Efficient methods for Z- or cis-selective cross-metathesis
The present invention generally relates to methods for performing metathesis reactions, including cross-metathesis reactions. Methods described herein exhibit enhanced activity and stereoselectivity, relative to known methods, and are useful in the synthesis of a large assortment of biologically and therapeutically significant agents.
1. A method, comprising:
reacting terminal alkene of formula:
H 2 C═C(R y )R z
wherein:
R y is a hydrogen or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; and
R z is an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl,
with an allylic amine of formula:
H 2 C═CH—C(R′) 2 N(R″) 2
wherein:
each R′ is independently hydrogen, —C(O)R a , or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl;
each R a is independently hydrogen or optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; and
each R″ is independently —C(O)R a , an amino protecting group, or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl,
to form a cross-metathesis product with a Z:E ratio greater than 1:1.
2. The method according to claim 1 , wherein the reacting step is performed in the presence of a chiral metal complex of formula I:
wherein:
M is Mo or W;
R 1 is an optionally substituted group selected from aryl, heteroaryl, aliphatic, or heteroaliphatic;
each of R 2 and R 3 is independently hydrogen, or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, or heteroaryl;
R 4 is an optionally substituted group selected from —O-alkyl, —O-heteroalkyl, —O-aryl, —O-heteroaryl, —N(R n )-alkyl, —N(R n )-heteroalkyl, —N(R n )-aryl, or —N(R n )-heteroaryl;
each R n is independently hydrogen, an amino protecting group, or an optionally substituted aliphatic; and
R 5 is halogen or an optionally substituted group selected from aryl, heteroaryl, aliphatic, heteroaliphatic, —O-alkyl, —O-heteroalkyl, —O-aryl, or —O-heteroaryl.
3. The method according to claim 2 , wherein R 4 is an optionally substituted asymmetric —O-aryl group and R 5 is an optionally substituted heteroaryl group.
4. The method according to claim 3 , wherein R 1 is an optionally substituted group selected from aryl or aliphatic.
5. The method according to claim 4 , wherein R 1 is
wherein each R 17 is independently hydrogen or a monovalent substituent.
6. The method according to claim 5 , wherein R 5 is an optionally substituted group selected from
7. The method according to claim 6 , wherein R 4 is an optionally substituted group selected from:
8. The method according to claim 2 , wherein the metal complex comprises any one of the catalysts depicted below:
wherein each X is bromo or iodo,
wherein Mes is 2,4,6-trimethylphenyl;
wherein each X is bromo, iodo, or —CF 3 ,
9. A method, comprising:
reacting terminal alkene of formula:
H 2 C═C(R y )R z
wherein:
R y is a hydrogen or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; and
R z is an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl,
with an enol ether of formula:
H 2 C═C(R b )OR
wherein:
R is —C(O)R a , a hydroxyl protecting group, or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl;
R a is hydrogen or optionally substituted group selected from aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; and
R b is hydrogen or optionally substituted aliphatic,
to form a cross-metathesis product with a Z:E ratio greater than 1:1.
10. The method according to claim 9 , wherein the reacting step is performed in the presence of a chiral metal complex of formula I:
wherein:
M is Mo or W;
R 1 is an optionally substituted group selected from aryl, heteroaryl, aliphatic, or heteroaliphatic;
each of R 2 and R 3 is independently hydrogen, or an optionally substituted group selected from aliphatic, heteroaliphatic, aryl, or heteroaryl;
R 4 is an optionally substituted group selected from —O-alkyl, —O-heteroalkyl, —O-aryl, —O-heteroaryl, —N(R n )-alkyl, —N(R n )-heteroalkyl, —N(R n )-aryl, or —N(R n )-heteroaryl;
each R n is independently hydrogen, an amino protecting group, or an optionally substituted aliphatic; and
R 5 is halogen or an optionally substituted group selected from aryl, heteroaryl, aliphatic, heteroaliphatic, —O-alkyl, —O-heteroalkyl, —O-aryl, or —O-heteroaryl.
11. The method according to claim 10 , wherein R 4 is an optionally substituted asymmetric —O-aryl group and R 5 is an optionally substituted heteroaryl group.
12. The method according to claim 11 , wherein R 1 is an optionally substituted group selected from aryl or aliphatic.
13. The method according to claim 12 , wherein R 1 is
wherein each R 17 is independently hydrogen or a monovalent substituent.
14. The method according to claim 13 , wherein R 5 is an optionally substituted group selected from
15. The method according to claim 14 , wherein R 4 is an optionally substituted group selected from:
16. The method according to claim 10 , wherein the metal complex comprises any one of the catalysts depicted below:
wherein each X is bromo or iodo,
wherein Mes is 2,4,6-trimethylphenyl;
wherein each X is bromo, iodo, or —CF 3 ,
17. The method according to claim 3 , wherein R 4 is a silyl-protected BINOL derivative.
18. The method according to claim 11 , wherein R 4 is a silyl-protected BINOL derivative.