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.