Total Synthesis of (&#177;)-Liphagal via Organic-Redox-Driven Palladium-Catalyzed Hydroxybenzofuran Formation

Catalyzed Hydroxybenzofuran Formation

Article

Total Synthesis of (± )-Liphagal via Organic-Redox-Driven Palladium-

Eriko Tao, Masaki Inoue, Taejoo Jeong, In Su Kim, and Takehiko Yoshimitsu*

Cite This: https://dx.doi.org/10.1021/acs.joc.0c00965

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sı Supporting Information

ABSTRACT: A synthetic route to liphagal, a natural PI3Kα

inhibitor isolated from Aka coralliphaga, was established. The

present route features an organic redox process where an

alkynylquinone undergoes reductive cyclization in the presence of

a hydroquinone derivative such as hydroxyquinol (1,2,4-benzene-

triol) and catalytic PdCl to provide a substituted benzofuran

suitable for accessing the natural product. The benzofuran

formation takes place via the redox transformation between the

alkynylquinone and the electron-rich hydroquinones followed by

the concomitant Pd(II)-catalyzed oxycyclization of the resultant

alkynylhydroquinone.

INTRODUCTION

alkenylated benzofuran derivatives constitutes one of the

powerful means to construct the tetracyclic molecular

architecture. Thus, an eﬃcient access to alkenylated benzofur-

ans that bear appropriate functionalities suitable for generating

the natural product is needed. However, there is still room for

devising a facile approach to the substituted benzofurans. In

the present study, we disclose a new synthetic route to

(±)-liphagal (1), which features a unique means of an organic-

redox-driven palladium-catalyzed hydroxybenzofuran forma-

tion directly from an alkynylated quinone.

■

Meroterpenoids are widely present in nature and exhibit a

broad range of biological activities relevant to medicinal

applications. Liphagal (1) is a unique tetracyclic meroterpe-

noid isolated from the marine sponge Aka coralliphaga

collected in Dominica and shows selective inhibitory activity

against PI3Kα that belongs to the phosphoinositide 3-kinase

family (Figure 1 ). As the inhibition of the PI3Kα-mediated

RESULTS AND DISCUSSION

■

In our retrosynthetic analysis, we envisioned that hydrox-

ybenzofuran 2, a reasonable precursor for polyene cyclization,

would be synthesized by Pd(II)-catalyzed oxycyclization of

alkynylhydroquinone 3 (Scheme 1). Compound 3 would, in

turn, be available from alkynylquinone 5, which would be

derived by palladium-catalyzed cross-coupling between alkyne

and iodoquinone 7. In addition to this picture of the

Figure 1. Chemical structure of liphagal (1).

synthetic strategy in mind, we also endeavored to streamline

the access to hydroxybenzofuran 2 from alkynylquinone 5

without isolating labile alkynylhydroquinone derivative 3. As

described below, these eﬀorts have eventually allowed us to

develop a unique access from 5 directly to 2 via a new

palladium-catalyzed oxycyclization under quinone−hydroqui-

biological process leads to the suppression of tumor

progression, PI3Kα inhibitors are expected to serve as

invaluable sources for developing anticancer agents. Because

of its pronounced biological property, liphagal (1) has gained

considerable attention from medicinal and synthetic chemists.

In this context, successful eﬀorts have been made independ-

Received: April 19, 2020

ently by the groups of Andersen, Mehta, George, Alvarez-

Manzaneda, Kumar, Stoltz, Katoh, Ferreira, and Wu to

chemically synthesize this natural product. In addition,

Winne and Zhu have reported the synthesis of C5-epi-

liphagal and C8-epi-liphagal, respectively. Among the synthetic

strategies developed so far, the polyene cyclization of

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 1. Retrosynthetic Analysis of (± )-Liphagal

hydrolysis of malonate 10 under Gassman conditions and

subsequent decarboxylation in reﬂuxing xylene gave carboxylic

acid (structure not shown), which was reduced with LiAlH to

provide alcohol 11 in 91% yield in three steps. The Swern

oxidation of alcohol 11 followed by the Corey−Fuchs

dibromoalkenylation furnished alkene 12 (75%). Alkyne 6

was secured by exposing alkene 12 to n-BuLi (95%). The

Sonogashira coupling of alkyne 6 with iodoquinone 7

smoothly took place to provide alkynylquinone 5 in 73% yield.

With quinone 5 in possession, we examined the preparation

of hydroquinone 3, a synthetic precursor of hydroxybenzofur-

an, with various reducing agents; however, none was found to

be fruitful. Hydroquinone 3 was found susceptible to

autoxidation in atmospheric air and readily reverted to starting

alkynylquinone 5. To circumvent the problem as well as to

streamline the synthetic pathway, we decided to directly

transform hydroquinone 3 generated in situ from alkynylqui-

none 5 into hydroxybenzofuran 2. This cascade transformation

requires an appropriate reducing agent compatible with the

transition metal that catalyzes the oxycyclization process. We

envisioned that the quinone−hydroquinone redox processes

where a hydroquinone serves as a mild reducing agent would

be applicable, and that resultant hydroquinone intermediate 3

might be amenable to the transition metal-catalyzed cycliza-

tion.

With this in mind, we screened hydroquinone and phenol

derivatives to elucidate if they would be able to reduce

alkynylquinone 5. For this purpose, H NMR analysis was

none redox conditions in the presence of the hydroquinone

reagent such as 4b.

carried out to monitor the redox reactions of 5 with

hydroquinone derivatives 4a−i (1.2 equiv) (Table 1). Analysis

showed that compounds 4b, 4c, and 4d led to the successful

reduction of 5, while derivatives 4a and 4e−i were found

insigniﬁcant. The thin-layer chromatography (TLC) analysis of

the reaction mixture also reasonably supported the results

Our synthesis commenced with the alkylation of diethyl

methylmalonate (9) with homogeranyl iodide (8) to furnish

malonate derivative 10 in 96% yield (Scheme 2). The

Scheme 2. Total Synthesis of (± )-Liphagal

obtained by NMR analysis. The catalytic use of 4b (0.1

equiv) led to the low yield of alkynylhydroquinone 3, which

indicates that the redox transformation requires a stoichio-

metric amount of the hydroquinone derivative. Hydrox-

yquinol (1,2,4-benzenetriol) (4b), 2-methoxyhydroquinone

(

4c), and 2-methylhydroquinone (4d), which are electron-

rich hydroquinone derivatives, promoted the reduction of 5,

suggesting that the eﬃcient redox process depends on the

electronic property of the hydroquinone reagents (entries 2−

4). This scenario was further supported by the results that

phenol derivatives 4e and 4f, both having an electron-

withdrawing group, did not provide 3 eﬃciently (entries 5

and 6). In addition to the electronic property (electron

density), the structural feature was also found important in

promoting the redox reactions. Catechol (4g), resorcinol (4h),

and phloroglucinol (4i) gave a trace of hydroquinone 3

(

entries 7−9). Although the reaction mechanism remains

elusive, their poor conversion may suggest the diﬃculty in

forming a quinhydrone-like complex required for electron/

hydrogen transfer in their redox processes (Figure 2).

Having these insights associated with the organic redox, we

examined the compatibility of the redox system to subsequent

catalytic palladium(II)-mediated cyclization (Table 2). When

hydroquinone 4a was applied to the transformation in

combination with PdCl (entry 1), hydroxybenzofuran 2

was produced in 53% yield. The chemical yield of desired

hydroxybenzofuran 2 was increased when using 4b−d, which

were shown to generally allow the eﬃcient reduction of 5

(

entries 2−4). Phenol derivatives 4e and 4f having electron-

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 1. H NMR Analysis of the Redox Reaction of

Table 2. Hydroxybenzofuran Formation with Catalytic

Quinone 5 Driven by Hydroquinone and Phenol

Derivatives 4

PdCl in Combination with Phenol Derivatives 4

entry

reagent

Time

yield (%)

90 min

50 min

30 min

2 h

The reaction was carried out using PdCl (0.2 equiv), 5 (1.0 equiv),

and 4 (1.2 equiv). Isolated yield. 5 (20%) was recovered. 5 (28%)

was recovered. 5 (17%) was recovered. Not determined because of

decomposition.

quinone derivative that can regenerate Pd(II) species necessary

for oxycyclization. Based on this hypothesis, further

investigation was made to allow the redox cyclization to

proceed in one-pot transformation (Scheme 3). Thus, alkyne 6

(1.0 equiv) and 4 (1.2 equiv) were used, and the reaction was

Scheme 3. One-Pot Transformation of Alkyne 6 into

Benzofuran 2

carried out in THF at room temperature. The ratio was determined

by H NMR analysis (CDCl ) of the residue obtained by removal of

THF under reduced pressure.

Figure 2. Possible transition state of the organic redox reaction.

withdrawing substituents were found poor in producing 2

was coupled with iodoquinone 7 with cat. Pd(OAc) and

K CO to aﬀord alkynylquinone 5 to which hydroxyquinol

(

entries 5 and 6). Interestingly, the reduction of quinone 5

(4b) was added. This one-pot protocol directly provided

benzofuran 2 in 40% yield. Although this protocol gave only a

moderate yield of 2, it represents a unique exploitation of three

individual chemical reactions in the same pot under organic

redox conditions.

with 4a was poor (5/3 = 5.3:1 in Table 1), but

hydroxybenzofuran 2 was produced in a moderate yield

(

53%). This observation suggests that quinone 5 and

hydroquinone 3 are in equilibrium in solution and that

hydroquinone 3 that is produced, despite its relatively small

quantity, undergoes cyclization with PdCl₂to make the

forward (cyclization) process favorable to deliver 2 in

moderate yields. If the formation of hydroquinone 3 in

equilibrium is too sluggish, however, such a transformation is

negligible because of the decomposition of quinone 5 during

the reaction.

Having succeeded in synthesizing hydroxybenzofuran 2, its

phenolic hydroxy group was methylated with MeI and K CO

to produce compound 13 in 92% yield (2 → 13 in Scheme 2).

Then, compound 13 was subjected to acid-mediated polyene

cyclization under Andersen’s conditions followed by the

lithiation−formylation sequence using n-BuLi/TMEDA/dime-

thylformamide (DMF) to give a separable mixture of aldehyde

14 and its diastereomer (dr = 1:1.8) in 51% combined yield

from 13. After separation of 14 from its isomer by high-

performance liquid chromatography (HPLC), aldehyde 14 was

We also envisaged that the palladium catalyst that promotes

the Sonogashira alkynylation would be applicable to

subsequent oxycyclization as the redox process generates a

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

reacted with BBr in CH Cl at −78 to −20 °C to furnish

Diethyl (E)-2-(4,8-Dimethylnona-3,7-dien-1-yl)-2-methyl-

malonate (10). To a stirred solution of diethyl methylmalonate

(

±)-liphagal (1) in 75% yield.

(

9) (2.96 mL, 17.3 mmol) in DMF (48 mL) at 0 °C was added NaH

60% w/w in oil; 636 mg, 15.9 mmol). After 15 min, a solution of

CONCLUSIONS

■

iodide 8 (4.02 g, 14.5 mmol) in DMF (10 mL) was added. After being

stirred for 14 h at room temperature, the mixture was treated with sat.

In conclusion, a new synthesis of (±)-liphagal, a potent natural

PI3Kα inhibitor isolated from A. coralliphaga, was accom-

plished. The present strategy features an organic redox process

wherein an alkynylquinone undergoes reductive cyclization in

NH Cl. The whole mixture was transferred to a separatory funnel

where it was extracted with Et O. The organic phase was separated,

dried over MgSO , ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by ﬂash silica gel column chromatography

the presence of hydroquinones and catalytic PdCl to produce

(

EtOAc/n-hexane 1:20 v/v) to give ester 10 (4.56 g, 96%) as

a highly substituted benzofuran derivative as a key intermediate

for the total synthesis of (±)-liphagal. The present study also

uncovered the compatibility of Pd(II) catalysis with hydro-

quinone-mediated organic redox processes that allow a new

mode of hydroxybenzofuran formation. Furthermore, the

redox reactions were found to be best performed using

electron-rich hydroquinones possessing the 1,4-dihydroxyben-

zene structural motif.

−1

colorless oil: IR (neat): ν 2980, 1732 cm ; H NMR (300 MHz,

CDCl ): δ 5.14−5.04 (m, 2H), 4.18 (q, 4H, J = 7.0 Hz), 2.11−1.83

(m, 8H), 1.68 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.42 (s, 3H), 1.25

(t, 6H J = 7.0 Hz); C{ H} NMR (100 MHz, CDCl

): δ 172.5,

36.0, 131.5, 124.3, 123.3, 61.2, 53.6, 39.7, 35.6, 26.7, 25.8, 23.0, 19.9,

7.8, 16.0, 14.2; HRMS (EI-Orbitrap) m/z: [M] calcd for C H O ,

19 32

24.2301; found, 324.2301.

E)-2,6,10-Trimethylundeca-5,9-dien-1-ol (11). To a stirred

(

solution of diester 10 (4.49 g, 13.9 mmol) in Et O (85 mL) at room

temperature was added H O (0.499 mL, 27.7 mmol). Then, the

EXPERIMENTAL SECTION

mixture was cooled to 0 °C, and t-BuOK (6.22 g, 55.4 mmol) was

added. The mixture was allowed to warm to room temperature and

stirred for 6.5 h. The mixture was transferred to a separatory funnel

■

General Methods. All moisture-sensitive reactions were per-

formed in an oven-dried glassware under an argon atmosphere unless

otherwise stated. Reagents and solvents were used as received from

commercial suppliers unless otherwise mentioned. CH Cl was freshly

where it was partitioned between CH Cl and H O. The aqueous

phase was separated, acidiﬁed with 2 N HCl, and extracted with

EtOAc. The organic phase was separated, dried over MgSO , ﬁltered,

distilled over P O prior to use. H NMR spectra (400 or 300 MHz)

_a_n_d1 C NMR spectra (100 or 75 MHz) were recorded on Varian

and concentrated under reduced pressure to aﬀord crude dicarboxylic

acid (4.51 g) as brownish oil. The crude product was used for the next

reaction without further puriﬁcation. Thus, the crude dicarboxylic

acid was dissolved in xylene (107 mL), and the mixture was heated at

reﬂux in an oil bath for 4 h. After removal of the solvent under

reduced pressure, the crude carboxylic acid (4.23 g) was obtained as

brownish oil. The crude acid (4.23 g) was dissolved in

tetrahydrofuran (THF) (49 mL), and the solution was cooled to 0

00-MR ASW (400 MHz) or Varian Mercury-300 (300 MHz) in the

speciﬁed solvents. Chemical shifts are reported in ppm relative to the

residual solvent signal [chloroform-d: 7.26 ppm ( H NMR) and 77.16

ppm ( C NMR)] as an internal standard. The Fourier transform

infrared (FT-IR) spectra were recorded for samples loaded as neat

ﬁlms on NaCl plates or samples ﬁnely pulverized into a KBr pellet

using a SHIMADZU IRAﬃnity-1 FT-IR spectrometer. High-

resolution mass spectra (HRMS) were recorded on JEOL JMS-700

using the speciﬁed technique. Flash column chromatography was

carried out using Silica Gel 60 (spherical; 40−100 μm; Kanto

Chemical Co., Ltd.). Analytical TLC was performed using Silica Gel

C. To the solution was added LiAlH (526 mg, 13.9 mmol), and the

mixture was then allowed to warm to room temperature. After being

stirred for 1.5 h, the mixture was again cooled to 0 °C and quenched

with 28% NH OH. The whole mixture was diluted with CH Cl and

stirred for 25 min. Celite was added to the mixture, and stirring was

continued for additional 40 min. The mixture was ﬁltered through a

pad of Celite, and the ﬁltrate was concentrated under reduced

pressure. The residue was puriﬁed by ﬂash silica gel column

chromatography (EtOAc/n-hexane 1:6 to 1:4 v/v) to give alcohol

0 F₂₅₄TLC Plate Wako (FUJIFILM Wako Pure Chemical Co., Ltd.),

and compounds were visualized under UV light (254 nm) and stained

with an anisaldehyde solution, a phosphomolybdic acid solution, a

KMnO solution, or iodine. HPLC was carried out using a Shimazu

Prominence (HPLC pump: LC-20AT, UV/vis detector: SPD-20A)

analytical system with which Develosil 60 (10 μm, size 10.0/250,

particle size 10 μm; Nomura Chemical Co., Ltd) was equipped.

Homogeranyl Iodide (8). To a stirred solution of homogeranyl

alcohol (3.47 g, 20.6 mmol) in CH Cl (110 mL) at 0 °C were added

−1 1

11 (2.65 g, 91%) as pale yellow oil: IR (neat): ν 3306, 2914 cm ; H

NMR (400 MHz, CDCl

): δ 5.14−5.05 (m, 2H), 3.52 (dd, 1H, J =

10.4, 5.7 Hz), 3.43 (dd, 1H, J = 10.4, 6.5 Hz), 2.12−1.93 (m, 6H),

1.68 (s, 3H), 1.64 (m, 1H), 1.60 (s, 6H), 1.44 (m, 1H), 1.29 (brs,

Ph P (7.57 g, 28.9 mmol), imidazole (2.12 g, 30.9 mmol), and I

1H), 1.16 (m, 1H), 0.93 (d, 3H, J = 6.7 Hz); C{ H} NMR (100

MHz, CDCl ): δ 135.2, 131.5, 124.6, 124.5, 68.5, 39.8, 35.4, 33.3₊,

26.8, 25.8, 25.4, 17.8, 16.7, 16.1; HRMS (EI-Orbitrap) m/z: [M]

calcd for C14 26O, 210.1984; found, 210.1986.

(E)-1,1-Dibromo-3,7,11-trimethyldodeca-1,6,10-triene (12).

To a stirred solution of (COCl) (1.21 mL, 14.3 mmol) in CH Cl

(17 mL) was added dimethyl sulfoxide (2.03 mL, 28.5 mmol) in

CH Cl (5 mL) at −78 °C. After 15 min, a solution of alcohol 11

(1.00 g, 4.75 mmol) in CH Cl (5 mL) was added. After 30 min, Et

(

6.82 g, 26.9 mmol). After being stirred for 5 min, the mixture was

allowed to warm to room temperature, and stirring was continued for

additional 5.2 h. Sat. NaHCO and sat. Na S O were added, and the

whole mixture was transferred to a separatory funnel where it was

extracted with CH Cl . After separation of the organic phase, TBHP

(70% w/v in H O) was added to the organic phase to oxidize the

residual Ph P. Then, the mixture was again extracted with CH Cl and

washed with sat. NaHCO and sat. Na S O . The organic phase was

separated, dried over MgSO , and ﬁltered. The solvent was removed

under reduced pressure to aﬀord a solid residue. To the residue was

added n-hexane to precipitate an insoluble material containing

(6.62 mL, 47.5 mmol) was added, and the mixture was stirred for 17

min. The mixture was allowed to warm to 0 °C, and stirring was

continued for 1 h. Sat. NH Cl was added at the same temperature,

Ph PO. The mixture was ﬁltered through a pad of Celite and

and the whole mixture was transferred to a separatory funnel where it

was extracted with Et O. The organic phase was separated, dried over

MgSO , ﬁltered, and concentrated under reduced pressure to aﬀord

crude aldehyde (1.48 g), which was subjected to the next reaction

without puriﬁcation. To a solution of the crude aldehyde in CH Cl

(28 mL) were added Ph P (3.74 g, 7.13 mmol) and CBr (2.36 g,

washed with n-hexane several times. The ﬁltrate was concentrated

under reduced pressure to give a residue which was puriﬁed by ﬂash

silica gel column chromatography (n-hexane) to give iodide 8 (4.13 g,

−

2%) as pale orange oil: IR (neat): ν 2924 cm ; H NMR (300

MHz, CDCl ): δ 5.14−5.06 (m, 2H), 3.11 (t, 2H, J = 7.3 Hz), 2.58

(

dt, 2H, J = 7.3, 7.3 Hz), 2.14−1.95 (m, 4H), 1.68 (d, 3H, J = 0.8

7.13 mmol) at 0 °C. After being stirred for 50 min, the mixture was

Hz), 1.61 (s, 6H); C{ H} NMR (100 MHz, CDCl ): δ 138.1, 131.6,

quenched with sat. NaHCO and sat. Na S O . The whole mixture

24.1, 123.1, 39.7, 32.5, 26.5, 25.8, 17.8, 16.4, 6.2; HRMS (EI-

was transferred to a separatory funnel where it was extracted with

Orbitrap) m/z: [M] calcd for C H I, 278.0531; found, 278.0529.

CH Cl . The organic phase was separated, dried over MgSO , ﬁltered,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

and concentrated under reduced pressure. The residue was diluted

with n-hexane, and the resultant suspension was ﬁltered through a pad

of Celite. The ﬁltrate was concentrated under reduced pressure to

provide the residue, which was puriﬁed by ﬂash silica gel column

chromatography (n-hexane) to give dibromoalkene 12 (1.30 g, 75%)

benzenetriol (hydroxyquinol) (4b) (4.8 mg, 0.0384 mmol). The

mixture was stirred under reﬂux in an oil bath for 50 min. The mixture

was transferred to a separatory funnel where it was partitioned

between EtOAc and H O. The organic phase was separated, dried

over MgSO , ﬁltered, and concentrated under reduced pressure. The

−

as colorless oil: IR (neat): ν 2926 cm ; H NMR (400 MHz,

residue was puriﬁed by ﬂash silica gel column chromatography

(EtOAc/n-hexane 1:8 v/v) to give benzofuran 2 (7.7 mg, 70%) as

CDCl ): δ 6.18 (d, 1H, J = 9.4 Hz), 5.13−5.06 (m, 2H), 2.47 (m,

−

1 1

H), 2.11−1.94 (m, 6H), 1.68 (d, 3H, J = 1.0 Hz), 1.60 (s, 6H),

pale yellow oil: IR (neat): ν 3545, 2928 cm ; H NMR (400 MHz,

.42−1.34 (m, 2H), 1.00 (d, 3H, J = 6.8 Hz); C{ H} NMR (100

CDCl ): δ 6.98 (m, 2H), 6.24 (m, 1H), 5.47 (brs, 1H), 5.15−5.05

MHz, CDCl ): δ 144.5, 135.8, 131.5, 124.5, 123.9, 87.5, 39.9, 38.1,

(m, 2H), 3.92 (s, 3H), 2.89 (sex, 1H, J = 7.0 Hz), 2.10−1.94 (m, 6H),

6.3, 26.9, 25.9, 25.7, 19.3, 17.9, 16.2; HRMS (EI-Orbitrap) m/z:

1.79 (m, 1H), 1.68 (d, 3H, J = 1.2 Hz), 1.60 (s, 3H), 1.59 (m, 1H),

[

M] calcd for C H Br , 362.0245; found, 362.0241.

1.56 (s, 3H, overlapped with H O), 1.29 (d, 3H, J = 6.8 Hz); C{ H}

(

E)-3,7,11-Trimethyldodeca-6,10-dien-1-yne (6). n-BuLi (1.57

NMR (75 MHz, CDCl ): δ 163.1, 148.7, 144.3, 142.3, 135.6, 131.5,

M in hexane; 5.68 mL, 8.92 mmol) was added slowly at −78 °C to a

stirred solution of dibromoalkene 12 (1.30 g, 3.57 mmol) in THF (46

124.5, 124.1, 121.5, 104.3, 100.7, 94.6, 56.5, 39.8, 35.6, 33.2, 26.8,

25.9, 25.6, 19.2, 17.8, 16.2; HRMS (EI-Orbitrap) m/z: [M] calcd for

mL). After 25 min, the mixture was quenched with sat. NH Cl, and

C H O , 342.2195; found, 342.2194.

the whole mixture was transferred to a separatory funnel where it was

extracted with CH Cl . The organic phase was separated, dried over

(

E)-2-(6,10-Dimethylundeca-5,9-dien-2-yl)-5,6-dimethoxybenzo-

furan (13). To a stirred solution of benzofuran 2 (279.2 mg, 0.815

MgSO , ﬁltered, and concentrated under reduced pressure. The

mmol) in DMF (16 mL) at room temperature were added K CO

residue was puriﬁed by ﬂash silica gel column chromatography (n-

(1.13 g, 8.15 mmol) and MeI (0.507 mL, 8.15 mmol). After 7 h, H O

hexane) to give alkyne 6 (707 mg, 95%) as colorless oil: IR (neat): ν

was added, and the whole mixture was transferred to a separatory

funnel where it was extracted with n-hexane. The organic phase was

−

(

310, 2926 cm ; H NMR (400 MHz, CDCl ): δ 5.13−5.05 (m,

H), 2.44 (m, 1H), 2.22−1.95 (m, 6H), 2.04 (d, 1H, J = 2.3 Hz), 1.68

separated, dried over MgSO , ﬁltered, and concentrated under

s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.57−1.38 (m, 2H), 1.18 (d, 3H, J

reduced pressure. The residue was puriﬁed by ﬂash silica gel column

chromatography (EtOAc/n-hexane 1:10 v/v) to give dimethoxyben-

zofuran 13 (267.3 mg, 92%) as pale yellow oil: IR (neat): ν 2926

6.8 Hz); ¹³C{ H} NMR (75 MHz, CDCl ): δ 135.9, 131.5, 124.5,

23.8, 89.4, 68.3, 39.9, 37.0, 26.8, 25.85, 25.77, 25.3, 21.1, 17.8, 16.1;

−

1 1

HRMS (EI-Orbitrap) m/z: [M] calcd for C H , 204.1878; found,

cm ; H NMR (400 MHz, CDCl ): δ 7.01 (d, 1H, J = 0.6 Hz), 6.95

04.1882.

(

s, 1H), 6.26 (dd, 1H, J = 0.8, 0.8 Hz), 5.16−5.05 (m, 2H), 3.91 (s,

(

E)-2-Methoxy-5-(3,7,11-trimethyldodeca-6,10-dien-1-yn-1-

H), 3.90 (s, 3H), 2.90 (sex, 1H, J = 7.0 Hz), 2.10−1.94 (m, 6H),

yl)cyclohexa-2,5-diene-1,4-dione (5). To a stirred solution of

alkyne 6 (380 mg, 1.86 mmol) in DMF (8.9 mL) at 25 °C (the

temperature was maintained by a water bath) were added

iodoquinone 7 (467 mg, 1.77 mmol), K CO (368 mg, 2.66

.81 (m, 1H), 1.68 (d, 3H, J = 1.0 Hz), 1.60 (s, 3H), 1.60 (m, 1H),

.56 (s, 3H, overlapped with H O), 1.30 (d, 3H, J = 7.0 Hz); C{ H}

NMR (100 MHz, CDCl ): δ 163.0, 149.1, 147.1, 146.2, 135.6, 131.5,

124.5, 124.1, 120.7, 102.2, 100.7, 95.4, 56.6, 56.4, 39.8, 35.6, 33.2,

mmol), and Pd(OAc) (19.9 mg, 0.0886 mmol). After being stirred

₆_.₈_,₂₅_.₈_,₂₅_.₇_,₁₉_.₃_,₁₇_.₈_,₁₆_.₁_;_H_R_M_S₍_E_I_-_O_r_b_i_t_r_a_p₎_m_/_z_:_[_M_]+

for 1.5 h, the mixture was ﬁltered through a pad of Celite and washed

calcd for C H O , 356.2351; found, 356.2353.

with Et O. The ﬁltrate was transferred to a separatory funnel where it

O,O-Dimethylliphagal (14). To a stirred solution of dimethox-

ybenzofuran 13 (267.3 mg, 0.750 mmol) in cyclohexane (38 mL) at

was washed with H O. The organic phase was separated, dried over

MgSO , ﬁltered, and concentrated under reduced pressure. The

room temperature was added HCO H (15 mL). After being heated at

residue was puriﬁed by ﬂash silica gel column chromatography

reﬂux in an oil bath for 35 h, the mixture was transferred to a

(

EtOAc/n-hexane 1:6 v/v) to give alkynylquinone 5 (439.7 mg, 73%)

separatory funnel where it was washed with H O several times. The

−

as yellowish brown oil: IR (neat): ν 2930, 2218, 1651 cm ; H NMR

400 MHz, CDCl ): δ 6.76 (d, 1H, J = 0.6 Hz), 5.93 (s, 1H), 5.14−

organic phase was separated and diluted with Et O. The organic phase

(

was again transferred to a separatory funnel and washed with sat.

NaHCO . The organic phase was separated, dried over MgSO ,

.04 (m, 2H), 3.82 (s, 3H), 2.75 (m, 1H), 2.20−1.95 (m, 6H), 1.67

d, 3H, J = 1.0 Hz), 1.62 (s, 3H), 1.60 (s, 3H), 1.60−1.49 (m, 2H),

ﬁltered, and concentrated under reduced pressure to give a crude

mixture which was used for the next reaction without further

puriﬁcation. After azeotropic dehydration of the crude mixture with

toluene, the resultant residue (278.1 mg) was dissolved in THF (17

mL). To this mixture were added TMEDA (0.225 mL, 1.50 mmol)

and n-BuLi (1.59 M in hexane; 0.943 mL, 1.50 mmol) at 0 °C. After

.26 (d, 3H, J = 6.7 Hz); C{ H} NMR (75 MHz, CDCl ): δ 183.4,

81.6, 158.9, 136.2, 134.6, 133.7, 131.5, 124.4, 123.5, 112.7, 107.5,

5.1, 56.5, 39.8, 36.6, 26.8, 26.7, 25.82, 25.80, 20.4, 17.8, 16.1; HRMS

(

EI-Orbitrap) m/z: [M]⁺calcd for C H O , 340.2038; found,

22 28 3

40.2039.

(

E)-2-Methoxy-5-(3,7,11-trimethyldodeca-6,10-dien-1-yn-1-

30 min of stirring at the same temperature, DMF (0.581 mL, 7.50

yl)cyclohexa-2,5-diene-1,4-diol (3). To a stirred solution of

alkynylquinone 5 (4.4 mg, 0.0129 mmol) in THF (1 mL) at room

temperature was added 1,2,4-benzenetriol (hydroxyquinol) (4b) (3.2

mg, 0.0258 mmol). After being stirred for 15 min at room

temperature, the mixture was concentrated under reduced pressure

to give the residue, which was puriﬁed by ﬂash silica gel column

chromatography (EtOAc/n-hexane 1:4 v/v) to give alkynylhydroqui-

none 3 (2.9 mg, 66%) as reddish brown oil. This compound was

mmol) was added. Sat. NH Cl was added, and the whole mixture was

transferred to a separatory funnel where it was extracted with Et O.

The organic phase was separated, dried over MgSO , ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash silica gel column chromatography (CH Cl /n-hexane 10:1 v/v)

to give an inseparable mixture of aldehyde 14 and C8-epi-14 (114.8

mg, 14/C8-epi-14 = 1:1.38) as a yellow solid and another fraction

containing aldehyde 14, C8-epi-14 and unidentiﬁed less polar

compounds (57.8 mg) as yellow oil. Further puriﬁcation of the latter

mixture by ﬂash silica gel column chromatography (CH Cl /n-hexane

found susceptible to autoxidation upon exposure to air (O ) during

the workup and puriﬁcation processes to readily aﬀord alkynylqui-

none 5. Therefore, only H NMR data were available. H NMR (400

10:1 v/v) gave an additional inseparable mixture of aldehyde 14 and

MHz, CDCl ): δ 6.82 (s, 1H), 6.49 (s, 1H), 5.49 (s, 1H), 5.14 (s,

C8-epi-14 (31.9 mg, 14/C8-epi-14 = 1:8.3) as a pale yellow solid.

Based on the total amounts of the products (146.7 mg, 14/C8-epi-14

H), 5.16−5.05 (m, 2H), 3.86 (s, 3H), 2.71 (m, 1H), 2.25−1.97 (m,

H), 1.71−1.50 (m, 2H), 1.68 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H),

.27 (d, 3H, J = 6.8 Hz).

1:1.8) obtained using the above-mentioned protocol, the yield of

the cyclized products was determined to be 51%. Diastereomerically

pure aldehyde 14 and aldehyde C8-epi-14 were obtained by

semipreparative HPLC (Develosil C60; EtOAc/n-hexane 9:95 (v/

v); ﬂow rate 5.0 mL). Their data were in good agreement with those

PdCl -Catalyzed Cyclization under Organic Redox Con-

ditions (Table 2). Typical Procedure for the Synthesis of

Benzofuran 2 (Table 2, Entry 2). To a stirred solution of

alkynylquinone 5 (10.9 mg, 0.0320 mmol) in THF (1 mL) at room

1,6a

temperature were added PdCl (1.1 mg, 0.0062 mmol) and 1,2,4-

reported in the literatures.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Sciences, Okayama University, Okayama 700-8530, Japan;

Article

O,O-Dimethylliphagal (14). t (minor) = 19.7 min; white solid; IR

orcid.org/0000-0001-7894-0842; Email: yoshimit@

okayama-u.ac.jp

−

1 1

(

KBr): ν 2932, 1690 cm ; H NMR (400 MHz, CDCl ): δ 10.56 (s,

H), 7.47 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.31 (sext, 1H, J = 7.0

Hz), 2.54 (m, 1H), 2.18 (m, 1H), 1.85 (m, 1H), 1.72 (m, 1H), 1.65−

.21 (m, 7H), 1,46 (d, 3H, J = 7.0 Hz), 1.37 (s, 3H), 0.99 (s, 3H),

Authors

.95 (s, 3H); ¹³C{ H} NMR (100 MHz, CDCl ): δ 188.6, 159.0,

Eriko Tao − Division of Pharmaceutical Sciences, Graduate

School of Medicine, Dentistry, and Pharmaceutical Sciences,

Okayama University, Okayama 700-8530, Japan

Masaki Inoue − Division of Pharmaceutical Sciences, Graduate

School of Medicine, Dentistry, and Pharmaceutical Sciences,

Okayama University, Okayama 700-8530, Japan

Taejoo Jeong − Division of Pharmaceutical Sciences, Graduate

School of Medicine, Dentistry, and Pharmaceutical Sciences,

Okayama University, Okayama 700-8530, Japan; School of

Pharmacy, Sungkyunkwan University, Suwon 16419, Republic

of Korea

49.6, 148.0, 146.5, 125.4, 124.7, 114.9, 113.2, 63.0, 57.4, 53.6, 42.0,

0.4, 39.6, 34.95, 34.91, 33.6, 33.4, 24, 2, 22.3, 22.1, 20.3, 19.0;

HRMS (EI-Orbitrap) m/z: [M] calcd for C H O , 384.2301;

found, 384.2298. C8-epi-14: t (major) = 17.1 min; white solid; IR

−

1 1

(

KBr): ν 2924, 1685 cm ; H NMR (400 MHz, CDCl ): δ 10.57 (s,

H), 7.41 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.33 (m, 1H), 2.51 (m,

H), 1.97−1.21 (m, 10H), 1.41 (d, 3H, J = 6.8 Hz), 1.41 (s, 3H),

.99 (s, 3H), 0.96 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ

88.5, 157.8, 149.4, 148.1, 146.3, 125.4, 124.2, 115.2, 112.5, 63.0,

7.3, 50.4, 42.1, 40.5, 39.3, 35.9, 34.7, 33.9, 31.3, 23.0, 22.5, 20.6,

9.1, 18.9; HRMS (EI-Orbitrap) m/z: [M]⁺calcd for C H O ,

84.2301; found, 384.2301.

±)-Liphagal (1). To a stirred solution of aldehyde 14 (18.3 mg,

.0476 mmol) in CH Cl (2 mL) at −78 °C was added BBr (1.0 M

In Su Kim − School of Pharmacy, Sungkyunkwan University,

Suwon 16419, Republic of Korea; orcid.org/0000-0002-

2665-9431

(

in CH Cl ; 0.476 mL, 0.476 mmol). The mixture was allowed to

warm to −20 °C over 3 h. At the same temperature, sat. NaHCO and

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c00965

sat. Na S O were added, and the whole mixture was transferred to a

separatory funnel where it was extracted with CH Cl . The organic

phase was separated, dried over MgSO , ﬁltered, and concentrated

under reduced pressure. The residue was puriﬁed by ﬂash silica gel

column chromatography (EtOAc/n-hexane 1:8 v/v) to give

Notes

The authors declare no competing ﬁnancial interest.

(

±)-liphagal (1) (13.5 mg, 75%) as yellow oil. The spectroscopic

and analytical data of this compound were in good agreement with

those reported in the literatures.

ACKNOWLEDGMENTS

,6a,9

■

(±)-Liphagal (1): IR (neat): ν

−

The authors acknowledge Prof. Toshikatsu Takanami, Tamami

Koseki, and Dr. Satoshi Hayashi at Meiji Pharmaceutical

University (MPU) for their mass spectroscopic analysis. This

work was supported by JSPS KAKENHI (grant number

JP18K06578) (to T.Y.).

420, 2930, 1651 cm ; H NMR (400 MHz, CDCl ): δ 11.24 (d,

H, J = 0.6 Hz), 10.44 (s, 1H), 7.55 (s, 1H), 5.32 (s, 1H), 3.21 (sext,

H, J = 7.0 Hz), 2.53 (m, 1H), 2.17 (m, 1H), 1.90−1.18 (m, 8H),

.43 (d, 3H, J = 7.0 Hz), 1.34 (s, 3H), 1.25 (m, 1H), 0.98 (s, 3H),

.94 (s, 3H); ¹³C{ H} NMR (100 MHz, CDCl ): δ 192.6, 156.6,

48.1, 145.4, 139.5, 125.6, 120.4, 116.1, 106.4, 53.9, 42.0, 40.4, 39.6,

5.3, 35.0, 33.8, 33.4, 24.3, 22.1, 21.8, 20.4, 18.9; HRMS (EI-

REFERENCES

Orbitrap) m/z: [M] calcd for C H O , 356.1988; found, 356.1987.

■

Experimental Procedure for One-Pot Benzofuran Formation

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(

in DMF (2 mL) at room temperature were added iodoquinone 7

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(

Pd(OAc) (4.2 mg, 0.0186 mmol). The mixture was stirred at the

same temperature for 1.5 h at which time TLC analysis indicated the

consumption of alkyne 6. Then, 1,2,4-benzenetriol (hydroxyquinol)

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The organic phase was separated, dried over MgSO , ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash silica gel column chromatography (EtOAc/n-hexane 1:10 v/v)

to give benzofuran 2 (13.3 mg, 40%) as pale brownish oil.

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c00965.

H/ C NMR spectra of new compounds; H NMR

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(

AUTHOR INFORMATION

Corresponding Author

Takehiko Yoshimitsu − Division of Pharmaceutical Sciences,

Graduate School of Medicine, Dentistry, and Pharmaceutical

■

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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(

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