Prolinamido-glycoside catalyzed asymmetric aldol reaction in aqueous media is reported. The reactions are rapid and highly stereoselective when water is used as solvent. The stereoselectivities were under influence of configurations of a prolyl residue of the catalyst and α-chiral aldehydes. Water soluble prolinamido-glycoside catalysts are easily separable from reaction mixture and can be recycled and re-used several times.
Proline catalyzed stereoselective aldol reaction is convenient method for the preparation of synthetic intermediates of natural products [
NMR spectra were recorded on JEOL JNM-A500 and Varian NB 600 spectrometers. All chemical shifts are quoted in ppm and were referenced to TMS and residual solvent as internal standards. HPLC analysis was performed using a Shimazu LC-10AD vp using Chiralpack AS-H and AD-H from Daicel Chemical Industries, Ltd. Mass spectra were recorded on JEOL JMS-T100CS spectrometer. Optical rotations were measured on JASCO Model DIP-1000 polarimeter. Melting points were determined in open glass capillaries in Yazawa apparatus, and are uncorrected. Evaporations were performed under diminished pressure with a rotaryevaporator at 40˚C or less unless otherwise stated. Thin-layer chromatography (TLC) was performed on pre-coated plates of silica gel (DC-Fertigpettenkiesge 160F 256, Merck). Spots were detected by spraying the plate with 10% aqueous H2SO4 or molybdic acid followed by heating. Column chromatography was performed on Wacogel C-200.
Methyl 2-(L-prolyl)-amido-α-D-glucopyranoside and methyl 2-(D-prolyl)-amido-α-D-glucopyranoside were obtained from D-glucosamine hydrochloride via methyl 2-amino-2-deoxy-α-D-glucopyranoside, followed by condensation with N-Boc-proline. Methyl 2-amino-2-deoxy-α-D-glucopyranoside was prepared from D-gluco- samine hydrochloride by adapting the procedure described by Suami [
2,3-O-Isopropylidene-D-glyceraldehyde was prepared from D-mannitol according to the procedure of Schmid [
Aldehyde (1.0 equiv) and ketone (10 equiv) were added to a stirred solution of the catalyst (0.05 - 0.3 equiv) in H2O as a sole solvent, and the solution was stirred at r.t. After TLC indicated consumption of the starting materials, the solution was extracted with EtOAc, washed with H2O, dried (Na2SO4), and concentrated to dryness. The residue was purified by column chromatography on silica gel to afford the aldol products. After completion of the reactions, the prolinamido-glycoside catalysts could be separated by an extraction. Concentration of the aqueous layer, followed by recrystallization from 2-PrOH gave ca. 75% recovery of the catalyst. Use of recovered catalysts for the aldol reactions showed that the second aldol reactions were indistinguishable from the first aldol reactions in terms of yield and stereoselectivity.
Various conditions were evaluated for the selective aldol reaction of acetone with isobutyraldehyde (Scheme 1), and the results are summarized in
Entry | Catalyst | Amount of catalyst (equiv) | Solvent | Time (h) | Yield (%) | eea (%) |
---|---|---|---|---|---|---|
1 | 1 | 0.3 | H2O | 0.5 | 98 | 86 (R) |
2 | 1 | 0.1 | H2O | 0.5 | 90 | 89 (R) |
3 | 1 | 0.05 | H2O | 2 | 82 | 89 (R) |
4 | 1 | 0.1 | DMSO | 48 | 11 | 19 (R) |
5 | 2 | 0.3 | H2O | 0.5 | 98 | 89 (S) |
6 | 2 | 0.1 | H2O | 0.5 | 89 | 91 (S) |
7 | 2 | 0.05 | H2O | 2 | 81 | 87 (S) |
8 | 2 | 0.1 | DMSO | 48 | 23 | 31 (S) |
9 | 3 | 0.3 | H2O | 24 | 32 | 83 (R) |
10 | 3 | 0.1 | H2O | 24 | 25 | 76 (R) |
11 | 3 | 0.05 | H2O | 48 | 26 | 81 (R) |
12 | 3 | 0.1 | DMSO | 48 | 11 | 68 (R) |
13 | 4 | 0.3 | H2O | 24 | 36 | 83 (S) |
14 | 4 | 0.1 | H2O | 24 | 22 | 79 (S) |
15 | 4 | 0.05 | H2O | 48 | 24 | 75 (S) |
16 | 4 | 0.1 | DMSO | 48 | 12 | 61 (S) |
aDetermined by HPLC analysis.
Scheme 1. Prolinamide-catalyzed aldol reaction of acetone with isobutyraldehyde.
Scheme 2. Prolinamide-catalyzed aldol reaction of acetone with 2,3-O-isopropylidene-D-glyceraldehyde.
Scheme 3. Prolinamide-catalyzed aldol reaction of acetone with D-glyceraldehyde in the free form.
Entry | Catalyst | Configuration of substrate | Time (h) | Yield (%) | dea (%) |
---|---|---|---|---|---|
1 | 1 | (2R) | 1 | 91 | 24 (syn) |
2 | 2 | (2R) | 1 | 88 | 94 (anti) |
3 | 3 | (2R) | 48 | 61 | 71 (syn) |
4 | 4 | (2R) | 48 | 52 | 79 (anti) |
5 | 1 | (2S) | 1 | 96 | 81 (anti) |
6 | 2 | (2S) | 1 | 75 | 63 (anti) |
aDetermined by 1H NMR analysis.
In a parallel series of experiments, known [
As shown in Scheme 4, the prolinamide catalyzed aldol reaction was applied to carbohydrate synthesis. Each of isopropylidene protected D-psicose and D-tagatose was obtained by treating 2,2-dimethyl-1,3-dioxan-5-one with 2,3-O-isopropylidene-D-glyceraldehyde in the presence of the prolinamido-glycoside in water at room temperature. L-Prolinamido-glycoside (1) catalyzed condition gave protected D-tagatose in 72% yield with 76% de, and D-prolinamido-glycoside (2) catalyzed condition gave protected D-psicose in 69% yield with 91% de, respectively. The isopropylidene protected D-psicose and D-tagatosehad properties concordant with those already reported [
Entry | Catalyst | Time (h) | Yield (h) | dea (%) |
---|---|---|---|---|
1 | 1 | 1 | 87 | 67 (syn) |
2 | 2 | 1 | 94 | 76 (anti) |
3 | 3 | 24 | 21 | 38 (syn) |
4 | 4 | 24 | 27 | 49 (anti) |
aDetermined by 1H NMR analysis.
Scheme 4. Synthesis of carbohydrates by prolinamide catalyzed aldol reaction.
conditions in aqueous media, each of D-xylulose [
Prolinamido-glycosides catalyzed stereoselective aldol reaction of acetone in aqueous media, and ketoses were stereoselectively synthesized. The diastereofacial selectivities in the aldol reaction were mainly controlled by the stereochemistry at the prolyl residue of the catalysts and the conformational disposition of α-chiral aldehydes, and were in general accordance with the Felkin-Anh model. The catalysts showed substrate selectivity for water soluble aldehyde, and well controlled stereochemical generation. Prolinamido-glycosides were also capable of catalyzing the aldol reaction of aldoses in unprotedted form and hence the prolinamido-glycosides catalyzed aldol reaction has potential for understanding prebiotic routes of carbohydrates.