Decarboxylative Arylation of α - CCC/UPCMLDccc.chem.pitt.edu/wipf/Current...
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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 ArCN Ir[ p-F( t Bu)-ppy] 3 CsF, DMSO 26 W CFL R NHBoc Ar Mike Frasso @ Wipf Group Page 1 of 14 4/13/2014
Transcript of Decarboxylative Arylation of α - CCC/UPCMLDccc.chem.pitt.edu/wipf/Current...
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
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