Asymmetric Aldol Reaction Research Articles

Chiral Bismuth-Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C-H Functionalization Nexus.

Heterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3-disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C-H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

Chiral Bismuth‐Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C−H Functionalization Nexus

AbstractHeterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3‐disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C−H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

Synthetic access to syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones: Evaluation of α-glucosidase inhibition activity, docking studies and pharmacokinetics prediction

A new series of syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones containing α,β-contiguous stereocenters were synthesized via a diphenylprolinol-catalysed asymmetric cross aldol reaction. The synthesized compounds were characterised and evaluated for their α-glucosidase inhibitory potential. The hydroxy pyrrolidine series (9a-9i) was found to be selectively more potent against the α-glucosidase enzyme as compared to the pyrrolidone series (10a-10i). Pyrrolidine 9b was the most efficacious analogue with an IC50 of 48.31 µM. Compounds 9c, 9d, &9f were also found to be more potent than the standard drugs acarbose, miglitol and deoxynojirimycin. Furthermore, these compounds were investigated by computational studies using the GLIDE docking module of the Schrödinger suite 2021-4 in which 9b and 9c showed more promising results than the standard drugs acarbose, miglitol, and deoxynojirimycin.

Calix[n]arenes in Action: Recent Applications in Organocatalysis

AbstractThe use of calix[n]arenes as organocatalysts has increasingly been considered a prime focus due to their adjustable three‐dimensional molecular structure, easy synthesis, and versatile structural modification at the upper and lower edges. For instance, these macromolecules have been described as efficient catalysts for asymmetric aldol reactions, asymmetric Michael addition, esterification and transesterification, dehydration, nucleophilic aromatic substitution, and multicomponent reactions. Furthermore, calix[n]arenes also tolerate aqueous or solvent‐free reaction systems and can be supported on solid and/or magnetic particles, showing cost, time and energy savings, easier experimental procedures, and chemical waste reduction.

Electrochemical Bottom-Up Synthesis of Chiral Carbon Dots from L-Proline and Their Application as Nano-Organocatalysts in a Stereoselective Aldol Reaction.

Chirality is undoubtedly a fundamental property of nature since the different interactions of optically active molecules in a chiral environment are essential for numerous applications. Thus, in the field of asymmetric synthesis, the search for efficient, sustainable, cost-effective and recyclable chiral catalysts is still the main challenge in organic chemistry. The field of carbon dots (CDs) has experienced tremendous development in the last 15 years, including their applications as achiral catalysts. Thus, understanding the implications of chirality in CDs chemistry could be of utmost importance to achieving sustainable and biocompatible chiral nanocatalysts. An efficient and cost-effective electrochemical synthetic methodology for the synthesis of L-Proline-based chiral carbon dots (CCDs) and EtOH-derived L-Proline-based chiral carbon dots (CCDs) is herein reported. The electrochemical set-up and reaction conditions have been thoroughly optimised and their effects on CCDs size, photoluminescence, as well as catalytic activity have been investigated. The obtained CCDs have been successfully employed to catalyze an asymmetric aldol reaction, showing excellent results in terms of yield, diastereo- and enantioselectivity. Moreover, the sustainable nature of the CCDs was demonstrated by recycling the catalysts for up to 3 cycles without any loss of reactivity or stereoselectivity.

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes.

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol (1), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.

Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

Comprehensive SummaryA total synthesis of 17‐membered macrocyclolipopeptide dysoxylactam A, a potent agent reversing P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) in cancer cells, was developed from the starting material (S)‐2‐methylbutanal in a linear sequence of 12 steps with 23.2% overall yield. The key steps include proline‐catalyzed asymmetric aldol reaction, Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment, and ring‐closing metathesis to furnish the macrocycle. This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure‐activity relationship exploration.

Silver‐Catalyzed Asymmetric Aldol Reaction of Isocyanoacetic Acid Derivatives Enabled by Cooperative Participation of Classical and Nonclassical Hydrogen Bonds

AbstractThe silver‐catalyzed asymmetric aldol reaction of isocyanoacetic acid derivatives with aldehydes has been developed by employing a chiral prolinol‐phosphine as a hydrogen‐bond‐donating P,N,O ligand. DFT calculations indicated that the reaction proceeds in a stepwise manner, involving C−C bond forming carbonyl addition and subsequent enantioselectivity‐determining oxazoline ring formation. An O−H⋅⋅⋅O/sp3‐C−H⋅⋅⋅O two‐point hydrogen bond donated by the prolinol moiety of the ligand activates the aldehyde in the C−C bond formation step and facilitates the subsequent cyclization under stereocontrol by the catalyst. The calculations further suggest that additional nonclassical C−H⋅⋅⋅O hydrogen bonds as well as London dispersion interactions may also participate synergistically in the stereocontrol.magnified image

Highly diastereoselective asymmetric syn-aldol reactions of (R)-(N-tosyl)phenylalaninol propionate-derived titanium enolate and bidentate aromatic and aliphatic aldehydes

Asymmetric aldol reactions of ester-derived titanium enolates of (R)-(N-tosyl)phenylalaninol propionate and bidentate aromatic aldehydes has been investigated. Substrate scope of this aldol reaction was examined with a variety of bidentate aromatic aldehydes to provide syn-aldol products with high diastereoselectivity and isolated yields. Both enantiomers of N-(tosyl)phenylalaninol are readily prepared from commercially available and optically active phenylalaninol. Mild saponification removed the chiral auxiliary and furnished optically active β-hydroxy carboxylic acids.

Asymmetric Aldol Reaction Catalyzed by a Chiral Proline-Substituted Porous Organic Cage

Asymmetric Aldol Reaction Catalyzed by a Chiral Proline-Substituted Porous Organic Cage

Polymer Supported Proline-Based Organocatalysts in Asymmetric Aldol Reactions: A Review

Abstract: The use of proline-based organocatalysts has acquired significant attention in organic synthesis, especially in enantioselective synthesis. Proline and its derivatives are proven to be quite effective chiral organocatalysts for a variety of transformations, including the aldol reaction, which is considered as one of the important C-C bond forming reactions in organic synthesis. The use of chiral organocatalysts has several advantages over its metal-mediated analogues. Subsequently, a large number of highly efficient proline-based organocatalysts, including polymer-supported chiral analogues, have been identified for aldol reaction. The use of polymer-supported organocatalysts exhibited remarkable stability under the reaction conditions and offered the best results, particularly in terms of its recyclability and reusability. These potential benefits along with their economic and green chemistry advantages have led to the search for many polymer-supported proline catalysts. In this review, recent developments in exploring various polymer immobilized proline- based chiral organocatalysts for asymmetric aldol reactions are described.

Direct and Asymmetric Aldol Reactions of N‐Azidoacetyl‐1,3‐thiazolidine‐2‐thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of β‐Hydroxy‐α‐Amino Acids

A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N‐azidoacetyl‐1,3‐thiazolidine‐2‐thione with aromatic aldehydes catalyzed by a chiral nickel(II)‐Tol‐BINAP complex has been developed (BINAP=2,2’‐bis(diphenylphosphino)‐1,1’‐binaphthyl). The catalytic protocol gives the corresponding anti α‐azido‐β‐silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di‐ and tripeptide blocks containing a β‐aryl‐β‐hydroxy‐α‐amino acid.

Asymmetric Synthesis of Spirooxazolidinone Oxindoles by the Thiourea‐Catalyzed Aldol Reaction of 2‐Isocyanatomalonate Diesters

AbstractA tertiary amino‐thiourea catalyzed asymmetric aldol reaction between 2‐isocyanatomalonate esters and isatins has been achieved. Optical active spirooxazolidinone oxindole derivatives could be obtained with excellent yields (80%–96%) and enantioselectivities (67%–99% ee) under mild conditions, providing an updated example to apply isatins as the electrophile in the asymmetric aldol reaction with 2‐isocyanatomalonate esters.magnified image

A Degenerate Metal-Templated Catalytic System with Redundant Functional Groups for the Asymmetric Aldol Reaction.

A degenerate zinc-templated catalytic system containing two bipyridine ligands with redundant functional groups for either enamine or hydrogen bond formation was applied to the asymmetric aldol reaction. This concept led to both a higher probability of reaction and rate acceleration. Thus, the catalyst loading could be decreased to a remarkable 2 mol % in what we think is a general approach.

Spick-and-span protocol for designing of silica-supported enantioselective organocatalyst for the asymmetric aldol reaction

In the present work, we report a ground-breaking strategy in the development of spick-and-span protocol for the synthesis of l-proline chiral scaffold tethered onto the silica matrix i.e., l-proline-(3°amine)-f-SiO2 via the reaction between l- proline methyl ester and N-methyl aminopropyl silica with absolutely no use of protecting/ deprotecting groups. The as-synthesized catalyst was well corroborated through various physicochemical techniques such as 13C CP MAS NMR, X-ray diffraction (XRD), HRTEM, N2 adsorption−desorption isotherms, elemental analysis and FT-IR spectral studies. Emphatically, l-proline-(3°amine)-f-SiO2 significantly promoted an asymmetric aldol reaction under ambient conditions with no use of redundant organic solvent, bestowing unprecedented activity with 100% conversion and (ee) > 99% enantioselectivity of S-isomer. Moreover, the as-synthesized catalyst was effortlessly recycled seven consecutive times with absolutely zero loss of activity as well.

Insights into Substituent Effects of Benzaldehyde Derivatives in a Heterogeneous Organocatalyzed Aldol Reaction

AbstractOrganocatalyst immobilization onto solid supports represents a promising method for enabling asymmetric organocatalysis while retaining the advantages of heterogeneous catalysts, including catalyst separation, recycling, and the use of fixed‐bed reactors. Understanding how such heterogenized catalytic systems work is fundamental to develop and tailor more efficient ones. Herein, we have elucidated the role of reactant molecular structure on surface interactions and reactivity for asymmetric aldol reactions between benzaldehyde derivatives and hydroxyacetone catalyzed by SBA‐15 immobilized L‐proline. NMR relaxation time analysis reveals that a stronger interaction between the aldehyde and the catalyst surface reduces catalytic reactivity, which is attributed to reduced access of hydroxyacetone to the L‐proline surface sites, hence inhibiting the formation of the enamine intermediate between hydroxyacetone and L‐proline. The results show that surface phenomena in these systems are important considerations for reactant selection, opening up new directions to explore in this area of research.

On the Influence of a Camphor‐based 1,3‐Diamine Fragment in a Proline‐Based Organocatalyst

AbstractMultifunctional C1‐symmetric organocatalysts were prepared incorporating a camphor‐ and a proline‐based moiety. The new catalysts were evaluated in an asymmetric aldol reaction of acetone and aromatic aldehydes. A significant increase in the catalytic activity was found for the new proline analogue with the camphor‐based 1,3‐diamine unit. This new organocatalyst has one free primary amine group next to the secondary amine group of the proline unit. High yields of up to 97 % with good enantioselectivities (83 % ee) were obtained in the aldol reaction between various aromatic aldehydes and acetone in a shorter reaction time compared with (S)‐proline. A camphor‐based prolineamide analogue with a thiourea group was an efficient multifunctional organocatalyst for the aldol reaction of p‐nitrobenzaldehyde and cyclohexanone with 86 % yield and up to 73 % ee. Moreover, matched‐mismatched studies with opposite stereocenters in the camphor‐based 1,3‐diamine fragment revealed a significant influence of this unit on the overall performance of the new organocatalyst.

New mechanistic approach in the enamine-based asymmetric organocatalysis

During the course of my research in asymmetric organocatalysis, inversion of enantioselectivity was observed in the asymmetric aldol reactions of acetone with different aldehydes catalyzed by amphiphilic proline derivatives in aqueous media by varying only achiral components. It was not possible to explain the explored dual stereocontrol with the existing models, therefore I proposed a new mechanism for asymmetric aldol reactions catalyzed by l-amino acid derivatives in aqueous media and explained the explored phenomenon of inversion of enantioselectivity with different structures of micelle-stabilized transition state described as a metal-free version of the Zimmerman-Traxler model with explicit participation of a water molecule. Contrary to the existing models, according to the proposed mechanism, the formation of new bonds proceeds directly in the transition state stabilized by a water molecule, without the additional step of product iminium ion hydrolysis. The proposed mechanism has universal character, it is consistent with experimental results and general theoretical conceptions, and it is applicable to all enamine-based asymmetric organocatalytic reactions carried out not only in aqueous, but in organic media as well, because the initial step of catalytic cycle, which involves the formation of an enamine from the carbonyl compound and proline (derivative), liberates one water molecule.

Synthesis of the Proposed Structure of Mohangic Acid C

The proposed structure of mohangic acid C (3) was stereoselectively synthesized via a catalytic asymmetric aldol reaction to install a p-aminoacetophenone moiety, Marshall propargylation furnishing two stereocenters, and Cu-mediated Stille-type coupling to construct the whole framework of 3.

New organocatalysts derived from tetrahydropapaverine for asymmetric aldol reaction

New organocatalysts derived from tetrahydropapaverine for asymmetric aldol reaction