cyclizations,of,ynamides to,...
TRANSCRIPT
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
8
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
10
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?
12
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
13
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
14
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
17
Rh-‐catalyzed asymmetric cyclization
18
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
19
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
20
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
21
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
22
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
28
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
29
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
30
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
31
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
35
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
36
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