Three approaches to the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group

Abstract

Three approaches to the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group as well as at C-3 and C-4 are described. In all three methods the stereogenic centre at C-2 was created with total stereocontrol via a one-pot, two-enzyme catalysed procedure involving hydrolysis and reductive amination of a 2-keto ester. However, the approaches vary in the synthesis of the isotopically labelled 2-keto esters and in the production of the stereogenic centre at C-4 which was achieved either via alkylation of a propionylated Evans’ auxiliary with labelled iodomethane or by the diastereoselective conjugate addition of a labelled organocopper reagent to crotonate tethered to a chiral sultam. The latter approach proved most efficient and using the (1R,2S,3R)-3-[N-phenylsulfonyl-N-(3,5-dimethyldiphenyl)aminobornan-2-ol ester 27, [5-¹³C]-L-leucine was prepared with >98% de at C-4 and in 49% overall yield from the first labelled intermediate 28.