byJeremy ZIMBRON

RhMe

Me

OO

R2

R1

chiral Cpx*Rh(I) complex, 1

O

NH

OBoc

R'

R"

R'"+2 mol% 1, 2 mol% DBPO

EtOH, 23°C, 16h

O

NH

R'R"

R'"

Literature Meeting November 27th, 2012

2

Cyclopentadienyl ligands (Cp)

1. H. Werner, Angew. Chem. Int. Ed. 2012, 51, 6052-6058.

Common anionic ancillary ligand in organometallic chemistry

Ferrocene is the classic cyclopentadienyl compound

Fe

Discovered and identified by Woodward, Wilkinson and Fischer in the 1950s1

Tigger important developments in modern organometallic chemistry

Wilkinson and Fischer dancing at the final reception of the Conference on Organometallic Chemistry in July 1974 in Ettal

3

Cyclopentadienyl ligands (Cp)

1. H. Werner, Angew. Chem. Int. Ed. 2012, 51, 6052-6058.2. Waymouth et al., Angew. Chem. Int. Ed. 1995, 34, 1143-1170.3. F. Viton, G. Bernardinelli and E. P. Kündig, J. Am. Chem. Soc., 2002, 124, 49684. A. D. Bolig, M. Brookhart, J. Am. Chem. Soc. 2007, 129, 14544.5. A. H. Hoveyda, J. P. Morken, Angew. Chem. Int. Ed. Engl. 1996, 35, 1262. 6. M. Zhou, N. D. Schley, R. H. Crabtree, J. Am. Chem. Soc. 2010, 132, 12550.

Present in some of the most active catalysts:

ZrCl

Cl

Stereospecific olefin

polymerization2

RuL

Ar2PP

OO

PhPh

Ar2

Enantioselective Diels-Alder3

Rh

Me3Si

SiMe3

Hydroacylation ofolefins with

aromatic aldehydes4

Enantioselective C-C and C-H Bond

Formation5

TiCl

ClHydroxylation of

alkanes6

Ir

ClCl

ClIr

Cl

4

About Cp and Cp* ligands

Inert to both nucleophilic or electrophilic reagents

Strong binding to metal centers

Large array of possible structural modifications of the ligand

In asymmetric catalysis Cp ligands have been bypassed by chiral ligands

Only few examples of chiral Cp inducing enantioselection

Co

O

N

R

h (= 420 nm)

N

R

O

82-93% ee

A. Gutnov et al., Angew. Chem. Int. Ed. 2004, 43, 3795 and A. Gutnov et al., Organometallics 2004, 23, 1002-1009.

5

Designing chiral Cp metal complexes1

ClCl

Ti

1. R. L. Halterman. Chem. Rev. 1992, 92, 965-994.

Cyclopentadienyl-derived chirality

OCPh3P

Fe

O

OCON

Mo

Cl

Metal-centered chirality

Combined metal-centered and Cp-derived chirality

XL

M

Y

R

X,Y: N, O, P

*

Mono-bidentate chiral ligands

6

Designing chiral Cp metal complexes1

1. R. L. Halterman. Chem. Rev. 1992, 92, 965-994.

Cyclopentadienyl-derived chirality

OCPh3P

Fe

O

OCON

Mo

Cl

Metal-centered chirality

Combined metal-centered and Cp-derived chirality

No C2 symmetry in chiral Cp ligands: form diastereomers during coordination of the metal

Separate diastereomeric complexes

ClCl

Ti

7

1,2-substituted cyclopentadiene with C2-symmetric Cp derivatives

Ligand features to achieve the required selectivity:

R

R

OO

R2

R1C2-symmetry coordination

of the metal R

R

OO

R2

R1

RhI

RhI

Provides onechiral complex

Designing chiral Cp ligand

8

1,2-substituted cyclopentadiene with C2-symmetric Cp derivatives

Ligand features to achieve the required selectivity:

Designing chiral Cp ligand

Restriction of rotation around the Cp moiety: a single preferential alignment of substrates

M

M

SS

SL

SSSL

M

SL

SS

stericclash

stericclash

M

SLSS

9

1,2-substituted cyclopentadiene with C2-symmetric Cp derivatives

Ligand features to achieve the required selectivity:

Designing chiral Cp ligand

Restriction of rotation around the Cp moiety: a single preferential alignment of substrates

A shield from a remote substituent: direct the approach of the incoming reactant

M

SL

SS

M

SLSS

Shield Rc

Shield RcSelective coordination M

SL

SS

RcAsymmetric reaction

10

Structure of chiral Cpx*Rh(I) complexes

Different backside shielding from the corresponding C2-symmetric Cp precursors

Relatively air-stable and easy to handle

11

Synthesis of chiral Cpx*Rh(I) complexes

Synthesis of the C2-symmetric cyclopentadienes 13

15-crown-5,THF54%

12

Synthesis of chiral Cpx*Rh(I) complexes

tBu2Si(OTf)22,6-lutidine, 56%

Xanthanone(OMe)2PPTS, 59%

(Ph)2C(OMe)2PPTS, 33%

13

C–H bond functionalization using Rh catalysts1

1. G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651-3678.2. D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 11098-11102.

Ar1 Ar2

NH+

R1

[{Rh(coe)2(OH)}2] (2.5 mol%),L (6 mol%)

toluene, 100-120°C, 16h

Ar2 NH2

R2

R1

R2

up to 98:2 er

P

P

MeO

MeO

tBu

OMe

tBu

tBu

OMe

tBu

2

2

L:

Cramer: enantioselective [3+2] cycloaddition2

imine directing group

[Rh]

NH

Ar

DTBM-MeOBiphep

14

C–H bond functionalization using Rh catalysts1

1. G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651-3678.2. D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 11098-11102.3. S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc. 2011, 133, 2350-2353.4. N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133, 6449-6457.

Ar1 Ar2

NH+

R1

[{Rh(coe)2(OH)}2] (2.5 mol%),L (6 mol%)

toluene, 100-120°C, 16h

Ar2 NH2

R2

R1

R2

up to 98:2 er

P

P

MeO

MeO

tBu

OMe

tBu

tBu

OMe

tBu

2

2

L:

Cramer: enantioselective [3+2] cycloaddition2

C-H functionalization using an oxidizing directing group3,4

• Glorius work3

• Fagnou work4

NH

O

H

+ R'

[Cp*RhCl2]2 (2.5 mol%),CsOPiv (30 mol%), PivOH (20 mol%)

EtOH, 80°C, 16h

NH

R

OOPiv

• Excellent directing group• Internal oxidant• Mild conditions• High functional group compatibility N

H

O

H

+R2

[Cp*RhCl2]2 (0.5 mol%), CsOAc (2 eq)

MeOH, RT, 16h

NH

R3

O

OPiv R3

R2

15

Optimization of the asymmetric C-H functionalization

R

R

16

Optimization of the asymmetric C-H functionalization

R

R

17

Optimization of the asymmetric C-H functionalization

R

R

18

Optimization of the asymmetric C-H functionalization

R

R

19

Optimization of the asymmetric C-H functionalization

R

R

20

Substrate scope: olefin acceptors

Variety of styrenes are competent reaction partners

21

Substrate scope: olefin acceptors

22

Substrate scope: aryl hydroxamates

23

Presumed catalytic cycle for the cyclization

24

Postulated model for the stereochemical preference

25

Presumed catalytic cycle for the cyclization

26

Presumed catalytic cycle for the cyclization

7-membered rhodacycle is stabilized with the extra coordination of the carbonyl oxygen of BOC

Migration of the OtBu from N to RhRh

N

OOBoc

Cpx*

R

(III)

N

R

RhCpx*

OBocO(III)

NRh

Cpx*

OBoc

O

Rh

N

O

R

OBoc

Cpx*(V)

nitrene intermediate

RhN

O O

Cpx*

R

(III) O

OtBu

Reductive elimination

L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, J. Org. Chem. 2012, 77, 3017.

27

Presumed catalytic cycle for the cyclization

28

Conclusion

A class of chiral Cpx* analogs with low molecular weight

Desymmetrize a Rh(III)-catalyzed directed C–H bond functionalization

Reaction proceeds under mild conditions and is high yielding and enantioselective

Unlock the potential of chiral Cp ligands in enantioselective catalysis with half-sandwich complexes

Asymmetric catalytic amination of alcohols

R. Kawahara, K-i. Fujita, R. Yamaguchi, Adv. Synth. Catal. 2011, 353, 1161–1168.

29

How to induce chirality with Cp complexes?

Coordination of chiral ligands: diamines or phosphines

Chiral, non racemic cyclopentadienyl ligands

Biochemical approach: Cp-complex embedded into a chiral protein environment

(R)

NH2(R)

NH

Ph Ph

S

O

O

(1R,2R)-(-)-N-p-Tosyl-1,2-diphenylethylenediamine

(1R,2R)-TsDPEN

(R) PPh2

PPh2

(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

(R)-BINAP

MMM

ML

L

L

host protein

spacer

Linker ML

L

L

NHO

H

HN

H S

O

NH

Biotinylated Cp complexSav protein

30

31

32

Oxidizing Directing Groups in CH Activation Reactions

Cui and Wu previous work1

1. J. Wu, X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem. Soc. 2009, 131, 13888.2. N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 6908

Fagnou previous work2

Quinoline N-oxides: directing group and internal oxidant

Benzhydroxamic acid: directing group and internal oxidant