Biomimetic combinatorial synthesis

A method for generating a library of isolated biomimetic compounds using an oxidative phenolic coupling reaction comprising:

• providing a first phenol comprising the following structure:
• 54
• wherein R1, R2, R4, and R5, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower aLkylamino, nitro, phenoxy, benzyloxy, hydrogen, or any derivative incorporating phosphorous;
• wherein R3 is an electron withdrawing group, or any of R2, R3, R4, and R5 taken together form a carbocycle or heterocycle having from 3 to 10 atoms in the ring,;
• providing a second phenol comprising the following structure:
• 55
• wherein R6, R7, R9, and R10 as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo,.hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, or hydrogen, any derivative incorporating phosphorous;
• wherein R8 is an electron donating group, or R7, R8, R9 and R10 taken together form a carbocycle or heterocycle having from 3 to 10 atoms in the ring,
• reacting the phenols to yield a complex scaffold structure comprising the following structure:
• 56
• wherein R1-R10, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulflhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• or wherein either any of R2, R3, R4, and R5 taken together, or any of R7, R8, and R9 taken together form a carbocycle or heterocycle having from 3 to 10 atoms in the ring;
• diversifying said complex scaffold structure at desired functional moieties to yield a library of complex natural product-like compounds.

A method for the synthesis of isolated biomimetic scaffold structures using an intramolecular oxidative phenolic coupling reaction comprising:

• providing two linked phenols having the following structure:
• 57
• wherein R1-R15, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched arninoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous wherein any of R1,-R15 taken together, as chemically permissible, form a carbocycle or heterocycle having from 3 to 10 atoms in the ring, and wherein at least one of R1, R2, R3, or R15 comprises a phenolic substrate.
• reacting said linked phenols to yield a biomimetic scaffold structure;
• diversifying said complex scaffold structure at desired functional moieties to yield a library of isolated biomimetic compounds.

A library of isolated biomimetic compounds having the following structure:

• 61
• wherein R1-R6, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulffhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• wherein Y is any of the above or a linking unit;
• and X is any sulfur, oxygen, nitrogen, phosphorous, or carbon functionality.

A library of biomimetic compounds comprising the following structure:

• 65
• wherein R1-R8, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• wherein Y is any of the above, a linking unit, or a biomolecule;
• and X is any sulfur, oxygen, nitrogen, phosphorous, or carbon functionality.

A library of biomimetic compounds comprising the following structure:

• 67
• wherein R1-R9, as valency and stability permit are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched amnino alkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, lin ear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• wherein Y is any of the above, a linking unit or a biomolecule;
• and X is any sulfur, oxygen, nitrogen, phosphorous, or carbon functionality.

A method for generating a library of isolated biomimetic compounds comprising:

• synthesizing a vinyl stannane from a substituted alkyne;
• reacting a cyclic β-keto ester with said vinyl stannane under conditions to generate a 2-vinyl-2-methoxycycloalkanone;
• reacting said cycloalkanone with a Grignard reagent to generate a biomimetic scaffold bicyclo [n.3.1] ring system;
• diversifying said biomimetic scaffold bicyclo [n.3.1] ring system at selected reactive moieties to generate a library of biomimetic bicyclo [n.3. 1] ring system compounds.

A method for generating a library of isolated biomimetic compounds comprising:

• synthesizing a vinyl stannane from a substituted alkyne;
• vinylating a cyclic β-keto ester to generate a 2-vinyl-2-methoxycycloalkanone;
• reacting said cycloalkanone with a vinyl Grignard reagent, and trapping with an electrophile to generate diversifiable medium ring structures;
• diversifying said biomimetic medium ring structures at selected reactive moieties to generate a library of biomimetic medium ring structures.

A library of isolated biomimetic medium ring structures comprising the following structure:

• 70
• wherein R1-R15, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulihydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• or wherein either any of R1-R15 taken together form a carbocycle or heterocycle having from 3 to 10 atoms in the ring;
• wherein E is a functionality resulting from reaction with an electrophile;
• and wherein n is 0-3.

A library of biomimetic fused medium ring structures having the following structure:

• 71
• wherein R0-R13, as valency and stability permit, are each independently selected from the group consisting of a linear or branched alkyl, alkenyl, linear or branched aminoalkyl, linear or branched acylamino, linear or branched acyloxy, linear or branched alkoxycarbonyl, linear or branched alkoxy, linear or branched alkylaryl, linear or branched hyrdoxyalkyl, linear or branched thioalkyl, acyl, amino, hydroxy, thio, aryloxy, arylalkoxy, hydrogen, alkynyl, halogen, cyano, sulfhydryl, carbamoyl, nitro, trifluoromethyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is substituted with 1-5 substituents selected from the group consisting of lower alkyl, halo, hydroxy, amino, thio, lower alkoxy, lower alkylthio, lower alkylamino, nitro, phenoxy, benzyloxy, hydrogen, and any derivative incorporating phosphorous;
• or wherein any of R0-R13 taken together form a carbocycle or heterocycle having from 0 to 10 atoms in the ring;
• wherein E1 and E3 are functionalities resulting from reaction with electrophiles;
• and wherein n is 0-3.