Electrophilic ‘Umpolung’ Cyclizations of Alkynes Synthesis ...
Cyclizations,of,Ynamides to,...
Transcript of Cyclizations,of,Ynamides to,...
Cyclizations of Ynamides to Generate Novel Ring Structures
John Milligan Frontiers of Chemistry SeminarWipfGroup Meeting July 23, 2016
1
N EWGR
TsNN
H Ph
OO
BocNMe CO2Me
NBn
Ts
NTs
O
Cl Ph
NBn
Ts
H
O
OHNO
CO2Me
R1N TsMe
R2
R3
MeO2C
MeO2C
N
CO2Et
O
NBoc
NO
NTs
H
NTs
OAc
n-BuPh
Ynamides
2
NR R
enamines:
First isolated in 1936
Storied history
Well understood reactivity
Ynamides
3
NNR R
enamines:
First isolated in 1936
Storied history
Well understood reactivity
RR
ynamines:
First isolated in1958
Infrequent and sporadic in theliterature
Major disadvantage:instability toward hydrolysis andpolymerization
Ynamides
4
NNR R
enamines:
First isolated in 1936
Storied history
Well understood reactivity
RR
ynamines:
First isolated in1958
Infrequent and sporadic in theliterature
Major disadvantage:instability toward hydrolysis andpolymerization
N EWGR
ynamides:
First isolated in1972
Of great interest inrecent years
Bench stable!
Synthesis of Ynamides: State of the Art Before 2003• Elimination
• Isomerization
5Janousek, Z.; Collard, J.; Viehe, H. G. Angew. Chem. Int. Ed. 1972, 11, 917Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A. Grebe, T. P. Org. Lett. 2002, 4, 2417
NHMe
OPh
NCl
ClCl
then NaHCO3NMe
NMe2
Ot-BuOK
THF, rt64%
NMe
NMe2
OPh
PhCl
t-BuOK(20 mol %)
THF, rt83%
N Ph
ON Ph
O
Discovery of Cu mediated coupling
6Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368
Zhang, Y.; Husng, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151
Br R2
CuSO4•5 H2O (cat.)1,10-phenanthroline
K3PO4
toluene, 60-95 °CN H
R1
EWGN
R1
EWGR2
Br R2
KHMDS, CuI
pyridine, rtN HR1
EWGN
R1
EWGR2
72003: Hsung and Danheiser each publish Cu-‐mediated ynamide syntheses
0
10
20
30
40
50
60
70
80
90
1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
Occurrence of "Ynamides" in the Literature(SciFinder search, 7/18/16)
Reactivity of Ynamides
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NR1
EWGR2 N
R1
EWG R2
additionto electrophiles
additionof nucleophiles
Major achievements: ca. 2002-‐2010• Hydrofunctionalization• Hydroboration, hydrostannylation, etc.
• Additions• Control of regioselectivity
• Classic alkyne cycloaddition chemistry• [2+2]/[3+2]/[4+2]/[2+2+2]
9DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064-‐5106Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840-‐2859
NR1
EWGR2
R3XN
R1
EWG
X
R3
R2
NR1
EWG
R3
XR2
(depending on nature of R3 and X,as well as conditions)
Where has the ynamide frontier grown in the last 2-‐3 years?
• Development of functional analogs of ynamides:
• Increasing array of additions/hydrofunctionalizations
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Lu, T.; Hsung, R. P. ARKIVOC 2014, 127-‐141Perrin, F. G.; Kiefer, G.; Jeanbourquin, L.; Racine, S.; Perrotta, D.; Waser, J.; Scopelliti, R.; Severin, K. Angew. Chem. Int. Ed. 2015, 54 (45), 13393-‐13396Wang, X.-‐N.; Yeom, H.-‐S.; Fang, L.-‐C.; He, S.; Ma, Z.-‐X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560-‐578
NNH
BocR
Boc
NS
R
O
N RNN
Where has the ynamide frontier grown in the last 2-‐3 years?
• Development of Cycloadditions and Cyclizations: focus of present talk• Cycloadducts of increasing complexity• Novel modes of reactivity/mechanistic aspects• Use of cheap and abundant catalysts/reagents
11Wang, X.-‐N.; Yeom, H.-‐S.; Fang, L.-‐C.; He, S.; Ma, Z.-‐X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560-‐578
What is the overarching problem to which ynamide cyclizations contribute?
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NHRHO
O
Solid phase peptide synthesis:
Established MethodologyNH
O
n
ORO
OR OROR
OROligosaccharide synthesis:
Challenging but a constantlydeveloping field
OO
OR OOR
OR
n
N
O
O
H
HH
H
N
strychnine
?
Polycyclic, complex molecules:
Strucure dependent, no general set of building blocks
A massive, long lasting problem!
What Paradigms Address this Problem?• Schriber-‐ Diversity Oriented Synthesis: Building Rapid Diversity into new chemical space
• Sharpless-‐ Click Chemistry: Diverse Chemical Function through a few good reactions
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OOOH
HO
N3
N3
OH
HO
N
N
NN
N NR
R
Schriber, S. L. Science 2000, 287, 1964-‐1969.Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-‐2021Burke, M. D. et al. Science 2015, 347, 1221-‐1226.
What Paradigms Address this Problem?• Schriber-‐ Diversity Oriented Synthesis: Building Rapid Diversity into new chemical space
• Sharpless-‐ Click Chemistry: Diverse Chemical Function through a few good reactions
• Burke-‐ “The Synthesis Machine”: Breaking complex molecules into simple building blocks
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OOOH
HO
N3
N3
OH
HO
N
N
NN
N NR
R
X BOO
O
OMeN
A A B C complexmolecule
cyclization/functionalization
Schriber, S. L. Science 2000, 287, 1964-‐1969.Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-‐2021Burke, M. D. et al. Science 2015, 347, 1221-‐1226.
Ynamides: Potential Contributors as Tunable, Reactive Building Blocks• A “building block” approach to to alkaloids and heterocycles
• R’s can be be linked in a variety of ways: many novel cyclic structures are possible 15
R1 NH2
R2
R4XR5X
Cl R3
OR1 N R3
(cyclization/couplingpartners)
R2
OR1 N R3
O
R2
R5R4
Cyclizations of Ynamides
Gold Catalyzed
Intramolecular
Intermolecular
Non-‐Gold Catalyzed
Intramolecular
Intermolecular 16
Part 1A: “Gold Free”, intramolecular• Transition metal catalyzed enyne/diyne cyclizations• Lewis acid mediated cyclizations
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Rh-‐catalyzed asymmetric cyclization
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NO
O
TsNPh
RhClL2(2 mol %)
DCE, 30 °C
95%, 97% ee
TsNN
H Ph
OO
Fc
Fc
FF
F
F
L:
Nishimura, T.; Takiguchi, Y.; Maeda, Y.; Hayashi, T. Adv. Synth. Catal. 2013, 355, 1374-‐1382
Rh-‐catalyzed asymmetric cyclization
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Nishimura, T.; Takiguchi, Y.; Maeda, Y.; Hayashi, T. Adv. Synth. Catal. 2013, 355, 1374-‐1382
NO
O
TsNPh
RhClL2(2 mol %)
DCE, 30 °C
95%, 97% ee
TsNN
H Ph
OO
Fc
Fc
FF
F
F
L:
NO
O
TsNPh
[M]
TsNNR2
H Ph
[M]
Oxidative Rh-‐catalyzed cyclization
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N
[Rh(CO)2Cl]2 (5 mol %)P[OCH(CF3)2]3 (20 mol %)
dioxane, rt, 2 h88%
Ts
NCl
Cl
O
TsN
O
Liu, R.; Winston-‐McPherson, G. N.; Yang, Z-‐Y.; Zhou, X.; Song, W.; Guzei, I. A.; Xu, X.; Tang, W.J. Am. Chem. Soc. 2013, 135, 8201-‐8204.
Anionic rearrangement
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Brioche, J.; Meyer, C.; Cossy, J. Org. Lett. 2013, 15, 1626-‐1629
NBn
TsO
O NHBoc
Me
LiHMDSZnCl2
THF, –78 °C Me NBn
Ts
BocHNCO2Me
1. MeI K2CO3 DMF
2. AgNO3 (5 mol %) acetone, rt 70% (3 steps)
BocNMe CO2Me
NBn
Ts
diastereoselective anionicClaisen rerrangement
Lewis acid mediated cyclization
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Yeh, M-‐C. P.; Shiue, Y.-‐S.; Lin, H.-‐H.; Yu, T-‐Y.; Hu, T.-‐C.; Hong, J.-‐J. Org. Lett. 2016, 18, 2407-‐2410
NTs
Ph FeCl2 (1.1 eq)
THF, 40 °Cdry air N
Ts
O
Cl Ph
Part 1B: “Gold Free”, intermolecular• [2+2] “Ficini” reactions• Lewis/Bronsted acid mediated cyclizations
• Dipolar cycloadditions
• Cyclizations involving azides or diazo compounds 23
R
NEWG
NuE
R
NEWGY Z
X
Ficini [2+2] addition
24
Ficini, J. Tetrahedron 1976, 32, 1449-‐1486
NEt2
via:
THF
O
ONEt2
O
NEt2
Modern ynamide Ficini reactions
25Yuan, Y.; Bai, L.; Nan, J.; Liu, J.; Luan, X. Org. Lett. 2014, 16, 4316-‐4319Enomoto, K.; Oyama, H.; Nakada, M. Chem. Eur. J. 2015, 21, 2798-‐2802
• Facile addition with activated alkene partner:
• Enantioselective addition:
N
Ph
Bn
Ts
H
HNTs Bn
Ph
O
NEt2
O
OMeDCE, 40 °C
then MeOH, rt70%
O
NEt2
O
BF4
NBn
Ts
H
NTs Bn
Cu(OTf)2–BOX ligand(20 mol%)
4Å MS
CH2Cl2, 0 °C97%, 96% ee
O
OHNO
CO2Me
O
OO
NH
MeO2C
Ficini adduct opening
26Wang, X.-‐N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2014,
136, 9802-‐9805Wang, X.-‐N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2015,
137, 5596-‐5601
AlCl3 (0.4 eq)
toluene, 105 °C68%
ON
Bn
Ns
H
HO
NBn
Ns
O
cis-trans cycloheptadieneone
R2NAlCl3
4πringopening
R2N
H
O
1,2-shift
AlCl3
Acid-‐mediated quinoline/pyridine syntheses
27Xie, L.-‐G.; Niyomchon, S.; Mota, A. J.; Gonzalez, L.; Maulide, N. Nat. Commun. 2016, DOI: 10.0138/ncomms10914
Zhang, J. Zhang, Q.; Xia, B.; Wu, J.; Wang, X.-‐N.; Chang, J. Org. Lett. 2016, DOI: 10.1021/acs.orglett.6b
NPh
MeCN
DMF, rt70%
OO TfOH (1.1 eq)
N
NOO
N
MeCN (0.6 eq)
CH2Cl2, rt>95%
Bn
Ts
TMSOTf (0.5 eq)
N
N
NBn
Ts
BnTs
Lewis acids: DA cyclopropaneactivation
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Mackay, W. D.; Fistikci, M.; Carris, R. M.; Johnson, J. S. Org. Lett. 2014, 16, 1626-‐1629
NTs
MeR1
Sc(OTf)3(10 mol %)
CH2Cl2, rt
CO2MeMeO2C
R3R2
R1
N TsMe
R2
R3
MeO2C
MeO2C
via:
R3R2
OMeOO
MeO
LA
N TsMe
R1
Lewis acids: DA cyclopropaneactivation
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Mackay, W. D.; Fistikci, M.; Carris, R. M.; Johnson, J. S. Org. Lett. 2014, 16, 1626-‐1629
NTs
MeC5H11
Sc(OTf)3(10 mol %)
CH2Cl2, rt89%
CO2MeMeO2C
C5H11
N TsMe
MeO2C
MeO2C
1. Na naphthalide THF
2. 3 M HCl, 125 °C
83%, >20:1 dr
C5H11
OOMe
OMe OMe
Dipolar cycloaddition
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Brioche, J.; Meyer, C.; Cossy, J. Org. Lett. 2015, 17, 2800-‐2803.
NO
NBoc
CO2EtN
CO2Et
O
K2CO3
DMF, rtN
Boc
70%
via:
N
O
NBoc
EtO2C
Vinylketene cascade
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Willumstad, T. P. Bordreau, P. D.; Danheiser, R. L. J. Org. Chem. 2015, 80, 11794-‐11805.
N2O
R1
R2 hνCH2Cl2, rt;
toluene, 110 °C
R3 NR4
R5
NCO2t-Bu
CO2t-Bu
R4
R5
HO
R2R1
R3
1. Tf2O, DMAP CH2Cl2; TFA
2. I2, NaHCO3, MeCN, rt
N R4HO
R2R1
R3
R5
I
Part 2A: Gold catalyzed, intramolecular• Diyne cyclizations• Enyne cyclizations• Cyclizations involving azides
32
Diyne cyclization
33Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. Eur. J. 2015, 21, 1009-‐1013
NTs
Ph
OAc
n-Bu
(Johnphos)Au(MeCN)SbF6 (5 mol %)4Å MS
CH2Cl2, rt, 83%
NTs
OAc
n-BuPh
Diyne cyclization
34Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. Eur. J. 2015, 21, 1009-‐1013
NTs
Ph
O
n-Bu
NTs
OAc
n-BuPh
O
[Au]
NTs
Ph
OO
[Au]
NTs
Ph
OAc
[Au]n-Bu n-Bu
NTs
Ph
OAc[Au]
Indole cyclization with tethered alcohol
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Zheng, N.; Chang, Y.-‐Y.; Zhang, L.-‐J.; Gong, J.-‐X.; Yang, Z. Chem. Asian J. 2016, 11, 371-‐375
NBn
NTs
OH
PPh3AuSbF6(5 mol %)
DCE, 25 °C89% N
Bn
O
NTs
H
Indole cyclization with tethered alcohol
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Zheng, N.; Chang, Y.-‐Y.; Zhang, L.-‐J.; Gong, J.-‐X.; Yang, Z. Chem. Asian J. 2016, 11, 371-‐375
NBn
NTs
OH
PPh3AuSbF6(5 mol %)
DCE, 25 °C NBn
O
NTs
H
NBn
NTs
OH
[Au]
NBn
NTs
OH
Gold Cyclization of Aryl Azide
37
Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2014, 16, 3138-‐3141
N3
NTs
Ph
P(p-CF3Ph)AuCl (5 mol %)AgOTf (5 mol %)
(ClCH2)2, rt94% N
NTs
HPh
Part 2B: Gold catalyzed, intermolecular• Alkyne partners• Heterocyclic partners• Azide partners
38
Alkyne coupling
39
Shen, C.-‐H.; Li, L.; Zhang, W.; Liu, S.; Shu, C.; Xie, Y.-‐E. Yu, Y.-‐F.; Ye, L.-‐W. J. Org. Chem. 2014, 79, 9313-‐9138
HN
n-C6H13
IPrAuNTf2 (5 mol %)
H2O, 80 °C, 3 h70%
N
Br
O(2 eq)
N
PhPh
Ts
Nn-C6H13
PhNPh
TsO
Isoxazole coupling
40
O N
O
Ph
(ArO)3PAuNTf2(5 mol %)
NO
N
Ph
N
O
O
O
DCE, 80 °C83%
Xiao, X.-‐ Y.; Zhou, A. H.; Shu, C.; Pan, F.; Li, T.; Ye, L.-‐W. Chem. Asian J. 2015, 10, 1854-‐1858
Azide coupling
41Shu, C.; Wang, Y.-‐H.; Zhou, B.; Li, X.-‐L.; Ping, Y.-‐F., Lu, X.; Ye, L.-‐W. J. Am. Chem. Soc. 2015, 137, 9567-‐9570
BrN3
PhN
MsPh
IPrAuNTf2(5 mol %)
4Å MSDCE, rt
85%NMs
NH
PhBr
Summary
Gold Catalyzed
Intramolecular
Intermolecular
Non-‐Gold Catalyzed
Intramolecular
Intermolecular 42
Final thought: Black Swans• Widely accepted conventional wisdom in 1976:• Gold is too unreactive to be of catalytic use• Palladium-‐catalyzed cross coupling can achieve C-‐C bond formation but not C-‐N bond formation
• Olefin metathesis is an ill-‐defined reaction of olefinic hydrocarbons and is of little use in synthesis
• Plausible addition: Molecules with a nitrogen connected to a triple bond (aka ynamide) are too unstable and reactive for widespread adoption in practical synthetic chemistry
43
Nugent, W. A. Angew. Chem. Int. Ed. 2012, 51, 8936-‐8949
Final thought: Black Swans
Nugent’s concluding remark:
“One can only imagine what extraordinary developments those of you currently beginning your careers in chemistry will witness in the next 35 or 40 years. In this regard, I envy you.”
44
Nugent, W. A. Angew. Chem. Int. Ed. 2012, 51, 8936-‐8949