Enantioselective Aldol Reactions and Michael Additions Using Proline Derivatives as Organocatalysts

Six compounds including five proline derivatives have been prepared and tested as chiral organocatalysts for enantioselective aldol reactions and Michael additions. The enantiomeric excesses, which are highly dependent on the molecular structure of catalysts as well as experimental conditions, have reached over 98%.


Introduction
The aldol reaction and the Michael addition are very precious tools of the synthetic organic chemist. Indeed, these reactions are widely applied to generate carbon-carbon bonds allowing to link building blocks to generate large and complex molecules. The steric control of chiral centers created during these reactions was initially attained using chiral auxiliaries as is the case, for instance, of chiral imines in Michael additions [1] [2]. For over a decade, many studies have been undertaken worldwide to extend the enantioselectivity in catalytic manner using small organic chiral molecules. These metal-free catalysts, highly efficient, more environmentally friendly, and often stable under both aerobic and aqueous reaction conditions, are always extensively investigated [3]- [8].
The synthesis of azapyridinomacrocycles N-oxides and their use as organocatalysts for enantioselective allylations of 4-nitrobenzaldehyde with allyltrichlorosilane were reported from our laboratory [9]. The described asymmetric inductions were interesting and promising but too low to afford synthetic applications. Therefore we

Aldol Reaction
With the new derivatives 1 -6 in hand, we began to evaluate their catalytic behavior in the classical aldol reaction between acetone and 4-nitrobenzaldehyde [21], and the results are displayed in Table 1. As can be seen, the reaction proceeded smoothly at room temperature under solvent free conditions and was almost total only beyond several dozen hours, except for catalyst 2 (entry 2). If the chemical yields were acceptable (catalysts 2 and 3), the enantiomeric excesses were very low except for catalyst 2. Indeed in that case, a very interesting enantioselectivity of the aldol product was obtained. Regarding the results, we observed the following facts: firstly, the catalyst 2 having proline moieties exhibited higher catalytic efficiencies compared to 1 (entries 1, 2); then, we could notice a strong mismatch effect related to the absolute stereochemistry of the cyclohexane moiety (entries 2, 3). After these initial investigations, catalyst 2, giving the best result, was selected to carry out the optimization of the reaction conditions. We first investigated the solvent effect with or without some additives and the results are displayed in Table 1. While no reaction occurred in aprotic polar solvents (entries 4, 5), apolar solvents (entries 6, 7) induced a significant decrease in catalytic efficiency. Moreover, a catalytic amount of TfOH (entry 9) induced a decrease both rate and yield without significantly affecting the enantiomeric excess. On the other hand, catalytic quantities of AcOH (entry 8) induced an increase of the yield, but involved a slightly decreasing of the enantiomeric excess. With water as additive (entries 10, 11) no significant variations were observed in the reaction rate and enantioselectivity. The reactions, carried out at lower temperatures, have shown as expected a positive effect on the catalytic efficiency and thus the best results were obtained at −20˚C but requiring prolonged reaction time (entries 12,15). Regarding the loading of the catalyst, the reactions carried out with only 10 mol% of 2 (entries 13 -15) provided the aldol product with almost the same enantioselectivity but with an expected decreasing of the reaction rate. In order to exclude a quite possible retro-aldol process that could lead to partial racemization, the enantiomeric excess of the reaction was measured several times throughout the reaction, showing no significant variation in value.
To explain the experimental results and especially the different behavior between catalysts 2 and 3, we proposed transition states displayed in Figure 2 for the aldol reaction. Thus, the enamine resulting from the condensation of the catalyst (S,R,R)-2 with acetone adding to the aromatic aldehyde forms a pseudo-cycle stabilized by strong binding interactions between the carbonyl oxygen and two acidic hydrogen atoms. In this cycle, the largest substituent "Ar" is located at the equatorial position. This compact and rigid transition state can explain the relative high enantiomeric excess (78%) promoting the R-isomer of the aldol product. With the isomer (S,S,S)-3 this binding interaction can arise with only one hydrogen, the second one being pushed to the rear of the figure induced by the reverse stereochemistry of the cyclohexane moiety. These very different behaviors between 2 and 3 allowed us to highlight one main characteristic required for catalysts, namely the ability to form a compact cyclic transition state induced by the presence of acidic hydrogen atoms [22]. Following these observations, we thought design proline derivatives 4, 5 and 6 having acidic hydrogen of a sulfonamide function. In addition, one could be expected a significant difference between the catalysts, given the presence in the catalyst 4 of an additional carbonyl group increasing the hydrogen acidity [23]. The experimental results of aldol reactions are displayed in

13
Entry 12a ( vents. Indeed, while no reaction took place in aprotic solvents, excellent results in solvent-free medium were observed (entries 16 -19, ee up to 96%). In contrast with catalyst 5 in the same conditions, the reaction provided aldol products in only 31% ee (entry 27). Again, with a lower catalyst loading (10%), the reaction occurred (entries 18,19) and provided the corresponding aldol product with the same high enantioselectivity (96% ee). Finally, the scope and limitation of this process with various aromatic aldehydes under optimized conditions were explored; the results are displayed in Table 1. In all cases, the enantiomeric excesses were of the same order of magnitude as those previously observed. However, some significant differences between aldehydes bearing withdrawing groups and those bearing donor groups can be noted. Indeed, the aldol reaction rate with compound 12h (entry 26, two donor groups) is lower than that observed with other aldehydes; these two donor groups reducing the electrophilicity of the aldehyde function. To conclude this chapter regarding aldol reactions, promising results were obtained showing, once again, that proline derivatives gave the best results.

Michael Addition
Following these encouraging results, we proposed to test some of these organocatalysts in Michael additions.
Organocatalyst activation of this type of reaction has already been intensively studied but still remains a great challenge for the synthetic chemists [13]- [17]. The tests were performed with 2, 4, 5, and 6 to establish their catalytic activities by achieving the reaction model: cyclohexanone/acetone-trans-β-nitrostyrene [24] [25]. The experimental results are displayed in Table 2. As can be seen, the reactions took place smoothly with an extensive reaction time. A surprising result was first obtained with catalyst 2 (entry 1): the enantiomeric excess is near zero while this catalyst was very efficient for the aldol reaction ( Table 1, entry 2). With catalyst 4 in acetonitrile, the enantiomeric excess was low at 25˚C (10% ee) with a good diastereomeric ratio (entry 2). However, catalyst 5 (entry 5) proved to be very promising since the enantiomeric excess reached almost 80% in the first experiment. Therefore we choose this catalyst as well as its regioisomer 6 to undertake optimization experiments in order to increase the enantiomeric excess. The influence of solvent and temperature as well as presence or absence of some additives on the steric course of the reaction was examined and the results are shown in Table 2. Before looking to the results in detail, we can observe that the enantiomeric excesses were generally good to excellent (entries 5 -19). In acetonitrile solution, addition of a catalytic amount of water or acetic acid (entries 7, 8) significantly increased the reaction rate and, more interestingly, the enantiomeric excesses without altering the diastereomeric ratios. On the other hand, addition of a strong acid (entry 9) induced an important decrease of the enantiomeric excess and reaction rate. We have also tested protic and aprotic solvents, iPrOH with acetic acid at room temperature giving almost the same results (entries 10, 11) and toluene with or without additives yielding better enantiomeric excesses (entries 12 -15). In the absence of solvent other than the ketone itself, the reaction provided adducts with enantiomeric excesses slightly higher than in acetonitrile (entries 5, 16 and 7, 17). Again a decrease in temperature led to better enantiomeric excesses, but slowed down the reaction rates (entries 11, 15, 18 vs. 10,14,17). It should be noted that a spectacular result was observed with catalyst 4 (entries 2 -4) with which a lowering of the temperature (from 25˚C to -15˚C) caused an important increase of the enantiomeric excess (from 10% to 60% ee). Similarly to the case of aldol reaction, using a lower catalyst loading (10 mol%, entry 6), the Michael adducts were obtained with a comparable enantiomeric excess but a large reduction of the reaction rate (220 h vs. 120 h). Some improvements of the enantiomeric excesses were observed with catalyst 6 involving the nitro group at the para-position. Enantiomeric excesses were occasionally higher than those obtained with catalyst 5 (entries 28, 15 and 25, 7). We observed a very excellent result (entry 28: 98% ee, 96:4 dr) with a catalytic amount of water in the toluene/cyclohexanone solution at 5˚C.
Opposite results were achieved with acetone and trans-β-nitrostyrene without solvent in presence of catalytic amounts of water (entries 29, 30). The enantiomeric excess (25% at 25˚C and 29% at 5˚C) were the worst results of all examples of Table 2 [26]. One reason that could explain this lower efficiency may be related to the lower size of acetone compared to cyclohexanone which leads to greater degrees of freedom in the transition state. Figure 3 displays the probable catalytic circle [27] of the Michael addition: the reactive enamine from the condensation between chiral secondary amine and cyclohexanone reacts with nitroolefin through the transition state stabilized by some hydrogen bonds including some water molecules [28] [29]. This transition state also explains the increasing of enantioselectivity by the presence of catalytic amounts of water.

Conclusion
Among the catalysts we have developed in this study, two of them have proved to be very efficient; catalyst 4 for the aldol reaction and catalyst 6 for the Michael addition. It should be noted that, once again, these two catalysts 4 and 6 both derived from a proline structure [30]. Additional studies are currently in progress in our laboratory to investigate further applications of these new catalysts.

General
The reactions were monitored by thin-layer chromatography (TLC) on aluminum plates (0.20 mm, 60 F 254 ) us-
To 100 mg (0.25 mmol) of 2, dissolved in minimum of HCl/MeOH solution, 25 mL of Et 2 O was added. After filtration the precipitate was washed with ether to give 103 mg (95% yield) of 2-HCl as yellow solid.

(S)-N-(2-Nitrophenylsulfonyl-pyrrolidinium)-2-carboxamide (4)
618 mg (1.55 mmol) of 9 in 8 mL of CF 3 CO 2 H/CH 2 Cl 2 (1/4) was stirred 1 h at room temperature and then concentrated under reduced pressure. 10 mL of H 2 O/CH 2 Cl 2 mixture was then added to the residue and the separated aqueous layer, basified by an excess of solid NaOH to pH > 10, was extracted with CH 2 Cl 2 . The combined organic layers were dried (MgSO 4 ) and evaporated. The residue was taken up in a minimum of 2.5 N HCl/ MeOH solution and then crystallized by addition of small amounts of ether. After filtration and washing with ether, 477 mg of compound 4-HCl was obtained (92% yield).

General Procedure
To 0.33 mmol of aldehyde 12 in 850 μL (11.5 mmol) of acetone, 66 μmol of organocatalyst 4 was added and the mixture was stirred for appropriate time and temperature (see Table 1). The reaction medium was concentrated under reduced pressure and the residue was purified through column chromatography (10% EtOAc in cyclohexane) to afford aldol 13.