The synthesis of macrolide and ionophore antibiotics is regarded as a very active and important area of synthetic organic research. The attractiveness of these target molecules is related to their broad range of biological and medicinal activity together with their complex macrocyclic structure and array of contiguous stereogenic centers. The development of an enantioselective methodology for the synthesis of the polypropionate chains of scytophycin C and lankanolide is the main goal of this proposal. The selection of these target molecules is based on their interesting and relevant biological activity and the challenge that represents the elaboration of the different carbon configurations found in their polypropionate units. In recent years a great interest in their study has been evidenced by the increasing scientific literature being generated in this area. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. We would like to demonstrate that epoxides are a viable advantageous alternative and that their use can be incorporated into a general, flexible and stereoselective route to these important target compounds. After our successful incursion into the synthesis of simpler polypropionate fragments of biologically important target molecules using a first-generation epoxide- based approach, we would like to apply our knowledge, experience and advances in the area of stereoselective preparation and regioselective cleavage of epoxides to the elaboration of these new more demanding targets. This will be achieved by developing and employing a more flexible and efficacious second- generation epoxide-based approach. Our newer approach is a simple and reiterative one, and is based on the stereoselective epoxidation of homoallylic or allylic alcohols followed by their cleavage using organoalane or alanate, or alkenyl Grignard chemistry. The major advantage of this approach is the stereospecific (SN2) nature of the cleavage reaction securing the chirality of the newly formed carbon-carbon bond. With this combined methodology, we can control the configuration of each methyl and hydroxy bearing carbon regardless of the required absolute configuration, which characterize each distinct polypropionate unit. Not only the desired chemical transformations proposed in this study will be accomplished. The scope, limitations, stereoselectivity and mechanistic implications of the key reactions will be examined. Although our methodology will be applied to these specific targets, in principle, it's should be applicable to many other polypropionate systems and will open the door for the synthesis of analogues which can presents opportunities for increased or modified biological activity and therapeutic potential.
The development of new and efficient methods for the synthesis of compounds with important biological and medicinal activities continues is of paramount importance in the biomedical sciences. Among the many families of compounds that have attracted the attention of the scientific community, the so-called polypropionate natural products have gained wide recognition and interest. We are proposing a new methodology for polypropionate synthesis that will open the door for the preparation these compounds and other analogues, which can present opportunities for improved biological activity and therapeutic potential.
|Cruz-Montañez, Alejandra; Morales-Rivera, Keyla F; Torres, Wildeliz et al. (2017) Reiterative epoxide-based strategies for the synthesis of stereo-n-ads and application to polypropionate synthesis. A Personal Account. Inorganica Chim Acta 468:28-37|
|Morales-Cruz, Moraima; Cruz-Montañez, Alejandra; Figueroa, Cindy M et al. (2016) Combining Stimulus-Triggered Release and Active Targeting Strategies Improves Cytotoxicity of Cytochrome c Nanoparticles in Tumor Cells. Mol Pharm 13:2844-54|
|Prieto, José A; Torres, Jaileen Rentas; Rodríguez-Berrios, Raul (2014) Regiocontrolled ring opening of monoprotected 2,3-epoxy-1,4-diols using alkynyl aluminum reagents. Synthesis of differentially monoprotected alkynyl triol derivatives. Synlett 25:433-437|
|Valentín, Elizabeth M; Mulero, Marlenne; Prieto, José A (2012) Concise epoxide-based synthesis of the C14-C25 bafilomycin A(1) polypropionate chain. Tetrahedron Lett 53:2199-2201|
|Torres, Wildeliz; Torres, Gerardo; Prieto, José A (2012) Synthesis of stereotetrads by regioselective cleavage of diastereomeric MEM-protected 2-methyl-3,4-epoxy alcohols with diethylpropynyl aluminum. Synlett 23:2534-2538|
|Rodríguez-Berríos, Raúl R; Torres, Gerardo; Prieto, José A (2011) Stereoselective VO(acac)(2) Catalyzed Epoxidation of Acyclic Homoallylic Diols. Complementary Preparation of C2-syn-3,4-Epoxy Alcohols. Tetrahedron 67:830-836|