Proline as organocatalyst

The origin of the dramatically increased enantioselectivity of a-alkylation of aldehydes when 2-methylproline is substituted for proline as organocatalyst has been investigated using DFT.299... 

Use of hydroxyacetone as donor in the asymmetric Mannich reaction led to the formation of optically active syn /i-amino alcohols bearing two stereogenic centers [22, 23], In the presence of 35 mol% L-proline as organocatalyst several types of syn / -amino alcohol syn-35 were successfully synthesized with enantioselectivity up to 99% ee and high diastereomeric ratio. For example, a high yield of 92%, a diaster-eomeric ratio of 20 1, and enantioselectivity >99% ee were observed by List et al. for formation of the syn yfi-amino alcohol 35a (Scheme 5.17) [23]. In addition to hydroxyacetone the methylated derivative methoxyacetone was also applied successfully in this reaction (93% yield, d.r. > 39 1, >99% ee). 

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... 

Enders and co-workers [162] have reported a protocol for the synthesis of aminopentoses and aminohexoses based on the use of 2,2-dimethyl-l,3-dioxan-5-one (25) as the ketone donor in a three-component Mannich reaction with several aldehydes and p-anisidine in the presence of L-proline or (fert-butyl)dimethylsilyloxy-L-proline as organocatalysts. 

Very recently, the first catalytic asymmetric intramolecular a-alkylation of an aldehyde has been achieved by the List group [70]. In the presence of a-methyl-substituted L-proline, (S)-61, as organocatalyst, ring-forming reactions leading to chiral cyclopentanes, cyclopropanes, and pyrrolidines proceed with high enantioselectivity - in the range 86-96% ee. Selected examples are shown in Scheme... 

Interestingly, however, another comparative study [24] revealed the capacity of other amines related to L-proline (S)-27 to function as organocatalysts in the Mannich reaction under modified reaction conditions [24]. As shown for a model reaction using preformed imines derived from o-anisidine, the thiazolidine carboxylic... 

Substrate range As aldol donor hydroxyacetone was investigated for its potential to form the corresponding optically active anti diols 78 as aldol products [92-94a]. As model reaction the conversion of cyclohexyl carboxaldehyde and hydroxyacetone to the aldol product was investigated in the presence of L-proline as catalyst (because this organocatalyst was found to be very efficient in previous reactions see also Section 6.2.1.1) [92]. With this catalyst high diastereoselectivity (d.r. > 20 1), and an excellent enantioselectivity (99% ee) were observed. The yield was in the... 

Once again proline functions as organocatalyst furnishing the desired aldol adducts 80 in yields of 41 to 85%. With the exception of alkylated aldehydes branched in the a-position, however, d.r. ratios were low, although good to excellent enantioselectivity of 85 to 97% ee was observed for all aldehydes, irrespective of their substitution pattern. The best result was obtained with isobutyraldehyde this afforded the anti-aldol product 80b in 68% yield, with diastereoselectivity of d.r. > 20.1, and enantioselectivity of 97% ee [94, 95]. 

In summary, the organocatalytic asymmetric a-aminooxylation of aldehydes and ketones with proline as catalyst is a highly enantioselective means of preparation of a-hydroxy carbonyl compounds, and their derivatives. Because this field has been developed only recently, more examples and work on extension of organocatalyst screening and process development can be expected in the near future. 

Diastereoselectivity and enantioselectivity were observed to increase substantially when proline-derived diamine salts were used as organocatalysts. In particular, the pyrrolidinium salt 41-2HC1 was found to be very useful, furnishing the target molecule 38 in 70% yield with diastereoselectivity of d.r. = 95 5 and enantioselec-... 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Proline was also ahached to crosslinked PS through a benzyl thioether linkage, as shown in Scheme 3.18. The PS-supported proline 62 was used as organocatalyst in the asymmetric aldol reachon between cyclohexanone 64 and subshtuted benzaldehyde 63 in water [41]. The reachon with p-cyanobenzaldehyde gave the aldol adduct in 98% conversion with a high level of enanhoselectivity (98% ee). The... 

Interest in proline as an organocatalyst is reflected in the variety of inorganic and organic supports on which the immobilization has been assayed very recently. 

Chiral nonracemic enamines formed in situ by reaction of aldehydes and ketones with proline-based organocatalysts also undergo stereoselective a-oxygenation. MacMillan and coworkers have achieved enantioselective a-oxidation of a range of aliphatic aldehydes such as (5.87) with 97-99% ee using proline in combination with nitrosobenzene (5.85). This method can be applied to the aminoxylation of six-membered cyclic ketones such as 1,4-cyclohexanedione monoethylene ketal (5.88). 59... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

Machuca E, Rojas Y, Juaristi E. Synthesis and evaluation of (5)-proline-containing a,p-dipeptides as organocatalysts in solvent-free asymmetric aldol reactions under ballmilling conditions. Asian J Org Chem 2015 4 46-53. 

Nevertheless, as was pointed out before, a straightforward solution to the rather limited substrate scope of the reaction with regard to the ketone reagent and also a good way to overcome the lack of reactivity of ketones toward enamine activation has been the use of primary amines as organocatalysts. In fact, literature examples indicate that primary amines are much more active catalysts for the Michael addition of both cyclic and acyclic ketones to nitroalkenes compared to the same reaction using a secondary amine catalyst like most of the proline-based derivatives already presented before. 

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