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