1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine

Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.

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(S)-1-((4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)ethane-1,2-diolC25H45NO5Si[α]D25 = +21.5 (c 1.0, CHCl3)Source of chirality: d-serineAbsolute configuration: (S)(4R,5R,6R)

(3S,4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-3,4-diolC18H41NO4Si[α]D25 = +55.5 (c 0.1, CHCl3)Source of chirality: d-serineAbsolute configuration: (3S,4R,5R,6R)

(2R,3R,4R,5S)-2-(Hydroxymethyl)piperidine-3,4,5-triolC6H13NO4[α]D25 = +40.8 (c 0.8, H2O)Source of chirality: d-serineAbsolute configuration: (2R,3R,4R,5S)

(S)-1-((4R,5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)allyl methanesulfonateC27H47NO6SSi2[α]D25 = +11.2 (c 0.47, CHCl3)Source of chirality: d-serineAbsolute configuration: (S)(4R,5R,6S)

(2R,3R,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethyl)pyrrolidin-3-olC18H41NO4Si2[α]D25 = +11.6 (c 0.5, CHCl3)Source of chirality: d-serineAbsolute configuration: (2R,3R,4R,5R)

(2R,3R,4R,5R)-2,5-Bis(hydroxymethyl)pyrrolidine-3,4-diolC6H13NO4[α]D25 = +55.2 (c 0.9, H2O)Source of chirality: d-serineAbsolute configuration: (2R,3R,4R,5R)