Proline catalysis

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

Proline catalysis leads to the anti products 3 and 4. Use of the designed imidazolidinone catalyst 11 leads to the complementary syn product 12. 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Recovery of organocatalysts for re-use after downstream-processing has already been reported for some processes (see also the discussion below on immobilization). For example, recovery and re-use has been investigated for L-proline catalysis [10]-... 

Schering chemists demonstrated that the target molecules 32 and 33 can also be synthesized in a one-pot reaction with enantioselectivity up to 84% ee when using 10-200 mol% proline as catalyst [65, 66], Because of easy access to the steroid precursors 28 and 29 from readily available raw materials, and the use of the economically attractive catalyst L-proline, this intramolecular aldol reaction has attracted commercial attention. At Schering L-proline catalysis has been conducted on a multi-kilogram scale [67]. 

Triketone (29) undergoes an intramolecular aldol reaction - the Hajos-Parrish-Eder-Sauer-Wiechert reaction - to give (30) and subsequently enone (31), in high ee with the stereochemistries indicated being found for D-proline catalysis.128 Now ahomochi-ral /3-amino acid, (1 W,2.S )-cispentacin (32) has been found to give comparable ee, and indeed does so for the cyclohexyl substrate also. 

Lam, Y.-h. Honk, K. N. Scheffler, U. Mahrwald, R. Stereoselectivities of histidine-catalyzed asymmetric aldol additions and contrasts with proline catalysis A quantum mechanical analysis, J. Am. Chem. Soc. 2012,134, 6286-6295. 

Seebach, D. Beck, A. K. Badine, D. M. Limbach, M. Eschenmoser, A. Treasury-wala, A. M. Hobi, R. Prikoszovich, W. Linder, B. Are oxazolidinones really unproductive, parasitic species in proline catalysis - Thoughts and experiments pointing to an alternative view, Helv. Chim. Acta 2007, 90, 425-471. 

Hydroxyacetone 96 is a reagent in an even more remarkable reaction the asymmetric direct three-component Mannich reaction. It is combined with an aromatic amine 98 and the inevitable isobutyraldehyde 89 with proline catalysis to give a very high yield of a compound 99 that might have been made by an asymmetric amino-hydroxylation. The proline enamine of hydroxyacetone, must react with the imine salt formed from the amine and isobutyraldehyde. This is a formidable organisation in the asymmetric step. 

The Rediscoveiy of Proline Catalysis Asymmetric Aldol Reactions... 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

After its initial discovery, proline catalysis went dormant once again before its striking comeback in 2000, with a now-widespread range of applications. 

Another issue is the formation of oxazolidinones, which has been the subject of study by several research groups and is considered to be part of a parasitic equilibrium for proline-catalysed aldol reactions. More recent studies have indicated that this parasitic equilibrium may not be true, and that reversible oxazolidinone formation may help keep proline in solu-tion. Figure 5.3 illustrates a generalised mechanism for proline catalysis involving enamine intermediates. As aforementioned, the formation of oxazolidinones may or may not be part of a parasitic equilibrium. 

To facilitate the use of p-amino-aldehydes or -alcohols, obtained through asymmetric Mannich reactions, List et al. provided a procedure to use N-Boc-protected, preformed imines (21, 22) (Scheme 5.13a). While this method requires the formation of the imines, it provides products that can be deprotected under mild conditions, as compared to the widely used and robust PMB-protection in these reactions. Even acetaldehyde is applicable as aldehyde source (Scheme 5.13b). The p-amino-aldehydes (23, 24) obtained from this transformation are extremely valuable building blocks in organic synthesis, making this discovery one of the most useful applications of proline catalysis to date. 

The challenge of asymmetric and racemic a-functionalisation of carbonyls has led to the development of novel innovative solutions. As one option, organocatalysis and in particular, L-proline-catalysis has offered new technologies to access valuable a-functionalised products in a greener, more sustainable manner. 

Proline catalysis was further extended to the a-sulfamidation of a,a-branched aldehydes (Scheme 5.34). The reaction of hydratropaldehyde with sulfonyl azides yields the sulfamidated products, such as 35 in moderate yields and selectivities. 

Scheme 5.39 Asymmetric proline catalysis in the s5mthesis of (+)-palitantin.

This overview about developments in the field of proline-catalysis unfortunately cannot take into full account the vast field of proline-derived catalysts, such as diarylprolinols, 4-silo)yprolines or proline-silyl-ether, to name only a few. These are covered in subsequent chapters of this volume. Furthermore, other great improvements have been made by using immobilised proline catalysts, such as PEG-supported proline or polyelectrolyte-bound pro-line. Going one step further, supported proline catalysts are then applicable in the striving field of continuous-flow reactions. Recent examples include aldol, a-amination reactions and Michael reactions under such conditions. ... 

SCHEME 2.4. Seebach s oxazolidinone pathway for proline catalysis. 

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