Tubulysins and processes for preparing

A process for converting a compound of the formula (I)

• wherein:
• n is an integer from 1 to 3;
• V is selected from the group consisting of H, OR2, and halo, and W is selected from the group consisting of H, OR2, and alkyl;
• or V and W are taken together with the attached carbon to form a carbonyl;
• Z is alkyl, and Y is O;
• or Z is alkyl or C(O)R4, and Y is absent;
• R is OH or a leaving group;
• or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
• R1 is H;
• or R1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR6;
• each R2 is independently selected from the group consisting of H, alkyl, and C(O)R5, provided that R2 is not H when both V and W are OR2;
• R4 is selected from the group consisting of alkyl, CF3, and aryl;
• each R5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
• R6 is selected from the group consisting of aryl, C(O)R7, P(O)(OR8)2, SO3R8, and a phenol protecting group;
• each R7 and R8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl;
• or R8 is a metal cation;
• and
• R10 is alkyl or alkenyl, each of which is optionally substituted;
• into a compound of the formula (II)
• wherein:
• n, V, W, Z, Y, R, R1, R2, R4, R5, R6, R7, R8, and R10 are as defined in formula I;
• X is CH2QR9;
• Q is —NH— or —S—, and each R9 is independently selected from the group consisting of hydrogen, C1-4 alkyl, alkenyl, aryl, and C(O)R11;
• or Q is —O—, and R9 is C(O)R11 or C5 alkyl;
• and
• each R11 is independently selected from the group consisting of C1-6 alkyl, alkenyl, aryl, and heteroaryl;
• the process comprising
• (a) mixing the compound of the formula (I) with an acid to form an intermediate;
• and
• (b) reacting the intermediate with a nucleophile.

A process for converting a compound of the formula (I)

• wherein:
• n is an integer from 1 to 3;
• V is selected from the group consisting of H, OR2, and halo, and W is selected from the group consisting of H, OR2, and alkyl;
• or V and W are taken together with the attached carbon to form a carbonyl;
• Z is alkyl, and Y is O;
• or Z is alkyl or C(O)R4, and Y is absent;
• R is OH or a leaving group;
• or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
• R1 is H;
• or R1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR6;
• each R2 is independently selected from the group consisting of H, alkyl, and C(O)R5, provided that R2 is not H when both V and W are OR2;
• R4 is selected from the group consisting of alkyl, CF3, and aryl;
• each R5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
• R6 is selected from the group consisting of aryl, C(O)R7, P(O)(OR8)2, SO3R8, and a phenol protecting group;
• each R7 and R8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl;
• or R8 is a metal cation;
• and
• R10 is alkyl or alkenyl;
• into a compound of the formula (II)
• wherein:
• n, V, W, Z, Y, R, R1, R2, R4, R5, R6, R7, R8, and R10 are as defined in formula I;
• X is selected from the group consisting of C1-4 alkyl, alkenyl, and CH2QR9;
• Q is selected from the group consisting of —NH—, —O—, and —S—;
• each R9 is independently selected from the group consisting of hydrogen, C1-5 alkyl, alkenyl, aryl, and C(O)R11;
• and
• each R11 is independently selected from the group consisting of C1-6 alkyl, alkenyl, aryl, and heteroaryl;
• the process comprising
• (a) mixing the compound of the formula (I) with trifluoroacetic acid to form an intermediate and
• (b) reacting the intermediate with a nucleophile.

A process for converting a compound of the formula (I)

• wherein:
• n is an integer from 1 to 3;
• V is selected from the group consisting of H, OR2, and halo, and W is selected from the group consisting of H, OR2, and alkyl;
• or V and W are taken together with the attached carbon to form a carbonyl;
• Z is alkyl, and Y is O;
• or Z is alkyl or C(O)R4, and Y is absent;
• R is OH or a leaving group;
• or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
• R1 is H;
• or R1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR6;
• each R2 is independently selected from the group consisting of H, alkyl, and C(O)R5, provided that R2 is not H when both V and W are OR2;
• R4 is selected from the group consisting of alkyl, CF3, and aryl;
• each R5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
• R6 is selected from the group consisting of aryl, C(O)R7, P(O)(OR8)2, SO3R8, and a phenol protecting group;
• each R7 and R8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl;
• or R8 is a metal cation;
• and
• R10 is alkyl or alkenyl;
• into a compound of the formula (II)
• wherein:
• n, V, W, Z, Y, R, R1, R2, R4, R5, R6, R7, R8, and R10 are as defined in formula I;
• X is CH2OR9;
• each R9 is independently selected from the group consisting of C1-5 alkyl, alkenyl, aryl, and C(O)R11;
• and
• each R11 is independently selected from the group consisting of C1-6 alkyl, alkenyl, aryl, or heteroaryl;
• the process comprising
• (a) mixing the compound of the formula (I) with trifluoroacetic acid to form an intermediate;
• and
• (b) reacting the intermediate with a nucleophile.