Synthesis of macrocyclic tetraamido compounds and new metal insertion process

A method for making a macrocyclic tetraamido compound having the structure

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• wherein Y1, Y3 and Y4 each represents a bridging group, having zero, one, two or three carbon containing nodes for substitution, and Y2 is a bridging group having at least one carbon containing node for substitution, each said node containing a C(R) or a C(R)2 unit and each R substituent is the same or different from the remaining R substituents and (i) is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, or phenoxy, CH2CF3, CF3 and combinations thereof, or (ii) forms a substituted or unsubstituted benzene ring of which two carbon atoms in the ring form nodes in the Y unit, or (iii) together with a paired R substituent bound to the same carbon atom forms a cycloalkyl or a cycloalkenyl ring, which may include an atom other than carbon, the method comprising:
• protecting an amino portion of an amino carboxylic acid at a first temperature sufficient to form the protected amino carboxylic acid;
• exposing the protected amino carboxylic acid to a first solvent;
• converting the carboxylic acid portion of the protected amino carboxylic acid to an activated carboxylic acid to form a protected amino activated carboxylic acid derivative;
• reacting the protected amino activated carboxylic acid derivative with a diamine in the presence of a second solvent and a base to form a protected diamide diamine intermediate;
• deprotecting the diamide diamine intermediate;
• and,
• reacting the diamide diamine intermediate with an activated diacid to form the macrocyclic tetraamido compound.