Novel L -threonine-based ionic liquid supported organocatalyst for asymmetric syn -aldol reactions: activity and recyclability design

A novel recyclable threonine-derived ionic-liquid-supported organocatalyst of asymmetric cross-aldol reactions has been developed. In its presence, aromatic aldehydes react with hydroxyacetone, methoxy-acetone and 2-butanone to afford the corresponding syn -aldol products in moderate to high yields with excellent diastereo-( syn / anti up to 96:4) and enantio-selectivity (up to 95 % ee ), which was retained over five recycling experiments.


Introduction
2][3] One of the most important organocatalytic reactions is the asymmetric aldol reaction, which occur in Nature and is widely used in chemical research for enantioselective formation of the carbon-carbon bonds in organic compounds. 49] Some of these native catalysts (aldolases of type II) have a peptide structure with primary amino acid fragments as active sites. 10Over the past decade, a number of similar syn-aldol reactions have been realized in laboratory (though, with a somewhat lower stereoselectivity) in the presence of properly designed primary aminocatalysts.Among them, O-protected serine or threonine amino acids, [11][12][13][14][15][16] their amides, 17 valine, 18 leucine, 19 iso-leucine 20 or tert-leucine derivatives 21 and some primary-tertiary 1,2-diamine organocatalysts [22][23][24][25][26][27] exhibited promising catalytic performance.However, unlike enzymes, these valuable catalysts could be used just once and until recently no information on their recovery and reuse in the catalytic process has been available.
A few years ago we presented the first "conditionally" recyclable catalyst 1a of syn-aldol reactions, an ionic-liquid-supported (S)-threonine amide bearing an α,α-diphenylvalinol structural unit (Scheme 1). 28nfortunately, the catalytic activity of compound 1a became lower after the first recovery and after the third one it became nearly inactive.Very recently, we discovered that main reason for this deactivation is the undesirable intramolecular O-N migration of the acyl fragment attached to ionic group which resulted in the amidation of the primary amino group which is key for the enamine catalysis. 29To make the migration thermodynamically unfavorable, we designed catalyst 1b, in which the acyl linker is located distantly from the amino group.Indeed, catalyst 1b appeared much more sustainable and could be recycled 7 times with complete retention of stereoselectivity and only a slight conversion decrease.Scheme 1. Research strategy.
We hypothesized that the parasitic rearrangement may also be suppressed by a Brønsted-acidic group, which being incorporated into the catalyst would reduce nucleophilicity of the threonine amino group via the protonation.Furthermore, we expected that a remote carboxyl group in catalyst 1c would simultaneously act as an acidic co-catalyst and reduce catalyst leaching during workup.A number of catalytic aldol reactions are known to proceed with a higher rate and better enantioselectivity in the presence of acidic additives. 5A few examples of favorable impact of the incorporated carboxy group on the catalytic performance and recyclability of ionic-liquid-supported primary-amine-based chiral organocatalysts in asymmetric Michael 30 and anti-aldol reactions 31 have also been reported.However, to the best of our knowledge, this approach has never been used to improve the catalytic performance of primary amino acid-derived supported organocatalysts in asymmetric syn-aldol reactions.

Results and Discussion
To verify this hypothesis, we synthesized the carboxylated analog 1c, in which the imidazolium cation is attached to a carboxylic group.The synthetic scheme included alkylation of O-protected 1-(4benzyloxycarboxybutyl)-imidazole 3 with bromoester 2 followed by the conversion of the imidazolium bromide 4 into the carboxylated IL-supported catalyst 1c via a sequence of anion exchange and catalytic hydrogenation (5% Pd/C) reactions (Scheme 2).

Scheme 2. Synthesis of carboxylated catalyst 1c.
Having catalyst 1c in hand, we at first optimized reaction conditions using hydroxyacetone 5a and 4-nitrobenzaldehyde 6a as model substrates (Table 1).It was found that in nonpolar aprotic solvent (e.g.toluene) product 7a was generated with higher selectivity and conversion of 6a than in other solvents.
Under optimal conditions, hydroxyacetone (5a) reacted with benzaldehyde derivatives (6a-i) bearing acceptor or donor substituents in the aromatic ring to afford corresponding syn-aldols 7a-i with high conversion and with good to excellent diastereo-and enantio-selectivity (for compounds 7a-h, the dr and ee values were similar or even higher that reported with catalyst 1a 28 ) (Scheme 3).The methoxyacetone (5b) also appeared a suitable ketone-donor for the catalytic syn-aldol reactions with aldehydes 6a and 6d to give corresponding aldols 7j and 7k with reasonably high diastereo-and enantio-selectively.In case of 2-butanone (5c) the conversion and dr and ee values of generated aldol 7l were significantly lower.

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It is worthy of note that the previously unknown compound 7i is a close structural analog of flavanonolan inhibitor of nitric oxide (NO) production in inflammatory cells (Figure 1). 32Finally, we examined the recyclability of catalyst 1c in the asymmetric syn-aldol reaction between compounds 5a and 6d (Table 2).After completion of the reaction, the solvent was evaporated under reduced pressure, aldol product 7d was extracted with Et 2 O, and a fresh solution of the starting compounds in toluene was added to the remaining catalyst.In this manner, catalyst 1c was successfully recycled five times without any reduction of the dr and ee values, though, with a slight conversion decrease.These data are in agreement with a favorable impact of the carboxy group in catalyst 1c on its sustainability and recyclability under proposed conditions as compared with catalyst 1a.

Conclusions
The obtained results show that simple modification with the carboxylic group may be considered as a promising approach to improve sustainability of IL-supported primary amino acid derived organocatalysts in asymmetric syn-aldol reactions.Based on this approach, a novel carboxylated threonine amide derived ILtagged catalyst of asymmetric aldol reactions between aromatic aldehydes and linear ketones has been ARKAT USA, Inc developed which exhibited improved catalytic activity and good diastereo-(syn/anti up to 96/4) and enantioselectivity (up to 95% ee) over five recycling experiments.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded with a Bruker AM 300 spectrometer in CDCl 3 and DMSO-d 6 .
The chemical shifts of 1 H and 13 C signals were measured relative to Me 4 Si or CDCl 3 , respectively.The highresolution mass spectra (HRMS) were measured with a Bruker microTOF II spectrometer using electrospray ionization (ESI).The measurements were taken either in the positive ion mode (interface capillary voltage 4500 V) or in the negative ion mode (3200 V) in a mass range m/z = 50-3000 Da; external or internal calibration was done with electrospray calibrant solution (Fluka).Syringe injection was used for solution in MeCN/H 2 O (1:1, v/v) (flow rate 3 μL/min).Nitrogen was applied as a dry gas, and the interface temperature was set at 180 °C.Silica gel 0.060-0.200µm (Acros) was used for column chromatography.Threonineamide (2) and benzyl 5-(1H-imidazol-1-yl)pentanoate (3) were synthesized according to known methods.Compounds 5 and 6 were purchased from Aldrich and used without purification.The solvents were purified by standard procedures.For experimental details and spectral or HPLC data see Supporting Information.

Table 1 .
Optimization of reaction conditions a c HPLC data (Daicel Chiralpak AD-H) for crude compound 7a.d Corresponding data for catalyst 1a are given in parentheses.Scheme 3. The reaction scope.