Process for the stereoselective synthesis of 3-substituted 2-sulfonylmethylpropionic acids, and intermediate products

A process for the stereoselective preparation of a compound of the formula I ##STR28## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or is substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;

• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or is substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups,
• and the compound of the formula I may be present in the R or S form, which process comprises
• I) reacting a mercaptan of the formula II
• R.sup.1 --SH II
• in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• in the presence of a base with a compound of the formula III ##STR29## in which Hal is iodine, bromine or chlorine and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, to give a compound of the formula IV ##STR30## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and
• II) reacting the compound of the formula IV with an ylide of the formula V
• R.sup.2 --CH.dbd.P (C.sub.6 H.sub.5).sub.3 V
• in which R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups to give an unsaturated compound of the formula VI ##STR31## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and
• III) converting the compound of the formula VI into a compound of the formula I, by
• A) subjecting the compound of the formula VI to alkaline hydrolysis to give a compound of the formula VII ##STR32## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and
• a) by enantioselective hydrogenation, converting the compound of the formula VII into a compound of the formula X ##STR33## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and, by subsequent oxidation, converting the compound of the formula X into a compound of the formula I, or
• b) by oxidation, reacting the compound of the formula VII to give a compound of the formula XI ##STR34## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and, by subsequent enantioselective hydrogenation of the compounds of the formula XI, obtaining a compound of the formula I, or
• B) subjecting the compound of the formula VI to enantioselective hydrogenation with a chiral catalyst to give a compound of the formula VIII ##STR35## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and
• a) by alkaline hydrolysis, converting the compound of the formula VIII into a compound of the formula X ##STR36## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and, by subsequent oxidation of the compound of the formula X, obtaining a compound of the formula I, or
• b) by oxidation of the compound of the formula VIII, obtaining a compound of the formula XII ##STR37## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and subsequently, by alkaline hydrolysis, converting the compound of the formula XII into a compound of the formula I, or
• c) oxidizing the compound of the formula VI to give a compound of the formula IX ##STR38## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and
• converting the compound of the formula IX into a compound of the formula I by
• a) alkaline hydrolysis of the compound of the formula IX to give a compound of the formula XI, ##STR39## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and subsequent enantioselective hydrogenation of the compound of the formula XI to give a compound of the formula I, or
• b) enantioselective hydrogenation of the compound of the formula IX to give a compound of the formula XII ##STR40## in which R.sup.1 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -cycloalkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or C.sub.6 -C.sub.12 -aryl or -heteroaryl or -heterocycloalkyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different hydroxyl, methoxy or trialkylsilyloxy groups;
• and R.sup.2 is C.sub.6 -C.sub.12 -aryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• is C.sub.3 -C.sub.9 -heteroaryl which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• or
• is C.sub.1 -C.sub.10 -alkyl, alkenyl or alkynyl, which is unsubstituted or substituted by 1, 2 or 3 identical or different methoxy, halogen, cyano, methyl, trifluoromethyl, isopropyl or nitro groups;
• and R.sup.3 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, and subsequent alkaline hydrolysis of the compound of the formula XII to give a compound of the formula I.