Proline catalyzed aldol reaction

The investigation of the driving forces and robnstness of proline-catalyzed aldol reaction is performed by ntilizing the methodology of reaction progress kinetic analysis. 

Visual models, additional information and exercises on Proline-Catalyzed Aldol Reactions can be found in the Digital Resource available at Springer.com/carey-sundberg. 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

The development of enamine catalysis parallels that of iminium catalysis (Scheme 3) [24], Like iminium catalysis, the concept took a long time to mature, and also required a key discovery - the discovery of intermolecular proline-catalyzed aldol reactions by List and coworkers in 2000 [23] - to set the field in motion. The timeline of historical developments of enamine catalysis is outlined in Scheme 4. 

List, Barbas and Lerner discover the intermolecular proline-catalyzed aldol reaction... 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Scheme 22 Proline-catalyzed aldol reaction in the synthesis of caUipeltoside C...

In similar works, a number of [AMIM] -containing ionic liquids were evaluated for proline-catalyzed aldol reactions. The catalyst in the ionic liquid with Cl as the anion was characterized by a higher reaction rate than the ionic liquids with the anions BF)T and PFg", but elimination products affected the yields in the latter ionic liquids (149). 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

Figure 7.13 1,1 -Bi-2-naphthol (BINOL) can dramatically enhance proline-catalyzed aldol reactions.

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

The substrate range scope and limitations Promising prospects for synthetic applications of the proline-catalyzed aldol reaction in the future were opened up by experimental studies of the range of substrates by the List [69, 70a, 73] and Barbas [71] groups. The reaction proceeds well when aromatic aldehydes are used as starting materials - enantioselectivity is 60 to 77% ee and yields are up to 94% (Scheme 6.19) [69, 70], The direct L-proline-catalyzed aldol reaction proceeds very efficiently when isobutyraldehyde is used as substrate - the product, (R)-38d, has been obtained in very good yield (97%) and with high enantioselectivity (96% ee). 

Extensions of the proline-catalyzed aldol reaction Recently interesting extensions of the enantioselective proline-catalyzed aldol reaction have been reported. An enan-tioselective proline-catalyzed self-aldolization of acetaldehyde was observed by Barbas and co-workers (Scheme 6.21) [77]. Starting from acetaldehyde, the valuable building block 5 -h ydroxy-( 2E)-hexcnal, (S)-43, was obtained as a product with up to 90% ee, although the yield did not exceed 13%, irrespective of the reaction conditions. This reaction requires a small amount catalyst only (ca. 2.5 mol%). 

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],... 

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]. 

Aldol reactions using L-proline as organocatalysts The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. and the Barbas... 

The reactions also led to high regioselectivity (> 20 1). For alkylated aldehydes unbranched in the a-position, however, low diastereoselectivity (d.r. 1.7 1) and yields of 38% were obtained, although enantioselectivity remained excellent (> 97% ee). Use of aromatic substrates resulted in a d.r. of 1 1 to 1.5 1 only, and the enantioselectivity was in the range 67 to 80% ee [93]. Some representative examples of the L-proline-catalyzed aldol reaction with hydroxyacetone are given in Scheme 6.35. 

On the basis of the success of these initial reports on the proline-catalyzed intramolecular aldol reaction several groups focused on extending this type of synthesis to bicyclic products bearing angular substituents other than methyl and ethyl reported earlier [97-101]. Preparation of bicyclic systems with protected hydroxymethyl substituents, e.g. 99, was reported by Uda et al. (Scheme 6.46, Eq. 1) [113, 114]. As a selected example, the aldol adduct 99 was formed in 70% yield and with 75% ee in the presence of one equivalent of L-proline. Synthesis of a related product with an angular phenylthio substituent, 101, was described by Watt and co-workers (Scheme 6.46, Eq. 2) [115]. After intramolecular proline-catalyzed aldol reaction, dehydration of the ketol intermediate, and subsequent recrystallization... 

It should be added that improved formation of products of type 126 was achieved by choosing a different reaction strategy [133], A typical proline-catalyzed aldol reaction (starting from aldehydes as donors and compounds 125 as acceptors), followed by conversion of the C=0 functionality of the aldol adduct into a nitrone group by condensation with a hydroxylamine component led to products of type 126 in good yield and with high enantioselectivity (up to 96% ee) [133],... 

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9]. The desired anti-diols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a dia-stereomeric ratio up to dr > 20 1 and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20 1. 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

Table 2.3 (S)-Proline-catalyzed aldol reactions of hydroxyacetone [6, 7].

Scheme 2.5 Syntheses of carbohydrate derivatives using the (S)-proline-catalyzed aldol reactions [26, 28].

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]. 

Both experimental and theoretical studies have contributed significantly to the elucidation of the reaction mechanism. We found that in contrast with earlier proposals (Agami et al. 1984, 1986, 1988 Puchot et al. 1986 Agami and Puchot 1986), proline-catalyzed aldol reactions... 

Bpgevig A, Poulsen TB, Zhuang W, Jprgensen KA (2003) Formation of optically active functionalized 3-hydroxy nitrones using a proline catalyzed aldol reaction of aldehydes with carbonyl compounds and hydroxylamines. Synlett 2003 1915-1918... 

List B (2004) Enamine catalysis is a powerful strategy for the catalytic generation and use of carbanion equivalents. Acc Chem Res 37 548-557 List B, Hoang L, Martin HJ (2004) New mechanistic studies on the proline-catalyzed aldol reaction. Proc Natl Acad Sci USA 101 5839-5842... 

After extensive optimization of the reaction conditions regarding yield as well as diastereo- and enantioselectivity, we were able to obtain the aldol product 26 with 60% yield and excellent diastereo- and enantiomeric excesses (>99% de, 95% ee). Thus, the simple (S)-proline-catalyzed aldol reaction of 4 with pentadecanal directly delivered gram-amounts of the selectively acetonide protected ketotriol precursor 26 of the core unit of phytosphingosines in excellent stereoisomeric purity (Scheme 7). 

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