Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization Approach

Article abstract of DOI:10.1021/jacs.6b10237

Optically pure hinckdentine A was synthesized on a 300 mg scale via an asymmetric catalysis-based strategy. The key steps to the first asymmetric synthesis involved (i) enantioselective dearomative cyclization of an achiral N-acyl indole that allowed for the efficient construction of the key polycyclic indoline intermediate with a crucial tetrasubstituted stereogenic carbon center, (ii) Beckmann fragmentation-mediated ring expansion, (iii) rearrangement-based introduction of an anilinic nitrogen atom, (iv) regioselective tribromination, and (v) final closure of the cyclic amidine moiety.

Full text of DOI:10.1021/jacs.6b10237

Communication
pubs.acs.org/JACS
Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic
Dearomatization Approach
Kazuya Douki,§,† Hiroyuki Ono,§,‡ Tohru Taniguchi,⊥ Jun Shimokawa,† Masato Kitamura,*,† and
Tohru Fukuyama*,†
†Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
‡Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
⊥Faculty of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University,
Kita 21 Nishi 11, Sapporo 001-0021, Japan
S
* Supporting Information
Scheme 1. Retrosynthetic Analysis
ABSTRACT: Optically pure hinckdentine A was synthe-
sized on a 300 mg scale via an asymmetric catalysis-based
strategy. The key steps to the first asymmetric synthesis
involved (i) enantioselective dearomative cyclization of an
achiral N-acyl indole that allowed for the efficient con-
struction of the key polycyclic indoline intermediate with a
crucial tetrasubstituted stereogenic carbon center, (ii) Beck-
mann fragmentation-mediated ring expansion, (iii) rear-
rangement-based introduction of an anilinic nitrogen atom,
(iv) regioselective tribromination, and (v) final closure of
the cyclic amidine moiety.
apid construction of architecturally complex polycyclic
Rsystems is one of the most important frontiers in the
inseparable mixture of various tribromides and tetrabromides.
field of natural products/pharmaceuticals synthesis.1 A potent
Accordingly, Kawasaki employed a protected cyclic aminal
solution to this challenging mission is a dearomatization strategy
intermediate for selective tribromination, leading to the sole
wherein a functionalized planar aromatic framework acquires a
example of a racemic total synthesis.10 We thus selected the
three-dimensional character. Catalytic asymmetric dearomative
cyclization is particularly attractive for the efficient construc-
indoline/anilide 2 as our key intermediate. Compound 2 was
expected to favor ortho−para -dibromination at C8 and C10 on
tion of chiral polycyclic systems. Substantial efforts have
the left-hand indoline as well as single para-bromination at C2
been devoted to this field2 after the pioneering works
on the right-hand anilide. The dearomatized indole 2, in which
of Buchwald,3 Bedford,4 and You.5 These dearomatization
an aromatic moiety was wedged into the indole 2-position at
strategies have been applied to the synthesis of a variety of
natural products and demonstrated their potential for con-
structing complex structures with rich sp3 architectures.6
It occurred to us that the application of this strategy could
be advantageous in the synthesis of the screw-shaped hinck-
dentine A (1), which was isolated from the marine bryozoan
Hincksinoflustra denticulata in 1987.7 The structure, unambig-
uously determined by single X-ray crystallographic analysis, is
characterized by a highly brominated indolo[1,2-c]quinazoline
core fused to a seven-membered lactam unit through the con-
secutive stereogenic centers at C12 and C17a, and a cyclic
amidine moiety. The biological activities of this compound have
not been reported due to a shortage of 1 isolated from natural
sources. A synthetic supply of this material,8 therefore, is clearly
important for uncovering the biological activity of 1 and its
derivatives.9
C17a, could be disconnected to form two planar synthons 3
and 4 on the basis of an asymmetric dearomative coupling. The
nitrogen functionalities in the azepanone moiety in 3 and the
acylamino group in 4 were retrosynthetically excised. The simple
N-acyl tetrahydrocarbazole 5 was thus chosen for the execution
of a pivotal asymmetric dearomative cyclization.
First, the palladium-catalyzed asymmetric dearomative Heck-
type cyclization of 5 to 6 was investigated. Table 1 summarizes
the results. The substrate 5 was prepared in 89% yield in two
steps from the known 5-oxo-tetrahydrocarbazole ethylene
ketal.11,12 A nonasymmetric variant using the related N-acyl
indoles have been reported originally by Grigg13 in 2001 and
later developed by Wu,14 Jia,15 and Lautens.16 We attempted to
render the reaction asymmetric by using an appropriate
chiral ligand. Extensive investigations revealed that Feringa’s
phosphoramidite ligands 717 gave the most promising results.
Scheme 1 shows our retrosynthetic analysis of 1. McWhorter’s
synthetic study8b indicated that the C8-selective bromination
of 8-desbromohinckdentine A would be problematic, giving an
Received: September 30, 2016
Published: October 22, 2016
© 2016 American Chemical Society
14578
DOI: 10.1021/jacs.6b10237
J. Am. Chem. Soc. 2016, 138, 14578−14581

Journal of the American Chemical Society
Communication
a
Table 1. Palladium-Catalyzed Dearomative Cyclization and
Optimization of the Reaction Conditions
Scheme 2. Construction of Seven-Membered Lactam
a
b
c
entry
ligand
solvent
t-BuOH
NMR yield
er
1
2
7a
7b
7c
7d
7c
7c
7c
7c
7c
7c
94
95
99
99
99
93
47
43
38
16
70/30
88/12
93/7
t-BuOH
3
t-BuOH
4
t-BuOH
66/34
67/33
68/32
91/9
5
DMA
6
DMSO
7
1,4-dioxane
CH3CN
a
8
85/15
86/14
93/7
Reagents and conditions: (a) Pd2(dba)3·CHCl3 (2.5 mol %), (R,S,S)-7c
9
1,2-dichloroethane
toluene
(25 mol %), NaOAc (1.5 equiv), t-BuOH, 100 °C, 18 h, 98%,
93:7 er; (b) LHMDS, TMSCl, THF, −78 °C, 1 h, then NOCl, 3 h,
79%; (c) SOCl2, 1,2-dichloroethane, 0 °C to rt, 1 h, then CF3CH2OH,
40 °C, 22 h, 77%; (d) H2 (1 atm), Pd/C (10 mol %), EtOAc, 40 °C,
17 h, 98%, washing with ice-cold EtOH, 81%, >99:1 er; (e) H2
(50 atm), Raney Ni, TFA, t-BuOH, 80 °C, 22 h, then NaHCO3 aq,
CH2Cl2, 40 °C, 18 h, 84% (2 steps). dba = dibenzylidene acetone,
TFE = 2,2,2-trifluoroethyl.
10
a
All reactions were carried out under standard reaction conditions: 5
(100 μmol), Pd2(dba)3·CHCl3 (2.5 mol %), 7 (25 mol %), NaOAc
b
(1.5 equiv), solvent (1.5 mL), 100 °C, 18 h. Determined by 1H NMR
c
analysis using dimethyl sulfone as an internal standard. The enantio-
meric ratio (er) was determined by HPLC analysis on DAICEL
CHIRALCEL OJ-H (n-hexane/i-PrOH = 60:40; 1.0 mL/min).
The reactivity and enantioselectivity were optimized by fixing
the standard conditions as follows: 5 (100 μmol), Pd2(dba)3·
CHCl3 (2.5 mol %), ligand 7 (25 mol %), NaOAc (1.5 equiv),
t-BuOH (1.5 mL), temp 100 °C, and time 18 h. Among the
ligands tested (7a−d), the phenyl-substituted ligand 7c gave
the best enantioselectivity (entries 1−4). In DMA and DMSO,
the selectivity decreased (entries 5 and 6). The reactivity
decreased when 1,4-dioxane, CH3CN, or 1,2-dichloroethane was
used as the solvent (entries 7−9), and the reaction was sluggish
in toluene (entry 10). Our preliminary experiments on the
application to other substrates also afforded the dearomatized
products with good enantiomeric ratio.18 The absolute stereo-
chemistry of the major enantiomer of 6 obtained through the
use of (S,R,R)-7c was determined to be S by comparing the
calculated and observed CD/VCD spectra.19,20
With the optimized reaction conditions (entry 3) in hand, we
turned to synthetic studies of 1 from the chiral intermediate 6
bearing the crucial tetrasubstituted stereogenic carbon center
(Scheme 2). The synthesis of the natural enantiomer of
hinckdentine A (1) required the (R)-6 intermediate. Thus, the
enantiomeric ligand (R,S,S)-7c was employed. The reproduci-
bility of the optimized conditions was confirmed on a 10 g scale
(98% isolated yield, R/S = 93:7). Subsequent transformations
from 6 to 11 represented the ring expansion of the cyclo-
hexenone moiety via the introduction of a nitrogen atom. Our
initial attempts at the Beckmann rearrangement via the corre-
sponding oxime tosylate afforded the complex mixture, which
may indicate the increased donation from the amide nitrogen
electron pair compared to the case of McWhorter’s.8b,16a There-
fore, the Beckmann fragmentation strategy was employed. An
oxime functionality was introduced at the α-position of the
ketone by treatment of the intermediary silyl enolate with NOCl
that was generated in situ from TMSCl and i-AmONO.21 The
Beckmann fragmentation of 8 was efficiently mediated by
SOCl2 and subsequent treatment with CF3CH2OH gave a 1:11
E/Z mixture of the α,β-unsaturated 2,2,2-trifluoroethyl esters 9
bearing a cyanomethyl group at C17a. Catalytic hydrogenation
of 9 occurred from the face opposite to the cyanomethyl group
with perfect diastereoselectivity, giving 1022 in 98% with 93:7 er.
The enantiomerically pure 10 was then obtained in 81% yield
simply by rinsing the crystals with ice-cold ethanol. The hetero-
chiral racemic crystals of 10 appear to be more soluble than the
homochiral crystals. The nitrile functionality in 10 was hydro-
genated on Raney nickel to provide the corresponding amine,
which spontaneously reacted with the 2,2,2-trifluoroethyl ester
group to give the seven-membered lactam intermediate 11.
The remaining obstacles to be cleared toward 1 involved
the conversion of 11 to the indoline/anilide intermediate
corresponding to 2, prior to the selective tribromination and
formation of the amidine moiety. The solutions are illustrated
in Scheme 3. Reduction of the tertiary amide functionality
in 11 was attained by a modified Soai’s method23 (NaBH4−
CH3OH−THF), leaving the secondary amide of the seven-
membered lactam intact to give the amino alcohol 12 in 78%
yield. After protection of the amino alcohol moiety as a TFA
amide and TES ether, the resulting 13 was oxidized with Jones
reagent to provide an aldehyde, which was immediately trans-
formed to the aldoxime 14, setting the stage for the modified
Kim’s protocol.24 Conversion of 14 to the nitrile oxide in situ,
followed by the reaction with tetrahydro-2-pyrimidinethione
(15) afforded the cycloaddition/rearrangement product,
isothiocyanate 16, as a sole product in 72% yield from 13.
The TFA group in 16 thus obtained was too labile under basic
conditions, readily forming the cyclic thiourea 17. Extensive
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DOI: 10.1021/jacs.6b10237
J. Am. Chem. Soc. 2016, 138, 14578−14581

Journal of the American Chemical Society
Communication
a
via in situ removal of the acetyl group from the amidinium
Scheme 3. Total Synthesis of Hinckdentine A
intermediate 21. This final process provided hinckdentine A
(1) on a 300 mg scale: [α]20 + 274 (c = 1.00, CHCl3).
D
In conclusion, we have achieved the first enantioselective
total synthesis of hinckdentine A (1) in 14 steps and in 8.8%
total yield from the readily available 5, establishing the basis
for future biological studies. Our unique synthetic strategy
consisted of five effective key processes: (i) palladium-catalyzed
asymmetric dearomative cyclization of 5 to 6, (ii) Beckmann
fragmentation/lactamization sequence leading to the seven-
membered lactam 11, (iii) rearrangement-based introduction of
a nitrogen atom into the anilide 18, (iv) regioselective tribro-
mination, and (v) the formation of the amidine moiety to afford
the indolo[1,2-c]quinazoline core. These processes eventually
realized a 300 mg scale total synthesis of 1. Further optimi-
zation of the present catalytic dearomatization, a mechanistic
study, and applications of the key reaction to other synthetic
targets are currently underway in our group.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b10237.
■
S
Experimental procedures, spectroscopic data, and
1H and 13C NMR spectra (PDF)
Crystallographic data of 10 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*kitamura@os.rcms.nagoya-u.ac.jp
*fukuyama@ps.nagoya-u.ac.jp
■
a
Reagents and conditions: (a) NaBH4 (50 equiv), CH3OH, THF,
65 °C, 10 h, 78%; (b) TESCl, pyridine, CH2Cl2, 0 °C, 30 min, then
TFAA, 0 °C, 30 min, 70%; (c) Jones reagent, acetone, 0 °C, 1 h;
(d) NH2OH·HCl, NaOAc, EtOH, 0 °C, 1 h; (e) NCS, DMF−THF,
65 °C, 15 min, then tetrahydro-2-pyrimidinethione (15), Et3N, 0 °C,
1 h, 72% (3 steps); (f) KSAc (5.0 equiv), CH3OH, 40 °C, 4 h, then
NaHCO3 aq, rt; (g) Br2 (3.0 equiv), CH3NO2, −20 °C to rt, 30 min,
then Br2 (8.0 equiv) rt, 1.5 h, then 2-methyl-2-butene, 0 °C, 64%
(2 steps); (h) HC(OCH3)3 (50 equiv), TFA (50 equiv), rt, 30 min,
then CH3OH−H2O, rt, 88%. TES = triethylsilyl, TFAA = trifluoroacetic
anhydride, NCS = N-chlorosuccinimide.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Kato Memorial Bioscience
Foundation, a Mitsubishi Tanabe Pharma Award in Synthetic
Organic Chemistry, Japan, JSPS KAKENHI Grant Numbers
23590003, 25221301, 15H05641, the Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan, and the Advanced Catalytic Transformation
Program for Carbon Utilization (ACT-C) from the Japan
Science and Technology Agency (JST). The authors thank Mr.
Yutaro Saito and Mr. Shin Suzuki (Nagoya University) for their
assistance with the UltraCOOL Probe NMR facilities. The
authors thank Mr. Kazuyuki Higashita (Nagoya University) for
his support in X-ray crystallographic analysis.
screening of the reaction conditions revealed that the prema-
ture removal of the TFA group could be suppressed by the
initial treatment of 16 with KSAc25 in CH3OH at 40 °C for 4 h,
followed by a hydrolytic workup with NaHCO3 aq. While
the indoline/acetanilide intermediate 18 thus obtained was
equipped with the electronic properties required for the crucial
tribromination, the bromination was difficult at best probably
due to the low solubility of 18 as well as the brominated
intermediates in the solvents typically used for bromination
(CH2Cl2, CHCl3), resulting in a facile cyclization to a methyl-
quinazoline 19, even at room temperature. Fortunately, the
undesired pathway was suppressed by employing CH3NO2 as
the solvent. Treatment of a clear solution of 18 in CH3NO2 at
−20 °C with 3.0 equiv of Br2 resulted in selective bromination
at C2 and C10. Further bromination with 8.0 equiv of Br2 at room
temperature proceeded at C8 without forming the byproduct 19.
The reaction was quenched with 2-methyl-2-butene to circum-
vent oxidative N−N bond formation, furnishing the penultimate
tribromide 20 in 64% yield from the isothiocyanate 16 in a
reproducible manner.26 Finally, the amidine moiety of 1 was
constructed in 88% yield by treating 20 with an excess amount
of HC(OCH3)3 (50 equiv) and TFA (50 equiv), presumably
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