Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

Abstract

N-Tosyl-(S_a)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in high levels of diastereo- and enantioselectivities achieving mainly anti aldol products.

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Solvents play a major role, making up generally the major source of the waste mass in any chemical process. Actually, the use of solvent accounts for more than 80% of the mass of any pharmaceutical batch processes, consuming about 60% of the overall energy used and accounting for 50% of the post treatment green house gas emissions.¹ Therefore, the appropriate solvent selection is a definitive factor in order to increase the greenness of a given process,² with the best option being the use of one of the reactants as the solvent (neat conditions) or the total absence of them (solvent-free conditions). However, this becomes difficult when labile reactants are used. This is the case for glyoxylic acid and glyoxylates, which are prone to suffer a facile hydration and polymerization processes. In fact, glyoxylic acid is commercially available as a monohydrate form or as a 50% aqueous solution due to its intrinsic instability. Although its aldol reaction with a carbonylic compound can lead to a direct entry to secondary α-hydroxycarboxylic acids, which are important intermediates for the synthesis of relevant and bioactive molecules,³ its use as an electrophile in this reaction has been scarcely reported. Only a few reports dealing with the use of glyoxylic acid monohydrate as an electrophile in a direct aldol reaction with ketones mediated by InCl₃ are found to afford racemic adducts.⁴

On the other hand, the use of asymmetric organocatalyzed methodologies has provided the chemical community with a powerful tool for the enantioselective synthesis of valuable chiral compounds,⁵ with the growth of this research area being closely related to the development of the direct aldol reaction using simple chiral organic molecules.⁶ Although the use of some substrates in this type of transformation remain a challenge,⁷ the use of the enamine catalyzed processes has allowed the synthesis of highly functionalized carbonyl compounds that are useful building blocks for the synthesis of natural products.⁸ However, these amine type catalysts typically require the use of an excess of reacting ketone or polar organic solvent as reaction media, with several derivatives leading to good results using water as the solvent.⁹ Some of these privileged organocatalysts are prolinamides derived from 1,1′-binaphthyl-2,2′-diamine (binam) 1¹⁰ and 2¹¹ (Fig. 1), which led to excellent results in the inter- and intramolecular aldol reactions under several reaction conditions, including aqueous^9b,e,f and solvent-free conditions.^10g,h,11,12

Fig. 1 Binam-prolinamide derivatives that have been used as catalysts in the aldol reaction.

We envisaged that this type of organocatalyst would be efficient in an asymmetric aldol reaction using challenging electrophiles such as glyoxylic acid, in its two commercially available forms, monohydrate and 50% aqueous solution, in order to prepare enantioenriched α-hydroxy-γ-keto carboxylic acids.

First, optimization of the reaction parameters was carried out in the reaction between cyclohexanone (3a) and glyoxylic acid (4), in both forms, as monohydrate (MH) and as 50% aqueous solution (AQ). The performance of the two different binam-prolinamide derivatives 1 and 2 and the influence of the stereochemical axis in the stereochemical outcome of the reaction was evaluated using glyoxylic acid monohydrate under solvent-free conditions or 50% aqueous solution at room temperature (Table 1 and Scheme 1). In order to determine the enantiomeric excess, the α-hydroxy glyoxylic acid product 5a was converted in situ into the corresponding methyl ester derivative 6a, by further treatment with Me₃SiCHN₂. The results achieved with catalyst 1 were slightly lower in terms of enantioselectivities than those achieved with catalyst 2. For this process, the chirality of the achieved aldol product was controlled by the chirality of the proline, affording compound 6a using catalysts 1a and 2a,¹³ and by using catalysts 1b and 2b, its enantiomer (ent-6a). Meanwhile, the influence of the stereochemical axis in the stereochemical outcome of the products was practically negligible, in contrast to what happens in the intermolecular aldol reaction between ketones and aromatic aldehydes using these catalysts under similar reaction conditions.^10h,i,11a Generally, the diastereoselectivities obtained with the glyoxylic acid in aqueous solution were higher than using the glyoxylic acid as monohydrate (Table 1, entries 1–8). Under these later conditions, the reaction catalyzed by the ent-2b, led, as expected, to product 6a with similar results to those achieved using catalyst 2b (Table 1, entry 9). Anyhow, both catalysts 1 and 2 were superior in terms of yields, diastereo- and enantioselectivities to those results obtained with L-proline (Table 1, entry 10 and 11). The optimization of the rest of the reaction parameters such as temperature, effect of the additives, catalyst loading and amount of nucleophile were done with catalyst 2a and both glyoxylic acid sources. Thus, decreasing the temperature to 0 °C, better results in terms of yields, diastereo- and enantioselectivities were achieved with both catalysts and glyoxylic acid sources (Table 1, compare entries 12 and 13 with 5 and 6, respectively). When, glyoxylic acid was used as monohydrate, the effect of the addition of a small amount of water (10 equiv.) in order to accelerate the reaction was evaluated,¹⁴ leading to a better enantioselectivity (Table 1, entry 14) in a shorter reaction time.

Table 1 Optimization of reaction conditions between cyclohexanone (3a) and glyoxylic acid (4)^a

Entry	Cat. (mol%)	T (°C)	4^b	t (h)	Conv.^c	Yield^d (%)	Anti/syn^e	ee^f (%)
a Reaction conditions: 3a (5 equiv.), 4 (0.25 mmol), unless otherwise stated.b MH: glyoxylic acid monohydrate; AQ: 50% aqueous solution of glyoxylic acid.c Conversion based on the unreacted aldehyde.d For the methyl ester 6a after purification by column chromatography.e Determined by ^1H NMR of the crude product.f Determined by chiral-phase HPLC analysis of the anti isomer of the corresponding methyl ester 6a.g The product achieved was ent-6a.h 10 equiv. of H2O were added to the reaction mixture.i 2 equiv. of ketone 3a were used.
1	1a (10)	25	MH	6	100	—	74/26	81
2	1a (10)	25	AQ	5	100	—	85/15	89
3	1b (10)	25	MH	6	100	76	79/21	83^g
4	1b (10)	25	AQ	5	100	51	83/17	83^g
5	2a (10)	25	MH	6	100	46	78/22	91
6	2a (10)	25	AQ	6	100	42	78/22	95
7	2b (10)	25	MH	6	100	—	81/19	92^g
8	2b (10)	25	AQ	6	100	—	84/16	84^g
9	ent-2b (10)	25	AQ	6	100	46	85/15	83
10	L-Pro	25	MH	72	60	21	60/40	29
11	L-Pro	25	AQ	72	70	18	55/45	24
12	2a (10)	0	MH	7	100	79	92/8	94
13	2a (10)	0	AQ	7	100	79	92/8	94
14	2a (10)^h	0	MH	5	100	76	96/4	97
15	2a (10)^h^,^i	0	MH	6	100	78	95/5	97
16	2a (10)^i	0	AQ	6	100	—	92/8	94

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Scheme 1 Aldol reaction of glyoxylic acid with ketones catalyzed by binam prolinamides.

Finally, using this catalyst 2a, the effect of the reduction of the amount of ketone to 2 equiv. in the reaction with either monohydrated or 50% aqueous solution glyoxylic acid was tested. In both cases, the obtained results were similar to those encountered using 5 equiv. of nucleophile (Table 1, compare entries 13 with 16, and 14 with 15).

Under the best reaction conditions and using both glyoxylic acid sources, the scope of the reaction was studied (Scheme 1, Table 2). In all cases, with the exception of cyclopentanone and 1,4-cyclohexanedione (Table 2, entries 3 and 4, 9 and 10, respectively) that gave poor diastereoselectivity and moderate enantioselectivity, the major isomer achieved was the anti isomer 6, even using unsymmetrical ketones such as 2-butanone (Table 2, entries 17 and 18). Only product 6h achieved by the reaction with acetone was obtained with low enantioselectivity (Table 2, entries 15 and 16). It seems that the achieved enantioselectivities are related to the steric hindrance of the nucleophilic ketones. Comparing the results obtained using glyoxylic acid in aqueous solution with those achieved using glyoxylic acid as monohydrate, generally, the later led to better diastereo- and enantioselectivities.

Table 2 Aldol reaction of glyoxylic acid with ketones^a

Entry	Major product	Yield^b (%)	4^c	Dr^d	ee^e (%)
a Reactions conditions: glyoxylic acid monohydrate (0.25 mmol, MH) and 10 equiv. of H2O or 50% aqueous solution of glyoxylic acid (0.25 mmol; AQ), ketone (2 equiv.), catalyst 2a (10 mol%) at 0 °C.b For methyl ester 6 after purification by column chromatography. In parenthesis, yields for the corresponding acid 5.c MH: glyoxylic acid monohydrate; AQ: 50% aqueous solution of glyoxylic acid.d Determined by ^1H NMR of the crude product.e Determined by chiral-phase HPLC analysis of the anti isomer of the corresponding methyl ester 6.f In parenthesis, results achieved for the corresponding product 5.
1^f		78 (71)	MH	95 : 5 (93:7)	97 (97)
2		79	AQ	93 : 7	94
3		84	MH	47 : 53	64
4		77	AQ	43 : 57	80
5		86	MH	89 : 11	86
6		76	AQ	84 : 16	84
7		53	MH	93 : 7	91
8		49	AQ	93 : 7	90
9		70	MH	40 : 60	71
10		64	AQ	49 : 51	51
11^f		46 (26)	MH	94 : 6 (89 : 11)	97 (97)
12		35	AQ	90 : 10	86
13		32	MH	76 : 24	80
14		35	AQ	68 : 32	62
15^f		69 (30)	MH	—	50 (50)
16		64	AQ		33
17		22	MH	90 : 10	80
18		17	AQ	76 : 24	63
19		80	MH	84 : 12 : 2 : 2	95
20		90	AQ	76 : 15 : 5 : 4	91

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Several products were isolated as α-hydroxy-γ-keto acids 5. Products 5 were soluble either in organic solvent or water and were prone to dehydration during purification with silica-gel. Thus, in order to isolate products 5, as pure compounds, a small amount of ethyl acetate was added to the reaction. This organic layer was thoroughly washed with water in order to displace the product to the aqueous layer. Then, the water was removed and 1,4-dioxane was added to precipitate the glyoxylic acid, leaving the pure products 5 soluble in dioxane. Following this procedure, compounds 5a, 5f and 5h were isolated in moderate yields, with slightly lower diastereoselectivities than the corresponding methyl ester 6 and with the same enantioselectivities (Table 2, entries 1, 12 and 16). In the case of using 4-methylcyclohexanone as the nucleophile, the major diastereoisomer formed (based on NOESY experiments) was the expected anti,anti-aldol with high enantioselectivity (Table 2, entries 19–20). Attempts to extend the reaction to other α-functionalized ketones such as α-alkoxy ketones,^10h α,β-unsaturated ketones such as tetralone,¹⁵ or aliphatic aldehydes failed.

Conclusions

We have demonstrated that glyoxylic acid can be used as the electrophile in aqueous organocatalyzed aldol reactions catalyzed by N-tosyl-binam-prolinamide. This chiral organocatalyst gave better results than L-proline in the synthesis of enantioenriched α-hydroxy-γ-keto carboxylic esters. For cyclic ketones, mainly anti-isomers were obtained as the major products in moderate to high enantioselectivities (up to 97%). The enantioenriched α-hydroxy-γ-keto acids can be isolated by aqueous extraction, without compromising the achieved enantioselectivities.

Acknowledgements

This work was financially supported by the Ministerio de Economia y Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider INGENIO CSD2007-0006), the Generalitat Valenciana Prometeo/2009/039, the University of Alicante and the EU (ORCA action CM0905). We thank to Rosa M. Ortiz for the synthesis of both enantiomers of [1,1′-binaphthalene]-2,2′-diamine.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, HPLC charts and NMR spectra of all compounds. See DOI: 10.1039/c3ra46800c

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