Organocatalysed Reactions

While the end of the last century was dominated by the use of metal catalysts, a change in perception has occurred during the last few years when several reports confirmed that relatively simple organic molecules could be 

96% ee. The best results were obtained with C4-aryl-substituted azlactones, which was remarkable given the fact that the highest enantiomeric excess previously reported for either enzymatic or non-enzymatic DKR of these substrates has been 75%. 

In 2005, Cordova s group reported highly chemo-, diastereo- and enantio-selective L-proline-eatalysed DYKATs of various /i-hydroxyaldehydes.The remarkably high seleetivity of L-proline was employed in the novel one-step 

In the same context, Daran s group has described the DKR of a chloro-phosphine accomplished by treatment with a chiral disulfide in the presence of 

In another context, an L-valine-derived formamide was applied by Kocov-sky s group as an organocatalyst to the asymmetric hydrosilylation of enam-ines, allowing a direct access to a range of jS-amino add derivatives. This method relied on the fast equilibration between the enamine and the imine 

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The use of ketenes as electrophilic partners in NHC-organocatalysed reactions has been reviewed in Chinese, and the involvement of NHC in organocatalytic redox processes has been discussed. ... 

In addition to simple enantioselective two-component tandem multi-organocatalysed reactions, several groups have recently reported multi-component reactions based on the enantioselective sequential multiorganocatalysis concept. For example, Cordova et al. disclosed in 2011 a highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine catalysis and iV-heterocyclic carbene catalysis, which allowed the synthesis of a range of chiral N-tert-butox-ycarbonyl and N-carbobenzyloxy-protected (3-amino acid esters to be... 

Diner P, Kjaersgaard A, Lie MA, Jprgensen KA. On the origin of the stereoselectivity in organocatalysed reactions with tri-methylsilyl-protected diarylprolinol. Chem. Eur. J. 2008 14 (1) 122-127. 

DFT has been used to investigate the Diels-Alder reactions of cyclopentadiene with a,/S-unsaturated aldehydes and ketones organocatalysed by MacMillan s chiral... 

If maximizing catalyst hydrophobicity is the key to success in the organocatalysed aldol reaction under liquid/liquid biphasic aqueous conditions using catalysts 3-16, this property does not generally provide practical recycling procedures. 

Palomo et al. have extended the range of nucleophiles amenable in asymmetric organocatalysed Michael reactions of nitronates and malonates to oc,P-unsaturated aldehydes Inspired by the prolinol motif, they proposed a series of derivatives, among which 21 was the most efficient catalyst for the nitro-Michael reaction of Scheme 1.11 and the Michael reaction of Scheme 1.12. These reactions required the use of benzoic acid as co-catalyst to optimize results. 

The pivotal step associated with our approach to compounds 31-34 was an organocatalysed, enantioselective and intramolecular Michael addition reaction of the nucleophilic C-2 carbon of a pyrrole to an iV-tethered a,p-unsaturated aldehyde residue and thereby estabhshing the required CD-ring system. Full details of the reaction sequence are shown in Scheme 4 and this involves initial reaction of the potassium salt, 35, of pyrrole with butyrolactone (36) to give, after acidic workup, compound 37 (60-90%). Conversion of this last species into the corresponding Weinreb amide 38 (87%) followed by its reaction with ethylmagnesium bromide then afforded the ethyl ketone 39 (95%) that was subjected to standard Homer-Wadsworth-Emmons (HWE) conditions and thereby generating the... 

Figure 7.6 Transition state of the organocatalysed anf/-Mannich reaction...

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

Electron-deficient alkenes undergo cyclopropanation by reaction with a range of metal-free ylides and some of the most recent work in this area has focussed on the development of an organocatalysed cyclopropanation using these species. 

Aromatic nitrogen heterocycles, especially triazoles and tetrazoles are the most common nucleophiles used in the organocatalysed aza-Michael reaction. 5-Phenyltetrazole undergoes conjugate addition with acyclic enals using the tri-fluoracetate salt of imidazolidinone (11.127), while the 1,4-addition of phenyl-tetrazole and 1,2,4-triazole (11.130) occurs with high ee using the enantiopure pyrrolidine catalyst (11.79). ... 

Fteproduced from GuiSena G, del Carmen Hita M. Nijera C, Vidzquez SF Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (SJ-binam-L-prolinamide. Tetrahedron Asymm 2007 18 2300-4. Copyright (2007). with permission from Elsevier. 

As an extension of the organocatalysed Diels-Alder reaction, the List group developed a three-component domino Knoevenagel-hetero-Diels-Alder using ketones, aldehydes and Meldrum s acid (Scheme 5.42). ... 

Organocatalysed aldol reaction has been extensively studied after being rediscovered in 2000 when List et al. developed the first proline-catalysed asymmetric direct intermolecular reaction. The aldol process is defined as the reaction of two carbonyl compounds to produce p-hydrojq carbonyl derivatives, and many combinations of starting compounds could be envisaged, but the most studied are summarised in Scheme 6.1. 

In contrast to aldol reactions, the major diastereoisomer formed in the Mannich reaction has syn configuration, because the orientation of the imine is opposite to that of the carbonyl in the transition state (figure C in Scheme 6.5). Carter et al. reported an organocatalysed domino Mannich-aza-Michael reaction for accessing nitrogen-containing [2.2.2]-bicyclic scaffolds promoted by 15e, in a highly enantioselective and diastereoselective manner (eqn. (3) in Scheme 6.5). 

Hartikka and Arvidsson demonstrated the high catalytic efficiency of catalyst 5a for the direct aldol reaction of acetone with various aldehydes. In the organocatalysed direct asymmetric aldol reaction, acetone reacted with aromatic and aliphatic aldehydes, resulting in formation of p-hydro) ketones with good yields and moderate to high enantiomeric excesses (Scheme 9.9). ... 

These first examples on the primary amino acid organocatalysed aldoli-sation prompted researchers to investigate two relevant parameters the need to study the mechanism in order to get a better understanding of the syn- or anh -selectivity, and the role displayed by water in the reaction medium. 

The first experiments of an organocatalysed aldol condensation between acetone and 4-nitrobenzaldehyde with aliphatic amino acids in anhydrous conditions (DMSO acetone 4 l) led to the desired adduct in very low yields (<10%). In 2005, Amedjkouh and Cordova independently showed the importance of additional water in the reaction medium to improve the yields. The concept was based on the hypothesis that a molecule of water would participate in a proton relay in the aldolase system, and would allow for a faster hydrolysis of the intermediates. A hydrophobic amino acid might be efficient in aqueous media by strong association with hydrophobic reactants. Furthermore, water would restore the catalyst from its deactivation by condensation with the aldehyde. 

Scheme 19.62 Organocatalysed domino Michael-aldol reaction for the construction of bispiro-oxindoles.

The use of C2-symmetric A,Ai -dioxide amides in a wide variety of chiral ligand-/metal-catalysed or organocatalysed asymmetric reactions has been reviewed. Other reviews include chiral spiro catalysts and the organic and carbohydrate chemistry relevant to biomass. " ... 

A prominent example of this catalytic methodology is the Stetter reaction. Although numerous NHC-organocatalysed versions of this reaction have been developed, it is only very recently that a mechanistic investigation has been detailed in the literature. The intramolecular asymmetric Stetter reaction of substrates (102) catalysed by triazolinylidene-based NHC (103) has been employed as the model reaction and the experimental results obtained have evidenced that the [l,2]-proton shift giving precisely Breslow intermediate (101) is not only slow but above all, the first irreversible step of the transformation. Also noteworthy is that (102) precursors are prone to cyclize not only to the expected six-membered Stetter products (104) but also to benzofurans (105), the latter resulting from a base-mediated mechanism related to the basic feature of the catalyst. 

The goal of this book is to cover the principal methods employed to obtain DKR by enzymatic or non-enzymatic methods that have been reported in the last fifteen years and to illustrate the diversity of useful produets that ean be obtained through this powerful coneept. The aim of this book is to demonstrate that some most important achievements, such as organocatalysed DKRs, and enzymatic or non-enzymatic transition metal-catalysed DKRs, have considerably expanded the synthetic scope of the proeess. Moreover, a great number of novel enzymatic DKRs have been developed. The atropose-lective reactions reported by Bringmann et al. and their application in the synthesis of natural products and chiral auxiliaries are also included. ... 

Wilson RM, Jen WS, MacMillan DWC (2005) Enantioselective organocatalysed intramolecular Diels-Alder reaction. The asymmetric synthesis of solanapyrone. J Am Chem Soc 127 11616-11617. doi 10.1021/ja054008q... 

In spite of the explosive growth of enantioselective organocatalysed domino reactions in the last decade,an increasing number of enantioselective metal-catalysed domino processes have been developed in the last few years. A domino reaction has been defined by Tietze as a reaction which involves two or more bond-forming transformations, taking place under the same reaction conditions, without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality... 

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