Organocatalytic Aldol Reaction Research Articles

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.

Catalytic Diastereo- and Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols through a Vinylogous Aldol Reaction of Alkylidenepyrazolones with Trifluoromethyl Ketones.

A diastereo- and enantioselective organocatalytic aldol reaction between alkylidenepyrazolones and trifluoromethyl ketones leading to chiral tertiary alcohols bearing a trifluoromethyl group is presented. The methodology is based on the use of a bifunctional organocatalyst in order to activate the γ-hydrogen atoms of the alkylidenepyrazolone nucleophile and the carbonyl group of the trifluoromethylarylketone providing highly functionalized trifluoromethyl alcohols with moderate yields, excellent diastereoselectivity, and moderate to good enantioselectivity. Experiments monitoring the conversion by 1H NMR and the enantiomeric excess by HPLC with the reaction time showed that full conversion of the starting materials is not achieved and that the enantiomeric excess decreases upon extended times, probably due to the reversibility of the reaction.

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates.

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Combination of Asymmetric Organo‐ and Biocatalysis in Flow Processes and Comparison with their Analogous Batch Syntheses

AbstractA sequential‐type as well as a tandem‐type chemoenzymatic flow cascade combining an organocatalytic aldol reaction and a biocatalytic reduction to form stereoselectively a 1,3‐diol with two stereogenic centers were developed. Initially, a comprehensive screening of 24 alcohol dehydrogenases was carried out and the identified candidates were applied in different multi‐step flow cascades. All four stereoisomers of the desired 1,3‐diol product are accessible via a sequential flow approach with product formation‐related conversions of up to 76 % over two steps, isolated yields of up to 64 % and enantiomeric excess of >99 % in all cases. In addition, a tandem‐type flow process, performing both reaction steps simultaneously, was established leading to 51 % conversion with >99 % ee and 8 : 1 d.r. and representing a combination of the fields of asymmetric chemocatalysis, biocatalysis and flow chemistry.

Organo-catalysis as emerging tools in organic synthesis: aldol and Michael reactions

Abstract Organocatalysis has occupied sustainable position in organic synthesis as a powerful tool for the synthesis of enantiomeric-rich compounds with multiple stereogenic centers. Among the various organic molecules for organocatalysis, the formation of carbon–carbon is viewed as a challenging issue in organic synthesis. The asymmetric aldol and Michael addition reactions are the most significant methods for C–C bond forming reactions. These protocols deliver a valuable path to access chiral molecules, which are useful synthetic hybrids in biologically potent candidates and desirable versatile pharmaceutical intermediates. This work highlighted the impact of organocatalytic aldol and Michael addition reactions in abundant solvent media. It focused on the crucial methods to construct valuable molecules with high enantio- and diastereo-selectivity.

A Continuous‐Flow Route to Enantioenriched 3‐Substituted‐3‐Hydroxyoxindoles: Organocatalytic Aldol Reactions of Isatin with Acetone

AbstractAn efficient L‐leucinol catalysed asymmetric synthesis of 3‐substitued‐3‐hydroxyoxindoles was for the first time completed under continuous flow, providing a safer route for accelerating the reaction at higher temperatures without adversely affecting enantioselectivity. Initial batch solvent screening of the isatin‐acetone aldol reaction revealed neat acetone as the media best suited in flow as it dissolved isatin and afforded (S)‐enantiomer of the adduct in 84 % ee. Solvents with Kamlet‐Taft basicity (β)>0.6 and proticity (α)≈0 had a higher solubility of isatin but poor reaction performance while solvents with β<0.2 and α<0.6 performed excellently in the reaction albeit with poor isatin solubility. The addition of 10 equivalents of water improved the neat reaction to afford 94 % yield in 93 % ee at 20 °C after 48 h. When transferred to continuous flow, complete conversion was observed in 12 h residence time at 40 °C without loss in enantioselectivity. Further substrate studies in flow were undertaken with a 4‐fold dilution and a 60 °C reaction temperature required for some derivatives. Excellent yields and enantioselectivities were obtained in most cases.

Three-Pot Synthesis of Chiral Anti-1,3-diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Epoxidation and Reductive Opening of the Epoxide.

A three-pot asymmetric synthesis of the anti-1,3-diol unit was developed. In the first pot, enantioselective aldol reaction of aldehydes proceeds, catalyzed by organocatalyst, followed by either Wittig or Horner-Wadsworth-Emmons reactions to afford δ-hydroxy α,β-unsaturated carbonyls with excellent enantioselectivity. Diastereoselective hydroxy-directed anti-epoxidation proceeds in the next pot by the use of tert-BuOOH and LiHMDS. Reductive opening of the epoxide proceeds in a third pot to afford anti-β,δ-hydroxy carbonyl compounds with excellent diastereo- and enantioselectivity.

Combining Organocatalyzed Aldolization and Reductive Amination: An Efficient Reaction Sequence for the Synthesis of Iminosugars

AbstractOver the past two decades, organocatalytic aldol reaction emerged as a powerful method for the enantioselective carbon–carbon bond formation, often offering more efficient, economical and environmentally friendly synthesis of chiral molecules. On the other hand, reductive amination is one of the most important reactions in synthesis of biologically active compounds and drug candidates. Coupling these two reactions results in a powerful combination that allows for a rapid, stereoselective access to substituted, highly functionalized five‐ and six‐membered N‐heterocycles. This minireview illustrates the applicability of this approach as the key feature in syntheses of various iminosugars – a class of polyhydroxylated alkaloids with a range of interesting biological activities and high pharmacological potential.

Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence.

We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn:anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.

Use of organocatalysis for the synthesis of phenyl-hydroxylated-butyric acids

The 4-(p-nitro)-phenyl-hydroxylated-butyric acids 1 (2,3-anti-3,4-syn) and 2 (2,3-syn-3,4-syn) were synthesized from TBS-dihydroxyacetone (TBS-DHA) and p-nitrobenzaldehyde using an organocatalyzed aldol reaction as the key step. The stereoselectivity of the syn-aldol coupling was suggested as resulting from a transition state (TS) including a low energy anti-Z enamine, derived from the condensation of TBS-DHA and O-tBu-L-threonine. The Houk-List TS, which shows a hydrogen-aldehyde stabilizing interaction, furnished a syn-adduct as the major product in high yield and diastereo- and enantioselectivity. Selective anti- and syn-carbonyl reduction of the carbonyl adducts led to 2,3-anti-3,4-syn and 2,3-syn-3,4-syn hydroxy compounds, respectively, which underwent the same sequence of transformations (ketal synthesis, primary TBS-deprotection, oxidation and deprotection) to afford 4-(p-nitro)-phenyl-hydroxylated-butyric acids 1 and 2 in seven steps and 22% and 24% overall yield, respectively.

Total Synthesis of Thromboxane B2 via a Key Bicyclic Enal Intermediate.

A 12-step asymmetric synthesis of thromboxane B2 (TxB2) from 2,5-dimethoxytetrahydrofuran is described. The synthesis employs our organocatalytic aldol reaction of succinaldehyde to give a key bicyclic enal intermediate. From here, the synthetic strategy involves a conjugate addition of an alkenyl side chain to the bicyclic enal, Baeyer-Villiger oxidation, and a highly Z-selective Wittig olefination of a hemiacetal. Key to success was minimizing redox operations and the manipulation of functional groups in the correct order.

A Simple and Efficient Protocol for Proline-Catalysed Asymmetric Aldol Reaction

The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.

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.

An Asymmetric Organocatalytic Aldol Reaction of a Hydrophobic Aldehyde in Aqueous Medium Running in Flow Mode

Reaction conditions have been identified to conduct a one-pot asymmetric organocatalytic aldol reaction with a hydrophobic substrate in aqueous medium via a process running in flow mode. By employing a mixture of water and 2-propanol, a hydrophobic aldehyde and 3.6 mol% of an organocatalyst, this microreactor process affords the desired aldol adduct with a conversion of 74% and an enantioselectivity of 89% after a reaction time of 60 minutes.

Probing the gas-phase structure of charge-tagged intermediates of a proline catalyzed aldol reaction - vibrational spectroscopy distinguishes oxazolidinone from enamine species.

An l-proline based catalyst with a charged phenyl-pyridium substituent (1) was used to analyze intermediates of an organocatalyzed aldol reaction by infrared multi-photon dissociation (IRMPD) mass spectrometry after transfer into the gas phase via electrospray ionization (ESI). IRMPD spectra were interpreted with the aid of density functional theory (DFT) computations. A structurally restricted enamine species was used as a reference molecule for the calculated vibrational frequencies. A close correlation between theory and experiment was found for the energetically most favoured oxazolidinone structures.

Two-Pot Synthesis of Chiral 1,3-syn-Diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Domino Hemiacetal/Oxy-Michael Reactions.

A two-pot synthetic method to construct the chiral syn-1,3-diol unit has been developed from three aldehydes and either Wittig or Horner-Wadsworth-Emmons reagents. In the first pot, chiral δ-hydroxy α,β-unsaturated ketones are synthesized with excellent enantioselectivity by the organocatalyst-mediated asymmetric direct aldol reaction of two different aldehydes, followed by either Wittig or Horner-Wadsworth-Emmons reactions. In the second pot, domino acetalization with an aldehyde and subsequent oxy-Michael reaction proceeds in the presence of NaClO4 and a catalytic amount of Bi(OTf)3 (OTf=trifluoromethanesulfonate) to provide the chiral 1,3-syn-diol derivative with excellent diastereoselectivity. Diospongin C and yashabushidiol A have been synthesized efficiently by using the present method as a key step.

An expeditious route to the synthesis of the enantioenriched tetracyclic core of ergot alkaloids via an organocatalytic aldol reaction.

The synthesis of the tetracyclic skeleton of ergot alkaloids has been developed via a key organocatalytic enantioselective aldol reaction using paraformaldehyde as the C1-unit in the presence of thiourea catalyst followed by a key Pd-catalyzed directed coupling accelerated by the DavePhos ligand. Utilizing the aforementioned strategy, we have synthesized a key tetracyclic intermediate in up to 95% ee with high yield.

Benjamin List

Benjamin List

First Tandem‐Type One‐Pot Process Combining Asymmetric Organo‐ and Biocatalytic Reactions in Aqueous Media Exemplified for the Enantioselective and Diastereoselective Synthesis of 1,3‐Diols

A suitable “process window” was identified for the combination of an asymmetric organocatalytic aldol reaction and subsequent biocatalytic reduction in aqueous medium, which thus enabled the enantio‐ and diastereoselective synthesis of 1,3‐diols in a tandem‐type, one‐pot process. A key feature of this one‐pot synthesis is the high 500 mm loading of the aldehyde substrate used as a starting material.

Automated reaction progress monitoring of heterogeneous reactions: crystallization-induced stereoselectivity in amine-catalyzed aldol reactions

A prototype solution/slurry automated sampling instrument reveals the origin of diastereoselectivity in this organocatalyzed aldol reaction.