Asymmetric organocatalysts Mannich reactions

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

An asymmetric Mannich reaction was recently successfully achieved by means of different types of catalyst, metal- and organocatalysts [20, 21]. With the latter the reaction can be performed asymmetrically by use of L-proline and related compounds as chiral organocatalyst [22-35]. A key advantage of the proline-catalyzed route is that unmodified ketones are used as donors, which is synthetically highly attractive. In contrast, many other asymmetric catalytic methods require preformed enolate equivalents as nucleophile. 

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). 

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. 

Other examples of asymmetric reactions involving organocatalysts are (i) Diels-Alder reactions, (ii) Michael reactions, (iii) Mannich reactions and (iv) Shi epoxida-tion and organocatalytic transfer hydrogenation. 

Zheng X, Qian YB, Wang Y (2010) 2-Pytrotidinecarboxyhc add ionic liquid as a highly efficient organocatalyst for the asymmetric one-pot Mannich reaction. Eur J Org Chem 515-522... 

Articles summarizing current state of asymmetric addition to imines and highlighting Mannich reaction are available. Special attention has also been devoted the employment of organocatalysts for the Mannich reaction. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

The development of a catalytic asymmetric addition of enolates to imines (Mannich reaction) has only recently received attention and it was not until 1998 that there were reports of this process giving products in over 90% enantiomeric excess. Since then a large number of both metal-based catalysts and organocatalysts for the asymmetric Mannich reaction have been investigated. 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

In 2004, Hayashi and coworkers found trans-4-TBSO-(5)-proline 29 to be more active than the parent proline organocatalyst for the asymmetric a-aminojylation of enolisable aldehydes 8 (R = H) or cyclic ketones 11 (X=-CH2-, -C(Me)2-, -S-) with nitrosobenzene to prepare optically pure (>99% ee) hydrojylamine derivatives 12 or 13 in 50-76% yield (Scheme 10.2). Compound 29 (30 mol%) also efficiently catalysed the a-aminojylation/intramolecular Michael cascade reaction of cyclohexenones 34 with nitrosobenzene to afford bicyclic compounds 35 with veiy high enantioselectivity (Scheme 10.7). Furthermore, in the presence of organocatalyst 29, three-component Mannich reactions of acetone 8 (R = Me, R = H) with benzaldehyde derivatives 9 (R = Ar) and 4-metho3yaniline produced the corresponding enantiomers (90-98% ee) of p-amino ketones 16 in mild experimental conditions (—20 °C) (Scheme 10.3). 

Y.-C. Teo, J.-J. Lau, M.-C. Wu, Tetrahedron Asymmetry 2008, 19, 186-190. Direct asymmetric three-component Mannich reactions catalyzed by a sUoxy serine organocatalyst in water. 

F.-F. Yong, Y.-C. Teo, Synth. Commun. 2011, 41, 1293-1300. Recyclable sUoxy serine organocatalyst for the direct asymmetric Mannich reactions in ionic liquids. 

In addition, various chiral amine-thioureas have been successfully applied to promote asymmetric Mannich reactions. As an example, Takemoto and Miyabe have employed a chiral bifunctional organocatalyst possessing a thiourea moiety and a tertiary amino group as catalyst of the Mannich reaction between ethyl malonate and A-Boc arylimines, which provided the corresponding products in excellent yields and enantioselectivities (93-98% ee), as shown in Scheme S.lb. The degree of enantioselectivity was shown to be dependent on the reaction temperature, with the best results obtained at low temperature. 

A chiral primary amine-thiourea organocatalyst was successfully applied for the first time by Tsogoeva et al. to the asymmetric Mannich reaction of ketones with readily available and stable a-hydrazonoesters, which proceeded with good yields and high enantioselectivities of up to 99% ee (Scheme 3.17). Interestingly, whereas acyclic ketones gave a tf-Mannich products, an excess of syn diastereomers was observed with the cyclic ketones. In both cases, only low... 

Among a wide variety of chiral organocatalysts that have been used in the asymmetric Mannich reaction, one of the most widely used remains proline itself, which generally provided excellent enantioselectivities for the Mannich products arisen from either three-component, one-pot reactions or reactions of preformed imines with aldol donors. While these reactions were mostly performed at a catalyst loading of 10mol %, Mannich reactions of enolisable aldehydes and ketones with imines catalysed by (i )-3-pyrrolidinecarboxylic... 

An A-Boc sulfone derivative has been used for in situ generation of an a-keto imine, which undergoes an asymmetric Mannich reaction, using a diarylprolinol silyl ether (17) as organocatalyst." 0... 

Although, simple acyclic amino acids, such as L-serine, L-alanine, L-valine, etc., proved to be similarly effective in promoting the asymmetric Mannich reaction [59], since the pioneering work by List and collaborators, L-proline has been the catalyst of choice probably due the fact that it has performed well in a multitude of cases besides its availability and low costs [60-62], However, the apphcation of L-proline is not without its flaws. As with other organocatalysts, typically high catalyst loadings of up to 30mol% are required. Additionally, reactions have to be executed in very polar solvents, snch as DMSO, DMF, MeOH, or H O, due to its poor solubihty. To overcome some of these limitations, novel... 

Connecting a thiourea moiety to a guanidinium base can improve catalysis further. Nagasawa and coworkers described the application of such an open-chain guani-dine/bisthiourea organocatalyst 127 in the asymmetric Mannich reaction between A/-Boc-protected imines and dimethyl malonate [87]. The stereochemical outcome of the reaction was strongly influenced by the reaction... 

As outlined in the previous paragraph, chiral Brpnsted base organocatalysts appear to be most effective when equipped with an additional Brpnsted acidic moiety, for example, hydrogen bond donors like (thio)urea. Apparently, both functionalities catalyze the asymmetric Mannich reaction in a cooperative fashion, that is, simultaneous activation of both the nucleophile and the electrophile. However, activation of the electrophile can also be accomplished with a single, enantiomerically pure Brpnsted acid. In this respect, readily available chiral phosphoric acids are most commonly applied [88-90]. In 2004, the groups of Akiyama and Terada independently from each other reported the first asymmetric Mannich reaction of silyl ketene acetals or acetyl acetone with imines utilizing chiral phosphoric acid catalysts, which... 

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