Problem Session (4)

Please provide the reasonable reaction mechanisms and explain the stereoselectivities.

2019/4/13 Takumi Fukuda

(1)

(2)

(3)

B (5 mol%)

THF, H2O (0.2 vol%)

-10 C

1. PDC (5 eq.), DMF

2. NaOAc (5 eq.), Ac2O, 140 C

68% (2 steps)

3. i-Bu2AlH (1.3 eq.), toluene

-78 C to rt, 85%

2-1

98% ee

2-2

73% (dr = 3:1, 97% ee)

A (2 mol%)

O2 (1 atm), (CH2Cl)2h (470 nm), 0 C, 4 h;

n-Bu4NF, 1 h;

CF3COOH, 10 min, 53%

1-1 1-2

OTBSO

O

O

O

H

H

H

HO

H

O

OBz

OAc

Me

O OH

H

OBz

2-3

11%

O OAc

H

OBz

3-1

(dr < 3:1)

O

H

OH

Cl

3-2

H

Cl

O

Ar

Ar Ar

BF4

A

(Ar = 4-MeOC6H4)

P AuI

t-But-Bu

NCMe

SbF6

B

*

NH

CrO

CrO

OO

OOO

2

PDC

OHO

*

Problem Session (4) Answer 2019/4/13 Takumi Fukuda

1-1. Reaction mechanism

1

(1)

Hart, J. D.; Burchill, L.; Day, A. J.; Newton, C. G.; Sumby, C. J.; Haung, D. M.; George, J. H. Angew. Chem. Int.

Ed. 2019, 58, 2791.

Topic: Recent total syntheses

A (2 mol%)

O2 (1 atm), (CH2Cl)2h (470 nm), 0 C, 4 h;

n-Bu4NF, 1 h;

CF3COOH, 10 min, 53%

1-1 nyingchinoid A (1-2)

OTBSO

O

O

O

H

H

H

HO

O

Ar

Ar Ar

BF4

A

(Ar = 4-MeOC6H4)

O

Ar

Ar Ar

h (470 nm)

O

Ar

Ar Ar

*

O

Ar

Ar Ar

+e-

SET

-e-

SET

Catalytic cycle of photocatalyst

4-MeO-TPT 4-MeO-TPT* 4-MeO-TPT

O

R

R R

R = HR = MeR = OMe

: TPT: 4-Me-TPT: 4-MeO-TPT

E1/2 (S*+/S•)

+2.28 V+2.03 V+1.74 V

E1/2 (S•+ /S) = +1.48 V

Martiny, M.; Steckhan, E.; Esch, T. Chem. Ber. 1993, 126, 1671.

Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett, 2016, 27, A-J.

E1/2 (S•+ /S) = +1.81 V

E1/2 (S•+ /S) = +2.36 V

OMe OMe

Me

E1/2 (S+/S•)

-0.37 V-0.27 V-0.60 V

Reduction potential vs. SCE

2

1-1

OTBSO

-e-

SET

1-3

OTBSO

1-4

OTBSO

HH

5-exo-trig

Discussion 1

O O

1-5

OTBSO

O

HH

O

n-Bu4NF

nyingchinoid B (1-10)

OO

HH

HO

O+H+

1-11

OHO

HH

HO

O-H+

Discussion 3

Discussion 2

1-5

OTBSO

O

HH

O

1-6

OTBSO

H

OO

HH+e-

SET

O

OO

O

Me H

H

1-9'

F

1-8

OO

H

OO

HH

SiMe

Me

t-Bu

1-7

OO

H

OO

HH

SiMe

Me

t-Bu

F

1-9

OO

H

OO

HH

Me

3

nyingchinoid A (1-2)

O

O

O

H

H

H

HO

1-2. Discussion

1-2-1. Stereoselectivity of 5-exo-trig cyclization (Discussion 1)

H

H

Me

O

HH

H

H

O

HH

1-4 (desired)

OTBSO

HH

1-4' (undesired)

OTBSO

HH

1-3

OTBSO

minimize1,3-allylic strain

TS-2 (unfavoured)

TS-1 (favoured)

TS-2 is unfavoured due to the boat-like transition state.

minimize1,3-allylic strain

OTBS

OTBS

chair-like conformation

boat-like conformation

1-4' (undesired)

OTBSO

HH

1-13

OTBSO

H

H

1-12

OTBSO

HH

H

1-14

OTBSO

H

HH

Re-oxidation of 1-14 by the excited photocatalyst (4-MeO-TPT*) could regenerate radical cation 1-3. Therefore,the kinetic 1-14 could be recycled to give 1-7 via radical cation 1-4.

5-exo-trig

5-exo-trig

4-exo-trig

+e-

-e-

4

O

OO

H

Me

1-2-2. Stereoselectivity of 1,2-dioxane formation (Discussion 2)

OTBS

1-6'

only access -face of

oxocarbenium ion

1-6

OTBSO

O

HH

O

1-7

OTBSO

H

OO

HH

1-2-3. Ring opening of epoxide and regeneration of aromaticity (Discussion 3)

1-11

OO

HH

HO

O

H

1-15

OO

H

HOH O

O

O

OMeH

OH

can not interact

with * of C-O

*

(1) C-C cleavage vs. C-O cleavage

(2) Stepwise mechanism

1-11

OHO

HH

HO

O

nyingchinoid A (1-2)

O

O

O

H

H

H

HO

O

O

HH

HO

HO

1-16

1-11'

C-C cleavage

regenerationof aromaticity

-H+

5-memberedring formation

C-O cleavage

2-1. Reaction mechanism

(2)

5

Branstatter, M; Freis, M.; Huwyler, N.; Carreira, E. M. Angew. Chem. Int. Ed. 2019, 58, 2490.

B (5 mol%)

THF, H2O (0.2 vol%)

-10 C

2-1

98% ee

2-2

73% (dr = 3:1, 97% ee)

H

O

OBz

OAc

Me

O OH

H

OBz

2-3

11%

O OAc

H

OBz

*

P AuIt-Bu

t-BuNCMe

SbF6

B

2-1H

O

OBz

OAc

Me+LnAuI

2-4H

O

OBz

O

Me

LnAuI

O

1,3-acyl

migration

Discussion 1

2-5H

O

OBz

-LnAuImetalla-Nazarov

Discussion 2

OO

LnAuIMe

2-6H

O

OBzOAc

•

Me

H

2-7

aldol reaction

Discussion 3

AcO

Me

O

OBz

H

O OH

H

OBz

2-2

4-exo-trig

2-2. Discussion

2-2-1. 1,3-acyl migration vs. 1,2-acyl migration (Discussion 1)

(1) 1,2-acyl migration and sequential 1,2-acyl migration (formal 1,3-acyl migration)

6

2-1H

O

OBz

OAc

Me+LnAuI

2-4H

O

OBz

O

Me

LnAuI

O

1,2-acylmigration

2-8H

O

OBz

+LnAuI

2-9

LnAuI

O

O

Me

H

O

LnAuIII

OAcMe

OBz

1,3-acyl migration product 2-6 can be formed from 1,2-acyl migration product 2-9 via additional 1,2-acyl

migration.

Both 1,2-acyl migration and 1,3-acyl migration were considered as reversible reaction. (Correa, A.; Marion,

N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L. Angew. Chem. Int. Ed. 2008, 47, 718. see

Appendix)

In contrast to 1,3-acyl migration, the chirarity of 2-1 is lost after 1,2-acyl migration. Therefore, 1,3-acyl

migration only occured in this case. For the same reason, sequential 1,2-acyl migration did not occur.

2-9

H

O

LnAuIII

OMe

OBzO

rac-2-10

H

O

OBzO

OMe

LnAuI

1,2-acylmigration

2-6H

O

OBzOAc

•

Me

H

ent-2-6H

O

OBzOAc

•

H

Me

loss of chirality

-LnAuI

7

2-2-2. metalla Nazarov cyclization (Discussion 2)

(1) 1-cordinated bent allene

Gandon, V.; Lemiere, G.; Hours, A.; Fensterbank, L.; Malacria, M. Angew. Chem. Int. Ed. 2008, 47, 7534.

Various coordination modes of allenes are known.

•

R4

R3R1

R2

AuI

•

R3

R4R2R1

AuI

AuI

R1

R2 R4

R3AuIII

R1

R2 R4

R3•

AuI

R1 R3

R4R2

2-cordination

1-cordination

Although the stereochemical information is maintained in species I, I' and II'', the axial chirality of the allene

seems to be lost in II and II'.

I I'

II'

(zwitterionic carbene)II''

(bent allene)

II

(allylic cation)

The orbital interactions between the unfilled 5p orbital of AuI and

the * orbitals of allene and the occupied 5d orbital of AuI and the

orbitals of allene exsist. (Chenier, J. H. B.; Howard, J. A.; Mile,

B. J. Am. Chem. Soc. 1985, 107, 4190.)

Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513.

The isotope labelling study conducted by Toste's group support 1,3-acyl migration route.

Ph

H18O

Ph

O

t-Bu Ph3PAuSbF6(1 mol%)MeNO2, rt

76%

O

Ph

18O

t-Bu

2-11 2-12

Ph

2-13

•

H

Ph

Ph

O

t-Bu

18O

1,3-acylmigration

18O label resided exclusively at the carbonyl oxygen of 2-12. It suggested that the sequential 1,2-acyl migrationdid not occur.

< 90

•

R4

R3R1

R2

R2

R4

R3

R1

R2

R4

R3

R1

AuI

AuI cordination (rotation)

< 180

8

•

OAcH

Me

AuI

•

AuI

H OAc

Me

2-14-I

(3.2 kcal/mol)

2-14-II''

(0.0 kcal/mol)

Malacria's group calculated the energies of 2-cordinated complex 2-14-I and 1-cordinated bent allene 2-14-II''

and 2-14-II''' and found that 2-14-II'' was more stable.

Therefore, Nazarov cyclization via 1-cordinated bent allene II'' was proposed, but the cyclization might occur

from chiral 2-cordinated complex I and I'.

Gandon, V.; Lemiere, G.; Hours, A.; Fensterbank, L.; Malacria, M. Angew. Chem. Int. Ed. 2008, 47, 7534.

•

AuI

H OAc

Me

2-14-II'''

(3.0 kcal/mol)

Me

AcO

H

AuI

Me

OAc

H

AuI

2-6H

O

OBzOAc

•

Me

H+LnAuI

2-151-cordinated bent allene

H

O

OBzOAc

•

HMe

LnAuI

2-16

AcO

Me

O

OBz

H

LnAuI

H

-H+

2-17

AcO

Me

O

OBz

H

LnAuI

+H+

2-7

AcO

Me

O

OBz

H

(2) reaction mechanisms

rotate to minimizethe steric repulsion

another possible mechanism from 2-16 to 2-7

2-16

AcO

Me

O

OBz

H

LnAuI

H

2-18

AcO

Me

O

OBz

H

LnAuI

H1,2-hydride shift

2-7

2-15'1-cordinated bent allene

H

O

OBzOAc

•

HMe

LnAuI

rotate to minimizethe steric repulsion

2-16

2-15 and 2-15' give the same enantiomer 2-16 after the cyclization.

9

2-7

AcO

Me

O

OBz

H

2-2-3. aldol reaction (Discussion 2)

O

OBz

AcO

Me

H

H

OBz

AcO

Me

O

sp3

sp2

LnAuI

AuILn

large stericrepulsion

2-19'

minor

AcO OH

H

OBz

2-19

major

AcO OH

H

OBz

aldolreaction

aldolreaction

TS-3

TS-4

2-19'

minor

AcO OH

H

OBz

2-2'

O OH

H

OBz

deprotection ofAc group by H2O

2-19

major

AcO OH

H

OBz

2-2

O OH

H

OBz

deprotection ofAc group by H2O

or intramolecularAc migration

2-3

O OAc

H

OBz

The Intramolecular Ac migration did not occured due to the long distance between hydroxy group and Acgroup.

3-1. Reaction mechanism

(3)

10

Branstatter, M; Freis, M.; Huwyler, N.; Carreira, E. M. Angew. Chem. Int. Ed. 2019, 58, 2490.

1. PDC (5 eq.), DMF

2. NaOAc (5 eq.), Ac2O, 140 C

68% (2 steps)

3. i-Bu2AlH (1.3 eq.), toluene

-78 C to rt, 85%

3-1

(dr < 3:1)

O

H

OH

Cl

3-2

H

Cl

OHO

*

3-1

O

H

OH

Cl

NH

CrOCrO

OO

OOO

2

PDC

CrVIOCrVI

O

OHHO

OOO

3-4

O

H

Cl

3-3

O

H

O

Cl

CrVIOHO

OH

HN

HO

CrIVO

OHHO–HO

CrVIO

OH

O

–

3-5

O

H

Cl

H2O CrVIO

OO

+

3-7

O

H

Cl

3-6

O

H

O

Cl

CrVIOHO

OH

HN

CrIVO

OHHO–

OH

OH

O

-H+

OH

HO

CrVIO

OO

Step 1

11

O

O

O

3-9

O

H

Cl

O

O

3-8

O

H

Cl

O

O

O

3-11

H

Cl

+i-Bu2AlH

3-10

HO

H

Cl

O

O

O

O

O

3-13

H

Cl

O

O

3-12

H

Cl

O

O

i-Bu2Al

H

Ali-Bu2

3-14

H

Cl

OO

i-Bu2Al

aldol reaction

3-2

H

Cl

OHO

-AcO

-AcO

Step 3

Step 2

12

Appendix

Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L. Angew. Chem. Int. Ed.2008, 47, 718.