presentation 31 10
TRANSCRIPT
-
7/30/2019 Presentation 31 10
1/17
-
7/30/2019 Presentation 31 10
2/17
-
7/30/2019 Presentation 31 10
3/17
-
7/30/2019 Presentation 31 10
4/17
-
7/30/2019 Presentation 31 10
5/17
-
7/30/2019 Presentation 31 10
6/17
-
7/30/2019 Presentation 31 10
7/17
-
7/30/2019 Presentation 31 10
8/17
-
7/30/2019 Presentation 31 10
9/17
-
7/30/2019 Presentation 31 10
10/17
Entry Cat. SM2 Solvent Yield(%) d.r e.r
1 I 2a DCM 78 91:9 40:60
2 II 2a DCM 65 80:20 70:30
3 III 2a DCM 83 83:17 58:42
4 IV 2a DCM 67 64:36 51:49
5 V 2a DCM 84 92:8 12:886 VI 2a DCM 81 80:20 90:10
7 VI 2a DCE 81 82:18 91:9
8 VI 2a C6H5CN 83 93:7 79:21
9 VI 2a C6H6 86 92:8 92:8
10 VI 2a C6H6 78 88:12 91:9
11 VII 2a DCM 93 >99:1 50:50
12 VIII 2a DCM 86 91:9 95:5
13 IX 2a DCM 74 90:10 86:14
14 X 2a DCM 85 91:9 90:10
15 VIII 2a C6H6 79 89:11 93:7
16 VIII 2a MeOH 90 94:6 52:48
17 VIII 2a DCE 86 90:10 95:5
18|| VIII 2a DCM 71 88:12 91:9
19 VIII 2b DCM 86 96:4 97:3
20 VIII 2b DCM 87 96:4 97:3Unless otherwise specified:
1a (0.05mol,1.0 equiv.) + 2a/2b (0.075 mol,1.5 equiv.) with 20 mol % catalyst, at room temperature (22
0
C) 00C, 36h ; || -150C, 48h; 15 mol% catalyst
-
7/30/2019 Presentation 31 10
11/17
Optimization of organocatalytic domino Michael-Aldol reaction
Analysis
Entry 1-18: Michael acceptor 2a (R=-COOMe)
Entry 1: good yield, good diastereoselectivity (d.s), moderate enantioselectivity (e.s)-> continue examine these conditions : solvent, t0 , ratio of catalyst (20 mol %)
Entry 5,6: higher d.s and e.s ->important role of tertiary amine and thiourea group
( but entry 5 : lower e.s in relation to entry 6 -> use catalyst VI )
Entry 7-10 : slight improvements accompanied changes in solvents + decrease t0
Entry 11: complete d.s >< totally non e.s
Entry 12: trifunctional S binaphthyl diamine (primary amine) (catalyst VIII)- > excellent result
Entry 13: trifunctional S binaphthyl diamine (hydroxy group) -> negatve affects
Entry 14: trifunctional R binaphthyl diamine (primary amine) -> negative affects
Entry 15-17: no significant improvements accompanied changes in solventsEntry 18: slight drop of d.s and e.s if t0 decreased
Entry 19,20 : Michael acceptor 2b (R= -COPh)
same excellent result, ratio of used catalyst in entry 20 (15 mol%) is lower - > economy
-
7/30/2019 Presentation 31 10
12/17
Entry R1 R2 R3 Yield (%) d.r e.r
1 Ph Ph H 3b, 84 96:4 97:3
2 Ph Ph 5-F 3c, 92 97:3 97:33 Ph Ph 5-Br 3d, 87 95:5 97:3
4 Ph 4-Cl- Ph H 3e, 89 96:4 97:3
5 4-F- Ph Ph H 3f, 81 98:2 95:5
6 3-OMe- Ph Ph H 3g, 79 95:5 98:2
7 2-Furanyl Ph H 3h, 94 >99:1 97:3
8 2-Thiophenyl Ph H 3i, 89 96:4 98:2
9 2-Thiophenyl 4-Cl- Ph H 3j, 88 >99:1 98:2
10 2-Thiophenyl Ph 5-F 3k, 92 >99:1 98:2
11 Ph 2-Me- Ph H 3l, 69 95:5 91:9
12|| Me Ph H 3m, 56 63:37 97:3
Unless otherwise specified:
1a (0.05mol,1.0 equiv.) + 2a/2b (0.075 mol,1.5 equiv.) with 15 mol % catalyst, at room temperature (22 0C) 48h ; || 12h, pure major diastereomer separated by Chomatography in 56 % yield.
-
7/30/2019 Presentation 31 10
13/17
Entry R1 R2 R3 R4 Yield (%) d.r e.r
1 Ph H H Me 3a, 78 91:9 95:5
2 3-OMe- Ph H H Me 3n, 79 91:9 95:5
3 2-Furanyl H H Me 3o, 86 93:7 96:4
4 Ph H 6-Cl Me 3p, 74 89:11 94:6
5 Ph 5-MeO H Me 3q, 77 88:12 96:4
6 Ph H H Et 3r, 81 89:11 95:5
-
7/30/2019 Presentation 31 10
14/17
-
7/30/2019 Presentation 31 10
15/17
-
7/30/2019 Presentation 31 10
16/17
-
7/30/2019 Presentation 31 10
17/17
Conclusion and desire of the group:
- Novel highly efficient organocatalytic construction of bispirooxindoles :+ direct
+ using simple starting materials
+ mild conditions
+ excellent stereocontrol
+ posibility of access to the opposite enantiomer
- Ambition in future
+ expasion of applcication of the new catalyst in other assymetric transformations
+ investagation of biological activity of compound synthesized
- > hopefully novel lead and therapeutic agents