Synthesis and Resolution of Substituted [5]Carbohelicenes

Article abstract of DOI:10.1021/acs.joc.5b00759

Three types of racemic [5]helicenyl acetates (1a, 2, and 3a) were synthesized. The synthesis of 2 was achieved by regioselective oxidation using o-iodoxybenzoic acid. The enzymatic kinetic resolution of 1a-3a was studied. The conversion with the highest rate and ee was obtained using 1a as the substrate and lipase Amano PS-IM as the enzyme. The two enantiomers of 1-[5]helicenol 3b were separated using (1S)-10-camphorsulfonyl chloride as the chiral resolving agent.

Full text of DOI:10.1021/acs.joc.5b00759

Note
pubs.acs.org/joc
Synthesis and Resolution of Substituted [5]Carbohelicenes
,
†
†
†
†
†
‡
Kazuteru Usui,* Kosuke Yamamoto, Takashi Shimizu, Mieko Okazumi, Biao Mei, Yosuke Demizu,
‡
,†
Masaaki Kurihara, and Hiroshi Suemune*
†
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Japan and Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan
‡
*
S Supporting Information
ABSTRACT: Three types of racemic [5]helicenyl acetates
1a, 2, and 3a) were synthesized. The synthesis of 2 was
(
achieved by regioselective oxidation using o-iodoxybenzoic
acid. The enzymatic kinetic resolution of 1a−3a was studied.
The conversion with the highest rate and ee was obtained using
1
a as the substrate and lipase Amano PS-IM as the enzyme.
The two enantiomers of 1-[5]helicenol 3b were separated
using (1S)-10-camphorsulfonyl chloride as the chiral resolving agent.
[
n]Helicene derivatives are ortho-annulated aromatic rings
quantitative yield. The subsequent oxidative aromatization of
6 with dichlorodicyanobenzoquinone (DDQ) gave compound
7 in quantitative yield. Finally, the Ohira-Bestmann mod-
ification of the Seyferth-Gilbert method afforded 8 in 93% yield.
showing helical chirality. Enantiopure [n]helicenes with n ≥ 6
and [4]- and [5]-helicenes with a substituent on the interior
side of the helical aromatic framework can be isolated at room1
temperature because of their high configurational stability.
Therefore, chiral-functionalized helicenes have received con-
siderable attention for applications in chiral materials2,
asymmetric catalysis, and chiral recognition of biomolecules.
For these purposes, the preparation of enantiomerically pure
helicenes is required.
Cycloisomerization of 8 with 5 mol % PtCl at 85 °C in toluene
2
resulted in the formation of (±)-2-methoxy[5]helicene (rac-1c)
as the sole product. Its bromide, rac-1d, was characterized by X-
ray crystallography to confirm its structure (Figure 1). Rac-1c
was then readily converted by demethylation using BBr to
3
(
±)-2-[5]helicenol (rac-1b) in quantitative yield. This
The enzymatic transformation of organic substrates is well-
known as a method for the preparation of optically active
compounds. Enzymes efficiently catalyze a broad range of
chemical reactions under mild and environmentally friendly
conditions, often with very high enantioselectivity. Although
several studies have investigated the lipase-catalyzed acylation
procedure may be employed to afford rac-1b in 63% overall
yield from 4.
For the synthesis of (±)-1,2-[5]helicenyl diacetate (rac-2),
rac-1b was treated with o-iodoxybenzoic acid (IBX) in DMF to
6
afford the desired [5]helicene o-quinone (rac-9), which was
converted to rac-2 in 68% yield by a sequence of reduction and
acetylation reactions (Scheme 2). The structure of rac-9 was
confirmed by COSY, HMBC, and NOESY spectra. A
3
of thiaheterohelicenes with primary alcohols, lipase-catalyzed
direct deacylation of phenolic acetates has been reported only
4
when [5]helicene-like 4-acetate is used as a substrate. In this
context, we recently reported the synthesis of 1-functionalized
computational DFT study was performed for the regioselective7
IBX oxidation of rac-1b (Figure 2). Based on previous studies,
[
5]helicenes and the separation of the enantiomers using chiral
HPLC.
In this work, we focused on the synthesis of [5]helicenes
5
rac-1b reacts with IBX to produce aryloxy-λ -iodane
intermediates IM1a/1b, which transfer oxygen to the ortho-
site via a sigmatropic-like [2,3]-rearrangement. During this
with functional groups on the sterically hindered 1- and/or 2-
position of the helix and the development of protocols for their
optical resolution. Herein, we report a concise synthesis of
3
process, the iodine(V) atom is reduced to the λ -iodanyl species
IM2a/2b, forming o-quinone. Thus, the regioselectivity in this
reaction could be determined by the transition state of the
[
5]helicenyl acetates (rac-1a−3a), their lipase-catalyzed kinetic
resolution, and the optical resolution of (±)-1-[5]helicenol
3b) using a resolving agent. Furthermore, to gain a deeper
[2,3]-rearrangement process. Indeed, the DFT results show
that the [2,3]-rearrangement step from IM1a/1b would give
IM2a/2b via TS1a/1b, involving energy barriers of 2.4 and 4.0
(
insight into the reactivity of lipase, we conducted computational
modeling studies using [5]helicenes.
−1
kcal mol , respectively. Thus, the difference in the computed
−1
free energy barriers (1.6 kcal mol ) for the internal positions
of the oxidation processes is in good agreement with the
Initially, (±)-2-[5]helicenyl acetate (rac-1a) was synthesized
via the route shown in Scheme 1. Synthesis of alkyne 8, a
precursor of rac-1a, proceeded via the Vilsmeier−Haack
8
experimental result.
reaction of 7-methoxy-1-tetralone 4 to afford β-chloroacrolein
5
5
in 91% yield. Suzuki-Miyaura cross-coupling of 5 with 1-
Received: April 7, 2015
naphthylboronic acid afforded coupling product 6 in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of 2-[5]Helicenyl Acetate 1a
Figure 1. ORTEP drawing of 1d with 50% ellipsoid probability.
Scheme 2. Synthesis of 1,2-[5]Helicenyl Diacetate 2
(
±)-1-[5]Helicenyl acetate (rac-3a) was synthesized by our
1a
previous procedure (see the Supporting Information).
Next, we examined the hydrolysis of rac-1a−3a using several
different enzymes in tert-butylmethyl ether (MTBE) containing
water. The enzymatic hydrolysis of rac-1a was performed using
lipases at 30 °C, and the reaction course was monitored by
chiral HPLC (Daicel, Chiral IA column). The results of the
kinetic resolutions are summarized in Table 1.
Figure 2. Computational investigation of the [2,3]rearrangement
−1
pathway. The relative free energies (kcal mol , at 298 K) for the
stationary points were calculated using B3LYP with the 6-31G* basis
set for O, C, and H, and LANL2DZ for iodine. Most of the hydrogen
atoms have been omitted for clarity. IM = intermediate, TS =
transition state.
Hydrolysis of rac-1a in the presence of Amano PS proceeded
to give (+)-(P)-1b with 38% ee in 59% yield, and (−)-(M)-1a
9
of 35% ee was recovered in 41% yield (entry 1). Furthermore,
‡
Amano PS IM (where IM indicates that the lipase is
immobilized on diatomaceous earth) showed higher reactivity
than Amano PS. Other lipases such as Amano M, F-Ap15, CAL,
Amano AK, and Amano AYS showed low reactivity and/or low
enantioselectivity when rac-1a was used as a substrate (entries
barriers for racemization (ΔG ) were found to be 23.0 kcal
−
1
−3
−1
mol (k = 5.2 × 10 min , t = 133 min at 303 K) and 23.2
1
/2
kcal mol− (k = 3.5 × 1010 min , t1 = 198 min at 303 K) for
1
−3
−1
/2
1a and 1b, respectively. In order to avoid racemization, we
changed the amount of lipase used and the reaction
temperature. As a result, racemization was suppressed, and 1a
and 1b were obtained with good enantioselectivity (entries 8−
10). The hydrolysis of the configurationally stable diacetate rac-
2 gave inseparable mixtures (Figure S2), and these compounds
3
−7). Although rac-1a showed good conversion yield at 30 °C
with Amano PS IM, its enantioselectivity was low (entry 2),
probably because of the racemization of the product under the
reaction conditions employed. In fact, the Gibbs’s free energy
B
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a,b
Table 1. Optical Resolution of 1a by Lipase Catalysts
eomers (M,S)-10 and (P,S)-10 were confirmed by X-ray
crystallography (Figure 3).
ee (%)
c
d
d
entry
enzyme
time (h)
(P)-1b
(M)-1a
c (%)
1
2
3
4
5
6
7
Amano PS
Amano PS IM
Amano M
24
4
38
35
35
45
59
59
18
48
72
72
72
0.2
0.5
1
23
18
56
F-Ap 15
4
2
51
CAL
―
―
―
76
―
―
―
29
―
―
―
27
Amano AK
Amano AYS
Amano PS IM
Amano PS IM
Amano PS IM
e
8
e
9
67
67
51
e
1
0
52
92
65
a
General conditions: 1 mmol (5 mg) of substrate, 5 mg of lipase in 1
b
mL of MTBE (0.25% H O), 30 °C. The conversion values and
enantiomeric excesses were determined by HPLC using a Chiralcel IA
column. Amano PS: Burkholderia cepacia lipase; Amano M: Mucor
2
c
javanicus lipase; F-Ap 15; Rhizopus oryzae lipase; CAL: Candida
antarctica lipase; Amano AK: Pseudomonas fluorescens lipase; Amano
d
AYS; Candida rugosa lipase. Absolute configurations were determined
e
using their circular dichroism spectra. 50 mg of lipase was used at 20
°C.
were converted readily into 9 by treatment with 1 M NaOH
Figure S3 and Scheme 3). Helicene catechol would be air-
(
Scheme 3. Optical Resolution of 2 by Amano PS IM
Figure 3. ORTEP drawing of (M,S)-10 and (P,S)-10 with 50%
ellipsoid probability.
Next, we performed Amano PS lipase (PDB code 1YS1)
docking studies in silico using transition state analogues ((P)-1′
and (P)-2′) to understand the interactions between these
molecules and lipase (Figure 4). The docking calculations were
performed using MacroModel, and it was predicted that the
phosphine oxide (P)-intermediate forms hydrogen bonds
with three amino acid residues, His286, Gln88, and Leu17,
which stabilize the tetrahedral intermediate. It is noteworthy
that in both intermediates the significant intramolecular H-
bond interactions of the lipase are not interrupted.
In summary, after developing the synthesis of racemic
[5]helicenyl acetates (1a−3a), we demonstrated their lipase-
catalyzed kinetic resolution. The reactivity of [5]helicene
toward enzymatic hydrolysis was found to be highly dependent
on the position of the acetate group, as the enzymatic
hydrolysis of substrate 3a did not occur. We expect that this
optical resolution protocol will prove to be useful in the
synthesis of chiral [5]helicene compounds.
6
sensitive and undergo oxidation to give corresponding 9.
Helicene 3a is recovered with 92% ee at 55% conversion, while
a solution of isolated 9 exhibited no optical activity due to the
13
−1
11
low racemization barrier (ΔG = 19.4 kcal mol by DFT).
The configurationally stable acetate rac-3a was not hydro-
lyzed at all by lipases. This may be due to the steric hindrance
caused by the bulky helicene scaffold. Next, rac-3a was resolved
to each enantiomer by using (1S)-10-camphorsulfonyl chloride
as a resolving agent. Treatment of rac-3a with (1S)-10-
camphorsulfonyl chloride and Et N in CH Cl at room
temperature led to a mixture of two diastereomeric helicene
camphorsulfonates, (M,S)-10 and (P,S)-10, in 87% combined
yield (Scheme 4). The diastereomers were separated on a silica
gel column to give (M,S)-10 (43%) and (P,S)-10 (44%). The
subsequent desulfonylation generated enantiomerically pure
12
3
2
2
(
M)-3b and (P)-3b. The relative configurations of diaster-
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were
purchased from commercial sources and were used as received
unless otherwise noted. Reagent grade solvents (CH Cl ,
Scheme 4. Enantiomeric Resolution of 3b with (1S)-10-
Camphorsulfonyl Chloride
2
2
toluene, DMSO, DMF) were distilled prior to use. Reactions
were monitored by TLC (silica gel 60 F254, 0.25 mm) analysis.
Flash column chromatography was performed on flash silica gel
6
0N (spherical neutral, particle size 40−50 μm). HPLC
analyses were conducted with a UV detector and a chiral
1
13
column: Daicel Chiralpak IA (4.6 mm × 250 mm). H and C
NMR were recorded in CDCl3 as solvent at ambient
temperature on a 400 or 500 MHz NMR spectrometer (100
C
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 4. Modeled complexes of Amano PS with transition state analogue ((P)-1′ (a) and (P)-2′ (b)) showing the front view of the active site.
or 125 MHz for 13C NMR). Chemical shifts were reported in
was purified by flash column chromatography on silica gel
eluting with hexane−EtOAc (8:1) to afford 1b (0.92 g, quant.)
parts per million (ppm) relative to internal tetramethylsilane (δ
1
20
−2
0
7
.00 ppm) or CDCl (δ 7.26 ppm) for H NMR and CDCl (δ
as a pale yellow solid. (P)-(+)-1b [α] = +2642 (c 2.1 × 10 ,
D
20
3
3
13
−2
7.0 ppm) for C NMR. Coupling constants were reported as J
CHCl ), (M)-(−)-1b [α] = −2811 (c 2.0 × 10 , CHCl );
3
D
3
−1
values in Hertz (Hz). Splitting patterns are designated as s
mp =188−191 °C; IR (neat, cm ) 3500, 2969, 1438, 1056,
(
(
(
singlet), d (doublet), t (triplet), dd (double of doublet), ddd
doublet of doublet of doublets), br (broad), and m
multiplet). Infrared spectra of neat samples were recorded in
1033, 1011, 873, 841, 829, 764, 714, 697; UV−vis (CHCl ):
3
λ
(log ε) = 337 (4.21), 305 (4.36), 271 (4.45), 241 (4.50)
max
1
nm; H NMR (400 MHz, CDCl ): δ 8.55 (d, J = 8.6 Hz,1H),
3
ATR (attenuated total reflectance) mode using an FT-IR
instrument. HRMS were recorded on a ESI-TOF spectrometer.
Optical rotations were measured with a polarimeter using a 0.5
dm cell. CD measurements were performed on a spectropo-
larimeter with an optical path length of 1.0 mm.
7.96−7.85 (m, 8H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.2
Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.13 (dd, J = 8.8, 2.5 Hz,
1H), 4.93 (s, 1H); 13C NMR (100 MHz, CDCl ,): δ 152.6,
3
132.8, 132.7, 132.1, 132.1, 130.3, 129.7, 129.3, 127.6, 127.3,
127.3, 127.1, 126.5, 126.1, 125.9, 124.2, 124.1, 112.5; HRMS
+
Dibenzo[c,g]phenanthren-9-yl acetate (1a). To a
(ESI, Pos) m/z: [M + Na] calcd for C H NaO 317.0937,
22
14
stirred solution of 1b (0.20 g, 0.68 mmol) in CH Cl (20
found 317.0944.
2
2
mL) at 0 °C under an argon atmosphere were added
triethylamine (0.47 mL, 3.34 mmol) and acetic anhydride
9-Methoxydibenzo[c,g]phenanthrene (1c). A solution
of 8 (3.45 g, 11.18 mmol) and PtCl (0.15 g, 5 mol %) in
2
(
0.13 mL, 1.36 mmol). The reaction mixture was allowed to
toluene (56 mL) was stirred at 85 °C for 8 h under an argon
atmosphere. After cooling to room temperature, the solvent
was evaporated and the residue was purified by flash column
chromatography on silica gel eluting with hexane−EtOAc
(95:5) to afford 1c (2.58 g, 75%) as a pale yellow solid. (P)-
warm to room temperature and stirred for 2 h. The reaction
was quenched with water at 0 °C. The aqueous layer was
extracted with CH Cl . The organic layers were combined,
2
2
washed with water and brine, dried over MgSO , filtered, and
4
20
−2
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel eluting with
hexane-EtOAc (9:1) to afford 1a (0.23 mg, quant.) as a pale
(+)-1c [α]D = +2463 (c 4.5 × 10 , CHCl ), (M)-(−)-1c
3
[α]D20 = −2258 (c 1.6 × 10 , CHCl ); mp =144−145 °C; IR
−3
3
−1
(neat, cm ) 2966, 1231, 1054, 1033, 1011, 873, 842, 747;
2
0
−3
yellow solid. (P)-(+)-1a [α] = +1860 (c 8.2 × 10 , CHCl ),
UV−vis (CHCl ): λ (log ε) = 401 (2.81), 381 (3.63), 304
D
3
3
max
20
−3
1
(
1
M)-(−)-1a [α]D = −1860 (c 8.2 × 10 , CHCl ); mp =166−
(4.41), 270 (4.48), 242 (4.53) nm; H NMR (400 MHz,
3
−1
67 °C; IR (neat, cm ) 1758, 1368, 1206, 1170, 1033, 915,
48, 763, 747, 672, 663; UV−vis (CHCl ): λ (log ε) = 332
CDCl ): δ 8.46 (d, J = 8.6 Hz,1H), 7.97−7.84 (m, 8H), 7.77
3
8
(
(d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.33 (t, J = 7.7 Hz,
3
max
1
13
4.16), 305 (4.43), 269 (4.51), 240 (4.44) nm; H NMR (500
1H), 7.17 (dd, J = 8.8, 2.6 Hz, 1H), 3.49 (s, 3H); C NMR
MHz, CDCl ): δ 8.55 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 1.0 Hz,
(100 MHz, CDCl ): δ 156.5, 132.7, 132.6, 132.1, 131.9, 130.2,
3
3
1
7
1
1
1
1
H), 7.95−7.83 (m, 8H), 7.51 (ddd, J = 8.0, 6.9, 1.1 Hz 1H),
129.7, 129.3, 127.9, 127.6, 127.4, 127.2, 127.1, 127.0, 126.4,
126.2, 126.1, 124.1, 124.0, 118.0, 109.2, 54.8; HRMS (ESI, Pos)
.32 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.25 (dd, J = 8.7, 2.3 Hz,
1
3
m/z: [M + Na]+ calcd for C H NaO 331.1093, found
H), 2.20 (s, 3H); C NMR (125 MHz, CDCl ): δ 169.7,
3
23 16
47.5, 132.7, 132.6, 132.3, 131.6, 130.7, 130.3, 129.2, 128.9,
27.8, 127.7, 127.6, 127.2, 127.1, 127.0, 126.7, 126.4, 126.3+,
24.9, 121.2, 120.7, 21.1; HRMS (ESI, Pos) m/z: [M + Na]
331.1093.
2-Bromo-12-methoxydibenzo[c,g]phenanthrene (1d).
Compound 1d was prepared according to Majetich’s
14
calcd for C H O Na 359.1043, found 359.1075.
procedure. To a solution of 1c (30.0 mg, 0.10 mmol) in
acetic acid (0.6 mL) were added dropwise 48% aqueous HBr
(0.9 mL) and DMSO (0.8 mL). The reaction mixture was
stirred at room temperature for 44 h. After cooling to 0 °C, the
reaction mixture was treated with saturated aqueous solution of
24
16
2
Dibenzo[c,g]phenanthren-9-ol (1b). To a solution of 1c
(
0.97 g, 3.15 mmol) in CH Cl (31 mL) at −10 °C under an
2
2
argon atmosphere was added dropwise a 1.0 M solution of BBr3
in CH Cl (6.3 mL, 6.30 mmol). The reaction mixture was
2
2
allowed to warm to room temperature and stirred for 3 h. The
reaction was quenched with water at 0 °C. The aqueous layer
was extracted and with CH Cl . The organic layers were
NaHCO to adjust to pH = 6 and then extracted with EtOAc,
3
dried over MgSO , filtered, and concentrated under reduced
4
pressure. The residue was purified by flash column chromatog-
raphy on silica gel eluting with hexane-CH Cl (9:1) to afford
2
2
combined, washed with water and brine, dried over MgSO4,
2
2
filtered, and concentrated under reduced pressure. The residue
1d (10.0 mg, 26%) as a yellow solid. mp = 204−206 °C; IR
D
DOI: 10.1021/acs.joc.5b00759
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The Journal of Organic Chemistry
Note
−
1
1
(
neat, cm ) 2938, 1231, 1056, 1033, 1012, 880, 840, 806, 753;
(4.42), 240 (4.41), 270 (4.45) nm; H NMR (500 MHz,
1
H NMR (400 MHz, CDCl ): δ 8.36 (t, J = 8.6 Hz, 2H), 8,20,
CDCl ): δ 8.14 (d, J = 8.5 Hz, 1H), 7.94−7.85 (m, 8H), 7.60
(t, J = 7.8 Hz, 1H), 7.52 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.26
(ddd, J = 7.8, 6.9, 1.4 Hz, 1H), 7.17 (dd, J = 8.7, 1.1 Hz, 1H),
1.03 (s, 3H); C NMR (125 MHz, CDCl
134.4, 132.9, 132.8, 131.2, 131.1, 127.9, 127.7, 127.5, 127.1,
127.0, 126.7, 126.3, 125.9, 125.8, 125.7, 125.4, 124.8, 122.3,
119.4, 19.7; HRMS (ESI, Pos) m/z: [M + Na] calcd for
Na 359.1043, found 359.1062.
Dibenzo[c,g]phenanthren-10-ol ((M)-(−)-3b and (P)-
(+)-3b). To a solution of 10 (25.0 mg, 0.05 mmol, dr 20:1) in 2
mL of THF/MeOH (3:1) was added 3 M NaOH (0.5 mL).
The reaction mixture was heated at 60 °C for 1 h. After cooling
to room temperature, the reaction mixture was neutralized with
3
3
(
(
3
1
1
5
s, 1H), 7.96−7.87 (m, 4H), 7.77−7.74 (m, 2H), 7.53−7.50
m, 1H), 7.34−7.30 (m, 1H), 7.18 (dd, J = 8.8, 2.4 Hz, 1H),
.45 (s, 3H); 13C NMR (100 MHz, CDCl ): δ 157.4, 133.2,
13
): δ 168.1, 147.9,
3
3
33.8, 131.7, 131.3, 130.7, 130.6, 130.0, 128.9, 128.4, 128.3,
278.0, 127.0, 126.8, 126.6, 126.4, 124.9, 119.0, 118.6, 110.7,
5.2; HRMS (ESI, Pos) m/z: [M + Na]+ calcd for
+
C H BrNaO 409.0198, found 409.0204.
C
24
H
16
O
2
2
3
15
Dibenzo[c,g]phenanthrene-9,10-diyl Diacetate (2). (a)
To a solution of 1b (30.0 mg, 0.10 mmol) in DMF (0.8 mL) at
°C under an argon atmosphere was added 81 mg (0.11
mmol) of stabilized 2-iodoxybenzoic acid (IBX) composition
39% w/w of IBX). The mixture was allowed to warm to room
temperature and stirred for 1 h. The reaction mixture was
diluted with hexane−EtOAc (4:1), and the organic layers were
washed with water and with brine. The organic layers was dried
over Na SO , filtered, and concentrated under reduced pressure
to give the crude product as a dark red solid. The crude mixture
was dried in vacuo for 1 h, and then subjected to the next
reaction without further purification. (b) To a crude solution of
in DMF (0.5 mL) at 0 °C under an argon atmosphere was
added NaBH (19 mg, 0.50 mmol). The mixture was allowed to
warm to room temperature and stirred for 0.5 h. To the
reaction mixture were added acetic anhydride (57 μL, 0.60
mmol) and Na CO (64 mg, 0.60 mmol). After 20 h, additional
acetic anhydride (57 μL, 0.6 mmol) was added and the mixture
was stirred overnight. The reaction was quenched with water at
°C. The aqueous layer was extracted and with hexane−EtOAc
4:1). The organic layers were combined, washed with water
and brine, dried over anhydrous Na SO , filtered, and
0
(
10% HCl and extracted with Et
combined; washed with saturated aqueous NaHCO
and brine; dried over MgSO ; filtered; and concentrated under
O. The organic layers were
2
, water,
3
4
reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with hexane−EtOAc (9:1)
to give 3b. (M)-(−)-3b (12.9 mg, 88%, 93% ee) was obtained
from (M,S)-10 as a pale yellow foam. (P)-(+)-3b (13.4 mg,
2
4
9
91%, 91% ee) was obtained from (P,S)-10 as a pale yellow
1
foam. (M)-(−)-3b: H NMR (500 MHz, CDCl
): δ 8.27 (d, J
3
4
= 8.6 Hz,1H), 8.00−7.93 (m, 6H), 7.85 (d, J = 8.5 Hz, 1H),
7.65 (d, J = 7.8 Hz, 1H), 7.59−7.55 (m, 2H), 7.31 (ddd, J = 8.4,
7.1, 1.3 Hz, 1H), 6.95 (dd, J = 7.6, 1.0 Hz, 1H), 5.11 (br s, 1H).
2
3
1
(P)-(−)-3b: H NMR (500 MHz, CDCl
): δ 8.27 (d, J = 8.6
3
Hz,1H), 8.00−7.93 (m, 6H), 7.85 (d, J = 8.5 Hz, 1H), 7.65 (d, J
= 7.9 Hz, 1H), 7.59−7.55 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H),
6.95 (d, J = 7.6 Hz, 1H), 5.11 (br s, 1H). Spectroscopic data are
0
(
1a
consistent with our previous report.
2
4
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel eluting with
1-Chloro-7-methoxy-3,4-dihydronaphthalene-2-car-
baldehyde (5). To a solution of DMF (4.4 mL, 56.70 mmol)
hexane−Et O (8:1) to give 2 (27.0 mg, 68%) as an ivory solid.
at 0 °C was added dropwise POCl (4.2 mL, 45.40 mmol). The
2
3
20
−3
(
P)-(+)-2 [α] = +1702 (c 11.3 × 10 , CHCl ), (M)-(−)-2
reaction mixture was warmed to 90 °C and stirred for 1 h to
form the Vilsmeier salt. After cooling to 0 °C, 7-methoxy-α-
tetralone (4) (5.0 g, 28.40 mmol) was added, and the reaction
mixture was stirred at 90 °C for 2 h. The reaction was
D
3
−3
[
(
α]D20 = −1665 (c 13.3 × 10 , CHCl ); mp = 213−215 °C; IR
3
−1
neat, cm ); 3276, 2969, 2331, 1764, 1371, 1205, 1159, 1057,
1
=
033, 1012, 841, 746, 675, 659; UV−vis (CHCl ): λ (log ε)
3
max
1
309 (4.57), 266 (4.43), 240 (4.49) nm; H NMR (500 MHz,
quenched with saturated aqueous NaHCO at 0 °C. The
3
CDCl ): δ 8.21 (d, J = 8.5 Hz, 1H), 7.91−7.77 (m, 8H), 7.50
aqueous layer was extracted and with CH Cl . The organic
3
2
2
(
(
ddd, J = 8.0, 7.0, 1.0 Hz 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.31
ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 2.18 (s, 3H), 1.03 (s, 3H); C
layers were combined, washed with water and brine, dried over
13
anhydrous Na SO , filtered, and concentrated under reduced
2
4
NMR (125 MHz, CDCl ): δ 168.8, 167.01, 140.8, 139.0, 133.2,
pressure. The residue was purified by flash column chromatog-
3
1
1
32.6, 132.1, 131.3, 131.0, 128.3, 127.6, 127.4, 127.3, 127.0,
raphy on silica gel eluting with hexane−EtOAc (9:1) to afford 5
1
26.9, 126.7, 126.4, 126.1, 126.0, 125.7, 122.3, 121.7, 20.7, 19.3;
(5.7 g, 91%) as an orange solid. H NMR (400 MHz, CDCl ):
3
+
HRMS (ESI, Pos) m/z: [M + Na] calcd for C H O Na
δ 10.39 (s, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.14 (d, J = 8.2 Hz,
1H), 6.92 (dd, J = 8.2, 2.6 Hz, 1H), 3.86 (s, 3H), 2.80−2.76
(m, 2H), 2.65−2.60 (m, 2H). Spectroscopic data are consistent
2
6
18
4
4
17.1097, found 417.1135.
Dibenzo[c,g]phenanthren-10-yl Acetate (3a). To a
stirred solution of 3b (50.0 mg, 0.17 mmol) in CH Cl (1.7
15
with the literature.
2
2
mL) at 0 °C under an argon atmosphere were added
7-Methoxy-3,4-dihydro-[1,1′-binaphthalene]-2-car-
baldehyde (6). A suspension of 5 (690 mg, 3.1 mmol), 1-
naphtylboronic acid (0.58 g, 3.40 mmol), tetrabutylammonium
triethylamine (36.0 μL, 0.25 mmol) and acetic anhydride
(24.0 μL, 0.25 mmol). The mixture was allowed to warm to
room temperature and stirred for 1.5 h. The reaction was
quenched with water at 0 °C. The aqueous layer was extracted
and with EtOAc. The organic layers were combined, washed
with water and brine, dried over anhydrous Na SO , filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel eluting
bromide (0.99 g, 3.10 mmol), Pd(OAc) (34.0 mg, 5 mol %),
2
and K CO (0.85 g, 6.10 mmol) in degassed water (6 mL) was
2
3
stirred at 45 °C under an argon atmosphere for 1.5 h. After
cooling to room temperature, the reaction mixture was diluted
with water and extracted with EtOAc. The organic layers were
combined, washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
eluting with hexane−EtOAc (9:1) to afford 6 (0.97 g, quant.)
2
4
with hexane−Et O (5:1) to give 3a (49.0 mg, 98%) as a white
2
2
0
−2
solid. (P)-(+)-3a [α] = +2046 (c 1.3 × 10 , CHCl ), (M)-
D
3
20
−2
(
1
6
−)-3a [α]D = −1815 (c 1.3 × 10 , CHCl ); mp = 155−
3
−1
−1
157 °C; IR (neat, cm ) 3462, 2328, 1755, 1203, 838, 751,
71, 659; UV−vis (CHCl ): λ (log ε) = 309 (4.55), 266
as a pale yellow solid. mp = 100−103 °C; IR (neat, cm ) 2928,
1655, 1566, 1362, 1300, 1232, 1124, 1044, 815, 798, 779, 747,
3
max
E
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
7
1
7
09; H NMR (400 MHz, CDCl ): δ 9.38 (s, 1H), 7.92 (dd, J =
(1:1) to give the compound 9 as a dark red solid (30 mg, 97%
yield). mp = 166 °C (decomposition); IR (neat, cm ) 2923,
3
−1
2.5, 8.2 Hz, 2H), 7.58−7.46 (m, 3H), 7.42−7.36 (m, 2H),
.22 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 8.2, 2.6 Hz, 1H), 6.21 (d,
J = 2.6 Hz, 1H), 3.21 (s, 3H), 3.00−2.83 (m, 3H), 2.73−2.64
m, 1H); C NMR (100 MHz, CDCl ): δ 193.0, 158.3, 152.9,
36.3, 136.1, 133.5, 132.7, 132.6, 130.3, 128.9, 128.5, 128.4,
26.8, 126.3, 125.8, 125.0, 114.8, 114.4, 55.1, 26.8, 20.5; HRMS
ESI, Pos) m/z: [M + Na] calcd for C H NaO 337.1199,
found 337.1195.
2
330, 1733, 1389, 1262, 1055, 1033, 1013, 808, 759, 724, 689,
6
56; UV−vis (CHCl ): λ (log ε) = 368 (3.42), 351 (3.39),
3
max
13
(
1
1
1
3
298 (4.06), 280 (4.07), 243 (4.23) nm; H NMR (500 MHz,
CDCl ): δ 8.41 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H)
3
7
3
.97−7.78 (m, 5H), 7.65 (d, J = 9.6 Hz, 1H), 7.54−7.47 (m,
+
(
2
2
18
2
13
H), 6.49 (d, J = 10.0 Hz, 1H); C NMR (125 MHz, CDCl ):
3
δ 185.0, 184.4, 146.8, 136.3, 135.9, 135.7, 134.8, 133.3, 133.3,
7
-Methoxy-[1,1′-binaphthalene]-2-carbaldehyde (7).
1
1
31.8, 130.0, 128.8, 128.7, 128.6, 128.5, 127.8, 127.6, 127.1,
27.0, 126.6, 126.3; HRMS (ESI, Pos) m/z: [M + Na] calcd
To a stirred solution of 6 (1.44 g, 4.60 mmol) in toluene (26
mL) was added DDQ (1.40 g, 5.7 mmol). The resulting
solution was heated at 60 °C for 3 h. After cooling to room
temperature, the resultant precipitate was removed by suction
filtration. The filtrate was washed with 1 N NaOH and
extracted with toluene. The organic layers were combined,
+
for C H O Na 331.0730, found 331.0744.
22 12
2
Dibenzo[c,g]phenanthren-10-yl ((1S)-7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate ((M,S)-
10 and (P,S)-10). To a stirred solution of rac-3b (48.0 mg,
0.16 mmol) and (1S)-camphorsulfonyl chloride (0.10 g, 0.40
mmol) in CH Cl at 0 °C under an argon atmosphere were
washed with water and brine, dried over MgSO , filtered, and
4
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel eluting with
hexane−EtOAc (9:1) to afford 7 (1.43 g, quant.) as a white
2
2
added triethylamine (81.0 mg, 0.80 mmol) and DMAP (2.4 mg,
0
.02 mmol). The reaction mixture was allowed to warm to
−1
solid. mp = 75−76 °C; IR (neat, cm ) 3007, 1688, 1620, 1506,
room temperature and stirred for 15 min. The reaction was
quenched with 10% HCl. The resultant solution was
1
7
(
454, 1425, 1275, 1178, 1070, 1027, 983, 843, 808, 790, 778,
1
30; H NMR (400 MHz, CDCl ): δ 9.64 (s, 1H), 8.04−7.94
3
neutralized with saturated aqueous NaHCO and extracted
3
m, 4H), 7.87 (d, J = 9.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H),
with CH Cl . The organic layers were combined, washed with
2
2
7
.53−7.48 (m, 2H), 7.32 (m, 1H), 7.28−7.23 (m,2H), 6.63 (d,
J = 7.7 Hz, 1H), 3.49 (s, 3H); C NMR (100 MHz, CDCl ): δ
92.5, 158.2, 143.3, 134.3, 133.3, 133.2, 133.1, 132.5, 131.6,
29.6, 129.0, 128.8, 128.3, 126.7, 126.2, 126.0, 125.0, 121.0,
13
water and brine, dried over MgSO , filtered, and concentrated
4
3
under reduced pressure. The diastereomixture was separated by
flash column chromatography on silica gel eluting with hexane-
1
1
1
+
Et O-EtOAc (8:1:1) to afford (M,S)-10 (early eluting fraction)
20.0, 106.2, 55.0; HRMS (ESI, Pos) m/z: [M + Na] calcd for
2
C H NaO 335.1043, found 335.1043.
as a white foam (35.0 mg, 43%, dr 20:1) and (P,S)-10 (late
eluting fraction) as white foam (36.0 mg, 44%, dr 20:1). (M,S)-
2
2
16
2
2
-Ethynyl-7-methoxy-1,1′-binaphthalene (8). To a
10: [α]D20 = −1350 (c 4.0 × 10 , CHCl ); mp = 222−225 °C;
−3
stirred suspension of 7 (3.75 g, 12.0 mmol) and K PO (3.31
3
4
3
−1
g, 15.6 mmol) in MeOH (120 mL) at room temperature under
an argon atmosphere was added a solution of Ohira-Bestmann
reagent (3.43 g, 15.6 mmol) in MeOH (15.6 mL). The reaction
mixture was stirred overnight at the same temperature. After
removing the MeOH under reduced pressure, the residue was
diluted with EtOAc and washed with H O. The organic layers
were combined, washed with water and brine, dried over
MgSO , filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
IR (neat, cm ) 1747, 1354, 1177, 1160, 1101, 1055, 996, 913,
8
43, 824, 674, 684; UV−vis (CHCl ): λ
(log ε) = 310
3
max
1
(
4.51), 266 (4.40), 240 (4.40) nm; H NMR (500 MHz,
CDCl ): δ 8.06 (d, J = 8.5 Hz, 1H), 8.00−7.86 (m, 8H), 7.62
3
(
(
t, J = 7.8 Hz, 1H), 7.54 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.46
dd, J = 7.6, 1.2 Hz, 1H), 7.28 (ddd, J = 8.5, 6.4, 1.4 Hz, 1H),
2
2
1
1
.48 (d, J = 14.8 Hz, 1H), 2.24 (ddd, J = 16.9, 3.8, 3.8 Hz, 1H),
4
.93−1.88 (m, 2H), 1.81−1.73 (m, 2H), 1.32 (d, J = 14.8 Hz,
1
3
H), 1.29−1.19 (m, 2H), 0.67 (s, 3H), 0.59 (s, 3H); C NMR
gel eluting with hexane−EtOAc (95:5) to afford 8 (3.45 g,
−1
(125 MHz, CDCl ): δ 213.1, 144.8, 134.7, 133.1, 132.6, 131.3,
9
3
1
3%) as a pale yellow solid. mp = 87−89 °C; IR (neat, cm )
3
1
31.1, 128.2, 128.1, 127.9, 127.8, 127.4, 126.94, 126.90, 126.7,
285, 2970, 1619, 1506, 1458, 1419, 1274, 1258, 1144, 1056,
1
033, 844, 781; H NMR (400 MHz, CDCl ): δ 7.95 (t, J = 8.8
126.6, 126.3, 125.7, 125.6, 125.5, 125.4, 122.1, 120.9, 57.2, 47.6,
3
Hz, 2H), 7.82 (dd, J = 8.7, 6.5 Hz, 2H), 7.70−7.75 (m, 2H),
.49−7.45 (m, 2H), 7.30−7.29 (m, 2H), 7.15 (dd, J = 9.0, 2.6
Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.47 (s, 3H), 2.77 (s, 1H);
47.1, 42.6, 42.3, 26.7, 24.3, 19.4, 19.3; HRMS (ESI, Pos) m/z:
+
7
[M + Na] calcd for C H NaO S 531.1601, found 531.1605.
3
2
28
4
(P,S)-10: [α]D20 = +1100 (c 4.0 × 10 , CHCl ); mp = 185−
−3
3
1
3
−
1
C NMR (100 MHz, CDCl ): δ 158.1, 140.7, 136.6, 134.0,
3
188 °C; IR (neat, cm ) 1747, 1357, 996, 913, 842, 675, 663;
UV−vis (CHCl ): λ (log ε) = 310 (4.55), 266 (4.43), 240
1
1
33.6, 132.4, 129.4, 128.7, 128.1, 128.1, 128.0, 127.5, 126.8,
3
max
1
26.1, 126.0, 126.0, 125.4, 120.6, 119.0, 105.5, 83.3, 80.8, 55.0;
(
4.42) nm; H NMR (500 MHz, CDCl ): δ 8.07 (d, J = 8.6 Hz,
3
+
HRMS (ESI, Pos) m/z: [M + Na] calcd for C H NaO
2
3
16
1H), 8.02−7.87 (m, 8H), 7.62 (t, J = 7.8 Hz, 1H), 7.53 (ddd, J
3
31.1093, found 331.1105.
Dibenzo[c,g]phenanthrene-9,10-dione (9). To a sol-
=
8.0, 6.9, 1.1 Hz, 1H), 7.42 (dd, J = 7.7, 1.3 Hz, 1H), 7.29−
7
.26 (m, 1H), 2.18 (ddd, J = 18.4, 4.7, 2.5 Hz, 1H), 2.00 (d, J =
ution of 1b (30 mg, 0.10 mmol) in DMF (mL) at 0 °C under
an argon atmosphere was added 81 mg (0.11 mmol) of
stabilized 2-iodoxybenzoic acid (IBX) composition (39% w/w
of IBX). The reaction mixture was allowed to warm to room
temperature and stirred for 1 h. The reaction mixture was
extracted with EtOAc, washed with water, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure to
1
4.8 Hz, 1H), 1.93−1.79 (m, 3H), 1.73 (s, 1H), 1.69 (d, J = 3.2
1
3
Hz, 1H), 1.25−1.22 (m, 2H), 0.78 (s, 3H), 0.58 (s, 3H);
NMR (125 MHz, CDCl ): δ 213.1, 145.5, 134.7, 133.1, 132.6,
C
3
1
1
1
31.4, 131.1, 128.3, 128.2, 127.8, 127.7, 127.4, 127.0, 126.9,
26.7, 126.40, 126.35, 125.6, 125.64, 125.58, 124.9, 121.9,
20.5, 57.3, 47.6, 46.9, 42.7, 42.2, 26.7, 24.7, 19.6, 19.4; HRMS
2
4
+
give the crude product. The crude product was purified by flash
(ESI, Pos) m/z: [M + Na] calcd for C32
H28NaO
4
S 531.1601,
column chromatography over silica gel with hexane−Et O
found 531.1606.
2
F
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
R. R. Org. Lett. 2002, 4, 285. (e) Nicolaou, K. C.; Montagnon, T.;
Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245.
ASSOCIATED CONTENT
■
*
S
Supporting Information
(8) The regioselectivity of oxygen insertion for rac-1b did not change
1
H and 13C NMR spectra of all new compounds, ORTEP/X-
from that of the 2-naphotol and 3-phenanthrenol building blocks.
(9) The absolute configuration of [5]helicenes was established by the
CD exciton chirality method (Figure S1).
ray and CIF data for single-crystal X-ray analyses of compounds
d (CCDC 901873), (M, S)-10 (CCDC 1051698), and (P, S)-
0 (CCDC 1051700), HPLC analysis graphs for enzymatic
hydrolysis experiments for compounds 1a and 2, kinetic data
for racemization for compounds 1a−c, computational details,
Cartesian coordinates for all calculated structures, ORTEP
drawings of compounds 1d, (P, S)-10, and (M, S)-10, CD
spectra of 1a, 1b, 1c, 2, 3a, and 10. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b00759.
1
1
‡
(10) Gibbs’s free energy barriers to racemization (ΔG ) of 1a and 1b
were measured on the basis of the time-dependent conversion rate (%
‡
ee) estimated from chiral HPLC analysis (Figure S4). The ΔG value
at 303 K of 1a and 1b were almost the same as that of [5]helicene.
‡
(
11) Gibb’s free energy barriers to racemization (ΔG ) of 9 could not
be determined because it decomposed. Hence, the racemization barrier
of 9 is estimated by DFT (Figure S6).
(
12) (a) Thongpanchang, T.; Paruch, K.; Katz, T. J.; Rheingold, A.
L.; Lam, K.-C.; Liable-Sands, L. J. Org. Chem. 2000, 65, 1850.
b) Braiek, M. B.; Aloui, F.; Hassine, B. B. Tetrahedron. Lett. 2013, 54,
(
AUTHOR INFORMATION
424. (c) Surampudi, S. K.; Nagarjuna, G.; Okamoto, D.; Chaudhuri, P.
D.; Venkataraman, D. J. Org. Chem. 2012, 77, 2074.
■
Corresponding Authors
E-mail: usui@phar.kyushu-u.ac.jp.
E-mail: suemune@phar.kyushu-u.ac.jp.
(13) Tanaka, M.; Demizu, Y.; Nagano, M.; Hama, M.; Yoshida, Y.;
*
Kurihara, M.; Suemune, H. J. Org. Chem. 2007, 72, 7750.
*
(14) Majetich, G.; Hicks, R.; Reister, S. J. Org. Chem. 1997, 62, 4321.
(
15) LaFrate, A. L.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen,
Notes
J. A. Bioorg. Med. Chem. 2008, 16, 10075.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid for
Scientific Research (C) from the Japan Society for the
Promotion of Science (No. 25410096) and Platform for
Drug Discovery, Informatics, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan. K.Y. acknowledges support from JSPS
research fellowship. We thank Amano Pharmaceutical Co., Ltd.,
for kindly providing lipases. We also thank Professor Masakazu
Tanaka (Nagasaki University) for the helpful discussions.
REFERENCES
■
(
1) (a) Yamamoto, K.; Okazumi, M.; Suemune, H.; Usui, K. Org.
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(
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(
(
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(
Kathan, M.; Shen, C.; Mazzolini, M.; Trapp, N.; Crassous, J.;
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(
7) Regioselective IBX oxidation, see: (a) Wu, A.; Duan, Y.; Xu, D.;
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(
́
Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 5908. (c) Pezzella, A.;
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(
d) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T.
G
DOI: 10.1021/acs.joc.5b00759
J. Org. Chem. XXXX, XXX, XXX−XXX