β-Mannosidase and β-hexosaminidase inhibitors: synthesis of 1,2-bis-epi-valienamine and 1-epi-2-acetamido-2-deoxy-valienamine from d-mannose

A partially protected C-5C-5a unsaturated carbasugar with α-lyxo configuration is synthesised in five steps and 26% overall yield from a known mannose-derived hemiacetal, using ring-closing metathesis as a key step. This carbasugar is converted into valienamine derivatives with β-lyxo (i.e., corresponding to β-manno at C-1–C-4), α-lyxo (i.e., corresponding to α-manno at C-1–C-4) and β-2-acetamido-2-deoxy-xylo (i.e., corresponding to β-GlcNAc at C-1–C-4) configurations. This is the first report of the synthesis of the β-lyxo compound, 1,2-bis-epi-valienamine, which was found to inhibit Cellulomonas fimi β-mannosidase (CfMan2A) with Ki 140 μM. We report the crystal structures of three protected C-5C-5a unsaturated carbasugars with lyxo configuration.

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(3R,4R,5R,6S)-1,3,4-Tri-O-benzyl-1,3,4,5,6-pentahydroxy-2-methylene-oct-7-eneC30H34O5Ee = 100%[α]D23=-22.9 (c 1.0, CHCl3)Source of chirality: d-mannose

(3R,4R,5R,6R)-1,3,4-Tri-O-benzyl-1,3,4,5,6-pentahydroxy-2-methylene-oct-7-eneC30H34O5Ee = 100%[α]D23=-0.3 (c 1.0, CHCl3)Source of chirality: d-mannose

3,4,6-Tri-O-benzyl-5a-carba-α-d-lyxo-hex-5(5a)-enopyranoseC28H30O5Ee = 100%[α]D23=-15.3 (c 1.0, CHCl3)Source of chirality: d-mannose

(3R,4S,5R,6S)-5,6-Di-O-acetyl-1,3,4-tri-O-benzyl-pentahydroxy-2-methylene-oct-7-eneC34H38O7Ee = 100%[α]D23=-28.3 (c 1.0, CHCl3)Source of chirality: d-mannose

1,2-Di-O-acetyl-3,4,6-tri-O-benzyl-5a-carba-α-d-lyxo-hex-5(5a)-enopyranoseC32H34O7Ee = 100%[α]D23=+63.9 (c 1.0, CHCl3)Source of chirality: d-mannose

(3R,4S,5R,6R)-5,6-Di-O-acetyl-1,3,4-tri-O-benzyl-pentahydroxy-2-methylene-oct-7-eneC34H38O7Ee = 100%[α]D22=-12.9 (c 1.0, CHCl3)Source of chirality: d-mannose

1,2-Di-O-acetyl-3,4,6-tri-O-benzyl-5a-carba-β-d-lyxo-hex-5(5a)-enopyranoseC32H34O7Ee = 100%[α]D23=-75.1 (c 1.0, CHCl3)Source of chirality: d-mannose

2-Azido-3,4,6-tri-O-benzyl-1,2-dideoxy-1-trichloroacetylamido-5a-carba-β-d-xylo-hex-5(5a)-enopyranoseC30H29Cl3N4O4Ee = 100%[α]D23=-97.8 (c 1.0, CHCl3)Source of chirality: d-mannose

2-Azido-3,4,6-tri-O-benzyl-1-(tert-butyloxycarbonylamino)-1,2-dideoxy-5a-carba-β-d-xylo-hex-5(5a)-enopyranoseC33H38N4O5Ee = 100%[α]D23=-98.1 (c 1.0, CHCl3)Source of chirality: d-mannose

2-Acetamido-3,4,6-tri-O-acetyl-1-(tert-butyloxycarbonylamino)-1,2-dideoxy-5a-carba-β-d-xylo-hex-5(5a)-enopyranoseC20H30N2O9Ee = 100%[α]D23=-65.6 (c 0.7, CHCl3)Source of chirality: d-mannose

1,2-Anhydro-3,4,6-tri-O-benzyl-5a-carba-β-d-lyxo-hex-5(5a)-enopyranose 16C28H28O4Ee = 100%[α]D22=+21.5 (c 1.0, CHCl3)Source of chirality: d-mannose