C-terminal Hsp90 inhibitors

A method of preparing a compound of the formula:

• wherein
• R1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether;
• R2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or —R9—OR10, wherein R9 is a covalent bond or alkyl, and R10 is hydrogen, alkyl, C-amido or acyl;
• or R2 together with R3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
• R3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R11—O—R12, wherein R11 is a covalent bond or alkyl, and R12 is alkyl, C-amido, or acyl;
• or R3 together with R2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
• R4 is hydrogen or alkyl;
• R5 is hydrogen or alkyl;
• R6 is hydrogen, hydroxy, sulfanyl, alkyl, or alkoxy;
• R7 is hydrogen or hydroxyl;
• R8 is hydrogen or hydroxyl;
• X is ═CR21— or ═N—, wherein R21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;
• R′ is hydrogen or alkyl;
• R″ is alkyl;
• Y is ═CR3— or ═N—;
• Z is CH or Z—Z1 is —C═C—;
• Z1 is CH or Z—Z1 is —C═C—;
• and
• n is 0, 1, 2, or 3;
• comprising reacting an aglycone of the formula:
• wherein:
• R1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether;
• R2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or
• —R9—OR10, wherein:
• R9 is a covalent bond or alkylene, and
• R10 is hydrogen, alkyl, C-amido, or acyl;
• or
• R2 together with R3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
• R3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or
• —R11—O—R12, wherein:
• R11 is a covalent bond or alkylene, and
• R12 is alkyl, C-amido, or acyl;
• or
• R3 together with R2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
• or
• R3 is absent when Y is ═N—;
• R′ is H or alkyl;
• R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl, or alkylamidoalkyl;
• X is ═CR21— or ═N—, wherein:
• R21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;
• and
• Y is ═CR3— or ═N—;
• with a sugar of the formula:
• wherein:
• R4 is hydrogen or alkyl;
• R5 is hydrogen or alkyl;
• R6 is hydrogen, hydroxy, sulfanyl, alkyl, or alkoxy;
• R7 is hydrogen or hydroxyl;
• R8 is hydrogen or hydroxyl;
• Z is CH or Z—Z1 is —C═C—;
• Z1 is CH or Z—Z1 is —C═C—;
• and
• n is 0, 1, 2, or 3;
• in the presence of a Lewis acid.