Asymmetric organocatalysts aldol reactions

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

In summary, several reports have shown that asymmetric modified aldol reactions using y-dienolates, nitroalkanes, or nitrones as donors can (in principal) be performed by use of organocatalysts. Often, however, enantioselectivity is moderate only, and must still be improved. Because these organocatalytic reactions give important intermediates, e.g. for synthesis of pharmaceuticals, it can be expected that this field of modified aldol reactions with organocatalysts will gain further synthetic importance in the future. 

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. 

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. ... 

Other chiral zinc based Lewis acid, such as zinc(II) complex with pybox, showed good stability in aqueous media and gave syn-adducts in moderate to excellent catalytic activity and enantioselectivity for asymmetric Mukaiyama aldol reactions (113,114). A simple combination of Lewis acidic zinc salt (Zn(OTf)2) and organocatalyst is also shown to be effective catalysts for the direct aldol reaction of acetone and aldehydes in the presence of water (115). 

Maikov, A.V., Kabeshov, M.A., Bella, M., Kysdka, O.E., Malyshev, D.A., Pluhackova, K.N., and Kocovsky, P. (2007) Vicinal amino alcohols as organocatalysts in asymmetric cross-aldol reaction of ketones application in the synthesis of convolutamydine A. Org. Lett., 9, 5473-5476. 

Zhou, L. and Wang, L. (2007) Chiral ionic liquid containing L-proline unit as a highly efficient and recyclable asymmetric organocatalyst for aldol reaction. Chem. Lett., 36 (5), 628-629. 

The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96... 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Structure-activity relationships have been probed in (S)-histidine-based dipeptides employed as organocatalysts for direct asymmetric aldol reactions, focusing on intramolecular cooperation between side-chain functions H-Leu-His-OH proved particularly useful.111... 

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. 

Cordova, A. Zou, W. Ibrahan, I. Reyes, E. Engqvist, M. Liao, W.-W. Acyclic amino acid-catalyzed direct asymmetric aldol reactions Alanine, the simplest stee-oselective organocatalyst, Chem. Common. 2005, 3586-3588. 

This class of catalysts covers chemocatalysts that do not contain a transition metal. The class has been known for many years, but it is relatively recently that the term organocatalyst has been used (209). A wide variety of transformations can be performed, which is currently an area of intense research (209-218). Table 5 (220-252) summarizes some key transformations in which organocatalysis can be useful. Reactions range from the asymmetric epoxidation of alkenes, which need not be conjugated to another functional group, to aldol reactions and... 

The aldol reachon is one of the most efficient methods for extending the carbon framework of an organic synthon. Since the discovery of the Lewis acid-catalyzed asymmetric aldol reaction of silyl enol ethers by Mukaiyama, numerous variations of this type of reaction have been reported [80]. Recently, more attention has been focused on the development of new organocatalysts for the asymmetric direct aldol... 

In this context, Agarwal and Peddinti synthesized novel a- and p-glu-cosamine organocatalyst 11, which was employed in the asymmetric aldol reaction between cyclohexanone and aryl-substituted aldehydes. These researchers observed that the ot-anomer catalyzes the reaction more efficiently than the p-anomer, affording the desired products in high enan-tioselectivities (Scheme 27) (11JOC3502). 

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. 

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. 

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. 

Reproduced with permission from Machuca E, Rojas Y, Juarlsti E Synthesis and evaluation of (S)-prolhe-contalnlng a. p-dipeptides as organocatalysts In solvent-free asymmetric aldol reactions under ball-milling conditions. Asian J Org Chem 2015 4 46-53. Copyright (2015), Wiley. 

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