Direct Catalytic Asymmetric Aldol Reactions Assisted by Zinc Complex in the Presence of Water

A combination of zinc triflate and chiral C₂‐symmetrical prolinamide ligand leads to high enantioselectivities in direct aldol reactions essentially assisted by water. The presence of 5 mol % of the catalyst affords an asymmetric intermolecular aldol reaction between unmodified ketones and aldehydes to give anti‐products with excellent enantioselectivities ranging from 86–98 % ee. The same bis(prolinamide) ligand is found to catalyze the direct aldol reactions in the presence of water (or in water) with excellent stereocontrol and furnish the corresponding aldols in up to 99 % ee. For the demonstrated catalytic systems organic solvent‐free conditions are applied.     

4,4′‐Disubstituted L‐Prolines as Highly Enantioselective Catalysts for Direct Aldol Reactions

A new series of 4,4′‐disubstituted prolines ( 1a–h ) has been developed and tested as organocatalysts in the direct catalytic asymmetric aldol reaction of several aliphatic ketones with aldehydes. Catalyst 1g affords the best enantioselectivities for this transformation. The reaction was carried out in DMF using a catalyst loading of 10 mol % at −10 °C to give the aldol products in up to 97 % ee for acetone. In the cases of cyclohexanone and cyclopentanone, the corresponding anti‐products were obtained in 94 % ee.     

Organocatalytic Asymmetric syn‐Aldol Reactions of Aldehydes with Long‐Chain Aliphatic Ketones on Water and with Dihydroxyacetone in Organic Solvents

An on‐water, asymmetric, and direct syn‐aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by a primary amino acid‐based organocatalyst afforded the syn‐aldol adducts in high yields with excellent diastereo‐ and enantioselectivities (up to > 20/1 dr, >99% ee), and a highly enantioselective syn‐aldol reaction of dihydroxyacetone with a variety of aldehydes in THF proceeded with 14/1 to >20/1 dr and 92 to >99% ee. Water not only accelerated the reaction, but also enhanced the enantioselectivity. This positive water effect might arise from the hydrogen bond formed between a pendant hydroxy group of surface water molecules at the hydrophobic interface with the amide oxygen of the organocatalyst, which increases the acidity of the amide NH and thereby strengthens the related hydrogen bond formed with the aldehyde.     

A 100 Gram‐Scale Production of a Key Building Block of Antibacterial Vancomycin: The Use of an Air‐Stable Chiral Zirconium Catalyst and Complete Recovery of a Silicon Source in Catalytic Asymmetric Mukaiyama Aldol Reaction

We have achieved a 100 gram‐scale production of anti‐(2S,3S)‐β‐(p‐benzyloxy‐m‐chloro)phenyl‐N‐trifluoroacetyl‐L ‐serine methyl ester ( 1 ) in high yield with high diastereo‐ and enantioselectivities based on a catalytic asymmetric Mukaiyama aldol reaction. The use of an air‐stable zirconium‐molecular sieves combined catalyst [(R)‐I₄‐ZrMS] facilitates easy manufacturing operation and reproducibility. Moreover, this is the first example of the complete recovery of the silicon source in a Mukaiyama aldol reaction.     

Stereoselective Lewis Base‐Catalyzed Asymmetric Hydrosilylation of α‐Acetamido‐β‐enamino Esters: Straightforward Approach for the Construction of α,β‐Diamino Acid Derivatives

The Lewis base‐organocatalyzed asymmetric hydrosilylation of α‐acetamido‐β‐enamino esters was investigated. Among various chiral Lewis base catalysts, a novel catalyst derived from L ‐serine was found to be the most efficient one which can promote the reaction to afford a series of α,β‐diamino acid derivatives with high yields (up to 99%), excellent enantioselectivities (up to 98% ee) and moderate diastereoselectivities (up to 80:20 dr). The absolute configuration of one of the products was determined by the X‐ray crystallographic analysis. In addition, the mechanism and the transition state of the reaction were proposed.     

Copper Complex of Aminoisoborneol Schiff Base Cu2(SBAIB‐d)2: An Efficient Catalyst for Direct Catalytic Asymmetric Nitroaldol (Henry) Reaction

A new bifunctional copper complex of the aminoisoborneol Schiff base – Cu₂(SBAIB‐d)₂ – has been developed for the effective direct catalytic asymmetric Henry reaction. One mol% of this catalyst produces the expected Henry products in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The utility of the present catalyst was also extended to the Henry reaction with nitroethane and 1‐nitropropane that furnished the corresponding products in moderate to high yields (up to 99%) with moderate to high enantioselectivities of syn (up to 98% ee) and anti (up to 98% ee) diastereomers. The highlights of this catalytic system are easy manipulation, air and moisture tolerance, the need for 1 mol% of an easily synthesizable catalyst and the high enantioselectivities achieved for a wide range of substrates.     

An Enantioselective Recyclable Polystyrene‐Supported Threonine‐Derived Organocatalyst for Aldol Reactions

A series of primary amino acids covalently supported onto polystyrene through alkyne–azide cycloaddition reactions has been synthesized and evaluated as catalysts in asymmetric aldol reactions. A polymer‐supported threonine behaves as an easily recyclable, highly reactive and stereoselective (up to 99% ee) catalyst in the aldol reaction of both cyclic and acyclic ketone donors with aromatic aldehydes in aqueous environments. While cyclic ketones react with anti diastereoselectivity, syn adducts are predominantly obtained with acyclic substrates. The heterogenized threonine catalyst has been used for the sequential synthesis of a small library of enantiopure aldol products.

     

A Novel Enantioselective Catalytic Tandem Oxa‐Michael–Henry Reaction: One‐Pot Organocatalytic Asymmetric Synthesis of 3‐Nitro‐2H‐chromenes

An enantioselective oxa‐Michael–Henry reaction of substituted salicylaldehydes with nitroolefins that proceeds though an aromatic iminium activation (AIA) has been developed by using a chiral secondary amine organocatalyst and salicylic acid as a co‐catalyst. The corresponding 3‐nitro‐2H‐chromenes were obtained in moderate‐to‐good yields with up to 91% ee under mild conditions. Based on the experimental results and ESI‐mass spectrometric detection of the intermediates, a plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.     

Doubly Stereocontrolled Asymmetric Aza‐Henry Reaction with in situ Generation of N‐Boc‐Imines Catalyzed by Novel Rosin‐Derived Amine Thiourea Catalysts

The doubly stereocontrolled organocatalytic aza‐Henry reaction of nitroalkanes to N‐Boc‐imines generated in situ from a variety of substituted α‐amido sulfones was investigated for the first time, in general, affording the corresponding products with high to excellent yields (up to 93% yield) and enantioselectivities (up to 98% ee), and satisfactory diastereoselectivies (anti/syn up to 98:2). Furthermore, these organocatalysts based on rosin have been proved to be the very effective promoters for this catalytic asymmetric process along side the Cinchona alkaloid‐derived catalysts.     

Polyvinylidene chloride supported L‐prolineamide as recoverable catalyst for asymmetric aldol reaction between ketone and aromatic aldehyde

A series of prolineamide modified by polyvinylidene chloride (PVDC) was synthesized and used as green recoverable organocatalysts for the asymmetric Aldol reactions between various ketones and aromatic aldehydes. The effects of solvent and catalyst dosage on the catalytic performances of as‐synthesized organocatalysts were investigated. It was found that as‐synthesized PVDC‐supported L ‐prolineamides possessed good catalytic performance for the asymmetric Aldol reactions between cyclohexanone and a variety of aromatic aldehydes, affording high yields of up to 99%, excellent diastereoselectivities of up to above 8 : 92 d.r. value, and high enantioselectivities of up to above 92.3% e.e. value. In general, the catalytic performance of as‐synthesized organocatalysts closely depended on the catalyst dosage and solvent type as well. Particularly, as‐synthesized organocatalyst 1c, at a dosage of 5 mol % in 10 μL of water, exhibited high catalytic activity and stereoselectivity for the asymmetric Aldol reaction between cyclohexanone and p‐nitrobenzaldehyde at room temperature. In the meantime, it could be easily recovered and recycled, while the activity and enantioselectivity were nearly completely retained even after five cycles of recovery, showing promising application as an efficient green organocatalyst for the aforementioned asymmetric Aldol reactions. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2‐Symmetrical Bisprolinamide Organocatalyst

A novel C₂‐symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (1–2.5 mol%) without the required use of additives, co‐catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to >99/1, anti/syn; ee range 33% to >99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra‐low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.     

Structure‐Reactivity Studies of Simple 4‐Hydroxyprolinamide Organocatalysts in the Asymmetric Michael Addition Reaction of Aldehydes to Nitroolefins

A series of simple 4‐hydroxyprolinamides was synthesised and they were found to act as organocatalysts for the asymmetric conjugate addition of aldehydes to nitroolefins in excellent yields (98%), with complete diastereoselectivity (99:1, syn:anti) and enantioselectivity (98% ee for syn). Furthermore, the use of low catalyst loadings (5 mol%) and a low aldehyde molar excess (1.5 equivalents) were achieved.     

Organocatalytic Asymmetric Michael Addition/Carbon‐Carbon Bond Cleavage of Trifluoromethyl α‐Fluorinated gem‐Diols to Nitroolefins

A new organocatalytic asymmetric Michael addition reaction by cleavage of carbon‐carbon bonds through a mild release of trifluoroacetate has been developed. The reported method generates the decarboxylated γ‐nitro‐α‐fluorocarbonyl products with excellent enantioselectivies (up to 98% ee) and good diastereoselectivies (up to 20:1 dr).     

Highly Efficient Ion‐Tagged Catalyst for the Enantioselective Michael Addition of Aldehydes to Nitroalkenes

The ion‐tagged diphenylprolinol silyl ether 6 very efficiently catalyzes the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes with ee of up to>99.5% at low catalyst loadings (0.25–5 mol%) and using only a slight excess of aldehydes (1.2–2 equiv.). This new organocatalyst can be used with the same outstanding efficiency in a wide variety of solvents and reaction conditions.     

Asymmetric Organocatalytic Cascade Michael/Hemiketalization/Retro‐Aldol Reaction of 2‐[(E)‐2‐Nitrovinyl]phenols with 2,4‐Dioxo‐4‐arylbutanoates: A Convenient Access to Chiral α‐Keto Esters

An unprecedented organocatalytic enantioselective cascade Michael/hemiketalization/retro‐aldol reaction of 2‐[(E)‐2‐nitrovinyl]phenols and 2,4‐dioxo‐4‐arylbutanoates is described. With a bifunctional squaramide catalyst incorporating (1R,2R)‐1,2‐diphenylethane‐1,2‐diamine, the reactions afford products in 75–99% yields with 80–98% ee. This process provides an enantioselective pathway for the synthesis of chiral α‐keto esters, precursors of 3‐arylproline derivatives, δ‐amino α‐keto acids or cyclic α‐keto lactams.

     

Asymmetric Synthesis of the Roche Ester and its Derivatives by Rhodium‐INDOLPHOS‐Catalyzed Hydrogenation

(S)‐3‐Hydroxy‐2‐methylpropionate, known as the Roche ester, and several of its derivatives were successfully synthesized through asymmetric rhodium‐catalyzed hydrogenation, using INDOLPHOS (diisopropyl{1‐[(S)‐3,5‐dioxa‐4‐phosphacyclohepta[2,1‐a;3,4‐a′]dinaphthalen‐4‐yl]‐3‐methyl‐2‐indolyl}phosphine) as the chiral ligand, in excellent yield and the highest ee reported up to now (TOF over 5500 h⁻¹ at 25 °C; up to 98% ee at −40 °C).     

Asymmetric Synthesis of Spirocyclic Oxindole‐Fused Tetrahydrothiophenes via N,N′‐Dioxide–Nickel(II) Catalyzed Domino Reaction of 1,4‐Dithiane‐2,5‐diol with 3‐Alkenyloxindoles

A highly efficient chiral N,N′‐dioxide–nickel(II) complex system has been developed to catalyze the domino thia‐Michael/aldol reaction of 1,4‐dithiane‐2,5‐diol with 3‐alkenyloxindoles. A series of the desired spirocyclic oxindole‐fused tetrahydrothiophenes was obtained in good yields with excellent ee and dr (up to 97% yield, 98% ee, >19:1 dr). Besides, based on the X‐ray crystal structure of the catalyst as well as the absolute configuration of the product, a catalytic model was proposed to explain the stereocontrol process.

     

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

A series of novel L ‐proline derived thioamides has been synthesised. They have been evaluated as organocatalysts in the direct asymmetric aldol reaction for the first time. Thioamides exhibit catalytic ability higher than proline itself and the model aldol reaction of 4‐cyanobenzaldehyde with acetone proceeds well in the presence of 5 mol % of catalyst (ee up to 100%). Other aromatic aldehydes gave aldol products with high ees and moderate yields. Small changes in the catalyst's structure [e.g., N‐Bn versus N‐CH(CH₃)Ph] as well as the addition of an acid have a profound effect on their activity. The unexpected formation of the catalyst‐derived cyclic adducts was observed and their reactivity was established giving valuable insight into the course of the reaction.     

Asymmetric Synthesis of Optically Pure Pharmacologically Relevant Amines Employing ω‐Transaminases

Various ω‐transaminases were tested for the synthesis of enantiomerically pure amines from the corresponding ketones employing D ‐ or L ‐alanine as amino donor and lactate dehydrogenase to remove the side‐product pyruvate to shift the unfavourable reaction equilibrium to the product side. Both enantiomers, (R)‐ and (S)‐amines, could be prepared with up to 99% ee and >99% conversions within 24 h at 50 mM substrate concentration. The activity and stereoselectivity of the amination reaction depended on the ω‐transaminase and substrate employed; furthermore the co‐solvent significantly influenced both the stereoselectivity and activity of the transaminases. Best results were obtained by employing ATA‐117 to obtain the (R)‐enantiomer and ATA‐113 or ATA‐103 to access the (S)‐enantiomer with 15% v v⁻¹ DMSO.     

One‐Pot Conversion of L‐Threonine into L‐Homoalanine: Biocatalytic Production of an Unnatural Amino Acid from a Natural One

A novel biocatalytic process for production of L ‐homoalanine from L ‐threonine has been developed using coupled enzyme reactions consisting of a threonine deaminase (TD) and an ω‐transaminase (ω‐TA). TD catalyzes the dehydration/deamination of L ‐threonine, leading to the generation of 2‐oxobutyrate which is asymmetrically converted to L ‐homoalanine via transamination with benzylamine executed by ω‐TA. To make up the coupled reaction system, we cloned and overexpressed a TD from Escherichia coli and an (S)‐specific ω‐TA from Paracoccus denitrificans. In the coupled reactions, L ‐threonine serves as a precursor of 2‐oxobutyrate for the ω‐TA reaction, eliminating the need for employing the expensive oxo acid as a starting reactant. In contrast to α‐transaminase reactions in which use of amino acids as an exclusive amino donor limits complete conversion, amines are exploited in the ω‐TA reaction and thus maximum conversion could reach 100%. The ω‐TA‐only reaction with 10 mM 2‐oxobutyrate and 20 mM benzylamine resulted in 94% yield of optically pure L ‐homoalanine (ee>99%). However, the ω‐TA‐only reaction did not produce any detectable amount of L ‐homoalanine from 10 mM L ‐threonine and 20 mM benzylamine, whereas the ω‐TA reaction coupled with TD led to 91% conversion of L ‐threonine to L ‐homoalanine.