Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l

A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase.

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1,2-O-Isopropylidene-β-d-idurono-3,6-lactoneC9H12O6Ee = 100%[α]D25=-105.6 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-5-deoxy-1,2-O-isopropylidene-α-l-glucurono-3,6-lactoneC9H11N3O5Ee = 100%[α]D21=-24.2 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-5-deoxy-1,2-O-isopropylidene-α-l-gluco-hexodialdo-1,4:3,6-difuranoseC9H13N3O5Ee = 100%[α]D21=+8.1 (c 1.5, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-5-deoxy-1,2-O-isopropylidene-α-l-glucofuranoseC9H15N3O5Ee = 100%[α]D21=+14.0 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

l-Deoxynojirimycin hydrochlorideC6H14ClNO4Ee = 100%[α]D24=-38.7 (c 1.0, H2O)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-5-deoxy-l-glucofuranoseC6H11N3O5Ee = 100%[α]D24=-24.2 (c 1.0, H2O)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-3,6-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-glucofuranoseC23H27N3O5Ee = 100%[α]D24=+23.6 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-3,6-di-O-benzyl-5-deoxy-l-glucofuranoseC20H23N3O5Ee = 100%[α]D25=+9.6 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

5-Azido-3,6-di-O-benzyl-5-deoxy-l-glucono-1,4-lactoneC20H21N3O5Ee = 100%[α]D25=-19.5 (c 1.0, CHCl3)Source of chirality: l-glucurono-3,6 lactone as starting material

2,5-Dideoxy-2,5-imino-l-mannitol (l-DMDP)[(2S,3S,4S,5S)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol]C6H13NO4Ee = 100%[α]D21=-56.6 (c 1.2, H2O)Source of chirality: l-glucurono-3,6 lactone as starting material

(2R,3S,4S,5S)-3,4-Dihydroxy-5-(hydroxymethyl)-d-proline[(3S)-3-hydroxy-d-bulgecinine]C6H11NO5Ee = 100%[α]D25=-15.1 (c 1.0, H2O)Source of chirality: l-glucurono-3,6 lactone as starting material