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

Three approaches to the synthesis of L-leucine selectively labelled with ca rbon-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 p rocedure involving hydrolysis and reductive amination of a 2-keto ester. Ho wever, 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 wa s achieved either via alkylation of a propionylated Evans' auxiliary with l abelled iodomethane or by the diastereoselective conjugate addition of a la belled organocopper reagent to crotonate tethered to a chiral sultam. The l atter approach proved most efficient and using the (1R,2S,3R)-3-[N-phenylsu lfonyl-N-(3,5-dimethyldiphenyl)aminobornan-2-ol ester 27, [5-C-13]-L-leucin e was prepared with > 98% de at C-4 and in 49% overall yield from the first labelled intermediate 28.