asymmetric palladium-catalyzed alkene …ccc.chem.pitt.edu/wipf/current...

ASYMMETRIC PALLADIUM-CATALYZED ALKENE CARBOAMINATION

REACTIONS FOR THE SYNTHESIS OF CYCLIC SULFAMIDES

Chem. Eur. J. 2016, 22, 5919 – 5922 Zachary J. Garlets, Kaia R. Parenti, and John P. Wolfe

James Johnson Wipf Group Current Literature

2-11-17

James Johnson @ Wipf Group of 19 3/4/2017

•  Ethylene is produced from from petroleum and natural gas by thermal cracking. •  Largest chemical produced organic compound.

•  Alkenes used extensively in the polymer industry. •  Carboamination

•  Inexpensive starting materials are rapidly functionalized in a single step •  Easily accessed heterocycles and amine building blocks (amino acids).

Alkene Difunctionalization: Carboamination

R RR1NR2R3

or R1R2RN

R3

RR2

2 James Johnson @ Wipf Group


Intramolecular Palladium-Catalyzed Carboamination Reactions

XY

NHR

n

[Pd]Ar-Br

XY ∗∗

NR

n

RBase

NR

Ar

N

n R

Ar

NH

R1R2

R3 R4R5R6

ON

O

R R1H

H ArN

O

R R1H

H Ar

NR

O

NR

P

NH

OR1

R2

R3 RN NR1

O

R2 R3R5

R4

N NBoc

R

R1 R2

O NBoc

R1 R2

NAr

R2

R1 R3

R4

N

NRR1

R2

R3O

NRR1

R2N

NX R

Ar

R1

Ar1

R-BrAr-B(OH)2

NSOO



Intermolecular Carboamination

Org. Lett. 2013, 15, 2502-2505; ACS Catal., 2016, 6 (10), pp 7183–7187

N

O

O

OR1

R

R2

R3

NiCl2(PMe3)2 (10 mol%)Zn dust (5 eq.)

toluene, 100 °C, 12 h N

O

R1R

R2

R3

20 examples 21-90%

RR1

N SO2PhPhO2S

F

SO2Ph

Cu(CH3CN)4BF4 (2.5 mol%)

OH

N

O 1.6 mol%

PhCN, 60 °C

SO2NR

R1SO2Ph

O NH

O

OR

O

R1

OH

HN

O

OR

R1O

[Cp*Co(CO)I2] (10 mol%)AgSbF6 (20 mol%)CsOAc (25 mol%)K3PO4 (25 mol%)

TFE, 3Å MS40 °C, 22 h

17 examples 30-88%

CbzHN BF3K

R

CbzN

RR1R1

Cu(OTf)2 (20 mol%)1,10-phen (25 mol%)

MnO2 (255 mol%)

DCE, 105 °C, 24 h35 examples 35-78%

O

H

NHNs

R1R3

N

NH

O

t-BuRN

Ns

R2

R3

R1

R2

O

HFe(phen)3(SbF6)3

DME, Na2HPO4-10 °C, 12 h

17 examples 50-88%2:1 dr to >20:1 dr; 87-96% ee

O

NHTf

R1R3 N

TfCHCl3, 2,6-lutadine

455 nm LEDs, rt, 24 h28 examples 35-77%

1.7:1 dr to 16:1 dr

N

Mes

PhBF4-

R5

R6

R7

R2

OR1R2

R3

R6R7

R54-MeO-PhSH

OAr

X

RO2SHN

Br R1

R2

R3 ONSO2R

X

Ar

R1R2

R3H

H

Pd2(dba)3 (2.5 mol%)CPhos (5 mol%) or L

LiOtBu

toluene:t-Amyl-OH110 °C, 24 h

OMePCy2L20 example 20-94%

dr 19:1 to 49:1; 63-73 % ee

Cat.

Cat. 5 mol%Cat. (20 mol%)

Cat.



Wolfe Group Chemistry

N NH

O CN 2 mol% [Pd2(dba)3]6 mol% (S)-Siphos-PE

NaOtBu

xylenes, 115 °C

Ar-Br

N N

O CN

Ar56-89% (77-95% ee)

NHBoc

RR

R1-BrPd2(dba)3 (2.5 mol%)

(R)-Siphos-PE (7.5 mol%)NaOtBu

BocN

RR

R1

toluene, 90 °C23 examples 61-80%

72-94% ee

NR1

H H

O2S NHPMP

R-OTfPd(OAc)2 (4 mol%)CPhos (10 mol%)

LiOtBu

tBuOH, 82 °C, 16 h9 examples 45-89%

5:1 to 13:1 dr

NR1

H H

O2S NPMP

H

R

NHH

C4H9

BnO

NH H

TMSC4H9

BnO

OtBuO OtBuO

Br TMSPd2(dba)3P(2-furyl)3

NaOtBu, xylenes140 °C

68% >20:1 dr

1) TFA2) PMBNCO N

H H

C4H9

BnO

NHOPMP

72%

Pd2(dba)3PCy3•HBF4

NaOtBu, toluene110 °C

91% >20:1 dr

NH H

C4H9

BnO

NOPMP

Et

NH

N

NH

H H

C4H9C4H9



Cyclic Sulfamides N N

O2S

F

N OO

NHAc

Active against gram-positivemethicillin and vancomycin

resistant bacteria

N SO2

N

ON

O

OMe

O

Low µM inhibitionof norovirusus N

NSO2N F

O

HOβ-secretase-1 inhibitor

•  Biologically active •  Enantioselective synthesis usually multi-step starting from amino acids

•  Only one previous asymmetric metal-catalyzed synthesis

NH2

OH

O

5 steps

N SO2

NBnO

R

SN N

O O

t-But-BuHN NH

S

R

O OPd2(dba)3 (2.5 mol%)10 mol% L

toluene, 65 °C, 3 h14 examples, 66-98%

90-93% ee

O

OP N

Ph

PhLOrg. Lett., 2013, 15 (4), pp 796–799



Anti-aminopalladation

Chem. Eur. J. 2014, 20, 8782 – 8790

N SBnO

NH


ArOTfPd(OAc)2 (2 mol%)Ru-Phos(5 mol%)

LiOtBu N NSBn

O

Bn

Ar

PhCF3, 100 °C14 examples51 to 92 %

BnO

O

D



Optimization of Cyclization with Ar-OTf



Syn vs Anti-aminopalladation

N SBnO

NH

DSyn-aminopalladation Anti-aminopalladation

PhBrPd(OAc)2 (2 mol%)

C-Phos(5 mol%)NaOtBu N N

SBnO

Bn

DPh

PhCF3, 100 °C90%, >20:1 dr

BnO

ON NSBn

O

Bn

DPh

OPhBr

Pd(OAc)2 (2 mol%)X-Phos(5 mol%)

NaOtBu

toluene, 100 °C47%, 4:1 dr

Mechanism highly solvent and ligand dependent Chem. Eur. J. 2014, 20, 8782 – 8790



Title Paper

James Johnson @ Wipf Group 13

N St-BuO

NH

Syn-aminopalladation

BnO

N NSt-Bu

O

Bn

DAr

O

Ar-BrPd2(dba)3 (1 mol%)

(S)-Siphos-PE (5 mol%)NaOtBu

xylenes120 °C, 18 h

Chem. Eur. J. 2016, 22, 5919 – 5922


Optimization of Protecting Groups



Reaction Scope

NS

N

O OBnt-Bu

96% (93:7 er)

NS

N

O OBnt-Bu N

SN

O OBnt-Bu

Ph

X = Br 95% (94:6 er)X = I 75% (75:25 er)

NMe2

85% (95:5 er)

NS

N

O OBnt-Bu

N ON

SN

O OBnt-Bu

75% (96:6 er)

NS

N

O OBnt-Bu N

SN

O OBnt-Bu

74% (92:8 er) 74% (90:10 er)

NS

N

O OBnt-Bu

CF3

OMe

OMe

O

OPh

O NS

N

O OBnt-Bu

69% (90:10 er)

NS

N

O OBnt-Bu

NS

N

O OBnt-Bu

72% (92:8 er)

58% (68:32 er)

NS

N

O OBnt-Bu

F

NBn77% (88:12 er)

F3C21% (62:38 er)

NS

N

O OBnt-Bu

34% (95:5 er)

NS

N

O OBnt-Bu

44% (94:6 er)TMS OMe

89% (94:6 er)



•  Olefin substitution not tolerated



Syn-aminopalladation


Deuterium Labeling Studies

•  EWD groups decrease dr •  anti-aminopalladation pathway

•  Addition of water (4b) improved yield. •  No effect on dr or er



Deprotection



Conclusions

• Developed enantioselective Pd-catalyzed alkene carboamination with good to high enantio selectivity

• Example of controlling syn vs anti-aminopalladation

• Expansion to intermolecular variant?



asymmetric palladium-catalyzed alkene …ccc.chem.pitt.edu/wipf/current...

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