DESCRIPTION: (Applicant's Abstract) The synthesis of biologically active compounds typically requires precise control of their three-dimensional structure, and in particular of their chirality. The importance of syntheses designed to give pure enantiomers is unquestioned in the pharmaceutical community, and despite great advances such syntheses remain a challenge. Most of the attention in this area is focused on carbon, but the purpose of this proposal is the synthesis of two types of compound that are chiral at phosphorus. One type will help direct the formation of chiral carbon compounds via catalytic organometallic reactions, while the other will be incorporated directly into the biologically active compounds themselves, specifically, chiral "antisense" oligonucleotides. Reaction of readily available N-sulfonyl amino acids with PhPCl2 gives enantiomerically pure chiral-at-phosphorus 1,3,2-oxazaphospholidinones. Chirality at the amino acid carbon is transmitted to the neighboring sulfonamide, and from there to the phosphorus atom. Extension to bis(PCl2) compounds will allow for the facile synthesis of C2-symmetric phosphorus compounds that may be excellent ligands for chiral tungsten nitrosyl Lewis acids that give asymmetric catalysis of the Diels-Alder reaction. Analogs derived from PPh2/PCl2 starting materials will give rise to mixed phosphine/sulfonylphosphoramides that will be of primary interest in rhodium-catalyzed asymmetric hydroformylation reactions. Similar methods will be used to synthesize chiral-at-phosphorus compounds that can be converted into phosphorothioate and methylphosphonate oligonucleotide analogs. For instance, reaction of PCl3 with the N-sulfonyl amino acid followed by reaction with a protected nucleoside will give a chiral trivalent phosphorus compound; sulfurization and coupling with another protected nucleoside followed by cleavage of the chiral amino acid auxiliary will give a chiral phosphorothioate. The order of sulfurization and coupling will be explored to give the best combination of yield and stereoselectivity. The method should be equally applicable to the methylphosphonate and mixed backbone oligonucleotides. Such chiral nuclease-resistant oligonucleotides can in principle be highly gene-selective pharmaceutical reagents.
NIH ExPorter
NIH ExPorter