Synthesis of template-fixed β-hairpin loop mimetics

A process for the manufacture of a library of numerous compounds of the general formula

• wherein
• Z is a chain of n α-amino acid residues which, if their α-C atom is asymmetric, have L-configuration, n being an integer from 4 to 20, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid;
• is one of the groups of formulae
• R1 is hydrogen or a protected amino group;
• R2 is hydrogen or a group of formula CH2—COOR10;
• R3 is an amino-protecting group;
• R4 is lower alkyl or aryl-lower alkyl;
• R5 is lower alkyl, lower alkoxy or aryl;
• R6 is hydrogen, lower alkyl, substituted lower alkyl, aryl, Br or NO2;
• R7 is hydrogen, lower alkyl, substituted lower alkyl, aryl, Br or NO2;
• R8 is lower alkyl, substituted lower alkyl or aryl-lower alkyl;
• R9 is lower alkyl, substituted lower alkyl or aryl-lower alkyl;
• and
• R10 is hydrogen, lower alkyl, substituted lower alkyl, aryl, aryl-lower alkyl, aroyl-lower alkyl or allyl;
• and of salts thereof, which process is carried out as parallel array synthesis to yield a library of numerous compounds of formula I, and which process comprises
• (a) coupling a solid support derived from polystyrene crosslinked with divinylbenzene which is functionalized by means of a 2-chlorotrityl linker with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position n/2, n/2+1 or n/2−1 if n is an even number and, respectively, in position n/2+½ or n/2−½ if n is an odd number, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
• (b) removing the N-protecting group from the product thus obtained;
• (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
• (d) removing the N-protecting group from the product thus obtained;
• (e) repeating, if necessary, steps (c) and (d) until the N-terminal amino acid residue has been introduced;
• (f) coupling the product thus obtained with a compound of the general formula
• is as defined above and X is an N-protecting group or, if
• is to be group (a), above, alternatively
• (fa) coupling the product obtained in step (d) or (e) with a compound of the general formula III
• wherein R1 and X are as defined above;
• (fb) removing the N-protecting group from the product thus obtained;
• and
• (fc) coupling the product thus obtained with an appropriately N-protected derivative of D-proline;
• (g) removing the N-protecting group from the product obtained in step (f) or (fc);
• (h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position n, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
• (i) removing the N-protecting group from the product thus obtained;
• (j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position n, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
• (k) removing the N-protecting group from the product thus obtained;
• (l) repeating, if necessary, steps (j) and (k) until all amino acid residues have been introduced;
• (m) detaching the product thus obtained from the solid support;
• (n) cyclising the product cleaved from the solid support by means of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (“HATU”)/7-aza-1-hydroxybenzotriazole (“HOAt”);
• (o) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule.