A facile synthesis of optically pure disubstituted amino acids

Project Summary Enantiopuredisubstituted amino acidsEDAAsare valuable fundamental building blocks for medical research in both academics and industryWhen an EDAA is incorporated into the framework of a peptide or a small moleculeboth substituents attached to thecarbon contribute to the moleculeandapos s shapebiological activity and physical propertiesEDAAs can be used to optimize stabilityclogPand solubilityproviding a drug candidate with a vastly improved cellular potencyECand pharmacokinetic profilePKThe commercial availability of diverse collections of these unique and three dimensional building blocks will allow for the production of libraries of peptides and small molecules that have the ability explore new conformational spaceThe unique properties and shapes have the potential to interact with a wide range of drug targetsHowevercommercially available EDAAs are confined to simple alanine derivativesReasonNo general method for the preparation of diverse EDAAs is availableWe will introduce a new general method for the preparation ofdisubstituted amino acids with a wide scope of functional groupsoverall aimPreliminary findings in our laboratory have validated the new method for producing an EDAA insteps from a ketone and gave both antipodes with equal and opposite optical rotationsThe reagents and conditions for each of thesteps of this new process will be presented and potential solutions to optimize for yieldscopeand efficiency will be proposedThis simplestraightforwardstep method begins with simple ketones that are designed to test the impact of these parametersaimWe will produce a library of EDAAs from a diverse set of commercially available ketones using the optimized general methodaimComplete characterization of the EDAA library using modern analytical techniquesNMRfor structure and eeLCMSoptical rotationwill be undertakenaimWe have observed in the literature that EDAAs have been used in academic research in protein peptide function and in drug discovery in both academics and in the pharmaceutical industryHerein particularwe know that a library of commercially available EDAAs would have a dramatic impact on medicinal chemistry SAR campaignsWe predict that availability of these diverse quaternary amino acids will produce fundamental achievements in science and medicine to benefit societyproviding better drugs with fewer side effectsProject Narrative Enantiopuredisubstituted amino acidsEDAAsplay a crucial role in drug discovery leading ultimately to more selectivebetter bindingand more potent therapeuticsThe goal of this proposal is to synthesize a diverse library ofunique EDAAs to examine the scope of a novelstep method followed by complete characterization of the unique quaternary amino acid libraryWe will develop a novel general synthetic method of producing enantiopuredisubstituted amino acidsEDAAsthat will greatly enable medical research