Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.

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2-(S)-Octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-uloseC16H26O5[α]D = +18.5 (c 1.1, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (1S,5S,2’S)

2-(S)-Octyl 3,4-dideoxy-α-d-erythro-hexopyranosideC14H28O4[α]D = +113.4 (c 1.0, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (1S,2R,5S,2’S)

2-(S)-Octyl 2,6-di-O-tosyl-3,4-dideoxy-α-d-erythro-hexopyranosideC28H40O8S2[α]D = +68.9 (c 1.0, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (1S,2R,5S,2’S)

2-(S)-Octyl 6-azido-2-O-tosyl-3,4,6-trideoxy-α-d-erythro-hexopyranosideC21H33N3O5S[α]D = +77.9 (c 1.0, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (1S,2R,5S,2’S)

6-Azido-2-O-tosyl-3,4,6-trideoxy-α,β-d-erythro-hexopyranoseC13H17N3O5S[α]D = +14.0 (c 1.1, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (2R,5S)

6-Azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactoneC13H15O5SN3Mp 77 °C[α]D = +9.2 (c 1.0, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (2R,5S)

Methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylateC7H11N3O3[α]D = −8.8 (c 0.2, CHCl3)Source of chirality: d-galactoseAbsolute configuration: (2S,5S)

(2S,5S)-5-(Azidomethyl)-tetrahydrofuran-2-carboxylic acidC6H9N3O3[α]D = −5.0 (c 0.7, H2O)Source of chirality: d-galactoseAbsolute configuration: (2S,5S)

(2S,5S)-5-(Aminomethyl)-tetrahydrofuran-2-carboxylic acidC6H11NO3[α]D = +20.4 (c 1.0, H2O)Source of chirality: d-galactoseAbsolute configuration: (2S,5S)