Stereoselective aldol addition reactions of Fischer carbene complexes via electronic tuning of the metal center for enolate reactivity

The aldol reactions of tetracarbonyl(phosphine)methyl(methoxy)methylene chromium complexes and pentacarbonylmethyl (dialkylamino)methylene chromium complexes with aldehydes and ketones were examined. The reactions of the phosphine complexes give only aldol condensation products, but the desired aldol addition products can be isolated from the reactions of amino carbene complexes. This was attributed to the greater reactivity of the enolates of amino carbene complexes which is supported by a determination of the thermodynamic acidity of the dimethylamino complex 13 (pK_a=20.4). The aldol reactions of amino complexes with -chiral aldehydes occur with very high facial selectivities rivaling the best methods that have been developed for facial selectivity in the aldol reaction. The aldol reactions of amino complexes can be considered as direct synthons for amides since amide functions can be obtained in the oxidative cleavage of the aldol adducts of these complexes. As illustrative of the versatility of carbene complexes, it is also demonstrated in a photo-induced carbon-homologative demetallation, that in combination with the aldol addition reaction the unique reactions of carbene complexes provide powerful and novel overall transformations.     

Theoretical insight into the influences of alpha-substituents in aliphatic aldehydes on the enantioselectivities of aldol reactions

Density functional theory has been applied to study the influences of alpha-substituents in aliphatic aldehydes on the enantioselectivities of the (S)-proline-catalyzed direct aldol reactions. Reaction scenarios of three kinds of aliphatic aldehydes were investigated. Four transition states associated with the stereocontrolling step of each reaction have been obtained. They are corresponding to the syn and anti arrangements of enamine intermediates and the si and re attacks to the carbonyl group of an aldehyde. The solvent effect of DMSO was investigated using self-consistent reaction field method based on the polarizable continuum model. The computed energies of transition states explain the origin of the catalysis and enantioselectivities for these (S)-proline-catalyzed aldol reactions and reveal the influences of alpha-substituents in aliphatic aldehydes on the enantioselectivities of these reactions.     

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids

This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-β-hydroxy and α,β-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.     

Synthesis of proline-derived dipeptides and their catalytic enantioselective direct aldol reactions: catalyst, solvent, additive and temperature effects

A series of dipeptides of l-proline-l-amino acid and l-proline-d-amino acid were synthesized to evaluate the catalytic effect for asymmetric direct aldol reactions. In the direct aldol reaction, a catalyst of l-proline-l-amino acid achieves better enantioselectivity than the corresponding l-proline-d-amino acid catalyst. Solubility of the dipeptide catalysts in the solvents is a key point for achieving a better yield of the direct aldol reaction, while hydrogen bonding of solvent does not play an important role in attaining better enantioselectivity and yield. Yield and enantioselectivity of the direct aldol reaction in water were improved by NMM and SDS additives, but the results that were done in plain DMSO were even better.     

Kinetic modelling of aldolase-catalyzed addition between dihydroxyacetone phosphate and (S)-alaninal

This paper is focused on the development of a kinetic model for an aldolase-catalyzed reaction. The aldol addition between dihydroxyacetone phosphate (DHAP) and (S)-benzyloxycarbonyl-alaninal ((S)-Cbz-alaninal) catalyzed by the four DHAP-dependent aldolases is a promising way for the synthesis of four complementary diastereoisomers with potential biological activity. The reaction catalyzed by fuculose-1-phosphate aldolase (FucA) conducts to a synthesis product with a 100% diastereomeric excess. A kinetic model has been proposed including both the synthesis and a parallel non-desired secondary reaction. The model involved an ordered two-substrate mechanism for the synthesis and non-competitive inhibition by (S)-Cbz-alaninal and competitive inhibition by methylglyoxal byproduct in both reactions. The values of the model kinetic parameters were determined and the model validated in batch and fed-batch synthesis reactions. The obtained model could be extended to explain the behavior of other class II DHAP-dependent aldolases and exploited in simulation for reactor design purposes.     

Green Asymmetric Synthesis: β‐Amino Alcohol‐Catalyzed Direct Asymmetric Aldol Reactions in Aqueous Micelles

The ability of chiral β‐amino alcohols to catalyze the direct asymmetric aldol reaction was evaluated for the first time in aqueous micellar media. A family of cheap and easily accessible β‐amino alcohols, obtained in one step from naturally occurring amino acids, was shown to successfully catalyze the asymmetric aldol reaction between a series of ketones and aromatic aldehydes. These aldol reactions furnished the corresponding β‐hydroxy ketones with up to 93% isolated yield and 89% ee. (S)‐2‐phenylglycinol and Triton X‐100 proved to be the best organocatalyst and surfactant, respectively. Chirality 25:119–125, 2013. © 2012 Wiley Periodicals, Inc.     

Asymmetric aldol reactions catalyzed by efficient and recyclable silica-supported proline-based peptides

A series of silica-supported proline-based peptides were synthesized and applied as catalysts for direct asymmetric intermolecular aldol reactions. Among these, a peptide with two L-proline units was found to be the most efficient one for the asymmetric aldol reactions between acetone and aromatic aldehydes. The reactions generated the corresponding products with satisfactory isolated yields (up to 97%) and enantiomeric excesses (up to 96%) in the presence of this catalyst (5 mol %). Furthermore, the silica-supported organocatalyst could be recovered and recycled by a simple filtration of the reaction solution and used for five consecutive trials without loss of its reactivity.     

Solid-supported and pegylated H-Pro-Pro-Asp-NHR as catalysts for asymmetric aldol reactions

H-Pro-Pro-Asp-NH2 is a highly active and selective catalyst for asymmetric aldol reactions. Here, the versatility of H-Pro-Pro-Asp-NH2 has been further improved by immobilization on a solid support and functionalization with a short polyethylene glycol linker at the C-terminus. The development, synthesis, and the catalytic properties in aldol reactions of H-Pro-Pro-Asp-resin and H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3 are described. For the solid-supported catalyst, TentaGel with a loading of 0.1-0.2 mmol g(-1) proved to be the optimal support. The solid-supported catalyst can be recycled at least three times without a significant drop in the catalytic activity or selectivity. Using the pegylated catalyst H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3, only 0.5 mol % are necessary to obtain aldol products in up to 96% yield and 91% enantiomeric excess. In all cases, enantioselectivities are comparable to those obtained with the parent catalyst H-Pro-Pro-Asp-NH2. Thus, immobilization of H-Pro-Pro-Asp-NH2 on Tentagel as well as pegylation led to catalysts with selectivities comparable to the nonmodified catalyst, exhibiting additional distinct advantages such as facile reusability, ease of handling, higher solubility, and thereby greater versatility. handling, higher solubility, and thereby greater versatility.     

Trypsin-catalyzed direct asymmetric aldol reaction

Unnatural catalytic activity of trypsin from porcine pancreas for direct asymmetric aldol reaction was discovered. The reactions between aromatic aldehydes and various ketones gave products in moderate yields and enantioselectivities in the presence of a small amount of water. The influences of solvent, water content, temperature, mole ratio of substrates, and enzyme concentration were investigated. The mechanism of trypsin-catalyzed aldol reaction was discussed. This enzymatic promiscuity widens the application of trypsin to new chemical transformations.     

beta-cyclodextrin-immobilized (4S)-phenoxy-(S)-proline as a catalyst for direct asymmetric aldol reactions

beta-Cyclodextrin-immobilized (4S)-phenoxy-(S)-proline was prepared conveniently by simply heating the amino acid and beta-cyclodextrin in ethanol-water (1/1, v/v) and removal of the solvent. This proved to be an efficient catalyst for direct asymmetric aldol reactions, and the catalyst could be recycled four times without loss of enantioselectivity.     

Synthesis and application of the first planar chiral strong Brønsted acid organocatalysts

The synthesis of planar chiral strong Brønsted acid organocatalysts derived from [2.2]paracyclophane is described. Resolution was accomplished according to a modified protocol involving pseudo‐ortho‐substituted [2.2]paracyclophane‐based sulfoxides for the synthesis of three new sulfonic acids. The first planar chiral phosphoric acid diester was obtained from the corresponding phenyl‐substituted diol derived from enantiopure 4‐bromo‐12‐hydroxy [2.2]paracyclophane. These new classes of catalysts were tested in an enantioselective Friedel–Crafts reaction as well as in a direct asymmetric Mannich reaction and gave yields of up to 93% and ee‐values of up to 38%. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Various Polar Tripeptides as Asymmetric Organocatalyst in Direct Aldol Reactions in Aqueous Media

A series of tripeptide organocatalysts containing a secondary amine group and two amino acids with polar side chain units were developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4‐nitrobenzaldehyde and cyclohexanone. The effectiveness of short polar peptides as asymmetric catalysts in aldol reactions to attain high yields of enantio‐ and diastereoselective isomers were investigated. In a comparison, glutamic acid and histidine produced higher % ee and yields when they were applied as the second amino acid in short trimeric peptides. These short polar peptides were found to be efficient organocatalysts for the asymmetric aldol addition reaction in aqueous media. Chirality 25:726–734, 2013. © 2013 Wiley Periodicals, Inc     

Promiscuous protease-catalyzed aldol reactions: a facile biocatalytic protocol for carbon-carbon bond formation in aqueous media

Several proteases, especially pepsin, were observed to directly catalyze asymmetric aldol reactions. Pepsin, which displays well-documented proteolytic activity under acidic conditions, exhibited distinct catalytic activity in a crossed aldol reaction between acetone and 4-nitrobenzaldehyde with high yield and moderate enantioselectivity. Fluorescence experiments indicated that under neutral pH conditions, pepsin maintains its native conformation and that the natural structure plays an important role in biocatalytic promiscuity. Moreover, no significant loss of enantioselectivity was found even after four cycles of catalyst recycling, showing the high stability of pepsin under the selected aqueous reaction conditions. This case of biocatalytic promiscuity not only expands the application of proteases to new chemical transformations, but also could be developed into a potentially valuable method for green organic synthesis.     

Asymmetric synthesis of bicyclic piperidines via L-proline catalyzed aldol reaction of 3-phthalimidopropanal

A highly enantioselective approach for preparing optically active bicyclic piperidines is described. The key step for introducing chiral centers was a L-proline catalyzed direct enantioselective aldol reaction of 3-phthalimidopropanal with aliphatic ketones. In the reactions with alicyclic ketones, a highly enantioselective formation of anti-2-(3-phthalimido-1-hydroxypropyl)cycloketones 1a-1b (>99% ee) was observed. The aldol products 1 could be subsequently converted into bicyclic piperidines 2 via a consecutive reductive deprotection, acylation, ring closure, and hydrolysis.     

One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic—Lasalocid acid

Seven Mannich base derivatives of polyether antibiotic Lasalocid acid (2a–2g) were synthesized and screened for their antiproliferative activity against various human cancer cell lines. A novel chemoselective one-pot synthesis of these Mannich bases was developed. Compounds 2a–2c and 2g with sterically smaller dialkylamine substituent, displayed potent antiproliferative activity (IC₅₀: 3.2–7.3 μM), and demonstrated higher than twofold selectivity for specific type of cancer. The nature of Mannich base substituent on C-2 atom at the aromatic ring may be critical in the search for selectivity towards a particular cancer cell.     

Multicomponent reactions in crop protection chemistry

An overview is given of the significance of multicomponent reactions in the synthesis of agrochemicals. The most important applications of multicomponent condensations, such as the Biginelli reaction, Bucherer-Bergs reaction, Hantzsch dihydropyridine synthesis, Kabachnik-Fields reaction, Mannich reaction, Passerini reaction, Petasis reaction, Strecker reaction, Ugi reaction and Willgerodt-Kindler reaction, to the synthesis of herbicidally, fungicidally and insecticidally active compounds are presented. Also the mode of action and biological activity of these multicomponent reaction products are reported.     

Performance of an immobilized fuculose-1-phosphate aldolase for stereoselective synthesis

A derivative of fuculose-1-phosphate aldolase, immobilized with high loading on glyoxal–agarose gels, has been characterized and evaluated as a biocatalyst for an aldol addition reaction. The reaction of the solid biocatalyst was diffusion-controlled for conversion of its natural substrate. Nevertheless, when catalyzing the synthesis of a biologically active aminopolyol, the lower reaction rate with non-natural substrates led to a process controlled by the intrinsic enzyme kinetics. The resulting biocatalyst has high synthetic specific activity and has been successfully used in batch synthesis reactions with high conversion. In addition, the immobilized aldolase has been employed in fed-batch synthesis, increasing the selectivity of the reaction and obtaining high conversion (88%).     

Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c]coumarin and pyrazolo[4,3-c]coumarin frameworks

Reaction of 4-chlorocoumarin-3-carbonitrile with ethyl thioglycolate and ethyl glycinate hydrochloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the hydrazino derivative which underwent various reactions to build new heterocyclic rings containing thienocoumarin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent nucleophilic substitution reactions with various amines. The following treatment with formaldehyde under Mannich conditions afforded the corresponding imidazo derivatives. Reaction of chloroacetylamino with potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile precursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbonitrile with hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substituted pyrimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethylaminotriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable antifungal and antibacterial activity in the in vitro test systems.     

Development of environmentally friendly syntheses: use of enzymes and biomimetic systems for the direct carboxylation of organic substrates

Carboxylation reactions widely occur in nature by the direct use of carbon dioxide or hydrogen carbonate and are mediated by enzymes, which may or may not have a metal as an active center. Such direct carboxylation reactions have found only very few applications for synthetic purposes at industrial level. In this paper we review a part of the work we have done on the use of carbon dioxide and describe: (i) the use of a carboxylation enzyme for the conversion of phenol into 4-OH benzoic acid; and (ii) the potential of biomimetic mixed anhydrides for the synthesis of compounds of industrial interest. The enzymatic production of acetic acid from carbon dioxide is compared with known and new transition metal catalyzed reactions that are fully biomimetic.     

Organocatalytic alkylation of carbohydrate‐containing aldehydes with dihydroquinoline N,O‐acetals: Absolute configuration of 1,2‐dihydroquinolines

The direct catalytic α‐amidoalkylation of dihydroquinolines with aldehydes bearing oxygen functionalities at different positions in a Mannich‐type reaction has been studied. β‐Alkoxy‐aldehyde 1d gave high enantioselectivity, albeit with an inherently poor diastereoselectivity, while the use of α‐alkoxy aldehydes 1c was detrimental also to enantioselectivity. Mannich‐type reactions have been studied for the first time using new chiral carbohydrate‐derived aldehydes 1a,b showing a reactivity markedly influenced by the presence of water. The chiral glycidic backbone showed a slight but significant influence on the overall stereochemical outcome only when present in α‐position of the aldehyde. The absolute stereochemistry of the products was studied by electronic circular dichroism (ECD) spectra and compared with theoretical calculations. ECD analysis easily provides the absolute configuration of 1,2‐dihydroquinoline derivatives such as quinoline‐1(2H)‐carboxylates.