Contribution to the synthesis of polyhydroxylated indolizidines starting from sugar isothiocyanates

A straightforward stereoselective route towards castanospermine analogues starting from the corresponding d-gluco- and l-ido-hexofuranose isothiocyanates (5S)-2 and (5R)-2 is described. The key transformations of this approach rely on ring-closing metathesis and reductive amination to form the final polyhydroxylated indolizidines 10–13 in good overall yields.

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3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(methoxycarbonylamino)-α-d-gluco-hept-6-enfuranoseC19H25NO6[α]D25 = +44.2 (c 0.33, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5R)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(methoxycarbonylamino)-β-l-ido-hept-6-enfuranoseC19H25NO6[α]D25 = +19.3 (c 0.25, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-amino-α-d-gluco-hept-6-enfuranoseC17H23NO4[α]D25 = −53.2 (c 0.13, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-amino-β-l-ido-hept-6-enfuranoseC17H23NO4[α]D24 = +14.0 (c 0.35, MeOH)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(benzyloxycarbonylamino)-α-d-gluco-hept-6-enfuranoseC17H23NO4[α]D25 = −10.9 (c 0.11, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5R)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(benzyloxycarbonylamino)-β-l-ido-hept-6-enfuranoseC17H23NO4[α]D25 = −52.1 (c 0.13, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-[allyl(benzyloxycarbonyl)amino]-α-d-gluco-hept-6-enfuranoseC28H33NO6[α]D25 = −44.2 (c 0.15, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5R)

3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-[allyl(benzyloxycarbonyl)amino]-β-l-ido-hept-6-enfuranoseC28H33NO6[α]D25 = −4.07 (c 0.11, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

(2′R,4R)-4-C-[1′-(Benzyloxycarbonyl)-2′,5′-dihydro-1′H-pyrrol-2′-yl]-3-O-benzyl-1,2-O-isopropylidene-α-d-gluco-furanoseC26H29NO6[α]D25 = +68.7 (c 0.11, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5R)

(2′S,4R)-4-C-[1′-(Benzyloxycarbonyl)-2′,5′-dihydro-1′H-pyrrol-2′-yl]-3-O-benzyl-1,2-O-isopropylidene-β-l-threo-furanoseC26H29NO6[α]D25 = −0.91 (c 0.11, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S)

(4R)-4-C-[(2′R,3′S,4′R)-1′-(Benzyloxycarbonyl)-3′,4′-dihydroxypyrrolidin-2′-yl]-3-O-benzyl-1,2-O-isopropylidene-α-d-gluco-furanoseC26H31NO8[α]D25 = +23.8 (c 0.16, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5R,6S,7R)

(4R)-4-C-[(2′S,3′R,4′S)-1′-(Benzyloxycarbonyl)-3′,4′-dihydroxypyrrolidin-2′-yl]-3-O-benzyl-1,2-O-isopropylidene-β-l-threofuranoseC26H31NO8[α]D25 = −52.9 (c 0.18, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (2R,3R,4S,4R,5S,6R,7S)

(6S,7R,8R,8aR)-6,7,8-Trihydroxyindolizidine (1-deoxycastanospermine)C8H15NO3[α]D25 = +50.2 (c 0.1, MeOH)Source of chirality: d-glucoseAbsolute configuration: (6S,7R,8R,8aR)

(6S,7R,8R,8aS)-6,7,8-Trihydroxyindolizidine (8a-epi-1-deoxycastanospermine)C8H15NO3[α]D20 = +42.2 (c 0.15, MeOH)Source of chirality: d-glucoseAbsolute configuration: (6S,7R,8R,8aS)

(1R,2S,6S,7R,8R,8aR)-1,2,6,7,8-PentahydroxyindolizidineC8H15NO5[α]D25 = −4.0 (c 1.0, MeOH)Source of chirality: d-glucoseAbsolute configuration: (1R,2S,6S,7R,8R,8aR)

(1S,2R,6S,7R,8R,8aS)-1,2,6,7,8-PentahydroxyindolizidineC8H15NO5[α]D25 = +20.1 (c 0.17, MeOH)Source of chirality: d-glucoseAbsolute configuration: (1S,2R,6S,7R,8R,8aS)