Chiral primary amine synthesis, steps

Auxiliary methods can hold current value when the auxiliary is inexpensive, available in both enantiomeric forms, and, for amine synthesis, can be incorporated with concomitant generation of the new stereogenic a chiral amine center. Reductive amination with chiral ammonia equivalents not only holds this potential but is now a proven and established method that allows chiral primary amine synthesis in two reaction steps (reductive amination and hydrogenolysis) from prochiral ketones. The approach is of interest because of its overall reaction step efficiency. 

Scheme 7.10 Two step chiral primary amine synthesis reductive amination followed by hydrogenolysis.

Although the strategies represented in Table 8.1 are comprehensive, but restricted based on their industrial promise or brevity, they do not represent cohesive general solutions to the problem of a-chiral primary amine synthesis. Instead they offer substrate specific solutions, and their individual limitations will be shortly discussed. Regardless, these methods represent significant advancement in know how regarding the number of reaction steps, yield, and ee, from just 5 to 10 years ago. 

A chiral auxiliary is a compound that is incorporated into a larger molecule, where it transmits its chirality information to newly formed chiral elements. It is cleaved from the target molecule in a later step of the reaction sequence and should in principle be recycled, to avoid loss of the precious chiral material. Among the ferrocene derivatives, chiral primary amines are typical auxiliaries for their synthesis, see Section 4.3.3. All applications involve the intermediate formation of imines with carbonyl compounds. 

These authors also developed the synthesis of three-fold axially chiral tri-podal ligands, since virtually no studies have been reported on the combination of Cs-symmetry and axial chirality (Scheme 5.51). The first step was the reaction between a chiral bromide with liquid ammonia giving the corresponding primary amine, which was further alkylated in situ with two additional equivalents of the chiral bromide. A final deprotection with BCI3 furnished the required tripodal ligand, the biarylic portions of which formed a cavity capable of incorporating oxophilic Lewis acidic elements. 

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