Compositions and methods for stereoselective aldehyde allylation and crotylation
View Patent ↗Compositions and methods for practical, stereoselective allylation and crotylation for aldehyde substrates are described. The compositions and methods comprise reagents for allylation and/or crotylation and acids. In some embodiments, the reagents and acids are pre-mixed.
1. A composition for crotylation of aldehydes comprising a compound of formula A,
wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, and alkyl; and
wherein at least one of R 1 and R 2 is alkyl; and
wherein R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; and
a Lewis acid.
2. The composition of claim 1 , wherein R a and R b are aryl.
3. The composition of claim 1 , wherein the compound of formula A is a compound of formula 1 or 2
4. The composition of claim 1 , wherein the compound is (R,R)-1 or (S,S)-1.
5. The composition of claim 1 , wherein the compound is (R,R)-2 or (S,S)-2.
6. The composition of claim 1 , wherein the Lewis acid is scandium triflate.
7. The composition of claim 1 , wherein the Lewis acid is present in about 10 mol % relative to the amount of compounds of formula A.
8. The composition of claim 1 , wherein the Lewis acid is present in about 5 mol % relative to the amount of compounds of formula A.
9. The composition of claim 1 , wherein the Lewis acid is present in about 4.4 mol % relative to the amount of compounds of formula A.
10. The composition of claim 1 , wherein the Lewis acid is present in about 2 mol % relative to the amount of compounds of formula A.
11. The composition of claim 1 , wherein the compound of formula A and the Lewis acid are pre-mixed prior to reaction with the aldehyde.
12. The composition of claim 1 , wherein the composition is pre-mixed and stored at ambient temperature prior to reaction with the aldehyde.
13. A composition for allylation of aldehydes comprising a compound of formula A,
wherein R 1 and R 2 are independently hydrogen or halogen; and
R 3 is selected from the group consisting of hydrogen, halogen, and alkyl; and
wherein R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; and
a Lewis acid.
14. The composition of claim 13 , wherein R a and R b are aryl.
15. The composition of claim 13 , wherein the compound of formula A is a compound of formula 13
16. The composition of claim 13 , wherein the compound is (R,R)-13 or (S,S)-13.
17. The composition of claim 13 , wherein the Lewis acid is scandium triflate.
18. The composition of claim 13 , wherein the Lewis acid is present in about 10 mol % relative to the amount of compounds of formula A.
19. The composition of claim 13 , wherein the Lewis acid is present in about 5 mol % relative to the amount of compounds of formula A.
20. The composition of claim 13 , wherein the Lewis acid is present in about 4.4 mol % relative to the amount of compounds of formula A.
21. The composition of claim 13 , wherein the Lewis acid is present in about 2 mol % relative to the amount of compounds of formula A.
22. The composition of claim 13 , wherein the compound of formula A and the Lewis acid are pre-mixed prior to reaction with the aldehyde.
23. The composition of claim 13 , wherein the composition is pre-mixed and stored at ambient temperature prior to reaction with the aldehyde.
24. A method for crotylation of an aldehyde comprising, reaction of the aldehyde with a compound of formula A,
wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, and alkyl; and
wherein at least one of R 1 and R 2 is alkyl; and
wherein R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; and
a Lewis acid.
25. The method of claim 24 , wherein R a and R b are aryl.
26. The method of claim 24 , wherein the compound of formula A is a compound of formula 1 or 2
27. The method of claim 24 , wherein the compound is (R,R)-1 or (S,S)-1.
28. The method of claim 24 , wherein the compound is (R,R)-2 or (S,S)-2.
29. The method of claim 24 , wherein the Lewis acid is scandium triflate.
30. The method of claim 24 , wherein the Lewis acid is used in a catalytic amount.
31. The method of claim 24 , wherein the reaction proceeds at ambient temperature.
32. The method of claim 24 , wherein the reaction proceeds at 0° C.
33. The method of claim 24 , wherein said aldehyde does not react in the absence of Lewis acid.
34. The method of claim 24 , wherein the reaction product is enriched in one enantiomer.
35. The method of claim 24 , wherein the reaction product is generated in >90% enantiomeric excess.
36. The method of claim 24 , wherein the reaction product is generated in >95% enantiomeric excess.
37. The method of claim 24 , wherein the reaction product is enriched in one diastereomer.
38. The method of claim 24 , wherein the reaction product is generated in >10:1 diastereoselectivity.
39. The method of claim 24 , wherein the reaction product is generated in >30:1 diastereoselectivity.
40. The method of claim 24 , wherein the reaction product is generated in >40:1 diastereoselectivity.
41. A method for allylation of an aldehyde comprising, reaction of the aldehyde with a compound of formula A,
wherein R 1 and R 2 are independently hydrogen or halogen; and
R 3 is selected from the group consisting of hydrogen, halogen, and alkyl; and
wherein R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; and
a Lewis acid.
42. The method of claim 41 , wherein R a and R b are aryl.
43. The method of claim 41 , wherein the compound of formula A is a compound of formula 13
44. The method of claim 41 , wherein the compound is (R,R)-13 or (S,S)-13.
45. The method of claim 41 , wherein the Lewis acid is scandium triflate.
46. The method of claim 41 , wherein the Lewis acid is used in a catalytic amount.
47. The method of claim 41 , wherein the reaction proceeds at ambient temperature.
48. The method of claim 41 , wherein the reaction proceeds at 0° C.
49. The method of claim 41 , wherein said aldehyde does not react in the absence of Lewis acid.
50. The method of claim 41 , wherein the reaction product is enriched in one enantiomer.
51. The method of claim 41 , wherein the reaction product is generated in >90% enantiomeric excess.
52. The method of claim 41 , wherein the reaction product is generated in >95% enantiomeric excess.
53. The method of claim 41 , wherein the reaction product is enriched in one diastereomer.
54. The method of claim 41 , wherein the reaction product is generated in >10:1 diastereoselectivity.
55. The method of claim 41 , wherein the reaction product is generated in >30:1 diastereoselectivity.
56. The method of claim 41 , wherein the reaction product is generated in >40:1 diastereoselectivity.