Synthesis of 2-alkoxy-2-phenylpropionic acids; and nitrogen- and chlorine-containing derivatives of combretastatin A-4

The area of asymmetric catalysis has had a great impact on the availability of new optically active materials that are used in many industrial syntheses of pharmaceuticals. Focus has been placed on the development of chiral non-racemic oxygen- and nitrogen-based ligands, particularly C2-symmetric 1,3-diketones and pyrazoles, for use as asymmetric catalysts. These compounds can be prepared by a condensation reaction between a methyl ketone and a carboxylic acid chloride. Synthetic limitations of terpene-derived pyrazoles used previously prompted the development of new routes to chiral alpha-quaternary acids based on the atrolactic acid (2-hydroxy-2-phenylpropanoic acid) framework. Catalysts derived from these compounds may have the advantage of additional coordination to the metal-center contributed by the alkoxy functionality. We have successfully synthesized a variety of racemic 2-alkoxy-2-phenylpropanoic acids using methodology which can be applied to large scale preparations. This new methodology was accomplished in two synthetic steps from alpha-methylstyrene. Epoxidation in alcohol solvents gave a variety of 2-alkoxy-2-phenylpropanols through an acid-catalyzed in-situ ring opening reaction. These alcohols were easily oxidized using a mild Heyns' oxidation in good yield. The resolution of 2-methoxy-2-phenylpropanoic acid was accomplished using (-)-brucine and (-)-alpha-methylbenzylamine. This work provides a suitable basis for the development of new ligands in asymmetric synthesis.;Our research has also concentrated on the design and synthesis of novel inhibitors of tubulin polymerization, designed to mimic the salient features of combretastatin A-4. One of the goals was to develop new compounds with an improved ability to target the newly-formed vasculature of tumors. We have successfully synthesized a number of CA-4 analogs which contain nitrogen and chlorine substitution, and these were evaluated for their biological activity. Substitution in these analogs was mainly confined to the B-ring of CA-4; however, several chlorinated compounds modified in the A-ring have also been prepared. Some of these compounds were found to have activities comparable to CA-4, and useful structure-activity relationships have been identified which may aid in the further development of vascular targeting agents.