Enantioselective Passerini Reaction

FIGURE 8.3 Scope of the [(salen)Al "Cl] 41-catalyzed enantioselective Passerini reaction. 

Scheme 9.14. Lewis base-catalyzed enantioselective Passerini-type reactions.

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. A SiCl4-mediated reaction in the presence of a chiral bis-phosphoramide gives an a-hydroxy amide with good enantioselectivity. The following mechanism has been postu-... 

Denmark, S. E., Fan, Y. The First Catalytic, Asymmetric a-Additions of Isocyanides. Lewis-Base-Catalyzed, Enantioselective Passerini-Type Reactions. J. Am. Chem. Soc. 2003, 125, 7825-7827. 

Scheme 5.41 Lewis base-catalyzed enantioselective truncated Passerini reaction.

We have developed a (salen)AlCl (141 (-catalyzed enantioselective three-component Passerini reaction (Scheme 5.44) [87]. In order to overcome the catalyst turnover dilemma, using a chiral catalyst with only one coordination site available was the working hypothesis of our research, and this turned out to be rewarding. A variety of non-chelating aldehydes, including a-branched compounds, carboxylic acids, and isocyanides participated in this catalytic enantioselective process to afford Passerini adducts in good to excellent ee. Unfortunately, aromatic aldehydes were not acceptable as substrates under these catalytic conditions. The similar catalyst (salen)AlMe... 

Titanium chelates of semi-salen 59 and salen 60 are used in asymmetric synthesis of a-cyanoalkyl ethyl carbonates from aldehydes and ethyl cyanoformate. By changing the metal atom to aluminum for complexing 60 a catalyst for elaborating a-acetoxy amides (Passerini reaction) is obtained (but enantioselectivity varies)/ ... 

A recently reported [1,59] enantioselective catalyst for the Passerini reaction is (12.381). Phosphorus-containing enantioselective catalytic metal complexes have been covalently attached to magnetic nanoparticles [60]. 

Wang S-X, Wang M-X, Wang D-X et al (2008) Catalytic enantioselective Passerini three-component reaction. Angew Chem Int Ed 47 388-391... 

Denmark has described several chiral bis-phosphoramides as Lewis base activators of weak Lewis acid SiCL and demonstrated their ability to mediate an enantioselective Passerini-type reaction. Catalytic bis-phosphoramide 36 and stoichiometric SiCU, in the presence of a proton scavenger (Htinig s base), promoted the formation of a-hydroxyamides with remarkably good enantioselectivity and yield. A variety of aromatic and unsaturated aldehydes and aryl, alkyl, and functionalized alkyl isocyanides proved to be useful and effective starting materials. High yields of Passerini products were attributed to the production of imidoyl chloride 37, which reduced the prevalence of the nitrilium intermediate and prevented the addition of a second equivalent of isonitrile. 

Almost simultaneously, the same research group disclosed a [(salen)Al "Me] 43-catalyzed enantioselective Passerini-type reaction of aldehydes, isocyanides, and hydrazoic acid 42, affording a great scope of tetrazole derivatives 44 with good to excellent enantioselectivities (51-95%) (Scheme 8.16) [39]. 

S.-X. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2008, 47, 388-391. Catalytic enantioselective Passerini three-component reaction. 

This organic reaction is the first multi-component reaction based on isocyanides it currently plays a central role in combinatorial chemistry. Recently S. E. Denmark and Y. Fans have developed an enantioselective catalyst for asymmetric Passerini reactions, whose reaction mechanism is not well understood even to this day [12]. 

Denmark SE, Fan Y (2003) The first catalytic, asymmetric alpha-additions of isocyanides. Lewis-base-catalyzed, enantioselective Passerini-type reactions. J Am Chem Soc 125 7825-7827... 

Yue T, Wang M-X, Wang D-X, Zhu J (2008) Asymmetric synthesis of 5-(l-hydroxyaIkyl) tetrazoles by catalytic enantioselective Passerini-type reactions. Angew Chem hit Ed 47 9454-9457... 

The sequential use of the organocatalytic a-amination of aldehydes by azodicar-boxylates with another process has provided a useful tool for the synthesis of complex molecules. Thus, the combination of the amination of linear aldehydes catalyzed by (5)-proline (20) and the Passerini reaction allowed the rapid access to norstatine based peptidomimetics albeit with low diastereoselectivities (36-98% yield, up to 4 1 dr) [27]. Moreover, the enantioselective synthesis of y-amino-a,P-unsaturated esters can be performed via the sequential a-amination-Homer-Wadsworth-Emmons olefination of aldehydes catalyzed by (5)-proline (20,10mol%) affording the expected products in high yields and enantioselectivities (85-90% yield, ee 92-99%) [28]. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

In a related study Denmark and Fan [22] investigated chiral Lewis base-catalyzed enantioselective a-additions of isocyanides to aldehydes in a Passerini-type reaction (Scheme 9.14). The development of the reaction was based on the concept of Lewis base activation of a weak Lewis acid such as SiCl4 forming a trichlorosilyl-Lewis base adduct which is capable of activating aldehydes towards nucleophilic attack. 

To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,p-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereo-genic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometaUic chiral catalysts and orga-nocatalysts [33, 34]. 

Schreiber and co-workers have described the use of a copper(II) complex with an aminoindanol-derived pyBOX ligand for the catalytic enantioselective addition of isonitriles to bidentate aldehydes to give a-acyloxyamides such as 38. Excellent yield and good enantioselectivity is observed in many cases and the protocol was also applied toward tandem Passerini-intramolecular Diels-Alder reactions for use in complexitygenerating diversity oriented synthesis. 

Denmark SE, Ean Y (2005) Catalytic, enantioselective a-additions of isocyanides Lewis base catalyzed Passerini-type reactions. J Org Chem 70 9667-9676... 

Lewis acid catalysis serves for the Passerini-type reaction of aldehydes with isocyanides forming a-hydroxyamides. The catalytic system consisting of SiCU and (107) provides high yield and good to excellent enantioselectivity for the addition of t-butyl isocyanide to a wide range of aldehydes [167]. The amide product is formed from the imidoyl chloride intermediate (110) by hydrolysis (Scheme 9.78). Treatment of the intermediate product with methanol followed by hydrolysis gives a-hydroxyesters with the retention of enantioselectivity. 

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