Aldol Addition Reactions Research Articles

ChemInform Abstract: Towards Direct Mukaiyama‐Type Reactions Catalytic in Silicon

AbstractReview: 24 refs.

Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols

The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by L-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-L-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-L-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis.

Origins of reversing diastereoselectivity of α,β-dichloro-γ-butenolides and γ-butyrolactams in direct vinylogous aldol addition: a computational study

Oxygenated five-membered ring compounds are more widespread in nature than the corresponding aza-analogues due to their more interesting biological activity. In our earlier studies, we have reported a simple methodology to synthesize novel synthons like 5-(1′-hydroxy)-γ-butenolide and 5-(1′-hydroxy)-γ-butyrolactam through the direct vinylogous aldol addition reaction. The observed diastereoselectivities for γ-butyrolactones and γ-butyrolactams were not understood in that report. We have reported herein a detailed computational study to understand the observed diastereoselectivity of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams. The transition state calculations performed with B3LYP/cc-pVDZ level of theory to examine the diastereoselectivity of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams have been found to be in good agreement with the observed experimental results. The origin of selectivity is examined by an activation strain model and molecular electrostatic potential (MESP) surfaces. The distortion energies calculated using the activation strain model revealed the origin of diastereoselectivities for butenolides and butyrolactams. The reversal in stereochemical outcome of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams is due to the presence of a large substituent at the nitrogen center of the γ-butyrolactams. We have further revealed the enhanced diastereoselectivity of these butenolides while reacting with the aromatic aldehydes bearing ortho substituents. The generated molecular electrostatic potential (MESP) surfaces have shown an additional Vmin of value = −115.0 kcal mol−1 responsible for enhanced diastereoselectivity with ortho-substituted benzaldehydes as compared to unsubstituted benzaldehyde. The difference in transition state distortion energies of syn and anti aldol products are found to correlate with their corresponding differences in activation energies.

Rational Design of Stereoselectivity in the Class II Pyruvate Aldolase BphI

BphI, a pyruvate-specific class II aldolase, catalyzes the reversible carbon-carbon bond formation of 4-hydroxy-2-oxoacids up to eight carbons in length. During the aldol addition catalyzed by BphI, the S-configured stereogenic center at C4 is created via attack of a pyruvate enolate intermediate on the si face of the aldehyde carbonyl of acetaldehyde to form 4(S)-hydroxy-2-oxopentanoate. Replacement of a Leu-87 residue within the active site of the enzyme with polar asparagine and bulky tryptophan led to enzymes with no detectable aldolase activity. These variants retained decarboxylase activity for the smaller oxaloacetate substrate, which is not inhibited by excess 4-hydroxy-2-oxopentanoate, confirming the results from molecular modeling that Leu-87 interacts with the C4-methyl of 4(S)-hydroxy-2-oxoacids. Double variants L87N;Y290F and L87W;Y290F were constructed to enable the binding of 4(R)-hydroxy-2-oxoacids by relieving the steric hindrance between the 5-methyl group of these compounds and the hydroxyl substituent on the phenyl ring of Tyr-290. The resultant enzymes were shown to exclusively utilize only 4(R)- and not 4(S)-hydroxy-2-oxopentanoate as the substrate. Polarimetric analysis confirmed that the double variants are able to synthesize 4-hydroxy-2-oxoacids up to eight carbons in length, which were the opposite stereoisomer compared to those produced by the wild-type enzyme. Overall the k(cat)/K(m) values for pyruvate and aldehydes in the aldol addition reactions were affected ≤10-fold in the double variants relative to the wild-type enzyme. Thus, stereocomplementary class II pyruvate aldolases are now available to create chiral 4-hydroxy-2-oxoacid skeletons as synthons for organic reactions.

Reversible immobilization of rhamnulose-1-phosphate aldolase for biocatalysis: Enzyme loading optimization and aldol addition kinetic modeling

Reusability of the usually expensive immobilization supports by means of reversible immobilization techniques helps reduce the overall cost of the biocatalytic process. One of these techniques, the reversible binding of the histidine residues of proteins with the metal chelated in affinity supports, has been extensively exploited in purification of His-tagged proteins in one-step. The use of these supports for immobilization of His-tagged recombinant enzymes allows performing simultaneously the enzyme purification and immobilization, thus further reducing the number of process steps, enzyme losses and costs. In this work, His-tagged rhamnulose-1-phosphate aldolase (RhuA) was immobilized onto iminodiacetic acid-functionalized agarose charged with cobalt (Co-IDA) for the catalysis of aldol addition reactions of industrial interest. Enzyme loading was optimized to maximize the immobilized activity avoiding diffusion limitations for both the RhuA natural reaction and the synthetic aldol addition between dihydroxyacetone phosphate (DHAP) and (S)-Cbz-alaninal (10 AU/mL of support and 25 AU/mL of support, respectively). RhuA:Co-IDA biocatalysts with high retained activity (92%) and enhanced stability (37 days of half life time) were obtained. Kinetic modeling of the synthetic aldol addition between DHAP and (S)-Cbz-alaninal and the unwanted secondary reaction catalyzed by soluble RhuA was carried out. RhuA:Co-IDA catalysis of the same reactions was found to follow the same kinetic model.

Probing the Molecular Basis of Substrate Specificity, Stereospecificity, and Catalysis in the Class II Pyruvate Aldolase, BphI

BphI, a pyruvate-specific class II aldolase found in the polychlorinated biphenyls (PCBs) degradation pathway, catalyzes the reversible C-C bond cleavage of (4S)-hydroxy-2-oxoacids to form pyruvate and an aldehyde. Mutations were introduced into bphI to probe the contribution of active site residues to substrate recognition and catalysis. In contrast to the wild-type enzyme that has similar specificities for acetaldehyde and propionaldehyde, the L87A variant exhibited a 40-fold preference for propionaldehyde over acetaldehyde. The specificity constant of the L89A variant in the aldol addition reaction using pentaldehyde is increased ∼50-fold, making it more catalytically efficient for pentaldehyde utilization compared to the wild-type utilization of the natural substrate, acetaldehyde. Replacement of Tyr-290 with phenylalanine or serine resulted in a loss of stereochemical control as the variants were able to utilize substrates with both R and S configurations at C4 with similar kinetic parameters. Aldol cleavage and pyruvate α-proton exchange activity were undetectable in the R16A variant, supporting the role of Arg-16 in stabilizing a pyruvate enolate intermediate. The pH dependence of the enzyme is consistent with a single deprotonation by a catalytic base with pK(a) values of approximately 7. In H20A and H20S variants, pH profiles show the dependence of enzyme activity on hydroxide concentration. On the basis of these results, a catalytic mechanism is proposed.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

Rephrasing Fuson's original formulation, the principle of vinylogy explains how the influence of a functional group may be relayed to a distant point in the molecule when these two sites are connected to by conjugated unsaturated linkages, such as double and triple bonds or aromatic moieties. This principle has been applied, over the years, to the majority of polar carbon-carbon bond-forming reactions of various repute, including the venerable Michael addition reaction, where the electrophilic -CdX site (1,2-addition) is “usurped” by a remote conjugated -RCdCR-CdX position (1,4-addition). The aldol addition reaction and the related Mannich process, both fundamental pillars of organic synthesis, have not escaped this fate, and both of their vinylogous extensions have emerged as extremely valuable synthetic methodologies.

Redesign of the Phosphate Binding Site of L‐Rhamnulose‐ 1‐Phosphate Aldolase towards a Dihydroxyacetone Dependent Aldolase

AbstractThe aldol addition of unphosphorylated dihydroxyacetone (DHA) to aldehydes catalyzed by L‐rhamnulose‐1‐phosphate aldolase (RhuA), a dihydroxyacetone phosphate‐dependent aldolase, is reported. Moreover, a single point mutation in the phosphate binding site of the RhuA wild type, that is, substitution of aspartate for asparagine at position N29, increased by 3‐fold the ${V{{app\hfill \atop {\rm max}\hfill}}}$ of aldol addition reactions of DHA to other aldehyde acceptors rather than the natural L‐lactaldehyde. The RhuA N29D mutant modified the optimum enzyme design for the natural substrate and changed its catalytic properties making the aldolase more versatile to other aldol additions of DHA.

Lipase CAL-B does not catalyze a promiscuous decarboxylative aldol addition or Knoevenagel reaction

Recently it was reported that lipase B from Candida antarctica (CAL-B) shows catalytic promiscuity in the decarboxylative aldol addition and Knoevenagel reaction between 4-nitrobenzaldehyde (4-NBA) and ethyl acetoacetate. We here provide experimental evidence that CAL-B simply catalyzed hydrolysis of the ester yielding the free acetoacetic acid, which under the reaction conditions readily reacts with 4-NBA to the described products.

Highly efficient aldol additions of DHA and DHAP to N-Cbz-amino aldehydes catalyzed by l-rhamnulose-1-phosphate and l-fuculose-1-phosphate aldolases in aqueous borate buffer

Aldol addition reactions of dihydroxyacetone (DHA) to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA) in the presence of borate buffer are reported. High yields of aldol adduct (e.g. 70-90%) were achieved with excellent (>98 : 2 syn/anti) stereoselectivity for most S or R configured acceptors, which compares favorably to the reactions performed with DHAP. The stereochemical outcome was different and depended on the N-Cbz-amino aldehyde enantiomer: the S acceptors gave the syn (3R,4S) aldol adduct whereas the R ones gave the anti (3R,4R) diastereomer. Moreover, the tactical use of Cbz protecting group allows simple and efficient elimination of borate and excess of DHA by reverse phase column chromatography or even by simple extraction. This, in addition to the use of unphosphorylated donor nucleophile, makes a useful and expedient methodology for the synthesis of structurally diverse iminocyclitols. The performance of aldol additions of dihydroxyacetone phosphate (DHAP) to N-Cbz-amino aldehydes using RhuA and L-fuculose-1-phosphate aldolase (FucA) catalyst in borate buffer was also evaluated. For FucA catalysts, including FucA F131A, the initial velocity of the aldol addition reactions using DHAP were between 2 and 10 times faster and the yields between 1.5 and 4 times higher than those in triethanolamine buffer. In this case, the retroaldol velocities measured for some aldol adducts were lower than those without borate buffer indicating some trapping effect that could explain the improvement of yields.

N-silyl oxyketene imines are underused yet highly versatile reagents for catalytic asymmetric synthesis

The reactions of acyl anion equivalents (d1 synthons) with carbonyl electrophiles allow for the construction of a wide range of molecules useful for the synthesis of biologically active compounds, natural products and chiral ligands. Despite their utility, significant challenges still exist for developing catalytic, enantioselective variants of these reactions. For example, the asymmetric benzoin process, arguably the most characteristic reaction of d synthetic equivalents, finds no general solution for reactions involving aliphatic acyl anions. In this Article, we introduce a new class of stable, isolable silyl ketene imines derived from protected cyanohydrins. These nucleophiles serve as acyl anion equivalents in Lewis base catalysed aldol addition reactions and allow for the preparation of cross-benzoin and glycolate-aldol products in high yield and with exceptional diastereo- and enantioselectivities.

ChemInform Abstract: A Two-Step Synthesis of (.+-.)-Blastmycinolactol Using Acylurea.

Abstract A convenient synthesis of natural (±)-blastmycino-lactol from the aldol addition reaction of n-pentanoylurea and (±)-2-benzyloxypropionaldehyde is described.

ChemInform Abstract: Aldol Addition Reaction of a Lithium Ester Enolate in the Solid State.

Abstract The first solid state aldol addition of the lithium enolate of methyl 3,3-dimethylbutanoate to aromatic aldehydes is reported. The diastereoselectivity of the reactions in the solid state is similar to that in solution, suggesting that the same reacting species and transition states might be involved.

ChemInform Abstract: Synthetic Studies in the Lysocellin Family of Polyether Antibiotics. The Total Synthesis of Ferensimycin B.

A convergent asymmetric synthesis of the polyether antibiotic ferensimycin B has been completed. Chiral enolate bond constructions were employed to establish seven of the 16 stereocenters of the subunits 35 and 52, which comprise the C& and CI&3 portions of ferensimycin B. The stereogenic centers at C3, C4, Cg, Clo, CI6, C,,, and CIS were incorporated through internal asymmetric induction, while those at Cm and C1l were established by using asymmetric epoxidation methodology. In this transformation, a vanadium-catalyzed internal epoxidation of a bis-homoallylic alcohol was employed to relay chirality from the C13 to the CI6 oxygen-bearing stereocenter. A final aldol addition reaction on intermediates devoid of protecting groups united the fragments 52 and 35 to provide synthetic ferensimycin B, whose absolute configuration was found to be

ChemInform Abstract: The Aldol Addition Reaction Between γ-Oxygenated Carboxylic Esters Derived from 2,6-Dimethylphenol and Piperonal.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Chelation Control in Metal-Assisted Aldol Addition Reactions of α -Halogenated Imide Enolates Leading to Predominantly Anti Stereoselectivity. An Example of a Stereocontrolled Darzens Reaction.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Addition of Acetone towards β‐Cyano‐α‐oxoesters Catalyzed by L‐Proline: Dynamic Kinetic Resolution

Abstractβ‐Cyano‐α‐oxoesters were found to undergo asymmetric aldol addition reaction with acetone in the presence of 10 mol% of L‐proline. With the racemic starting material, dynamic kinetic resolution (DKR) was achieved in quantitative yields with good diastreroselectivity of up to 85:15 dr and excellent ee up to 99% for the major diastereomer.

ChemInform Abstract: 1,2-Asymmetric Induction in the Aldol Addition Reaction of Malonate Ester Enolate to α-Alkoxy Aldehyde.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Asymmetric Aldol Addition Reactions of Fluorocarbonyl Compounds

ChemInform Abstract: Asymmetric Aldol Addition Reactions of Fluorocarbonyl Compounds

Chemical activation of piperidine by formaldehyde and formation of lysine-specific Maillard reaction products

Piperidine is considered as a lysine-specific Maillard reaction product that can be formed from free lysine through decarboxylation and deamination reactions or through cyclization of pent-4-en-1-amine, the counterpart of acrylamide from lysine. Due to the importance and reactivity of piperidine its further interaction products in glucose/lysine model system was investigated. A useful strategy based on Py-GC/MS analysis was developed using an isotope labelling technique to identify reaction products incorporating piperidine moieties. Products simultaneously possessing five lysine carbon atoms (C2′–C6′) and the Nε-amino group from lysine in addition to glucose carbon atoms were targeted using specifically labelled precursors such as [ 15Nα]Lysine·2HCl, [ 15Nε]Lysine·2HCl, [U- 13C 6]Lysine·2HCl, [ 13C-6]Lysine·2HCl and [U- 13C 6]Glucose. Detailed labelling studies using specifically 13C-enriched sugars have shown that the piperidine can form reactive 1-methylidenepiperidinium ion with formaldehyde, which is able to undergo further aldol addition reactions to form compounds, such as 3-(piperidin-1-yl)propanal and 3-(pyridin-1(4 H)-yl)propanal. Furthermore, these studies have also demonstrated that oxidation of piperidine into di- and tetrahydropyridine derivatives can generate reactive eneamine moieties capable of nucleophilic attack at carbonyl groups and formation of pyridine derivatives.