Robust and straightforward chemo-enzymatic enantiopure dipeptide syntheses and diketopiperazines thereof

We have explored the scope of the synthetic route towards d-phenylglycyl diketopiperazines, involving a penicillin acylase catalysed formation of d-phenylglycyl dipeptides of l-amino acids with functional groups in the side chain. The synthesis of dipeptides from serine, threonine, glutamic acid, glutamine and methionine was successful. In contrast, aspartic acid, asparagine and cysteine only afforded trace amounts of dipeptides while no dipeptide was detected with arginine, lysine and tyrosine. Isolated dipeptide yields varied from 10% to 76%. The dipeptides were successfully converted into their corresponding enantiopure diketopiperazines by chemical esterification and cyclization under alkaline conditions, in 35–43% yield. In the case of glutamic acid, the procedure yielded the diketopiperazine with an esterified side chain. Remarkably with glutamine, the amide function in the side chain was transformed into an ester moiety, resulting in the same diketopiperazine as with glutamic acid.

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(2S)-2-{[(2R)-2-Amino-2-phenylacetyl]amino}-3-hydroxypropanoic acidC11H14N2O4[α]D20 = −68.9 (c 1, 2.5 M HCl)Absolute configuration: (2S,2′R)

(2S)-2-{[(2R)-2-Amino-2-phenylacetyl]amino}-3-hydroxybutanoic acidC12H16N2O4[α]D24 = −27.8 (c 1, 2.5 M HCl)Absolute configuration: (2S,2′R)

(2S)-2-{[(2R)-2-Amino-2-phenylacetyl]amino}pentanedioic acidC13H16N2O5[α]D24 = −87.5 (c 1, 2.5 M HCl)Absolute configuration: (2S,2′R)

(2S)-5-Amino-2-{[(2R)-2-amino-2-phenylacetyl]amino}-4-carbamoylbutyric acidC13H17N3O4[α]D24 = −89.5 (c 1, 2.5 M HCl)Absolute configuration: (2S,2′R)

(2S)-2-{[(2R)-2-Amino-2-phenylacetyl]amino}-4-(methylsulfanyl)butanoic acidC12H15N3O4[α]D24 = −97.9 (c 1, 2.5 M HCl)Absolute configuration: (2S,2′R)

(3S,6R)-3-(Hydroxymethyl)-6-phenylpiperazine-2,5-dioneC11H12N2O3[α]D24 = −59.9 (c 1, DMSO)Absolute configuration: (3S,6R)

(3S,6R)-3-(1-Hydroxyethyl)-6-phenylpiperazine-2,5-dioneC12H14N2O3[α]D24 = −71.4 (c 1, DMSO)Absolute configuration: (3S,6R)

(3S,6R)-3-[2-(Methylsulfanyl)ethyl]-6-phenylpiperazine-2,5-dioneC13H16N2O2S[α]D24 = −47.6 (c 1, DMSO)Absolute configuration: (3S,6R)

Methyl 3-[(2S,5R)-3,6-dioxo-5-phenylpiperazin-2-yl]propanoateC14H16N2O4[α]D24 = −43.8 (c 1, DMSO)Absolute configuration: (2S,5R)