Design and Synthesis of Optically Pure Dibenzo-difuso-azacentrotriquinacene-based Pseudo-C2-Symmetric Cyclic Hydroxamic Acid

Article abstract of DOI:10.1246/cl.190592

Cyclic hydroxamic acids are found in various natural products and bioactive compounds, which exhibit various bioactivities, such as HDAC inhibition and MMP inhibition. Furthermore, they have relatively high metal binding ability, therefore they can form v

Full text of DOI:10.1246/cl.190592

CL-190592
Received: July 24, 2019 | Accepted: August 15, 2019 | Web Released: October 12, 2019
Design and Synthesis of Optically Pure Dibenzo-difuso-azacentrotriquinacene-based
Pseudo-C2-Symmetric Cyclic Hydroxamic Acid
Naoya Ohtsuka, Masato Seki, Yujiro Hoshino,* and Kiyoshi Honda*
Graduate School of Environment and Information Sciences, Yokohama National University,
Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
E-mail: hoshino-yujiro-hy@ynu.ac.jp
Cyclic hydroxamic acids are found in various natural
products and bioactive compounds, which exhibit various
bioactivities, such as HDAC inhibition and MMP inhibition.
Furthermore, they have relatively high metal binding ability,
therefore they can form various metal-complexes. Herein, we
report design, synthesis and optical resolution of dibenzo-
difuso-azacentrotriquinacene-based chiral cyclic hydroxamic
acid (CHA). CHA was synthesized from dibenzosuberenone
over 16 steps in 11% overall yield, including triflation of enol
followed by reduction of triflates using Pd catalyst and oxidation
of amide with MoO5¢2DMF as key steps. The optical resolution
was achieved by recrystallization, and the structure and absolute
configuration were determined by X-ray crystal analysis.
acids to asymmetric reaction as chiral ligands. Therefore, we
planned to synthesize a novel pseudo C2 symmetric chiral cyclic
hydroxamic acid as a ligand. It is generally considered that
durability and C2 symmetry will be required as features of chiral
ligands for application to asymmetric reactions. The use of ligand
having a rigid core is one of the methods to create a stronger
and more stable asymmetric environment. We focused on the
centrotriquinacenes as a rigid structure. Since the first synthesis
of triquinacene was reported by Woodward et al in 1964,8 many
structural features and synthetic studies of centrotriquinacenes
have been reported9 because they are attractive as a stable
hydrocarbon framework. We thought that the centrotriquinacene
could be used as a novel rigid core in chiral ligand.
On the other hand, pseudo C2 symmetrical chiral ligands also
have been reported as efficient chiral sources.10 For example,
Moberg et al. reported synthesis of pseudo C2 symmetric N,P-
ligand. They were applied to palladium catalyzed allylic alkyla-
tion as a chiral ligand, and good yields and high enantioselectiv-
ities were reported.10a Although reports of pseudo C2 symmetric
ligands are rare, it has been shown in the literature that the pseudo
C2 symmetric ligands are also efficient ligand. Therefore, within
development of novel pseudo C2 symmetric ligands remains
room for research, and synthesis of novel pseudo C2 symmetric
molecules is important. We designed a novel dibenzo-difuso-
azacentrotoriquinacene-based cyclic hydroxamic acid. Herein,
we report the establishment of a synthetic route and optical
resolution of pseudo-C2 CHA 1 (Scheme 1).
Our synthetic strategy toward cyclic hydroxamic acid is
shown in Scheme 2. According to Hashimoto’s report,11 3,3¤-
dioxo-1,1¤-spirobiindane-2,2¤-dicarboxylic acid dimethyl ester 7
would be prepared from dibenzosuberenone 2 in 6 steps. The
hydroxyl function of 7 could be removed via reduction to afford
diester 10. A half-ester 12 could be obtained from diester 10 via
hydrolysis, condensation of dicarboxylic acid into cyclic acid
anhydride, and ring-opening reaction with NaOMe. By exposing
the carboxylic acid 12 to Curtius rearrangement conditions, it
would be converted to isocyanate, followed by hydrolysis and
intramolecular cyclization to give an azacentrotriquinacene 13.
Finally, oxidation of 13 could afford CHA 1.
Keywords: Cyclic hydroxamic acid
|
Difuso-centrotriquinacene
|
Pseudo C2 symmetry
Hydroxamic acid was first synthesized by H. Lossen in
1869, from diethyl oxalate and hydroxylamine.1 It is known that
it is a family of weak organic acids and has good metal-binding
ability. The ability to chelate metal ions, such as Fe3+ and Zn2+
,
has been widely explored in biology and medicine.2,3 Among
them, the cyclic hydroxamic acids are also found in natural
products and bioactive compounds, such as HDAC inhibitors
and MMP inhibitors4 (Figure 1). Furthermore, the hydroxamic
acids are also used in synthetic organic chemistry as chiral
ligands. Since Sharpless et al. reported vanadium-catalyzed
asymmetric epoxidation of allylic alcohols with hydroxamate as
a chiral ligand in 1977,5 various hydroxamate ligands were
developed and applied to asymmetric reactions.6
Recently, Nolan et al. reported the synthesis and X-ray
crystal structure analysis of metal complexes having cyclic
hydroxamic acid as a ligand.7 Consequently, this report implies
that cyclic hydroxamic acid could form a stable metal complex
with various metal ions in bidentate chelation manner. However,
little has been reported on the application of cyclic hydroxamic
HN
NH
HO
OH
N
NH2
O
H
H
H
N
N
N
N
H3N
N
OH
H
O
O
O
O
O
This work
centrotriquinacenes
Siderophore
H3N
H
O
O
O
N
O
O
OH
OH
S
N
H
HO
O
N
NH
triquinacene difuso-centroquinacene
pseudo-C2 CHA 1
HDAC
inhibitor
MMP
inhibitor
Figure 1. Cyclic hydroxamic acids as bioactive compounds.
Scheme 1. Purpose of this study.
1328 | Chem. Lett. 2019, 48, 1328–1331 | doi:10.1246/cl.190592
© 2019 The Chemical Society of Japan

OH
OH
OTf
OH
O
Tf2O
pyridine
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CH2Cl2
rt, 18 h
Y. 99%
56% ee
OH
O
OTf
OH
10
2
7
8
7a
OTf
7b
Et3SiH
Pd(OAc)2 (10 mol%)
PPh3 (40 mol%)
Filtrate
H
H
CO2Me
CO2Me
CO2Me
CO2Me
recrystallization
nHexane
O
O
CO2Me
CO2H
97% ee of 8
Y. 56%
CH2Cl2
/
DMF, 80 °C, 18 h
Y. 97%
N
NH
OH
H
H
OTf
9
8
1
13
12
Scheme 4. Reduction of 7.
Scheme 2. Synthetic strategy of CHA 1.
O
CO2H
CO2H
HO2C
O
CO2H
(a)
(b)
3
4
2
N2
OMe
OMe
(c)
(d)
O
O
O
O
O
O
N2
6
OMe
OMe
5
O
O
Figure 2. ORTEP diagram of 8. X-ray crystal data for 8: space
groupe P-1; a = 9.968 (2) ¡, b = 11.092 (2) ¡, c = 12.423
(2) ¡; ¢ = 75.14°; V = 1259.08 (5) ¡3; Z = 2; Cu Kα radiation
(¹50 °C); R = 0.0041, Rw = 0.116.
OH
OH
(e)
CO2Me
CO2Me
CO2Me
CO2Me
OH
O
7b
presence of Tf2O and various bases in CH2Cl2 (See ESI). After
some trials, we obtained optimized conditions: Tf2O (5.0 equiv.),
pyridine (10.0 equiv.), and DMAP (10 mol %) in CH2Cl2 at
ambient temperature for 18 h, giving the triflate 8 in 99% yield.
The optical purity was found by chiral HPLC to be 56% ee,
which was slightly lower than Hashimoto’s reported value (68%
ee, after decarboxylation of 7).11 Triflate 8 could be recrystal-
lized in CH2Cl2/hexane to afford colorless crystal. The optical
purity of the crystal 8 was checked by chiral HPLC analysis to
be racemic. On the other hand, the optical purity of the filtrate of
8 was 97% ee. These results suggested that the crystal of triflate
8 formed a racemic compound. Indeed, it could be determined
by X-ray crystal analysis (Figure 2). The reduction of enantio-
merically enriched triflate 8 with triethylsilane in the presence of
a catalytic amount of Pd(OAc)2 in DMF afforded the spirobiin-
dene 9 in 97% yield.
Next, we examined selective 1,4-reduction of α,β-unsat-
urated ester of spirobiindene 9 (Scheme 5). Various conditions
were tried, e.g. H2/Pd-C, Pd(OH)2, and NaBH4 etc, but the
reactions were not completed (See ESI) to give a mixture of
starting material, mono reductant and spirobiindane 10. Then, we
examined one-electron reduction by Mg/MeOH. It occurred
smoothly to give spirobiindane 10 in 99% yield. A hydrolysis of
diester of 10 was performed in the presence of KOH in MeOH,
THF and H2O under reflux conditions for 1 h to give dicarboxylic
acid 11 in 99% yield. The dicarboxylic acid 11 was condensed in
Ac2O at 100 °C for 18 h to give cyclic carboxylic acid anhydride.
Without further purification, it was immediately subjected to
ring opening reaction with NaOMe in MeOH to afford half-ester
12 in 99% yield. To obtain azacentrotriquinacene 13, we
examined Curtius rearrangement using DPPA, subsequently
hydrolysis/intramolecular cyclization. Half-ester 12 was ex-
7a
Scheme 3. (a) KMnO4 Na2CO3/acetone, H2O, rt, 24 h. (b) Zn,
CuSO4 5H2O/28% NH3 aq., H2O, 110 °C, 36 h. (c) i) SOCl2,
DMF/toluene, reflux, 16 h, ii) MeOAc, nBuLi, Pr2NH/THF,
i
¹78 °C to 0 °C, 1 h. (d) MsN3 Et3N/CH3CN, rt, 1 h. (e) Rh2[S-
PTTL]4 2EtOAc/toluene, 0 °C, 1 h.
We initially prepared keto-dicarboxylic acid 3 from com-
mercially available dibenzosuberenone via oxidation with
KMnO4 (99% yield). Compound 3 was exposed to activated
zinc powder (13.0 equiv) in the presence of a catalytic amount
of CuSO4¢5H2O in 28%-NH3 aq. and H2O at 110 °C for 36 h to
afford dicarboxylic acid 4 in good yield. Treatment of 4 with
thionyl chloride (10.0 equiv.) in the presence of a catalytic
amount of DMF in toluene at reflux for 18 h afforded the
corresponding acid chloride, which was then reacted with
methyl acetate and LDA in THF to furnish β-keto ester 5 in 85%
1
yield (keto vs enol = 2:1, determined by H NMR). The treat-
ment of β-keto ester 5 with MsN3 in CH3CN at room tem-
perature for 1 h gave diazo 6 in 96% yield. The intramolecular
benzylic C-H insertion of carbenoid derived from diazo 6 in the
presence of a catalytic amount of Rh2[S-PTTL]4 in toluene gave
the 1,1¤-spirobiindane dimethyl ester 7 in 92% yield. It was
obtained as an equilibrium mixture of bisenol form 7a and
1
keto-enol form 7b, the ratio was 1:3.6 determined by H NMR
(Scheme 3).
With spirobiindane dimethyl ester 7 in hand, we examined
reduction of 7 (Scheme 4). The reduction of 7 was then
examined via derivatization of enol into trifluoromethanesulfo-
nate followed by silane reduction using Pd catalyst. Reaction
conditions for the synthesis of triflate were examined in the
Chem. Lett. 2019, 48, 1328–1331 | doi:10.1246/cl.190592
© 2019 The Chemical Society of Japan | 1329

H
H
(c)
O
O
1) BSA
CH3CN, reflux, 1 h
(a)
CO2Me
CO2Me
CO2R
CO2R
CO2Me
CO2H
NH
N
2) oxidant
OH
H
H
CH3CN, 35 °C 18 h
12
10 R = Me
11 R = H
9
(b)
13
1
(d)
entry
oxidant
MoOPH
yield (%)
N.R.
H
O
1
2
(e)
CO2Me
MoO5•2DMF
53
NH
H
N
C O
H
H
13
MOMCl
iPr2NEt
O
O
N
N
Scheme 5. (a) Mg/MeOH, rt, 1 h. (b) KOH/MeOH, THF,
H2O, reflux, 1 h. (c) i) Ac2O reflux, 18 h, ii) NaOMe/MeOH, rt,
1 h. (d) DPPA, Et3N/toluene, reflux, 18 h. (e) Et3N, KOH/1,4-
dioxane, H2O, 130 °C, 72 h.
OH
OMOM
CH2Cl2, rt
18 h
Y. 89%
60% ee
H
H
1
14
Scheme 6. The oxidation of azacentrotriquinacene 13 and
MOM protection.
posed to Curtius rearrangement conditions (DPPA, Et3N in
toluene at reflux for 18 h) to give isocyanate, which was then
hydrolyzed by alkaline solution and followed by intramolecular
cyclization with Et3N in 2M-KOH and 1,4-dioxane at 130 °C for
72 h to give the azacentrotriquinacene 13 in 54% yield.
Finally, we examined oxidation of amide 13 to CHA 1.
Typically, oxidation of amide to hydroxamate was performed
by silylation with N,O-bis(trimethylsilyl)acetoamide (BSA)
followed by oxidation with Vedjes reagent (MoOPH).12 We
attempted the oxidation of azacentrotriquinacene 13 under these
conditions, but it did not proceed. We thought that MoOPH was
decomposed by heating. Therefore, we chose MoO5¢2DMF,
which is reported as a stable oxidant of amide to hydroxamic
acid.13 The oxidation was performed by silylation with BSA
in CH3CN for 1 hour at 80 °C followed by treatment with
MoO5¢2DMF in CH3CN for 18 h at 35 °C to give CHA 1 in 53%
yield. With CHA 1 in hand, the optical purity was measured
by chiral HPLC after the hydroxy group of hydroxamic acid 1
was protected with MOMCl in 89% yield. The optical purity
was 60% ee, and it suggested that some steps would induce
racemization (Scheme 6).
H
H
O
O
2M-HCl aq.
recrystallization
EtOAc
(R)-1
MeOH, 50 °C
4 h
Y. 99%
N
N
Y. 53%
99% ee
OMOM
OH
H
H
Scheme 7. Optical resolution of 1.
Figure 3. ORTEP diagram of (R)-1. X-ray crystal date
for (R)-1: space group P32; a = 10.443 (10) ¡, b = 10.443
(10) ¡, c = 11.111 (10) ¡; ¢ = 90.00°; V = 1049.34 (2) ¡3;
Z = 3; Cu Kα radiation (¹50 °C); R = 0.0030, Rw = 0.076.
It was thought that the racemization would occur when
hydrolysis of diester 9 and/or preparation steps of azacentro-
triquinacene 13. To obtain the optically pure 1, we examined
optical resolution of 1. At this stage, various optical resolution
agents were also tested; however, optically pure 1 was not
obtained.
Then, we tried recrystallization of CHA 1, but crystals did
not appear. It was thought that the obstruction of crystallization
might be metal impurities within hydroxamic acid 1. To remove
the impurities from 1, first, CHA 1 was converted to O-MOM
product 14, which was purified by silica-gel column chroma-
tography. Next, the O-MOM hydroxamic acid 14 was removed
under acidic conditions at 50 °C to give the SpiroCHA 1 in
excellent yield (Scheme 7). The hydroxamic acid was recrystal-
lized from EtOAc. Fortunately, single crystals of 1 grew from
EtOAc solution at ambient temperature. The structure of 1 could
be determined by X-ray crystallographical analysis, and we
succeeded in obtaining optically pure (R)-CHA 1 in 53% yield
(Figure 3).
dibenzosuberenone was achieved in 11% overall yield in 16
steps. Although racemization occurred slightly in some steps,
the optical resolution of 1 was sufficient for recrystallization
after removing impurities to give the optically pure (R)-1 in 53%
yield. The structure of 1 was successfully verified by X-ray
crystal analysis. Further studies are in progress to apply the
cyclic hydroxamic acid 1 to asymmetric oxidation as a chiral
ligand.
This work was partly supported by Nanotechnology
Platform Program (Molecule and Material Synthesis) of the
Ministry of Education Culture, Sports, Science and Technology
(MEXT), Japan.
Supporting Information is available on https://doi.org/
10.1246/cl.190592.
Reference
In conclusion, we have designed and synthesized a novel
dibenzo-difoso-azacentrotriquinacene-based chiral cyclic hy-
droxamic acid. Synthesis of the cyclic hydroxamic acid from
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Chem. Lett. 2019, 48, 1328–1331 | doi:10.1246/cl.190592
© 2019 The Chemical Society of Japan | 1331