Synthesis of fr901464 and analogs with antitumor activity

A compound having Formula (II) or stereoisomer, pharmaceutically acceptable salt or ester thereof:

• wherein:
• X′ is selected from the group consisting of 0 and C(R22)2;
• wherein R22 is H, C1-6-alkyl, or halo(C1-6-alkyl);
• and
• Y′ is selected from the group consisting of C, CH, C(R22)2 and O;
• Z′ is selected from the group consisting of C and CH;
• represents a single or a double bond between Y′ and Z′;
• R16 is selected from the group consisting of an optionally substituted polyethylene glycol moiety and H;
• R17 and R18 are independently selected from the group consisting of H, C1-6-alkyl, and C1-6-alkyl substituted with one to three groups independently selected from halo, hydroxy, and C1-6-alkoxy;
• or R17 and R18, together with the carbon atom to which they are bound, form a carbonyl group;
• R19 and R20 are independently selected from the group consisting of hydrogen, halo(C1-6-alkyl), C(O)R22, F, Cl, NO2, and B(OR22)2, wherein at least one of R19 and R20 is other than hydrogen when represents a single bond, and wherein R22 is as defined above;
• or R19 and R20, together with the carbon atom to which they are bound, form an epoxide ring or a carbonyl group;
• or R19 and R20 together represent a substituent selected from the group consisting of ═NHNH2 and ═NHOH;
• or R16, R19, and R20 together with the carbon atoms to which they are bound, represent the following structure:

A process for preparing a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof having Formula (Ia):

• wherein:
• R1 is selected from the group consisting of H, Pg, C1-6-alkyl, halo(C1-6-alkyl), C(O)R11, C(O)OR11, and C(O)NR12R13,
• wherein each R11 is independently H, C1-6-alkyl, or halo(C1-6-alkyl), and
• wherein R12 and R13 are independently selected from the group consisting of H, C1-6-alkyl, and halo(C1-6-alkyl);
• or R12 and R13, together with the nitrogen atom to which they are bound, form a heterocyclic or heteroaromatic ring;
• R2, R3, R4, R5, and R6 are independently selected from the group consisting of H, C1-6-alkyl, and halo(C1-6-alkyl);
• R7 is selected from the group consisting of H, C1-6-alkyl and halo(C1-6-alkyl);
• and
• R8′ is H or an optionally substituted polyethylene glycol moiety, and
• R9 and R10 are independently selected from the group consisting of H, C1-6-alkyl, and C1-6-alkyl substituted with one to three groups independently selected from halo, hydroxy, C1-6-alkoxy, and OPg;
• R14 or R15 are independently selected from the group consisting of hydrogen, halo(C1-6-alkyl), C(O)R11, F, Cl, NO2, and B(OR11)2, wherein at least one of R14 and R15 is other than hydrogen, and wherein R11 is as defined above;
• and
• each Pg is independently a hydroxy protecting group;
• said method comprising the steps of:
• (A) contacting a compound of Formula (III):
• wherein R1, R2, R3, R4, R5, R6, and R7 are as defined above,
• with a compound of Formula (IIa):
• wherein R16 is hydrogen and R17, R18, R19, and R20 are as defined above,
• in the presence of an olefin metathesis catalyst;
• and if R8′ is an optionally substituted polyethylene glycol moiety, then the method further comprises:
• (B) contacting the product of step (A) with a compound of the formula (IV)
• wherein:
• R21 is selected from the group consisting of azide, tetrazole and triazole with hydrogen, alkyl, or substituted alkyl substituents;
• n is an integer selected from 1, 2, 3, 4, 5, and 6;
• and
• LG is a leaving group.