Asymmetric Passerini Reactions

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]. 

A recent screening of various chiral carboxylic acids has allowed the selection of galacturonic derivative 12 as a very efficient control in the stereochemical course of some Passerini reactions (Scheme 1.5). Although the de seems to be strongly dependent on the isocyanide employed, this result suggests the possibility of employing carboxylic acids as easily removable chiral auxiliaries in the asymmetric synthesis of biologically important mandelamides [16]. 

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

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)/ ... 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

In sharp contrast to the importance acquired by asymmetric catalysis in the last decades, and although asymmetric induction has been achieved in Passerini reaction through diastereoselective approaches by using chiral substrates and/or chiral auxiliaries [33], the number of catalytic asymmetric procedures reported is still limited for this reaction and it remains as a significant challenge [34], Several drawbacks exist that make this task particularly difficult to... 

In 2008, Wang and Zhu s group reported the catalytic asymmetric Passerini-type reaction of aldehydes, isocyanides and hydrazoic acid with... 

Scheme 19.61 Asymmetric Passerini-type reactions catalysed by Al(salen).

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]. 

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. 

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

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... 

Sehlinger A, de Espinosa LM, Meier MAR (2013) Synthesis of diverse asymmetric a,co-dienes via the Passerini three-component reaction for head-to-tail ADMET polymerization. Macromol Chem Phys 214(24) 2821-2828... 

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... 

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