Method for preparing (2S, 3R, 4S)-4-hydroxyisoleucine and analogues thereof

A method for synthesizing compounds of the following general formula (2S)-1:

• wherein the group R1 represents a hydrogen atom, a benzyl, (S)-(+)-p-toluenesulfino, (S)-1-phenylethyl or (S)-1-phenyl-2-hydroxyethyl group or a group of formula —COOR2 wherein group R2 represents an aryl group, an aralkyl group or a C1-C6 alkyl group, comprising the steps of:
• a) diastereo- and enantioselective reduction of the compound of the following formula 2:
• using the microorganism Geotrichum candidum in order to obtain the compound of the following formula 3:
• with an enantiomeric excess of at least about 85% and a diastereomeric excess of at least about 90%;
• b) protecting the OH group of the alcohol of formula 3 with a group Y;
• c) reducing the group —COOEt to an alcohol;
• d) oxidizing the unprotected OH group obtained in c) to obtain the aldehyde of the following general formula II:
• wherein group Y represents a benzyl, t-butyl or tetrahydropyran group, and wherein said method of synthesis is further comprised of either one of two routes of synthesis identified as method A and method B, wherein method A comprises the steps of:
• e1) treating the compound of general formula II with a sulfinamide having the configuration (S)(+) in order to obtain the compound of the following general formula IV:
• wherein group Y represents a benzyl, t-butyl or tetrahydropyran group and group R4 represents a C1-C6 alkyl, aryl or aralkyl group;
• f1) treating the compound of general formula IV with ethylisopropyloxyaluminim cyanide (EtAl(OiPr)CN) in order to obtain the aminonitrile of the following general formula V:
• wherein group Y represents a benzyl, t-butyl or tetrahydropyran group and group R4 represents a C1-C6 alkyl, aryl or aralkyl group;
• g1) treating the aminonitrile of general formula V with an inorganic acid in order to obtain the salt of the lactone of the following formula 9:
• h1) alkaline hydrolysis of the salt of the lactone of formula 9 in order to obtain the compound of general formula (2S)-I wherein group R1 represents a hydrogen atom, and wherein method B comprises the steps of:
• e2) treating the compound of general formula II in order to obtain the aminonitrile of the following general formula III:
• wherein group Y represents a benzyl, t-butyl or tetrahydropyran group and group R3 represents a benzyl, (S)-(+)-p-toluenesulfino, (S)-1-phenylethyl or (S)-1-phenyl-2-hydroxyethyl group;
• f2) treating with an acid of the aminonitrile of general formula III in order to obtain the lactone of the following general formula VI:
• wherein R3 represents hydrogen atom or a group protecting the amine group, however if R3 represents a benzyl, (S)-(+)-p-toluenesulfino, (S)-1-phenylethyl or (S)-1-phenyl-2-hydroxyethyl group or if R1 does not represent a hydrogen atom and R3 represents a hydrogen atom, step f2 is followed by an additional step f2.1) which consists of treating the lactone of general formula VI in order to obtain the lactone of the following general formula VII:
• and wherein group R2 represents an aryl group, an aralkyl group or an C1-C6 alkyl group;
• and
• g2) diastereoselective hydrolysis of the lactone of general formula VI or VII in order to obtain the compound of general formula (2S)-I.