Bouvardin, conformation

Cyclic hexapeptides can be considered as the classical and the most prominent representatives among cyclic peptides. Natural products are numerous and widespread (see Scheme 11), e.g. segetalin A,[278] bouvardin/279280 RA-IIlJ281-283 or pneumocandin B0,[284 286] and this type of ring structure has frequently been used to stabilize conformational preferences of bioactive portions of larger peptides or even proteins. 

Later, the crystal structures of RA-VI (152) (Fig. 25) [95] and isomerized RA-VII (174) (Fig. 26) [96], neither showing antitumor activity, were reported. The backbone conformation of these molecules differ from that of the 18-membered ring of RA-VII and bouvardin. 

The presence of two conformers in chloroform solution was suggested by HPLC analysis [97]. However, separation on a preparative scale was not achieved because of fast exchange at room temperature. Conformational analysis of the two states in chloroform solution was performed using NMR and computational methods. R. B. Bates et al. indicated that the predominant stereoisomer and conformer in solution for deoxybouvardin and bouvardin is the same as that found in the solid state by X-ray diffraction [98]. A minor stereoisomer (ca. 15%) separated by a 20.6 kcal/mol barrier was detected and is believed to contain a rotation about the Tyr and/or Tyr amide bond, however its precise conformation could not be deduced. 

Fig. 24. Perspective view of the X-ray structure of RA-V p-bromobenzoate. The backbone conformation possesses almost the same characteristics as bouvardin (Fig. 23).

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