chemistry of dehydro-diels-alder reaction
TRANSCRIPT
Chemistry ofDehydro-Diels-Alder Reaction
LS 2016.10.24
Takahiro Kawamata
1
2
Contents
1-1. Concept of dehydro-Diels-Alder (DDA) reactions1-2. Overview of benzyne chemistry
2-1. Initial studies by Johnson and Ueda (1997~2008)2-2. Studies by Hoye group (2012~present)
Diels-Alder Reaction
3
HH
HH
HOMO
LUMO
dienedienophile
+
two C C bonds formationeight possible stereoisomers
Specific types or variants of Diels-Alder reactions
intramolecular (IMDA) reaction inverse electron demand HDA reaction
hetero-Diels-Alder (HDA) reaction dehydro-Diels-Alder (DDA) reaction
+X
+
X = O, N, S
X
O
+
OMeO MeO
4
Dehydro-Diels-Alder Reaction
+
+
+
+
+
Didehydro-Diels-Alder (DDDA) reaction Tetradehydro-Diels-Alder (TDDA) reaction
Hexadehydro-Diels-Alder (HDDA) reaction
ortho-benzynecumulene
Wessig, P.; Müller, G. Chem. Rev. 2008, 108, 2051.
5
Landmark Events
Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.; Hoye, T. R. Nature Protocols 2013, 8, 501.
6
Methods for the Generation of o-Benzyne
H
X
Conventional method of benzyne generation
Benzyne from benzenediazonium 2-carboxylate
Benzyne generation from 2-(trimethylsilyl)aryl triflate (widely used Kobayashi method)
X
(–) requirement of harsh conditions(–) base sensitive substrate not tolerable
CO2H
NH2 R-ONO
base X–
CO2
N2 N2–
CO2–
(–) explosive nature of diazonium compounds
OH
Brone-pot
three stepsOTf
TMS F
(+) mild and base-free protocol(+) compatibility with various substrates
BuLi, t-BuOK
TMSF, TfO
Bhojgude, S. S.; Bhunia, A.; Biju, A. T. Acc. Chem. Res. 2016, 49, 1658.
7
o-Benzyne Generation and Trapping
Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140.
8
Contents
9
Johnson’s Discovery
Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119, 9917.
10
Deuterium Labeling Study
Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119, 9917.
11
Studies by Ueda Group
HO
TMS
RO
XO
TMS
O
time
benzene (50 mM)25 °C, time
A : X = HB : X = R
Ph
Ph
Ph
O
48
72
72
72
48
A : 45%, B : 38%
A : 66%, B : 6.3%
A : 53%, B : 14%
A : 40%, B : 3.3%benzophenone : 6.0%
A : 52%, B : not detected
timeresults resultsR R
Me
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1997, 38, 3943.
12
HO
TMS
O
Ph
Ph
TMS
O
HO
TMS
OH
Ph
Ph
A : 40%
B : 3.3%
Ph
Ph O2
6.0%
PhPh
O
Ph
Ph
TMS
O
Ph Ph
HO
H+
O
TMS
O
Ph
Ph
?
–HO
?
–H
25 °C
?
Proposed Mechanism by Ueda Group
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1997, 38, 3943.
13
My Proposal of the Mechanism
14
Evidence of Arylcarbene Formation
HO
TMS
O
Ar =
C2H5
C2H5
OMe
XO
TMS
OAr
ArAr
Ph ArCH2OMe
ArCH2OCOMe
Ar
H
+
A : X = HB : X = CH2Ar
C1 C2
C3
C4
solvent
25 °C, 72 hunder Ar
solvent
benzene
concentration
30 mM
3.0 mM
0.3 mM
126 mM
3.0 mM
3.0 mM
A B C
44% 13% C1 : 16%
benzene
benzene
styrene
MeOH
MeCO2H
47% 13% C1 : 23%
55% 4% C1 : 37%
33% 7% C2 : 5%
62% 0% C3 : 60%
71% 0% C4 : 66%
carbene species
entry
1
2
3
4
5
6
Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futai, M. Tetrahedron Lett. 1999, 40, 319.
15
Application for DNA Cleavage
HO
R
MeO
S no reaction
O
R
MeO
S
R
MeO
O
DNA cleavage
Radical intermediate:abstraction of H atomfrom deoxyribose
R
O
O
Me
alkylation ofDNA base
H
37 °C
MnO2 oxidation
rt
Hypothesis of dual DNA cleavage pathway
R = t-Bu
HNCO2H
OMe
Me
O
OH
O
O
OH
OH
dynemicin A(ene-diyne antitumor agent)
Torikai, K.; Otsuka, Y.; Nishimura, M.; Sumida, M.; Kawai, T.; Sekiguchi, K.; Ueda, I. Bioorg. Med. Chem. 2008, 16, 5441.
16
Direct Observation of Plasmid DNA by AFM
Torikai, K.; Otsuka, Y.; Nishimura, M.; Sumida, M.; Kawai, T.; Sekiguchi, K.; Ueda, I. Bioorg. Med. Chem. 2008, 16, 5441.
17
Contents
18
Revelation of HDDA reaction by Hoye Group
HO OTBS
OTBS O
TBSO
O
TBS
MnO2, CH2Cl2rt, 5 h
53%
RO
OTBS O
RO
TBS
retro-Brook rearrangement
R =
OTBS
trapping bynucleophilic oxygen atom
Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature, 2012, 490, 208.
19
Substrate Scope of HDDA Reaction
Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature, 2012, 490, 208.
20
Application : Alkane Desaturation
TMS
Me
OMe
TMS
O
Me
TMS
O
entry yield2H donor krel G‡ (kcal/mol)
1
3
4
97%
94%
84%
cyclooctane
cycloheptane
cyclopentane
17.6
18.7
24.120%cyclohexane
A
H
H
A
H
H
A
H
H
+ +
H
Hcyclichydrocarbon(2H donor)
0.01 M95 °C, 14 h
2
H
H
2.6
2.3 17.7
1.0
0.01
saturated
Concept
desaturated
H
H
boat-likeform
+ cycloalkene
Niu, D.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature, 2013, 501, 531.
21
Application : Aromatic Ene Reaction (1)
Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34.
Brinkley, Y. J.; Friedman, L. Tetrahedron Lett. 1972, 13, 4141.
22
Application : Aromatic Ene Reaction (2)
Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34.
23
Mechanistic Study of HDDA Reaction
O
R1
O
R2
concerted TS
stepwise TS1
R1
OR2
O
O
O R1
R2
stepwise TS2
concerted or stepwise ?
Wang, T.; Niu, D. Hoye, T. R. J. Am. Chem. Soc. 2016, 138, 7832.
24
Relative Rates of the HDDA Reactions
N
R
Ts
TBSO
N O
R
TBSTs
N
R
TBSTs
Me
R
CHO
COMe
CO2Me
CONEt2
H
CF3
entry
1
2
3
4
5
6
7
krel p RSE (kcal/mol)
320
100
16
9.1
1
<<1
<<1
0.03
0.42
0.34
0.34
0.26
0
0.54
–12.1
–7.7
–6.7
–4.9
–4.9
0
+1.9
N
R
Ts
concerted
stepwise
p : Hammet constant, RSE : radical-stabilizing energy
conditions : p-nitrotoluene, 110 °C
conditions
Wang, T.; Niu, D. Hoye, T. R. J. Am. Chem. Soc. 2016, 138, 7832.
25
Relative Rates of Diels-Alder Cycloadditions
Wang, T.; Niu, D. Hoye, T. R. J. Am. Chem. Soc. 2016, 138, 7832.
26
Conclusion of Mechanistic Study
Wang, T.; Niu, D. Hoye, T. R. J. Am. Chem. Soc. 2016, 138, 7832.
27
Pentadehydro-Diels-Alder Reaction
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
28
Scope of the PDDA Cascades of Substrates
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
29
Aza-PDDA Reactions
N
TsN
Me
N
TsN
N
Me
H
0.05 M in piperidine
23 °C, 2 h70%
N
TsN
Me
150 °Co-dichlorobenzeneAcOH (20 eq.)
TsN
HH
NMe
N
TsN
Me
H H
H
HPDDA
HDDA
deprotonation by piperidineaddition ofpiperidine
not obtained
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
30
Scope of the Aza-PDDA Cascades of Substrates
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
31
Mechanistic Aspects of the PDDA Reaction
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
32
Evidence of Allenyne Intermediate
Me
n-Pr
OR
R = HR = PPh2
n-Pr
H
PPh2
Me
O
n-Pr
POPh2
Me
n-Pr
POPh2
Me
X
H
85% (isolated)
rearrangement ofdiphenylphosphine oxide
Ph2PCl, Et3NCDCl3, 0 °C
23 °C, 10 h(t1/2 = 2.5 h)
MeOH orH2O/MeCN (1:3)
X = OMe (91%)X = OH (83%)
Wang, T.; Naredla, R. R.; Thompson, S. K.; Hoye, T. R. Nature, 2016, 532, 484.
33
Summary
+
Hexadehydro-Diels-Alder (HDDA) reaction
ortho-benzyne
X+
X
Pentadehydro-Diels-Alder (PDDA) reaction
X
X = CH, NH
1. alkane desaturation2. aromatic ene reaction
trapping reactiveintermediate
reagent-freeconditions
,3-dehydro(aza)toluene
X
Nu
HNu H The PDDA proceeds rapidly, much more
quickly than the HDDA cyclization.
The PDDA enables to synthesizepyridine-containing products which areimpposible to obtain by the HDDA cyclization
highly substitutedbenzenoid product
34
35
O
MeH
N
O
O
H
PhN
O
O
MeHPhN
O
H
O
MeH
N
OH
PhN
O
O
OH
NO
OOH
N
OO
O
N
Me
OH
O
PhN
O
dr = 4:1
*
aromatic ene
Alder ene
Stereoselectivity of Aromatic Ene/Alder Ene Cascade
Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34.
36
Competition between Aromatic ene and DA reaction
Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34.
37
Mechanism of Radical Fragmentation
http://molecules.a.la9.jp/Anticancer.html
38Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature, 2012, 490, 208.
Geometry of Benzyne and Comparison of Energies
Comparison of computed free energy changes
Geomety of benzyne
39Marell, D. J.; Furan, L. R.; Woods, B. P.; Lei, X.; Bendelsmith, A. J.; Cramer, C. J.; Hoye, T. R.; Kuwata, K. T. J. Org. Chem.2015, 80, 11744.
O
H
O
H
O
O H
H
Comparison of Energies at B3LYP-D3BJ Level
40
Dimerization of Phenylpropynoic Acid in 1898
Michael, A.; Bucher, J. E. Chem. Zentrblt 1898, 731.
41
Substrate Synthesis by Ueda
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1997, 38, 3943.