Direct Cross-Aldol Research Articles

An approach towards (+)-allokainic acid via diphenylprolinol-catalyzed direct cross-aldol reaction.

This article describes an enantioselective strategy for the synthesis of the kainoid component, (+)-allokainic acid using an organocatalytic approach. A cross-aldol reaction catalyzed by diphenylprolinol yielded a highly functionalized γ-lactam with excellent enantio- and diastereoselectivity, and the resulting hydroxy pyrrolidone was then utilized to synthesize Ganem's intermediate of (+)-allokainic acid. Krapcho decarboxylation and Wittig olefination were pivotal transformations towards the final trans-substituted Ganem's intermediate.

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.

One-Pot Regiodirected Annulations for the Rapid Synthesis of π-Extended Oligomers.

We demonstrate the broad applicability of the annulation protocol combining, in one pot, a direct arylation and cross aldol condensation for the straightforward synthesis at gram-scale of π-extended thiophene-based scaffolds. The regiospecific direct arylation drives the subsequent cross-aldol condensation proceed under the same basic conditions, and the overall protocol has broad applicability in the synthesis of extended aromatics wherein the thiophene ring is annulated with furans, pyridines, indoles, benzothiophenes, and benzofurans. These scaffolds can be further elaborated into π-extended, highly fluorescent oligomers with a central deficient benzothiadiazole unit with up to nine aromatic rings through coupling reactions.

Diarylprolinol-Mediated Asymmetric Direct Cross-Aldol Reaction of α,β-Unsaturated Aldehyde as an Electrophilic Aldehyde.

The diarylprolinol-mediated asymmetric direct cross-aldol reaction of α,β-unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ-position of the α,β-unsaturated aldehyde. Synthetically useful γ,δ-unsaturated β-hydroxy aldehydes were obtained with high anti-selectivity and excellent enantioselectivity.

Scalable Synthesis of Naphthothiophene and Benzodithiophene Scaffolds as π-Conjugated Synthons for Organic Materials

The synthesis on a gram-scale and the full characterization of naphtho[1,2-b]thiophene and benzo[1,2-b:6,5-b']dithiophene 4-carboxylate esters bearing 2-octyldodecyl side chains, and their stannylated and brominated derivatives, suitable for their insertion into π-conjugated polymers is described. The fully soluble and processable synthons are obtained through a cascade sequence of reactions, namely direct arylation and cross aldol condensation, which create an effective pathway for the annulation and π-extension of suitable, commercially available reagents. The newly reported synthesis are compared, whenever possible, using ‘green chemistry metrics’ with literature synthesis, showing dramatic improvements.

Research and Development of an Efficient Synthesis of a Key Building Block for Anti-AIDS Drugs by Diphenylprolinol-Catalyzed Enantio- and Diastereoselective Direct Cross Aldol Reaction

An efficient method for synthesizing 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (1), a key building block for HIV protease inhibitors, has been developed. A diphenylprolinol-catalyzed highly enantio- and diastereoselective cross aldol reaction of polymeric ethyl glyoxylate with an aldehyde was used as the key step. Acetalized aldol adduct was reduced with NaBH4 to give the diol intermediate in quantitative yield. The acetal exchange reaction followed by hydrogenation with Pd/C catalyst afforded 1′ in 95% yield over 2 steps. The condensation of 1′ with a carbonate gave crystalline 1 (>99/1 dr, > 99% ee) after single crystallization. This is a highly practical synthetic method since environmentally benign organocatalysis is utilized, the amount of catalyst is reduced to 3 mol %, and all of the intermediates before 1′ can be used without any purification.

Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α-Keto Amides.

The first enantioselective direct cross-aldol reaction of α-keto amides with aldehydes, mediated by a bifunctional ureidopeptide-based Brønsted base catalyst, is described. The appropriate combination of a tertiary amine base and an aminal, and urea hydrogen-bond donor groups in the catalyst structure promoted the exclusive generation of the α-keto amide enolate which reacted with either non-enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side-products resulting from dehydration, α-keto amide self-condensation, aldehyde enolization, and isotetronic acid formation.

Strain-driven direct cross-aldol and -ketol reactions of four-membered heterocyclic ketones.

Owing to the ring strain and α-heteroatom effect, the four-membered heterocyclic ketones can undergo direct cross-aldol and -ketol reactions without the need for preformed enol or "enolate-like" intermediates. Besides the organocatalyzed cross-ketol addition onto their highly active carbonyl group, their ability to act as a nucleophilic donor has also been explored. As a result, a number of discrete aldol adducts were synthesized and the distinct reactivities were successfully combined into a double-aldol one-pot reaction.

Catalytic enantioselective quick route to aldol-tethered 1,6- and 1,7-enynes from ω-unsaturated aldehydes.

An effective asymmetric route to functionalized 1,6- and 1,7-enynes has been developed based on a direct cross-aldol reaction between ω-unsaturated aldehydes and propargylic aldehydes (α,β-ynals) promoted by combined α,α-dialkylprolinol ether/Brønsted acid catalysis. This synergistic activation strategy is key to accessing the corresponding aldol adducts with high stereoselectivity, both enantio- and diastereoselectivity. The aldol reaction also proceeds well with propargylic ketones (α,β-ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson-Khand conditions.

Theoretical Study of Stereoselectivity for <i>Syn</i>-Selective Cross-Aldol Reactions of Aldehydes Catalyzed by Chiral Diamine Organocatalysts

Quantum mechanical calculations have been performed to study the stereoselectivities in the direct cross-aldol reactions of aldehydes catalyzed by simple chiral diamines. The detailed computational studies on the stereochemistry-controlling step of the subject reactions have been presented by DFT calculations at the B3LYP/6-31G* level. The poor agreement between the calculated and the observed diastereomeric ratio and enantiomeric excess values is obtained for all diamines catalysts. Further M06-2X calculations can provide a reasonable explanation for the observed syn-selectivities of the asymmetric cross-aldol reaction between propionaldehyde and 4-nitrobenzaldehyde.

Organocatalytic asymmetric cross-aldol reaction of 2-chloroethoxy acetaldehyde: diversity-oriented synthesis of chiral substituted 1,4-dioxanes and morpholines

Herein we report a facile organocatalytic asymmetric direct cross-aldol reaction of 2-chloroethoxy acetaldehyde with aromatic aldehydes using (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol as an organocatalyst to afford anti-2-(2-chloroethoxy)-1-arylpropane-1,3-diols with excellent enantioselectivities (95–98%) and moderate diastereoselectivities (3.5–7:1). The 1,3-diols, obtained after the aldehyde reduction, represent highly functional intermediates that allow for further diversification into both chiral 1,4-dioxanes and morpholines, compounds that frequently display interesting biological activities.

ChemInform Abstract: Bio‐Inspired Chiral Primary Amine Catalysis

AbstractReview: ca. 80 refs.

Bio-inspired Chiral Primary Amine Catalysis

The search for new catalysts with superior performance and broad applicability remains a central theme in asymmetric organocatalysis. Inspired by Nature as well as by numerous previous efforts, we have developed chiral primary–tertiary diamines as both functional and mechanistic enzyme mimics, showing unprecedented scope in enamine-aldol reactions and significant potential in the reactions of acroleins. Our endeavors focusing on this type of catalysts are summarized in this account. 1 Introduction 2 General Features of Primary–Tertiary Vicinal Diamine/TfOH; Multifunctional Catalysis 3 Asymmetric Supramolecular Primary Amine Catalysis; Roles of the Hydrophobic Cavity 4 Asymmetric Direct Aldol Reaction of Aliphatic Ketones 5 Asymmetric Direct Cross-Aldol Reaction of Aldehydes 6 Asymmetric Retro-Aldol and Transfer-Aldol Reactions 7 Iminium Catalysis with Chiral Primary–Tertiary Diamines 8 Bifunctional Catalysis of Primary–Tertiary Diamines in the Baylis–Hillman Reaction 9 Conclusion, Remarks, and Outlook

Efficient Organocatalytic Cross-Aldol Reaction between Aliphatic Aldehydes through Their Functional Differentiation

A chemo- and stereoselective asymmetric direct cross-aldol reaction between aliphatic aldehydes and α-chloroaldehydes has been developed as a method for the formation of the sole cross-aldol adduct with both enantio- and diastereocontrol, and either anti- or syn-aldol adducts were obtained in good to excellent stereoselectivities by use of proline or a novel axially chiral amino sulfonamide as catalyst.

Asymmetric Organocatalyzed Direct Aldol Additions of Enolizable Aldehydes

The enantioselective direct cross-aldol addition between enolizable aldehydes is of great importance because this transformation provides access to configurationally defined β-hydroxyaldehydes. These products in turn are valuable building blocks in total syntheses of natural polyketide structures. This account gives an overview of advances made in this field of organocatalysis. 1 Introduction 2 Direct Aldol Additions of Enolizable Aldehydes Catalyzed by Proline, Proline Derivatives, and Imidazolidinone 2.1 Direct Aldol Additions Catalyzed by Proline and Proline Derivatives 2.2 Direct Aldol Additions Catalyzed by Imidazolidinone 3 Direct Aldol Additions of Enolizable Aldehydes Catalyzed by Histidine 4 Conclusion

Recyclable enamine catalysts for asymmetric direct cross-aldol reaction of aldehydes in emulsion media

Highly diastereo- and enantioselective cross-aldol reactions of aldehydes (>20 : 1 dr, 99% ee), catalyzed by chiral diamine-polyoxometalate acid combined enamine catalysts in emulsion media, are reported. This type of catalysts can be recycled several times without significant deterioration of activity and selectivity.

Asymmetric Histidine-Catalyzed Cross-Aldol Reactions of Enolizable Aldehydes: Access to Defined Configured Quaternary Stereogenic Centers

A histidine-catalyzed asymmetric direct cross-aldol reaction of enolizable aldehydes is described. In contrast to proline, histidine is able to clearly differentiate the reactivity of various aldehydes. In addition, this approach provides access to syn-configured beta-hydroxyaldehydes. Thus, by application of this new methodology, defined-configuration quaternary stereocenters can be constructed with ease. The utility of this method is demonstrated in several total syntheses of branched-chain carbohydrates.

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric anti‐Selective Mannich Reactions and syn‐Selective Cross‐Aldol Reactions

A direct asymmetric Mannich reaction using a novel axially chiral amino sulfonamide (S)-3 that is highly anti- and enantioselective has been developed. For instance, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and alpha-imino esters proceeded smoothly to give anti Mannich products with a significantly higher anti/syn ratio and enantioselectivity than previously possible. By utilizing N-Boc-protected aromatic imines instead of alpha-imino esters, the synthetically useful Boc protecting group and various aromatic or heteroaromatic substituents were installed into the anti Mannich products and consequently the substrate scope of the anti-selective Mannich reaction and the synthetic utility of the anti Mannich products have been expanded. The axially chiral amino sulfonamide (S)-3 has also been successfully applied to asymmetric direct cross-aldol reaction between two different aldehydes. The catalyst (S)-3 has the advantage of giving mainly syn products, whereas proline shows the opposite anti selectivity.

Syn-Selective Direct Asymmetric Cross-Aldol Reaction

<i>syn</i>-Selective Direct Asymmetric Cross-Aldol Reaction

Syn‐Selective and Enantioselective Direct Cross‐Aldol Reactions between Aldehydes Catalyzed by an Axially Chiral Amino Sulfonamide

Complementary to proline: An axially chiral amino sulfonamide (S)-1 was successfully applied as the catalyst to the direct cross-aldol reaction between two different aldehydes (see scheme; NMP=N-methylpyrrolidone). This catalyst has the advantage of giving mainly syn products, while proline shows the opposite anti selectivity.