Synthesis of both enantiomers of cyclic methionine analogue: (R)- and (S)-3-aminotetrahydrothiophene-3-carboxylic acids

A method of synthesizing an optically active cyclic methionine analogue, 3-aminotetrahydrothiophene-3-carboxylic acid (At5c), is described. A Bucherer–Bergs reaction of 4,5-dihydro-3(2H)-thiophenone and the subsequent alkaline hydrolysis of a hydantoin, followed by Cbz protection of the amine, afforded racemic Cbz-At5c (±)-3 in excellent yield. Diastereomeric esters derived from Cbz-At5c (±)-3 and (R)-BINOL could be separated by column chromatography to give both diastereomers with >99% de. X-ray crystallographic analysis revealed the absolute configuration of the synthesized amino acid derived from the less polar diastereomeric ester to be (S).

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(3S)-(Benzyloxycarbonylamino)tetrahydrothiophene-3-carboxylic acid (R)-2′-hydroxy-[1,1′]-binaphthyl esterC33H27NO5S[α]D26=+4.6 (c 1.06, MeOH)Absolute configuration: (3S),(R)

(3R)-(Benzyloxycarbonylamino)tetrahydrothiophene-3-carboxylic acid (R)-2′-hydroxy-[1,1′]-binaphthyl esterC33H27NO5S[α]D26=+12.9 (c 1.05, MeOH)Absolute configuration: (3R),(R)

(S)-3-(Benzyloxycarbonylamino)tetrahydrothiophene-3-carboxylic acid [Cbz-(S)-At5c]C13H15NO4S[α]D26=-3.4 (c 1.00, MeOH)Absolute configuration: (S)

(3S)-(Benzyloxycarbonylamino)tertrahydrothiophene-3-carboxylic acid (1S,2R,5S)-2-isopropyl-5-methyl-cyclohexyl esterC23H32NO4S[α]D25=+7.2 (c 1.00, CHCl3)Absolute configuration: (3S),(1S,2R,5S)