Biocatalytic synthesis of cryptophycin anticancer agents

A compound, or pharmaceutically acceptable salt thereof, having a structure of formula I:

• wherein
• Ar is a 5- or 6-membered heterocyclic aryl group having 1 to 3 ring N heteroatoms, and is optionally substituted with 1-3 substituents independently selected from C1-5 alkyl and L-R6;
• R1 is chlorine, bromine, or iodine;
• R2 is OH or OC(O)CH2NHR;
• or
• R1 and R2 together (1) indicate a double bond between the carbons to which they are attached or (2) form a β-epoxide ring with the carbons to which they are attached;
• each of R3 and R4 is independently H, C1-6alkyl, C0-6alkylene-OH or C0-6alkylene-NH(R);
• or
• R3 and R4 together with the carbon atom to which they are attached form a spiro C3-5 cycloalkyl or a spiro 3- to 5-membered heterocycloalkyl having one nitrogen ring atom;
• R5 is C1-6alkyl, C0-6alkylene-OH or C0-6alkylene-NH(R);
• and
• R is H, C1-6alkyl, or L-R6;
• L is a linker;
• R6 is a maleimido group, a maleimidocaproyl group, a maleimido PEG group, a bromoacetamide group, a N-hydroxysuccinimide ester, an O-alkyl hydroxylamine, or a combination thereof;
• and
• X is 0, NH or NMe,
• with the proviso that the compound or salt has 0 or 1 L-R6.