2-n-substituted or unsubstituted-2-amino-5-methylpiperidine-3,4-diols and processes for the preparation thereof

A process for the preparation of (2R,3S,4R,5R)-2-amino-5-methylpiperidine-3,4-diol or a (2S,3S,4R,5R)-2-N-substituted-2-amino-5-methylpiperidine-3,4-diol represented by formula (I):

• wherein R1 and R2 each are a hydrogen atom, or R1 is a hydrogen atom and R2 is a lower alkanoyl group or a lower ω-trihaloalkanoyl group, or R1 and R2 together denote phthaloyl group, characterized in that the process comprises:
• eliminating the hydroxyl-protecting group (R4) at the 4-position of a (2S,3S or 3R,4R)-5-N-protected-2,3,4-O-tri-protected-5-aminopentane-1,2,3,4-tetraol represented by formula (II):
• wherein R3 is an amino-protecting group, R4 is a hydroxyl-protecting group, and X1 and X2 each are a hydroxyl-protecting group, or X1 and X2 together denote one divalent hydroxyl-protecting group having the formula:
• where R5 and R6 may be the same or different and each denote a hydrogen atom, an alkyl group or an aryl group, especially phenyl group, or X1 and X2 together denote a cycloalkylidene group or tetrapyranylidene group, to give a (2S,3R,4R)-5-N-protected-2,3-O-di-protected-5-aminopentane-1,2,3,4-tetraol represented by formula (III):
• wherein R3, X1 and X2 have the same meanings as above;
• protecting the hydroxyl group at the 1-position of the compound of formula (III) with a hydroxyl-protecting group (R7), to prepare a (2S,3R,4R)-5-N-protected-1,2,3-O-tri-protected-5-aminopentane-1,2,3,4-tetraol represented by formula (IV):
• wherein R3, X1 and X2 have the same meanings as above and R7 denotes a hydroxyl-protecting group;
• oxidizing the hydroxyl group at the 4-position of the compound of formula (IV), to prepare a (2S,3S)-5-N-protected-1,2,3-O-tri-protected-4-keto-5-aminopentane-1,2,3-triol represented by formula (V):
• wherein R3, X1, X2 and R7 have the same meanings as above;
• subjecting the oxo group at the 4-position of the compound of formula (V) to the Wittig reaction so as to convert the oxo group into a methylene group, thereby producing a (2S,3S)-5-N-protected-1,2,3-O-tri-protected-4-methylene-5-aminopentane-1,2,3-triol represented by formula (VI):
• wherein R3, R7, X1 and X2 have the same meanings as above;
• eliminating the hydroxyl-protecting group (R7) at the 1-position of the compound of formula (VI), to prepare a (2S,3S)-5-N-protected-2,3-O-di-protected-4-methylene-5-aminopentane-1,2,3-triol represented by formula (VII):
• wherein R3, X1 and X2 have the same meanings as above;
• oxidizing the hydroxyl group at the 1-position of the compound of formula (VII) with accompanying cyclization, to prepare a (2R,3R,4S)-1-N-protected-3,4-O-di-protected-5-methylenepiperidine-2,3,4-triol represented by formula (VIII):
• wherein R3, X1 and X2 have the same meanings as above;
• conducting the Mitsunobu reaction on the hydroxyl group at the 2-position of the compound of formula (VIII) by reaction with phthalimide, to prepare a (2S,3S,4S)-1-N-protected-3,4-O-di-protected-5-methylene-2-phthalimido-piperidine-3,4-diol represented by formula (IX):
• wherein R3, X1 and X2 have the same meanings as above;
• reducing the double bond at the 5-position of the compound of formula (IX) to convert the methylene group at the 5-position into a methyl group, thereby preparing a (2S,3S,4R,5R)-1-N-protected-3,4-O-di-protected-5-methyl-2-phthalimidopiperidine-3,4-diol represented by formula (X):
• wherein R3, X1 and X2 have the same meanings as above;
• eliminating the phthaloyl group from the 2-amino group of the compound of formula (X) by treatment with hydrazine or an acid, to prepare a (2R,3S,4R,5R)-2-amino-1-N-protected-3,4-O-di-protected-5-methylpiperidine-3,4-diol represented by formula (XI):
• wherein R3, X1 and X2 have the same meanings as above;
• protecting the amino group at the 2-position of the compound of formula (XI) with a lower alkanoyl group or a lower ω-trihaloalkanoyl group (R2), to prepare a compound represented by formula (XII):
• wherein R3, X1 and X2 have the same meanings as above, R1 is a hydrogen atom and R2 is a lower alkanoyl group or a lower ω-trihaloalkanoyl group;
• and then
• eliminating both the imino-protecting group (R3) and the hydroxyl-protecting groups (X1 and X2) of the compound of formula (XII), or alternatively eliminating the imino-protecting group and the hydroxyl-protecting groups (X1 and X2) immediately from the compound of formula (X) or (XI), to give the compound of the formula (I).