Synthesis of 4-hydroxy-2-methylproline derivatives via pyrrolidine ring assembly: chromatographic resolution and diastereoselective synthesis approaches

4-Hydroxy-2-methylproline diastereomers are successfully prepared without the use of an external chiral auxiliary. Dihydroxylation of the key intermediate 2 resulted in lactone 4 as a mixture of diastereomers in good yield. Mesylation, hydrogenation and concomitant intramolecular cyclization of 4 led to the formation of both (2R,4R)- and (2R,4S)-4-hydroxy-2-methylprolines as a mixture of diastereomers. Appropriate protection followed by chromatographic separation resulted in isolation of both cis- and trans-diastereomers in enantiomerically pure form and in equal quantity. In subsequent experiments, the synthesis of the more challenging diastereomers (2R,4R)- and (2S,4S)-4-hydroxy-2-methylproline was achieved by diastereoselective iodolactonization of (R)- or (S)-allylalanine obtained after hydrolysis of intermediate 2, followed by pyrrolidine ring closer under mild alkaline conditions. After selective protection and deprotection, Fmoc-(2R,4R)-α-Me-Hyp(tBu)-OH 14, a building block suitable for solid phase peptide synthesis was obtained.

Figure optionsDownload as PowerPoint slide

(2S,4R)-Benzyl-4-allyl-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylateC21H22NO4[α]D21 = −63.4 (c 0.73, CHCl3)Source of Chirality: Enantioretantive allylationAbsolute configuration: (2S,4R)

(1R,4R)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylateC14H15NO4[α]D21 = −18.8 (c 0.13, CH3OH)Source of Chirality: Diastereospecific cyclizationAbsolute configuration: (1R,4R)

(2R,4R)-1-(Benzyloxycarbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxylic acidC14H17NO5[α]D21 = +6.0 (c 0.22, CH3OH)Source of Chirality: (1R,4R)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylateAbsolute configuration: (2R,4R)

(2R,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-tert-butoxy-2-methylpyrrolidine-2-carboxylic acidC18H36NO5Si[α]D21 = +2.6 (c 0.08, CH3OH)Source of Chirality: (2R,4R)-1-(Benzyloxycarbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxylic acidAbsolute configuration: (2R,4R)

(1S,4S)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylateC14H15NO4[α]D21 = +40.7 (c 0.15, CH3OH)Source of Chirality: Diastereospecific cyclizationAbsolute configuration: (1S,4S)

(2S,4S)-1-(Benzyloxycarbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxylic acidC14H17NO5[α]D21 = −6.7 (c 0.10, CH3OH)Source of Chirality: (1S,4S)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylateAbsolute configuration: (2S,4S)