Hydrolytic kinetic resolution of cyclic substrates
The present invention relates to a process for stereoselective or regioselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic, chiral catalyst to produce a stereoisomerically- and/or regioisomerically-enriched product. The present invention also relates to hydrolytic kinetic resolutions of racemic and diastereomeric mixtures of epoxides.
1. A method of hydrolytic kinetic resolution represented by Scheme 1:
wherein
the terminal epoxide substrate is a racemic mixture;
the salen catalyst is present in less than or equal to about 2 mol % relative to the racemic terminal epoxide substrate;
M represents Co or Co(O 2 CR″);
H 2 O is present in less than or equal to about 55 mol % relative to the racemic terminal epoxide substrate;
the diol product has an enantiomeric excess greater than or equal to about 70%;
R represents independently for each occurrence H, alkyl, aralkyl, or aryl;
R′ represents haloalkyl, aralkyloxyalkyl, acyloxyalkyl, or silyloxyalkyl; and
R″ represents methyl or phenyl.
2. A method of hydrolytic kinetic resolution represented by Scheme 2:
wherein
the terminal epoxide substrate is a racemic mixture;
the salen catalyst is present in less than or equal to about 2 mol % relative to the racemic terminal epoxide substrate;
M represents Co or Co(O 2 CR″);
H 2 O is present in less than or equal to about 55 mol % relative to the racemic terminal epoxide substrate;
the diol product has an enantiomeric excess greater than or equal to about 70%;
R represents independently for each occurrence H, alkyl, aralkyl, or aryl;
R′ represents haloalkyl, aralkyloxyalkyl, acyloxyalkyl, or silyloxyalkyl; and
R″ represents methyl or phenyl.
3. The method of claim 1 or 2 , wherein R represents independently for each occurrence alkyl.
4. The method of claim 1 or 2 , wherein R represents independently for each occurrence tert-butyl.
5. The method of claim 1 or 2 wherein R′ represents —CH 2 Cl, —CH 2 Br, —CH 2 OCH 2 Ph, —CH 2 OSi(tert-butyl)(CH 3 ) 2 or —CH 2 OC(O)CH 2 CH 2 CH 3 .
6. The method of claim 1 or 2 , wherein the diol product has an enantiomeric excess greater than or equal to about 80%.
7. The method of claim 1 or 2 , wherein the diol product has an enantiomeric excess greater than or equal to about 90%.
8. The method of claim 1 or 2 , wherein the diol product has an enantiomeric excess greater than or equal to about 95%.
9. A method of hydrolytic kinetic resolution represented by Scheme 3:
wherein
the terminal epoxide substrate is a racemic mixture;
the salen catalyst is present in less than or equal to about 2 mol % relative to the racemic terminal epoxide substrate;
M represents Co or Co(O 2 CR″);
H 2 O is present in less than or equal to about 55 mol % relative to the racemic terminal epoxide substrate;
the terminal epoxide product has an enantiomeric excess greater than or equal to about 70%;
R represents independently for each occurrence H, alkyl, aralkyl, or aryl;
R′ represents haloalkyl, aralkyloxyalkyl, acyloxyalkyl, or silyloxyalkyl; and
R″ represents methyl or phenyl.
10. A method of hydrolytic kinetic resolution represented by Scheme 4:
wherein
the terminal epoxide substrate is a racemic mixture;
the salen catalyst is present in less than or equal to about 2 mol % relative to the racemic terminal epoxide substrate;
M represents Co or Co(O 2 CR″);
H 2 O is present in less than or equal to about 55 mol % relative to the racemic terminal epoxide substrate;
the terminal epoxide product has an enantiomeric excess greater than or equal to about 70%;
R represents independently for each occurrence H, alkyl, aralkyl, or aryl;
R′ represents haloalkyl, aralkyloxyalkyl, acyloxyalkyl, or silyloxyalkyl; and
R″ represents methyl or phenyl.
11. The method of claim 9 or 10 , wherein R represents independently for each occurrence alkyl.
12. The method of claim 9 or 10 , wherein R represents independently for each occurrence tert-butyl.
13. The method of claim 9 or 10 wherein R′ represents —CH 2 Cl, —CH 2 Br, —CH 2 OCH 2 Ph, —CH 2 OSi(tert-butyl)(CH 3 ) 2 or —CH 2 OC(O)CH 2 CH 2 CH 3 .
14. The method of claim 9 or 10 , wherein the terminal epoxide product has an enantiomeric excess greater than or equal to about 80%.
15. The method of claim 9 or 10 , wherein the terminal epoxide product has an enantiomeric excess greater than or equal to about 90%.
16. The method of claim 9 or 10 , wherein the terminal epoxide product has an enantiomeric excess greater than or equal to about 95%.