Hydroxy-L -prolines as asymmetric catalysts for aldol, Michael addition and Mannich reactions

The hydroxyprolines (Hyps) 2 - 6 are tested as organocatalysts for aldol, Michael additions, and Mannich reactions. The results are compared with the well-known analogous L -proline ( 1 ).The effect of the additional hydroxyl group and chiral center was investigated in the three types of reactions. Catalyst 2 shows an enhancement in the stereoselectivity of the aldol reaction, while 3 in Michael addition and 5 in Mannich reaction give the best results. Derivatives of hydroxyprolines show diversity in the catalytic behavior like 6 .

7][28][29][30][31][32] The effect of chiral centers on the amide group was also studied.4][35][36] Another thought was to exchange the carboxylate group with other functional groups.][42] The hydroxyprolines 2-5 and some of their derivatives like 6 are supposed to be very valuable L-proline derivatives.Hydroxprolines 2-5 are prepared from L-proline via enzymatic hydroxylation reactions.These hydroxylations were carried out by Hüttel and Klein, 43,44 and were performed at gram scales.The trans-4-isomers and some derivatives have been known for a long time and tested as catalysts for aldol additions and other reactions. 9,19,45Very few studies are reported on cis-isomers.7][48] The hydroxyprolines 2-5 and the tert-butyl ether 6 are the targets of this study.The results of all hydroxyprolines and their derivatives are compared with L-proline (1)  under the same conditions.Three asymmetric reactions are studied: aldol addition reactions, Mannich reactions, and the Michael addition reactions.Here, enzymatic 43 or microbial [49][50][51] access of all regio-and stereoisomeric hydroxyprolines is combined with a thorough investigation of the influence on stereoselectivity in asymmetric catalysis.Scheme 1. Hydroxyprolines and some proposed derivatives.
Recently, Müller et al. published results of aldol reactions using a Zn-complex of some chorismate metabolites such as trans-2,3-CHA and trans-3,4-CHA which showed high enantioselectivity in the aldol addition. 52,53Hüttel et al. studied the influence of hydroxyproline derivatives and some other non-proteinogenic amino acids on the aldol addition and on Michael and Mannich reactions.

Results and Discussion
Aldol reaction A summary of the results of the reaction of 4-nitrobenzaldehyde with acetone is given in Table 1 using the hydroxyprolines 2-5 and ether 6 as catalysts.As mentioned above, the trans-isomers have been tested as organocatalysts, but the cis-isomers are rarely cited in the literature.To make a complete study, it is better to test all hydroxyprolines 2-5 under the same conditions.All results are compared with the naturally L-proline (1).It is obvious from the results that the cis-3-hydroxyproline (2) gave the best outcome of about 91% conversion and 74% ee, while L-proline (1) showed a quantitative conversion and 65% ee.It seems that the hydroxyl group in the cis-isomer 2 affects the transition state via intramolecular hydrogen bonding and assists the attack from one side which enhances the ee (Scheme 1, I-IV).The yield and the ee of the trans-3-Hyp (3) are significantly less under the same conditions.The inversion of stereocenter at position 3 diminishes the stereoselectivity of the aldol addition reaction.The intermolecular hydrogen bond made by the hydroxy group at position 3 of trans-isomer (3) could be the reason for this decrease in the enantioselectivity.
In the case of the 4-Hyp, both cis-isomer (4) and trans-isomer (5) gave a very good yield and almost similar enantioselectivities, (ee of about 55-57%).As the hydroxyl group is located further away from the carboxylic acid group, this could result in weakening of H-bonding in both Scheme 2. Description of imine/enamine intermediate of the aldol mechamism.
cases by preventing the intramolecular interaction between the hydroxy and the carboxylic acid groups (Scheme 2, V).Intermolecular hydrogen bonding is suggested.This led to a decrease in the stereoselectivity by about 10-20% compared with L-proline (1) (65% ee) and cis-3hydroxyproline (2) (74% ee).
Some calculations were carried out using the ChemDraw program.They showed an indication of the effect of the intramolecular hydrogen-bonding in both cases of 3-cis-(2) and 4cis-Hyp (4), while the hydroxy groups in both cases of 3 and 5 have no intramolecular interaction (Figure 1) The hydroxyl group in the trans-4-Hyp (5) is substituted with a bulky tert-butyl-group in compound 6.That results in the enhancement of the ee of compound 9. Ether 6 almost shows the same selectivity (ee = 69%, coversion of 89%) as that for L-proline (1) (ee = 65%, conversion of 100%) and lower conversion.The termination of intermolecular hydrogen bonding is suggested to be responsible for this result.Catalyst 6 behaves as if it were L-proline (1).Also, the tert-butyl group partially blocks one side and assists the attack to come from the other side.Hydroxyprolines 1-6 were studied in a Michael addition reaction (Table 2).In general, it seems that the presence of the hydroxy group does affect the enantiomeric excess (ee).In most cases, an ee of < 5% was observed.In the case of trans-3-Hyp (3) as catalyst, the ee was similar to that observed for L-proline (1) itself.It is proposed that the hydroxy group attached to the proline ring disturbs the hydrogen bonding in the imine/enamine intermediate.This results in decreased enantioselectivity.In the case of catalyst 6, substitution of the hydroxyl group by tertbutoxy group enhances the conversion as well as the enantioselectivity of the Michael reaction.

Mannich reaction
L-Proline (1) and hydroxyprolines 2-6 were studied as catalysts in the Mannich reaction of 4nitrobenzaldehyde 7, acetone 8, and aniline 13 with conversions in the range 75-95%.Therefore, they almost have the same effect on the yield.However, a dramatic effect is seen on enantioselectivity.Both cis-and trans-3-Hyps (2 and 3 respectively) showed a decrease in the ee in comparison with L-proline (1).The presence of the hydroxyl group adjacent to the carboxyl group inhibits the selectivity of the reaction because of the strong intramolecular hydrogen bonding (Table 3).Whereas in the case of the cis-and trans-4-Hyps (4 and 5 respectively), the ee is enhanced in comparison with the result of L-proline (1).As the distance between carboxyl group and hydroxyl group increases, the intramolecular forces decrease and the selectivity of Mannich reaction increases.In the Hyp-derivative 6, the substitution of hydroxyl with t-butoxy group showed no effect on the conversion and had a strong effect on the stereoselectivity in comparison with its precursor 5 (Table 3)

Conclusions
Hydroxyprolines 2 and 4 are available on a gram scale via chemoenzymatic synthesis while 3, 5 and 6 are commercially available.Each of these showed variable behaviors as organo-catalysts in aldol addition, Michael, and Mannich reactions.Study of the derivative 6 indicates the diversity in the behavior of each hydroxyproline and its possible derivatives.The substitution of the hydroxy group with another group (X = halogen, OR and NH2,….. etc.) will generate diverse organo-catalysts with different selectivities and efficiencies toward the three reactions and other organo-synthetic reactions.

Aldol reaction
Product (9).p-Nitrobenzaldehyde (7) (151 mg, 1.0 mmol) was dissolved in 2 mL acetone (8).A solution of 23 mg (0.2 mmol) of 1 in 10 mL DMSO was added and the mixture stirred overnight at rt.The reaction mixture was diluted with ethyl acetate and washed twice with water.The organic layer (the product 9) was dried over anhydrous Na2SO4. 1

Figure 1 .
Figure 1.The close contact between the hydroxyl and the carboxylic acid groups in Hyps.

Table 1 .
Summary of the results of aldol-addition reaction

Table 2 .
Summary of the results of Michael addition reaction

Table 3 .
Summary of the results of Mannich reaction