total synthesis enabled by...
TRANSCRIPT
Total Synthesis Enabled by Cross-Coupling
Xiaheng ZhangMacMillan Group Meeting
May 30th��2019
O
O OBnO
O
OPMB
HH
H
H HH
OTBS
O
TfO
O
OO
OO
O O
O OTBS
Me
H
HH
HH
H
H
H
H
HH
HH
Me
H
H
OO
O O
O O
OO
OOTBS
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
O
O
O
OBn
O
PMBO
H
H
HH
H
H
TBSO
H
Pd
Why Do People Care About Total Synthesis
■ invent, test and develop new methodology
■ produce bioactive molecules
■ prepare analogs for drug discovery
■ foundamental study cases for process chemistry
Strychnine(Woodward, 1954)
Erythronolide B(Corey, 1978)
Taxol(Nicolaou, 1994)
Why Do People Care About Total Synthesis
All new approved drugs 1981−2014■ S = Synthetic drug
■ More than 50% approved drugs are synthetic drugs
Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2016, 79, 629.
The Most Common Synthetic Tools in the Total Synthesis
What’s next? Cross-Coupling Reaction
Ph
O
Me
H Ph
O
Aldol reactionPh
O
Me
Ph
OH
R3MgBr
Grignard reaction
R1 R2
O
R1 R2
OH
R3
Diels-Alder reaction Wittig reaction
R1 R2
O
R1 R2Ph3PR3
R4
R4R3
Total Synthesis Enabled by Cross-Coupling
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Outline
Pd
Iron-Catalyzed Cross- Coupling in Total Synthesis
Fe
Copper-Catalyzed Cross-Coupling in Total Synthesis
Cu
Nickel-Catalyzed Cross- Coupling in Total Synthesis
Ni
Total Synthesis Enabled by Cross-Coupling
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Outline
Pd
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Suzuki, Stille, Negishi reaction
R1 R2YX R1 R2
Pd
X = ZnBr, B(OR)2, SnR3 Y = Cl, Br, I, OTf
Heck reaction
R4Y
Pd
Y = Cl, Br, I, OTf
R2
R1
H
R3
R2
R1
R4
R3
Sonogashira reaction
R2Y
Pd
Y = Cl, Br, I, OTfR1
H
R1
R2
Sequential Heck Reactions in the Enantioselective Synthesis of Estrone
L. F. Tietze, T. NVbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971.
Pd(OAc)2, PPh3, 50%MeO
BrBr
Me
H
OtBu intermolecular Heck reactionMeO
BrPdLn
Me
H
OtBu
Me
H
OtBu
MeO
Br
Me
H
OtBu
MeO
H
H H
PPd
O O
PdOO P
Me
Me
o-Tol o-Tol
o-Tol o-Tol
intramolecular Heck reaction99%
Me
H
HO
H
H
O
estrone
Intramolecular Heck Reactions in the Total Synthesis of Dehydrotubifoline
V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030.
N
CO2MeH
N
Me
N
CO2MeH
NI
Me
Pd(OAc)2, K2CO3, 84%
N
N
Me
PdLnO
MeON
NHMe
PdLn
CO2Me
bond rotation
N
NMe
CO2Me
PdLn
Intramolecular Heck Reactions in the Total Synthesis of Dehydrotubifoline
V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030.
NH H
NI
Me
N
N
Me
dehydrotubifoline
Pd(OAc)2, K2CO3, 79%
NH
N
Me
PdLn
Intramolecular Heck Cascade for the Total Synthesis of Scopadulcic Acid B
L. E. Overman, D. J. Ricca, V. D. Tran, J. Am. Chem. Soc. 1993, 115, 2042.
Pd(OAc)2, PPh3
Me
OTBS
IO
O
H
OTBS
PdLn
Me
1,2-insertion
H
OTBS
Me
PdLn
β-hydride elimination
H
OTBS
Me
O
O
H
OBz
Me
O
HO2C
HO
H
scopadulcic acid B
The Use of Heck Reaction in the Commercial Synthesis of Singulair
Merck Team. J. Org. Chem. 1993, 58, 3731.Merck Team. J. Org. Chem. 1996, 61, 3398.
Me MeOH
NCl S
CO2H
Singulair, by Merck
prevent asthma attacks
intermolecular Heck
NCl OH I
CO2Me
The Use of Heck Reaction in the Commercial Synthesis of Singulair
Merck Team. J. Org. Chem. 1993, 58, 3731.Merck Team. J. Org. Chem. 1996, 61, 3398.
Singulair
NCl OH
I
CO2Me
CO2MeNCl OHPd(OAc)2, 83%
HPdLn
CO2MeNCl Oβ-hydride elimination
tautomerization
‘Stitching Cyclization’ Route to the Enediyene Core Synthesis
M. D. Shair, T.-Y. Yoon, K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 1996, 118, 9509.M. D. Shair, T.-Y. Yoon, S. J. Danishefsky, Angew. Chem. Int. Ed. 1995, 34, 1721.
Pd(PPh3)4, 81%TeocN
O
Me
OH
OH
II
OTBS
TeocNO
Me
OH
OH
OTBS
Me3Sn SnMe3
tandem Stille coupling
HNO
Me
CO2H
OMe
OH
OH
OH O
O
(±)-dynemicin
N
Me
OH
OH
II
OTBS
O
MeO
Palladium-Catalyzed Cross-Coupling in the Total Synthesis of Chalcitrin
Yang, M.; Yin, F.; Fujno, H.; Snyder, S. J. Am. Chem. Soc. 2019, 141, 4515.
O
O
H
OH
O
O
O
O
CO2HHO2C
HOOH
OH
HO
chalcitrin
O
O
H
OH
O
O
O
O
CO2BnBnO2C
BnOOBn
OBn
BnO
O
O
H
OH
O
O
CO2Bn
OBn
BnOPd
O
O
CO2Bn
OBn
BnO
I
Heck reaction
Palladium-Catalyzed Cross-Coupling in the Total Synthesis of Chalcitrin
Yang, M.; Yin, F.; Fujno, H.; Snyder, S. J. Am. Chem. Soc. 2019, 141, 4515.
O
O
H
OH
O
O
H
OH
Me3Sn
SnMe3
O
O
O
O
CO2HHO2C
HOOH
OH
HO
chalcitrin
O
O
H
OH
O
O
O
O
CO2BnBnO2C
BnOOBn
OBn
BnO
Pd
O
O
CO2Bn
OBn
BnO
I
tandem Stille coupling
Palladium-Catalyzed Cross-Coupling in the Total Synthesis of Chalcitrin
Yang, M.; Yin, F.; Fujno, H.; Snyder, S. J. Am. Chem. Soc. 2019, 141, 4515.
O
O
H
OH
O
O
H
OH
I
Br
O
O
O
O
CO2HHO2C
HOOH
OH
HO
chalcitrin
O
O
H
OH
O
O
O
O
CO2BnBnO2C
BnOOBn
OBn
BnO
Pd
O
O
CO2Bn
OBn
BnO
SnBu3
tandem Stille coupling
BBr3
52% two steps
Carbopalladation/Stille Coupling Cascade for the Synthesis of Ileabethoxazole
Yang, M.; Yang, X.; Sun, H.; Li, A. Angew. Chem., Int. Ed. 2016, 55, 2851.
Pd(PPh3)4, 55%Me
OTf
MeO
Si
Me
iPr iPrN
O
Bu3Sn
TIPS
Me
Me OSi
Me
PdLn
iPr
iPr
Me
Me OSi
MeiPr
iPr
NO
TIPS
6π-electrocyclizationaromatization
Me
Me
NO
TIPS
Si
Me
OiPr
iPr
Me
Me
NO
Me
Me OHMe
Ileabethoxazole
Suzuki-Miyaura Coupling in the Total Synthesis of Gymnocin A
Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003, 125, 14294.
O
O OBnO
O
OPMB
HH
H
H HH
OTBS
O
TfO
O
OO
OO
O O
O OTBS
Me
H
HH
HH
H
H
H
H
HH
HH
Me
H
H
OO
O O
O O
OO
OOTBS
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
O
O
O
OBn
O
PMBO
H
H
HH
H
H
TBSO
H
81%
Pd(PPh3)4
Iterative Cross-Coupling in the Total Synthesis of Synechoxanthin
Fujii, S.; Chang, S. Y.; Burke, M. D. Angew. Chem., Int. Ed. 2011, 50, 7862.
Me
Me
HOOC
MeMe
Me Me Me
Me
COOH
Synechoxanthin
Me
Me
MeO2C
I B
Me
BO
OMe
Me
MeMe
OO
MeN
OO
IBr
MIDA boronates
Iterative Cross-Coupling in the Total Synthesis of Synechoxanthin
Fujii, S.; Chang, S. Y.; Burke, M. D. Angew. Chem., Int. Ed. 2011, 50, 7862.
Me
Me
MeO2C
I
B
Me
BO
OMe
Me
MeMe
OO
MeN
OO
MIDA boronates
PdCl2dppf, K3PO4
70%
B
MeOO
MeN
OO
Me
Me
MeO2C
NaOMe, I2
99%I
Me
Me
Me
MeO2C
B
MeOO
MeN
OO
Me
Me
Me
MeO2CPdCl2dppf, K3PO4
65%
MIDA boronates
Iterative Cross-Coupling in the Total Synthesis of Synechoxanthin
Fujii, S.; Chang, S. Y.; Burke, M. D. Angew. Chem., Int. Ed. 2011, 50, 7862.
Pd(OAc)2, XPhos, NaOH53% overallB
MeOO
MeN
OO
Me
Me
Me
MeO2C
IBr
then deprotection
Me
Me
HOOC
MeMe
Me Me Me
Me
COOH
Synechoxanthin
double cross-coupling
Palladium-Catalyzed Macrocyclization in Total Synthesis
Zhu, X.; McAtee, C. C.; Schindler, C. S. Org. Lett. 2018, 20, 2862. Zhu, X.; McAtee, C. C.; Schindler, C. S. J. Am. Chem. Soc. 2019, 141, 3409.
81%
NBn
N
O
O
I I OBnMeO
Pd(dppf)3CH2Cl2B2Pin2, DMSO/H2O
NBn
N
O
O
BnOOMe
NNH
H
H
HO
O
herquline B
MeMe
NBn
N
O
O
Bin Bin OBnMeO
Me
Palladium-Catalyzed Macrocyclization in Total Synthesis
He, C.; Stratton, T. P.; Baran, P. S. J. Am. Chem. Soc. 2019, 141, 29.
60%
NH
N
O
O
I I OMeMeO
Pd(dppf)3CH2Cl2B2Pin2, DMSO/H2O
NH
N
O
O
MeOOMe
NNH
H
H
HO
O
herquline B
MeMe
Palladium-Catalyzed Macrocyclization in Total Synthesis
Cox, J. B.; Kimishima, Aoi.; Wood, J. L. J. Am. Chem. Soc. 2019, 141, 25.
37%
NH
NH
O
O
I I OHMeO
Pd(dppf)3CH2Cl2B2Pin2, DMSO/H2O
NH
NH
O
O
HOOMe
NNH
H
H
HO
O
herquline B
BocBoc MeO
MeO
Palladium-Catalyzed Carbonylation in the Total Synthesis
Bai, Y.; Shen, X.; Li, Y.; Dai, M. J. Am. Chem. Soc. 2016, 138, 10838.
OTBDPS
H
HI
OOPMB
Me
OHMe
OTBDPS
H
H
OOPMB
Me
OHMe H
PdLn
Pd(OAc)2, P(2-furyl)3CO (3 atm)
43%
OTBDPS
H
H
OOPMB
Me
OHMe H
OLnPd
OTBDPS
H
H
OOPMB
Me
OMe H
O
Spinosyn A core structure
C-H Arylation in the Total Synthesis of Piperarborenine B
Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076.
Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed. 2012, 51, 7507.
Pd(OAc)2, Ag2CO3, 52%O
NH
HMeO2C
SMe OMe
OMe
OMe
I
O
NH
MeO2C
SMe
OMe
OMeMeO
O
NH
MeO2C
SMe
OMe
OMeMeO
LiOtBu79%
Pd(OAc)2, 52%
OMe
OMe
I
O
NH
MeO2C
SMe
OMe
OMeMeO
MeOOMe
3 steps
O
N
OMe
OMeMeO
MeOOMe
O
N
O
O
Piperarborenine B
C-H Arylation in the Total Synthesis of Podophyllotoxin
Ting, C. P.; Maimone, T. J. Angew. Chem. Int. Ed. 2014, 53, 3115.
Pd(OAc)2, Ag2CO3O
O
OTIPS
CO2Me
O
NHArI
OMe
OMe
OMe
O
O
OTIPS
CO2Me
N ON
30%
O
O
OTIPS
CO2Me
LnPd N
O
N
O
O
OH
MeO
OMe
OMe
O
O
H
H
Podophyllotoxin
C-H Arylation in the Total Synthesis of Podophyllotoxin
Ting, C. P.; Maimone, T. J. Angew. Chem. Int. Ed. 2014, 53, 3115.
Pd(OAc)2, K2CO3O
O O
NHI
OMe
OMe
OMe
O
O
OH
MeO
OMe
OMe
O
O
H
H
Podophyllotoxin
OO
Me Me
SMe
O
O O
NHDG
OO
Me Me
MeO
OMe
OMe
45% single diastereomer
C-H Alkenylation in the Total Synthesis of Psiguadial
Chapman, L. M.; Beck, J. C.; Wu, L.; Reisman, S. E. J. Am. Chem. Soc. 2016, 138, 9803.
Pd(OAc)2, Ag2CO3, 72%Me
Me
O
NH N
H
Me
Me
O
NH N
O
O
O
O
I
Me
Me
O
Key structure of psiguadial
Decarboxylative Alkenylation in the Total Synthesis of (+)-Dihydro-β-erythroidine
Clementson, S.; Jessing, M.; Pedersen, H.; Vital, P.; Kristensen, J. L. J. Am. Chem. Soc. 2019, ASAP
[PdCl(allyl)]2, S-Phos, 110 oC
(+)-Dihydro-β-erythroidine
NTBSO
TfO
H
MeO
NTBSO
H
MeO
NC
NO
H
MeO
OHCl, one pot
KO
O
CN
54% yield
Palladium-Catalyzed Decarboxylative Coupling of Cyanoacetate Salts with ArX
Shang, R.; Ji, D.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem. Int. Ed. 2011, 50, 4470.
[PdCl(allyl)]2, S-Phos, 120 oC
83% yield 82% yield 71% yield
OTf
85% yield
CNKOOC CN
CN
OMe
CN
MeO2C
MeMe
CN
Me
ClCN
F3C
Total Synthesis Enabled by Cross-Coupling
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Outline
Pd
Iron-Catalyzed Cross- Coupling in Total Synthesis
Fe
Copper-Catalyzed Cross-Coupling in Total Synthesis
Cu
Nickel-Catalyzed Cross- Coupling in Total Synthesis
Ni
Iron-Catalyzed Cross-Coupling in Total Synthesis
Kumada type coupling
R ArXMgBr R Ar
Fe
R = alkyl X = Br, Cl, OTf, SPh, SO2R
Iron-Catalyzed Cross-Coupling in the Total Synthesis of (R)-(+)-muscopyridine
Scheiper, B.; Glorius, F.; Leitner, A.; Furstner, A. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11960.Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308.
N OTfClBrMg
Me
Fe (5 mol%), 0 oC, 20 minNCl
Me
OFe
N
O
N
tBu
tButBu
tBu Cl
BrMg
Fe (5 mol%), 0 oC, 30 min
N
Me
64% two steps
N
Me
(R)-(+)-muscopyridine
Iron-Catalyzed bis-Methylation in the Total Synthesis of Cylindrocyclophane A
K. C. Nicolaou, Y.-P. Sun, H. Korman, D. Sarlah, Angew. Chem., Int. Ed. 2010, 49, 5875.
MeMgBr
Fe(acac)3 (30 mol%), 0 oC
OTf
n-C4H9
n-C4H9
OTf
MeO OMe
OMeMeO
H
HMe
n-C4H9
n-C4H9
Me
MeO OMe
OMeMeO
H
H
80%
Me
n-C4H9
n-C4H9
Me
HO OH
OHHO
H
HHO
OH
Cylindrocyclophane A
Iron-Catalyzed Ring-Opening/Cross-Coupling in the Synthesis of Pateamine A
Sun, C.-L.; Fürstner, A. Angew. Chem., Int. Ed. 2013, 52, 13071.Zhuo, C.-X.; Fürstner, A. Angew. Chem., Int. Ed. 2016, 55, 6051.Zhuo, C.-X.; Fürstner, A. J. Am. Chem. Soc. 2018, 140, 10514.
MeMgBr
Fe(acac)3
64%
N
SOH
OTBDPS
OO
O
Me
O
N
SOH
OTBDPS
OO
CO2H
Me Me
N
S
O
OO
Me
Me
O
R
Pateamine A
O O
RMe
FeLn
proposed intermediate
Iron-Catalyzed Cyclopropylation in the Synthesis of Pharmaceutical Ingredient
C. Risatti, K. J. Natalie, Z. Shi and D. A. Conlon, Org. Process Res. Dev. 2013, 17, 257.
Fe(acac)3 (5 mol%), 0 oC
96%
MgBrN MeCl
CF3
N Me
CF3
N
OF
H Me
N
CF3
Cl
NK1/serotonin receptor antagonistBMS
Total Synthesis Enabled by Cross-Coupling
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Outline
Pd
Iron-Catalyzed Cross- Coupling in Total Synthesis
Fe
Copper-Catalyzed Cross-Coupling in Total Synthesis
Cu
Nickel-Catalyzed Cross- Coupling in Total Synthesis
Ni
Copper-Catalyzed Cross-Coupling in Total Synthesis
Copper catalysis C-X bond formation
R NuHX R Nu
Cu
X = Cl��%U��,��%�2+��
Ullmann-type Coupling Chan-Lam-Evans-type Coupling
X
R3
R2
R1
X B(OH)2
R3
R2
R1
B(OH)2
N-nucleophileNH
NH2
O
NH2
NH
O-nucleophile ROH ArOH RCOOH
other-nucleophile RSH ArSH CF3 CN
Copper-Catalyzed Cross-Coupling in Total Synthesis
Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459 Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189;
1) CuI, K2CO32) SOCl2
martinellic acid
I
I CO2Me
H2NOH
72%
CO2Me
NH
OH
I
NH
N
HO2C
HN
HN
Me
Me
HN
HN
NH
Me
Me
Copper-Catalyzed Cross-Coupling in Total Synthesis
Kanakis, A. A.; Sarli, V. Org. Lett. 2010, 12, 4872.
OMe O
N
Br
Ts O
NH
OMe
Cu(OAc)2, DBU
43%
OMe O
NTs
O
N
OMe
OH O
HN
O
N
OH
Cl
Cl
Cl
Cl
Marinopyrrole A
Copper-Catalyzed Cross-Coupling in Total Synthesis
Salih, M. Q.; Beaudry, C. M. Org. Lett. 2013, 15, 4540.
CuI, proline, K3PO4
Myricatomentogenin
24%
Br
OMe
Me
O O
OMe
OH
Me
Me
OMe
Me
O
OMeO
O
Me Me
BCl3, 44%
HO
O
OHMeO
O
Copper-Catalyzed Cross-Coupling in Total Synthesis of Peptides
Li, H.; Tsu, C.; Blackburn, C.; Li, G.; Hales, P.; Dick, L.; Bogyo, M. J. Am. Chem. Soc. 2014, 136, 13562.
BocNH
HN
NH
O
O
O
�+2��B
HN
Me
OH
Cu(OA)2, MeOH Et3N, rt Boc
NH
HN
NH
O
O
O
O
HN
Me
HCl
H2N
HN
NH
O
O
O
O
HN
Me
Copper-Catalyzed Cross-Coupling in the Total Synthesis of Paliurine F
M. Toumi, F. Couty and G. Evano, Angew. Chem., Int. Ed. 2007, 46, 572.
NBoc
OH
OTBSOMe
OI
CuI, Phen, Cs2CO3
75%
OMe
O
NBoc
O
OTBS
OMe
NBoc
O
OI
HN
Me
O
NH2
NH HNMe Me
CuI
70%
OMe
NBoc
O
O
HN
Me
ONH
Core structure of Paliurine F
Copper-Catalyzed Cross-Coupling in the Total Synthesis of Paliurine F
M. Toumi, F. Couty and G. Evano, Angew. Chem., Int. Ed. 2007, 46, 572.
OMe
NBoc
O
OI
HN
Me
O
NH2
NH HNMe Me
CuI
70%
OMe
NBoc
O
O
HN
Me
ONH
Core structure of Paliurine F
OMe
NBoc
O
O
HN
Me
O
NH221%
OMe
NBoc
O
O
HN
Me
ONH
Core structure of Paliurine F
PdCl2, CuCl2
aza-Wacker reaction
Previous route
Copper-Catalyzed Cross-Coupling in the Synthesis of Nicergoline
Moon, P. J.; Yin, S. K.; Lundgren, R. J. J. Am. Chem. Soc. 2016, 138, 13826.
N
Me
NMe
O
O
N
BrH
MeO
Me
N
Me
NMe
O
O
N
H
MeO
Me
O
OEt
Nicergoline
1) PdCl2MeCN2, dippf, B2(neop)2, 95%
2) Cu(OTf)2, Et3N, 57%
O
OEtHOOC
Copper-catalyzed decarboxylative C-C bond formation
Copper-Catalyzed Decarboxylative Arylation of Malonate
Moon, P. J.; Yin, S. K.; Lundgren, R. J. J. Am. Chem. Soc. 2016, 138, 13826.
Cu(OTf)2, Et3N, air, rt
75% yield
B(neop)2
HOOC
O
OEt
O
OEt
O
OEt
Ac
67% yield
NO
OEt
54% yield
O
OEt
Br
F
68% yield
O
OEt
NO2
47% yield
NO
OEtBr
Cl
84% yield
O
NPh2
I
58% yield
O
Br
N
77% yield
NO
OEt
F3C
Total Synthesis Enabled by Cross-Coupling
Palladium-Catalyzed Cross-Coupling in Total Synthesis
Outline
Pd
Iron-Catalyzed Cross- Coupling in Total Synthesis
Fe
Copper-Catalyzed Cross-Coupling in Total Synthesis
Cu
Nickel-Catalyzed Cross- Coupling in Total Synthesis
Ni
Nickel-Catalyzed Cross-Coupling in Total Synthesis
C-C bond formation
R1 R2YX R1 R2
Ni
X = Br, I, B(OR)2, COOH Y = Cl, Br, I, OTf
Nozaki-Hiyama-Kishi reaction
NiX
O
R
Cr
R
OH
Nickel-Catalyzed Cross-Coupling in Total Synthesis
� First Nickel-mediated reductive coupling—Farben, 1943
Cl
MeMe
Me
Ni(CO)4, MeOH, reflux, 80%
I.G. Farben. Belgian Patent 448884. February 27, 1943; Chem. Abstr. 1947, 41, 6576.
Corey, E. J.; Hamanaka, E. J. Am. Chem. Soc. 1964, 86, 1641.Corey, E. J.; Hamanaka, E. J. Am. Chem. Soc. 1967, 89, 2758.
Br
Me
MeBr Me
Me
Ni(CO)4, NMPMe
MeMe
MeMe
MeMe
Me
(PhS)2, hv
� Corey’s synthesis of Humulene
Nickel-Catalyzed Cross-Coupling in Total Synthesis
� First Nickel-mediated reductive coupling—Farben, 1943
Cl
MeMe
Me
Ni(CO)4, MeOH, reflux, 80%
I.G. Farben. Belgian Patent 448884. February 27, 1943; Chem. Abstr. 1947, 41, 6576.
Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89, 2755.
� Corey’s synthesis of epi-β-santalene
Me
I
DMF, 90%
NiBr2
Me Me
2
Me
Me
Me
epi-β-santalene
Nickel-Catalyzed Cross-Coupling in Total Synthesis
Chen, W.-W.; Zhao, Q.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 1072.
OMe
MeO
MeO
Br O
H
NiCl2(PPh3)2, Bu4Ni, Zn
67%, 68% ee
OMe
MeO
MeO CHO
MeO
MeO
OMe
CHO
O
OP N N Ph
MeO
MeO
MeOMeO
MeO
OMe
OH
Me
isoschizandrin
Nickel-Catalyzed Cross-Coupling in Total Synthesis
Watson, A. T.; Park, K.; Wiemer, D. F.; Scott, W. J. J. Org. Chem. 1995, 66, 5102.
MeMe
I
Me
H
BrMg
OMe
OMe
NiCl2(dppf) (20 mol%), 0 oC
44%
MeMe
Me
H
MeO
OMesp2-sp3 coupling
MeMe
Me
H
HO
OH
arenarol
Nozaki-Hiyama-Kishi Reaction in the Total Synthesis of Palytoxin
Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644
OO
I
Me
MeMe
Me OAc
O
OBn
BnO OBnOAc
H
O
MeO
O
OBn
BnO OBnOAc
OH
MeO OO
Me
MeMe
MeAcO
86% yield
NiCl2, CrCl3
Nozaki-Hiyama-Kishi Reaction in the Total Synthesis of Palytoxin
Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644
Ni(0)
OO
I
Me
MeMe
Me OAc
oxidative addition OO
NiII
Me
MeMe
Me OAc
CrCl3
OO
CrIII
Me
MeMe
Me OAc
O
OBn
BnO OBnOAc
H
O
MeO
carbonyl addition
transmetallation
O
OBn
BnO OBnOAc
OH
MeO OO
Me
MeMe
MeAcO
86% yield
Nozaki-Hiyama-Kishi Reaction in the Total Synthesis of Eleutherobin
Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 6563.
NiCl2 (1.0 eq), CrCl3 (5.0 eq)TBDPSO
O
O
H
MeMe
MeBr
OTBDPS
O
OHMeMe
Me
74%
O
O
MeMe
Me
OMeN
N
Me
OMe
O
O
OAc
OH
OH
Eleutherobin
Nozaki-Hiyama-Kishi Reaction in the Total Synthesis of Chromodorolide
Tao, D. J.; Stutskyy, Y.; Overman, L. E. J. J. Am. Chem. Soc. 2016, 138, 2186.
NiCl2 (3 mol%)CrCl2 (100 mol%)
66%, dr >20:1
Me
Me MeH
I
O
O
O
Me
Me
H
MeO2C
OBn
Me
Me MeH
O
OHO Me
Me
MeO2COBn
Core structure of chromodorolide
N
O
MsHN
Me
MeMe
Nozaki-Hiyama-Kishi Allylation in Total Synthesis
Zhu, L.; Tong, R. Org. Lett. 2015, 17, 1966.
CrCl2 (20 eq)
95%, single isomer
OCO2Me
Me
TESO
Me
Me
OAc
Br
OTBS
CHO
O
Me
TESO
Me
Me
OAc
OTBS
HO
CO2Me
O
Me
OH
Me
Me
OAc
OTBSO
O
uprolide F
Cr
OR1
R2
Zimmerman-Traxlertransition state
Diastereoselective Allylation of Aldehydes
Schwarz, J. L.; Schafë rs, F.; Tlahuext-Aca, A.; Lückemeier, L.; Glorius, F. J. Am. Chem. Soc. 2018, 140, 12705.
95% yield, dr >19:1
H
OCr Ph
OH
homoallylic alcohol
Ph
OHOMe
OMe
CrCl2 (10 mol%)
PhN
OH
85% yield, dr >19:1
Ph
PhNPh2
OH
90% yield, dr >19:1
Ph
NPh2
OH
56% yield, dr >19:1
NPh2
OH
82% yield, dr >19:1
NBoc
NPh2
OH
86% yield, dr >19:1
I
Nickel-Catalyzed Alkyne-Aldehyde Reductive Coupling in Total Synthesis
Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297
O
*O
O
O
Me
HO
Me
Me
Me
amphidinolide T1
Ph
MeR H
O Ni(cod)2 (5 mol%), Bu3P (20 mol%)Et3B 2.0 eq, rt Ph Ph
Me
OH
Ph
MeNi(cod)2 (5 mol%), Bu3P (20 mol%)
Et3B 2.0 eq, rt Ph
Me
O R OH
R
Decarboxylative Coupling via Nickel Catalysis in Total Synthesis
Merchant, R. R.; Oberg, K. M.; Lin, Y.; Novak, A. J. E.; Felding, J.; Baran, P. S J. Am. Chem. Soc. 2018, 140, 7462.
CO2Me
Me
O
Me
OTES
O
CO2Me
Me
O
Me
COOHHH
1) PPTS2) TPAP, NMO 1) DIC, TCNHPI
ClZnMe
MeNi
CO2Me
Me
O
Me
HH
OTES
Me
Me
2)
3) TiCl2, PdCl2, Zn, CH2I2
28% (5 steps)
Me
O
Me
HH
Me
MeO
O
MeMe
OH
subglutinol B
4 steps
Decarboxylative Coupling via Nickel Catalysis in Total Synthesis
Merchant, R. R.; Oberg, K. M.; Lin, Y.; Novak, A. J. E.; Felding, J.; Baran, P. S J. Am. Chem. Soc. 2018, 140, 7462.
Me
O
Me1) DIC, TCNHPI
ClZnMe
MeNi
OTES
2)
Me
O
Me
Me
Me
O
O
MeMe
OH
higginsianin A
HO
COOH
Me
O
MeOTES
HO
H
Me
Me
dr 1.3:1single isomer
H
Me
O
Me
HH
Me
MeO
O
MeMe
OH
subglutinol B
42%
Decarboxylative Coupling via Nickel Catalysis in Total Synthesis
Zhang, J.; Li, Z.; Zhuo, J.; Cui, Y.; Han, T.; Li, C. J. Am. Chem. Soc. 2019, 141, 8372.
PhZnCl
Me
O
O O
O N
O
O OO
Me
H
Ph
Me
TBSO OTBS OBn
COOHMe
HO OH O
O
O
longirabdiol
Ni or Fe
Me
O
O
Ph
direct coupling
Decarboxylative Coupling via Nickel Catalysis in Total Synthesis
Zhang, J.; Li, Z.; Zhuo, J.; Cui, Y.; Han, T.; Li, C. J. Am. Chem. Soc. 2019, 141, 8372.
PhBr
Me
O
O O
O N
O
O OO
Me
H
Ph
Zn
60% yield, dr 4.2:1
Me
TBSO OTBS OBn
COOHMe
HO OH O
O
O
longirabdiol
CuCl2 (5 mol%)
PCy2
Me2N
DavePhos
Me
Br
O
OH (7 mol%)