An efficient and practical EPC synthesis of β‐amino acids from L‐asparagine

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Abstract
The synthesis of enantiomerically pure β‐arnino acids (1a‐c) via an O‐activated equivalent of β‐homoserine is discussed. The chiral synthon 2 was planned to be represented by (S)‐3‐N,N‐dibenzylamino‐4‐mesyloxybutanoic acid methyl ester (3) or by (S)‐3‐N,N‐dibenzylamino‐4‐mesyloxybutanenitrile (6). Both intermediates should be approached from L‐aspartic acid 4 or L‐asparagine 5 through selective reduction of the α‐carboxyl group. It turned out that only nitrile 6 was suitable for the envisioned β‐amino acid synthesis, since alcohol 14 ‐ the synthetic precursor of 3 ‐ was unstable towards intramolecular nucleophilic attack to accomplish the chiral building block 15. Reaction of mesylate 6 with different ‘Gilman cuprates’ afforded the 3‐N,N‐dibenzylamino nitrile derivatives 22a‐c, which could be readily deprotected to give the target compounds 1a‐c in 23‐36% overall yield from asparagine. In contrast Me2Cu(CN)Li2 as an example for higher order ‘Lipshutz cuprates’ did not afford the desired substitution product 22a. The optical integrity of the synthesis was established by coupling of the methyl ester 24 with chiral 1‐phenylethyl isocyanate followed by appropriate NMR studies of carbamate 25.