Chiral isocyanide, isonitrile

While chiral isocyanides such as a-substituted isocyanoacetates also usually react with low stereoselectivity, the specially designed, camphor-derived, isonitrile 11... 

Of the four components reacting in the Ugi reaction, the isocyanide and the carboxylic acid have only limited influence on the overall stereoselection. For instance, in the synthesis of 13-demethyldysidenin (R)-l and 13-demethylisodysidenin (S)-l from a chiral aldehyde, chiral carboxylic acid, isonitrile and methylamine79. 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

The four-component condensation of isocyanides (also called isonitriles), discovered by Ugi in the late 1950s (Ugi four component reaction, Ugi-4CR) [176], provides another alternative to the classical methods of peptide synthesis in solution [177-180], The Ugi-4CR has been extensively studied in every conceivable aspect and several variants of the general scheme give different products. In one variant that is particularly relevant to the topic of this article, an N-protected peptide or amino acid, a chiral primary amine, an aldehyde and an isonitrile peptide fragment are combined to yield, via a spontaneous rearrangement of an unstable a-adduct, a compound 74 in which a new peptide segment has formed (Scheme 5.38, see also Section 5.4.1 above for an application of Ugi-4CRto PNA synthesis). 

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. 

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