Aldol Addition Reactions Research Articles

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling, thioester substrates, and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.

Beryllium-Induced Conversion of Aldehydes.

Aldehydes play a key role in the human metabolism. Therefore, it is essential to know their reactivity with beryllium compounds in order to assess its effects in the body. The reactivity of simple aldehydes towards beryllium halides (F, Cl, Br, I) was studied through solution and solid‐state techniques and revealed distinctively different reactivities of the beryllium halides, with BeF2 being the least and BeI2 the most reactive. Rearrangement and aldol condensation reactions were observed and monitored by in situ NMR spectroscopy. Crystal structures of various compounds obtained by Be2+‐catalyzed cyclization, rearrangement, and aldol addition reactions or ligation of beryllium halides have been determined, including unprecedented one‐dimensional BeCl2 chains and the first structurally characterized example of an 1‐iodo‐alkoxide. Long‐term studies showed that only aldehydes without a β‐H can form stable beryllium complexes, whereas other aldehydes are oligo‐ and polymerized or decomposed by beryllium halides.

Insights into the role of zirconium in proline functionalized metal-organic frameworks attaining high enantio- and diastereoselectivity

A chiral zirconium-based catalyst, DUT-67-Pro containing 8-connected Zr6-clusters is obtained by post synthetic functionalization of Zr6O6(OH)2(TDC)4(HCOO)2 (DUT-67, TDC = 2,5-thiophenedicarboxylate) with the chiral monocarboxylic acid, L-proline. 13C and 15N solid state MAS and DNP NMR studies of DUT-67-Pro confirm the integration of L-proline into the porous framework. The chiral MOF catalyst exhibits an excellent catalytic activity at low temperature (298 K) with an unprecedented syn-(S,S)-product selectivity in an asymmetric aldol addition reaction of cyclohexanone to 4-nitrobenzaldehyde (yield = 95%, ee = 96%). Comparative catalytic studies using a molecular Zr6-cluster model compound indicate the Zr6-moiety to be responsible for this inverse diastereoselectivity compared to well-established L-proline organocatalysis and a mechanism is proposed to explain the Zr6-cluster-mediated syn-selectivity. Masking residual acidic active sites in the cluster of the framework was found to be a key prerequisite to achieve the high enantioselectivity. The purely heterogeneous catalytic system based on DUT-67-Pro is highly stable and can be recycled several times.

Enzymatic Synthesis of Trideuterated Sialosides.

Sialic acids are a family of acidic monosaccharides often found on the termini of cell surface proteins or lipid glycoconjugates of higher animals. Herein we describe the enzymatic synthesis of the two isotopically labeled sialic acid derivatives d3-X-Gal-α-2,3-Neu5Ac and d3-X-Gal-α-2,3-Neu5Gc. Using deuterium oxide as the reaction solvent, deuterium atoms could be successfully introduced during the enzymatic epimerization and aldol addition reactions when the sialosides were generated. NMR and mass spectrometric analyses confirmed that the resulting sialosides were indeed tri-deuterated. These compounds may be of interest as internal standards in liquid chromatography/mass spectrometric assays for biochemical or clinical studies of sialic acids. This was further exemplified by the use of this tri-deuterated sialosides as internal standards for the quantification of sialic acids in meat and egg samples.

Nanoporous Aluminosilicate-Catalyzed Telescoped Acetalization-Direct Aldol Reactions of Acetals with 1,3-Dicarbonyl Compounds.

Nanoporous aluminosilicate materials, synthesized by an evaporation-induced self-assembly process, catalyze the direct aldol reaction of acyclic acetals with a range of 1,3-dicarbonyl compounds to produce the corresponding aldol addition products in high yield, rather than the expected Knoevenagel elimination products. By carrying out the reaction in the presence of either dimethoxy propane or the corresponding orthoester, it is possible to capitalize on the ability of these aluminosilicate materials to catalyze the corresponding acetalization reaction leading to the development of novel telescoped, acetalization-direct aldol addition reaction protocols.

Base-Mediated Cascade Aldol Addition and Fragmentation Reactions of Dihydroxyfumaric Acid and Aromatic Aldehydes: Controlling Chemodivergence via Choice of Base, Solvent, and Substituents.

The diester derivative of dihydroxyfumaric acid (DHF) has been used exclusively as an electrophile in organic synthesis. However, the synthetic utility of DHF's nucleophilic reactivity, contained in the ene-diol moiety, has been underexplored. Inspired by recently observed pH-dependent chemodivergent nucleophilic aldol reactions of dihydroxyfumarate (DHF2-) with glyoxylate and formaldehyde, we report herein the control and synthetic application of base-controlled chemodivergent reactions between dihydroxyfumarate and aromatic and heteroaromatic aldehydes. With hydroxide as the base in a predominantly aqueous medium, aldol addition followed by deoxalation occurs to provide various 3-aryl-2,3-dihydroxypropanoic acids. With triethylamine as the base in THF, 1-aryl-2,3-dihydroxypropanones are the products of the reaction. In order to understand the difference in reactivity between DHF, its dicarboxylate, and its dimethyl ester, we undertook computational and experimental studies that provide a rationale as to why the dihydroxyfumarate (DHF2-) is a nucleophile while the corresponding diester reacts as an electrophile.

New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from d-Fructose 6-Phosphate Aldolase.

d-Fructose 6-phosphate aldolase (FSA) catalyzes the asymmetric cross-aldol addition of phenylacetaldehyde and hydroxyacetone. We conducted structure-guided saturation mutagenesis of noncatalytic active-site residues to produce new FSA variants, with the goal of widening the substrate scope of the wild-type enzyme toward a range of para- and meta-substituted arylated aldehydes. After a single generation of mutagenesis and selection, enzymes with diverse substrate selectivity scopes were identified. The kinetic parameters and stereoselectivities for a subset of enzyme/substrate combinations were determined for the reactions in both the aldol addition and cleavage reaction directions. The achieved collection of new aldolase enzymes provides new tools for controlled asymmetric synthesis of substituted aldols.

Multifunctional hollow mesoporous organic polymeric nanospheres (HMOPs) as effective heterogeneous catalysts with enhanced activity in green asymmetric organocatalysis

Based on the unique advantages including hollow interior, mesoporous shell, well-defined morphology and good compatibility with organic reactants, the first controllable fabrication of hollow mesoporous organic polymeric nanospheres (HMOPs) with pure intriguing mesopores was developed using low-cost and commonly available materials via metal ion adsorption in outer shell, in-situ forming metal hydroxide or phosphate expansion and removal of templates. After being sulfonated by ClSO3H, the resulting Co(OH)2-templated HMOPs with the highest acid exchange capacity (2.67 mmol g−1) could effectively immobilize versatile 9-amino(9- deoxy)epi-cinchonidine organocatalyst (0.98 mmol g−1) via acid-base interaction without multi-step chemical modification. In the green asymmetric aldol addition and double-Michael organocascade reaction, the mesopore- abundant HMOPs exhibited significantly higher catalytic performances in yields, diastereoselectivities and enantioselectivities than mesopore-deficient HNs due to the ordered mesoporous (2–15 nm), amphipathic shell and hollow interior. Based on the unchanged spherical morphology and hollow mesoporous structure, HMOPs was proved to possess a good mechanical stability in recycled processes.

L-proline modulated zirconium metal organic frameworks: Simple chiral catalysts for the aldol addition reaction

Three l-proline modulated zirconium based MOFs denoted as UiO-66, Zr-NDC (NDC = 2,6-Naphthalenedicarboxylate) and UiO-67 were synthesized, characterized and explored as heterogeneous catalyst in diastereoselective aldol addition reactions between 4-nitrobenzaldehyde and linear/cyclic ketones. Upon l-proline modulation, chirality was introduced into these Zr-MOFs which were consequently explored as chiral catalysts for asymmetric reactions. A systematic study was conducted to look into the effect of the synthesis temperature on the modulation in each Zr-MOF. The modulated UiO-66 material synthesized at 120 °C exhibited full conversion and a good diastereoselectivity whereas the homogeneous l-proline catalyst showed only 61% conversion and a reversed diastereoselectivity. The catalyst exhibited no leaching of the catalytically active species and was reused for at least three additional cycles. The observed high catalytic activity is a result of the electron withdrawing nature of the Zr-node coordinated to l-proline.

Branched aldehydes as linchpins for the enantioselective and stereodivergent synthesis of 1,3-aminoalcohols featuring a quaternary stereocentre

The atom-economic conversion of chemical feedstocks into biologically relevant complex molecules in a stereocontrolled fashion remains a continuous challenge to synthetic chemists. In this context, the use of simple ambiphilic starting materials as linchpins allows a bidirectional increase of molecular complexity from widely available precursors. Here, we report the use of branched aldehydes as versatile linchpins for various Zn-ProPhenol-catalysed C–C bond-forming reactions to efficiently construct enantioenriched 1,3-aminoalcohols bearing an acyclic quaternary stereogenic centre. The ability of the Zn-ProPhenol catalyst to selectively activate ambiphilic aldehydes first as nucleophiles for Mannich reactions and then as electrophiles for aldol, Henry and alkyne addition reactions allows for the one-pot synthesis of complex stereotriads from common building blocks. Moreover, this approach can be diastereodivergent by simply selecting the proper catalyst combination. Overall, this catalytic method directly transforms simple and readily available aldehydes into highly functionalized compounds and provides streamlined access to valuable 1,3-aminoalcohols relevant to the synthesis of biologically important molecules. Organic synthesis relies on the ability to convert simple starting materials into compounds with greater molecular complexity. Here, Trost and co-workers use branched aldehydes as nucleophiles for asymmetric Mannich reactions, and the products of these reactions as electrophiles for the addition of a range of carbon nucleophiles. This provides a simple, stereodivergent route to 1,3-aminoalcohols.

Proline-Glycine Dipeptidic Derivatives of Chiral Phosphoramides as Organocatalysts for the Enantiodivergent Aldol Reaction of Aryl Aldehydes and Isatins with Cyclohexanone in the Presence of Water

The synthesis of several novel organocatalysts derived from (R)- and (S)-proline-glycine dipeptides and incorporating a chiral phosphoramide fragment was accomplished. These chiral compounds catalyze the enantioselective aldol addition reaction of cyclohexanone to prochiral aryl aldehydes and isatins in the presence of water. These chiral organocatalysts represent some of the few proline-derived compounds capable to catalyze aldol-type addition of cyclohexanone to isatins, a C–C bond forming transformation for which chiral primary amines are usually more successful. Additionally, these phosphoramide-containing catalysts afforded excellent results in the addition of cyclohexanone to aryl aldehydes, as anticipated by the presence of the proline moiety. The present report includes a detailed evaluation of the new multifunctional catalysts that are able to afford either enantiomer of the chiral product by adequate selection of the configuration of the proline residue.

Nucleophile Promiscuity of Natural and Engineered Aldolases.

The asymmetric aldol addition reaction mediated by aldolases is recognized as a green and sustainable method for carbon-carbon bond formation. Research in this area has unveiled their unprecedented synthetic potential toward diverse, new chemical structures; novel product families; and even as a technology for industrial manufacturing processes. Despite these advances, aldolases have long been regarded as strictly selective catalysts, particularly for nucleophilic substrates, which limits their broad applicability. In recent years, advances in screening technologies and metagenomics have uncovered novel C-C biocatalysts from superfamilies of widely known lyases. Moreover, protein engineering has revealed the extraordinary malleability of different carboligases to offer a toolbox of biocatalysts active towards a large structural diversity of nucleophile substrates. Herein, the nucleophile ambiguity of native and engineered aldolases is discussed with recent examples to prove this novel concept.

Efficient Asymmetric Synthesis of Carbohydrates by Aldolase Nano-Confined in Lipidic Cubic Mesophases

Class-I aldolases are known for efficiently catalyzing stereoselective aldol-addition reactions in bulk aqueous media, and considerable efforts are currently being devoted to engineer the enzyme in order to optimize its activity and stability, primarily by modulating the hydrophobicity of the catalytic active site. Here, we opt for a different strategy based on choosing a nanoconfined environment favorable to the enzyme. We report the observation of enhanced activity and stability of a class-I aldolase, d-fructose-6-phosphate aldolase from E. coli (FSA), when incorporated into lipidic cubic mesophases (LCMs), a class of biomimetic amphiphilic complex fluids employed in several nanotechnology applications. We infer that this improved in-meso performance is achieved by optimal location of the FSA in the LCMs, as a result of the known interaction between the residues of FSA and the glycerol moieties, which serve as the lipid head groups and thus locate along the amphiphilic interface encompassing the whole L...

Nucleophile Promiscuity of Engineered Class II Pyruvate Aldolase YfaU from E. Coli

AbstractPyruvate‐dependent aldolases exhibit a stringent selectivity for pyruvate, limiting application of their synthetic potential, which is a drawback shared with other existing aldolases. Structure‐guided rational protein engineering rendered a 2‐keto‐3‐deoxy‐l‐rhamnonate aldolase variant, fused with a maltose‐binding protein (MBP‐YfaU W23V/L216A), capable of efficiently converting larger pyruvate analogues, for example, those with linear and branched aliphatic chains, in aldol addition reactions. Combination of these nucleophiles with N‐Cbz‐alaninal (Cbz=benzyloxycarbonyl) and N‐Cbz‐prolinal electrophiles gave access to chiral building blocks, for example, derivatives of (2S,3S,4R)‐4‐amino‐3‐hydroxy‐2‐methylpentanoic acid (68 %, d.r. 90:10) and the enantiomer of dolaproine (33 %, d.r. 94:6) as well as a collection of unprecedented α‐amino acid derivatives of the proline and pyrrolizidine type. Conversions varied between 6–93 % and diastereomeric ratios from 50:50 to 95:5 depending on the nucleophilic and electrophilic components.

Nucleophile Promiscuity of Engineered Class II Pyruvate Aldolase YfaU from E. Coli.

Pyruvate-dependent aldolases exhibit a stringent selectivity for pyruvate, limiting application of their synthetic potential, which is a drawback shared with other existing aldolases. Structure-guided rational protein engineering rendered a 2-keto-3-deoxy-l-rhamnonate aldolase variant, fused with a maltose-binding protein (MBP-YfaU W23V/L216A), capable of efficiently converting larger pyruvate analogues, for example, those with linear and branched aliphatic chains, in aldol addition reactions. Combination of these nucleophiles with N-Cbz-alaninal (Cbz=benzyloxycarbonyl) and N-Cbz-prolinal electrophiles gave access to chiral building blocks, for example, derivatives of (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid (68 %, d.r. 90:10) and the enantiomer of dolaproine (33 %, d.r. 94:6) as well as a collection of unprecedented α-amino acid derivatives of the proline and pyrrolizidine type. Conversions varied between 6-93 % and diastereomeric ratios from 50:50 to 95:5 depending on the nucleophilic and electrophilic components.

(R)- and (S)-Proline-Derived Chiral Phosphoramides as Organo­catalysts for the Enantiodivergent Aldol Reaction of Isatins with Cyclohexanone in the Presence of Water

Novel organocatalysts derived from (R)- and (S)-proline and incorporating a chiral phosphoramide fragment were rationally designed and subsequently synthesized. These chiral compounds catalyze the enantioselective aldol addition reaction of cyclohexanone to prochiral isatins in the presence of water. These observations are particularly relevant since reports of asymmetric aldol reactions between cyclohexanone­ and isatins catalyzed by chiral secondary amines remain scarce, with primary amines being the most studied and successful catalysts. The present report includes a thorough evaluation of the new bifunctional catalysts that actually give rise to either enantiomer of the chiral product by proper selection of the configuration of the proline moiety.

Stereoselective Arene-Forming Aldol Condensation: Catalyst-Controlled Synthesis of Axially Chiral Compounds.

The fundamental role that aldol chemistry adopts in various disciplines, such as stereoselective catalysis or the biosynthesis of aromatic polyketides, illustrates its exceptional versatility. On the one hand, numerous aldol addition reactions reliably transfer the stereochemical information from catalysts into various valuable products. On the other hand, countless aromatic polyketide natural products are produced by an ingenious biosynthetic machinery based on arene-forming aldol condensations. With the aim of complementing aldol methodology that controls stereocenter configuration, we recently combined these two tenets by investigating small-molecule-catalyzed aldol condensation reactions that stereoselectively form diverse axially chiral compounds through the construction of a new aromatic ring.

A ceric ammonium nitrate based oxidative cleavage pathway for the asymmetric aldol adducts of oxadiazinones derived from (1R,2S)-N-p-methoxybenzylnorephedrine

An N4-p-methoxybenzyloxadiazinone has been prepared from (1R,2S)-norephedrine through a process of reductive amination, N-nitrosation, reduction, and cyclization. The oxadiazinone was acylated and employed in the asymmetric aldol addition reaction with aromatic and aliphatic aldehydes to yield aldol adducts in isolated yields ranging from 54% to 90%. Selected aldol adducts were treated with ceric ammonium nitrate in aqueous acetonitrile to afford the desired β-hydroxycarboxylic acids through a tandem process of oxidative cleavage of the N4-p-methoxybenzyl group and acidic hydrolysis of the N3-acyl side chain. The β-hydroxycarboxylic acids were recovered in high diastereomeric purity as determined by 500MHz 1H NMR spectroscopy and the absolute configuration was confirmed by polarimetry. The chiral auxiliary unit, the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone), was converted into its corresponding 3,6-dihydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) through an oxidative pathway promoted by the ceric ammonium nitrate.

Catalytic asymmetric aldol addition reactions of 3-fluoro-indolinone derived enolates.

Reported herein is a Cu(i)/bisoxazoline ligand-catalyzed aldol reaction of unprotected tertiary enolates generated in situ from 3-(1,1-dihydroxy-2,2,2-trifluoroethyl)-substituted derivatives of 3-fluoro-2-oxindoles. A range of α-fluoro-β-aryl/hetaryl/alkyl-β-hydroxy-indolin-2-ones containing C-F quaternary stereogenic centers of high pharmaceutical importance were furnished in good yields and satisfactory diastereo- and enantioselectivities. The reactions were conducted under operationally convenient conditions and displayed wide substrate/functional group generality including unprotected N-H on the tertiary enolates, and aromatic, hetero-aromatic and aliphatic aldehydes.

Syn-Diastereoselective glycolate aldol addition reactions of an N(3)-(p-methoxyphenoxy)acetyloxazolidine-2-thione

An N3-(p-methoxyphenoxy)acetyloxazolidine-2-thione has been synthesized and employed in glycolate asymmetric aldol addition reactions with aromatic and aliphatic aldehydes. It was determined that the titanium tetrachloride medicated aldol reaction afforded diastereoselectivities that ranged from 75:25 to 94:6 when the reaction was conducted at −78°C. The absolute stereochemistry of the aldol adducts was determined by 1H NMR spectroscopy and X-ray crystallography. The 1H NMR spectra of the aldol adducts contained a signal (the α-proton of the glycolate position of the aldol side chain) that was highly deshielded due to conformational restriction about the N(3)-(p-methoxyphenoxy)acetyl side chain and the oxazolidine-2-thione auxiliary.