Synthetic isonitrile derivatives

The linear macrocycle precursor 84 is formed in one step by Ugi reaction between tyrosamine-derived isonitrile 85, a-methylene acids 86, and simple aldehydes and amines (route A). This synthesis plan combines the generation of significant molecular complexity with a short synthetic sequence and several possibilities for variation. 

Isonitriles are a unique class of organic compounds, as they are the only stable derivatives (apart from carbon monoxide) containing formally a bivalent carbon. Their discovery by Lieke, Gautier, and Hofmann dates back more than 130 years, but up to the 1960s only a relatively small number of studies concerning their chemistry had been reported [1], This was probably because of the virtual absence of convenient, generally applicable synthetic methods, as well as their very penetrating, unpleasant smell. 

The potent antitumor agents camptothecin (11) and its derivatives are targets of extensive synthetic activities. [7] A major contribution to this research area came from the laboratory of D. R Curran [3] in Pittsburgh with a total synthesis of camptothecin relying on radical chemistry. In the key step of his synthesis (Scheme 2) the iodoalkyne 9 was allowed to react with phenyl isonitrile to provide the target compound 11. 

Silyl cyanides react enantioselectively with such electrophiles as aldehydes, ketones, imines, activated azines, or,/ unsaturated carbonyl compounds, epoxides, and aziridines in the presence of chiral Lewis acid catalysts to give functionalized nitriles, versatile synthetic intermediates for hydroxy carboxylic acids, amino acids, and amino alcohols (Tables 3-6, 3-7, 3-8, and 3-9, Figures 3-6, 3-7, and 3-8, and Scheme 3-154). ° Soft Lewis acid catalytst, the reaction of epoxides with trimethylsilyl cyanide often leads to isonitriles, which are derived from silylisonitrile spiecies (Schemes 3-155 and 3-156). Soft Lewis base such as phosphine oxide also catalyzes the reaction and cyanohydrin silyl ethers of high ee s are isolated. 

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