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Career-in-Review: Neil K. Garg
Zhen Liu 01/07/2016
Prof. Neil K. Garg
1996–2000 New York University (Sc. B.)
2000–2005 Caltech (Ph. D.)Supervisor: Brian M. Stoltz
2005–2007 UC Irvine (Postdoc)Supervisor: Larry E. Overman
2007–2012 Assistant Professor (UCLA)
2012–2013 Associate Professor (UCLA)
2013–present Full Professor (UCLA)
Selected Awards 2010 Thieme Chemistry Journal Award2010 NSF CAREER Award2015 Arthur C. Cope Scholar Award2016 Tetrahedron Young Investigator Award……
Contents
– Aryne Chemistry
– Interrupted Fischer Indolization
– Metal-Catalyzed Cross-Coupling Reactions
– Summary and Outlook
3
Contents
– Aryne Chemistry
– Interrupted Fischer Indolization
– Metal-Catalyzed Cross-Coupling Reactions
– Summary and Outlook
4
Aryne Chemistry
5
Benzyne Electrophilic Character
Hoffmann, R.; Imamura, A.; Hehre, W. J. J. Am. Chem. Soc. 1968, 90, 1499.
Aryne Chemistry
6
Goetz, A. E.; Bronner, S. M.; Cisneros, J. D.; Melamed, J. M.; Paton, R. S.; Houk, K. N.; Garg, N. K. Angew. Chem. Int. Ed. 2012, 51, 2758.
Three Categories
Aryne Chemistry
7Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74, 8842.
X strong base TMSOTf
F
OH iPrN=C=O O NHiPr
O
i. TMEDA, TBSOTf
ii. TMEDA, nBuLi
O N
OTBS
iPr
LiN N
TMSClacidic workup
O NHiPr
OTMS
DBU, Et2NH OH
TMS
PhNTf2
66%
OTf
TMS
Himeshima, Y.; Sonada, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
Cl
HO
TMS
TMSO
nBuLi, then Tf2O
86%
Kobayashi, 1983
TMS
TfO
8
Selected Examples
entry trapping agent products yield (ratio)
Me
OH
N3 Bn
NMe
65%
1
2
3
NMe
O
Me
+
NMe
O
Me
80%(3:1)
NMe
+
NNNBn
NMe
NNN
Bn
86%(2.4:1)
Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007.
Aryne Chemistry
NH
BnO
NMe
HO iPrN=C=ONMe
OHN
OiPr
i. TMEDA, TBSOTf
ii. TMEDA, nBuLiNMe
OHN
OiPr
TMSDBU, Et2NH
then PhNTf2 NMe
TfOTMS
i. NaH, MeI
ii. H2, Pd/C94%, 2 steps
90%
84% 88%
F
NMe
9
Aryne Chemistry
Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007.
NH
BnO
NMe
HO iPrN=C=ONMe
OHN
OiPr
i. TMEDA, TBSOTf
ii. TMEDA, nBuLiNMe
OHN
OiPr
TMSDBU, Et2NH
then PhNTf2 NMe
TfOTMS
i. NaH, MeI
ii. H2, Pd/C94%, 2 steps
90%
84% 88%
F
NMe
NMe
OHN
OiPr
DBU, Et2NH
then PhNTf2 NMe
TfO
88%TMS TMS
NMe
OO
TBAF92%
CsF73%
NH2
NMe
HN
NMeN
H
+ (3:1)
Aryne Chemistry—Aryne Distortion Model
10
Im, G-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.
11
Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 15798.
Aryne Chemistry—Aryne Distortion Model
12
Goetz, A. E.; Garg, N. K. Nat. Chem. 2013, 5, 54.
Aryne Chemistry
N
XTMS
OTf
N
XCsFTrapping
agent N
X R
Selected Examples
entry trapping agent products yield (ratio)
HN
N
1
2
+
X = H1.9:1(77%)
X = Br1:5.8(64%)
N
+N
O
MeN
XNMe
N
NMe
X
Ph
tBu
O
X
PhtBu
N
ONtBu X = H
1.9:1(76%)
X = Br1:3.3(60%)
X
Ph
N
TMSOTf
N
CsFTrapping
agent N
R
entry trapping agent products yield (ratio)
HN
N
3
4
+
X = H1.9:1(77%)
X = OSO2NMe2>15:1(64%)
MeN
NMe
Ph
tBu
O
X = H1.9:1(76%)
X = OSO2NMe210.7:1(61%)
X X X
X N
NMe
X
N
+N
O
X
PhtBu
N
ONtBu
X
Ph
Cycloalkyne Chemistry
13
Medina, J. M.; McMahon, T. C.; Jiménez-Osés, G.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 14706.
OTf
TMS
OTf
TMS
CsFTrappingagent
X
Y
CsFTrappingagent
X
Y
N
OTf
TMS
CsFTrappingagent
N N
X
YCbz Cbz Cbz
orN
Nuc
Cbz
McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082.
14
Cycloalkyne Chemistry
McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082.
entry trapping agent products yield (ratio)
N
2
3
99%(>20:1)
N
+N
OPh
tBu
O
PhtBu
Cbz
tBu
PhON
N
84%(12.7:1)
N
OTf
TMS
CsFTrapping
agentN
X
YCbz Cbz
orN
Nuc
Cbz
1 78%(>20:1)
Selected Examples
N NHN
N
Cbz
N
NH
O
N
N
Cbz
O
Cbz
15
Applications of Aryne Chemistry
NMe
OO
SCNH
MeMe
MeCl
NMe
OO
CNH
MeMe
MeO
O
(–)-N-methylwelwitindolinoneC isothiocyanate
N-methylwelwitindolinoneD isonitrile
NH
NO
HNMe
MeMe OH
(–)-indolactam V
NMe
OO
SCNH
MeMe
MeCl
(–)-N-methylwelwitindolinoneB isothiocyanate
NH
MeMe
OH
Me Me
tubingensin A
NH
NO
HNMe
MeMe OH
(–)-pendolmycin (–)-lyngbyatoxin AMeMe
NH
NO
HNMe
MeMe OH
Me
MeMe(–)-teleocidin A-2
NH
NO
HNMe
MeMe OH
Me
MeMe
J. Am. Chem. Soc. 2011, 133, 15797. Angew. Chem. Int. Ed. 2013, 52,12422. J. Am. Chem. Soc. 2014, 136, 14710. J. Am. Chem. Soc. 2014, 136, 3036.
J. Am. Chem. Soc. 2011, 133, 3832. Chem. Sci. 2014, 5, 2184. Chem. Sci. 2014, 5, 2184. Chem. Sci. 2014, 5, 2184.
(–)-N-Methylwelwitindolinone C Isothiocyanate—Retrosynthetic Analysis
16
Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.
NMe
OO
SCNH
MeMe
MeCl
(–)-N-methylwelwitindolinoneC isothiocyanate
NMe
OO
HH
MeMe
MeCl
NMe
OH
H
MeMe
MeRO
NMe
O
H
MeMe
MeRO
NMe
BrO
Me
Me
ORMe
Late-StageBridgehead
Functionalization
IndolyneCyclization
NMe
Br O
OHMe
MeMe
17
Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.
(–)-N-Methylwelwitindolinone C Isothiocyanate—Total Synthesis
OMe
Me(S)-carvone
MgBr
CuBr•SMe2
O
Me
Me
OPivMe
80%C2
i. K2CO3, MeOH
ii. I2,
NMe
Br
54%, 2 stepsNMe
Br
C3
O
Me
Me
OPiv
C1
Me
O
Me
Me
OPiv
C1
Me
TBSCl, imidazoleO
OHMe
MeMe
NMe
Br O
OTBSMe
MeMe
C4
90%
46%
NaNH2
NMe
OH
H
MeMe
MeOTBS
+
NMe
OMeMe
Me OTBS
2.5 : 1
C5 C6
18
(–)-N-Methylwelwitindolinone C Isothiocyanate—Total Synthesis
Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.
NMe
OH
H
MeMe
MeOTBS
C5
i. TBAFii. Dess–Martin [O]
95%, 2 stepsNMe
OH
H
MeMe
MeO
C7
74%, 2 stepsNMe
OH
H
MeMe
Me
C8
SnMe3
75%
CuCl2
NMe
OH
H
MeMe
Me
C9
Cl
i. NBSii. HCl, 80 °C
89%, 2 stepsNMe
OH
H
MeMe
Me
C10
Cl
OH
i. KHMDS; –78 °C, Comins' reagentii. (Me3Sn)2, Pd(PPh3)4, LiCl
i. iBu2AlHii. Cl3C(O)NCO; K2CO3, MeOH
86%, 2 steps NMe
MeMe
C11
O
H
ClMe
HHOH2N
O33% yield +
25% recovered C10
AgOTf, PhI(OAc)2 bathophenanthroline
NMe
MeMe
C12
O
H
ClMe
HOO
HN
i. Ba(OH)2•8H2O
48%, 2 steps NMe
OH2N
H
MeMe
Me
C13
Cl
OH
77%DMAP, 90 °C
NMe
OO
SCNH
MeMe
MeCl
(–)-N-methylwelwitindolinoneC isothiocyanate
N O
S
O N
ii. IBX, TFA
– Aryne Chemistry
– Interrupted Fischer Indolization
– Metal-Catalyzed Cross-Coupling Reactions
– Summary and Outlook
19
Contents
Fischer Indole Synthesis
20
Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241.
NH
NH2+ O
R1
R2 H+R1
R2
NH
Fischer, 1883
NH
N
R1R2
H+
NH
NH
R1R2
NHNH
R1R2
H+
NH2
R1R2
NH2NH2
HR1
NH2
R2
R1
R2
NH
– H+
– NH3
Interrupted Fischer Indolization
21
NR
NH2+ H2O, AcOH
R'XHO
R''R'
NR
X
R''
H
X = O, NTs
XHO
R''H+n
O
R'' n
H
XH
Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458.
HXR''
NH2
H
– NH3
NH2
NH
HNH3
R'' HX
NH
R'' HX
R' R' R'NR
X
R''
H
n
NH2NH2
HXR''R''
NHNH
HXR''
NNH
HXH+ H+
R'
n nn
nn
R'R'R'
22
NMe
NMeO
O
HNPh
H
Me
(+)-phenserineAlzheimer's therapeutic
NH
NTsH
NO
O
Br
tetracyclic indoline coreof perophoramidine
NHN
Br
Cl
Cl
NMeN
perophoramidine
HN
NOHC
CO2Me
MeO
H
H
(±)-Aspidophylline A
HN
N
CO2Me
MeO
H
H
Picrinine
N
N
CO2Me
Me
H
H
Strictamine
Applications of Interrupted Fischer Indolization
J. Org. Chem. 2012, 77, 725. Org. Lett. 2012, 14, 4556.
J. Am. Chem. Soc. 2011, 133, 8877. J. Am. Chem. Soc. 2014, 136, 4504. J. Am. Chem. Soc. 2014, 136, 4504.
(±)-Aspidophylline A—Retrosynthetic Analysis
23
Zu, L.; Ben, W. B.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877.
HN
NOHC
CO2Me
MeO
H
H
(±)-Aspidophylline A
HN NH2
+O
RNH
H MeH CO2Me
HO
CO2Me
RNRO
ROX
MeRNH
H MeCO2Me
RORO
RN
OO
CO2HCO2H
Late-Stage Interrupted Fischer Indolization
Heck Cyclization
24
TsNH
H MeCO2Me
O
O
TsNH
H MeH CO2Me
HO
HN
NTs
CO2Me
MeO
H
Hphenylhydrazinevarious acids
A9
A10A12
(±)-Aspidophylline A—Total Synthesis
NBn
BnO
O
O OO
PhMe, reflux
BnN
BnOO
O
O
OHH
BnN
OO
HN
MeOO
MeO
CO2Me
NHTsMeO
MeO
CO2Me
TsNMeO
MeOI
Me TsNH
H MeCO2Me
MeOMeO
TsNH
H MeCO2Me
OTsNH
H MeCO2Me
O
Cu2O, H2O
150 °C, microwave
i. HC(OCH3)3, heat p-TsOH, MeOH
ii. Na, NH3
i. nBuLi, TsClii. K2CO3, MeOH
IMeBr
Pd(PPh3)4
MeCN, 70 °C
dr 8:1
i. FeCl3•6H2O
ii. In, EtOH, 90 °C aq. NH4Cl
50–69% 87%, 2 steps
90%, 2 steps70%
95–99%
90%
i. LiHMDS, DMPUii. allyl iodide
AI A2 A3 A4
A5
A4
A6 A7
A8 A9
75%
NMe
MeMe MeMe
25
TsNH
H MeCO2Me
O
TsNH
H MeCO2Me
O
PivO N
NTs
CO2Me
MePivO
H
Hphenylhydrazine
various acids
A9
A11A13
(±)-Aspidophylline A—Total Synthesis
NBn
BnO
O
O OO
PhMe, reflux
BnN
BnOO
O
O
OHH
BnN
OO
HN
MeOO
MeO
CO2Me
NHTsMeO
MeO
CO2Me
TsNMeO
MeOI
Me TsNH
H MeCO2Me
MeOMeO
TsNH
H MeCO2Me
OTsNH
H MeCO2Me
O
Cu2O, H2O
150 °C, microwave
i. HC(OCH3)3, heat p-TsOH, MeOH
ii. Na, NH3
i. nBuLi, TsClii. K2CO3, MeOH
IMeBr
Pd(PPh3)4
MeCN, 70 °C
dr 8:1
i. FeCl3•6H2O
ii. In, EtOH, 90 °C aq. NH4Cl
50–69% 87%, 2 steps
90%, 2 steps70%
95–99%
90%
i. LiHMDS, DMPUii. allyl iodide
AI A2 A3 A4
A5
A4
A6 A7
A8 A9
75%
NMe
MeMe MeMe
26
(±)-Aspidophylline A—Total Synthesis
HN
NOHC
CO2Me
MeO
H
H
(±)-Aspidophylline A
TsNH
H MeCO2Me
O
A9
NaBH4
TsNH
H MeCO2Me
A14
HO
98%
i. OsO4, NaIO4
ii. NaBH4
83%, 2 steps
TsNH
H MeCO2Me
A15
HO
HO
i. H2SO4
ii. Dess–Martin [O]
76%, 2 steps
TsNH
H Me
A16
O
O O
TFA
HN NH2
N
NTs
Me
H
H
A17 (not isolated)O
O
HN
NTs
CO2Me
MeO
H
H
A12
K2CO3
70%(one pot, from A16)
i. Mg, NH4Cl
ii. formic acid, DIC, DMAP
68%, 2 steps
– Aryne Chemistry
– Interrupted Fischer Indolization
– Metal-Catalyzed Cross-Coupling Reactions
– Summary and Outlook
27
Contents
C–O Bond Activation
28
Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422.
ORtransition
metal catalyst MORL
LR' R'M' Ar Ar
R'
C-C Bond Formation
Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748.
Ar OPivB(OH)2
R+Ar
RNiCl2(PCy3)2, K3PO4
Ar1 OR +NiCl2(PCy3)2, K3PO4
Ar2 B(OH)2 Ar1 Ar2
R = C(O)NEt2, CO2tBu, SO2NMe2
toluene, heat, 24 h
toluene, heat, 24 h
Traditionally difficult when anything other than OTf
29
Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.
O NMe2
O
C–O Bond Activation
30
Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.
C–O Bond Activation
31
Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg, N. K. Angew. Chem. Int. Ed. 2011, 50, 2171.
Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Fine Nathel, N. F.; Hong, Xin; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766.
Hie, L.; Ramgren, S. D.; Mesganaw, T.; Garg, N. K. Org. Lett. 2012, 14, 4182.Fine Nathel, N. F.; Kim, J.; Hie, L.; Jiang, X. Y.; Garg, N. K. ACS Catal. 2014, 4, 3289.
OSO2NMe2R + HN R'
R''
[Ni(cod)2]SIPr•HClNaOtBu
dioxane, heat
NR
R'
R''
OCONEt2R + HN R'
R''
[Ni(cod)2]SIPr•HClNaOtBu
dioxane, heat
NR
R'
R''
X + HN R'
R''
NiCl2(DME)SIPr•HCl
NaOtBu, Ph–B(pin)2-Me-THF, heat
(Het)Ar Ar(Het) NR'
R''
X = Cl or OSO2NMe2green solvent
C–O Bond Activation
N NiPr
iPr
iPr
iPr
Cl
SIPr•HCl
32
Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918.
OC(O)NEt2 toluene, heat(Het)Ar (Het)Ar1 H
NiCl2(PCy3)TMDSO, K3PO4 O SiSi Me
Me
Me
Me
H HTMDSO
R'OC(O)NEt2
X
carbamate-directedfunctionalization reductive cleavage
of carbamates
R'OC(O)NEt2 cine substitution
R'
X X = C(O)R, Alkyl, Silyl ......
C–O Bond Activation
33
Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79.
Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75.
Ar N
OR2
R1
R1, R2 ≠ H
+ HO R
[Ni(cod)2]SIPr
toluene, heat Ar OR
O+ HN R2
R1
(Het)Ar1 N
OR
Boc+
(Het)Ar2 [Ni(cod)2]SIPr
K3PO4, H2Otoluene, heat
(Het)Ar1 (Het)Ar2
O+ HN R
Boc
B(OH)2
or
(Het)Ar2 B(pin)
R = Me or Bn
C–N Bond Activation
34
[Ni(cod)2], SIPrK3PO4, H2Otoluene, heat
N
O
N
OBn
H Boc
Bn
O
(pin)B
O
N
OBn
HO
[Ni(cod)2], SIPr, toluene, heat
O
O
O
O
Me
MeMei. Boc2O, DMAP, CH3CN, rt.A
C
OH
Me
MeMe
(–)-mentholB
NH
O
O
O
Me
Me MeBni. Boc2O, DMAP, CH3CN, rt.ii. A, [Ni(cod)2], SIPr, K3PO4
H2O, toluene, heat
ii. B, [Ni(cod)2], SIPrtoluene, heat
C–N Bond Activation
35
C–N Bond Activation
Other Metal-catalyzed Coupling Reactions
36
Mesganaw, T.; Im, G-Y. J.; Garg, N. K. J. Org. Chem. 2013, 78, 3391.
Silberstein, A. L.; Ramgren, S. D.; Garg, N. K. Org. Lett. 2012, 14, 3796.
Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15, 3950.
Ramgren, S. D.; Garg, N. K. Org. Lett. 2014, 16, 824.
OAc
Pd(OAc)2PPh3 resin, Et3N
EtCN, 105 °C
diphenylhexatriene
• gram scale• useful compound (fluorescent probes)
ROR' FeCl2
SIMes•HCl
DCM-THF+ ClMg alkyl R
alkyl
R' = OCONEt2 or OSO2NMe2
NNMesMes
Cl
SIMes•HCl
X +NiCl2(PCy3)2
K3PO42-Me-THF or tamyl alcohol
heat(Het)Ar1 (Het)Ar1
X = Br, I, Cl or OSO2NMe2 green solvent
(Het)Ar2 B(OH)2 (Het)Ar2
X +Pd(PPh3)4
KFDCM, heat
(Het)Ar
X = Br, I or OTf
O
MeTMS
O
Me(Het)Ar
Summary
37
– Aryne Chemistry • Aryne Distortion Model• Alkaloid Total Synthesis (e.g., (–)-N-methylwelwitindolinone C Isothiocyanate)
– Interrupted Fischer Indolization • Methodology Development• Alkaloid Total Synthesis (e.g., (±)-Aspidophylline A)
– Metal-catalyzed Cross Coupling Reactions • C–O Bond Activation• C–N Bond Activation
Outlook and Possible Future Directions
38
• Total Synthesis and Drug Development
• Develop Ni(II)-Catalyzed C–N Bond Activation Reactions
• Kinetic Study of the C–N Bond Activation Reactions
• Photoredox Chemistry
Acknowledgements
• Keary
• All Group members
39
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