Novel Methods for Selective Fluorination of Organic Compounds: Design and Synthesis of Fluorinated Antimetabolites (1978)

Abstract Since 1970 we developed three novel methods of fluoro‐organic synthesis in our laboratory, namely: photofluorination (R‐H→‐F); fluorodehydrozylation (R‐OH→‐F); fluorodesulfurization (R‐SH→‐F). The general idea suggesting the development of the first two of these reactions was to find one‐step methods for transforming readily available and relatively complex organic compounds into the corresponding fluorine derivatives. The third method emerged as a chance discovery in an attempt to photofluorinate penicillamine, an amino acid with an SH group. The primary motivation of our search was to develop straightforward and routine syntheses of fluorine‐containing antimetabolites including enzyme inhibitors. Therefore, it was very attractive to find methods of fluorination capable of transforming a metabolite into an antimetabolite in one single step. The general concept that C‐fluorinated metabolites can represent antimetabolites was already established. However, F analogs of metabolites in general were considered probes for understanding the behavior of the desfluoro metabolites rather than compounds of practical use, e.g., as drugs. In contrast, introduction of F for improvement of drugs was well established before 1970. By that time, the pioneering discovery of Josef Fried of the beneficial effect of introducing F into corticosteroids had already led to a widely accepted and employed approach for the “molecular manipulation” of a wide range of drugs. A striking advance in organofluorine synthesis occurred shortly before our own concentrated effort commenced when Sir Derek Barton and co‐workers published the first general method for the direct introduction of F into olefins and aromatic compounds of nucleophilic character so as to react with the electrophilic fluorinating reagent, fluoroxytrifluoromethane (CF 3 OF). Nonetheless, it appeared to us that the “state of art” of organofluorine synthesis was not yet advanced enough for the routine synthesis of fluorinated metabolites and for the direct introduction of F into drugs. Two objectives determined our efforts from the beginning: Our first goal was to elevate the “state of art” in respect to synthesis. The second was to attempt to sharpen the selection process in the choice of metabolites which were to serve as substrates for generation of drugs, that is of antimetabolites of great selectivity and practical utility. Both photofluorination and fluorodehydroxylation were developed to serve a particular principle in design of antimetabolites and drugs, namely the principle of isogeometric modification of metabolites with maximal shift of electron‐distribution to generate specific and active antimetabolites. The work to be reviewed here led to the discovery of an antimetabolite (3‐fluoro‐ D ‐alanine‐2 d (code‐named MK‐641)) which is the unorthodox component of the experimental antibacterial combination drug, MK‐641/MK‐642. Analysis of the mechanism of action of this antimetabolite suggests that it belongs to the class of “suicide enzyme inhibitors,” which currently attract great interest.