Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof

A process for preparing a compound of Formula III,

• wherein:
• X represents a cis- or trans-alkenyl group represented by —CH═CH)1—;
• and
• R1 and R2 are hydrogen;
• the process comprising:
• a) contacting cis- or trans-combretastatin A-4 in a solvent with a di(arylmethyl)phosphite in the presence of a tetrahalomethane, a tertiary amine, and an acylation catalyst to form a protected phosphate ester of Formula I,
• wherein R3 is an arylmethyl phosphate protecting group;
• and
• b) contacting the protected phosphate ester of Formula I with a trialkylhalo silane for a period of time sufficient to generate the phosphoric acid compound of Formula II
• and
• c) converting the phosphoric acid compound of Formula II into the compound of Formula III.

A process for preparing a compound of Formula III,

• wherein:
• X represents a cis- or trans-alkenyl group represented by —CH═CH)1—;
• one of —OR1 or —OR2 is O−Q+ or —O—Q, and the other is hydroxyl, —O−Q+, or —O—Q and
• Q is an alkali metal, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, or a nitrogen-containing antibiotic,
• the process comprising:
• (a) contacting cis- or trans-combretastatin A-4 in a solvent with 1H-tetrazole, a phosphine, and an oxidizing agent at a temperature for a period of time sufficient to form a protected phosphate ester of Formula I,
• wherein R3 is an aryl, arylmethyl or alkyl phosphate protecting group;
• and
• (b) contacting the protected phosphate ester of Formula I with a trialkylhalo silane for a period of time sufficient to generate the phosphoric acid compound of Formula II,
• and
• (c) converting the phosphoric acid compound of Formula II into the compound of Formula III.

A process for preparing a compound of Formula VI

• wherein,
• one of —OR1 or —OR2 is O−Q+ or —O—Q, and the other is hydroxyl, —O−Q+, or —O—Q and
• Q is an alkali metal, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, or a nitrogen-containing antibiotic,
• the process comprising:
• (a) contacting cis-combretastatin A-4 in a solvent with di(benzyl)phosphite in the presence of tetrahalomethane, a tertiary amine, and an acylation catalyst to form a protected phosphate ester of Formula IV;
• (b) contacting the protected phosphate ester of Formula IV with a trialkylhalo silane for a period of time sufficient to generate the phosphoric acid compound of Formula V;
• and
• (c) contacting the phosphoric acid compound of Formula V with an alkali metal hydroxide, alkali metal alkoxide, alkali earth metal hydroxide, alkali earth metal alkoxide, transition metal hydroxide, transition metal alkoxide, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, a nitrogen-containing antibiotic, or a salt thereof to generate a compound of Formula VI.

A compound of Formula III,

• wherein:
• X represents a cis- or trans-alkenyl group represented by |CH═CH)1—;
• one of —OR1 or —OR2 is O−Q+ or —O—Q, and the other is hydroxyl, —O−Q+, or —I—Q;
• and
• Q is an alkali metal other than sodium or potassium, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, a nitrogen-containing antibiotic, or any combination thereof.

A compound having a general structure of the formula VI:

• wherein:
• one of —OR1 or —OR2 is O−Q+ or —O—-Q, and the other is hydroxyl, —O−Q+, or —O—Q;
• and
• Q is an alkali metal other than sodium or potassium, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, or a nitrogen-containing antibiotic, or any combination thereof.

A method of modulating tumor growth or metastasis in an animal comprising the administration of an effective amount of a compound having a general structure of the formula VI:

• wherein:
• one of —OR1 or —OR2 is O−Q+ or —O—Q, and the other is hydroxyl, —O−Q+, or —O—Q;
• and
• Q is an alkali metal other than sodium or potassium, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, or a nitrogen-containing antibiotic or any combination thereof.

A method of modulating microbial growth in an animal comprising the administration of an effective amount of a compound having a general structure of the formula VI:

• wherein:
• one of —OR1 or —OR2 is O−Q+ or —O—Q, and the other is hydroxyl, —O−Q+, or —O—Q;
• and
• Q is an alkali metal, an alkali earth metal, a transition metal, a heteroarylene, a heterocyclyl, a nucleoside, a nucleotide, an alkaloid, an amino-sugar, an amino-nitrile, or a nitrogen-containing antibiotic or any combination thereof.

A process for preparing a compound of Formula VI

• wherein one of R1 or R2 is sodium and the other is sodium or hydrogen,
• the process comprising:
• (a) contacting cis-combretastatin A-4 in a solvent with di(benzyl)phosphite in the presence of tetrahalomethane, a tertiary amine, and an acylation catalyst to form a protected phosphate ester of Formula IV;
• (b) contacting the protected phosphate ester of Formula IV with a trialkylhalo silane for a period of time sufficient to generate the phosphoric acid compound of Formula V;
• and
• (c) contacting the phosphoric acid compound of Formula V with an alkali metal hydroxide, alkali metal alkoxide, or a salt thereof to generate a compound of Formula VI.