Synthesis of resorcylic acid lactones useful as therapeutic agents

A compound of formula I or I′, or a tautomer thereof, a pharmaceutically acceptable salt, solvate, ester or prodrug thereof:

• wherein:
• X is O, S or NR;
• Y is —OR, —O—(CH2)mCOOR, —O—(CH2)mCON(R)2, —N(R)2, —N(R)SOR or —N(R)SO2R, wherein the groups bound to the nitrogen atom may be in Z- or E-configuration;
• R1 and R2 are independently hydrogen, halogen, OR, N(R)2, SR, azido, nitro, cyano, aliphatic, aryl, alkylaryl, arylalkyl, heterocyclyl, heteroaryl, —S(O)R, —S(O)2R, —SO2N(R)2, —N(R)SO2R, —N(CO)R, —N(CO)N(R)2, —N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)N(R)2, —O(CO)OR, or —O(CO)N(R)2;
• R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, halogen, azido, nitro, cyano, aliphatic, alkylaryl, aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, N(R)2, SR, —O(CH2)mN(R)C(O)(CH2)pR, —O(CH2)mOC(O)(CH2)pR, —O(CH2)mC(O)(CH2)pN(R)2, —O(CH2)mC(O)(CH2)pOR, —O(CH2)mN(R)C(O)(CH2)pOR, —O(CH2)mN(R)C(O)(CH2)pN(R)2, —O(CH2)mOC(O)(CH2)pOR, —O(CH2)mOC(O)(CH2)pN(R)2, —NR(CH2)mN(R)C(O)(CH2)pR, —NR(CH2)mOC(O)(CH2)pR, —NR(CH2)mC(O)(CH2)pN(R)2, —NR(CH2)mC(O)(CH2)pOR, —NR(CH2)mN(R)C(O)(CH2)pOR, —NR(CH2)mN(R)C(O)(CH2)pN(R)2, —NR(CH2)mOC(O)(CH2)pOR, —NR(CH2)mOC(O)(CH2)pN(R)2, —(CH2)mN(R)C(O)CH2)pR, —(CH2)mOC(O)(CH2)pR, —(CH2)mC(O)CH2)pN(R)2, —(CH2)mC(O)(CH2)pOR, —(CH2)mN(R)C(O)(CH2)pOR, —(CH2)mN(R)C(O)(CH2)mN(R)2, —(CH2)mOC(O)(CH2)pOR, —(CH2)mOC(O)(CH2)pN(R)2, —(CH2)mN3, —O(CH2)mN3—(CH2)mN(R)2, —(CH2)mOR, —(CH2)mS(O)(CH2)pR, —(CH2)mS(O)2(CH2)pR, —(CH2)mSO2(CH2)pN(R)2, or —(CH2)mN(CH2)SO2(CH2)pR;
• and
• each R is independently R11, hydrogen, aliphatic, amino, azido, cyano, nitro, alkylamino, dialkylamino, OH, alkoxy, carbonylamino, aminocarbonyl, alkoxycarbonyl, carbonyloxy, carboxy, acyl, aryl, alkaryl, arylalkyl including benzyl, heteroalkyl, heteroaryl, heterocyclyl, or a protecting group;
• or two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclic or heteroaryl ring;
• wherein where a group contains more than one R substituent;
• wherein R is optionally substituted, and each R can be the same or different;
• R11 is the group:
• where Z is an inorganic or organic counterion;
• n is 0, 1 or 2;
• m and p are independently 0, 1, 2, 3, 4 or 5;
• and the dashed lines indicate either a single or a double bond, where the valence requirements are fulfilled by additional hydrogen atoms;
• and
• wherein in formula I′, when n is 1, and X is O and a double bond is present between the carbon atoms bearing R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 is not hydrogen;
• and
• wherein in formula I′, when n is 1 and X is O and the bond between the carbon atoms bearing R9 and R10 is a single bond, then at least one of R5, R6, R7 or R8 is not hydrogen.