Decarboxylative Arylation of α - CCC/UPCMLDccc.chem.pitt.edu/wipf/Current Literature/MikeF_3.pdf · metal oxidation, ligand reduction! • As ligands becomes more electron donating,

Decarboxylative Arylation of α-Amino Acids via Photoredox

Catalysis!

Zhiwei Zuo and David W. C. MacMillan !J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

!Michael Frasso!

Current Literature!April 12, 2014!

R

NHBoc

O

OH

ArCNIr[p-F(tBu)-ppy]3

CsF, DMSO26 W CFL

R

NHBoc

Ar

Mike Frasso @ Wipf Group Page 1 of 14 4/13/2014

Top Selling Drugs!

http://cbc.arizona.edu/njardarson/group/sites/default/files/Top200%20Pharmacetical%20Products%20by%20US%20Retail%20Sales%20in%202012_0.pdf!

Cl

N

O O

S

Plavtix(Clopidogrel)antiplatelet

N

OHO

O BuNNHN

N

Diovan(Valsartan)

hypertension, cogestive heart failure, MI

Gleevec(Imatinib)anticancer

F3CHN

Sensipar(Cinacalcet)

Parathyroid regulation

N

N

O

NH

NH

N

N

N

Mike Frasso @ Wipf Group Page 2 of 14 4/13/2014

Amaryllidaceae Alkaloids!

Nat. Prod. Rep. 2007, 24, 886-905!

O

N

H

R2

R3

R1O

Galanthamine-type

R1O

R2O N

H

OR4R3O

H

Lycorine-type

R1O

R2O NH

Crinine-type

R6

R4

R3

R5

R4

Mike Frasso @ Wipf Group Page 3 of 14 4/13/2014

Previous Methods!

Org. Lett. 2008,10, 3923-3925!J. Am. Chem. Soc. 2006, 128, 3538-3539!

1. s-BuLi, (-)-sparteine2. ZnCl2

3. Pd(OAc)2, tBu3P-HBF4,ArBr

N NBoc Boc

Ar

N NBoc Boc

1. s-BuLi, TMEDA2. ZnCl2

3. Pd(OAc)2, tBu3P-HBF4,ArBr

Ar

Mike Frasso @ Wipf Group Page 4 of 14 4/13/2014

Biphasic Viologen/Photoredox Catalysis!

J. Org. Chem. 1983,105, 7764-7765!

N NC8H17 C8H17

N NC8H17 C8H17 N NC8H17 C8H17

C8V

EtOAc

H2O

C8V2+ C8V.+

Ph Ph

Br

BrPh Ph

Br2x

C8V.+

C8V2+

*Ru(bpy)32+ Ru(bpy)33+

Ru(bpy)32+

h!

(NH4)3ETDA

(NH4)3ETDA.+

Ph Ph

Br

Br

N NC8H17 C8H17

2Br-

C8V2+.

Ru(bpy)3Cl2(NH4)3ETDA, EtOAc/H2O

vis. light

Ph Ph

Mike Frasso @ Wipf Group Page 5 of 14 4/13/2014

Dual Enzymatic/Photoredox Catalysis!

J. Am. Chem. Soc. 1986,108, 1080-1082!

N NC8H17 C8H17

N NC8H17 C8H17 N NC8H17 C8H17

C8V

EtOAc

C8V2+ C8V.+

Ph Ph

Br2x

C8V.+

C8V2+

*Ru(bpy)32+ Ru(bpy)33+

Ru(bpy)32+

h!

NADH EtOH

NAD+

Ph Ph

Br

Br

C8V2+.2Br,Ru(bpy)3Cl2

NAD+

EtOH, EtOAc/H2Ovis. light

Ph Ph

SepharoseBead

H

O

alcoholdehydrogenase

alcohol dehydrogenaseon sepharose beads

A

A

Mike Frasso @ Wipf Group Page 6 of 14 4/13/2014

Inspiration for Current Work!

NPh

X

CN

CN

Ir(ppy)3

NaOAc, DMA26 W CFL

NPh

X

CN

NPh

NPh

NPh

NPh

N NPh

N NPh

CO2Et CO2EtN N

NN

NH

NN

NPh

80% 54% 44%

72% 61% 49%

Science 2011, 334, 1114-1117!

Mike Frasso @ Wipf Group Page 7 of 14 4/13/2014

Proposed Mechanism!

IrIII(ppy)3

*IrIII(ppy)3Reductanth!

X

CN

X

CN

IrIV(ppy)3Oxidant

A

RNHBoc

OH

O

RNHBoc

A

RNHBoc

X

Ir(ppy)3

Base, DMSO26 W CFL

N COOH

NC

CN

N CNBoc Boc

J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

Mike Frasso @ Wipf Group Page 8 of 14 4/13/2014

General  Comments!•  Redox properties of Ir3+ described primarily as

metal oxidation, ligand reduction!•  As ligands becomes more electron donating,

complex becomes more reducing!•  As ligands become more electron withdrawing,

complex becomes more oxidizing!

J. Org. Chem. 2012, 77, 1617-1622!

Mike Frasso @ Wipf Group Page 9 of 14 4/13/2014

Conditions Screen!

N

R1 R2

R3

R1 = R2 = R3 = H Ir(ppy)3

R1 = H, R2 = R3 = F Ir(dFppy)3

R1 = R2 = H, R3 = F Ir(p-F-ppy)3

R1 = tBu R2 = R3 = F Ir[dF(tBu)-ppy]3

R1 = tBu, R2 = H, R3 = F Ir[p-F(tBu)-ppy]3

R1, R2, R3 Catalyst

J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

2 mol% cat.

Base, DMSO26 W CFL

N COOH

NC

CN

N CN

Entry Catalyst Base % yield

1

2

3

4

5

6

7

8*

9

10

*no visible light

Ir(ppy)3

Ir(p-F-ppy)3

Ir(dFppy)3

Ir[dF(CF3)ppy]2(dtbbpy)2

Ir[p-F(tBu)-ppy]3

Ir[dF(tBu)-ppy]3

Ir[p-F(tBu)-ppy]3

Ir[p-F(tBu)-ppy]3

none

Ir[p-F(tBu)-ppy]3

K2HPO4

K2HPO4

K2HPO4

K2HPO4

K2HPO4

K2HPO4

CsF

CsF

CsF

none

12

58

54

trace

73

68

83

0

0

trace

Boc Boc

Mike Frasso @ Wipf Group Page 10 of 14 4/13/2014

Amino Acid Scope!

J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

NCN

NCN

N

CN

N

O

CN

PhNHBoc

CN

NHBoc

CN

R

O

82%

75%

80%

70%

78%

R = NHTrt 78%R = OBn 72%

NHBoc

CN

S

81%

NHBoc

CN

BocN

NHBoc

CN

85%

BnONHBoc

CN

64%

NHBoc

CN

81%

NHBoc

CN

67% 89%

Cbz

Boc

Boc

Boc

Ir[p-F(tBu)-ppy]3

CsF, DMSO26 W CFL

R1 N COOH

NC

CN

R1 N CNR2 R2

Mike Frasso @ Wipf Group Page 11 of 14 4/13/2014

Cyanoarene Scope!

J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

NCN

NCO2Me

85%

52%

65% 73%

NCN

77%

N

70%

O

O

NSO2Ph

64%

N N

83%

Boc

Boc

Boc

Boc

Boc

Boc

N NBoc

NPO(OEt)2Boc

Ir[p-F(tBu)-ppy]3

CsF, DMSO26 W CFL

N COOH

X

NC

N XBoc Boc

Mike Frasso @ Wipf Group Page 12 of 14 4/13/2014

α-Arylation of Ethers!

Ir[p-F(tBu)-ppy]3

CsF, DMSO26 W CFL

65%

O COOH

NC

CN

O CN

Ir[p-F(tBu)-ppy]3

CsF, DMSO26 W CFL

93%

N

NC

Ph COOH

OMe

Ph

OMe

N

J. Am. Chem. Soc. ASAP, doi: 10.1021/ja501621q!

Mike Frasso @ Wipf Group Page 13 of 14 4/13/2014

Issues to Address!•  Currently not scalable!– Reactions performed on 0.4 mmol scale,

0.02 M, 48 h reaction times!•  No stereocontrol!

Mike Frasso @ Wipf Group Page 14 of 14 4/13/2014