1. Using a single multifunctional organocatalyst
in a single-step construction of
bispirooxindoles with 3 quaternary stereocentres
LY-NGUYEN Hai Du - 31/10
Tan, B., Candeias, N. R, & Barbas, C. F. Nat. Chem. 2011, 3, 473

2. BISPIROOXINDOLES, WHY?
Spirocyclicooxindole scaffold
F
Cl
H H
N H N
OH N
HN
NH
NHMe NO2 H H
N O
O O OMeN N
N Cl
N MeO N HO H
H H
O O
O
Strychnofoline NITD609
Citrinadin B Cyclopiamine B
Sructural features: > = 1 C */ enantiomerically pure backbone => efficient asymmetric synthetic methods
IN REALITY???
Few transformations meet this requirement
Ar
Cycloaddition processes O O
P R4
OH
R2 O
NH
Ar
R2 CO2R6
R5
Ar = -Naphthyl R5
R4 CHO R1 O R1 O
H2N CO2R6 CH2Cl2 ,RT, N
N
R3 R3
Up to 98% ee
Intramolecular Heck reactions
CO2Me Cyclohexen CO2Me
Pd(OAc)2, (R ) - BINAP
I Ag2CO3, NMP,600C
H
About 46% ee

4. Inherent benefits of using organic molecules as catalysts ?
- available from bio-matter
- intensitive to moisture and air
- non-toxic
- inexpensive and operationally easy to handle
- rich ???
Generic mode of activation commonly used in organocatalysis
Iminium catalysis Enamine catalysis
O N+ N+ more electrophilic O N
NH
H H H H
R' - H2O R' R' - H2O R'
R R R R
more acidic more nucleophilic
more electrophilic
H-bonding catalysis
S
S
X N N
NH NH
H H
R R' X
X= O,NR
R,R',R''= alkyl, aryl R R'
more electrophilic

5. Inherent benefits of using organic molecules as catalysts ?
- available from bio-matter
- intensitive to moisture and air
- non-toxic
- inexpensive and operationally easy to handle
- rich ???
Generic mode of activation commonly used in organocatalysis
Iminium catalysis Enamine catalysis
O N+ N+ more electrophilic O N
NH
H H H H
R' - H2O R' R' - H2O R'
R R R R
more acidic more nucleophilic
more electrophilic
H-bonding catalysis
S
S
X N N
NH NH
H H
R R' X
X= O,NR
R,R',R''= alkyl, aryl R R'
more electrophilic

6. Cinchona alkaloid derivatives activate
electrophile
OMe OMe
6' 6'
OH OH
4' N N 4'
9 8 8 9
N H H N
Quinidine Quinie
activate activate
nucleophile electrophile
activate
electrophile
OH OH OH OH
6' 6' 6' 6'
OR OR O NH2
4' N N 4' 4' N 4' N
9 8 8 9 9 9 8
8
N H H N N N H
QD-1 Q-1 activate QD-3
activate QD-2 nucleophile
nucleophile
Deng et al., 2004
Addition 1,4 of malonates to nitroolefins COOMe COOMe
NO2 QD-1/Q-1(10mol%) 97-99% yield,
R COOMe COOMe NO2 93-96% ee
0
THF,-20 C,36h R
R=aryl, heteroaryl
O O OH O
Baylis-Hilman reaction QD-2
R1 H R2 R1 R2
Guofu Zhong et al. , 2008
R1 O O
O O
Michael-Henry reaction QD-3 O R1
NO2 R 85% =94% yield
O R up to 99 .99% ee
NO2 up to 99:1 dr
O OH

8. 3-substituted oxindoles - efficient Michael donors F3C
Maruoka et al, 2009
O Catalyst CF3
Br
Bu
O P
Catalyst (1-3mol %)
Toluen Bu
O O
Potassium benzoate
N 2-18h,-60-00 C
N CF3
Boc Boc
>96% yield, 90-99%ee F3C
Barbas et al, 2009 R1 Catalyst
S
R R NO2
Ar
NH NH
Catalyst (10 mol %)
NO2 O N
O R1 Ar (CH2)3 (CH2)3 Ar CF3
CHCl3, 24h, -200 C
N N
Ar=
Boc Boc
R=alkyl R1=aryl, heteroaryl >90%yield, >90% ee CF3
Methyleneidolinones - highly reactive Michael acceptors
Chung Chen et al, 2009
Catalyst
ROOC
CHO
R2 OHC R2 Ph
Catalyst (20 mol %)
BA(20 mol %) Ph
OH
DCE,rt to 350C R3 COOR NH OTMS
R1 R1
CHO O
O R3 O
NPG NPG

9. Cinchona alkaloid derivatives used in this study
R4 I :R1= Me, R2=OH, R3=H, R4=CH2=CH Quinine
II :R1= Me, R2=H, R3=NH2, R4=CH3CH2 Hydroquinine amine
R3 N III:R1= Ph, R2=H, R3=OH, R4=CH2=CH Deng's catalyst 1
R2 IV:R1= H, R2=OBz,R3=H, R4=CH2=CH Deng's catalyst 2
R1O
N
N
F3C NH NH N N N
F3C NH NH N
N
S S OMe MeO
CF3 CF3
N N N
VI VII
V
R N NH2 N
NH2 N
NH NH NH NH
NH NH
S OMe S OMe
S OMe
N N
N
X VIII:R=NH2, IX:R=OH XI
R-Diamine S-Diamine

10. 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 12:88
6 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 C 6H6 86 92:8 92:8
10§ VI 2a C 6H6 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 C 6H6 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 97:3
Unless otherwise specified:
1a (0.05mol,1.0 equiv.) + 2a/2b (0.075 mol,1.5 equiv.) with 20 mol % catalyst, at room temperature (22 0C)
§ 00C, 36h ; || -150C, 48h; ¶ 15 mol% catalyst

11. 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 solvents
Entry 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

12. 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 97:3
3 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.

13. 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

15. Investigation of a different protecting group and deprotection of Bispirooxindoles
NH2 N
NH NH
S OMe
Me NAc
PhOC N O
O
(S) OH
15 mol% VIII (S)
83% yield
PhOC Ph 95:5 d.r
(S) (S) 95:5 e.r
O O DCM, rt, 24h
NPG NAc O
NPG
PG=4-Br-Bz
4 2b 5
NAc NH
O O
(S) OH (S) OH
(S)
(S)
Ph HCl (conc.) PhOC Ph
PhOC (R) (S)
(R) (S)
EtOH,800C,2h
O O
NBn NBn
3b (97:3 e.r) 6 (97:3 e.r)

16. Proposed activation mode of catalyst and substrates
S
CHIRAL R'
SCAFFOLD R''
N N N
Ph
H H BnN H
O
II
O I O O
H
N O N
H
R
Control experiment for mechanistic studies
Ph NAc
O Ph O
(S) OH
15 mol% catalyst VIII (S)
Ph Ph
(R) (S)
O O DCM, rt, 24h
NBn NAc O
NBn
PG=4-Br-Bz
4 2b 5
No reaction at all (no hydrogen bond acceptor part like ester or ketone)

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