Direct Aldol Addition Research Articles

A Squaramide‐Tagged Proline‐Mediated Direct Asymmetric Aldol Addition in the Presence of Water

A squaramide moiety introduced at the C‐4 position of proline produced an organocatalyst that promoted the direct asymmetric aldol addition in the presence of water. A variety of aldol adducts, majorly from the reaction cyclohexanone with aldehydes, were obtained in yields generally in the range of 53‐99%, accompanied by 71‐97% ee and 82:18 to >99:1 diastereomeric ratios. An asymmetric desymmetrization of 4‐alkyl cyclohexanones was also achieved using the transformation.

Cooperative assistance of a sulfonamide in a proline-mediated direct asymmetric aldol addition

A sulfonamide moiety was introduced at the C-4 position of proline, cis to the –COOH group, to examine a possible synergistic interaction between the two groups and the consequent influence on the enamine mediated asymmetric aldol reaction.

Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis.

To improve the field of catalysis, there is a substantial and growing need for novel high-performance catalysts providing new reactivity. To date, however, the set of reactions that can be reliably performed to prepare chiral compounds in largely one enantiomeric form using chiral catalysts still represents a small fraction of the toolkit of known transformations. In this context, chiral Brønsted bases have played an expanding role in catalyzing enantioselective reactions between various carbon- and heteroatom-centered acids and a host of electrophilic reagents. This Account describes our recent efforts developing and applying a new family of chiral Brønsted bases incorporating an H-bond donor moiety and a strongly basic iminophosphorane, which we have named BIMPs (Bifunctional IMinoPhosphoranes), as efficient catalysts for reactions currently out of reach of more widespread tertiary amine centered bifunctional catalysts. The iminophosphorane Brønsted base is easily generated by the Staudinger reaction of a chiral organoazide and commercially available phosphine, which allows easy modification of the catalyst structure and fine-tuning of the iminophosphorane pKBH+. We have demonstrated that BIMP catalysts can efficiently promote the enantioselective addition of nitromethane to low reactivity N-diphenylphosphinoyl (DPP)-protected imines of ketones (ketimines) to access valuable chiral diamine and α-quaternary amino acid building blocks, and later extended this methodology to phosphite nucleophiles. Subsequently, the reaction scope was expanded to include the Michael addition of high pKa alkyl thiols to α-substituted acrylate esters, β-substituted α,β-unsaturated esters, and alkenyl benzimidazoles as well as the challenging direct aldol addition of aryl ketones to α-fluorinated ketones. Finally, BIMP catalysts were shown to be used in key steps in the synthesis of complex alkaloid natural products (-)-nakadomarin A and (-)-himalensine A, as well as in polymer synthesis. In most cases, the predictable nature of the BIMP promoted reactions was demonstrated by multigram scale-up while employing low catalyst loadings (down to 0.05 mol%). Furthermore, it was shown that BIMP catalysts can be easily immobilized onto a solid support in one-step for increased catalyst recycling and flow chemistry applications. Alongside our own work, this Account also includes elegant work by Johnson and co-workers utilizing the BIMP catalyst system, when alternative catalysts proved suboptimal.

Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones.

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. 1 H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.

Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α‐Fluorinated Ketones

AbstractThe catalytic enantioselective synthesis of α‐fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi‐gram scalability has been demonstrated along with catalyst recovery and recycling. 1H NMR studies identified a 1400‐fold rate enhancement under BIMP catalysis, compared to the prior state‐of‐the‐art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3‐aminoalcohol, 1,3‐diol, oxetane, and isoxazoline derivatives.

Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2-Carbaldehydes.

A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2-carbaldehyde N-oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo- and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N-oxide group yields enantiopure carbinol-tethered quaternary hydantoin-azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6-31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen-bond-assisted activation of the squaramide moiety in the transition state of the catalytic reaction.

Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl Acetamide

A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted by a cooperative acid/base catalyst in a stereodivergent manner. The key structural element, a 7-azaindoline moiety, facilitated catalytic enolization, allowing for subsequent stereoselective aldol addition. Enantioselective synthesis of the key intermediate of blumiolide C and kainic acid supported the synthetic utility of this protocol.

Direct Catalytic Asymmetric Aldol Addition of an α-CF3 Amide to Arylglyoxal Hydrates.

Direct asymmetric aldol addition of an α-CF3 amide to arylglyoxal hydrates was promoted by a chiral catalyst comprising a soft Lewis acidic Cu(I), a chiral bisphosphine ligand, and DBU. The 7-azaindoline moiety of the amide facilitates its enolization and stabilizes the thus-generated Cu enolate, furnishing enantioenriched aldol adducts.

A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr2·OEt2 and i-Pr2NEt. At −78°C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.

ChemInform Abstract: Influence of a Remote Sulfinyl Group on L‐Proline‐Catalyzed Direct Asymmetric Aldol Addition of Acetone.

Abstract The addition of acetone to rac-2-methylsulfinyl-benzaldehyde, catalyzed by secondary amines (morpholine, piperidine, l -proline, l -prolinamide and (S)-(–)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether), was realized. Interesting aspects, such as 1,4-asymmetric induction by the remote sulfinyl group of the aldehyde but also the stereochemical control and kinetic resolution of the racemic substrate by the chiral organocatalyst were examined. Finally, an unexpected stereoselective retro-aldol reaction catalyzed by l -proline was pointed out.

L-Hydroxyproline Immobilized on MCM-41 by Ionic Liquid as a Hetero - geneous Organocatalyst for Direct Asymmetric Aldol Addition

A new heterogenized silica-based organocatalyst was prepared via anion exchange of imidazolium ionic liquid with L– hydroxyproline material. This was evaluated as a heterogenous organocatalyst for the asymmetric aldol reaction of nitrobenzaldehydes, cyclohexanone and cyclopentanone by performing the reaction under different conditions by using several solvents and reaction temperatures. Excellent isolated yields of the aldol products of up to %90 were achieved. In addition, excellent selectivity (ee up to %98) was obtained. In one case, dr reached up to > 99:1. Keywords: Asymmetric synthesis, imidazolium ionic liquid, hydroxy proline, aldol addition, organocatalyst, MCM-41.

Influence of a remote sulfinyl group on l-proline-catalyzed direct asymmetric aldol addition of acetone

The addition of acetone to rac-2-methylsulfinyl-benzaldehyde, catalyzed by secondary amines (morpholine, piperidine, l-proline, l-prolinamide and (S)-(–)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether), was realized. Interesting aspects, such as 1,4-asymmetric induction by the remote sulfinyl group of the aldehyde but also the stereochemical control and kinetic resolution of the racemic substrate by the chiral organocatalyst were examined. Finally, an unexpected stereoselective retro-aldol reaction catalyzed by l-proline was pointed out.

ChemInform Abstract: Synthesis of Zirconium Phosphonate Supported L‐Proline as an Effective Organocatalyst for Direct Asymmetric Aldol Addition.

AbstractThe catalyst is easily recoverable and can be used at least 6 times without any significant loss in activity.

Synthesis of Zirconium Phosphonate Supported L‐Proline as an Effective Organocatalyst for Direct Asymmetric Aldol Addition

AbstractStable L‐proline‐functionalized zirconium methyl‐ and/or phenylphosphonates have been prepared as amorphous solids by the precipitation of (4R)‐4‐[(4′‐phosphonobenzyl)oxy]‐L‐proline and methyl‐ and/or phenylphosphonic acid with ZrOCl2. The supported L‐proline catalysts were tested in the direct asymmetric aldol addition between several ketones and p‐substituted benzaldehydes. High yields, diastereoselectivities (anti/syn up to 92:8) and enantiomeric excesses (up to 99 % ee) have been achieved. Moreover, an easy protocol for the efficient recovery of the catalytic system by simple centrifugation has been defined, and the effective reuse of the catalyst has been reported in the representative aldol addition of cyclohexanone with p‐nitrobenzaldehyde. This study has shown that these L‐proline immobilized catalytic systems can be used at least six times without loss of activity and with reproducible anti/syn and ee values.

ChemInform Abstract: Highly Enantioselective Construction of 3‐Hydroxy Oxindoles Through a Decarboxylative Aldol Addition of Trifluoromethyl α‐Fluorinated gem‐Diols to N‐Benzyl Isatins.

AbstractAn organocatalytic asymmetric direct aldol addition reaction of gem‐diols to isatins is developed.

Validity of Inorganic Nanosheets as an Efficient Planar Substituent To Enhance the Enantioselectivity of Transition‐Metal‐Catalyzed Asymmetric Synthesis

Effectively enhancing the enantioselectivity is a persistent challenge in heterogeneous asymmetric catalysis. Here, the validity of a layered double hydroxides (LDH) nanosheet as an efficient planar substituent to enhance the enantioselectivity has been investigated theoretically; first in vanadium-catalyzed asymmetric epoxidation of allylic alcohols, and then in zinc-catalyzed direct asymmetric aldol addition. The computational predication is further confirmed experimentally in zinc-catalyzed direct asymmetric aldol addition by controlling the location of catalytic sites.

ChemInform Abstract: Direct Asymmetric Aldol Addition—Isomerization of α,β‐Unsaturated γ‐Butyrolactam with Aryl α‐Ketoesters: Synthesis of MBH‐Type Products.

AbstractThe title reaction affords Morita—Baylis—Hillman type adducts containing a quaternary stereocenter in high yields and with excellent enantioselectivities.

Highly Enantioselective Construction of 3‐Hydroxy Oxindoles through a Decarboxylative Aldol Addition of Trifluoromethyl α‐Fluorinated gem‐Diols to N‐Benzyl Isatins

An organocatalytic asymmetric direct aldol addition reaction that involves cleavage of a carbon–carbon bond through the release of trifluoroacetate was developed. The protocol is wide in scope, generating the desired oxindoles of biological interest in nearly quantitative yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) and diastereoselectivities (up to 99:1 d.r.).

Recent Progress in the Chemistry of Mucohalic Acids: Versatile Building Blocks in Organic Synthesis

This account documents our recent progress in exposing some of the potential of mucohalic acids in synthetic applications. Understanding their stability and reactivity in different reaction media allows the development of mild and regioselective methods to access various substituted butenolides, butenolactams, and 4,5-di­halopyridazin-3(2H)-ones and to create other novel, multifunctionalized building blocks. 1 Introduction 2 The Rationale for the Reinvestigation of Mucohalic Acid Chemistry 3 Understanding the Stability of Mucohalic Acids 4 One-Pot Synthesis of a 4,5-Dihalopyridazin-3(2H)-one and the Process Chemistry of ABT-963 5 Reductive Amination of Mucochloric Acid and Synthesis of Antiseizure Drug Levetiracetam (Keppra) 6 Reduction of Mucohalic Acids and Synthesis of Anti-­inflammatory Agent Rofecoxib (Vioxx) 7 Lewis Acid Catalyzed Knoevenagel Aldol Reaction 8 Lewis and Bronsted Acid Promoted Friedel–Crafts ­Hydroxyalkylation 9 Lewis Acid Facilitated Mukaiyama Aldol Reaction 10 Indium-Mediated Allylation in Water 11 Palladium-Free Regioselective Etherification and Amination 12 Novel Building Blocks Derived from Mucohalic Acids 13 Direct Vinylogous Aldol Addition Using α,β-Dihalo-­Substituted Butenolides and Butenolactams 14 Other Applications 15 Summary and Conclusion

Direct asymmetric aldol addition–isomerization of α,β-unsaturated γ-butyrolactam with aryl α-ketoesters: synthesis of MBH-type products

A highly efficient direct asymmetric aldol addition-isomerization reaction at the α-position of α,β-unsaturated γ-butyrolactam and aryl α-ketoesters by using a bifunctional thiourea catalyst was achieved. Morita-Baylis-Hillman type adducts containing a quaternary stereocenter can be obtained in high yields and with excellent enantioselectivities (up to 99% ee).