic acid as catalyst. The reactions give both syn- and anti-products (dr=1.4-2:1) with high enantioselectivities (>98% ee). In contrast, (S)-proline-catalyzed reactions give mainly syn-products with high enantioselectivities. Computational studies reveal that the energetic preference between the transition structures involving the s-cis-enamine and the s-trans-enamine is smaller for the pipecolic acid as compared to proline, yielding the (2S,3R)-anti and the (2S,3S)-syn Mannich product in nearly equal amounts.

5‐(Pyrrolidin‐2‐yl)‐1H‐tetrazole and 5‐[(Pyrrolidin‐2‐yl)methyl]‐1H‐tetrazole: Proline Surrogates with Increased Potential in Asymmetric Catalysis

Catalytic enantioselective methodology has dramatically been enriched by the re-discovery of the simple amino acid proline as a chiral catalyst in the year 2000. Although no catalyst offers such a simple and broad access to quite complex reaction products, as does proline, its synthetic potential is not unrestricted, what is especially connected to its poor solubility in organic media. Exchange of the carboxylic moiety by a tetrazole unit leads to proline surrogates, that by far outperform proline with respect to yield, enantioselectivity, reaction time, substrate and solvent scope, catalyst loading, and stoichiometry of the compounds used in excess. These factors are discussed and critically compared with selected representative proline-catalyzed reactions.

Direct Amino Acid Catalyzed Asymmetric Synthesis of Polyketide Sugars.

AbstractFor Abstract see ChemInform Abstract in Full Text.