Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids

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Abstract
A team from Harvard's Department of Chemistry and Chemical Biology reports the culmination of a long-term project, the development of a practical and adaptable method for synthesizing α-amino acids, the building blocks of proteins. The synthesis is based on an organic chemistry classic, the Strecker reaction. A simple chiral amido-thiourea molecule is used to catalyse the addition of hydrogen cyanide to imines with high selectivity and under conditions that allow its use on large scales. New and unusual amino acids can be synthesized, with broad application to a wide range of fields including medicinal chemistry, protein science and material science. Efficient methods for the synthesis of enantioenriched α-amino acids — the building blocks of proteins — have been developed, but it remains a challenge to obtain non-natural amino acids. A new catalytic asymmetric method is now reported for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple and robust chiral amido-thiourea catalyst. The method also uses a safer source of cyanide. α-Amino acids are the building blocks of proteins and are widely used as components of medicinally active molecules and chiral catalysts1,2,3,4,5. Efficient chemo-enzymatic methods for the synthesis of enantioenriched α-amino acids have been developed, but it is still a challenge to obtain non-natural amino acids6,7. Alkene hydrogenation is broadly useful for the enantioselective catalytic synthesis of many classes of amino acids8,9, but it is not possible to obtain α-amino acids bearing aryl or quaternary alkyl α-substituents using this method. The Strecker synthesis—the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis—is an especially versatile chemical method for the synthesis of racemic α-amino acids10,11. Asymmetric Strecker syntheses using stoichiometric amounts of a chiral reagent have been applied successfully on gram-to-kilogram scales, yielding enantiomerically enriched α-amino acids12,13,14. In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent could provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen limited use on preparative scales (more than a gram)15,16. The limited utility of existing catalytic methods may be due to several important factors, including the relatively complex and precious nature of the catalysts and the requisite use of hazardous cyanide sources. Here we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. This catalyst is robust, without sensitive functional groups, so it is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources; this makes the method adaptable to large-scale synthesis. We have used this new method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.