problem session (1) 2020.12.12 junichi taguchi
TRANSCRIPT
Problem Session (1) 2020.12.12 Junichi Taguchi
(1)
(2)
Please provide the reaction mechanism.
1-1
1. VO(acac)2 (0.2 eq.), t-BuOOH (2.5 eq.), CH2Cl2, 0 °C to rt; Et3N (3.8 eq.), Boc2O (1.5 eq.), DMAP (0.5 eq.), 0 °C, 79% (2 steps)2. TMP (1.5 eq.), MeCN, 150 °C, 38%
3. DIBAL-H (2.5 eq.), THF, -78 °C, 98 %4. m-CPBA (1.1 eq.), CH2Cl2, rt, 79 %5. BF3·Et2O (5 eq.), CH2Cl2, rt, 60 %
1-2
VO(acac)2
2-1
1. PdCl2 (0.5 eq.), Cu(OAc)2 (1.0 eq.), MeCN/H2O (9/1), O2 (1 atm), 120 ºC, 70 %2. TMSOTf (6.9 eq.), Me2NEt (19 eq.), CH2Cl2, rt, 81 %
3*. hν (Hg lamp), MeCN/acetone (10/1), 68 %4*. hν (Hg lamp), MeCN/acetone (10/1), 54 %
2-2
* The authors do not mention the temperature** The authors tried to extend the time of irradiation for one-pot synthesis from step 3 to step 4, but a trace of 2-2 was detected.
O
O OH
OH
OH
MeO
MeONHAc
OMe
OMeO
MeONHAc
OMe
VO
O O
OO
DMAP
N
N
TMP
NH
DIBAL-H
AlH
m-CPBA
OO
O
H
H
Cl
HO
MeO MeO
O
i-Pr
(-)-vinigrolJ. Am. Chem. Soc. 2019, 141, 15773
Angew. Chem. Int. Ed. 2013, 52, 620See also 180421_PS_Yinghua_Wang See also 130112_PS_Satoshi_Hashimoto
190622_PS_Tsukasa_Shimakawa
See also 191207_LS_Yuto_Hikone
O
O
OR
R = Ac, Boc, CH2CF3
Baseheat O
O
oxidopyrylium ylide
O
O
O
O
O
O
[4,4,1] system
[5,4,1] system
[4,3,1] system
cyclocitrinolcerorubenic acid-III
eurifoloid A(problem 1)
(-)-vinigrol([5,3,1] system)
ring contraction
ring contraction [3,3,1] system [4,2,1] system
Coote, S. C. ACC. Chem. Res. 2020, 53, 703Mei, G.; Liu, X.; Quo, C.; Chen, W.; Li, C. C. Angew. Chem. 2015, 127, 1774
-1-
O
OHO
OMe
Me
Me
Problem Session (1) -Answer- 2020.12.12. Junichi Taguchi
Topic: Works by Prof. Chuang-Chuang Li
1997-2001 B.S. in Chemistry @ China Agricultural University (Prof. Dao-Quan Wang)2001-2006 Ph.D. @ Peking University (Prof. Zhen Yang)2006-2008 Postdoctoral Associate @ The Scripps Research Institute (Prof. Phil S. Baran)2008-2013 Associate Professor @ Peking University2014-2017 Research Professor (tenure-track) @ Southern University of Science and Technology (SUSTech)2018- Full Professor with tenure @ SUSTech
Key strategy: type II [5+2] cycloaddition
OHO H
H
Me
H
MeHO OH
H
cyclocitrinolJ. Am. Chem. Soc. 2018, 140, 5365
CO2H
Me
Me
HH
H
HMe
cerorubenic acid-IIIJ. Am. Chem. Soc. 2019, 141, 2872
N
O
ON
O
OO
H
H
H
HO
H
H
(-)-flueggine A (+)-virosaine B
ON
OHH
HO
O
HH
H
OO
HO
HMe
OH
H
H
HH
Me
H
Me
bufospirostenin AJ. Am. Chem. Soc. 2020, 142, 12602
O
O
MeO
MeMe
hypocrolide AOrg. Lett. 2016, 18, 4932
OH
MeH H
HOHMe
OH
avoiding steric hindrance with Me group of 7-membered ring
DIBAL-H
1-3 1-4
1-5 1-6
1-7
1-8 1-9 1-10
1-11 1-12
step 1
step 2
-2-
HN
see from this side
Stepovik, L.; Gulenova, M. Russ. J. Gen. Chem. 2009, 79, 1663.
A
A
-acac
Liu, X.; Liu, J.; Zhao, J.: Li, S.; Li, C. C. Org. Lett. 2017, 19, 2742.
1-1O
O
OH
activation of vanadium catalyst
VO(acac)2
VIVO
O O
OO t-BuOOH
- acacVIV
O
O
O
O
Ot-Bu
O
OVIVO
O
Ot-Bu
-H+
O
O
OHO
O
O
OHO
O
HOO
O
O
OHO
O
-H+
+H+
Et3N, Boc2O, DMAP
t-BuO N
O
N
O
OBocO
O
HNEt3
O
O
O
O
O
O
(1)
O
O
O
Discussion 1
intermolecular [5+2] cycloaddition AlHO O
O
H
1-1
1. VO(acac)2 (0.2 eq.), t-BuOOH (2.5 eq.), CH2Cl2, 0 °C to rt; Et3N (3.8 eq.), Boc2O (1.5 eq.), DMAP (0.5 eq.), 0 °C, 79% (2 steps)2. TMP (1.5 eq.), MeCN, 150 °C, 38%
3. DIBAL-H (2.5 eq.), THF, -78 °C, 98 %4. m-CPBA (1.1 eq.), CH2Cl2, rt, 79 %5. BF3·Et2O (5 eq.), CH2Cl2, rt, 60 %
1-2
O
O OH
OH
OH
HHO
O
Boc2O + DMAP
OOO
Me H
BocO H
DIBAL-Happroaching from the sterically accesible site
1-13 1-14’
1-12
step 3
step 4 step 5
-3-
1-15
1-20
HH
H
H H
favored1-12’ 1-12’’ 1-12’’’
highly strained ring system
+2H+
steric repulsion
H
HHO OH
O
HHO OH
OO Discussion 2
rearrangementHHO OH
O OH
Discussion 1: intermolecular [5+2] cycloaddition
AlH
m-CPBAOH
OAr
O
- m-CBA
more electron-rich tri-substituted olefin reacts
1-2
O
O
O
O
O
O
Me O
O
Me
O
O
O
O
MeO
O
Me
O
steric repulsion
O
O
O
Me O
O
Me
O
HMe
O
O
O
H
HO
Me
O
O
TS-1 TS-3TS-2 TS-4
exoendo
HO O
O
HO O
O
disfavored
poor orbital interactions
disfavoreddisfavored
O
O
O H
O
O
O H
H
or
O
O
O
m-CPBA
m-CPBA
endo exo
endo exo
HH
OO
Me H
O[Al]
O
Me H
HO OH
1-14
proposed mechanism 2 (my proposal): a pathway involved concerted Meinwald rearrangement
1-141-2β
1-15 1-16 1-17
1-18 1-19
-4-
Considering form this result, 1-2 would be more stable than 1-2β.
HHO OH
O OH
1-2β
H HH H
HHO OH
O OH
1-2
Saunders, M. J. Comput. Chem. 1989, 10, 203.
37.52 kcal/mol 27.19 kcal/mol
MM2 Calculated Steric Energies of Lowest Energy Conformations of bicyclo[4,4,1]undecane
<more stable
<
H
OBF3
HO
Discussion 2: rearrangement
The authors attempted Meinwald rearrangement reaction for the synthesis of 1-2β through stereospecific intramolecular hydrogen transfer.
HHO OH
OOMeinwald rearrangement
HHO OH
O O
H
HOHO
HO
OO
H
H
OO
eurifoloid A
However, the desired product 1-2β was not obtained and the undesired diastreomer 1-2 was obtained.
Background
proposed mechanism 1 (by authors) : a pathway involved an initial inversion proceeding through a Payne-type rearrangement
HO OH
OBF3·Et2O
HHO HO
OO
BF3
H
O
Payne-type rearrangement O
BF3
O-H+
HHO
OO
H
a suprafacial1,2 - hydride shift
HHO
OO
H
OR
R = BF3 or H
HHO
OO
OHH
HHO OH
O OH
1-2
transannular oxonium cation is another sourse of stabilization of
the carbonium ion?
+H+
±H+
O
Me H
HOO
H
HH
H
HHH
1-18’
1-20
BF3
HO OH
O
HH
O BF3·Et2O
HO OH
OO
BF3 Meinwaldrearrangement
-H+HHHO OH
O OH tautomerization
HHO OH
O OH
HHO OH
O OH
1-15 1-16 1-2β
1-21-21
-5-
irreversible?
proposed mechanism 3 : a pathway involved stepwise Meinwald rearrangement
OO
H
OBF3 O
H
BF3
HO OH
O
HH
O BF3·Et2O
HO OH
OO
BF3
H
1-15 1-16
HHO OH
OH
1-16
OBF3
BF3O
HO
1-2
Me H
more stable structure?
Me H
OHOH
Me2NEt
TMS
Liu, X.; Hu, Y. -J.; Chen, B.: Min, L.; Peng, X, -S.; Zhao, J.; Li, S.; Wong, H. N. C.; Li, C. C. Org. Lett. 2017, 19, 4612.
2-3
2-4 2-5
2-6 2-7
2-8 2-9 (colchicine)
step 1
OTfTMS
step 2-6-
TMS
TMS
OTfTMS
H
(2)
2-1
1. PdCl2 (0.5 eq.), Cu(OAc)2 (1.0 eq.), MeCN/H2O (9/1), O2 (1 atm), 120 ºC, 70 %2. TMSOTf (6.9 eq.), Me2NEt (19 eq.), CH2Cl2, rt, 81 %
3*. hν (Hg lamp), MeCN/acetone (10/1), 68 %4*. hν (Hg lamp), MeCN/acetone (10/1), 54 %
2-2
MeO
MeONHAc
OMe
OMeO
MeONHAc
OMe
MeO MeO
2-1
MeO
MeONHAc
OMe
OMeO
PdIICl2, H2OWacker oxidation
Discussion 1:regioselectivity
MeO
MeONHAc
OMe
OMeOOH
PdIICl
β elimination;keto-enol tautomerization
-PdII
-HCl
Pd0Ln PdIICl2
2CuIICl2 2CuICl
H2O 1/2 O2 + 2HCl
MeO
MeONHAc
OMe
OMeOO
MeO
MeONHAc
OMe
OMeOOTMS
MeO
MeONHAc
OMe
OMeOOTMS
MeO
MeONHAc
OMe
MeOO
Me2NEt
MeO
MeONHAc
OMe
MeOO
MeO
MeONHAc
OMe
MeOO
hν[2+2] cycloaddition
Discussion 2:regioselectivity
HCl
H
TMSO H
TMSO
axial proton
MeO
MeONHAc
OMe
OMeO
see from this side
H2O
electron donating OMe group
= stabilization of transition state
direct by amide group
favoredβ elimination;
keto-enol tautomerization
MeO
MeONHAc
OMe
OMeOO
approaching from the sterically accesible site
MeO
MeONHAc
MeO
OMe
HH O
Discussion 3:
decarbonylation;aromatization
avoiding steric hindrance with OMe2-10
2-11 (β-lumicolchicine)
2-1
2-12 2-13
2-4
step 3 step 4
-7-
see from this side
NHAc
OOMe
HMeO
MeONHAc
OMe
MeOO
2-2
MeO
MeONHAc
OMe
MeO
Discussion 1: regioselectivity
OMeO
NH
H
MeO
MeO OMePdIICl2
Cl2PdII MeO
OMeO
NH
H
MeO
MeO OMe
PdIIMeOCl
Cl direct by amide group
OMeONH
H
MeO
MeO OMe
MeOPdIIH
HO
Cl
OMeONHAc
H
MeO
MeO OMe
O
2-1’
H
HH
hydrogen bond
3 possibilities for the electroisomerization of tropolone systems
OOR
type A
type B
type C
OR
O
CHOOR
OR
-CO
ORO
O
OR
Chapman, O. L.; Pasto, D. J. J. Am. Chem. Soc. 1960, 82, 3642
Reaction type A rarely happens in the troponoid series, but is much more widespread in cycloheptatrienes.
My proposal: the reasons why the reaction type A seldom happens are follows;
MeO
MeONHAc
OMe
MeOO
type BMeO
MeONHAc
MeO
MeO
MeONHAc
MeO
OMe
HH O
OMeOO
MeO
MeO
MeO
OMe
disfavored
steric repulsion between OMe and Ar group
(not obtained)
favored
type C
2-9 (colchicine)
2-11’
-8-
O O
aromatic 6 electron system
>>plainer
It would be difficult to approach.Since tropolones are aromatic, their structures are plainer than cycloheptatrienes. It causes difficult to close to each end of the conjugated triene.
In this problem, reaction type A is not expected to occur for the above reasons as well.
NHAc
Discussion 2: regioselectivity of [2+2] cycloaddition
sp3sp2
・the poor overlap among π orbitals of tropolones
・trans 3/6 fused ring which is highly strainedO
H Hhighly strained ring system
NHAc
OOMe
H
Authors’ proposal
MeO
MeONHAc
MeO
OMe
HH O
2-2
MeO
MeONHAc
OMe
MeOMeO
MeONHAc
MeOH
HOMe
decarbonylationelectrocyclicring opening
MeO
MeONHAc
MeO
OMe
HH O
proposed mechanism 1 (based on authors’ opinion): Norrish reaction type I
MeO
MeONHAc
MeO
OMe
HO
MeO
MeONHAc
MeOH
HOMe
2-2
MeO
MeONHAc
OMe
MeO
H
retro-4π-electrocyclization
hν
proposed mechanism 2 (based on authors’ opinion)
-CO
MeO
MeONHAc
MeO
OMe
HH O
hνMeO
MeONHAc
MeO
OMe
HH O
see from this side
OMe
HH O
slightly poor overlap?OMe
HH O
2-11 (β-lumicolchicine) 2-15
2-14
2-14 (not isolated)2-11 (β-lumicolchicine)
2-11 (β-lumicolchicine) 2-17
2-17’ 2-18 -9-
MeO
MeONHAc
MeO
OMe
HH
2-16
The authors does not show the reaction mechanism from 2-11 to 2-2.
Discussion 3: decarbonylation; aromatization (reaction mechanism)
H
MeO
MeONHAc
MeOH
HO
OMe
MeO
MeONHAc
MeOH
HOMe
O
-COMeO
MeONHAc
MeOH
HOMe
(same as the above)
2-19
2-20 2-14
-10-
OMe
HH O
2-2
H
2-19’
MeO
MeONHAc
MeO
OMe
HH O
proposed mechanism 3
MeO
MeONHAc
MeO
OMe
HO
MeO
MeONHAc
MeOH
H
OMe
2-2
MeO
MeONHAc
OMe
MeO
H
decarbonylation
hν
2-11 (β-lumicolchicine) 2-15
2-22
MeO
MeONHAc
MeO
OMe
HH
2-21
CO
O
MeO
MeONHAc
MeOH
HOMe
retro-4π-electrocyclization
2-14
Discussion 4: The reason why one-pot synthesis of compound 2-2 was unsuccessful
Photoisomerization of Colchicine
MeO
MeONHAc
MeO
OMe
HH O
MeO
MeONHAc
MeO
OMe
HH O
β-lumicolchicine γ-lumicolchicine
The irradiation of colchisine leads to the formation of β-lumicolchicine and γ-lumicolchicine. Prolonged irradiation times lead to the formation of α-lumicolchicine (dimer of β-lumicolchicine).
OMe
OMeAcNH
OMeH
HOMeO H
α-lumicolchicine
Bussotti, L.; Cacelli, I.; D’Auria, M.; Foggi, P.; Lesma, G.; Silvani, A.; Villani, V. J. Phys. Chem. A. 2003, 107, 9079
According to the main paper 2, α-lumicolchicine was NOT obtained in the step 3.
Although the authors does not mention, α-lumicolchicine was thought to be a major product when the reaction time was extended.
HMeO
OH
H
AcHN
OMe OMe
OMe
Irradiation of colchicine utilized sunlight in H2O solution for 2 months to give α,β,γ-lumicolchicines together.
Grewe, R.; Wulf, W. Chem. Ber. 1951, 84, 621
Discussion 5: The reason why β-lumicolchicine should be purified
The opinion of the authors:
- Probably, other unidentified compounds made the reaction more complex, with the time extend and the temperature of the solution increased.
My proposal:
α-Lumicolchicine is quantitatibely converted to β-Lumicolchicine on heating to the melting point or heating above 100 ºC in solution.
Chapman, O.L.; Smith, H. G. J. Am. Chem. Soc. 1961, 83, 3914
The conditions of the two reactions are completely the same (including concentration and solvent, temperature).
→The three types of lumicolchicines are irreversibly generated from colchicine, so once the intramolecular cyclization reaction occurs, colchicine cannot be generated again.
→β-lumicolchicines and α-lumicolchicines (dimer of β-lumicolchicine) would be formed by a reversible cyclization reaction and are in equilibrium in the solution. In addition, α-lumicolchicines would be relatively stable.
→ γ-lumicolchicine??
-11-
β-lumicolchicine
γ-lumicolchicine(not mentioned in the main paper 2,
but this compound would be produced as a byproduct)
α-lumicolchicine(dimer of β-lumicolchicine)
OMe
OMeAcNH
OMeH
HOMeO H
HMeO
OH
H
AcHN
OMe OMe
OMe
+
stable compound
2-9 (colchicine)
MeO
MeONHAc
OMe
MeOO
2-2
MeO
MeONHAc
OMe
MeO
Colchicine has two aromatic rings and a long conjugation system. This suggests that colchicine would be a compound with strong intermolecular interactions to some extent.
irreversibly
It is thought that β-lumicolchicines formed a relatively stable dimer, α-lumicolchicine, before the decarbonylation. This would cause the result that a trace amount of the desired compound 2-2 was obtained when the reaction time was extended.
It is thought that β-lumicolchicines would not have such strong intermolecular interactions as colchicines. In my opinion, the purification is expected to reduce the rate of dimerization and cause aromatic cyclization bydecarbonylation.
-12-