Backbone cyclisation

In vivo, formation of the disulphide bridges in cyclotides might be facilitated by a protein disulphide isomerase (PDI) recently isolated from O. affinis,129 whereas backbone cyclisation is mediated by an asparaginyl endopepti-dase.130,131 Support for the latter proposal comes from the fact that a C-terminal Asn residue is essential for cyclisation of the peptide backbone. Violacin... 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

The dithiadecalin (34) was used to provide the carbon backbone for C-3 to C-8 and C-9 to C-13. Compound (34) was obtained in an optically active form by a route involving an enantioselective (36% e.e.) aldol cyclisation catalyzed by (R)-proline71). 

Our coverage includes bacterial, plant and animal toxins and we focus mainly on the period from approximately 2003 onwards, with some early examples also included for historical perspective, or for completeness in defining the scope of structures determined. For the examples we describe in more depth, there is an emphasis on studies from our laboratory, but these are illustrative of a wide range of studies from other laboratories. Our laboratory has had a particular interest in peptides that have head-to-tail cyclised backbones and so a number of the examples fit this theme. 

Figure 3.3 Mechanism of action of esperamicin A i. Reduction of the trisulfide and Michael-type addition increases the freedom of movement within the enediyne allowing the formation of a diradical intermediate by means of a Bergman cyclisation. When bound to DNA, the diradical abstracts hydrogens from the DNA backbones which are subsequently trapped by oxygen and lead to strand cleavage. The star notes the location of the reactive enediyne functionality of esperamicin Ai.

Tilting of the N-aryl ring of U relative to the imidazolidine ring positioned the ortfto-eyelohexyl substituent anti to the backbone phenyl group and distal to nickel. This orientation then positioned the ort/zo-methyl substituent syn to the backbone phenyl group and proximal to nickel. It was the ortho-methyl substituent that thus dictated the selectivity of aldehyde binding according to this model. Oxidative cyclisation of U to metallacycle V then led to the formation of the final product. 

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