Stereoselectivity Passerini reactions

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. 

Both Ugi and Passerini reactions have been explored, using 3-substituted propy-noic acids as dienophiles. The multicomponent adducts 93 have been submitted to IMDA under different conditions, depending upon the heteroatom X in the tether Ugi adducts could be converted smoothly, usually under thermal conditions, to give 94 as the major stereoisomer (less than 10% of any other stereoisomer detected). On the contrary, Passerini adducts proved to be unreactive under thermal conditions, but reacted cleanly under Me2AlCl catalysis to give bicyclic lactones in a highly stereoselective way (Scheme 1.33) [83],... 

Frey, R., Galbraith, S. G., Guelfi, S., Lamberth, C., Zeller, M. First examples of a highly stereoselective Passerini reaction A new access to enantiopure mandelamides. Syn/eff 2003, 1536-1538. 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

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-... 

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]. 

Ruijter and coworkers elegantly combined stereoselective MCR chemistry with biocatalysis to obtain telaprevir 47, which is a pharmaceutical drug (Incivek or Incivo ) for the treatment of hepatitis C (Scheme 6.4) [21]. In the fu-st step, a Passerini three-component reaction gives access to form 42, which is, upon treatment with NMM (A-methyhnorpho-line) and triphosgene, converted to isocyanide 43. The latter further reacts with the pyrroUne derivative 45 (arose from the desymmetrization of the 3,4-disubstituted meso-pyrro-lidine with monoamine oxidase-N (MAO-N, derived from... 

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