Rh-Catalyzed Asymmetric Additions: The Rise of Chiral Dienes

1

Rh-Catalyzed Asymmetric Additions: The Rise of Chiral

Dienes

Daniela SustacFebruary 16, 2010

Tamio Hayashi Erick Carreira

2

Outline

Chiral Diene

O

R

O

NR

O

O

NR

O

O

R

Ar1

Ar2 O

H Ar1 H

O

PhMe2Si CO2MeAr

PhMe2Si CO2Me

Ar1 H

NTs

Ar1 Ar2

NHTs

EE

R

R

E

E

RR

Ar1 CO2Me

CN Ar1 CO2Me

CN

Ar2

R

HEE

OHCHO

REE

TsNR

R

TsNR

R

3

Transition Metal – Olefin Complexes• Alkenes not very basic, backbonding necessary to stabilize M-olefin

bond;• Olefins considered labile, easily displaced from M center.

M M

backbonding increases

lenghten C-C bond

shorten M-C bond

C becomes more sp3

"metallacyclopropane"

Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

4

Transition Metal – Strained Alkene Complexes

H

H

sp2, 120

M

H

HM

more sp3, 109relieves strainvery strained

• Strained alkenes (cyclopropene, norbornene) bind very strongly to metals;

• Rehybridization on binding relieves ring strain.

Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

5

Examples of Olefins in Complexes and Catalysis

• Prepared by Zeise in 1827;• Structure elucidated in the 1950’s;

Pt ClCl

Cl

HHH H

H3C OH PtCl4KCl

Zeise's Salt

InBuI

CO2MePd(OAc)2 (10 mol %) K2CO3, DMF, RT

(1 equiv)

nBu

nBuCO2Me

93%

• Norbornene in the Catellani reaction: “a sort of scaffold to be removed after the building of the molecule is complete; behaves as catalyst, excess necessary to push the reaction”

Wunderlich, A.J.; Mellor, D.P. Acta Crystallogr. 1955, 8, 57.

Catellani, M; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. 2007, 36, 119.

6

Who Binds the Strongest?

Ni(P(o-tol)3)3 olefinKeq

Ni

(o-tol)3P

(o-tol)3P

R

P(o-tol)3

O OO > CN > Ph nBu> MenPr

>

4.0x106 4.0x104 10 0.5 2.3x10-3

> > > >

4.4 6.2x10-2 2.6x10-2 2.3x10-2 3.5x10-4

• Electron deficient alkenes bind tighter;

• Stronger binding with strained alkenes.

Tolman, A.C. Organometallics 1983, 2, 614.

7

Rh-Catalyzed 1,4-Addition (before chiral dienes)

O

PhB(OH)2[Rh(acac)(S-binap)] (3 mol %)

dioxane/H2O (10/1) 100 C, 5 h

O

Ph

93%97% ee

Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.

Consequently, the reaction can be done using directly [Rh(OH)(S-binap)]2 at 35 ºC.

O

O[Rh]

PhB(OH)2

acac-H[Rh]-Ph

[Rh]-OH

O

Ph

[Rh]

O

path B

path A

H2O

O

Ph

acac-H

H2O

PhB(OH)2

H2O

transmetalationphenylrhodation

hydrolysis

8

Chiral Dienes: First ContactO

RB(OH)2 or (RBO)3

Rh/chiral diene complex (3 mol %)

KOH, dioxane/water, 20-50 C

O

R

Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

Hydrosylilation: Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.

PhPh

PPh2

MeO

(R)-MeO-Mop

1. HSiCl3 cat. Pd/(R)-MeO-mop

2. H2O2, KHF2

1. Swern

2. HOCH2CH2OH

OO

O

1. LDA, PyNTf2, 87%

2. PhCH2MgBr cat. Pd, 97%

O

O

Ph

1. HCl, 94%2. LDA, PyNTf2, 70%


PhPh

HH

HOOH

24.7 mg(R,R)-Bn-nbd

Rh Rh

Cl

ClPh

Ph

9

The (Only) One with A Lot of ScopeO

RB(OH)2 or (RBO)3

Rh/chiral diene complex (3 mol %)


O

R

O

94%96% ee

O

OMe

O

OMe

92%97% ee

89%95% ee

O

Me

88%96% ee

O

Cl

92%93% ee

O

CF3

90%99% ee

O O

F

91%97% ee

96%96% ee

O O O

O

O

88%88% ee

81%90% ee

81%97% ee

73%92% ee

PhPh


10

Explaining StereochemistryPh

Ph


11

Chiral Dienes: First Contact

1. HSiCl3 cat. Pd/(R)-MeO-mop

2. H2O2, KHF2

1. Swern

2. HOCH2CH2OH

OO

O

1. LDA, PyNTf2, 87%


O

O

Ph

1. HCl, 94%2. LDA, PyNTf2, 70%


PhPh

HH

HOOH

24.7 mg

Advantages

• Highest catalytic activity of all rhodium catalysts used for 1,4-addition;

• Among the highest enantioselectivities (most over 90% ee);

Disadvantages

• Long synthesis of chiral diene;

• Bistriflate intermediate hard to isolate.

TfO

OTf


12

New Route to Chiral Dienes

TfO

OTf BnMgCl, cat.

THF Bn

Bn

Ph

Ph

1 2

entry T ( C) t (min) 1/2 yield (%)cat. (mol %)

1

2

3

4

NiCl2(dppe), 1

PdCl2(dppf), 1

Co(acac)3, 5

Fe(acac)3, 5

40

40

0

0

60

60

15

15

0.7

0.6

0.6

13

44

45

28

98

O

O KHMDS

PyNTf2-78 C

TfO

OTf unstable (prone to decomposition in presence of acid)must be stored over anhydrous K2CO3

(R,R) (R,R) 85%10 mmol scale

Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.

Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363.

13

One Unstable Chiral Diene, One Stable Rh Complex

Ph

Ph

TfO

OTf

(R,R)

Fe(acac)3, PhMgBrTHF/NMP, 0 C, 5 min

unstable, inseparable from biphenyl

(R,R)-Ph-nbd

[RhCl(C2H4)2]2 (0.5 equiv.)toluene, RT, 2 h

Ph

RhCl

2Ph

stable!

Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.

O

Ph

89%97% ee

14

One More Carbon

• Optical resolution by recrystallization inefficient route;• Alternatively, can do racemic synthesis and separate by chiral HPLC,

either intermediate or final product.

O

O 1. RNHNH2

2. recryst. N

NNH

O

O

HN Ph

MeHN

O

O

NH

Ph

Me

1. aq H2SO4

2. recryst. O

O

rac

(R,R)

4.5%

1. LDA, PyNTf2

2. BnMgBr, cat. Pd Bn

Bn

41%(R,R)-Bn-bod

stable

Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503.

15

To Be Stable or Not to Be Stable

PhPh

stable

Ph

Phunstable

Ph

Ph

"indefinitely" stableFree Diene

Rh complexPh

Ph Ph

Ph> Ph

Ph

Bn-nbd Ph-nbd Ph-bod

16

The One with iMean ArylationNTs

H (ArBO)3[RhCl(C2H4)2]2/L* (3 mol %)

KOH/H2Odioxane, 60 °C, 6 h Cl

NHTs

Cl

PPh2PPh2

(R)-Binap

O

O

O

O

PPh2PPh2

(R)-SegPhos

28%, 31% ee

30%, 70% ee

Ph

Ph(R,R)-Ph-bod*

PhPh

(R,R)-Bn-bod*

PhPh

(R,R)-Bn-nbd*

96%, 98% ee

98%, 94% ee

98%, 92% ee

Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

17

Stereochemistry is Explained


18

The One with (a Bit) of ScopeNTs

H (ArBO)3[RhCl(C2H4)2]2/L* (3 mol%)

KOH/H2Odioxane, 60 °C, 6 h Cl

NHTs

X

X

NHTs

X Yield ee

Cl

CF3

OMe

NMe2

o-OMe

Np

96% 98%

97% 95%

96% 99%

94% 98%

98% 99%

95% 98%

ONHTs

99%99% ee

X

NHTs

X Yield ee

Cl

OMe

o-Me

99% 99%

97% 96%

96% 99%


19

The One where They Do It Better?

Ar

N

H

PO

PhPh

Me2Zn

Cu(OTf)2 (5 mol %)(R,R)-BozPhos (5 mol %)

3 equiv.toluene, RT, 48 h Ar

HN

Me

PO

PhPh

Ar Yield(%) ee (%)

Ph 87 97

3-MeC6H4

2-furyl

80 92

90 89

P

PO

(R,R)-BozPhos

3 entries

Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.

Ar H

NTsMe2Zn

1.5 equiv

[RhCl(C2H4)2]2 (3 mol %) (R,R)-Ph-bod (6 mol %)

dioxane, 50 C, 3-6 h Ar Me

NHTs

Ar Yield(%) ee (%)

Ph 82 97

3-MeC6H4

4-CF3C6H4

82 98

83 94

10 entries Ph

Ph

(R,R)-Ph-bod

Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

20

The One with the iMean Mechanism


[RhMe(diene)]Ar H

NTs Rh Me

Ar H

NTs

[Rh]

Me

Ar H

NTs

Me2Zn

NZnMe

Ts H

ArMe

H2O HN

Ts H

ArMe

-bond methathesis

methyl transfer

[RhCl(diene)]

21

More Stereochemistry Explained


22

Is Nine the Lucky Number?O

O

PhLi/CeCl3

THF, -78 C, 6 h Ph

PhOHHO

POCl3, pyr

reflux, 12 h Ph

Ph

chiral HPLC

resolution

95% (2 steps)

Ph

Ph

(R,R)-Ph-bnd

Ph

Ph

(S,S)-Ph-bnd

[RhCl(C2H4)2]2(R,R)-Ph-bnd

benzene, 50 C, 12 h [RhCl(R,R)-Ph-bnd]287%

Ar1 H

NNs

(Ar2BO)3[RhCl(R,R)-Ph-bnd]2

KOH/H2O, dioxane, 60 C, 6 h Ar1 Ar2

HNNs

12 examples 94-99% 95-99% ee

Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

23

The One with the Deprotection

Ar Me

HNP

O Ph

Ph HCl, MeOH

RT, 4h Ar Me

NH2

99% ee99% ee quant.

Ar Me

HNTs Li, NH3

-78 C, 15 min

79%99% eeAr Me

NH2

99% ee

Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.


Ar Ar

NHNs

PhSH, K2CO3

DMF, rt, 4 h Ar Ar

NH2

98% ee 96% 98% ee

Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

By far the mildest approach!

24

The One with the Cyclization of Alkynals

BnO

BnO CHO

Me [RhCl(C2H4)2]2 (7 mol %) ligand (7.5 mol %)

KOH, dioxane/H2O, 60 C, 4h

BnO

BnO

Me

Ph

OH

PhB(OH)2

Entry Ligand Yield (%)

1 (S)-binap 24

2 Dppp 23

3 Dppb 20

4 Dppf 27

5 PPh3 20

6 Cod 73

7* Cod 76

*[Rh(OH)(cod)]2 used directly

BnO

BnO

Et

Ph

OH

93%

Me

Ph

OH

76%

Me

PhMeO2C

MeO2C

OH

75%

TsN

OH

Et

Ph

64%

Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

25

The One with the Mechanism


BnO

BnO CHO

Me

[Rh]-OH

BnO

BnO

MePh

[Rh]

O

BnO

BnO

Me

Ph

OH

BnO

BnO

Me

Ph

O [Rh][Rh]-Ph

PhB(OH)2

H2O transmetalation

alkyne insertion

hydrolysis

CO insertion

26

The One with the Cyclization of Alkynals

BnO

BnO CHO

Me [RhCl(C2H4)2]2 (7 mol %) ligand (7.5 mol %)

KOH, dioxane/H2O, 60 C, 4h

BnO

BnO

Me

Ph

OH

ArB(OH)2

PPh2PPh2

Bn

Bn

(S)-binap

(S,S)-Bn-bod

Bn

Bn(R,R)-Bn-nbd

24%76% ee

76%94% ee

78%95% ee

Entry Ar Yield (%)

ee (%)

1* Ph 89 94

2 4-MeOPh 71 93

3 4-FPh 77 93

4 3-ClPh 71 96

5 2-naphtyl 78 96

*Et instead of Me.


27

Let’s Do Some CycloadditionsMeO2CMeO2C

Ph[RhCl(ligand)2]2 (2 mol %) AgSbF4 (4 mol %)

DCM, RTMeO2CMeO2C

PhMe

Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

28

[4+2]MeO2CMeO2C

Ph[RhCl(diene)2]2 (5 mol %) AgSbF4 (10 mol %)

DCM, RT

MeO2CMeO2C

PhMe

Ph

Ph

Ph

PhPh

Ph

(S,S)-Ph-bod 87% 94% ee

(S,S)-Bn-bod 86% 5% ee

(S,S)-Ph-bnd 58% 35% ee


MeO2CMeO2C

R

R1

[RhCl(diene)2]2 (5 mol %) AgSbF4 (10 mol %)

DCM, RT

MeO2CMeO2C

RR1

8 examples 87-95%83-99% ee

HR2

R2

R = Ph, PhBr, Me, iPr R1 = Me, Ph R2 = H, Ph

29

Cycloaddition Mechanism


RhI

X

Ph

Me

RhI

X RhIII

H

RhIII

X

Ph

Me

H

XPh

X

PhMe

H

coordination

oxidative cyclization

1,3-allylicmigration (supra)

reductiveelimination

30

Stereochemistry Explained


31

1,6-Enynes Cycloisomerization

TsN Ph

[{RhCl(P-P)}2] (5 mol %) PPh3 (5 mol %) NaBArF

4 (10 mol %)DCE, 50 C, 24 h

TsN

PhH

dppe

(R)-binap

0%

F

FF

F

R

R

0%

7%

23%

R = H

R = Me

R = pentyl

R = CH2OCH2OCH3

2%

48% (50% ee)

64% (56% ee)

94% (80% ee)

Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

O

PhH

PhPh

86%90% ee

O

OPhPh

84%99% ee

Selected Scope

32

Tfb (tetrafluorobenzobarrelene) Diene Synthesis

F

FF

F

F

HF

FF

F

F

FF

F

O

OBuLi

OiPr

OiPr

aq. TFA

chiral HPLCresolution

(S,S) + (R,R)

F

FF

F

O

O

(S,S)

2-PyNTf2KHMDS, THF

F

FF

F

TfO

OTf

(S,S)

78%

40%

RMgBr

PdCl2(dppf), THF

F

FF

F

R

R

(S,S)

R = C5H11 (37%)

rac

Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun. 2009, 5713.

• Chiral HPLC to separate enantiomers;

• Low yielding steps.

33

The One with the Catalyst Design

[{RhCl(diene)}2] PPh3

DCM[RhPPh3(diene)]


A chiral diene and a phosphine on the same catalyst!

34

“Dig” the Mechanism


RhPPh3

RhPPh3

TsN

Ph

A

B

RhPPh3

TsNH

H PhC

TsN Ph

Rh Carbenoid

TsN

PhH

TsNPh

[Rh]

coordination

6-endo-dig

-H shift

35

Stereochemistry Explained


36

More Chiral Dienes

Me

Me2AlClCO2Me

H73% Me

CO2Me

(R)-(-)--phellandrene

Me

Me Me

OMe

Me

OMe

$27.35 (5 mL)

98.8% ee

Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.

O [RhCl(C2H4)2]2 (3 mol %) diene (3.3 mol %)


O

R

RB(OH)2

O

R

O

R

> 90%99% ee

> 90%98-99% ee

Me

Me Me

OMeMe

Me Me

OH

Most effective ligands reported so far for Rh-catalyzed asymmetric addition!

37

Last Stereochemistry Picture

Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.

38

Hayashi’s Dienes: SummaryO

PhB(OH)2[RhCl(C2H4)2]2 /ligand

KOH, dioxane/H2O

O

Ph

PhPh

94%96% ee

97%96% ee

Ph

Ph

Ph

Ph

93%83% ee

Ph

Ph

98%90% ee

Me

Me Me

OH

(R,R)-Bn-nbd (R,R)-Ph-bod

(R,R)-Ph-bnd (R,R)-Ph-bdd

90%99% ee

39

Ir-Catalyzed Allylic Displacement

R

OCO2Me [IrCl(alkene)2]2 (1.5 mol %)

PhOH (0.5 equiv.) DCM, RT

R

OPh

R = alkyl, aryl

Alkene

COD (cycloctadiene)

COE (cyclooctene)

100% conversion in 24 h at RT

inactive catalyst

Comments

Norbornadiene partial conversion after 4 days

Ph

Phdoes not form complex with Ir

rac

OMeMe

Ar

equal reactivity to COD

rac

Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

Potential for the diene to be synthesized asymmetrically from cheap (R) or (S)-carvone.

40

Spin-Off: Carreira’s Diene

R

OCO2Me [IrCl(COE)2]2 (1.5 mol %)

PhOH (0.5 equiv.) DCM, RT

OMeMe

R

OCO2Me

R

OPh

27-46% 80-98% ee 50-71% ee

R = alkyl, aryl

tBu

O

1. NBS, MeOH2. tBuOK, tBuOH

(R)-(-)-carvone

O

OMeMe

+ diastereomer

1. LDA, PhNTf2

2. ArZnCl, cat. Pd

OMeMe

Ar

68% 46%


[RhCl(C2H4)2]2 (1.5 mol %) diene (3.3 mol %)

KOH, dioxane/water, RTPhB(OH)2

O

Ph

O

52%71% ee

41

Carreira’s Dienes Generation II“The Long Way Home”

Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.

OMeMe OMeMe

Ph

PhOMeMe

Ph

OMeMe

Ph

OMeMe

Ph

O

1. R1MgBr, Et2O

2. PCC, DCMR1O

1. NBS, MeOH

2. KOtBu, THFO

OMeMe

R1

LDA, R2-Br

O

OMeMe

R1

R2 1. LiNEt2, PhNTf2, THF

2. Pd(OAc)2, Ph3P, HCO2H, DMF

OMeMe

R1

R2

52% (iBu) 54%

87% (iBu, allyl) 62%

42

Again with the Enones?

OMeMe

87%95% ee

OMeMe

Ph

Ph

91%88% ee

OMeMe

Ph

91%91% ee

OMeMe

Ph

85%82% ee

OMeMe

Ph

63%93% ee


KOH, dioxane/water, RTRB(OH)2

O

Ph

O

Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.

• Additional substrates in the scope (not covered by Hayashi)

O

O

Ph

80%90% ee

O O

43%98% ee

Ph

Ph2N

O

MeO

OPh Ph

98%93% ee

93%98% ee

43

One Ligand, One Day, Two Papers

Ar1

O

H Ar2B(OH)2

diene (3.3 mol %)[RhCl(C2H4)2]2 (1.5 mol %)

KOH, MeOH/H2O 50 C, 1.25 h

Ar1

O

H

Ar2

Me

Ph Me

Me

Me OMe 63-90%89-93% ee

Ar1

O

OtBu Ar2B(OH)2

diene (3.3 mol %)[RhCl(C2H4)2]2 (1.5 mol %)

KOH, MeOH/H2O 50 C, 18 h

Ar1

O

OtBu

Ar2

76-95%89-94% ee

Paquin, J.-F.; Defieber, C.; Stephenson, C.R.J.; Carreira, E.M. J. Am. Chem. Soc. 2005, 127, 10850.

Paquin, J.-F.; Stephenson, C.R.J.; Defieber, C.; Carreira, E.M. Org. Lett. 2005, 7, 3821.

Me

Ph Me

Me

Me OMe

44

The Short Way Home

O


O

OMeMeLDA, PhNTf2

THF, -78 COTf

OMeMe

+ diastereomer

Pd(OAc)2, dppfArB(OH)2, K2CO3

PdCl2(PhCN), dppf RMgBr, Et2O R

OMeMe

81%68%

• Ortho substituted boronic acids a challenge;

• Most accessible route;

• Library of 14 ligands;

• High enantioselectivities (over 90%).

Carreira

Darses



O

Ph

O

Carreira's diene: 71% ee Darses' dienes: 39% ee (Bn) >90% ee (rest)

Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem. Int. Ed. 2008, 47, 7669.


O


(R)-(-)-carvone

O

OMeMe

+ diastereomer

1. LDA, PhNTf2

2. ArZnCl, cat. Pd

OMeMe

68% 46%tBu

45

Enantioselective Diene Synthesis

Cl

O

OR

NB O

Ph

H

H Ph

o-tolTf2N-

20 mol %

DCM, -78 C, 15 hClCO2R

R = CH2CF3

1. LiHMDS, THF, -78 C, 0.5 h2. MeLi, THF, -78 C, 0.5 h

OH

90%

99%>98% ee

KH, MeI, 0 C, 1 h

BOMCl, iPr2NEt, DCM, RT, 1h

or OR

R = Me (94%)R = BOM (82%)



O

Ph

O

OR R = Me (90%, 96% ee)R = BOM (95%, 96% ee)

Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

46

Order of Addition Is ImportantOBOM



O

Ph

O

Order of Addition

1. Stir Rh, diene in dioxane for 30 min2. Add KOH, stir 10 min3. Add PhB(OH)2, stir 10 min4. Add enone

1. Stir Rh, diene in dioxane for 30 min2. Add KOH, stir 10 min3. Add enone4. Add PhB(OH)2

<2% enone conversion >98% enone conversion

• Diene is inhibited

OBOMKOH, dioxane/water, RT

[RhCl(C2H4)2]2, PhB(OH)2 OBOM

Ph

• Less strained system necessary


47

Adding One More Carbon

O

OCH2CF3

NB O

Ph

H

H Ph

o-tolTf2N-

10 mol %

NaOMe, MeOH, RT, 15 min

4 C, 15 h

CO2Me 90%99% ee

i. LDA, Et2O, -78 C, 0.5 h

ii. -78 C, 45 min

PhS

Cl

NtBu

CO2Me

60-70%

RLi, CeCl3

THF, -78 C, 15 min OH

R R

R = Me (85%)R = iBu (71%)




O

Ph

O

98%96% eeOH

OH 98%95% ee

Me

iBu

Me

iBu

48

Summary

Reviews:

Defieber, C.; Grutzmacher, H.; Carreira, E.M. Angew. Chem. Int. Ed. 2008, 47, 4482.

Johnson, B.J.; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840.

Chiral Diene

O

R

O

NR

O

O

NR

O

O

R

Ar1

Ar2 O

H Ar1 H

O

PhMe2Si CO2MeAr

PhMe2Si CO2Me

Ar1 H

NTs

Ar1 Ar2

NHTs

EE

R

R

E

E

RR

Ar1 CO2Me

CN Ar1 CO2Me

CN

Ar2

R

HEE

OHCHO

REE

TsNR

R

TsNR

R

49

A Bit of Shopping: Chiral Dienes at Aldrich

Ph

Ph

$161.50 (100 mg)

O

O

rac $65.80 (100 mg)

$90.30 (100 mg)

OMeMe

Bn

$211.50 (100 mg)

Documents

Rh-Catalyzed Asymmetric Additions: The Rise of Chiral Dienes