Methods for synthesis of amino-tetrahydroisoquinoline ring compounds

A method of preparing a combinatorial library of amino-substituted-tetrahydroisoquinoline ring compounds;

• wherein said compound comprises a structure selected from the group consisting of:
• represents a heterocycle, aryl, or hydrocarbocycle;
• represents a heterocycle;
• R1 is alkyl, aryl, heterocyclic moiety, amide, sulfonamide, urea, thiourea, or alcohol and R2 is alkyl, aryl, heterocyclic moiety, amide, sulfonamide, urea, thiourea, hydrogen, or alcohol;
• R3 and R4 are each independently an alkyl or aryl;
• n is from 0 to 1;
• R5 is the side chain of an amino acid and Z is NH, O or S;
• wherein the amino acid side chain may be selected from the group consisting of side chains of natural and synthetic amino acids;
• comprising the steps of (a) providing a support-bound amino-substituted-tetrahydroisoquinoline-carboxylic acid having the structure:
• wherein W represents a solid support and R1 is alkyl, aryl, heterocyclic moiety, amide, sulfonamide, urea, thiourea, or alcohol;
• (b) forming a first support-bound intermediate by reacting a first portion of a support-bound amino-substituted-tetrahydroisoquinoline carboxylic acid with a first reagent and forming a second support-bound intermediate by reacting a second portion of the support-bound amino-substituted-tetrahydroisoquinoline-carboxylic acid with a second reagent;
• and (c) cyclizatively cleaving the first and second support-bound intermediates to form first and second amino-substituted-tetrahydroisoquinoline ring compounds, respectively, wherein the first and second reagents are selected from the group consisting of (i) isocyanates having the structure R3NCO wherein R3 is an alkyl or aryl, (ii) thioisocyanates having the structure R4NCS wherein R4 is an alkyl or aryl, (iii) protected amino acids having the structure:
• wherein P is a protecting group, n is from 0 to 1, and R5 is the side chain of an amino acid, (iv) protected cyclic amino acids having the structure:
• represents a heterocycle, P is a protecting group, and Y is NO2, NHP, OP, or SP and (v) protected cyclic amino acids having the structure:
• represents a heterocycle, aryl, or hydrocarbocycle, P is a protecting group, and Y is NO2, NHP, OP, or SP;
• provided that when the first and second reagents are both isocyanates, the first reagent is a different isocyanate than the second reagent;
• when the first and second reagents are both thioisocyanates, the first reagent is a different thioisocyanate than the second reagent;
• when the first and second reagents are both protected non-cyclic amino acids, the first reagent is a different protected amino acid than the second reagent;
• and when the first and second reagents are both protected cyclic amino acids, the first reagent is a different protected cyclic amino acid than the second reagent.