Single multifunctional organocatalyst
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Transcript of Single multifunctional organocatalyst
Tan, B., Candeias, N. R, & Barbas, C. F. Nat. Chem. 2011, 3, 473
LY-NGUYEN Hai Du - 31/10
Using a single multifunctional organocatalystin a single-step construction of
bispirooxindoles with 3 quaternary stereocentres
BISPIROOXINDOLES, WHY?
OO
NH
O
NH
OH
NHMe
Citrinadin B
NO
NH
H
NO2
O
MeO NH
OHO
N
MeN
HNH
NH
OCl
NHHN
FCl
Cyclopiamine B Strychnofoline NITD609
Spirocyclicooxindole scaffold
Sructural features: > = 1 C */ enantiomerically pure backbone => efficient asymmetric synthetic methods
Cycloaddition processes
Few transformations meet this requirement
Intramolecular Heck reactions
NOR1
R3
R4 CHO H2N CO2R6
R5
NHR2
R4
R5
CO2R6
NOR1
R3
R2
O
O
Ar
Ar
PO
OH
Ar = -Naphthyl
CH2Cl2 ,RT,
Up to 98% ee
I
CO2Me CO2Me
H
CyclohexenPd(OAc)2, (R ) - BINAP
Ag2CO3, NMP,600C
IN REALITY???
About 46% ee
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
O
R'R
N+
H HN+
R'R
H
more electrophilic
more electrophilic
more acidic
O
R'R
H NHN
R'R- H2O - H2O
more nucleophilic
Enamine catalysis
H-bonding catalysis
X
R'R
S
NHNH
S
NN
X
R'R
H H
more electrophilic
X= O,NRR,R',R''= alkyl, aryl
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
O
R'R
N+
H HN+
R'R
H
more electrophilic
more electrophilic
more acidic
O
R'R
H NHN
R'R- H2O - H2O
more nucleophilic
Enamine catalysis
H-bonding catalysis
X
R'R
S
NHNH
S
NN
X
R'R
H H
more electrophilic
X= O,NRR,R',R''= alkyl, aryl
Cinchona alkaloid derivatives
6'
N
4'9 8
N
OMe
H
OH6'
N
4'98
N
OMe
H
OH
Quinidine Quinie
6'
N
4'9 8
OH
activateelectrophile
activatenucleophile
6'
N
4'9 8
N
OH
H
OR6'
N
4'98
N
OH
H
OR
activateelectrophile
activatenucleophile
NO
6'
N
4'9 8
N
OH
H
NH2
QD-3
activateelectrophile
activatenucleophileQD-1 Q-1 QD-2
RNO2 COOMe COOMe
RNO2
COOMeCOOMeQD-1/Q-1(10mol%)
THF,-200C,36hR=aryl, heteroaryl
97-99% yield,93-96% ee
Deng et al., 2004
R1 H
O O
R2 R1 R2
OOHQD-2
Guofu Zhong et al. , 2008
Michael-Henry reactionO O
O
O
R1
RNO2
QD-3 O R1
O O
R
NO2OH
Baylis-Hilman reaction
Addition 1,4 of malonates to nitroolefins
85% =94% yieldup to 99 .99% eeup to 99:1 dr
3-substituted oxindoles - efficient Michael donorsMaruoka et al, 2009
Barbas et al, 2009
Chung Chen et al, 2009Methyleneidolinones - highly reactive Michael acceptors
NBoc
O
NBoc
O
O O
Catalyst (1-3mol %)Toluen
Potassium benzoate2-18h,-60-00 C
>96% yield, 90-99%ee
PBu
Bu
Br
CF3
F3C
CF3
F3C
Catalyst
N
R
Boc
O R1NO2
R=alkyl R1=aryl, heteroaryl
Catalyst (10 mol %)
CHCl3, 24h, -200 C N
R
Boc
O
NO2
R1Catalyst
NH NHArS
N(CH2)3 (CH2)3
Ar=
CF3
CF3>90%yield, >90% ee
NPGO
ROOC
OH
R2CHO
R3CHO
Catalyst (20 mol %)BA(20 mol %)
DCE,rt to 350C
NPGO
R3
OHC
COOR
O
R2
R1R1
Catalyst
NH
PhPh
OTMS
Ar Ar
Cinchona alkaloid derivatives used in this study
N
R2N
R4
R1O
R3
N
NHN
NHF3C
CF3
S
N
NHN
NHF3C
CF3
S OMe
N
N
MeO
N
N
N
N
NHN
NH
S
R
OMe
N
NHN
NH
S
NH2
OMe
N
NHN
NH
S
NH2
OMe
I :R1= Me, R2=OH, R3=H, R4=CH2=CH QuinineII :R1= Me, R2=H, R3=NH2, R4=CH3CH2 Hydroquinine amineIII:R1= Ph, R2=H, R3=OH, R4=CH2=CH Deng's catalyst 1IV:R1= H, R2=OBz,R3=H, R4=CH2=CH Deng's catalyst 2
V VI VII
VIII:R=NH2, IX:R=OHS-Diamine
XR-Diamine
XI
Entry Cat. SM2 Solvent Yield(%) d.r e.r1 I 2a DCM 78 91:9 40:602 II 2a DCM 65 80:20 70:303 III 2a DCM 83 83:17 58:424 IV 2a DCM 67 64:36 51:495 V 2a DCM 84 92:8 12:886 VI 2a DCM 81 80:20 90:107 VI 2a DCE 81 82:18 91:98 VI 2a C6H5CN 83 93:7 79:219 VI 2a C6H6 86 92:8 92:810§ VI 2a C6H6 78 88:12 91:911 VII 2a DCM 93 >99:1 50:5012 VIII 2a DCM 86 91:9 95:513 IX 2a DCM 74 90:10 86:1414 X 2a DCM 85 91:9 90:1015 VIII 2a C6H6 79 89:11 93:716 VIII 2a MeOH 90 94:6 52:4817 VIII 2a DCE 86 90:10 95:518|| VIII 2a DCM 71 88:12 91:919 VIII 2b DCM 86 96:4 97:320¶ 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
Optimization of organocatalytic domino Michael-Aldol reactionAnalysis
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 resultEntry 13: trifunctional S – binaphthyl diamine (hydroxy group) -> negatve affectsEntry 14: trifunctional R – binaphthyl diamine (primary amine) -> negative affectsEntry 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
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.
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
Investigation of a different protecting group and deprotection of Bispirooxindoles
(S)
NAc
(S) (S)
(S)
NPG
O
O
OH
PhPhOC
5
NPGO
NAc
PhOC
O
O
Me
15 mol% VIII
DCM, rt, 24h
4 2b
N
NHN
NHS
NH2
OMe
83% yield95:5 d.r95:5 e.r
PG=4-Br-Bz
(S)
NAc
(R) (S)
(S)
NBn
O
O
OH
PhPhOC
3b (97:3 e.r)
HCl (conc.)
EtOH,800C,2h
(S)
NH
(R) (S)
(S)
NBn
O
O
OHPhPhOC
6 (97:3 e.r)
Proposed activation mode of catalyst and substrates
N
N
H
N
H
CHIRALSCAFFOLD N
R'R''
H
HN
OO
R
O
HBnN
O
Ph
O
S
III
(S)
NAc
(R) (S)
(S)
NBn
O
O
OH
PhPh
5
NBnO
NAc
Ph
O
O
Ph
15 mol% catalyst VIII
DCM, rt, 24h
4 2b
PG=4-Br-Bz
Control experiment for mechanistic studies
No reaction at all (no hydrogen bond acceptor part like ester or ketone)
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