Synthesis of (2S,3R,4R)-4,5-dihydroxyisoleucine and derivatives

A method for the preparation of a (2S,3R, 4R)-4,5-dihydroxyisoleucine derivative (400)

• wherein:
• R1 is H or a carboxylic acid moiety protecting group,
• R2 is H or an amino moiety protecting group and
• R3 and R4 are independently from another selected from H and a hydroxyl moiety protecting group, or both R3 and R4 are one single vicinal diol protecting group moiety, from a crotyl glycinester derivative (200), wherein said method comprises the method for the preparation of
• is converted to yield (2S,3S)-2-amino-3-methylpent-4-enoic acid (30)
• (2S,3S)-2-amino-3-methylpent-4-enoic acid (30),
• wherein said method comprises
• a) the Claisen rearrangement step of reacting a Z-crotyl-glycin ester derivative 200
• wherein R2A is amino protecting group stable under conditions favourable to Claisen rearrangement,
• in the presence of a chiral ligand to yield 2-amino-3-methylpent-4-enoic acid derivative (300)
• and
• b) an enzymatic resolution step, wherein 2-amino-3-methylpent-4-enoic acid derivative (310) and further comprises
• a) a Sharpless dihydroxylation step, wherein 2-amino-3-methylpent-4-enoic acid derivative (330)
• is reacted in the presence of Os(VIII) complexed by a chiral ligand, particularly by hydroquinidine 1,4-phthalazinediyl diether, to the 2-amino-3-methyl-4,5-dihydroxypentanoic acid derivative (430)
• or
• b) a Sharpless epoxidation step, wherein 2-amino-3-methylpent-4-enoic acid derivative (330)
• is reacted in the presence of a chiral ligand and a catalyst comprising titanium isopropoxide to a (2S,3S, 4R)-2-amino-3-methyl-4,5-epoxy-pentanoic acid derivative (360),
• and and subsequent enzymatic conversion catalysed by an epoxide hydrolase into 2-amino-3-methyl-4,5-dihydroxypentanoic acid derivative (430),
• and wherein optionally, subsequent to step a) or b),
• any amino group protecting moiety R2C and/or carboxylic acid group protecting moiety R1C is selectively removed from (430) to yield the free (2S,3R, 4R)-4,5-dihydroxyisoleucine, or (430) is reacted with a vicinal diol protecting group, particularly to yield a compound selected from
• wherein R1C and R2C have the same meaning as defined above and R5 and R5′ are independently selected from H and CH3.