1. Substrate Control

2. Auxiliary control

3. Reagent control

4. Catalyst control

S* P*R

S+A* P-A* P*R -A*

S P*

S* P*

R*

R*

S P*Cat*

S P*Cat/L*

Ling, G.; Cheng, Y.; Cheng, X.; Li, Y. Asymmetric synthesis---Enantioselective reactions and their applications. Science Publishing, Beijing, 2000

Conventional Model: (1) Rigid, conformationally constricted auxiliary or ligand is usually required

(2) Stereogenic center would better be close to prochiral reactive site

Conformationally flexible species:

NNH

O

R

PAr2PAr2

Pyrazolidinone

1

2

BIPHEP

Seyden-Penne, J. Chiral Auxiliary and Ligands in Asymmetric Catalysis; Wiley: New York, 1995

NH

COOHH Ph

PhOHOH

(R)-VAPOLL-Proline

* *

First explicitly proposed by Davies in 1998 as follows: “an achiral conformationally flexible group is inserted between the stereogenic center and the prochiral reaction center……In ideal circumstances, the conformationally flexible group should serve to both relay, and amplify the stereochemical information of the existing stereogenic center, thus enabling efficient control of diastereoselectivity”

*A group of sloppy lazy men are trained into aggressive Spartans with iron will by a strict commander.

Bull, S. D.; Davis, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R. Pure Appl. Chem. 1998, 70, 1501

X Prochiralreaction center

attacking group

Xprochiral reaction center

attacking groupConventional remote asymmetric induction chiral relay involved asymmetric induction

**

relay group

1. Chiral relay in auxiliary

a. Stereogenic center fixed on the auxiliary

b. Lewis acid mediated chiral relay

2. Chiral relay in catalyst

a. Cooperative functions of flexible ligand and chiral ligand

b. Independent function of flexible ligand

Sugg, E. E.; Griffin, J. F.; Portoghese, P. S. J. Org. Chem. 1985, 50, 5032-5037

N

O

P

O

PhNaHMDS

R1N

O

P

O

Ph

Cl-H3N+ OEtR1

O

N

O

P

O

Ph R1

O

R1

Cl-H3N+ OEt

1:1 THF/DMER1X

Pd0, H2, EtOHHCl, 80oC

1trans Cis

Pd0, H2, EtOHHCl, 80oC

+

P: protecting groupR1: benzyl

Entry Protecting group X Trans:Cis Yield1 Boc (-OCO-tBu) Br 200:1 78%2 Cbz (-COOCH2Ph) I 200:1 85%3 Bn (-CH2Ph) Br 1:17 83%4 Me Br 1:18

Effects being considered for the conformational preference:

1. Electronic effect

2. Steric effect

Sugg, E. E.; Griffin, J. F.; Portoghese, P. S. J. Org. Chem. 1985, 50, 5032-5037

N

O

P

O-

Ph

ON

H O-

preferred half-chair conformation of the enolate

55

E+

6

6

Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett, 1998, 55

NTs

Ts

R1

N+

R1S

Si

Re

NTs

R1R21 2

4Me3Al or Et2AlCl or CH2=CHCH2TMS/SnCl4

or tBuCOCH2OTBS/SnCl4

Nu-

Nu-

exclusive product

Transition state

R1=i-Pr, i-Bu, Bn R2=allyl

OO

Bull, S. D.; Davies, S. G.; Epstein, S. W. Ouzman, J. V. A. J. Chem. Soc., Chem. Commun. 1998, 659

Relay network

N

O

O

PhOMe

PhOMe

N

NN

O-

O

OMe

OMe

MeI

N

N O

O

PhOMe

PhOMe

Me

d.e=93%

LHMDS, THF

-78oC, MeI

When N-protecting groups replaced by methyl d.e=33%

1

34

2Diketopiperazine (DKP)

Transition State

6

43

1

Tertiary amide as relay group

Clayden, J.; Pink, J. H.; Yasin, S. A. Tet. Lett. 1998, 39, 105

Clayden, J.; Lai, L. W.; Helliwell, M. Tet. Asymmetry 2001, 12, 695-698

ON

NO

Ph ON

NO

PhPhMgBr ON

NO

PhOH

1) S-BuLi/THF

2) DMF

quant, 95% d.e.

H

3

O

Re

NO SiMe2PhN

ON

O SiMe2PhN

O

PhMe2Si

1) S-BuLi/THF

2) PhMe2SiCl

77% yield, only one diastereomer

123

4

Clayden, J.; Lai, L. W.; Helliwell, M. Tet. Asymmetry 2001, 12, 695-698

For review of asymmetric allylic alkylation, see Trost. B. M. Chem. Rew. 1996, 96, 395-422

Ph Ph

OAc

O

NO

PhN

ClPPh2

Ph Ph

CO2MeMeO2C

O

NO

PhN

Ph2P ON

NO

PhN

O

Ph2P

Ligand 3a Ligand 3b

Dimethyl malonate(allyl PdCl)2 (1mol%)

ligand 3a/3b (3mol%)

Ligand 3a: (S)-(-), 82%ee, 93% yieldLigand 3b: (R)-(+), 53%ee, 85% yield

1) S-BuLi/THF

2) DMF

N

NH

O

R

N

N

OM

O

L*L*

N

N

OM

O

L*L*

not 1:1

Pyrazolidinone

1

2

Interconversion of Pyrazolidinone complex

X2

X1 X3

M

L**L

prochiral reaction center

attacking group

achiral template

Sibi, M. P.; Venkatraman, L.; Liu, M.; Jaspere, C. P. J. Am. Chem. Soc. 2001, 123, 8444-8445

Chiral relay controlled by labile group

Sibi, M. P.; Venkatraman, L.; Liu, M.; Jaspere, C. P. J. Am. Chem. Soc. 2001, 123, 8444-8445

Run Substrate7ee(endo)

8ee(endo)

9ee(endo)

1 4a R=H 29% 08% 03%2 4b R=Et 64% 56% 55%3 4c R=Bn 71% 71% 71%4 4d R=2-CH2Naph 79% 65% 69%5 4e R=1-CH2Naph 86% 92% 85%

NN

OO

R

+O Z

1. Cu(OTf)2 Chiral ligand

2. LiOBn

4a R=H; 4b R=Et4c R=Bn; 4d R=2-CH2Naph4e R=1-CH2Naph

5 Z=Relay unit6 Z=OBn

N

OON N

OON

Me2HC CHMe2

N

OON

PhH2C CH2Ph

7 8 9bisoxazoline ligand with C2 axis

endo-(2S,3R)

Re

N

OO

NR

NN

OCuO

BnRe

N

OO

NR R

NN

OCuO

Bn

Complex with C1 ligand

4 4' 4 4'

Complex with C2 ligand

Evans, D. A.; Miller, S. J.; Lectka, T.; Matt, P. V. J. Am. Chem. Soc. 1999, 121, 7559-7573

Sibi, M. P.; Venkatraman, L.; Liu, M.; Jaspere, C. P. J. Am. Chem. Soc. 2001, 123, 8444-8445

Run Substrate10ee(endo)

11ee(endo)

12ee(endo)

1 4a R=H 04% 01% 01%2 4b R=Et 29% 12% 26%3 4c R=Bn 47% 38% 51%4 4d R=2-CH2Naph 56% 59% 58%5 4e R=1-CH2Naph 69% 66% 71%

NN

OO

R

+O Z

1. Cu(OTf)2 Chiral ligand

2. LiOBn

4a R=H; 4b R=Et4c R=Bn; 4d R=2-CH2Naph4e R=1-CH2Naph

5 Z=Relay unit6 Z=OBn

O

NO

NN

OO

NN

NH2

10 11 12

C1 ligand

endo-(2S,3R)

Sibi, M. P.; Liu, M. Org. Lett. 2001, 3, 4181-4184

* The unusually high ee is presumably attributed to a very different chelation pattern

run SubstrateCatalyst A

Yield ee%Catalyst B

Yield ee%1 R1=Me, R=H 75% 76(R)* 74% 28(S)2 R1=Me, R=Et 70% 52(R) 74% 49(S)3 R1=Me, R=Bn 67% 78(R) 71% 68(S)4 R1=Me, R=2-CH2Naph 75% 78(R) 73% 70(S)5 R1=Me, R=1-CH2Naph 77% 81(R) 75% 75(S)

NN

R1

OO

R

N

OO

N

R1

Mg(ClO4)2

N

OON

Zn(OTf)2

NOO

OMeChiral Lewis acid

4-MeOBnNHOH

+ Relay template

Catalyst A Catalyst B

*

Chiral relay controlled by axis

Quaranta, L.; Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 39-42

NO

R

OMO

L*L*

NO

OMO

L*L*

not 1:1

RRe

Si

Benzoxazol acrylamide

Quaranta, L.; Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 39-42

N

R

O

OO

CH2Cl2

N

OO

NPh Ph

O N

OO

R

(R)-18

+MgBr2 (30mol%), (R)-18 (s)

Run R Yield (endo/exo) ee (endo)1 H 98%(22:1) 14%(s)2 Me 97%(32:1) 74%(s)3 Et 97%(33:1) 76%(s)4 Bn 97%(11:1) 86%(s)5 PMB 98%(16:1) 88%(s)6 CH2t-Bu 98%(20:1) 10%(s)7 CH(Ph)2 97%(17:1) 72%(s)8 SiMe3 95%(40:1) 40%(s)

Chiral relay controlled by selectively binding to lone pair

Aggarwal, V. K.; Jones, D. E.; Martin-Castro, A. M. Eur. J. Org. Chem. 2000, 2939-2945

M

*L L*

R S OR

O

Si

SOR

O

M

*L L*

R

SOR

O

M

*L L*

R

Re

SR

COOEt

SR

COOEt

endo-(R)

endo-(S)

not 1:1Pro-S

Proposed transition state

Aggarwal, V. K.; Jones, D. E.; Martin-Castro, A. M. Eur. J. Org. Chem. 2000, 2939-2945

PhS COOEt

2SbF6-

Cu NN

OO

S O

OEt

R RPh

SPh

COOEt

endo-(R)

CuBr2 (20mol%)bisoxazoline (30mol%)AgSbF6

CH2Cl2-78oC, 2h

2+

R exo/endo ee% Yield

Ph 1:15 >95% 92%tBu 1:5.6 78% 64%

α-thioacrylate

Entry R Chiral ligand Lewsi acid Yield ee1 p-Tol 3a Mg(OTf)2 65% 52%2 p-Tol 3b Mg(OTf)2 41% 83%3 p-Tol 3c Ti(O-ipr)4 44% 50%4 methyl 3c Ti(O-ipr)4 33% 5%

Hiroi, K.; Ishii, M. Tet. Lett. 2000, 41, 7071-7074

Me N S

Br

O

Bn

S S..

p-Tol

O

p-Tol:

O

HO SPh Ph

p-Tol:

O

N SO2RO

BnMe H

PhPh

OH

PhPh

OH

O O

1a R=Me1b R=Tol

(S)-2a R=Me(S)-2b R=p-Tol

Chiral Ligand

Lewis acidAllyl (tri-n-butyl) Stannane

Chiral Ligand: 3a 3b 3c

R

O O Pro-RPro-S

Hiroi, K.; Ishii, M. Tet. Lett. 2000, 41, 7071-7074

SOMO

O S N

O H

Me

BnO

p-Tol

..p-Tol S

OMO S

NO

HMe

BnOp-Tol

..p-Tol O S

OMO S

NO

Me

Bnp-TolO

..p-Tol O

H..

.

.

4a 4b 4c

Pro-R Pro-S

Illustration of the chiral relay in catalyst with the original stereogenic center

M M* ** substrate S

S*

dashed line: flexible ligandsolid line: rigid chiral l igand

Hashihayata, T; Ito, Y.; Katsuki, T. Synlett 1996, 1079-1081

Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron, 1997, 53, 9541

NN

Mn

OO

R2

R3

R2

R1R1 O

R3

**R*

R

R*

R

R=alkyl groupR*=pi-electron rich and radicalstabilizing group: aryl, alkenyl, and alkyl groups

NN

MnO

R2

R3

R1 O **

O

R1R

R*

R3 R2

Oxo Mn-Salen Complex Major metallaoxetane

Enantiofaceselectiveprocess

R*R O

(major enantiomer)

fast

NN

Mn

OO

R2

R3

R2

R1

R1R1

R1

O

L*R3

NN

Mn

OO

R2

R3

R2

R1

R1

R1

R1

O

L*R3

ent-1919

OO2N

AcNH

OMn

N

O

N

R2R1

R2

R1

R3

R4

R3

R4

OO2N

AcNH

Mn-Salen complex

chiral ligand, PhIO/CH2Cl2,0oC

meso Mn-Salen complex

N NHN

N

H

H

NHN OH

15 16 17chiral ligand

13

14

O(3R, 4R)

Entry Mn-Salen complex Ligand ee1 Mn(OAc)2 or Mn(OAc)3 16 0%2 14a: R1=R2=R3=R4=t-Bu, X=PF6 15 3%3 14b: R1=R2=H, R3=R4=t-Bu, X=OAc 15 6%4 14c: n=R1=R2=H, R3=R4=t-Bu, X=OAc 16 18%5 14f: R1=R2=Me, R3=R4=t-Bu, X=PF6 16 60%6 14i: R1=R2=Me, R3=OSi(Pr-i)3, R4=t-Bu, X=PF6 16 52%

Miura, K.; Katsuki, T. Synlett 1999, 6, 783-785

R1

R2

O

OMn

N

O

N

t-Bu

t-Bu

t-Bu

t-BuPF6

- N+ N+

O- O-

OR1

R2 O

Mn-Salen complex

chiral ligand, PhIO/CH2Cl2,0oC

meso Mn-Salen complex

13(3S, 4S)

+

(+)3,3'-dimethyl-2,2'-bipyridine N,N'-dioxide Chiral Ligand

Entry R1 R2 Yield ee Config.1 NO2 AcHN 65% 82% 3S,4S2 H NC 59% 77% 3S,4S3 =N(O)-O-N= 90% 78% 3S,4S

NHR

NHR

NHR

RHN

N

N TiL2

ArO2S

ArO2SN

NL2Ti

SO2Ar

SO2Ar

interconversion of diaminocyclohexane

desymmetrization when chelate to chiral LA

Bassells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802-1803

Bassells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802-1803

run R Ligand Ar ee1 i-pr (R,R)-19 2,4-C6H3-Me2 79%(S)2 s-CHPhEt (R,R)-19 2,4-C6H3-Me2 84%(S)3 s-CHPhEt (S,S)-19 2,4-C6H3-Me2 81%(R)4 s-CHPhEt --- --- 42%(S)5 s-CHPhEt 20a 4-C6H4-CMe3 84%(R)6 s-CHPhEt 20b 4-C6H3-OMe 78%(R)

CH3

CHO

ZnEt2 Ti(O-R)4Tol HHO Et

+ +

1.2eq 1.2eq

Bis(sulfonamide)

Toluene/Hexane-45oC

1. OR=O-i-pr2. OR=(s)-OCHPhEt

NHSO2Ar

NHSO2Ar

NHSO2Ar

NHSO2Ar

meso-20

Bis(sulfonamide)

(R,R)-19

*

Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3, 2161

O

tBu

Ti

O

tBu

X

X

HH

O

OTi

SX

X

Substrate=s

OHR

R''

OHR

R''R'R'

2,2'-methylene-Bisphenol (MBP)

O

OTi

SX

X

Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3, 2161

CH3

CHO

ZnEt2 Ti(OR)4

OHR

R''

OHR

R''R'R'

MBP

HEt OH

H3C

+ +

3eq 1.2eq

Achiral Bis(phenol)

20mol%CH2Cl2/hexane-20oCOR=s-CH(Tol)Et

Entry Ligand R R’ R’’ ee%1 No MBP 39(S)2 1a H H H 1(S)3 1c Cl Cl Cl 24(S)4 1d Me H Me 16(S)5 1e Ph H H 36(S)6 1f t-Bu H t-Bu 68(S)7 1g t-Bu H Me 79(S)8 1h t-Bu H H 73(S)9 li Adamantyl H Me 83(S)

Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem. Int. Ed. 1999, 38, 495-497 * The experiment was performed under -35oC instead of 28oC as in other entries

Entry Phosphane (S)/(S,S):(R)/(S,S) ee Yield1 DM-BIPHEP 1:1 63% 99%2 DM-BIPHEP 2:1 73% 99%3 DM-BIPHEP 3:1 84% 99%4* DM-BIPHEP 3:1 92% 99%

PAr2

PAr2

PAr2

PAr2

RuCl2

PhPh

H2N NH2

Ar2P

PAr2

Ru

H2N

NH2

PhHHPh

+

(S)-1 (R)-11 : 1

(S,S)-2 (S)-1/(S,S)-2

+

(R)-1/S,S)-21 1:

(S)-1/(S,S)-2 (R)-1/(S,S)-2+

3 : 1

Racemic DM-BIPHEP

(S,S)-DPEN

[D8]2-propanol

(unresolvable)

Ar2P

PAr2

Ru

H2N

NH2

PhHHPh

O OHH2, 1(0.4mol%)

(S,S)-2 (0.4mol%)KOH (0.8mol%)2-propanol (R)-4

rt. for 3hr or 80oC for 30min

PhCHO ZnEt2 Ph

OH+

(S)-Ph2-BINOL

Achiral Ligand *

N N

N N

N N

N N

Entry Achiral Ligand ee/ 0oC(config.) Entry Achiral Ligand ee/ 0oC(config.)

1 38%(S)4

54%(R)

225%(R) 5 38%(S)

327%(S) 6 89%(R)

NMes Mes

N

N N

Cl

Cl

Cl

Cl

Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J. Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929-6941

Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J. Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929-6941

M*ligand substitution substrate S

S*M M* **

dashed line: flexible ligandsolide line: rigid chiral ligand

Huttenloch, M. E.; Dorer, B.; Rief, U.; Prosenc, M-H.; Schmidt, K.; Bringtzinger, H. H.; J. Organomet. Chem. 1997, 541, 219

Ringwald, M.; Sturmer, R.; Brintzinger, H. H. J. Am. Chem. Soc. 1999, 121, 1524-1527

(R)-M-Me2

M

CH3

CH3

2Me2SiCl2

(R)-M-Cl2

M

Cl

Cl

(S)-M-Me2

(R)-M-Me2

M

CH3

CH3

M

CH3

CH3

MO

O

AlMe3

1eq (R)-BINOLToluene 100oC

0.5

0.5 M=1: ZrM=2: Ti (R)-M-(R)-BINOL

Toluene, -20oC

(enantiopure diastereomer)

__K+

K+

ansa-metalocene

NBn

N Ph NH

Ph

NHBn

0.1mol% (R)-2-Cl20.2mol% n-BuLi

150 bar H2Toluene, 80oC, 12h

95% yield76% ee

96% yield98% ee

Ringwald, M.; Sturmer, R.; Brintzinger, H. H. J. Am. Chem. Soc. 1999, 121, 1524-1527

PPh2

PPh2PtCO3

(S)

(S)

PtOO

PPh2

PPh2

PtOO

PPh2

PPh2

(S) 100%

PtOO

PPh2

PPh2

PtOO

PPh2

PPh2

(S) 95:5

HOTf

HCl

HCl

PPh2

ClPPh2

PtCl

-PtCl2

PtClCl

PPh2

PPh2

-PtCl2

-Pt+2

PPh2

PPh2

PtOTfOTf

(S)-BINOL

λ

δ

δ

λ

1:1Toluene, 90oC

δ

Recrystallization

λ λ

* (λ/δ) are arbitrarily assigned to the biphep stereochemistry in terms of its skew conformation

Tudor, M. D.; Becker, J. J; White, P. S.; Gagne, M. R. Organometallics 2000, 19, 4376

Becker, J. J.; White, P. S.; Gagne, M. R. J. Am. Chem. Soc. 2001, 123, 9478-9479

Tudor, M. D.; Becker, J. J; White, P. S.; Gagne, M. R. Organometallics 2000, 19, 4376

Becker, J. J.; White, P. S.; Gagne, M. R. J. Am. Chem. Soc. 2001, 123, 9478-9479

ON

O O

H OEtO

O

N OOO

H

OEtOH

O

+*

10mol% P2Pt(OTf)2

CH2Cl2, -55oC

-Pt+2: (S)-20, 92-94% ee, 93:7 endo/exo-Pt+2 : (R)-20, 92-94% ee, 94:6 endo/exo

+

2mol% P2PtCl24mol% AgSbF6

CH2Cl2, 0oC

-PtCl2 : (S)-21, 71%ee-PtCl2 : (R)-21, 70%ee

20

21

δλ

δλ

(1) Straightforward experimental evidence is inadequate to support the relay mechanism. Stereochemical outcome is still not predictable in a majority of reactions.

(2) The role of relay ligand has not been well decoupled with chiral ligand. It’s still hard to determine which one plays a major part in catalyst.

For review, Vogel, E. M.; Groger, H; Shibasaki, M. Angew. Chem. Int. Ed. 1999, 38, 1570-1577

Long, J; Ding, K. Angew. Chem. Int. Ed. 2001, 40, 452-457

Faller, J. W.; Lavorie, A. R.; Grimmond, B. J. Organometallics 2002, 21, 1662-1666

(3) Some other concepts describing the similar events in catalysts have been proposed, such as achiral additives,[24] ligand acceleration,[18] asymmetric activation,[25] and asymmetric poisoning,[26] It is difficulty to conclude which one is closer to the real picture at least by now.

Re

N

OON

R R

NN

OCu

O

Bn

4 4'

O

OTi

SL

L

(1) Mechanism elucidation

(2) Experimental evidence for the relay process

(3) Kinetic study for decoupling different pathways

(4) Efficient design of relay template and ligand

(5) Theoretic modeling may provide insight for relay process

1. Chiral relay is a conceptually novel idea and has been successfully applied in many reaction systems.

2. The mechanism of chiral relay is not very clear and problems still exist.

3. Future work should be done to elucidate the mechanism and direct the design of novel chiral relay groups.

Professor Wulff

Professor Borhan

Professor Jackson

Dr. Pat, Dr. Mitchell

Manish, Vijay, Victor,

Yu, Chunrui, Jie, Yiqian,

Andreiv, Shi Feng,

Yang Jian, Yana