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-