Organocatalytic transformation

Major advances in the application of NHCs in organocatalysis have been achieved, and this arena has become a focus of considerable research. The use of chiral NHCs has allowed access to highly enantioselective organocatalytic transformations and the breadth and depth of reactivity that can be accessed is ever expanding. 

Although dimeric Sharpless ligands as catalysts showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 5.12) [70]. These compounds are bifunctional catalysts in the presence of acid additives one of the two amine function of the dimers forms a salt and serves as an effective Bronsted acid, while another tertiary amine of the catalyst acts as a nucleophile. Whereas salts derived from (DHQD)2PYR, or (DHQD)2PHAL afforded trace amounts of products in the addition of methyl acrylate 8a and electron-deficient aromatic aldehydes such as 27, (DHQD)2AQN, 56, mediated the same transformation in ee up to 77%, albeit in low yield. It should be noted that, without acid, the reaction afforded the opposite enantiomer in a slow conversion. 

The asymmetric organocatalytic transformation of a ketone into an alcohol may be realized with the combination achiral silanexhiral phase-transfer catalyst, such a quaternary ammonium salt. The final alcohol is then recovered by an additional hydrolytic step. The asymmetric reduction of aryl alkyl ketones with silanes has been reported (ee-values up to 70%), the catalysts utilized being ammonium fluorides prepared from the quinine/quinidine series (e.g., 18 in Scheme 11.6) [19]. (For experimental details see Chapter 14.21.1). The more appropriated silanes were (Me3SiO)3SiH or (MeO)3SiH (some examples are... 

This chapter provides sample procedures of asymmetric organocatalytic transformations organized according to reaction types. 

It is the aim of this book to provide a concise and comprehensive treatment of this rapidly evolving field, focusing on the preparative aspect of this chemistry. In fact, the use of organocatalytic transformations in a multistep synthesis remains scare. This book wishes to promote the application of these reactions, giving solid synthetic evidence. Additionally, a collection of sample procedures of typical... 

Apart form a great number of chiral NHC carbenes that have been used as ligands in enantioselective transition-metal catalysis (Gade and Bellemin-Laponnanz 2007), some less usual heterazolium salts have been tested in organocatalytic transformations. A planar-chiral thia-zolium salt (Pesch et al. 2004) and a rotaxane-derived precatalyst were reported (Tachibana et al. 2004), as well as catalytically active peptides containing an unnatural thiazolium-substituted alanine amino acid (Fig. 3 Mennen et al. 2005a,b). 

Sentman AC, Csihony S, Waymouth RM et al. (2005) Silver(I)-carbene complexes/ionic liquids novel N-heterocyclic carbene delivery agents for organocatalytic transformations. J Org Chem 70 2391-2393... 

An extremely useful summaiy of low-loading asymmetric, organocatalytic transformations has been compiled by Giacalone and Gruttadauria et al7 Apart from the chemical transformations that have been developed and are described herein, tremendous efforts have been made to render... 

Michael additions are among the most important organocatalytic transformations.The ability of prolinol silyl ethers to form enamines, diena-mines, trienamines or iminium ions makes them appealing in a number of chemical transformations based on addition of a nucleophile to an a,p-unsaturated carbonyl compound or other Michael acceptor. The first example of Michael addition catalysed by a prolinol silyl ether was published by Hayashi and coworkers. Aliphatic aldehydes added to a range of aryl-substituted nitroalkenes. Prolinol silyl ether Cla presumably formed chiral enamines with aldehydes. The F-anh-enamine was formed and it reacted with nitroalkene via an acyclic synclinal transition state, originally proposed... 

While in principle many different substituents may be introduced stereoselectively using this methodology, only (S)-a-2-methyl-proline (7a, R = CH3) and derivatives have been applied in organocatalytic transformations. 

Hydroxy-proline trans-12) is a much less common natural amino acid found in mammalian collagen, whereas the cis diastereoisomer may eventually be synthesised in multigram scale by the baker s yeast reduction of the corresponding 3-keto-ester, with excellent selectivities. Thus, 12 or its derivatives have rarely been used in organocatalytic transformations. 

Recently, a detailed study on the use of unprotected hydroxy-prolines in several asymmetric organocatalytic transformations was reported by Al-Momani. In the benchmark aldol addition between acetone and p-nitro-benzaldehyde, ds-3-hydroxy-proline (ds-12) afforded the best enantio-selectivity, with excellent activity (Scheme 11.13A). On the other hand, in the analogous Mannich addition, cis-12 afforded the worst enantioselectivities, albeit maintaining good catalytic activities (Scheme 11.13B). 

In 2013 Cozzi et al. prepared the 2-(diethylferrocenyl) pyrrolidine (S)-36 starting from ferrocenyl ethyl ketone (Scheme 11.37) and proved its effectiveness in different organocatalytic transformations, namely the Michael addition of aliphatic aldehydes to aromatic nitroalkenes (Scheme 11.38A) and the SNl-asymmetric a-allgflation of carhonyl compounds (Scheme 11.38B). ... 

Although dimeric Sharpless ligands, as another kind of cinchona catalyst, showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 2.78). These compounds can act as bifunctional catalysts in the presence of acid... 

Figure 18.2 Simple preparation of imidazolidinone catalysts and imidazolidinone catalysts used in organocatalytic transformations.

Very recently, by utiUzing alkylthiols as nucleophile, Cheng and co-workers [ 144] reported the first example of chiral allyhc thiols synthesis based on organocatalytic transformation of BH carbonates. (DHQD)2PHAL (74) was found to be the best catalyst, rendering the product in modest to excellent yields and with good... 

Another successful example can be found in Hayashi total synthesis of (-l-)-cyto-trienin A (27), a translation inhibitor that induces ectodomain shedding of TNF receptor [12]. There are two organocatalytic transformations in this quite complex but fascinating synthesis (Scheme 17.4). First, the key intermediate diol 20 was obtained in large scale through an organocatalytic aldol reaction between two... 

The examples depicted so far have made use primarily of single organocatalytic transformations conducted typically quite early in the multi-step sequences applied towards the syntheses of complex natural products. In contrast, more and more reports describing organocatalytic cascade reactions or combined approaches using different organocatalytic key transformations to achieve a complex synthesis have been reported over the last several years (30, 32, 176-178). In this chapter, the application of combined enamine-catalyzed approaches for the syntheses of natural products will be described. Examples using different activation modes (e.g. enamine and iminium activation) will be discussed later. 

Scheme 113 Organocatalytic transformation in the total syntheses of (—)-lycoramine (525), (—)-galanthamine (526), and (+)-lunarine (527)...

Given the huge diversity and rapid growth in organocatalysis, can this area continually progress The power of many organocatalytic transformations lies in their simple experimental protocols and catalyst designs combined with the... 

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