Cyclization of side chains

Cyclization of side chain nitriles has found extensive use in the synthesis of benzocyclobutenes (70 n = 2),104 the versatile synthons which open on mild thermolysis to give o-quinodimethanes for inter- and intra-molecular [4 + 2] trapping.108 The nitrile group in (70) can be manipulated into a variety of functionalities for appending the dienophile portion. For example, in the synthesis of chelidonine, the nitrile (71) was converted, by hydrolysis followed by Curtius degradation and reaction of the formed isocyanate with benzyl alcohol, to a urethane (72). The latter was then condensed with a benzyl bromide to get the compound (73), which was elaborated further as shown in Scheme 14.109... 

Cyclization of side chains may also occur vithout bond scission as in polyacrylonitrile (see Section 15.4.6.3). 

The combination of our solid-phase methods for a-ketoacid and N-terminal hydroxylamine syntheses invited their application to the synthesis of macrocychc peptides by the cyclization of side-chain unprotected linear peptides. Cyclic peptide is an important and rapidly growing area of new therapeutics, and novel methods for their facile preparation are in great demand. We reasoned that our methods could be used to prepare suitably functionalized linear peptides that should cyclize simply upon warming them in an appropriate solvent. 

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