Antamanide synthesis

A precise calculation of AGd as a function of the cationic radius would be very difficult because it would involve a complete conformational analysis of a large and complicated ligand system (82). Nevertheless, the dependency of the cation selectivity on steric interactions is capable of illustration. The term AGd can be estimated very crudely by using Hooke s law. As is shown in Fig. 16, ligands that are differentiated only by the radius of their equilibrium cavities can easily discriminate between cations of different size. This may explain why valinomycin and antamanide, two antibiotics with similar coordination spheres (54, 66), do not prefer the same cation (82). As it is no easy task to predict the exact dimensions of the cavity for a proposed ligand, the tailored synthesis of such ligands is conceivable yet problematic. 

After the sulfation of alcohols and phenols was reported to proceed efficiently with DCC/ H2S04, 75 76 Wieland et al. 81 applied this procedure for the sulfation of the tyrosine residue in D-Tyr6-a//-D-retro-antamanide. This contains no reactive group in addition to the phenolic group, and the desired product was obtained in satisfactory yields. Despite these promising initial results, this type of sulfation reaction has been adopted only sporadically, e.g. for sulfation of the CCK-8 derivative Boc-Asp(OtBu)-Tyr-Met-Gly-Trp(For)-Met-Asp-(OtBu)-Phe-NH2 with 70% yield1 2 or for the preparation of an intermediate fragment in the synthesis of CCK-related peptides (Scheme 3). 83 ... 

N-Methylmorpholine [1, 690]. In the mixed anhydride synthesis of peptides, N-methylmorpholine was found to give little or no racemization in cases where triethylamine, the commonly used base, caused extensive racemization.1 Trimethyl-amine, a potent racemizer, can be used successfully if an excess is avoided. N-Methylmorpholine was used by Wieland2 in the synthesis of antamanide, a cyclic decapeptide of Amanita phalloides, which counteracts the lethal action of Amanita toxins. 

In a shortened synthesis program one can combine the wash-out of the urea derivative with the subsequent deprotection reaction [61]. The acidic reagents used on that step, such as trifluoroacetic acid/dichloromethane or hydrogen-chloride/acetic acid, are excellent solvents for the urea by-product. Under these circumstances, however, the repetition of the actual peptide synthesis step, which eventually enhances its completion, is no longer possible, since the next cycle of operations is already initiated with the N-terminal deprotection of the just elongated sequence. We utilized this time-saving, shortened program successfully in the synthesis of several uncomplicated decapeptide precursors of the cyclic antamanide from Boc-amino acids. 

The coupling method with symmetric anhydrides prepared with phosgene and used in situ with permanent monitoring of the anhydride by flowthrough IR measurement was practized in the synthesis of several linear decapeptide precursors of antamanide. These were obtained in yields between 84% and 96% and in the synthesis of fully protected somatostatin [71], which was built up on polymer with 83% yield as determined by analytically quantified Edman degradation on pol)oner. 

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