L-proline/cholesterol and diosgenin based thiourea cooperative system for the direct asymmetric aldol reaction in the presence of water

A series of cholesterol and based hydrophobic urea and thiourea compounds were synthesized and successfully used as a cocatalyst for ﻿L-proline catalyzed aldol reactions in the presence of water. The anticonfigured products were obtained with good yields (up to 94%), high diastereoselectivities (up to 95:5), and high enantiomeric excesses (up to 93% ee ). ﻿The successful results for catalytic efficiency of L-proline in the presence of water reveal the importance of the hydrophobic nature of cholesterol and diosgenin parts of thiourea on the reactivity and selectivity in the presence of water.

amphiphilic structures of cholesterol and diosgenin molecules, it is surprising that their use as a hydrophobic part of water-compatible organocatalysts has only received limited attention [33].
We are still keenly interested in improving the efficiency of L-proline catalyzed aldol reactions in water. Previously, we have successfully established that calixarene-linked thiourea was an effective cocatalyst for the highly stereoselective intermolecular aldol reaction in the presence of water [15]. The results clearly confirmed that the hydrophobic calix [4]arene part of thiourea has a positive effect on both reactivity and stereoselectivity. Since the development of suitable cocatalysts that form assemblies with proline, direct aldol reactions in the presence of water are still desirable; herein we turned our attention to the synthesis of new thiourea and urea derivatives bearing cholesterol and diosgenin moieties as hydrophobic motifs. The aim of this study was to develop a small cocatalyst library of cholesterol and diosgenin based (thio)ureas which can self-assemble with L-proline to catalyze the asymmetric aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water.

Results and discussion
The synthetic route to a series of thiourea catalysts is illustrated in Scheme 1. Carbamate derivatives 4a and 4b were synthesized according to a published procedure [33,34]. First, the reaction of cholesterol (1) and diosgenin (2) with triphosgene gave chloroformate derivatives 3a and 3b, respectively. Then, the compounds 3a and 3b were reacted with ethylenediamine, and the corresponding carbamate derivatives 4a and 4b were obtained. Finally, these carbamate derivatives were converted into their thiourea derivatives 6 and 8 by treatment with phenyl isothiocyanate. A similar synthetic route was used to prepare the urea derivatives 5 and 7. The structures of compounds 3-8 were fully identified by using 1 H and 13 C NMR and mass spectroscopy.
With the desired cholesterol and diosgenin (thio)urea derivatives in hand, we next studied the possibility of using these thiourea derivatives 5-8 as new cocatalysts in the L-proline catalyzed aldol reaction in the presence of water. As a test reaction, the aldol reaction of cyclohexanone and p-nitrobenzaldehyde was conducted in the presence of water. As shown in Table 1, all the examined cocatalysts 5-8 showed similar levels of catalytic efficiencies, with high conversions, diastereoand enantioselectivities. The best result in terms of selectivity was obtained by using L-proline (10 mol %) / cholesterolbased thiourea 6 (10 mol %), and the reaction furnished the expected product in nearly full conversion with 93% ee (entry 2, Table 1). Next, we screened the amount of water and found that our system showed high catalytic efficiency in 0.250 mL of water. We observed that an increase in the amount of water (0.5 mL) decreases the enantioselectivity of the aldol product (entry 5, Table 1). Reducing the amount of water to 0.125 mL also reduced enantioselectivity (entry 6, Table 1). Next, we examined the effect of additives on the enantioselectivity of the reaction. However, no enhancement in selectivity was observed with different acidic additives (entries 7-9; Table 1). L-proline was found to not help the reaction (entry 12; Table 1). It was also found that cholesterol-thiourea (6) was not effective when L-proline was not used (entry 11, Table 1).
Scheme1. Synthesis of urea derivatives 5-8. With these optimal reaction conditions in hand, we next studied the substrate scope of the aldol reaction of different aldehydes with cyclohexanone, and the results are presented in Table 2. The results indicated that L-proline-cholesterol based thiourea 6 host-guest complex can catalyze the aldol reaction very well in the presence of water. As seen, various substituted aromatic aldehydes with electron-withdrawing groups can be tolerated. The reaction can provide aldol products 11a to 11l in good yields with moderate to good enantioselectivity and diastereoselectivity.
Among the substituted benzaldehydes, the best enantioselectivities were obtained with the p-nitrobenzaldehyde and p-chlorobenzaldehyde, giving high enantioselectivities with 93% and 91% ee, respectively (entries 1 and 4, Table  2). Also, the reaction is tolerant of other p-substituted benzaldehydes, which affords the aldol product with moderate to good enantioselectivities ranging from 83% to 90%. Besides, the reaction allowed electron-withdrawing substituents at the o-and m-positions of the phenyl ring (entries 2, 3, 5, and 6, Table 2). Anisaldehyde, an electron-rich aromatic aldehyde, reacted with cyclohexanone, and the corresponding antialdol product 11k was obtained in only low yields and low enantioselectivity (36% ee) (entry 11, Table 2). We also found that cyclopentanone underwent a smooth reaction with p-nitrobenzaldehyde to give mainly the syn-product in high yield with low enantioselectivities (entry 12, Table 2).
In conclusion, we have synthesized a series of novel cholesterol-(thio)urea and diosgenin-(thio)urea conjugates as a cocatalyst that can self-assemble with L-proline to catalyze the direct aldol reactions of cyclohexanone with benzaldehyde derivatives in the presence of water. Under the optimum reaction conditions, the reaction of electron-deficient aromatic aldehydes with cyclohexanone gave anticonfigured aldol products in moderate to high ee values (up to 93% ee) in the presence of water. The successful results for catalytic efficiency of L-proline indicate the importance of the hydrophobic nature of cholesterol and diosgenin parts of thiourea on both the reactivity and selectivity in the presence of water at room temperature.

General
All reagents were used as received without purification. 1 H NMR(400 MHz) and 13 C NMR(100 MHz) spectra were taken on a Bruker Avance 400 spectrometer. TMS was used as internal standard. Precoated Merck 60 F254TLC plates were used for thin layer chromatography (TLC). Flash column chromatography was performed using silica gel (60-mesh; Merck). The 1 H NMR, 13 C NMR, and HRMS spectra for compounds 5-8 and HPLC chromatograms of compounds 11a-11l can be found under the 'supplementary information' given at the end of the article.

Acknowledgment
We thank the Scientific and Technological Research Council of Turkey (TÜBİTAK) for financial support (project no. 114Z050).