Current applications of organocatalysts in asymmetric aldol reactions: An update

The aldol reaction is one of the most important carbon–carbon bond formations in synthetic organic chemistry. An enantioselective aldol reaction should provide an enantioenriched product. The organocatalytic asymmetric aldol reaction via an in situ generated enamine intermediate is one of the most powerful synthetic tools to achieve enantiomerically pure products. This approach is often used to obtain chiral β-hydroxycarbonyl compounds with excellent enantioselectivity. In this report, we update our previous review regarding the applications of organocatalysts in asymmetric aldol reactions leading to chiral β-hydroxycarbonyl compounds as versatile synthetic motifs frequently found in pharmaceutically desired intermediates and biologically active naturally occurring compounds.     

Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.     

Carbohydrate-based organocatalysts in direct asymmetric aqueous aldol reaction

Aldol reaction involving chiral amines as organocatalysts through enamine formation, like class-I aldolases, is one of the thriving areas of general interest and widely applicable asymmetric reactions. There are many natural and synthetic chiral templates known to work as efficient organocatalysts, but using carbohydrate templates for chiral induction in asymmetric aldol reactions is a relatively new area developed in the recent years. This review focuses on carbohydrates alone or their conjugates with previously known chiral moieties as organocatalysts for asymmetric aldol reactions.     

The Total Synthesis of Inostamycin A

The first total synthesis of inostamycin A is described. With efficient and stereoselective synthetic routes to aldehyde 3 and ketone 4 developed through asymmetric aldol reactions, addition reactions and reduction, and with chiral building blocks, the two large fragments were coupled with remarkable anti stereoselectivity and efficiency by aldol condensation. The coupling reaction provided the complete carbon skeleton with all the requisite functional groups and stereogenic centers for inostamycin A. The two quaternary carbons at C20 and C16 of ketone 4 were elaborated in a highly stereocontrolled manner by addition reactions of the transmetallated 5 to ethyl ketone 6 and the transmetallated 7 to methyl ketone 8 , respectively, in which the use of LaCl₃ for transmetallation was critical for high coupling efficiency.     

Amino oxazolines as a new class of organocatalyst for the direct intermolecular asymmetric aldol reaction between acetone and aromatic aldehydes

A series of chiral amino oxazolines were synthesized and screened as organocatalysts for asymmetric intermolecular aldol reactions between acetone and aromatic aldehydes. The reaction works well with a range of aromatic aldehydes showing good to high selectivity. The present new system of the organocatalyst was effective for the asymmetric aldol reaction for a wide range of aromatic aldehydes and isatin to carry out an asymmetric carbon–carbon bond forming reaction with a high enantioselectivity of up to 91%.     

Amino Acids Catalyzed Direct Aldol Reactions in Aqueous Micelles

Since the discovery of its roles as a good small-organic-molecule catalyst in intramolecular aldol reactions, pro line has drawn considerable attention in synthetic chemistry due to its similarity to the type-Ⅰ aldolases. Recently,List and others have reported some new direct asymmetric intermolecular reactions catalyzed by proline, including aldol, Mannich, Michael, and other analogous reactions. Except for two recent examples, [1,2] proline catalyzed aldol reactions in aqueous micelles have not been reported, nor have other amino acids as organocatalysts in directly catalyzing aldol reaction been reported. Herein we wish to present our recent results regarding environmentally be nign direct aldol reactions catalyzed by amino acids including proline, histidine and arginine in aqueous media.     

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.     

Enantioselective aldol reactions of α,β-unsaturated ketones with trifluoroacetophenone catalyzed by a chiral primary amine

Chiral primary amine catalyzed direct asymmetric aldol reactions of ketones with trifluoroacetophenone, afforded trifluoromethylated β-hydroxycarbonyl aldol products bearing a quaternary carbon stereogenic center in high yields (up to 93% yield) and with high to excellent enantioselectivities of up to 99% ee.     

Recent advances in the application of the Oppolzer camphorsultam as a chiral auxiliary

Oppolzer’s camphorsultam has attracted much attention as an efficient chiral auxiliary, and is one of the most powerful synthetic tools in asymmetric synthesis. The sultam chiral auxiliary can be applied in a variety of different reactions such as alkylations, allylations, 1,3-dipolar cycloadditions, cyclopropanation, reductions, Diels–Alder, aldol and ene reactions. These applications have been highly successful in the stereoselective construction of a number of important natural products via total synthesis. The present review is focused on the utility and versatility of the sultam in various asymmetric reactions.     

The dihydroxyacetone unit--a versatile C(3) building block in organic synthesis

Nature employs dihydroxyacetone phosphate (DHAP) as the donor component in various enzyme-catalyzed aldol reactions. Probably the most significant example in this regard is photosynthesis, in which D-glucose, the most widespread natural product, is formed in just a few steps from DHAP. In recent years a number of synthetic equivalents of DHAP have been reported that deserve particular attention, as their applicability in organic synthesis is not limited to (stereoselective) aldol reactions. The power of these reagents has also been demonstrated convincingly in numerous other asymmetric electrophilic alpha-substitution reactions in target-oriented syntheses. Furthermore, the related 1,3-dioxins are useful equivalents of 2-substituted acrolein derivatives.     

Asymmetric Aldol Reaction with Formaldehyde: a Challenging Process

The asymmetric aldol reaction with formaldehyde is a fundamental carbon‐carbon bond‐forming reaction in organic synthesis, as well as in the quest of the origin of life, as it is thought to have been the first “molecular brick” involved in the synthetic path to complex sugars. Products of aldol reactions, i.e., the β‐hydroxy carbonyl compounds, are versatile building blocks used to access a great variety of functionalised molecules. The employment of formaldehyde, as a C1 symmetric electrophile, in aldol reactions can be likely considered the most challenging, yet simplest, process to introduce a hydroxymethyl group in an asymmetric fashion. In this account, an overview of the progress achieved in the asymmetric metal‐ and organocatalysed aldol reaction, using readily available formalin or paraformaldehyde sources, is illustrated. Our recent contribution to this area, with the application of asymmetric hydroxymethylation in cascade processes for the synthesis of γ‐butyrolactones, is also shown.

     

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.     

Storable, powdered chiral zirconium complex for asymmetric aldol and hetero Diels-Alder reactions

A storable, powdered chiral zirconium catalyst for asymmetric aldol and hetero Diels-Alder reactions has been developed. The catalyst has the same activity as that prepared in situ even after being stored for 3 months. Moreover, this chiral Zr catalyst worked efficiently not only for asymmetric aldol reactions but also for asymmetric hetero Diels-Alder reactions affording the corresponding addition products with high enantioselectivities.     

Acyclic amino acid-catalyzed direct asymmetric aldol reactions: alanine, the simplest stereoselective organocatalyst

The linear amino acid-catalyzed direct asymmetric intermolecular aldol reaction is presented; simple amino acids such as alanine, valine, isoleucine, aspartate, alanine tetrazole and serine catalyzed the direct catalytic asymmetric intermolecular aldol reactions between unmodified ketones and aldehydes with excellent stereocontrol and furnished the corresponding aldol products in up to 98% yield and with up to > 99% ee.     

脯氨酸催化不对称羟醛缩合反应机理研究进展

脯氨酸催化不对称直接羟醛缩合反应是近年来不对称合成研究的热点. 综述并讨论了分子内和分子间不对称直接羟醛缩合的反应机理及其微观过程.     

Enantioselective organocatalytic aldol reaction using small organic molecules

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Enantioselective reactions catalyzed by small organic molecules (asymmetric organocatalysis) are a comparatively new and popular segment in the area of contemporary research in asymmetric synthesis. The great synthetic utility of the aldol reaction for the formation of C–C bonds has geared up for a hard battle for research in this area resulting in a rapid evolution of tremendous highly enantioselective chiral catalysts. This review emphasizes asymmetric direct aldol reactions catalyzed by small enantioenriched organic molecules, particularly those involving enamine catalysis through primary and secondary amines. We have made significant efforts to include several important contributions from different groups in this area.     

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.     

Asymmetric solution-phase mixture aldol reaction using oligomeric ethylene glycol tagged chiral oxazolidinones

Sorting tags are oligomeric structures that can be used as protecting groups or chiral auxiliaries enabling solution-phase mixture syntheses of multiple tagged compounds in one pot and allowing for facile and predictable chromatographic separation of products at the end of synthetic sequences. Perfluorinated hydrocarbon and oligomeric ethylene glycol (OEG) derivatives are known classes of sorting tags. Herein we describe the preparation of OEGylated chiral oxazolidinones and their use in asymmetric solution-phase mixture aldol reactions. Through the use of such oxazolidinones based on tyrosine four different individually tagged aldol adducts were obtained as a mixture, chromatographically demixed, detagged, and it was shown that these processes gave the desired aldol products in good yield and enantioselectivity.     

Diels–Alder/Oxidative Aromatization Approach towards the All‐Carbon DEF Tricyclic Skeleton of Daphenylline

Daphenylline is a recently isolated Daphniphyllum alkaloid with an unprecedented novel hexacyclic scaffold. In this study, the synthesis of the fused all‐carbon DEF tricyclic skeleton of daphenylline has been accomplished. Key steps of the reported sequence involve Evans asymmetric allylation, aldol condensation, Diels–Alder reaction, and oxidative aromatization reactions. The developed strategy might lead to the total synthesis of daphenylline.