Proline-catalyzed direct aldol additions

Scheme 4. Synthesis of (S)-ipsenol using the proline-catalyzed direct aldol addition reaction as key transformation, (a) L-Proline (10-20mol%), acetone (solvent), 3-7days, 34% (73% ee). (b) TBSCI, imidazole ...

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

Hajos and Parrish at Hoffmann La Roche discovered that proline-catalyzed intramolecular aldol reactions of triketones such as 104 and 107 furnish al-dols 105 and 108 in good yields and vith high enantioselectivity (Scheme 4.17). Acid-catalyzed dehydration of the aldol addition products then gave condensation products 106 and 109 (Eqs. (1) and (2)). Independently, Eder, Sauer, and Wiechert at Schering AG in Germany directly isolated the aldol condensation products vhen the same cyclizations vere conducted in the presence of proline (10-200 mol%) and an acid co-catalyst (Eqs. (3) and (4)). 

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. 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

What is the role of water under these conditions It has been suggested that water suppresses the formation of proHne-oxazoUdinone, which has been considered to be a parasitic species [11]. Then, the role of water is to prevent deactivation rather than to promote activity. Studies, carried out on the proUne-catalyzed reaction between acetone and 2-chlorobenzaldehyde allow one to hypothesize a conflicting role of water. Water increases the total catalyst concentration due to suppression of unproductive species and decreases the relative concentration of productive intermediates by shifting the iminium ion back to proline [12]. Addition of water suppresses formation of both on- and ofF-cyde iminium ions 1 and 2 by Le Chatelier s principle (Scheme 24.2a). The net effect of added water on the globally observed rate will depend on the relative concentrations of iminium ions 1 and 2, which may be different for different aldehydes and can be a function of substrate concentrations and rate and equilibrium constants. Seebach and Eschen-moser have raised doubts about the fact that oxazoUdinones are unproductive and parasitic species in proline-catalyzed aldol reactions [13]. The small excess of water will potentially facilitate proton-transfer in the transition state (Scheme 24.2b), which both lowers the LUMO of the incoming electrophile as well as directs the enantioselectivity of the newly formed stereocenters. 

One of the simplest stractures is prolinamide 37 (Figure 24.13), which catalyzed the direct aldol reaction of acetone with 4-nitrobenzaldehyde in water in 50% ee. In the absence of water no reaction took place [59]. Further experiments were carried out using proline-thioamide 38 (Figure 24.13). Brine was found to be a suitable reaction medium for the aldol reaction of several cyclic ketones with electron-deficient aldehydes catalyzed by 38 (5mol%) and in the presence of CI2CHCOOH as additive [60]. 

Recent developments in this area have considerably expanded the scope of the process to include a wide range of ketone and aldehyde components [98-100). Direct proline-catalyzed cross-coupling aldol reactions from ketones (Equation 16) [98] and aldehydes (Equation 17) [101] have been reported. Moreover, domino processes are possible thus, the proline-catalyzed aldol addition reaction of acetaldehyde proceeds through a double aldol addition and elimination to give useful building blocks for asymmetric synthesis (Equation 18) [100], As with any catalytic process, these processes are in essence multivariable problems, consisting of multiple steps and reactive intermediates, the reactivities and stabilities of which are finely balanced. 

The first asymmetric direct intermolecular aldol reaction catalyzed by L-proline was disclosed by List, Lemer, and Barbas III in 2000 [5]. Other amino acids possessing secondary amine groups were also screened but at best exhibited the same activity [14]. Both functional groups present on an amino acid are essential for good catalytic activity. Additionally, enantioselectivity is dependent on the distance between the amino and carboxylic groups, with (3-amino acids exhibiting lower enantioselectiv-ities [8f, 15]. 

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