Organocatalysts proline based

A newer method of oxidation that is attracting considerable attention is the reaction of ketones with nitrosobenzene and proline-based organocatalysts (Figure 1.52). Effective hydroxylation of the ketone is achieved in exceptionally high... 

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. 

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. 

In contrast to the early recognition of the importance of proline and proline-based secondary amine peptide catalysts as enzyme mimics, the potential of primary amines in asymmetric catalysis was much underestimated at that time, probably because of their known lower basicity in comparison to secondary amines. This is particularly surprising taking into consideration the fact that primary amino acid catalysis is of enormous importance in enzyme catalysis. For example, primaiy amines occur in the catalytic sites of several enzymes, such as type I aldolases, dehydratases, and decarboxylases. Therefore, primary amines as organocatalysts possess particular appeal. 

The development of catalytic strategies towards the enantioenriched generation of p-hydroxy ketones via an aldol reaction was intensively promoted in recent years. In particular, the application of proline and proline-based amides and peptides as organocatalysts for the asymmetric direct aldol reaction was successfully investigated, by contributions from several researchers. ... 

Indollne-2-carboxylic acid [79815-20-6] M 163.2, m 177"(dec), [a] -114" (c 1, N HCl). It is purified as the racemate (see [78348-24-0] in Heterocyclic Compound, Chapter 4). The S-(-)-hydrochloride [82923-76-0] M 199.7, m 133"(dec), [a] -70" (c 1, EtOH) crystallises from Et20/propan-2-ol. It is a proline based organocatalyst which promotes the enantioseleetive formation of cyclopropanes by reaction between 2-(dimethyl- 4-sulfanylidene)-l-phenyl-ethanone (for stable sulfonium ylides see Ratts Yao J Org Chem 31 1185 1966) and but-2-enals in high yields and very high stereoselectivity involving Direct Electrostatic Activation (DEA) [Kunz Mac Millan Chem Soc 127 3240 2005.]... 

Simple A/-proline-based dipeptides catalyse direct aldols of aldehydes with a wide range of ketones, giving yield/de/ee up to 99/>98 (syn)/97%, at room temperature in 0 brine, with 2,4-dinitrophenol as co-catalyst. A simple organocatalyst, the methyl 0 ester of (S)-proline-(S)-phenylalanine, promotes high-yielding aldols with up to 95% ee and 82% de (anti-) under solvent-free conditions at —20 °C. Lack of solvent should 0 maximize substrate-catalyst noncovalent interactions. 0... 

A series of new robust proline-based dipeptides with two amide units were evaluated by Peng et al. as organocatalysts for the asymmetric aldolisation of cyclohexanone in organic solvents. The reactions proceeded smoothly in the presence of an additive, such as AcOH or 0-T0ICO2H, providing high yields and enantio- and diastereoselectivities of up to 98% ee and 98% de, respectively (Scheme 2.17). In order to explain the enantioselectivity of the reaction,... 

A novel class of chiral organocatalysts derived from proline, such as L-proline-based phosphamides, was studied by Li et These authors... 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

Over the past 12 years or so, significant progresses of the "direct" aldol reaction have been achieved. In particular, the aldol-type reactions of pyruvic acid and its derivatives are useful for the synthesis of isotetronic acid derivatives. In 2000, Jorgensen et al. [23] reported the first example of asymmetric homoaldol reaction of ethyl pyruvate 26a in this work, chiral (R)-f-Bu-bis(l,3-oxazolin-2 -yl)methane (BOX)-Cu(OTf)2 catalyst was used (Scheme 11). Organocata-lytic version of similar reactions has been investigated. For instance, Dondoni et al. examined catalyst efficiency of several prolin-based organocatalysts for homoaldol reaction of 26a and foxmd that a combination of (S)-l-(2-pyrro-lidinylmethyl)pyrrolidine 29 and trifluoroacetic acid is effective [24]. 

Figure 1.1 Major classes of proline-based organocatalysts.

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol condensation of propionaldehyde in water have revealed that the stereoselectivity can be attributed to differences in transition-state solvation pattems. " The hydrogen bond concept has been applied to design new proline-based organocatalysts. " 4-Hydroxyproline derivatives bearing hydrophobic groups in well-defined orientations have been explored as catalysts in water an advantage of aromatic substituents syn to the carboxylic acid moiety has been attributed to a stabilizing transition-state hydrophobic interaction and this is supported by quantum mechanics (QM) calculations. " Catalysts and solvents were screened for reaction between cyclohexanone andp-nitrobenzaldehyde. 

Figure 1.6 Representative examples of proline-based heterocyclic organocatalysts.

Sterically and electronically tuneable and bifunctional organocatalysts based on diamides derived from proline are particularly selective in reactions of heterocyclic ketones with aldehydes.109... 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

Under the reaction conditions used in the one-pot Mannich reaction described above, L-proline (S)-27 was clearly found to be the preferred organocatalyst. As is apparent from Scheme 5.14, the best yield (90%) and enantioselectivity (93% ee) were obtained by use of this organocatalyst [23]. The suitability of all other organo-catalysts used in this one-pot reaction, using 3-methylbutanal as aldehyde, was poor. Remarkably lower yields and poor enantioselectivity were obtained when the thiazolidine catalyst (S)-31 and other pyrrolidine-based organocatalysts were used. 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

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. 

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. 

Enamine-Based Organocatalysts with Proline and Diamines The Development of Direct Catalytic Asymmetric Aldol ... 

The methodologies herein illustrated have a major appealing feature based on the use of commercially or readily available organocatalysts derived from L-proline, which is a cheap source. Important chiral nonracemic targets are obtained working under mild reaction conditions. With a view to large-scale applications, attempts aimed at employing water and alcohols as solvents or cosolvents have been addressed. 

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