Enantioselective Total Synthesis of (+)-Hinckdentine A
via a Catalytic Dearomatization Approach
K. Douki, H. Ono, T. Taniguchi, J. Shimokawa, M. Kitamura*, and T.
Cameron McConnell
Professor S.-Y. Liu
12/21/2016
Fukuyama*
Introduction
The authors performed the first enantioselective synthesis of (+)-hinckdentine A, a natural product isolated from the marine
bryozoan Hincksinoflustra denticulata. The biological properties of (+)-hinckdentine A have not been reported. The authors
were able to prepare 300 mg of product from readily available intermediate 5 in 14 steps and in 8.8% yield. The total
synthesis features a key enantioselective dearomative coupling step to simultaneously prepare a quaternary stereocenter
and to attach the aryl group to the carbazole core. The dearomative coupling/cyclization strategy could be applied to the
synthesis of other natural products of interest.
Retrosynthetic Analysis
O
O
O
Br
NH
Br
Br
N
N
NH
regioselective
tribromination
formation of
amide
(+)-hinckdentine A 1
N
H
HN
R
dearomative
coupling
NH
N
H
O
2
N
HN
R
J. Am. Chem. Soc. 2016, 138(44), 14578-14581.
O
strategic
simplification
4
O
I
5
O
page 1
Preparation of Starting Material 5
O
O
PhNHNH 2
O
NaH, DMAP
O
EtOH
O
O
O
Cl
N
H
O
p-TsOH
O
N I
I
N I
O
O
5
Fischer Indole Synthesis
O
O
O
OH
O
O
O
O
O
O
N
H
NH 2
O
H
PT
N
H
O
OH
NH
N
H
NH
N
H
NH
NH
NH
rearomatization
O
O
O
O
O
O
—NH 3
N
H
PT
NH
NH 2
N
H NH 2
Ketal Deprotection
OH
O
O
O
H
OH
N I
O
HO
OH
OH2
N I
O
OH
O
N I
O
O
PT
PT
N I
O
N I
—glycol
O
page 2
Palladium-Catalyzed Dearomative Cyclization
Ph
O
O P N
O
Ph
R,S,S
O
N I
R
N
Pd 2(dba) 3CHCl 3
NaOAc, t-BuOH
O
O
5
98%
93:7 er
6
I
R
deprotonation/
elimination
oxidative
addition
Pd 0
NaOAc
O
O
PdHI
Heck-type mechanism
N
N
O
I H
O
Pd
beta-hydride
elimination
N
Pd
I
O
migratory
insertion
O
page 3
Construction of Seven-Membered Lactam
O
O
LHMDS, TMSCl
then NOCl
CO2TFE
SOCl2
then CF 3CH2OH
N
OH
N
N
O
N
O
6
O
8
O
9
H 2, Raney Ni
THF, t-BuOH
NH
CN
10 (>99:1 er)
N
O
O
11
10 (93:7 er)
Cl
SiMe 3
Ketoxime Synthesis
O
Li
O
Cl
O SiMe 3
O
H
H 2 Pd/C
EtOAc
CO2TFE
ice-cold
EtOH
then NaHCO 3 aq
N
N
CN
N
Si
Si
N
N
O
O
O
N
H Cl
O
N
Cl
N
O
O
O
O
OH
N
N
O
OH
N
Cl
PT
N
O
page 4
Beckmann Fragmentation, Hydrogenation, Amide Formation
O
OH
N
Cl
O
S
Cl
O
Cl
N
N
O
11
O
Cl O S O
N
Cl
O S O
N
Cl
Cl
N
O
amide
formation
O
—SO 2
—Cl
O
O
O
O
O
OTFE
OTFE
OTFE
N
H 2 Raney Ni
NH 2
O
H 2, Pd
N
N
N
N
N
N
O
CF 3CH2OH
O
Conversion of 11 to Indoline/Anilide 2
O
O
NaBH 4
CH 3OH
NH
N
O
NH
NH
then TFAA
N
H
O
TESCl
pyridine
Jones
Reagent
NH
N
TFA
N
TFA
13 OTES
HO 12
11
O
13a
O
Oxidation with Jones Reagent
O
R
SiEt 3
H
O
O
Cr
OH2
O
H
O
H 2SO 4
Jones
Reagent
R
SiEt 3
OH
R
O
O
Cr
H
O
PT
R
O
O
Cr
O OH
O
R
page 5
Conversion of 11 to Indoline/Anilide 2 contd.
O
O
NH
NH
NH 2OH HCl
NaOAc
N
TFA
13a
O
14
O
N
NH
NCS, then
NEt 3
N
TFA
S
NH
KSAc
N
TFA
N
HN
OH
O
N
H
S
N
H
AcHN
then NaHCO 3
aq workup
16
18
Modified Kim's Protocol
O
O
NH
O
NH
O
NH
NH
NEt 3
N
TFA
O
O
N Cl
N
OH
N
N
TFA
Cl
H N
OH
N
TFA
Cl
N
N
TFA
—NEt 3HCl
O
OH
N
S
HN
O
NH
O
O
O
O
O
O
NH
18
aq workup
N
TFA
AcN
NH
—CS 2
NH
O
N
TFA
N
S
N
TFA
N
S
O
S
S
16
HN
—
NH
NH
N
TFA
NH S
NH O
N
page 6
Tribromination and Forming the Final 5-Membered Ring
O
O
O
Br
NH
N
H
AcHN
64%, 2 steps
18
HC(OCH 3)3
TFA
NH
Br 2 CH 3NO 2
Br
Br
NH
Br
N
H
AcHN
O
Br
Br
N
Br
NH
Br
N
20
Br
N
N
(+)-hinckdentine A 1
O
21
Methylene Insertion and Deprotection
H
OCH3
H
H 3CO
OCH3
OHCH3
H
H 3CO
OCH3
OCH3
H 3CO
N
H
H
AcHN
PT H 3COH
H
N
N
OCH3 NHAc
H
H 3CO
NHAc
PT
N
N
N
N
N
O
H 3CO
H
N
Ac
OH2
Conclusion
In conclusion, the authors acheived the total synthesis of enantiomerically pure (+)-hinckdentine A in 17 steps
from commercially available starting materials. They prepared 300 mg of the target compound in 8.8% yield from
intermediate 5.
page 7