Synthesis of the Common Monomeric Unit of Uroleuconaphins and Viridaphins via Hauser-Kraus Annulation

Article abstract of DOI:10.1055/a-1334-6982

A stereoselective synthesis of a pyranonaphthoquinone derivative found in aromatic polyketide-derived aphid pigments is reported herein. This approach features the anionic [4+2]-annulation of phthalides with a carbohydrate-derived optically active enone.

Full text of DOI:10.1055/a-1334-6982

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1629–1635
paper
1629
en
K. Kitamura et al.
Paper
Synthesis
Synthesis of the Common Monomeric Unit of Uroleuconaphins
and Viridaphins via Hauser–Kraus Annulation
Kei Kitamura*
Hinano Kanagawa
Chiharu Ozakai
Taichi Nishimura
Hayato Tokuda
Tetsuto Tsunoda
Hiroto Kaku*
OH
O
O
O
O
BnO
BnO
t-BuOLi
O
O
+
OH
O
O
HO
X
BnO
Hauser–Kraus
annulation
BnO
OH
O
O
HO
(X = SO2Ph, CN)
OH
O
HO
OH
BnO
O
H
O
HO
O
BnO
O
uroleuconaphin B1
Faculty of Pharmaceutical Sciences, Tokushima
Bunri University, 180 Nishihama, Yamashiro-cho, Tokushima
770-8514, Japan
kkitamura@ph.bunri-u.ac.jp
kaku@ph.bunri-u.ac.jp
Corresponding Authors
Received: 27.11.2020
Accepted after revision: 10.12.2020
Published online: 10.12.2020
O
O
HO
O
OH
O
O
OH
DOI: 10.1055/a-1334-6982; Art ID: ss-2020-f0609-op
R
O
HO
O
O
HO
OH
HO
Abstract A stereoselective synthesis of a pyranonaphthoquinone de-
rivative found in aromatic polyketide-derived aphid pigments is report-
ed herein. This approach features the anionic [4+2]-annulation of
phthalides with a carbohydrate-derived optically active enone. Addi-
tional synthetic steps provide access to the monomer fragment of uro-
leuconaphins and viridaphins. The optimization for a facile preparation
of phthalides bearing sulfonyl or cyano groups are also studied.
O
O
OH
HO
O
HO
O
O
1
H
HO
O
O
OH
uroleuconaphin A1 (R = H)
uroleuconaphin B1 (R = OH)
viridaphin A1
Figure 1 Structure of dimeric aphid pigments
Key words aphid pigment, polyketide, dimeric pyranonaphthoqui-
none, total synthesis, natural product, anionic annulation, Hauser–
Kraus annulation
enone 6 (Scheme 1). The synthetic routes for the prepara-
tion of the substituted phthalides 4 and 5 are well-estab-
lished.9 However, their syntheses often involve long syn-
thetic steps from commercially available compounds and
we aim to optimize their synthesis to be more concise and
practical.
Uroleuconaphins and viridaphins (Figure 1) are a family
of aphid insect pigments,1 which possess structurally com-
plicated, polyketide-derived dimeric pyranonaphthoqui-
nones.2,3 They exhibit biological activities, such as antimi-
crobial activity and cytotoxicity.4,5 In addition, these pig-
ments can act as chemopreventive agents in the host
defense system against infections caused by entomopatho-
genic fungi.6 Regarding our long-standing interest in the
synthesis of a series of aphid pigments,7 the dimeric pyra-
nonaphthoquinones, such as the uroleuconaphins, are a
particularly difficult class of compounds for total synthesis.
We report herein the concise synthesis of optically active
pyranonaphthoquinone 1, the monomer unit of the aphid
pigments, by utilizing an anionic annulation of an activated
phthalide with a carbohydrate-derived chiral enone as a
key step.
O
OH
OH
O
BnO
BnO
O
O
BnO
O
BnO
OH
2
3
O
O
BnO
O
+
O
X
BnO
6
4: X = SO2Ph
5: X = CN
We envisioned that the dibenzyl-protected pyra-
nonaphthoquinone 2 would be a suitable synthetic precur-
sor to 1, which could be potentially derived from hydroqui-
none 3 by redox operations. The preparation of 3 could be
achieved via Hauser–Kraus annulation of phthalide anion
generated from 4 or 5,8 which could be combined with
Scheme 1 Synthetic plan of monomer 2
We initiated our study by using 3,5-dihydroxybenzoic
acid (7) as the starting material. Treatment of 7 with BnBr
(3 equiv) and K2CO3 (6 equiv) resulted in tribenzylation to
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1629–1635
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1630
K. Kitamura et al.
Paper
Synthesis
give ester 8 (Scheme 2). The conversion of the benzyl ester
in 8 into the corresponding N,N-diethylamide was per-
formed by treatment with diethylamine in the presence of
AlMe3 as Lewis acid in refluxing toluene.10 After separation
of the resulting benzyl alcohol by silica gel column chroma-
tography, diethylamide 9 was obtained in 93% yield.
Fortunately, the reaction performed with p-TsOH in toluene
proceeded to give the desired formation of 4 in 35% yield
(toluene, 60 °C). Homogeneous acidic conditions using 1 M
HCl in THF did not give the desired product and the starting
material was recovered.15 Interestingly, the reaction pro-
ceeded smoothly under biphasic conditions in toluene to
afford the desired sulfone 4 in 65% yield. Presumably, the
generation of the sulfinic acid in the aqueous phase might
be essential. Changing the acid to 1 M H2SO4 proceeded
more efficiently, giving the product in 89% yield.
BnBr
K2CO3
AlMe3
HNEt2
HO
CO2H
BnO
CO2Bn
BnO
CONEt2
DMF, rt
toluene, reflux
HO
BnO
BnO
quant
93%
7
8
9
Table 2 Synthesis of sulfonylphthalide 4
Scheme 2 Synthesis of N,N-diethylamide 9
O
BnO
CONEt2
CHO
BnO
PhSO2Na (3 equiv)
The optimization for ortho-formylation of amide 9 to al-
dehyde 10 is shown in Table 1. Although a two-step proce-
dure for the introduction of the formyl group via bromina-
tion for 9 was reported,11 direct C-formylation with DMF
was examined. First, treatment of 9 with t-BuLi (1.2 equiv)
and TMEDA (1.2 equiv) in Et2O gave no desired product due
to poor solubility. Changing the solvent to THF gave the
product in moderate yield (46%) and some of the starting
material was also recovered (43%). Increasing the amount of
t-BuLi (1.8 equiv) led to the formation of unidentified by-
products. Changing the formylating agent from DMF to
4-formylmorpholine12 gave a higher yield of the product.
Finally, using 2-methyltetrahydrofuran (2-MeTHF) as the
solvent gave aldehyde 10 in better yield (71%). This result is
possibly attributed to the increased chemical stability of
2-MeTHF to organolithium compounds rather than THF.13
O
conditions
SO2Ph
BnO
10
BnO
4
Entry
Reagent
Solvent
Temp (°C)
Yield (%)
1
2
3
4
5
6
AcOH
–
80
100
60
0
0
CSAa
DMF
p-TsOHa
1 M HCl
1 M HCl
toluene
THF
35
0
80
toluene
toluene
80
65
89
1 M H2SO4
80
a 3 equiv of acid.
Cyanophthalide 5, another precursor for annulation,
was prepared following a reported procedure (Scheme 3).16
Aldehyde 10 was reacted with cyanotrimethylsilane in the
presence of a catalytic amount of KCN and 18-crown-6 to
produce the corresponding cyanohydrin, which was direct-
ly converted into cyanophthalide 5 in 87% yield by exposure
to AcOH. Recrystallization from CHCl3/hexane produced
single crystals of 5 amenable for X-ray analysis (Figure 2).17
Table 1 Regioselective formylation of 9
t-BuLi (x euqiv)
TMEDA (x equiv)
–90 °C;
BnO
CONEt2
BnO
CONEt2
CHO
then
formylating reagent
BnO
BnO
9
10
O
TMSCN (1.5 equiv)
KCN (25 mol%)
18-crown-6 (10 mol%)
BnO
CONEt2
CHO
BnO
Entry
x equiv
Solventa
Reagentb
Yield (%)
O
1
2
3
4
5
1.2
1.2
1.8
1.2
1.2
Et2O
DMF
DMF
DMF
0
46
41
59
71
CH2Cl2, rt;
then AcOH
CN
BnO
10
BnO
THF
5
87%
THF
Scheme 3 Synthesis of cyanophthalide 5
THF
4-formylmorpholine
4-formylmorpholine
2-MeTHF
The optically active enone 6 was prepared starting from
the commercially available D-fucose (11). A three-step pro-
cedure18 involving peracetylation, bromination, and reduc-
tion was performed to give glycal 12 in 85% overall yield.
Treatment of 12 with TiCl4 and AlMe3 resulted in stereospe-
cific alkylation to introduce the methyl group19 affording
13. To convert acetate 13 into enone 6 via alcohol 14, the
hydrolysis of 13 was initially attempted in the presence of
LiOH in THF/MeOH/H2O. However, the extraction of 14 after
an acidic workup proved to be troublesome due to the high
a 0.1 M solution.
b 12 equiv of reagent.
Next, the direct conversion of aldehyde 10 into sulfonyl-
phthalide 4 using sodium benzenesulfinate was examined
(Table 2). By using the reaction conditions reported by
Tatsuta,14 treatment of 10 with AcOH at elevated tempera-
tures led to no reaction with full recovery of the starting
material. The use of a strong acid, such as CSA, led to
decomposition of the starting material (DMF, 100 °C).
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K. Kitamura et al.
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Synthesis
O
O
O
BnO
6
O
78%
LHMDS
THF
–78 °C to rt
OH
O
SO2Ph
BnO
BnO
4
O
O
BnO
OH
BnO
6
O
3
96%
t-BuOLi
THF
–78 °C to rt
CN
BnO
5
Figure 2 X-ray crystal structure of cyanophthalide 5
Scheme 5 Anionic [4+2] cycloaddition of phthalides 4 and 5
solubility of 14 in water. Accordingly, we developed a one-
pot procedure to access 6 by a hydrolysis–oxidation se-
quence in order to circumvent the difficult extraction pro-
cess. Treatment of 13 with LiOH in aqueous DMSO at 50 °C
followed by subsequent addition of IBX20 at 60 °C afforded
enone 6 in 71% yield (Scheme 4).
OH
O
4
OH OH
BnO
BnO
3
NaBH4
O
O
CH2Cl2, MeOH
0 ºC
1
BnO
OH
BnO
OH
15
3
Ce(NH4)2(NO3)6
MeCN, H2O
0 °C
OH
OAc
HO
1) Ac2O, HClO4
TiCl4, AlMe3
AcO
O
OH
4
O
2) HBr, AcOH
3) Zn, NaH2PO4 aq.
CH2Cl2
–78 to 0 ºC
O
HO
BnO
3
OH
11
O
1
12
85%
94%
BnO
O
2
98% (2 steps)
OAc
O
OH
O
LiOH•H2O, 50 °C;
Scheme 6 Synthesis of naphthoquinone 2
O
then IBX
DMSO, H2O
60 ºC
O
The stereochemistry of alcohol 2 was assigned by 1H
NMR study (J3,4 = 8.0 Hz).23 The 1,3-trans relationship of the
C1 methyl and C3 methyl groups in 2 was also confirmed by
NOESY spectroscopy (Figure 3A). The stereochemical model
showing the reduction of 3 is depicted in Figure 3B, where
the C1 and C3 methyl groups are positioned at the pseudo-
axial and equatorial positions, respectively. Thus, the hy-
dride agent approached from the -face for the axial attack.
71%
13
6
14
Scheme 4 Preparation of the optically active enone 6
With both the synthetic fragments in hand, we exam-
ined the anionic [4+2] cycloaddition using phthalides 4 and
5 with enone 6 (Scheme 5). First, sulfonylphthalide 4 was
treated with LHMDS (3.0 equiv) at –78 °C, which was then
reacted with 6 (1.0 equiv) by gradual warming to room
temperature to give hydroquinone 3 in 78% yield.21 Al-
though various strong bases were screened for this reac-
tion, the yield of the product could not be improved. Com-
paratively, the use of cyanophthalide 5 resulted in a higher
yield of 3. By treatment with t-BuOLi (THF, –78 °C → rt),
product 3 was obtained in 96% yield.22 In both cases the epi-
merization at the C3 position in hydroquinone 3 was not
observed.
A)
B)
O
OH
CH3
H3B–
BnO
H
O
HO
H
OH
Ha
O
O
CH3
1
CH3
3
BnO
O
Hb
H3C
H
NOESY
Ha: δ 3.88 (dq, J = 8.0, 6.2 Hz)
Hb: δ 4.97 (q, J = 6.8 Hz)
Figure 3 Stereochemical analysis of 2 and stereochemical reduction
model
The carbonyl group in hydroquinone 3 was stereoselec-
tively reduced by NaBH4 at 0 °C to afford alcohol 15 as a sin-
gle diastereomer. Although alcohol 15 was slowly oxidized
upon exposure to air, the cerium(IV)-mediated oxidation
proceeded quickly and cleanly to afford naphthoquinone 2
in 98% yield over two steps (Scheme 6).
In summary, we developed a facile and practical syn-
thetic route to optically active pyranonaphthoquinone,
which is commonly found in aphid insect pigments. Further
efforts towards the total syntheses of uroleuconaphins and
viridaphins are currently underway in our laboratory.
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K. Kitamura et al.
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Synthesis
10 min at this temperature. After further stirring for 2 h at rt, the re-
action was quenched with H2O. The products were extracted with
EtOAc (×3) and the combined extracts were washed with brine, and
dried (Na2SO4). Concentration and purification by column chromatog-
raphy (silica gel, hexane/EtOAc = 75:25 to 6:4) gave aldehyde 10 (585
mg, 71%) as a white solid; mp 112–113 °C.
All experiments dealing with air- and moisture-sensitive compounds
were conducted under an atmosphere of dry argon. THF, toluene,
DMF, and CH2Cl2 (dehydrated; Kanto Chemical Co., Inc.) were used as
received. For thin-layer chromatography (TLC) analysis, Merck pre-
coated plates (silica gel 60 F254, Art 5715, 0.25 mm) were used. For
column chromatography, Fuji Silysia BW-127ZH silica (100–270
mesh) was used. Optical rotations were measured with a JASCO P-
2300 polarimeter. Melting points were determined on a Büchi B-545
apparatus and were uncorrected. Infrared (IR) spectra were recorded
using a JASCO Model FTIR-410 spectrophotometer. 1H and 13C NMR
were measured on a Bruker AVANCE III HD-500 (500 MHz/125 MHz).
High resolution mass spectra (HRMS) were recorded with a JEOL JMS-
700 (EI/CI), Waters SYNAPT G2-Si HDMS (ESI), or a JEOL SpiralTOF
JMS-S3000 mass spectrometers (MALDI).
IR (ATR): 1678, 1592, 1427, 1323, 1219, 1163, 1054, 773, 696 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 10.39 (s, 1 H), 7.31–7.42 (m, 10 H), 6.59
(d, J = 1.8 Hz, 1 H), 6.42 (d, J = 1.8 Hz, 1 H), 5.13 (s, 2 H), 5.09 (s, 2 H),
3.56 (br, 2 H), 3.04 (q, J = 7.1 Hz, 2 H), 1.31 (t, J = 7.1 Hz, 3 H), 0.93 (t,
J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 125 MHz):  = 187.4, 169.5, 164.4, 163.1, 141.2,
135.5, 128.7, 128.4, 128.3, 127.4, 127.2, 115.5, 105.6, 100.1, 70.7, 70.4,
42.2, 38.5, 13.4, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C26H27NNaO4: 440.1838; found:
440.1836.
Benzyl Ester 8
To a solution of 3,5-dihydroxybenzoic acid (7; 2.01 g, 13.0 mmol) in
DMF (26 mL) were successively added K2CO3 (10.8 g, 77.9 mmol) and
BnBr (4.8 mL, 40 mmol) at rt. After stirring for 24 h at this tempera-
ture, the reaction was quenched with 2 M aq HCl at 0 °C. The products
were extracted with Et2O (×3) and the combined extracts were
washed with sat. aq NaHCO3 and brine, and dried (Na2SO4). Concen-
tration and purification by column chromatography (silica gel, hex-
ane/EtOAc 95:5 to 9:1) gave benzyl ester 8 (5.53 g, quant) as a white
solid; mp 65–66 °C.
Sulfonylphthalide 4
To a mixture of aldehyde 10 (216 mg, 0.517 mmol) in 1 M aq H2SO4
(5.2 mL) and toluene (5.2 mL) was added PhSO2Na (255 mg, 1.55
mmol). The mixture was stirred at 80 °C for 9 h and then diluted with
EtOAc and sat. aq NaHCO3. The products were extracted with EtOAc
(×3) and the combined extracts were washed with brine, and dried
(Na2SO4). Concentration and purification by column chromatography
(silica gel, hexane/EtOAc 8:2) gave sulfonylphthalide 4 (225 mg, 89%)
as a white solid; mp 155–156 °C.
IR (ATR): 1715, 1596, 1455, 1347, 1297, 1220, 1164, 1030, 771, 696
cm–1
.
IR (ATR): 2987, 1792, 1621, 1502, 1449, 1382, 1321, 1143, 1010, 837,
1H NMR (CDCl3, 500 MHz):  = 7.30–7.44 (m, 17 H), 6.80 (t, J = 2.2 Hz,
1 H), 5.34 (s, 2 H), 5.06 (s, 4 H).
737, 688, 583 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.85–7.89 (m, 2 H), 7.62–7.66 (m, 1 H),
7.56–7.59 (m, 2 H), 7.47–7.52 (m, 2 H), 7.34–7.45 (m, 8 H), 6.93 (d, J =
2.0 Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 6.25 (s, 1 H), 5.25 (d, J = 12.1 Hz, 1
H), 5.18 (d, J = 12.1 Hz, 1 H), 5.06 (s, 2 H).
13C NMR (CDCl3, 125 MHz):  = 167.6, 163.2, 155.8, 135.49, 135.45,
135.4, 134.6, 129.8, 129.4, 129.1, 128.8, 128.7, 128.5, 128.3, 127.6,
127.3, 120.6, 107.7, 101.2, 90.2, 71.0, 70.8.
13C NMR (CDCl3, 125 MHz):  = 166.1, 159.7, 136.4, 135.9, 132.0,
128.61, 128.57, 128.2, 128.13, 128.11, 127.6, 108.5, 107.2, 70.3, 66.8.
HRMS (ESI): m/z [M + Na]+ calcd for C28H24NaO4: 447.1572; found:
447.1565.
Diethylamide 9
To a solution of HNEt2 (5.2 mL, 50 mmol) in toluene (15 mL) was add-
ed AlMe3 (2.0 M in hexane, 13.7 mL, 27.4 mmol) at 0 °C. To this mix-
ture was added a solution of benzyl ester 8 (5.53 g, 13.0 mmol) in tol-
uene (20 mL) at rt. After stirring for 10 h under reflux, the mixture
was cooled to 0 °C and then carefully poured into ice-cold 2 M aq HCl.
The products were extracted with EtOAc (×3) and the combined ex-
tracts were washed with H2O and brine, and dried (Na2SO4). Concen-
tration and purification by column chromatography (silica gel, hex-
ane/Et2O 7:3 to 5:5) gave diethylamide 9 (4.70 g, 93%) as a white sol-
id; mp 90.6–91.1 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C28H22NaO6S: 509.1035; found:
509.1039.
Cyanophthalide 5
To a solution of aldehyde 10 (2.01 g, 4.81 mmol) in CH2Cl2 (20 mL)
were successively added TMSCN (900 L, 7.21 mmol), KCN (80.1 mg,
1.23 mmol), and 18-crown-6 (122 mg, 0.46 mmol) at 0 °C. After stir-
ring for 15 h at rt, AcOH (18 mL) was added and the mixture was fur-
ther stirred for 8 h. The reaction was quenched with 2 M aq NaOH and
the products were extracted with EtOAc (×3) and the combined ex-
tracts were washed with brine, and dried (MgSO4). Concentration and
purification by column chromatography (silica gel, hexane/EtOAc 7:3)
gave cyanophthalide 5 (1.55 g, 87%) as a white solid; mp 139.8–140.4
°C.
IR (ATR): 1643, 1594, 1509, 1429, 1295, 1220, 1160, 1037, 773 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.30–7.42 (m, 10 H), 6.63 (t, J = 2.3 Hz,
1 H), 6.58 (d, J = 2.3 Hz, 2 H), 5.04 (s, 4 H), 3.51 (br, 2 H), 3.21 (br, 2 H),
1.22 (br, 3 H), 1.02 (br, 3 H).
13C NMR (CDCl3, 125 MHz):  = 170.7, 159.9, 139.1, 136.6, 128.6,
128.0, 127.5, 105.4, 103.0, 70.2, 43.2, 39.1, 14.2, 12.8.
IR (ATR): 2359, 1780, 1610, 1506, 1328, 1220, 1166, 1093, 1009, 843,
772, 696 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO3: 390.2069; found:
390.2072.
1H NMR (CDCl3, 500 MHz):  = 7.34–7.46 (m, 10 H), 7.03 (d, J = 1.9 Hz,
1 H), 6.90 (d, J = 1.9 Hz, 1 H), 5.93 (s, 1 H), 5.21 (d, J = 11.8 Hz, 1 H),
5.16 (d, J = 11.8 Hz, 1 H), 5.09 (s, 2 H).
13C NMR (CDCl3, 125 MHz):  = 167.6, 163.2, 154.2, 135.4, 134.9,
128.9, 128.8, 128.6, 128.5, 127.6, 127.4, 127.0, 122.8, 113.3, 107.6,
101.0, 71.0, 70.9, 64.1.
Aldehyde 10
To a mixture of amide 9 (772 mg, 1.98 mmol) and TMEDA (360 L,
2.40 mmol) in 2-MeTHF (20 mL) was added t-BuLi (1.60 M in pentane,
1.5 mL, 2.4 mmol) at –90 °C. After stirring for 5 min, 4-formylmor-
pholine (2.4 mL, 24 mmol) was added and the mixture was stirred for
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1629–1635

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K. Kitamura et al.
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Synthesis
HRMS (ESI): m/z [M – H]– calcd for C23H16NO4: 370.1079; found:
370.1083.
tion and purification by column chromatography (silica gel, hexane/
Et2O 4:1) gave enone 6 (199 mg, 71%) as a colorless oil; []D21 –112 (c
1.07, CHCl3).
IR (ATR): 2980, 1689, 1449, 1373, 1232, 1096, 1023, 818, 736 cm–1
.
Diacetate 12
1H NMR (CDCl3, 500 MHz):  = 6.92 (dd, J = 2.3, 10.4 Hz, 1 H), 6.22 (dd,
J = 1.3, 10.4 Hz, 1 H), 4.61 (ddq, J = 1.3, 2.3, 7.0 Hz, 1 H), 4.34 (q, J = 7.0
Hz, 1 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.38 (d, J = 7.0 Hz, 3 H).
13C NMR (CDCl3, 125 MHz):  = 197.1, 151.8, 124.5, 73.2, 65.8, 18.7,
15.1.
To a suspension of D-fucose (11; 5.31 g, 32.4 mmol) in Ac2O (25 mL)
was added one drop of HClO4 (60%) at 0 °C. After stirring at rt for 2 h,
the mixture was concentrated in vacuo to give the corresponding per-
acetate as a colorless syrup. The peracetate was dissolved in CH2Cl2
(15 mL), which was treated with HBr (30% in AcOH, 10 mL). After stir-
ring at rt for 12 h, the mixture was diluted with CH2Cl2 and H2O and
then neutralized with sat. aq NaHCO3. The organic phase was separat-
ed and concentrated in vacuo to give the bromide as a brown oil. To
the mixture of the bromide in EtOAc (99 mL) and sat. aq NaH2PO4 (49
mL) was added Zn (21 g) and it was vigorously stirred at rt for 19 h.
The mixture was passed through a Celite® pad and the products were
extracted with EtOAc (×3) and the combined extracts were succes-
sively washed with sat. aq NaHCO3 and brine, and dried (Na2SO4).
Concentration and purification by column chromatography (silica gel,
hexane/EtOAc 8:2) gave diacetate 12 (5.88 g, 85% over 3 steps) as a
colorless oil; []D22 –14.0 (c 1.03, CHCl3).
HRMS (EI): m/z [M]+ calcd for C7H10O2: 126.0675; found: 126.0689.
Hydroquinone 3
From sulfone 4: To a solution of sulfone 4 (513 mg, 1.06 mmol) in THF
(18 mL) was added LHMDS (1.0 M in THF, 3.0 mL, 3.0 mmol) at –78 °C.
After stirring for 30 min, a solution of enone 6 (126 mg, 1.00 mmol)
was added dropwise at this temperature. The mixture was gradually
warmed to rt and stirring was continued for 6 h. The reaction was
quenched with sat. aq NH4Cl at 0 °C. The products were extracted
with EtOAc (×4) and the combined extracts were washed with brine,
and dried (MgSO4). Concentration and purification by column chro-
matography (silica gel, hexane/acetone 9:1) gave hydroquinone 3
(369 mg, 78%) as a yellow solid; mp 171–172 °C; []D22 –20.1 (c 0.45,
CHCl3).
IR (ATR): 1740, 1650, 1369, 1281, 1029, 926, 803, 731, 625 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 6.47 (dd, J = 6.3, 1.5 Hz, 1 H), 5.58 (dd,
J = 4.7, 1.5 Hz, 1 H), 5.29 (d, J = 4.7 Hz, 1 H), 4.64 (brd, J = 6.3 Hz, 1 H),
4.22 (brq, J = 6.7 Hz, 1 H), 2.16 (s, 3 H), 2.02 (s, 3 H), 1.28 (d, J = 6.7 Hz,
3 H).
13C NMR (CDCl3, 125 MHz):  = 170.7, 170.4, 146.1, 98.2, 71.5, 66.2,
65.0, 20.8, 20.7, 16.5.
From cyanide 5: To a solution of t-BuOH (320 L, 3.35 mmol) in THF (4
mL) was added n-BuLi (1.59 M in hexane, 1.9 mL, 3.0 mmol) at 0 °C.
After stirring for 10 min, cyanophthalide 5 (411 mg, 1.11 mmol) was
added at –78 °C in one portion and the mixture was stirred for 15
min. A solution of enone 6 (140 mg, 1.11 mmol) in THF (1 mL) was
then added dropwise and the mixture was gradually warmed to rt.
After further stirring for 2 h, the reaction was quenched with sat. aq
NH4Cl at 0 °C. The products were extracted with EtOAc (×4) and the
combined extracts were washed with brine, and dried (MgSO4). Con-
centration and purification by column chromatography (silica gel,
hexane/EtOAc 9:1) gave hydroquinone 3 (501 mg, 96%) as a yellow
solid.
HRMS (MALDI): m/z [M + Na]+ calcd for C10H14NaO5: 237.0733; found:
237.0733.
Allyl Acetate 13
To a solution of diacetate 12 (2.01 g, 9.36 mmol) in CH2Cl2 (46 mL)
was added TiCl4 (1.2 mL, 11 mmol) at –78 °C. After stirring for 15 min,
AlMe3 (2.0 M in hexane, 7.0 mL, 14 mmol) was added to this mixture.
After gradual warming to 0 °C, the mixture was stirred for 5 h. The
reaction was carefully quenched by sat. aq NaHCO3 and the mixture
was filtered through a Celite® pad. The products were extracted with
CH2Cl2 (×3) and the combined extracts were washed with brine, and
dried (Na2SO4). Concentration and purification by column chromatog-
raphy (silica gel, pentane/Et2O 4:1) gave allyl acetate 13 (1.49 g, 94%)
as a pale yellow oil; []D22 –377 (c 1.02, CHCl3).
IR (ATR): 3378, 3016, 1617, 1582, 1365, 1219, 1145, 966, 773, 696 cm–
1
.
1H NMR (CDCl3, 500 MHz):  = 12.75 (s, 1 H), 8.79 (s, 1 H), 7.33–7.51
(m, 11 H), 6.85 (s, 1 H), 5.41 (q, J = 6.7 Hz, 1 H), 5.21 (s, 2 H), 5.18 (s, 2
H), 4.67 (q, J = 6.6 Hz, 1 H), 1.60 (d, J = 6.7 Hz, 3 H), 1.52 (d, J = 6.6 Hz,
3 H).
13C NMR (CDCl3, 125 MHz):  = 203.1, 156.6, 156.0, 153.2, 139.6,
136.3, 134.6, 129.14, 129.11, 128.7, 128.3, 128.1, 127.9, 126.5, 119.0,
115.5, 108.1, 103.7, 97.3, 72.0, 70.4, 69.4, 67.3, 17.5, 16.3.
IR (ATR): 1729, 1367, 1232, 1054, 917, 823, 739 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 5.99 (ddd, J = 0.65, 3.1, 10.2 Hz, 1 H),
5.87 (ddd, J = 2.1, 5.1, 10.2 Hz, 1 H), 4.99 (ddd, J = 2.1, 2.8, 3.1 Hz, 1 H),
4.43 (ddq, J = 0.65, 5.1, 6.9 Hz, 1 H), 4.05 (dq, J = 2.8, 6.5 Hz, 1 H), 2.11
(s, 3 H), 1.26 (d, J = 6.9 Hz, 3 H), 1.20 (d, J = 6.5 Hz, 3 H).
HRMS (MALDI): m/z [M + Na]+ calcd for C29H26NaO6: 493.1622; found:
493.1607.
13C NMR (CDCl3, 125 MHz):  = 170.9, 136.2, 121.7, 68.5, 66.2, 65.4,
21.0, 18.2, 16.1.
Naphthoquinone 2
HRMS (CI): m/z [M + H]+ calcd for C9H15O3: 171.1016; found:
To a suspension of hydroquinone 3 (482 mg, 1.03 mmol) in CH2Cl2 (12
mL) and MeOH (12 mL) was added NaBH4 (89.0 mg, 2.35 mmol) at 0
°C. After stirring for 20 min at this temperature, the reaction was
quenched with 1 M aq HCl. The products were extracted with CH2Cl2
(×3) and the combined extracts were washed with brine, and dried
(MgSO4). After concentration, the crude alcohol 15 was diluted with
MeCN (18 mL) and H2O (2 mL) and then Ce(NH4)2(NO3)6 (1.27 g, 2.31
mmol) was added at 0 °C. After stirring for 30 min at this tempera-
ture, the mixture was diluted with H2O. The products were extracted
with CH2Cl2 (×3) and the combined extracts were washed with brine,
and dried (MgSO4). Concentration and purification by column
171.1016.
Enone 6
To a mixture of acetate 13 (376 mg, 2.21 mmol) in DMSO (10 mL) and
H2O (1 mL) was added LiOH·H2O (278 mg, 6.63 mmol). After stirring
at 50 °C for 5 h, the mixture was cooled to rt and then IBX (1.87 g, 6.69
mmol) was added. The mixture was stirred at 60 °C for 24 h and the
reaction was quenched with 2 M aq Na2S2O3 at 0 °C. The products
were extracted with CH2Cl2 (×3) and the combined extracts were suc-
cessively washed with H2O and brine, and dried (Na2SO4). Concentra-
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 1629–1635

1634
K. Kitamura et al.
Paper
Synthesis
chromatography (silica gel, hexane/acetone 80:20) gave naphthoqui-
none 2 (471 mg, 98% over 2 steps) as a yellow solid; mp 186–187 °C;
[]D22 –24.7 (c 0.72, CHCl3).
(8) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
(b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19, 2263.
(c) Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892. (d) Rathwell,
K.; Brimble, M. A. Synthesis 2007, 643. (e) Mal, D. Anionic Annu-
lations in Organic Synthesis: A Versatile and Prolific Class of Ring-
Forming Reactions; Elsevier: Amsterdam, 2019.
(9) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213.
(10) (a) Švenda, J.; Hill, N.; Myers, A. G. Proc. Natl. Acad. Sci. U. S. A.
2011, 108, 6709. (b) Magauer, T.; Smaltz, D. J.; Myers, A. G. Nat.
Chem. 2013, 5, 886. (c) Nicolaou, K. C.; Wang, Y.; Lu, M.; Mandal,
D.; Pattanayak, M. R.; Yu, R.; Shah, A. A.; Chen, J. S.; Zhang, H.;
Crawford, J. J.; Pasunoori, L.; Poudel, Y. B.; Chowdari, N. S.; Pan,
C.; Nazeer, A.; Gangwar, S.; Vite, G.; Pitsinos, E. N. J. Am. Chem.
Soc. 2016, 138, 8235.
IR (ATR): 3539, 2891, 1647, 1592, 1437, 1314, 1270, 1167, 1060, 822,
733, 694, 630, 503 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.50–7.54 (m, 2 H), 7.30–7.43 (m, 9 H),
6.83 (d, J = 2.2 Hz, 1 H), 5.21 (s, 2 H), 5.15 (s, 2 H), 4.97 (q, J = 6.8 Hz, 1
H), 4.44 (brd, J = 8.0 Hz, 1 H), 3.88 (dq, J = 8.0, 6.2 Hz, 1 H), 3.79 (brs, 1
H), 1.60 (d, J = 6.8 Hz, 3 H), 1.40 (d, J = 6.2 Hz, 3 H).
13C NMR (CDCl3, 125 MHz):  = 186.2, 181.1, 163.6, 160.8, 149.5,
138.1, 135.8, 135.5, 135.4, 128.8, 128.7, 128.6, 128.0, 127.6, 126.6,
114.8, 106.7, 104.6, 70.9, 70.7, 67.61, 67.57, 67.2, 19.2, 18.6.
HRMS (ESI): m/z [M + Na]+ calcd for C29H26NaO6: 493.1627; found:
493.1632.
(11) Shinozuka, T.; Yamamoto, Y.; Hasegawa, T.; Saito, K.; Naito, S.
Tetrahedron Lett. 2008, 49, 1619.
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49, 3856. (b) Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Chem.
Rev. 1987, 87, 671.
Funding Information
(13) (a) Aycock, D. F. Org. Process Res. Dev. 2007, 11, 156. (b) Bates, R.
B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972, 37, 560.
(14) Tatsuta, K.; Inukai, T.; Itoh, S.; Kawarasaki, M.; Nakano, Y. J. Anti-
biot. 2002, 55, 1076.
This work was supported by Grant-in-Aid for Scientific Research (C)
(No. 19K05427 and No. 20K06955) from Japan Society for the Promo-
tion of Science (JSPS).
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(15) (a) Lu, G.-p.; Cai, C.; Chen, F.; Ye, R.-l.; Zhou, B.-j. ACS Sustainable
Chem. Eng. 2016, 4, 1804. (b) Kuchukulla, R. R.; Tang, Q.; Huang,
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7169.
(17) CCDC 2041183 (5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
(18) Gagarinov, I. A.; Fang, T.; Liu, L.; Srivastava, A. D.; Boons, G.-J.
Org. Lett. 2015, 17, 928.
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455.
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M.; Ohno, Y.; Kinoshita, M. J. Antibiot. 1985, 680. (b) Tatsuta, K.;
Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. Bull. Chem. Soc.
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Hirabauashi, T.; Kojima, M.; Suzuki, Y.; Ogura, T. J. Antibiot.
2004, 57, 291. (g) Tatsuta, K.; Suzuki, Y.; Toriumi, T.; Furuya, Y.;
Hosokawa, S. Tetrahedron Lett. 2007, 48, 8018.
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Roth, B.; Sugimoto, H.; Prugh, S. J. Org. Chem. 1983, 48, 3439.
(b) Okazaki, K.; Nomura, K.; Yoshii, E. J. Chem. Soc., Chem.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1334-6982.
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