Diastereoselective Passerini Reaction

There are many examples of Passerini-tj e reactions mediated by Lewis acids with TiCU having the most widespread use. Passerini-type reactions using TiCU are compatible with a variety of functional groups as can be seen in the nearly quantitative reaction of a-isocyano phosphonate ester 25 with benzaldehyde. An examination of TiCU-mediated diastereoselective Passerini reaction failed to show any clear stereoselection with chiral isocyanide 26 among many other cases. Weaker Lewis acids such as SiCL can also mediate Passerini-twe reactions, but effectively do so only in the presence of a Lewis base. Demnark demonstrated that a-hydroxyamides, such as 27, could be formed in good yields, by using Lewis bases such as pyridine-7V-oxide to activate the SiCU-... 

P. R. Krishna, G. Dayaker, P. V. N. Reddy, Tetrahedron Lett. 2006, 47, 5977-5980. Diastereoselective Passerini reactions using /)-toluenesulfonyhnethyl isocyanide (TosMlC) as the isonitrile component. 

In the discussion of the various examples, we will concentrate more on the secondary transformations than on the Ugi or Passerini reaction themselves, which are in most cases carried out under standard conditions (alcoholic solvents for the Ugi and apolar solvents for the Passerini). Classical IMCRs are well known to be, in most cases, poorly diastereoselective and thus the stereochemical aspect, aheady described in a previous review [13], will be mostly ignored in this chapter. 

Most attempts to construct diastereoselective variants of the Passerini reaction have met with a certain degree of failure. Undoubtedly, the numerous uncertainties of the reaction mechanism have contributed to these difficulties. The usual low levels of control for the Passerini reaction have also impeded efforts to establish empirical trends in the diastereofacial selectivity. This is exemplified in the construction of peptidomimetics, a class of molecules which has stimulated numerous applications of the Passerini reaction, where the diastereoselectivity is typically in the range of 1 1 to 4 1, A survey of results of the diastereofacial selectivity of carbonyl addition does not consistently follow a clear trend of either the Felkin-Anh or chelation-controlled models of carbonyl addition. ... 

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... 

Diverse sugar-derived aldehydes 15 (Scheme 11.6) were used as chiral auxiliaries to perform the diastereoselective three-component Passerini reaction by reaction with p-toluenesulfonylmethyl isocyanide (17a, TosMIC) and carboxylic acids 16, giving... 

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]. 

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]. 

For the classic P-3CR there are only a few examples of auxiliary-controlled highly diastereoselective reactions. Ugi developed a camphor-based nonracemic isonitrile which gave good yields of Passerini products with high diastereoselection (92-93% de). However, this methodology was demonstrated for only a very limited number of simple alkyl aldehydes. 

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