Reactions proline-catalyzed

The proline-catalyzed reaction has been extend to the reaction of propanal, butanal, and pentanal with a number of aromatic aldehydes and proceeds with high syn selectivity.197 The reaction can also be carried out under conditions in which the imine is formed in situ. Under these conditions, the conjugative stabilization of the aryl imines leads to the preference for the aryl imine to act as the electrophile. A good yield of the expected P-aminoalcohol was obtained with propanal serving as both the nucleophilic and the electrophilic component. The product was isolated as a 7-amino alcohol after reduction with NaBH4. 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

Figure 7.8 Ylide formation can be a major side reaction if proline-catalyzed reactions are not run with a high catalyst loading.

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

Despite their high synthetic potential, when L-proline-catalyzed reactions are evaluated, catalytic amounts in the range 20 to 35% and use of excess ketone (usually 20% v/v) represent reaction parameters to be optimized. Experimental studies addressing this issue have been conducted and impressive solutions were found by the List group [23], As a model reaction the Mannich synthesis using p-nitro-... 

The concept The possibility of using a simple organic molecule from the chiral pool to act like an enzyme for the catalytic intermolecular aldol reaction has recently been reported by the List and Barbas groups [69-71]. L-proline, (S)-37, was chosen as the simple unmodified catalytic molecule from the chiral pool . The proline-catalyzed reaction of acetone with an aldehyde, 36, at room temperature resulted in the formation of the desired aldol products 38 in satisfactory to very good yields and with enantioselectivity up to >99% ee (Scheme 6.18) [69, 70a],... 

Another interesting extension of the proline-catalyzed aldol reaction was recently reported by the Jorgensen group (Scheme 6.22), who used keto malonates as acceptors and a-substituted acetone derivatives as donors [78]. In contrast with the classic proline-catalyzed reaction discussed above, in this reaction the stereogenic center is formed at the nucleophilic carbon atom of the donor. The resulting products of type 46 are formed in good yields, from 88% to 94%, and with enantioselectivity between 84 and 90% ee (Scheme 6.22). The reactions were performed with a catalytic amount of 50 mol% [78],... 

Promising prospects for synthetic applications in the future were opened up by List et al. s experimental studies into the substrate range (Scheme 1). The proline-catalyzed reaction proceeds well when using aromatic aldehydes as a starting material with enantioselectivities of 60 to 77% ee and yields of up to 94%. The direct L-proline-catalyzed aldol reaction proceeds very efficiently when using isobutyraldehyde as a substrate. For this reaction the... 

The regioselectivities of the aldol reactions of hydroxyacetone were reversed from those of the proline-catalyzed reactions when small peptide catalyst 6 or 7 containing (S)-proline at the N-terminal was used, as shown in Table 2.5 [20]. 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

Whereas the (S)-proline-catalyzed Mannich reactions afforded (2S,3S)-syn-isomers as the major products, (3R,5ft)-5-methyl-3-pyrrolidinecarboxylic acid (13) catalyzed the reactions and afforded (2S,3R)-anti-products in good yield with high, almost perfect, diastereo- and enantioselectivities (Table 2.12) [73]. The reaction rates of the 13-catalyzed Mannich reactions were approximately two- to threefold faster than the corresponding (S)-proline-catalyzed reactions that afford the syn-products. Thus, the reactions with only 0.01 or 0.02 equiv. of 13 afforded the desired products in reasonable yields within a few hours. 

Note that catalyst 13 was designed for anti-selective Mannich reactions based on the study of proline-catalyzed Mannich reactions. Four considerations are key for the diastereo- and enantioselectivities observed in the (S)-proline-catalyzed reactions (Scheme 2.15a) ... 

In order to form the anti-products enantioselectively, the reaction face of either the enamine or the imine must be opposite that utilized in the proline-catalyzed reactions. In the reactions catalyzed by 13 (Scheme 2.15b), the methyl group at 5-position of the pyrrolidine ring acts to fix the conformation of the enamine and the acid functionality at the 3-position controls the enamine and imine face selection in the transition state (Scheme 2.15b). In order to avoid steric interactions between the substituent at the 5-position of this catalyst and the imine in the transition state, catalyst 13 has a trans configuration for substituents at the... 

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

S)-proline-catalyzed reaction using propionaldehyde as donor and the results showed that the imine reactivity was approximately sevenfold higher than that of the aldehyde [83]. Under basic conditions, it is generally accepted that nucleophilic addition to an aldehyde is typically faster than addition to an aldimine, but nucleophilic addition to an aldimine is faster than addition to an aldehyde when protonation of the imine nitrogen occurs [83]. In the (S)-proline-catalyzed three-component Mannich reactions in the absence of arylaldehyde, self-Mannich products were obtained with moderate to high diastereo- and enantioselectivities (Scheme 2.19) [71b, 82]. 

The partial steps of the conjugate addition in aminocatalytic reactions are in dynamic equilibrium, and thus products are formed under thermodynamic control. This fact is translated also in the geometry of the enamine intermediates, leading to the product, which can be either E or Z (Fig. 2.9). The geometry of the enamine depends on the catalyst structure and also on the substrate. Whilst proline-catalyzed reactions form preferentially, with a-alkyl substituted ketones, the. E-isomer, enamines derived from pipecolic acid afford an approximate 1 1 mixture of the E and Z isomers [6], In turn, small- and medium-sized cyclic ketones afford the E isomer. 

Enamines derived from ketones undergo some of the same reactions described for enol ethers, for example with arenesulfonyloxy carbamates as in Eq. 96120 121 3" and with ethyl azidoformate as in Eq. 98.302 303 The reaction with activated azo compounds occurs readily at room temperature or below and diamination often cannot be avoided with the more electrophilic reagents (Eq. lOl).400,401 The proline-catalyzed reaction of ketones with azodicarboxylic esters, which proceeds by way of the enamines, has been mentioned above (Eq. 91). 

Following the seminal work on proline-catalyzed reactions, a range of proline- and proline derivative-catalyzed asymmetric reactions, including the Mannich reaction, Michael reaction, a-functionalization of carbonyl compounds, and cycloaddition reactions, have been developed [33]. 

Notes Chiral preparations include the proline-catalyzed reactions and recently an aldolase antibody 38C2 method has been reported. See also ... 

Methyl-4-hydroxy-2-pentanone (diacetone alcohol) could be used as nucleophile instead of acetone (3a) [15], giving the expected aldol products 4 (R =H) with lower enantioselectivities (48-86% ee). A tandem organo- and biocatalytic process has been designed [16], with the aim of improving the achieved enantioselectivities for the a-hydroxy ketones 4 (R =H), using Pseudomonas cepacia lipase (Amano 1) as catalyst for the kinetic resolution of the mixture of aldol adducts obtained after the proline-catalyzed reaction. 

Recently, Dominguez de Maria and co-workers [45] have studied experimentally the influence of the organocatalyst on the outcome of the aldol reaction reaction between acetone and isobutyraldehyde. Qrganocatalysts able to form bicyclic oxazolidine intermediates (proUne and prolinol) led predominantly to aldol adducts, while organocatalysts unable to form these oxazolidines (pyrrolidine, O-methyl prolinol and proline tcrt-butyl ester) afforded preferently (>2.5 1) the condensation product. In summary, most of the experimental evidence points toward a distinct catalytic role of oxazoUdinone intermediates in proline-catalyzed reactions. It should be pointed out, however, that DPT studies of the proline-catalyzed self-aldol reaction of propanal, in which the enamine carboxylic acid and the oxazoUdinone pathways were compared, concluded that the Seebach model was inadequate for rationalizing... 

SCHEME 3.2. L-Proline-catalyzed reaction of acetone (1) with 4-nitrobenzaldehyde (2a). 

For reactive aldehydes, proline-derived 7V-sulfonylcarboxamides were investigated as catalysts by Ley and co-workers [45], Berkessel et al. [46], and Kokotos and co-workers [47]. Not only did amino acid derivatives promote the aldol reaction, but also chiral diamines in the presence of an acid were also found to be effective [48]. The yield and enantioselectivity were the same as for the proline-catalyzed reactions. In combination with polyoxometalate acid, a diamine could be used in 0.33 mol%, but for less reactive aldehydes the yields are still low [49]. 

Aliphatic aldehydes are more difficult substrates because the presence of two enolizable carbonyls results in decreased reaction selectivity. Such aldehydes may be used as acceptors in the proline-catalyzed reaction with acetone, but as expected, only branched aldehydes give good yields and stereoselectivities [14, 50]. The best results are obtained using Wennemers tetrapeptide 18 (Table 3.1) [25a]. 

Using a ball milling technique, the desired aldols 58a can be synthesized in a proline-catalyzed reaction (10 mol% catalyst loading) with no solvent added [77]. In addition to proline, a variety of primary amino acids catalyze this reaction, indicating that the five-membered ring is not crucial to catalytic efficacy [62, 78, 79, 80]. The results are very impressive for aldehyde 2a but less so for benzaldehydes with electron-donating groups. 

Reactions of heterocyclic ketones with aliphatic aldehydes are even less well explored. In spite of long reaction times and high catalyst loading (50 mol%), L-proline-catalyzed reactions give satisfactory results (Chart 3.9) [91]. Using an asymmetrical diamide, Xiao was able to decrease the catalyst loading to 20 mol% [92]. 

Aliphatic aldehydes as acceptors were studied by List et al. [50]. The proline-catalyzed reaction of cyclopentanone (78) with isovaleraldehyde (2n) in chloroform afforded predominantly the anti-a Ao in 77% yield. 

---