Aldol organocatalytic reaction

Scheme 2.63. Organocatalytic synthesis of 2-271 by a domino O-nitroso-aldol/Michael reaction.

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. 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

When a-alkoxyaldehyde substrates were subjected to organocatalytic conditions, a highly enantioselective aldol dimerization reaction occurred6 (Scheme 2.3f). Substrates bearing relatively electron-rich alkoxy groups provide dimers... 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

One of the first synthetically useful organocatalytic C-N bond forming cycloaddition reaction came with the work of Yamamoto et al. [125] reported in 2004. Based on enamine activation, they developed the tandem 0-nitroso aldol/Michael reactions of cyclic enones to generate nitroso Diels-Alder adducts in moderate yields and high enantioselectivities (Scheme 11.44). 

Asymmetric C-C bond formation based on catalytic aldol addition reactions remains one of the most challenging subjects in synthetic organic chemistry. Although many successful nonbiological strategies have been developed [1355, 1356], most of them are not without drawbacks. They are often stoichiometric in auxiliary reagent and require the use of a metal or organocatalytic enolate complex to achieve stereoselectivity [1357-1360]. Due to the instability of such complexes... 

For other example of the use of same type of catalyst, in the obtainment of indole derivatives, see D. Enders, C. Wang, M. Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447-2449. Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenyhnethyl)-indoles via a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation reaction. 

Wang, J., Li, H., Xie, H., Zu, L., Shen, X., Wang, W. (2007). Organocatalytic enantioselective cascade Michael-aldol condensation reactions efficient assembly of densely function-aUzed chiral cyclopentenes. Angewandte Chemie International Edition, 46, 9050-9053. 

Bor-Cherng, H., Nitin, S. D., Che-Sheng, H., Ju-Hsiou, L. (2010). Sequential organocatalytic Stetter and Michael-Aldol condensation reaction asymmetric synthesis of fuUy substituted cyclopentenes via a [I -l- 2 -I- 2] annulation strategy. Organic Letters, 12, 4812-4815. 

Jhuo, D.-H., Hong, B.-C., Chang, C.-W., Lee, G.-H. (2014). One-pot organocatalytic enantioselective Michael-Michael-Aldol-Henry reaction cascade. A facile entry to the steroid system with six contiguous stereogenic centers. Organic Letters, 16, 2724-2727. 

The aldol reaction is one of the oldest and most important methods for the construction of carbon-carbon bonds in organic chemistry (17), and numerous organocatalytic reactions target this important transformahon. 

Organocatalytic reactions have been investigated using water in small (1-3 equiv.) or higher amounts. It was reported that the proUne-catalyzed reaction of acetone and 4-nitrobenzaldehyde tolerated a small amount of water (<4 vol.%) without affecting the enantiomeric excess of the aldol product However, increasing the amount of water (20 vol.%) severely compromised the enantioselectivity and decreased the rate of formation of the aldol product [5b]. 

Scheme 36.19 Organocatalytic intramolecular aldol/lactonization reaction.

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

Scheme 15 Use of organocatalytic aldol-Michael reactions to tetrahydrofurans by McQuade etal. [13]...

Synthetic peptide dendrimers, catalytic antibodies, RNA catalysts, peptide foldamers as well as other native or modified enzymes with completely different fxmctions were discovered to catalyze carbon-carbon bond formation [15]. 4-Oxalocrotonate tau-tomerase (4-OT) catalyzes in vivo the conversion of 2-hydroxy-2,4-hexadienedioate (136) to 2-oxo-3-hexenedioate (137) (Scheme 10.33a), and it belongs to the catabolic pathway for aromatic hydrocarbons in P. putida mt-2 [200]. This enzyme carries a catalytic amino-terminal proline, which could act as catalyst in the same fashion as the proline mediated by organocatalytic reactions. Initial studies demonstrate that this enzyme was able to catalyze aldol condensations of acetaldehyde to a variety of electrophiles 138 (Scheme 10.33b) [200]. This enzyme was also examined as a potential catalyst for carbon-carbon bond forming Michael-type reactions of acetaldehyde to nitroolefins 139 (Scheme 10.33c) [201,202]. 

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