Homochiral carbon branched piperidines from carbon branched sugar lactones: 4-C-methyl-deoxyfuconojirimycin (DFJ) and its enantiomer—removal of glycosidase inhibition

The value of readily available 2-C-methyl aldonic acids in short syntheses of carbon branched piperidines containing quaternary centers is demonstrated. The effect of the introduction of a 4-C-methyl group into piperidine imino sugar inhibitors of l-fucosidases and d-galactosidases is reported.

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2,3-O-Isopropylidene-2-C-methyl-d-ribono-1,4-lactoneC9H14O5Ee = 100%[α]D19=-35.6 (c 1.4, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,3-O-Isopropylidene-5-O-methanesulfony1-2-C-methyl-d-ribono-1,4-lactoneC10H16O7SEe = 100%[α]D24=-24.7 (c 1.0, CHCl3)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,3-O-Isopropylidene-2-C-methyl-l-lyxono-1,4-lactoneC9H14O5Ee = 100%[α]D22=-74.1 (c 0.6, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,3-O-Isopropylidene-2-C-methyl-d-lyxono-1,4-lactoneC9H14O5Ee = 100%[α]D23=+77.2 (c 1.8, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

2,3-O-Isopropylidene-2-C-methyl-5-O-trifluoromethanesulfonyl-l-lyxono-1,4-lactoneC10H13F3O7SEe = 100%[α]D21=-55.9 (c 2.0, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,3-O-Isopropylidene-2-C-methyl-5-O-trifluoromethanesulfonyl-d- lyxono-1,4-lactoneC10H13F3O7SEe = 100%[α]D21=+60.9 (c 0.6, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-methyl-l-lyxono-1,4-lactoneC9H13N3O4Ee = 100%[α]D21=-72.0 (c 0.4, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-methyl-d-lyxono-1,4-lactoneC9H13N3O4Ee = 100%[α]D20=+73.9 (c 0.9, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

6-Azido-1,6-dideoxy-3,4-O-isopropylidene-3-C-methyl-l-tagatofuranoseC10H17N3O4Ee = 100%[α]D24=-5.1 (c 0.5, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

6-Azido-1,6-dideoxy-3,4-O-isopropylidene-3-C-methyl-d-tagatofuranoseC10H17N3O4Ee = 100%[α]D24=+7.1 (c 0.5, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-trideoxy-l-tagatopyranose [(3S,4R,5S)-5,6-dimethyl-4,5-O-isopropylidene-2,3,4,5-tetrahydropyridine-3,4,5-triol]C10H17NO3Ee = 100%[α]D21=-46.0 (c 1.5, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-trideoxy-d-tagatopyranose [(3R,4S,5R)-5,6-dimethyl-4,5-O-isopropylidene-2,3,4,5-tetrahydropyridine-3,4,5-triol]C10H17NO3Ee = 100%[α]D20=+49.0 (c 1.6, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

2,6-Imino-3-C-methyl-1,2,6-trideoxy-l-tagatopyranose [(3S,4R,5S)-5,6-dimethyl-2,3,4,5-tetrahydropyridine-3,4,5-triol]C7H13NO3Ee = 100%[α]D21=+30.6 (c 1.4, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

2,6-Imino-3-C-methyl-1,2,6-trideoxy-d-tagatopyranose [(3R,4S,5R)-5,6-dimethyl-2,3,4,5-tetrahydropyridine-3,4,5-triol]C7H13NO3Ee = 100%[α]D21=-34.7 (c 0.3, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-l-altritolC10H19NO3Ee = 100%[α]D21=-23.1 (c 1.6, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-d-altritolC10H19NO3Ee = 100%[α]D22=+17.5 (c 1.2, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

1,5-Dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-d-fucitolC10H19NO3Ee = 100%[α]D21=-13.0 (c 0.2, acetone)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

1,5-Dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-l-fucitolC10H19NO3Ee = 100%[α]D22=+8.2 (c 2.2, acetone)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

1,5-Dideoxy-1,5-imino-4-C-methyl-d-fucitolC7H15NO3Ee = 100%[α]D21=+33.7 (c 0.4, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

4-C-Methyl DFJ [1,5-dideoxy-1,5-imino-4-C-methyl-l-fucitol]C7H15NO3Ee = 100%[α]D21=-25.1 (c 0.7, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

1,5-Imino-4-C-methyl-1,5,6-trideoxy-l-altritolC7H15NO3Ee = 100%[α]D21=+5.1 (c 0.4, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

1,5-Imino-4-C-methyl-1,5,6-trideoxy-d-altritolC7H15NO3Ee = 100%[α]D21=-3.9 (c 0.5, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

N-Butyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-d-fucitolC14H27NO3Ee = 100%[α]D22=+8.1 (c 0.4, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

N-Butyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-l-fucitolC14H27NO3Ee = 100%[α]D23=-2.4(c 1.4, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

N-Butyl-1,5-imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-l-altritolC14H27NO3Ee = 100%[α]D22=+13.0 (c 0.3, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

N-Butyl-1,5-imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-d-altritolC14H27NO3Ee = 100%[α]D22=-9.9 (c 0.8, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

N-Butyl-1,5-dideoxy-1,5-imino-4-C-methyl-d-fucitolC11H23NO3Ee = 100%[α]D21=+1.0 (c 0.7, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

N-Butyl-1,5-dideoxy-1,5-imino-4-C-methyl-l-fucitolC11H23NO3Ee = 100%[α]D22=-4.2 (c 0.2, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material

N-Butyl-1,5-imino-4-C-methyl-1,5,6-trideoxy-l-altritolC11H23NO3Ee = 100%[α]D21=+22.1 (c 0.8, MeOH)Source of chirality: 2-C-methyl-d-ribono-1,4-lactone as starting material

N-Butyl-1,5-imino-4-C-methyl-1,5,6-trideoxy-d-altritolC11H23NO3Ee = 100%[α]D21=-13.4 (c 0.7, MeOH)Source of chirality: 2-C-methyl-d-lyxono-1,4-lactone as starting material