Fructose-6-phosphate aldolases as versatile biocatalysts for nitrocyclitol syntheses

Efficient and stereoselective polyhydroxylated nitrocyclitol syntheses were performed via biocatalysed aldol reactions. The key step was based on a one-pot/one-enzyme cascade reaction process where two reactions occur: aldolase-catalysed aldolisation and spontaneous intramolecular nitroaldolisation. The synthetic methodology was investigated using fructose-6-phosphate aldolase A129S for the synthesis of known nitrocyclitols. Improvements were obtained which involved less steps and increased yields. Several new nitrocyclitols were also prepared using hydroxyacetone (HA) as the donor and FSA wt. From nitrocyclitol stereochemical analyses, the intramolecular nitro-Henry reaction stereoselectivity was dependent on the donor substrate used, HA or dihydroxyacetone (DHA). Whereas DHA provided two stereoisomers, four were obtained using HA.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

1,1-Diethoxybut-3-en-2-olC8H16O3ee = 96%[α]D25=-29 (c 1.0, CHCl3)Source of chirality: Lipase resolutionAbsolute configuration: (S)

1-(1,1-Diethoxy)prop-2-enyl acetateC10H18O4ee >98%[α]D25=+27 (c 1.0, CHCl3)Source of chirality: Lipase resolutionAbsolute configuration: (R)

2-Acetoxy-3,3-diethoxypropanalC9H16O5ee >98%[α]D25=+29 (c 1.0, CHCl3)Source of chirality: Lipase resolutionAbsolute configuration: (R)

1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrolC7H13NO6[α]D25=+13 (c 1.0, CH3OH)Source of chirality: Biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,5S,6R)

1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrolC7H13NO6[α]D25=-15 (c 1.0, CH3OH)Source of chirality: Biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,5R,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrolC7H13NO6[α]D25=+32 (c 1.0, CH3OH)Source of chirality: Biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,5R,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrolC7H13NO6[α]D25=-35 (c 1.0, CH3OH)Source of chirality: Biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,5S,6R)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=+28 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,4R,5R,6R)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=-16 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,4R,5S,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=+33 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,4R,5S,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=-35 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,4R,5R,6R)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=+27 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,4S,5R,6R)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=-15 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,4S,5S,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7[α]D25=+25 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1R,2S,3R,4S,5S,6S)

1-Methyl-6-nitrocyclohexane-1,2,3,4,5-pentolC7H13NO7g[α]D25=-25 (c 1.0, CH3OH)Source of chirality: Lipase resolution and biocatalytic aldolisationAbsolute configuration: (1S,2S,3R,4S,5R,6R)