metal-catalyzed asymmetric cross-coupling...

Metal-Catalyzed Asymmetric Cross-Coupling Reactions

181215_LS_Daiki_Kamakura

Cross-Coupling Reactions Using sp3-Substrates

Choi, J.; Fu, G. C. Science, 2017, 356, 1 1

M X+

sp2-sp2 cross cpupling


+ X

+ MR’’

R

R’’

R

R’’

RM

R’’

RX


R’’

RM X

R’’’

R’’’’

+R‘’’

R’’’’R’’

R

Pd, Ni,….

M = BR2, ZnR, SnR3, SiR3,…; X = I, Br, Cl, OTf,….

Strategies for Asymmetric Cross-Coupling Reactions

2Choi, J.; Fu, G. C. Science, 2017, 356, 1

+ MR’’

R

R’’

RX

racemic

*M

L*

R’’

R*

if ent-L* is used,…

+ X

R’’

R

R’’

RM

*

M

L’

mechanism A(stereo retentive)

mechanism B(stereo invertive)

R’’

R*

L* = chiral ligand

L

M

chiral sunstrate

*

Contents1. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins (Fu, 2018)

2. Enantiodivergent Pd-Catalyzed C–C Bond Formation Enabled through Ligand Parameterization (Sigman, Biscoe, 2018)

3

+ R”’MR’’

RR”’

R’’

RX

racemic

*Ni

L*

+ X

R’’

R

R’’

RM

*

Pd

L’



R’’

R*

L* = chiral ligand

L

Pd

chiral sunstrate

*

R”’’

R’’

RXR”’ +

R’’

R*

Ni

L*R”’

R”’’



4

+ R”’MR’’

RR”’

R’’

RX

racemic

*Ni

L*

+ X

R’’

R

R’’

RM

*

Pd

L’



R’’

R*

L* = chiral ligand

L

Pd

chiral sunstrate

*

R”’’

R’’

RXR”’ +

R’’

R*

Ni

L*R”’

R”’’

Fu’s Previous Works

5

• Enantioselective cross coupling of propargyl bromide with diphenylzinc

TMSn-Bu

Br

TMSn-Bu

PhNiIICl2•DME

L1* NO

N NOH

H H

H

L1* = (–)-indenyl-pybox

• Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling

DME, –20 ºC

80%, 91%ee

Ph2Zn

+

BocN Zn

2MeHN NHMe

Ar Ar

(S, S)-L2*

Ar = 1-Naphthyl

+I Ni(acac)2

(S,S)-L2*

THF/Et2O, rt

68% yield, 92%ee

CF3CF3

HNBoc

d.r. = >99 : 1

Smith, S. W.; Fu, G. C. J. Am. Che. Soc. 2008, 130, 12645.Schley, N. D.; Fu, G. C. J. Am. Che. Soc. 2014, 136, 16588.

via

TMSn-Bu

racemicd.r. = >99 : 1

racemic

Mu, X.; Shibata, Y.; Makida, Y.; Fu, G. C. Angew. Chem. Int. Ed. 2017, 56, 5821.

(NiI was an initiator)

Construction of Quaternary Carbon Center

6

R”’’M

racemic

Ni

L*

L* = chiral ligand

R’’

RXR”’

R’’

RR”’’

*R”’

• Enantioselective cross coupling of tert-haloalkane

+

It is difficult to quaternary carbon center by cross-coupling reaction

• Reported methods

Ph Br

CyMe+ ClMg

Ph

CyMeCoCl2dppp

THF, –20 ºC83%

Tsuji, T.; Yorimitsu, H.: Oshima, K. Angew. Chem. Int. Ed, 2002, 41, 4147.

Br+ (9-BBN)–Ph

NiBr2•diglymeL3

THF, –20 ºCL3

N NPh

–––> Asymmetric construction of quaternary carbon center has not been achieved.

Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624.

Ni-Catalyzed Reaction of sec-Bromide with Olefin

7Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.

EtO

NHPhBr

racemic

n-Bu+

NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)

HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N

OOPhPh Ph

Ph

Ph Ph(R,R)-L3*

2-methyl-THF–5 ºC, 40 h

EtO

NHPhH

n-Bu84%, 94%ee

variation from the “standard conditions”Entry

1

ee (%)yield

2

3

under air 66% 94%

with H2O (1.0 eq.) 78% 95%

88% 94%gram scale

<substrate scope>O

NHPhH

n-Bu

71%, 94%ee

BrEt

O

NH

CF2CF3

H

79%, 90%ee

Ph

OAc

O

Bn

64%, 96%ee

Design of Substrate


RO

NR’2Br

R’’

In order to reduce steric hindrance in the vicinity of the reactive site, cyclic substrate was designed.

NPh

O

Me Br

α-halo-β-lactamracemic

ter-bromide

HN

O

BrBrMe

NaOH aq.

88%

EtO

NHPhBr

racemic

n-Bu+


HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N

OOPhPh Ph

Ph

Ph Ph(R,R)-L3*

2-methyl-THF–5 ºC, 40 h

EtO

NHPhH

n-Bu84%, 94%ee

Ni-Catalyzed Reaction of tert-Bromide with Olefin


N N

OOPhPh Ph

Ph

Ph Ph(R,R)-L3*

NR2

O

R1 BrR3

+NR2

O

R1

R3racemic

NPh

O

R

n-BuR1 = Me: 90%, 99%eeR1 = Et: 94%, 99%eeR1 = Bn: 85%, 98%eeR1 = i-Pr: 76%, 98%ee

NPh

O

Et

SiPh378%, 95%ee

NR

O

Et

n-BuR2 = n-Bu: 92%, 99%eeR2 = c-hex: 94%, 99%eeR2 = CHPh2: 88%, 99%eeR2 = OBn: 59%, 97%ee

NBoc

O

Me

n-Bu85%, 97%ee


HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.)

2-methyl-THF5 ºC, 40 h

Transformations of Obtained Compound

10

NBoc

O

Me

n-Bu85%, 97%ee

KCN, MeOH

rtMen-hex

BocHN OMe

O

77%, 97%ee

Men-hex

BocHN OH

68%, 97%ee

LiAlH4 THF, 0 ºC

THF, –40 ºC

ArMgBrMe

n-hexBocHN Ar

O

93%, 97%eeAr = p-MeOC5H4

Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.

Initially Proposed Mechanism


NiBr2•glyme(R,R)-L3*N

Ph

O

Et Brn-Bu

(EtO)3Si+

NPh

O

Et

n-Bu<2% yield

R3

(EtO)3Si NR’

O

R1 NiIIL*Br

+K3PO4•H2O

NR’

O

R NiIIL*

R3

NR2

O

R1 Br

NiBr2•glyme(R,R)-L3*HSi(OEt)3

K3PO4•H2O

2-methyl-THF0ºC, 40 h

R3+

NR2

O

R1

R3racemicNi0L3

*

H–Si(OEt)3

hydrosilylation

transmetalation

• Initially proposed mechanism

• Reaction with alkylsilane

K3PO4•H2O2-methyl-THF

0ºC–––> Alkylsilane was not reaction intermediate

Mechanistic Study


Ni0(cod)2(R,R)-L*

n-pentane, rt

BrL*NiII

SiPh3

SiPh3

Br

+

complex A: 54%

NPh

O

Et Br

BrHNPh

O

Et

SiPh3

SiPh3+

complex A(10 mol%)

86%, 93%ee

L*NiIIBr2 + H–SiOR3 L*BrNiII–HR

H

RL*BrNi

NPh

O

Et BrNPh

O

Et

SiPh380%, 95%ee

1.2 eq.

2-Me-THF–10 ºC

• Reaction of complex A with tert-bromide

–––> complex A would be the active species of the reaction

<possible mechanism to give alkyl–NiII>

– BrSi(OEt)3

Proposed Catalytic Cycle


L*NiIBr

Alkyl–Br

L*BrNiII–BrAlkyl H–Si(OEt)3

Br–Si(OEt)3

L*BrNiII–H

R3

L*BrNiIIR

H

L*BrNiIIIR

H

Alkyl

NR2

O

R1 Br

NR2

O

R1

R3=

Short Summary


EtO

NHPhBr

racemicsec-bromide

n-Bu+

NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N

OOPhPh Ph

Ph

Ph Ph(R,R)-L3*

2-methyl-THF–5 ºC

EtO

NHPhH

n-Bu84%, 94%ee

NR2

O

R1 Br

α-halo-β-lactam

R3+

NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.)

2-methyl-THF0 ºC

NR2

O

R1

R359–94% yield

95–99%ee



15

+ R”’MR’’

RR”’

R’’

RX

racemic

*Ni

L*

+ X

R’’

R

R’’

RM

*

Pd

L’



R’’

R*

L* = chiral ligand

L

Pd

chiral sunstrate

*

R”’’

R’’

RXR”’ +

R’’

R*

Ni

L*R”’

R”’’

Cross-Coupling of Chiral Boronic Esters

16

Ph Me

Bpin

+

Ar–I

Ph Me

Ar

48-86%, 84-94% es

Ph NH

Bpin

Me

O

+

Pd2(dba)3XPhos

K2CO3, H2Otoluene

Ar–Br

HN OBR2

Ph HL(Ar)PdII

Ph NH

Ar

Me

O

95%, 59%es

Pd2(dba)3

PPh3Ag2O

Imao, D,; Veronique, G.; Laberge, S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024.

88%ee

• Stereoretentive reaction

PCy2i-Pr i-Pr

i-PrXPhos

• Stereoretentive reaction

Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.87%ee

Cross-Coupling of Chiral Boronic Esters

17Wang, Z.; Yin, H.; u, G. C. Science, 2018, 563, 379.

Cl

Et Me

BF3K+

PdII NH2t-Bu3P OMs

K2CO3toluene/H2O (2 : 1)

OMe

Et Me

OMe

93% (95%es)

The factors controlling the dominant mechanism of transmetallation are not understood.

Et Me

BF3K+Ar Cl

Et Me

ArAr

Me Et

Pd/Pt-Bu3Pd/L

Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. J. Am. Chem. Soc. 2014, 136, 14027.

(stereo invertive)

98%ee

(stereo retentive)Aim of this research:

• Development of the ligand-controlled enatiodivergent cross-coupling reaction• To reveal the factors that control the the transfer of stereochemistry

Effects of the Substituent and Ligand

18Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.

Cl

Et Me

BF3K+

PdII NH2L OMs


100 ºC

Z

Et Me

Z

98%ee

Z

OMe

Me

CO2Et

CF3

CN

σpara

–0.27

–0.17

0.45

0.54

0.66

ee (L = Pt-Bu3)

–91%

–89%

–79%

–72%

–67%

L solid angle ee (Z = CO2Et)

Pt-Bu3 150º –79%

150º +4%PAd2n-Bu

PPh3 126º +12%

Pt-Bu2Ph 145º +21%

Po-tol3 153º +65%

–––> No obvious correation was observed between these results and the steric properties (solid angle).

*

Ad = adamantyl

General Scheme of Model Development

19

a A conformational search was performed for all phosphines using OPLS3 force field and low frequency- mode conformational search. Conformers within 15kcal/mol were considered for further computations. b All structures were fully optimized at the PBE0/6-31+G(d) level and frequency analysis was performed at the same level. c Multivariate model development was performed using MATLAB R2017a with forward stepwise linear regression. Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.

28 ligands

conformersearch

MM a

computation

representativeset of comformers

DFT b

caluculation

individual conformer’s properties* • electronic propaties

• steric propaties

statistical analysis c

multivariate regression

ΔΔG‡ (measured)

= –RTln(x/y)propaty X

ΔΔ

G‡

(mea

sure

d)(1) (2)

ΔΔG‡ (measured)

ΔΔ

G‡

(pre

dict

ed) ΔΔG‡

(predicted) = aX + …

Reveal the factors that control the transfer of

stereochemistry

predictive statistical modelligand design

Experimental Workflow


P

1

PPh2OMeMeO

2

PCy2OMeMeO

3

4 5 6

Pt-Bu2

7Pt-Bu3

8 9PAd3

3

PPh3 PEt3 PMe3

+ other 19 phosphines

28 ligands

electronic propaties

steric propaties• percent buried volume• Sterimol values• Solid angle

* obtaine four kinds of values (min, max, Boltz, MC)with one propaty

MM, DFTcaluculation

<steric propaties>%Vbur Sterimol values

experiments

R–BF3KAr–Cl, Pd

R–Arxx%ee correlation?

• P chemical shift• P lone pair and P–C antibonding orbital energies• P partial charge• P lone pair electrostatic potential

Initial Investigations


Cl

Et Me

BF3K+

PdII NH2L OMs


100 ºC

CO2Et

Et Me

CO2Et

98%ee

L

*

P

1

ee

65%

ArPPh2

2Ar = 2, 6-di-MeOC6H3

52%

L ee

Pt-Bu2

7

Pt-Bu38

9PAd3

–68%

–79%

–93%

Epimerization via β-Hydride Elimination


PEt3 9%5

Cl

Et Me

BF3K+

PdII NH2L OMs


100 ºC

CO2Et

Et Me

CO2Et

98%ee *

L ee

PMe3 6%6

<proposed epimerized pathway>

PdIIL Ar

MeEt

PdIIL Ar

Et

PdIIL Ar

MeEt

Et Me

Ar

Et Me

Ar

epimerizedcompound

EtPdIIArL

EtAr

linear compound (undesired)

H


Enantiospecificity Trend

A correlation between enantioselectivity and Vmin was observed

only ligands providing high selectivity were further investigated (>30%ee)

P

19

PAd3

Vm i nB o l t z : M i n i m u m o f t h e

molecular electrostatic potential in the phosphorus lone pair region


New Ligands were designed



Enantiospecificity Trend



desired ligand

P

19

PAd3

Vm i nB o l t z : M i n i m u m o f t h e

molecular electrostatic potential in the phosphorus lone pair region

New Ligand Design


P(CF3)n

Ar2

RR

R

Ar1

electron-poor

bulky

Ar1 = 2,6-di-MeOC6H3

Ar2 =

CF3

CF3

CF3Me

10 Vmin

Bolz = –0.04011

–0.03012

–0.055

13–0.038

14 –0.029

15 –0.052

New ligand design

2

desired ligand

(as validation)

Ar1 = 2,4,6-tri-i-PrC6H2

Effects of New Ligands


Cl

Et Me

BF3K+

PdII NH2L OMs


100 ºC

CO2Et

Et Me

CO2Et

98%ee *

Ar1 = 2,6-di-MeOC6H3

Ar2 =

CF3

CF3

CF3Me

10 Vmin

Bolz = –0.04075%ee

7.4 : 1 (b: l)

11 –0.03090%ee

45 : 1 (b: l)

12 –0.05535%ee

1 : 2.1 (b: l)

13–0.03890%ee

43 : 1 (b: l)

14 –0.02990%ee

69 : 1 (b: l)

15 –0.05281%ee

(11 :1 b: l)

(as validation)

Ar1 = 2,4,6-tri-i-PrC6H2

Substrate Scope


+ conditions A or B

PdII–L (3–15mol%)PdII–L =

Ar–X

conditions A1L = 11, Cs2CO3

toluene/H2O = 1 : 1

conditions A2L = 14, K2CO3

toluene/H2O = 1 : 1

conditions BL = PAd3 (9), K2CO3toluene/H2O = 2 : 1

R1 R2

BF3K

R1 R2

Ar

*

PdII NH2L OMs

Et Me

Ph

X = Cl, conditions A290%yield, 92%es

Et Me

Ph

X = Cl, conditions B92%yield, 98%es

MeX = Cl, conditions A2

87%yield, 97%es

MeX = Cl, conditions B

90%yield, 99%es

OMe OMe

PhPh

MeX = Br, conditions A1

81%yield, 95%es

MeX = Cl, conditions B

84%yield, 91%es

PhPh

CF3 CF3

X = Cl, conditions A177%yield, 99%es

X = Cl, conditions B78%yield, 77%es

PhPh

Ph Ph

Limitation of the Reaction


+ conditions A or B

PdII–L (3–15mol%)PdII–L =

Ar–X

conditions A1L = 11, Cs2CO3

toluene/H2O = 1 : 1

conditions A2L = 14, K2CO3

toluene/H2O = 1 : 1

conditions BL = PAd3 (9), K2CO3toluene/H2O = 2 : 1

R1 R2

BF3K

R1 R2

Ar

*

MeO S MeO S

X = Cl, conditions A286%, d.r. = 30 : 1

X = Cl, conditions B65%, d.r. = 5 : 1

X = Cl, conditions A271% yield*

*conditions B results in low conversion of SM.

Ph

S

X = Br, conditions B52% yield, 95%es

Ph

S

X = Br, conditions B43% yield, 94%es

PdII NH2L OMs

Multivariate Regression Analysis


Cl

Me

BF3K+

PdII NH2L OMs


100 ºC

CO2Et

Me

CO2Et

97%ee *

Ph

Multivariate linear regression

17 training sets

+

7 varidations

Additionally, 24 ligands were tested

–90% ~ +98%eeΔΔG‡ range: 5.5 kcal/mol

Ph

omit smaller 4 ligands (B1

Boltz<4)

(10 mol%)

Results of Multivariate Linear Regression


Eσ*(P−C)ave ••• The average energy of the P−C antibonding (σ*) orbitals

ELP(P) ••• the energy of the lone pair orbital of phosphorus

9

11

PAr2OMeMeO

11Ar = 3,5-di-CF3C6H3

9

PAd3

It was found that enantioselectivity d e p e n d s o n t h e e l e c t r i c a l properties of the ligands

Proposed Reaction Mechanism


PdII NH2L OMs

PAr2OMeMeO

11Ar = 3,5-di-CF3C6H3

PAr2i-Pri-Pr

14Ar = 3,5-di-CF3C6H2

i-Pr

PdII–L =

Ar–ClPd0–L PdII

Ar

LCl

H2O, K2CO3

PdII

Ar

LHO

L = 11, 14,…

L = PAd3, Pt-Bu3,…

X2B

PdIIL

OH

ArR1

R2

X = F or OH

R1

BX3K

R2

R1HR2

BX3

X = F or OH

ClPdII(Ar)L

R1

Ar

R2

R1

Ar

R2

RBX3K RBX2

X =F or OH

H2O, K2CO3

X =F or OH

X =F or OH

R1

BX2

R2

X =F or OH

Summary


racemic

R3+

NiBr2•glyme(R,R)-L3*HSi(OEt)3K3PO4•H2O

2-methyl-THF

NR2

O

R1 Br

NR2

O

R1

R3

N N

OOPhPh Ph

Ph

Ph Ph(R,R)-L3*

R1

BF3K

R2+Ar–Cl

R1 R2

Ar

R1 R2

ArPdII–LL = PAd3

ΔΔG‡ = 1.5 + 0.62Eσ*(P-C)aveBoltz – 1.2ELP(P)

Bolz

PAr2OMeMeO

11Ar = 3,5-di-CF3C6H3

PAr2i-Pri-Pr

14Ar = 3,5-di-CF3C6H2

i-Pr

PdII–LL = 11, 14

stereo retentive

stereo invertive

33

Appendix

Branched : linear ratio


The Ratio of Branched Compounds


Preparation of Substrates


R O N(i-Pr)2

OHSHR B(pin)O

N(i-Pr)2OR

Ets-BuLi

(–)-sparteineEt2O, –78 ºC

; (pin)BEt MgBr2 reflux

Stymiest, J. L.; Dutheuil, G. D.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.Homologation reaction using lithiated carbamate: 140614_LS_Keiichiro_Fukushima

Et

R B(pin)

90%, 96%ee

MgBr2

R = Ph(CH2)2

Ligand Set (1)


Ligand Set (2)


Data Set


Parameters (1)


Parameters (2)


Parameters (3)


Initial Investigations


metal-catalyzed asymmetric cross-coupling...

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