Chemo-enzymatic synthesis of the azasugars 1,4-dideoxyallonojirimycin and 1,4-dideoxymannojirimycin

The enzymatic resolution of the N-phenylacetyl derivative of racemic homoserine lactone with penicillin G acylase immobilized on Eupergit C gave (R)-(+)-α-amino-γ-butyrolactone and (S)-(−)-α-N-phenylacetamido-γ-butyrolactone in high enantiomeric purity (ee >99%) and 46–47% yields for each enantiomer. The enantiomers were converted into azasugars 1,4-dideoxyallonojirimycin and 1,4-dideoxymannojirimycin using Wittig olefination, catalytic ring-closing metathesis (RCM), and stereoselective dihydroxylation with OsO4 in 29% overall yield over 11 high yielding steps. Enzyme inhibition studies showed that 1,4-dideoxyallonojirimycin is a better β-glucosidase inhibitor (IC50 32.4 μM toward β-glucosidase from almonds) and a better β-galactosidase inhibitor (IC50 5.9 mM for β-galactosidase from Aspergillusoryzae) than 1,4-dideoxymannojirimycin (IC50 2.86 mM and 12.5 mM for β-glucosidase and β-galactosidase, respectively).

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(R)-3-Amino-dihydrofuran-2(3H)-one hydrochlorideC4H8Cl No4[α]D25=+27 (c 1, H2O)Source of chirality: enzymatic resolutionAbsolute configuration: (3R)

(S)-N-(2-Oxo-tetrahydrofuran-3-yl)-2-phenylacetamideC12H13NO3[α]D25=-15 (c 1, MeOH)E.e. = >99%Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl 4-(2-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylateC12H23NO4[α]D25=-10 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl 4-allyl-2,2-dimethyloxazolidine-3-carboxylateC13H23NO3[α]D25=+32 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl 1-hydroxypent-4-en-2-ylcarbamateC10H19No3[α]D25=+13.5 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamateC16H33NO3Si[α]D25=-6.0 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl allyl(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)carbamateC19H37NO3Si[α]D25=-3.5 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-tert-Butyl 6-((tert-butyldimethylsilyloxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylateC17H33NO3Si[α]D25=-10.0 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(2S,4S,5R)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-4,5-dihydroxypiperidine-1-carboxylateC17H35NO5Si[α]D25=+14 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (2S,4R,5S)

(2S,4S,5R)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-4,5-dihydroxypiperidine-1-carboxylateC17H35NO5Si[α]D25=-26 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (2S,4S,5R)

(3S,4R,6S)-6-(Hydroxymethyl)piperidine-3,4-diolC6H13NO3[α]D25=+60 (c 1, H2O)Source of chirality: enzymatic resolutionAbsolute configuration: (3S,4R,6S)

(3R,4S,6S)-6-(Hydroxymethyl)piperidine-3,4-diolC6H13NO3[α]D25=-39 (c 1, H2O)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S,6S)