Three-component coupling reaction, Strecker

This three-component coupling reaction, with its greater than 150 year history, continues to enjoy great utility. It is the most efficient synthesis of non-natural amino acids due to its generality, simplicity, and low cost. These attributes are particularly attractive to process chemists where the cost of goods is a key driver for the scale up and development of chemical matter. Initial studies around this reaction gave rise to racemic versions of the product. However, more recent examples of the Strecker reaction have focused on asymmetric variations to provide optically active a-aminonitriles or a-amino acids. 

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

The Strecker reaction [48], discovered in 1850 [1], is the most practical and efficient tool for the preparation of a-amino acids [49] via the formation of a-aminonitriles (Scheme 10.15) [50]. This three-component coupling between an amine or its equivalent, a carbonyl compound (generally an aldehyde), and hydrogen cyanide or its alkaline metal cyanides can be also made enantioselectively through the use of both metal-based catalysts and chiral organocatalysts. 

A variety of fused 3-aminoimidazoles have been synthesized by Sc(OTf)3-catalyzed Ugi three-component coupling (3CC) reaction in methanol with or without a microwave irradiation [60, 61]. Polymer-supported Sc(OTf)3 have been used in sequential Ugi-Strecker reactions of a-amino-pyridines, aldehydes, and TMSCN... 

Kobayashi has developed the zirconium-BINOL-derived complex 148 as a catalyst for enantioselective Strecker reactions with Bu3SnCN as the cyanide source [106], Subsequent investigations led to a protocol for the three-component in situ coupling of aldehydes, amines, and HCN (Equation 21) [107]. For example, aminonitrile 149 can be prepared in 99% yield and 94% ee in the presence of 5 mol% of zirconium catalyst 148. 

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