Synthesis and evaluation of the analogues of penicillide against cholesterol ester transfer protein

FULL PAPER

DOI: 10.1002/cjoc.201200977

Synthesis and Evaluation of the Analogues of Penicillide

against Cholesterol Ester Transfer Protein^†

Qiao Zhang,^a,bChunlin Deng,^aLisong Fang,^aWenwei Xu,^cQun Zhao,^aJiange Zhang,*^,b

Yiping Wang,^cand Xinsheng Lei*^,a

^aSchool of Pharmacy, Fudan University, Shanghai 201203, China

^bDepartment of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University,

Zhengzhou, Henan 450001, China

^cShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

A series of penicillide analogues, with modifications at C-3 and C-9 positions, are synthesized as potential cho-

lesteryl ester transfer protein (CETP) inhibitors. The preliminary in vitro inhibition assay provided some valuable

structure-activity relationship information about penicillide.

Keywords cross-coupling, lactone, inhibitors, cholesterol ester transfer protein, penicillide

Introduction

CETP inhibitor, attracted our greatest interest. Just re-

cently, we accomplished the total synthesis of racemic

penicillide.^[7]As a continuation of this work, herein we

present the synthesis of a variety of penicillide ana-

logues and the preliminary data of their CETP inhibi-

tion.

Cholesteryl ester transfer protein (CETP), a plasma

glycoprotein responsible for the transfer of cholesteryl

esters from the cardioprotective high density lipoprotein

cholesterol (HDL-C) to the potentially atherogenic low

or very low density lipoprotein cholesterol (LDL-C or

VLDL-C), has been viewed as a promising therapeutic

target for treatment of dyslipidaemia.^[1]Up to now, sev-

eral CETP inhibitors have evolved into human clinical

trials, including torcetrapid, anacetrapid, dalcetrapid and

evacetrapid.^[2]However, some of them are not success-

ful at late-stage of clinical development. For example,

torcetrapid was withdrawn in phase III due to its in-

creased risk in cardiovascular events, possibly associ-

ated with torcetrapid-specific off-target effects involv-

ing increasing aldosterone level and extending QT in-

terval.^[3]Nowadays, the natural product-based strategy

to discover novel CETP inhibitors becomes an alterna-

tive approach in this medical field, due to its relatively

higher statistic probability of success in drug develop-

ment.^[4]

O

OH

O

OH

O

3

Cl

7

O

1

9

O

11

HO

Penicillide

1

Figure 1 The structures of penicillide and its representative

derivative as CETP inhibitor.

Results and Discussion

Although the co-crystal structure of CETP and a

natural substrate has been disclosed,^[8]the detailed

binding domain for the CETP inhibitors including 1 is

not yet fully elucidated due to the large pocket.^[9]Due to

the limitation of semi-synthesis starting from penicillide,

previous SAR study was focused on various O-sub-

stituents at C-11 position, as well as different alkyl side

chains at C-3 position.^[5]Therefore, we became inter-

ested in exploring analogues at C-9 position to probe its

steric and lipophilic requirement. In addition, we would

Penicillide (Figure 1), is a metabolite produced by a

filamentous fungus (Penicillium sp.), which was iso-

lated and identified by Sassa, Udagawa, and co-work-

ers.^[5]Recently, its derivative 1, which was identified by

optimization through medicinal chemistry efforts in

Bayer Pharma (Figure 1),^[6]showed sufficient stability

in rat plasma along with potent CETP inhibition (IC₅₀＝

－

1

15 nmol•L ). This tricyclic skeleton fused by an eight-

membered lactone, as well as its potential application as

*

E-mail: leixs@fudan.edu.cn; Tel.: 0086-021-51980128; Fax: 0086-021-51980128

Received October 6, 2012; accepted December 26, 2012; published online January 28, 2013.

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200977 or from the author.

Dedicated to Professor Guoqiang Lin on the Occasion of his 70th birthday.

†

Chin. J. Chem. 2013, 31, 355—370

355

Zhang et al.

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like to find out the effect of hydroxyl group at C-3 side

chain by replacing it with proton or fluorine.

Thus, the iodide 3b was produced from 2 using ICl/

Pyridine in 88% yield.^[11]After the selective THP pro-

tection of benzylic hydroxy group, the desired sulfone

8e was successfully obtained in 52% yield through an

L-proline-promoted CuI-catalyzed coupling reaction.^[14]

Due to its low reactivity in the following Ullmann cou-

pling with the bromide 10, the corresponding alkylthio

ethers 8f－8g were prepared as follows. The two hy-

droxy groups in 7d was protected as acetonide 9 using

2,2-dimethoxypropane in 95% yield, which was then

converted to corresponding thioethers according to Ma’s

protocol.^[15]The subsequent cleavage of the ketal pro-

tecting group and selective THP protection of the ben-

zylic hydroxy afforded the desired phenols 8f and 8g

successfully in 66% and 68% yields (based on 9), re-

spectively.

Several penicillide analogues, as shown in Figure 2,

were designed to target the above ideas, and their retro

synthetic analysis led to the advanced intermediate aryl

bromide 10^[7]and the corresponding phenols 8 with

pre-installed substituents. These two building blocks

could go through Ullmann coupling reaction and further

lactonization to give the tricyclic core, then the alde-

hyde group would allow for nucleophilic attack by

various organometalics to afford alcohols, in which the

hydroxy group could be further reduced or replaced by

fluorine.

As shown in Scheme 1, our synthesis started from

commercially available 2,3-dihydroxybenzaldehyde.

Selective benzylation of one phenolic hydroxyl group

was conducted, according to the known method,^[10]us-

ing NaH (2.0 equiv.) and benzyl bromide (1.0 equiv.) to

obtain compound 2 in 65% yield. The reduction of 2 by

NaBH₄in MeOH at r.t. produced 7a in 98% yield, and

subsequent protection of the free hydroxyl with THP

afforded the desired phenol 8a in 96% yield.

Next, we turned to the preparation of substituted

phenols 8b－8c and 8e－8g. The bromination of 2 was

achieved using NBS/NH₄OAc in CH₃CN to give the

bromide 3a in 85% yield,^[11]which allowed for the in-

troduction of 4-methoxyphenyl or methyl groups

through Suzuki or Negishi coupling. The Suzuki reac-

tion of 3a with 4-methoxyphenylboronic acid produced

3c in 84% yield,^[13]which was subjected to further re-

duction and THP protection as above to give the desired

phenol 8c in 79% yield over two steps. The Negishi re-

action of 3a or 3b with Me₂Zn did not provide the de-

sired product with an acceptable yield, thus required the

protection of hydroxy group. Fortunately, the silyl pro-

tected bromide 4 reacted smoothly with Me₂Zn in the

presence of Pd(dppf)Cl₂in refluxing 1,4-dioxane, af-

fording the aldehyde 5 in 82% yield.^[12]Further reduc-

tion of the aldehyde and subsequent modifications of

protection groups resulted in the desired phenol 8b in

72% yield over three steps.

With the desired phenols (8a－8c, 8e－8g) in hand,

the advanced intermediate 10, prepared from the com-

mercially available 5-amino-2-methylphenol in

7

steps,^[7]was coupled with them through Ullmann reac-

tion under our previous conditions (Scheme 2).^[7]This

transformation was catalyzed by Cu powder/CuO sys-

tem in the presence of DMAP in refluxing CH₃CN. The

phenols bearing electron-donating groups could be

converted into the desired aryl ethers (11a－11c, 11f－

11g) in satisfying yields, while the phenol (8e) bearing a

methylsulfonyl group gave 11e (R³＝SO₂Me) in quite

low yield (18%), possibly due to an unfavorable elec-

tronic effect of the strong electron-withdrawing group.

The sequence to construct the tricyclic core from

aryl ethers (11a－11c, 11f－11g) is similar to our pre-

vious synthesis of penicillide.^[7]Removal of the THP

protecting group under acidic conditions led to the al-

dehydes (12a－12c, 12f－12g). Then, the formyl group

was protected as its dimethyl acetal by the treatment

with MeOH in the presence of a catalytic amount of

TsOH. The subsequent saponification of the ester with

KOH in refluxing MeOH and acidification with aqueous

3 N HCl gave the acids (13a－13c, 13f－13g) in excel-

lent yields, which were further cyclized using the

Mukaiyama’s reagent^[16]in refluxing MeCN for 12 h to

afford the desired lactones (14a－14c, 14f－14g) in

satisfactory yields

As for the preparation of phenols 8e－8g, the forma-

tion of C－S bond usually requires aryl iodide substrate.

Dehydroxylation or

dehydroxylative fluorination

Mukaiyama's lactonization

R²

O

THPO

O

3

R¹

O

CO₂Me

Br

HO

H

+

O

Addition

R³

O

R³

BnO

O

9

11

R³

10

O

8

BnO

Ullmann reaction

Acylation

R¹: Et, Me₂CHCH₂, Me₃CCH₂

R²: H, F, OH

R³: H, Me, SO₂Me, SO₂Et, 4-MeO-C₆H₄

Figure 2 The retro synthetic analysis of designed compounds.

356

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

Scheme 1 The synthesis of the suitable phenols 8

The introduction of C-3 alkyl chains was realized

through the reaction with the fresh-prepared neopentyl-

magnesium chloride to give the corresponding adducts

(15a－15c, 15f－15g) in acceptable yields. Among

them, the alkylthio ethers (15f－15g) were selectively

oxidized by oxone to give the alkylsulfonyl compounds

(15h－15i) in almost quantitative yields.^[17]

in compound 15 (15a－15c, 15h, 15i, 15l) was realized

by hydrogenation in the presence of 10% Pd/C in

AcOEt/MeOH at room temperature to give the phenols

(16a－16c, 16h, 16i, 16k, 16l) in excellent yields.

However, 15f－15g did not react under the same condi-

tions due to the toxicity of alkylthio ether to the catalyst.

In the case of 15j, both the C－C double bond and the

benzyl group were reduced to give 16k (65%), together

with the further dehydroxylated product 16m (34%).

Acylation of the resulting phenols (16a－16c, 16h,

16i, 16k, 16l, 16m) with the bulky aliphatic acyl chlo-

ride, which was in situ prepared from 7-methylbicyclo-

[2.2.1]heptane-7-carboxylic acid^[18]and oxalyl dichlo-

ride, was conducted after the treatment with NaH, lead-

ing to the desired products (17a－17c, 17h, 17i, 17k,

17l, 17m) in rewarding yields. Furthermore, 17b and

17h could be fluorinated with DAST at －78 ℃^[19]to

furnish the dehydroxy fluorinated products 17n (74%)

Attempts to obtain 15k (R¹＝Me₂CHCH₂, R³＝Me)

by a direct nucleophilic addition of 2-methylpropyl

Grignard reagent or (2-methylpropyl)lithium to com-

pound 14b (R³＝Me) mainly resulted in the corre-

sponding benzyl alcohol due to the reduction of the

formyl group. Alternatively, a 2-methylprop-2-en-1-yl

Grignard reagent was applied to react with 14b in anhy-

drous THF at 0－10 ℃ for 1 h, giving 15j in 82%

yield. In a similar way, EtMgBr was added to 14b, pro-

ducing 15l in 57% yield.

The selective removal of the protective benzyl group

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357

Zhang et al.

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Scheme 2 The synthetic route to the target compounds

O

H

OMe

H

OMe

H

OH

O

a

b

c

H

OMe

O

8a 8c 8e 8g

-

,

-

BnO

Br

OH

OTHP

OH

10

R³

11a - 11c, 11f - 11g

12a - 12c, 12f - 12g

13a 13c 13f 13g

- , -

R²

O

OH

O

R¹

d

H

e

f

h

O

R³

HO

BnO

14a - 14c, 14f - 14g

BnO

15a - 15c: R¹= Me₃CCH₂, R³= H; Me; 4-MeO-C₆H₄

16a - 16c, 16h - 16i, 16l: R²= OH

16k: R¹= Me₂CHCH₂, R²= OH, R³= Me

15f 15g

-

: R¹= Me₃CCH₂, R³= SMe; SEt

: R¹= Me₃CCH₂, R³= SO₂Me; SO₂Et

g

15h 15i

-

: R¹= Me₂CHCH₂, R²= H, R³= Me

16m

1

3

15j

: R = 2-MeAllyl, R = Me

15l: R¹= Et, R³= Me

R²

O

17a: R¹= Me₃CCH₂, R²= OH, R³= H; 17b: R¹= Me₃CCH₂, R²= OH, R³= Me; 17c: R¹= Me₃CCH₂, R²= OH,

O

R¹

R

³= 4-MeO-C₆H₄; 17h: R¹= Me₃CCH₂, R²= OH, R³= SO₂Me; 17i: R¹= Me₃CCH₂, R²= OH, R³= SO₂Et;

1

: R¹= Me₂CHCH₂, R²= OH, R³= Me;

: R¹= Et, R²= OH, R³= Me;

: R = Me₂CHCH₂, R²= H, R³= Me;

17k

17l

17m

O

R³

,

: R¹= Me₃CCH₂, R²= OH, R³= Me; SO₂Me

17b 17h

i

O

,

: R¹= Me₃CCH₂, R²= F, R³= Me; SO₂Me

17n 17o

Reagents and conditions: a. Cu, CuO, DMAP, CH₃CN, reflux, 12 h, for 11a: 73%; 11b: 60%; 11c: 69%; 11f: 67%; 11g: 70%; b. p-TsOH•H₂O,

i-PrOH/H₂O, reflux, 12 h, for 12a: 88%; 12b: 93%; 12c: 95%; 12f: 85%; 12g: quant. yield; c. (i) p-TsOH•H₂O, MeOH, 1 h; (ii) KOH, reflux, 12 h, then aq.

3 mol•L^－¹HCl; d. Et₃N, 2-chloro-1-methylpyridinium iodide (Mukaiyama's reagent), CH₃CN, reflux, overall yields based on 12, for 14a: 55%; 14b: 51%;

14c: 18%; 14f: 67%; 14g: 56%; e. Me₃CCH₂MgCl, 2-methylallyl magnesium chloride or EtMgBr, THF, -10 ℃, 1 h, 15a: 97%; 15b: 98%; 15c: 77%; 15f:

83%; 15g: 68%; 15j: 82%; 15l: 57%; f. 10% Pd/C, H₂(1 atm), MeOH/AcOEt, r.t., 3 h, for 16a: 85%; 16b: 87%; 16c: 93%; 16h: quant. yield; 16i: quant.

yield; 16l: quant. yield; 16k: 65% together with 16m: 35%; g. Oxone, THF/H₂O, 0 ℃－r.t., for 15h: 94%; 15i: 93%; h. NaH, RCOCl, THF, r.t., 1 h, for

17a: 58%; 17b: 89%; 17c: 72%; 17h: 89%; 17i: 87%; 17k: 86%; 17l: 76%; 17m: 87%; i. DAST, CH₂Cl₂, −78 ℃－r.t., for 17n: 74%; 17o: 80%.

Conclusions

and 17o (80%), respectively.

The synthetic penicillide analogues (17a － 17c,

17h, 17i, 17k－17o) were tested in inhibiting CETP-

mediated transfer of H-CE from HDL to LDL in hu-

In summary, we synthesized a series of the penicil-

lide analogues, with modification at C-3 and C-9 posi-

tions. The preliminary data in inhibiting CETP sug-

gested the importance of the H-bond donator in the side

chain of penicillide, the more tolerance of C-3 alkyl

chain, as well as the less tolerance at C-9 position in

order to retain CETP inhibition.

3

man serum,^{[1c, 20]}with the data shown in Table 1. The

preliminary results indicated that the C-9 methyl group

(Table 1, R³) in penicillide could be replaced with hy-

drogen (17a, 17b), but an aromatic substitution (17c) or

a small hydrophilic group (17h, 17i) significantly re-

duced the inhibition. The side-chain modification (Table

1, R¹) suggested that this moiety might tolerate a lipo-

philic group with different steric bulkiness, particularly

the Et group gave an increasing inhibition (17b, 17k,

17l). However, the free hydroxyl (Table 1, R²) in the

side chain played an important role in retaining the in-

hibition, as its replacement by hydrogen or an H-bond

acceptor (fluorine atom) dramatically decreased the in-

hibition (17b, 17m, 17n, 17o).

Experimental

General information: Solvents were distilled from

the appropriate drying agents before use. All the re-

agents were purchased from Acros, Alfa Aesar, and Na-

tional Chemical Reagents Group Co. Ltd, P. R. China.

Unless otherwise stated, all the reactions were per-

formed under Ar. Column chromatography: Commer-

cial silica gel (Qingdao Hai Yang Chemical Group Co.;

300－400 mesh). Spots on the TLC plates (GF 254,

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

1

Table 1 The inhibition of the penicillide analogues against

CETP

ether/AcOEt＝10∶1): R_f0.42. H NMR (CDCl₃, 300

MHz) δ: 11.12 (s, 1H, OH), 9.92 (s, 1H, CHO), 7.47－

7.32 (m, 5H, ArH), 7.20 (dd, J＝7.8, 1.4 Hz, 1H, ArH),

7.13 (d, J＝7.8 Hz, 1H, ArH), 6.90 (dd, J＝7.8 Hz, J'＝

7.8 Hz, 1H, ArH), 5.20 (s, 2H, CH₂). MS (ESI): 229.1

[M＋H].

R²

O

R¹

O

R³

3-(Benzyloxy)-5-bromo-2-hydroxybenzaldehyde (3a):

To a solution of 2 (4.00 g, 17.5 mmol) in MeCN (90

mL), was added AcONH₄(137 mg, 1.75 mmol) and

NBS (3.28 g, 18.4 mmol). The resulting mixture was

stirred for 4 h at r.t., then concentrated. H₂O (100 mL)

was added to the residue, the mixture was extracted with

AcOEt (30 mL×3), the combined organic extracts were

dried over MgSO₄and concentrated. The residue was

subjected to column chromatography (SiO₂petroleum

ether/AcOEt＝20∶1) to give a yellowish solid 3a (4.59

g, 85%). m.p. 116－117 ℃; TLC (petroleum ether/

CH₂Cl₂＝2∶1): R_f0.35. ¹H NMR (CDCl₃, 400 MHz) δ:

10.96 (s, 1H, OH), 9.86 (s, 1H, CHO), 7.46－7.35 (m,

5H, ArH), 7.33 (d, J＝2.4 Hz, 1H, ArH), 7.23 (d, J＝2.0

Hz, 1H, ArH), 5.16 (s, 2H, CH₂). MS (ESI): 329.0,

331.1 [M＋Na].

O

Compd.

17a

R¹

R²

R³

Inhibition^a

Me₃CCH₂

Me₂CHCH₂

Et

OH

H

56

59 (3)^b

17b

17c

Me

4-MeO-C₆H₄

SO₂Me

SO₂Et

Me

8

17h

17i

10

0

17k

17l

96 (63)^b

89 (89)^b

Me

17m

17n

17o

Me₂CHCH₂

Me₃CCH₂

Me

16

25

0

F

Me

F

SO₂Me

3-(Benzyloxy)-5-iodo-2-hydroxybenzaldehyde (3b):

A solution of ICl (1.29 g, 7.95 mmol) in CHCl₃(8 mL)

was added dropwise to pyridine (20 mL) at r.t. After the

mixture was stirred for 15 min, it was added to a solu-

tion of 2,3-dihydroxybenzaldehyde (1.01 g, 6.00 mmol)

in CHCl₃(10 mL), and the resulting mixture was stirred

at r.t. for 6 h. After the reaction was completed (moni-

tored by TLC), the reaction mixture was evaporated in

vacuo, and the residue was diluted with CHCl₃(50 mL),

washed with 1 N HCl aq. (50 mL), 5% NaS₂O₃aq. (50

mL), and water (50 mL). The organic phase was dried

over Na₂SO₄. After filtered and evaporated, the residue

was purified by column chromatography (SiO₂petro-

leum ether/AcOEt＝20∶1) to give a yellowish solid 3b

(1.59 g, 88%). m.p. 87－88 ℃; TLC (petroleum ether/

AcOEt＝4∶1): R_f0.29. ¹H NMR (CDCl₃, 300 MHz) δ:

11.01 (s, 1H, OH), 9.84 (s, 1H, CHO), 7.50－7.20 (m,

7H, ArH), 5.13 (s, 2H, OCH₂). MS (ESI): 276.9 [M−H].

5-(Benzyloxy)-4-hydroxy-4'-methoxy-[1,1'-biphenyl]-

3-carbaldehyde (3c): A dry flask was charged with 3a

(1.04 g, 3.40 mmol), 4-methoxyphenylboronic acid

(0.62 g, 4.08 mmol), Pd(PPh₃)₄(0.35 g, 0.34 mmol), 2

N K₂CO₃(3.4 mL, 6.08 mmol) and MeOH (15 mL), the

resulting mixture was stirred at 80 ℃ overnight. The

solid was removed by filtration through a pad of celite,

the filtrate was evaporated, and the residue was diluted

with water/AcOEt (100 mL/100 mL). After separation,

the organic phase was washed with water (100 mL),

brine (100 mL), dried over MgSO₄, and concentrated.

The residue was subjected to column chromatography

(SiO₂, AcOEt/petroleum ether＝1∶20) to give a white

solid 3c (0.95 g, 84%). TLC (petroleum ether/AcOEt

10∶1): R_f0.16. ¹H NMR (CDCl₃, 400 MHz) δ: 11.00 (s,

1H, OH), 9.98 (s, 1H, CHO), 7.49－7.47 (m, 2H, ArH),

7.41－7.33 (m, 7H, ArH), 6.97－6.95 (m, 2H, ArH),

5.25 (s, 2H, CH₂), 3.85 (s, 3H, OCH₃); ¹³C NMR

O

N

H

100 (82)^b

S

O

Dalcetrapid

The inhibition at 10 μmol•L^－of tested compounds. ^bIn the

parentheses, the inhibition at 1 μmol•L .

a

1

－

1

Yantai Jiangyou Silica R&D Co. Ltd., P. R. China) were

detected under UV light or with iodine. The meltimg

points of some compounds were obtained in an uncor-

rected melting instrument. H and ¹³C NMR spectra:

1

Varian Mercury-Plus (300 or 400 MHz for H, and 100

MHz for ¹³C) spectrometer; chemical shifts δ in ppm,

with residual CHCl₃[δ (H) 7.26; δ (C) 77.0] as internal

standard; J in Hz. EI-MS, ESI-MS and HR-APCI/ESI-

MS: Finnigan Mat-95 mass spectrometer; in m/z.

3-(Benzyloxy)-2-hydroxybenzaldehyde (2): To a

suspension of 60% NaH (5.80 g, 144 mmol) in dry THF

(150 mL) was added dropwise a solution of 2,3-di-

hydroxybenzaldehyde (10.0 g, 72 mmol) in dry THF

under stirring. The resulting mixture was stirred at r.t.

for 1 h. Then benzyl bromide (12.3 g, 72 mmol) was

added dropwise at 25 ℃ and continued to stir for 24 h.

After the reaction was quenched with H₂O (300 mL),

the mixture was acidified with aq. HCl to pH＝2 and

extracted with CH₂Cl₂(100 mL×3). The combined

organic phases were washed with 1 mol•L^－HCl, dried

1

over MgSO₄and concentrated. The residue was sub-

jected to column chromatography (short SiO₂column,

petroleum ether/AcOEt＝20∶1) to give the crude prod-

uct, which was further purified by recrystalization from

EtOH: white solid 2 (10.7 g, 65%). TLC (petroleum

Chin. J. Chem. 2013, 31, 355—370

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359

Zhang et al.

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(CDCl₃, 100 MHz) δ: 196.5, 159.1, 151.1, 147.3, 136.4,

132.8, 132.0, 128.6 (2C), 128.1, 127.6 (2C), 127.4 (2C),

122.9, 121.0, 119.7, 114.3 (2C), 71.5, 55.3. MS (ESI):

335.2 [M＋H]. HRMS (APCI): Calcd for C₂₁H₁₉O₄

[M＋H]: 335.1283, found 335.1262

9H), 0.06 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 148.9,

140.1, 136.5, 132.0, 130.7, 128.4 (2C), 128.2 (2C),

128.0, 121.0, 113.1, 70.6, 61.7, 25.9 (3C), 21.0, 18.6,

4.0 (2C). MS (ESI): 381.2 [M＋Na].

2-(Benzyloxy)-6-(hydroxymethyl)phenol (7a): Pre-

pared according to the procedure for 6 except that a dif-

ferent substrate 2 was used. Colorless oil, yield: 98%.

¹H NMR (CDCl₃, 300 MHz) δ: 7.42－7.36 (m, 5H,

ArH), 6.91－6.79 (m, 3H, ArH), 6.08 (s, 1H, OH), 5.11

(s, 2H, CH₂), 4.74 (s, 2H, CH₂), 2.33 (br s, 1H, OH).

MS (ESI): 253.0 [M＋Na].

3-(Benzyloxy)-2-(hydroxy)-5-methylbenzenemetha-

nol (7b): To a cold (0 ℃) solution of 6 (323 mg, 0.90

mmol) in dry THF (9 mL) was added Bu₄NF•xH₂O (471

mg, 1.8 mmol). The resulting mixture was stirred at r.t.

for 0.5 h. The reaction was quenched with H₂O (20 mL),

then extracted with AcOEt (20 mL×3), the combined

organic extracts were washed with H₂O, brine, dried

over Na₂SO₄and concentrated. The residue was purified

by column chromatography (SiO₂, petroleum ether/

AcOEt＝4∶1) to give a colorless oil 7b (206 mg, 94%).

TLC (petroleum ether/AcOEt＝3∶1): R_f0.26. ¹H NMR

(CDCl₃, 400 MHz) δ: 7.43－7.37 (m, 5H, ArH), 6.73 (s,

1H, ArH), 6.70 (s, 1H, ArH), 5.91 (s, 1H, OH), 5.09 (s,

2H, CH₂), 4.70 (s, 2H, CH₂), 2.36 (s, 1H, OH), 2.28 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 145.4, 141.5,

136.3, 129.2, 128.7 (2C), 128.3, 127.8 (2C), 126.3,

121.5, 112.6, 71.1, 61.8, 21.0. MS (ESI): 267.1 [M＋

Na].

3-(Benzyloxy)-5-bromo-2-{[(tert-butyl)dimethylsilyl]-

oxy}benzaldehyde (4): To a solution of 3a (307 mg, 1.1

mmol) in DMF (1 mL) was added N,N-diisopropyl-

ethylamine (0.35 mL, 2.0 mmol). After the mixture was

stirred for 10 min, t-BuMe₂SiCl (301 mg, 2.0 mmol)

was added, and the resulting mixture was stirred at r.t.

for 1 h. The reaction was quenched with H₂O (50 mL),

the mixture was extracted with AcOEt (50 mL×3), the

combined organic extracts were washed with H₂O, brine,

dried over MgSO₄, and concentrated. The residue was

subjected to column chromatography (SiO₂, petroleum

ether/AcOEt＝100∶1) to give a yellow solid 4 (401 mg,

95%). m.p. 74－75 ℃; TLC (petroleum ether/AcOEt＝

15∶1): R_f0.78. ¹H NMR (CDCl₃, 400 MHz) δ: 10.40 (s,

1H), 7.52 (d, J＝2.4 Hz, 1H), 7.42－7.41 (m, 5H), 7.21

(d, J＝2.4 Hz, 1H), 5.03 (s, 2H), 0.92 (s, 9H), 0.07 (s,

6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 188.7, 151.3,

148.5, 135.0, 128.9, 128.7 (2C), 128.4 (2C), 121.9,

121.1, 113.7, 71.4, 25.7 (3C), 18.7, 4.3 (2C). ESI-MS:

421.1, 423.1 [M＋H].

3-(Benzyloxy)-2-{[(tert-butyl)dimethylsilyl]oxy}-5-

methylbenzaldehyde (5): To a flame-dried flask were

added 4 (2.21 g, 5.24 mmol), [Pd(dppf)Cl₂] (58 mg,

0.08 mmol), 1.2 mol•L^－dimethylzinc in toluene (5.2

1

mL, 6.29 mmol) and dry 1,4-dioxane (15 mL), the re-

sulting suspension was heated at 110 ℃ for 1 h. After

cooling, the mixture was quenched with aq. 1 N HCl (50

mL) and extracted with AcOEt (50 mL×2). The com-

bined extracts were washed with H₂O, brine, dried over

MgSO₄, and concentrated. The residue was subjected to

column chromatography (SiO₂, petroleum ether/AcOEt

＝40∶1) to give a yellow solid 5 (1.53 g, 82%). m.p.

72－73 ℃; TLC (petroleum ether/AcOEt＝15∶1): R_f

0.57. ¹H NMR (CDCl₃, 400 MHz) δ: 10.46 (s, 1H), 7.44

－7.35 (m, 5H), 7.21 (s, 1H), 6.94 (d, J＝1.6 Hz, 1H),

5.05 (s, 2H), 2.28 (s, 3 H), 0.94 (s, 9H), 0.08 (s, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ: 190.5, 150.1, 147.2,

136.0, 130.9, 128.6 (2C), 128.3, 128.2 (2C), 127.7,

119.7, 119.2, 71.0, 25.8 (3C), 21.0, 18.8, −4.3 (2C). MS

(ESI): 357.2 [M＋H].

(3-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-5-

methylphenyl)methanol (6): NaBH₄(378 mg, 10.0

mmol) was added in portions to a stirred solution of 5

(891 mg, 2.5 mmol) in MeOH (200 mL) at 0 ℃. The

resulting mixture was stirred for 4 h at r.t. and then

concentrated. The residue was dissolved in aq. 3 N HCl

(50 mL), then extracted with CH₂Cl₂(20 mL×3). The

combined CH₂Cl₂extracts were washed with H₂O (50

mL×3), dried over Na₂SO₄, and concentrated to give a

colorless oil 6 (812 mg, 91%). TLC (petroleum ether/

AcOEt＝ 10∶1): R_f0.41. ¹H NMR (CDCl₃, 400 MHz)

δ: 7.42－7.30 (m, 5H), 6.75 (s, 1H), 6.68 (s, 1H), 5.02

(s, 2H), 4.67 (s, 2H), 2.26 (s, 3H), 2.23 (s, 1H), 0.94 (s,

3-(Benzyloxy)-5-(hydroxymethyl)-4'-methoxy-[1,1'-

biphenyl]-4-ol (7c): Prepared according to the procedure

for 6 except that a different substrate 3c was used. col-

orless oil, yield: 86%. TLC (petroleum ether/AcOEt＝

3∶1): R_f0.21. ¹H NMR (CDCl₃, 400 MHz) δ: 7.45－

7.44 (m, 7H, ArH), 7.08－7.07 (m, 2H, ArH), 6.96－

6.94 (m, 2H, ArH), 6.10 (s, 1H, OH), 5.17 (s, 2H, CH₂),

4.79 (s, 2H, CH₂), 3.84 (s, 3H, OCH₃) , 2.40 (br s, 1H,

OH); ¹³C NMR (CDCl₃, 100 MHz) δ: 158.7, 145.8,

143.0, 136.2, 133.5, 132.9, 128.7 (2C), 128.4, 127.8

(2C), 127.7 (2C), 126.8, 119.5, 114.1 (2C), 110.5, 71.3,

61.8, 55.3. MS (ESI): 335.2 [M−H]. HRMS (APCI):

Calcd for C₂₁H₁₉O₄[M−H]: 335.1284, found: 335.1261.

2-(Benzyloxy)-6-(hydroxymethyl)-4-iodophenol (7d):

Prepared according to the procedure for 6 except that a

different substrate 3b was used. Colorless oil, yield:

1

95%. H NMR (400 MHz, CDCl₃) δ: 7.50－7.32 (m,

5H), 7.24 (s, 1H), 7.17 (d, J＝1.7 Hz, 1H), 6.08 (s, 1H),

5.06 (s, 2H), 4.66 (s, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ: 146.4, 143.8, 135.6, 129.9, 128.9, 128.8 (2C), 128.6,

128.0 (2C), 120.6, 80.7, 71.5, 60.8. MS (ESI): 379.0

[M ＋ Na]. HRMS (EI): Calcd for C₁₄H₁₃IO₃[M]:

355.9909, found: 355.9909.

8-(Benzyloxy)-6-iodo-2,2-dimethyl-4H-benzo[d][1,3]-

dioxine (9): To a solution of 7d (7.08 g, 19.9 mmol) in

dry CH₂Cl₂(100 mL) were added TsOH•H₂O (0.380 g,

2.0 mmol) and 2,2-dimethoxypropane (12.3 mL, 99.5

mmol), the resulting mixture continued to stir at r.t. for

0.5 h. The reaction solution was washed with sat. aq.

360

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

NaHCO₃(100 mL), brine (100 mL), and dried over

Na₂SO₄. The solvent was evaporated and the residue

was subjected to column chromatography (SiO₂, petro-

leum ether/AcOEt＝4∶1), giving a colorless oil 9 (7.00

g, 95%). TLC R_f＝0.8 (petroleum ether/AcOEt＝1∶3).

¹H NMR (400 MHz, CDCl₃) δ: 7.45－7.29 (m, 5H),

7.06 (s, 1H), 6.93 (d, J＝1.0 Hz, 1H), 5.10 (s, 2H), 4.77

(s, 2H), 1.57 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ:

148.2, 141.8, 136.6, 128.5 (2C), 127.9, 127.2, 126.1,

122.5, 122.3 (2C), 100.1, 81.2, 71.4, 60.0, 24.6 (2C).

MS (ESI): 418.9 [M＋Na]. HRMS (ESI): Calcd for

C₁₇H₁₇IO₃Na [M＋Na]: 419.0120, found: 419.0114.

2-(Benzyloxy)-6-(hydroxymethyl)-4-(methylthio)phe-

nol (7f): A dry flask was charged with 9 (0.198 g, 0.50

mmol), CuI (10 mg, 0.050 mmol), sulfur powder (48 mg,

1.5 mmol), K₂CO₃(0.138 g, 1.0 mmol) and dry DMF

(2.0 mL), the mixture was stirred at 90 ℃ for 10 h.

After 9 disappeared as monitored by TLC (R_f0.19, pe-

troleum ether/AcOEt＝1∶10), the reaction mixture was

cooled, and NaBH₄(57 mg, 1.5 mmol) was added. The

resulting mixture was stirred at 40 ℃ overnight, lead-

ing to the corresponding thiol (TLC: R_f0.19, petroleum

ether/AcOEt＝10∶1). After that, CH₃I (50 µL, 1.5

mmol) was added to the reaction mixture in one portion,

and the reaction was stirred at r.t. overnight. The reac-

tion mixture was diluted with AcOEt (10 mL), filtered

through a pad of celite, and the filtrate was poured into a

solution of water (40 mL) and sat. aq. NH₄Cl (20 mL),

then extracted with AcOEt (20 mL×3). The combined

organic phases were washed with brine (50 mL), dried

over Na₂SO₄, and evaporated. The residue was sub-

jected to column chromatography (SiO₂, petroleum

ether/AcOEt＝5∶1, R_f0.60), yielding 0.181 g of me-

thylthio compound as a colorless oil.

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.6, 143.2,

136.0, 128.7 (2C), 128.4, 127.8 (2C), 127.1, 125.5,

124.5, 115.5, 71.2, 61.3, 29.8, 14.5. MS (ESI): 289.1

[M−H]. HRMS (ESI): Calcd for C₁₆H₁₈NaO₃S [M＋Na]:

313.0874, found: 313.0853.

2-(Benzyloxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)-

methyl)phenol (8a): To a cold (－10 ℃) solution of 7a

(0.300 g, 1.3 mmol) in dry CH₂Cl₂(20 mL) was added

TsOH•H₂O (0.024 g, 0.13 mmol), the resulting mixture

was stirred at −10 ℃ for 15 min. Then 3,4-dihydro-

2H-pyran (0.35 mL, 3.84 mmol) was added dropwise

and the solution was stirred at r.t. overnight. The reac-

tion was quenched with Et₃N (1 mL), the mixture was

washed with brine, dried over MgSO₄, and evaporated.

The residue was subjected to column chromatography

(SiO₂, petroleum ether/AcOEt＝20∶1) to give a white

solid 8a (0.393 g, 96%). m.p. 76 － 77 ℃ ; TLC

1

(petroleum ether/AcOEt＝6∶1): R_f0.60. H NMR

(CDCl₃, 400 MHz) δ: 7.44－7.33 (m, 5H, ArH), 6.94

(dd, J＝7.6, 1.2 Hz, 1H, ArH), 6.87 (dd, J＝7.8, 1.2 Hz,

1H, ArH), 6.80 (dd, J＝7.8 Hz, J'＝7.8 Hz, 1H, ArH),

6.38 (s, 1H, OH), 5.11 (s, 2H, CH₂), 4.86 (d, J＝12.0 Hz,

1H, CH₂), 4.76 (t, J＝3.8 Hz, 1H, CH₂), 4.63 (d, J＝

12.0 Hz, 1H, CH₂), 3.96－3.93 (m, 1H, CH₂), 3.58－

3.55 (m, 1H, CH₂), 1.86－1.52 (m, 6H). MS (ESI):

337.2 [M＋Na].

2-(Benzyloxy)-4-methyl-6-(((tetrahydro-2H-pyran-2-

yl)oxy)methyl)phenol (8b): Prepared according to the

procedure for 8a except that a different substrate 7b was

used. White solid, yield: 84%. m.p. 98－99 ℃; TLC R_f

0.67 (petroleum ether/AcOEt＝4∶1). ¹H NMR (CDCl₃,

400 MHz) δ: 7.44－7.34 (m, 5H), 6.74 (s, 1H), 6.71 (s,

1H), 6.23 (s, 1H), 5.08 (s, 2H), 4.82 (d, J＝12.0 Hz, 1H),

4.75 (t, J＝3.3 Hz, 1H), 4.58 (d, J＝12.0 Hz, 1H), 4.00

－3.95 (m, 1H), 3.60－3.50 (m, 1H), 2.26 (s, 3H), 1.88

－1.53 (m, 6H). MS (ESI): 351.1 [M＋Na]. HRMS

(ESI): Calcd for C₂₀H₂₃O₄[M−H]: 327.1597, found:

328.1610.

The above methylthio compound was dissolved in aq.

1 N HCl (6.0 mL) and THF (6.0 mL), and refluxed for 2

h. After cooled, the solution was diluted with AcOEt

(20 mL) and water (20 mL). The aq. phase was ex-

tracted with AcOEt (20 mL×2), and the combined or-

ganic phases were washed with brine (50 mL), dried

over Na₂SO₄, and evaporated. The residue was sub-

jected to column chromatography (petroleum ether/

AcOEt＝5∶1), furnishing a colorless oil 7f (0.116 g,

84% overall yield). TLC R_f0.54 (petroleum ether/

3-(Benzyloxy)-4'-methoxy-5-(((tetrahydro-2H-pyran-

2-yl)oxy)methyl)-[1,1'-biphenyl]-4-ol (8c): Prepared

according to the procedure for 8a except that a different

substrate 7c was used. White solid, yield: 92%. m.p.

83－84 ℃; TLC R_f0.57 (petroleum ether/AcOEt＝3∶

1

1). H NMR (CDCl₃, 400 MHz) δ: 7.46－7.35 (m, 7H,

1

AcOEt＝3∶1). H NMR (400 MHz, CDCl₃) δ: 7.73－

ArH), 7.12 (d, J＝1.6 Hz, 1H, ArH), 7.07 (d, J＝2.0 Hz,

1H, ArH), 6.95－6.92 (m, 2H, ArH), 6.40 (s, 1H, OH),

5.17 (s, 2H, CH₂), 4.90 (d, J＝12.0 Hz, 1H, CH₂), 4.79

(t, J＝3.5 Hz, 1H, CH), 4.67 (d, J＝12.0 Hz, 1H, CH₂),

4.01－3.95 (m, 1H, CH₂), 3.83 (s, 3H, OCH₃), 3.60－

3.56 (m, 1H, CH₂), 1.89－1.54 (m, 6H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 158.6, 146.2, 143.6, 136.5, 133.7,

132.6, 128.6 (2C), 128.2, 127.8 (2C), 127.7 (2C), 124.0,

120.3, 114.0 (2C), 111.0, 98.2, 71.3, 64.9, 62.5, 55.3,

30.5, 25.3, 19.5. MS (ESI): 443.2 [M＋Na]. HRMS

(APCI): Calcd for C₂₆H₂₇O₅[M−H]: 419.1859, found:

419.1823.

7.29 (m, 5H), 7.10－6.70 (m, 2H), 6.06 (s, 1H), 5.08 (s,

2H), 4.69 (s, 2H), 2.42 (s, 3H), 2.38 (brs, 1H); ¹³C NMR

(100 MHz, CDCl₃) δ: 145.8, 142.4, 136.0, 128.7 (2C),

128.5, 128.0, 127.9 (2C), 127.2, 121.4, 112.9, 71.4, 61.4,

18.1. MS (ESI): 275.0 [M−H]. HRMS (ESI): Calcd for

C₁₅H₁₅O₃S [M−H]: 275.0742, found: 275.0755.

2-(Benzyloxy)-4-(ethylthio)-6-(hydroxymethyl)phe-

nol (7g): Prepared according to the procedure for 7f ex-

cept that a different substrate (EtI) was used. Colorless

oil, yield: 83%. TLC R_f0.18 (petroleum ether/AcOEt＝

1

4∶1). H NMR (400 MHz, CDCl₃) δ: 7.39－7.34 (m,

5H), 6.95 (s, 2H), 6.28 (s, 1H), 5.06 (s, 2H), 4.66 (s, 2H),

2.80 (q, J＝7.2 Hz, 2H), 2.62 (brs, 1H), 1.20 (t, J＝7.2

2-(Benzyloxy)-4-iodo-6-(((tetrahydro-2H-pyran-2-yl)-

oxy)methyl)phenol (8d): Prepared according to the pro-

Chin. J. Chem. 2013, 31, 355—370

www.cjc.wiley-vch.de

361

Zhang et al.

FULL PAPER

cedure for 8a except that a different substrate 7d was

used. White solid, quantitative yield. TLC R_f0.1

(petroleum ether/AcOEt＝4∶1). The crude product was

directly used in next step.

3.55 mmol), 10 (0.808 g, 2.96 mmol), activated Cu

powder (0.474 g, 7.40 mmol), CuO black (0.592 g, 7.40

mmol), DMAP (1.08 g, 8.88 mmol) and dry MeCN (25

mL), the resulting suspension was refluxed for 17 h.

After cooling, the mixture was diluted with CH₂Cl₂(20

mL) and filtered through a pad of celite, the filter cake

was washed with CH₂Cl₂(10 mL×3), the filtrate was

concentrated, and the residue was subjected to column

chromatography (SiO₂, petroleum ether/AcOEt＝6∶1)

to give a yellowish oil 11a (1.10 g, 73%). TLC

2-(Benzyloxy)-4-(methylsulfonyl)-6-(((tetrahydro-

2H-pyran-2-yl)oxy)methyl)phenol (8e): A dry flask was

charged with 8d (0.127 g, 0.29 mmol), CuI (6 mg, 0.03

mmol), CH₃SO₂Na (0.036 g, 0.35 mmol), L-proline (12

mg, 0.06 mmol), NaOH (5 mg, 0.1 mmol) and dry

DMSO (2 mL), the mixture was stirred at 85 ℃ for 36

h. After cooled, the reaction mixture was diluted with

AcOEt (40 mL) and filtered through a pad of celite. The

filtrate was washed with a solution of water 40 (mL)

and sat. aq. NH₄Cl (20 mL), the separated aq. phase was

extracted with AcOEt (20 mL×4), and the combined

organic phases were washed with brine (100 mL), dried

over Na₂SO₄, and subjected to column chromatography

(SiO₂, petroleum ether/AcOEt＝2.8∶1), yielding a

white solid 8e (59 mg, 52%). TLC R_f0.1 (petroleum

1

(petroleum ether/AcOEt＝10∶1): R_f0.11. H NMR

(CDCl₃, 400 MHz) δ: 10.22 (s, 1H, CHO), 7.71 (d, J＝

4.7 Hz, 1H, ArH), 7.27－7.13 (m, 7H, ArH), 6.99 (dd,

J＝8.1, 1.4 Hz, 1H, ArH), 6.43 (d, J＝8.8 Hz, 1H, ArH),

5.02 (s, 2H, CH₂), 4.73 (d, J＝12.0 Hz, 1H, CH₂),

4.67－4.66 (m, 1H, CH), 4.48 (d, J＝12.0 Hz, 1H, CH₂),

3.99 (s, 3H, OCH₃), 3.94 (s, 3H, OCH₃), 3.83－3.76 (m,

1H, CH₂), 3.51－3.45 (m, 1H, CH₂), 1.65－1.43 (m,

6H). MS (ESI): 529.2 [M＋Na].

1

ether/AcOEt＝4∶1). H NMR (400 MHz, CDCl₃) δ:

Methyl 6-(2-(benzyloxy)-4-methyl-6-(((tetrahydro-

2H-pyran-2-yl)oxy)methyl)phenoxy)-3-formyl-2-meth-

oxybenzoate (11b): Prepared according to the procedure

for 11a except that a different substrate 8b was used.

Yellowish oil, yield: 60%. TLC R_f0.09 (petroleum

7.60 (s, 1H), 7.47－7.35 (m, 6H), 7.04 (d, J＝6.3 Hz,

1H), 5.17 (s, 2H), 4.89 (d, J＝12.8 Hz, 1H), 4.75 (s, 1H),

4.62 (d, J＝12.8 Hz, 1H), 4.00－3.95 (m, 1H), 3.60－

3.50 (m, 1H), 3.00 (s, 3H), 1.88－1.56 (m, 6H). MS

(ESI): 391.1 [M−H].

1

ether/AcOEt＝10∶1). H NMR (CDCl₃, 400 MHz) δ:

2-(Benzyloxy)-4-(methylthio)-6-(((tetrahydro-2H-

pyran-2-yl)oxy)methyl)phenol (8f): Prepared according

to the procedure for 8a except that a different substrate

7f was used. White solid, yield: 78%. TLC R_f0.74

10.22 (s, 1H, CHO), 7.76 (d, J＝8.7 Hz, 1H, ArH), 7.28

－7.16 (m, 5H, ArH), 6.94 (s, 1H, ArH), 6.83 (s, 1H,

ArH), 6.46 (d, J＝9.1 Hz, 1H, ArH), 5.00 (s, 2H, CH₂),

4.69 (d, J＝12 Hz, 1H, CH₂), 4.75－4.60 (m, 1H, CH),

4.43 (d, J＝12 Hz, 1H, CH₂), 3.99 (s, 3H, OCH₃), 3.95

(s, 3H, OCH₃), 3.85－3.75 (m, 1H, CH₂), 3.55－3.40

(m, 1H, CH₂), 2.36 (s, 3H, CH₃), 1.66－1.41 (m, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ: 187.7, 165.3, 161.7,

161.5, 150.1, 138.3, 136.5, 136.4, 132,2, 131.0, 128.2

(2C), 127.6, 126.7 (2C), 122.9, 122.5, 117.8, 114.9,

110.3, 98.4, 70.4, 64.7, 64.3, 61.8, 52.6, 30.2, 25.3, 21.4,

19.0. MS (ESI): 543.4 [M＋Na]. HRMS (ESI): Calcd

for C₃₀H₃₂O₈Na [M＋Na]: 543.1995, found 543.1968.

Methyl 6-((3-(benzyloxy)-4'-methoxy-5-(((tetrahy-

dro-2H-pyran-2-yl)oxy)methyl)-[1,1'-biphenyl]-4-yl)-

oxy)-3-formyl-2-methoxybenzoate (11c): Prepared ac-

cording to the procedure for 11a except that a different

substrate 8c was used. Yellowish oil, yield: 69%. TLC

1

(petroleum ether/AcOEt＝4∶1). H NMR (400 MHz,

CDCl₃) δ: 7.51－7.29 (m, 4H), 6.94 (d, J＝2.0 Hz, 1H),

6.89 (d, J＝2.0 Hz, 1H), 6.35 (s, 1H), 5.10 (s, 2H), 4.82

(d, J＝12.3 Hz, 1H), 4.80－4.70 (m, 1H), 4.59 (d, J＝

12.3 Hz, 1H), 4.00－3.95 (m, 1H), 3.60－3.50 (m, 1H),

13

2.41 (s, 3H), 1.89－1.50 (m, 6H); C NMR (100 MHz,

CDCl₃) δ: 146.2, 143.0, 136.2, 128.6 (2C), 128.3, 127.7

(2C), 127.5, 124.6, 122.2, 113.4, 98.2, 71.3, 64.5, 62.4,

30.5, 25.3, 19.4, 18.1. HRMS (ESI): Calcd for

C₂₀H₂₃O₄S [M−H]: 359.1317, found 359.1337.

2-(Benzyloxy)-4-(ethylthio)-6-(((tetrahydro-2H-py-

ran-2-yl)oxy)methyl)phenol (8g): Prepared according to

the procedure for 8a except that a different substrate 7g

was used. White solid, yield: 82%. TLC R_f0.6

1

(petroleum ether/AcOEt＝5∶1). H NMR (400 MHz,

R_f0.32 (petroleum ether/AcOEt＝5∶1). H NMR

CDCl₃) δ: 7.46－7.29 (m, 5H), 7.02 (d, J＝1.2 Hz, 1H),

6.95 (s, 1H), 6.42 (s, 1H), 5.09 (s, 2H), 4.82 (d, J＝12.3

Hz, 1H), 4.80－4.70 (m, 1H), 4.59 (d, J＝12.3 Hz, 1H),

3.94 (dd, J＝13.6, 5.8 Hz, 1H), 3.60－3.50 (m, 1H),

2.80 (q, J＝7.3 Hz, 2H), 1.90－1.69 (m, 2H), 1.69－

1.49 (m, 4H), 1.20 (t, J＝7.3 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 145.9, 143.6, 136.2, 128.6 (2C), 128.2,

127.6 (2C), 125.2, 125.1, 124.4, 115.9, 98.2, 71.2, 64.4,

62.4, 30.4, 29.8, 25.3, 19.4, 14.5. MS (ESI): 397.1 [M＋

Na]. HRMS (ESI): Calcd for C₂₁H₂₆NaO₄S [M＋Na]:

397.1449, found 397.1430.

(CDCl₃, 400 MHz) δ: 10.23 (s, 1H, CHO), 7.74 (d, J＝

8.7 Hz, 1H, ArH), 7.50－7.47 (m, 2H, ArH), 7.31－

7.16 (m, 7H, ArH), 7.00－6.97 (m, 2H, ArH), 6.53 (d,

J＝8.7 Hz, 1H, ArH), 5.08 (s, 2H, CH₂), 4.77 (d, J＝12

Hz, 1H, CH₂), 4.71－4.70 (m, 1H, CH), 4.51 (d, J＝12

Hz, 1H, CH₂), 4.00 (s, 3H, OCH₃), 3.96 (s, 3H, OCH₃),

3.86 (s, 3H, OCH₃), 3.84－3.78 (m, 1H, CH₂), 3.52－

3.47 (m, 1H, CH₂), 1.64－1.42 (m, 6H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 187.8, 165.3, 161.7, 161.3, 159.3,

150.5, 139.6, 139.4, 136.3, 132.9, 132.8, 131.1, 128.3

(2C), 128.1 (2C), 127.7, 126.8 (2C), 123.1, 120.3, 117.9,

114.2 (2C), 112.6, 110.4, 98.5, 70.6, 64.8, 64.4, 61.8,

55.3, 52.7, 30.2, 25.3, 19.1. MS (ESI): 635.1 [M＋Na].

HRMS (ESI): Calcd for C₃₆H₃₇O₉[M＋H]: 613.2438,

Methyl 6-(2-(Benzyloxy)-6-(((tetrahydro-2H-pyran-

2-yl)oxy)methyl)phenoxy)-3-formyl-2-methoxybenzo-

ate (11a): To a flame-dried flask were added 8a (1.12 g,

362

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

found 613.2395.

MS (EI): 422 [M]. HRMS (ESI): calcd for C₂₄H₂₂O₇Na

Methyl 6-(2-(benzyloxy)-4-(methylthio)-6-(((tetra-

hydro-2H-pyran-2-yl)oxy)methyl)phenoxy)-3-formyl-2-

methoxybenzoate (11f): Prepared according to the pro-

cedure for 11a except that a different substrate 8f was

used. Yellowish oil, yield: 67%. TLC R_f0.12

[M＋Na]: 445.1263, found 445.1262.

Methyl 6-(2-(benzyloxy)-6-(hydroxymethyl)-4-meth-

ylphenoxy)-3-formyl-2-methoxybenzoate (12b): Pre-

pared according to the procedure for 12a except that a

different substrate 11b was used. Colorless oil, yield:

1

(petroleum ether/AcOEt＝10∶1). H NMR (400 MHz,

93%. TLC R_f0.20 (petroleum ether/AcOEt＝3∶1). H

CDCl₃) δ: 10.21 (s, 1H), 7.72 (d, J＝8.9 Hz, 1H),

7.35－7.19 (m, 3H), 7.20－7.10 (m, 1H), 7.14 (s, 1H),

7.01 (s, 1H), 6.88 (s, 1H), 6.45 (d, J＝8.8 Hz, 1H), 5.00

(s, 2H), 4.68 (d, J＝12.5 Hz, 1H), 4.66 (s, 1H), 4.44 (d,

J＝12.5 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.90－3.70

(m, 1H), 3.55－3.45 (m, 1H), 2.48 (s, 3H), 1.69－1.32

(m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.7, 165.2,

161.7, 161.2, 150.4, 138.1, 136.6, 136.0, 133.2, 131.0,

128.2, 127.7, 126.7, 123.1, 119.4, 117.8, 112.4, 110.1,

98.4, 70.6, 64.7, 64.0, 61.8, 52.6, 30.2, 25.2, 19.0, 16.1.

MS (ESI): 575.2 [M＋Na]. HRMS (ESI): Calcd for

C₃₀H₃₂NaO₈S [M＋Na]: 575.1716, found 575.1719.

Methyl 6-(2-(benzyloxy)-4-(ethylthio)-6-(((tetrahy-

dro-2H-pyran-2-yl)oxy)methyl)phenoxy)-3-formyl-2-

methoxybenzoate (11g): Prepared according to the pro-

cedure for 11a except that a different substrate 8g was

used. White solid, yield: 70%. TLC R_f0.11 (petroleum

NMR (CDCl₃, 400 MHz) δ: 10.22 (s, 1H, CHO), 7.74 (d,

J＝9.0 Hz, 1H, ArH), 7.29－7.16 (m, 5H, ArH), 6.88 (s,

1H, ArH), 6.83 (s, 1H, ArH), 6.46 (d, J＝9.0 Hz, 1H,

ArH), 5.02 (s, 2H, CH₂), 4.56 (s, 2H, CH₂), 3.40 (s, 3H,

OCH₃), 3.96 (s, 3H, OCH₃), 2.78 (br s, 1H, OH), 2.35 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 187.7, 165.6,

161.9, 160.9, 150.2, 138.0, 136.8, 136.3, 134.6, 131.6,

128.3 (2C), 127.7, 126.7 (2C), 123.3, 121.9, 117.4,

114.7, 109.9, 70.5, 64.7, 60.7, 52.9, 21.4. MS (ESI):

459.3 [M＋Na]. HRMS (ESI): Calcd for C₂₅H₂₄O₇Na

[M＋Na]: 459.1420, found 459.1409.

Methyl 6-((3-(benzyloxy)-5-(hydroxymethyl)-4'-

methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-formyl-2-methoxy-

benzoate (12c): Prepared according to the procedure for

12a except that a different substrate 11c was used. Col-

orless oil, yield: 95%. TLC R_f0.14 (petroleum ether/

AcOEt＝3∶1). ¹H NMR (CDCl₃, 400 MHz) δ: 10.23 (s,

1H, CHO), 7.77 (d, J＝9.1 Hz, 1H, ArH), 7.49－7.46

(m, 2H, ArH), 7.29－7.16 (m, 7H, ArH), 6.99－6.96 (m,

2H, ArH), 6.53 (d, J＝9.1 Hz, 1H, ArH), 5.09 (s, 2H,

CH₂), 4.65 (d, J＝6.0 Hz, 2H, CH₂), 4.01 (s, 3H, OCH₃),

3.97 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 2.74 (t, J＝6.0

Hz, 1H, OH); ¹³C NMR (CDCl₃, 100 MHz) δ: 187.7,

165.5, 161.9, 160.8, 159.4, 150.7, 139.7, 139.2, 136.2,

135.2, 132.7, 131.6, 128.4 (2C), 128.1 (2C), 127.9,

126.9 (2C), 123.5, 119.8, 117.5, 114.2 (2C), 112.5,

110.1, 70.7, 64.8, 61.0, 55.3, 52.9. MS (ESI): 528.7 [M

＋H]. HRMS (APCI): calcd for C₃₁H₂₉O₈[M＋H]:

529.1862, found 529.1850.

Methyl 6-(2-(benzyloxy)-6-(hydroxymethyl)-4-

(methylthio)phenoxy)-3-formyl-2-methoxybenzoate

(12f): Prepared according to the procedure for 12a ex-

cept that a different substrate 11f was used. Colorless oil,

quantitative yield. TLC R_f0.15 (petroleum ether/

AcOEt＝3∶1). ¹H NMR (400 MHz, CDCl₃) δ: 10.20 (s,

1H), 7.73 (d, J＝8.8 Hz, 1H), 7.33－7.19 (m, 3H), 7.19

－7.08 (m, 2H), 6.96 (s, 1H), 6.88 (d, J＝1.5 Hz, 1H),

6.45 (d, J＝8.8 Hz, 1H), 5.01 (s, 2H), 4.57 (d, J＝3.8

Hz, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 2.92 (brs, 1H), 2.46

(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.6, 165.5,

161.8, 160.7, 150.5, 137.6, 137.0, 135.9, 135.5, 131.6,

128.3, 127.8, 126.8, 123.4, 118.7, 117.4, 112.1, 109.8,

70.6, 64.7, 60.4, 52.8, 16.0. HRMS (ESI): Calcd for

C₂₅H₂₅O₇S [M＋H]: 469.1321, found 469.1324.

1

ether/AcOEt＝10∶1). H NMR (400 MHz, CDCl₃) δ:

10.21 (s, 1H), 7.72 (d, J＝8.8 Hz, 1H), 7.31－7.19 (m,

3H), 7.17－7.11 (m, 2H), 7.09 (d, J＝2.0 Hz, 1H), 6.95

(d, J＝2.0 Hz, 1H), 6.46 (d, J＝8.8 Hz, 1H), 5.00 (s,

2H), 4.70－4.66 (m, 2H), 4.44 (d, J＝12.3 Hz, 1H),

3.98 (s, 3H), 3.94 (s, 3H), 3.90－3.70 (m, 1H), 3.55－

3.45 (m, 1H), 2.93 (q, J＝7.4 Hz, 2H), 1.60－1.35 (m,

6H), 1.29 (t, J＝7.4 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ: 187.7, 165.2, 161.7, 161.2, 150.4, 138.7,

136.1, 134.9, 133.3, 131.1, 128.3 (2C), 127.8, 126.8

(2C), 123.2, 121.9, 117.9, 114.6, 110.3, 98.4, 70.6, 64.8,

64.0, 61.9, 52.7, 30.2, 27.9, 25.3, 19.0, 14.3. HRMS

(ESI): Calcd for C₃₁H₃₄NaO₈S [M＋Na]: 589.1827,

found 589.1849.

Methyl 6-(2-(benzyloxy)-6-(hydroxymethyl)phe-

noxy)-3-formyl-2-methoxybenzoate (12a): To a flame-

dried flask were added 11a (1.01 g, 2.0 mmol), TsOH•

H₂O (2 mg), i-PrOH (10 mL), and H₂O (3 mL), and the

resulting solution was refluxed overnight. After cooling,

the mixture was extracted with AcOEt (30 mL×3). The

combined extracts were washed with H₂O, brine, dried

over Na₂SO₄, and concentrated. The residue was sub-

jected to column chromatography (SiO₂, petroleum

ether/AcOEt＝3∶1) to give a colorless oil 12a (0.72 g,

88%). TLC (petroleum ether/AcOEt＝3∶1): R_f0.14.

¹H NMR (CDCl₃, 400 MHz) δ: 10.20 (s, 1H, CHO),

7.73 (d, J＝8.6 Hz, 1H, ArH), 7.26－7.14 (m, 6H, ArH),

7.07 (d, J＝7.2 Hz, 1H, ArH), 6.99 (d, J＝8.4 Hz, 1H,

ArH), 6.43 (d, J＝9.0 Hz, 1H, ArH), 5.02 (s, 2H, CH₂),

4.60 (s, 2H, CH₂), 3.98 (s, 3H, OCH₃), 3.94 (s, 3H,

OCH₃), 2.74 (br s, 1H, OH); ¹³C NMR (CDCl₃, 100

MHz) δ: 187.7, 165.5, 161.9, 160.7, 150.5, 140.2, 136.3,

135.3, 131.6, 128.3 (2C), 127.8, 126.8 (2C), 126.7,

123.4, 121.3, 117.5, 114.0, 110.0, 70.5, 64.7, 60.5, 52.9.

Methyl 6-(2-(benzyloxy)-4-(ethylthio)-6-(hydroxy-

methyl)phenoxy)-3-formyl-2-methoxybenzoate (12g):

Prepared according to the procedure for 12a except that

a different substrate 11g was used. Colorless oil, quan-

titative yield. TLC R_f0.18 (petroleum ether/AcOEt＝

1

3∶1). H NMR (400 MHz, CDCl₃) δ: 10.16 (s, 1H),

7.70 (d, J＝8.8 Hz, 1H), 7.26－7.18 (m, 3H), 7.16－

Chin. J. Chem. 2013, 31, 355—370

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363

Zhang et al.

FULL PAPER

7.09 (m, 2H), 7.07 (d, J＝1.8 Hz, 1H), 6.93 (d, J＝1.8

Hz, 1H), 6.44 (d, J＝8.8 Hz, 1H), 4.98 (s, 2H), 4.57 (s,

2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.51 (brs, 1H), 2.89 (q,

J＝7.3 Hz, 2H), 1.26 (t, J＝7.3 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 187.8, 165.5, 161.8, 160.8, 150.4,

138.0, 136.1, 135.8, 135.2, 131.6, 128.3 (2C), 127.8,

126.8 (2C), 123.4, 120.9, 117.5, 114.1, 110.0, 70.6, 64.7,

59.9, 52.8, 27.8, 14.2. HRMS (APCI): Calcd for

C₂₆H₂₇O₇S [M＋H]: 483.1477, found 483.1454.

a different substrate 13b was used, a white solid 14b

(51% based on 12b). m.p. 57－58 ℃; TLC (petroleum

ether/AcOEt＝2∶1): R_f0.80. H NMR (CDCl₃, 400

1

MHz) δ: 10.35 (d, J＝0.6 Hz, 1H, CHO), 7.98 (d, J＝

8.6 Hz, 1H, ArH), 7.51－7.35 (m, 5H, ArH), 7.03 (dd,

J＝8.6, 0.6 Hz, 1H, ArH), 6.89 (d, J＝1.4 Hz, 1H, ArH),

6.48 (d, J＝1.4 Hz, 1H, ArH), 5.20 (s, 2H, CH₂), 5.13 (s,

2H, CH₂), 4.12 (s, 3H, OCH₃), 2.28 (s, 3H, CH₃); ¹³C

NMR (CDCl₃, 100 MHz) δ: 187.8, 166.1, 161.2, 158.0,

150.4, 143.2, 136.5, 135.3, 133.3, 128.7 (2C), 128.1,

127.32, 127.27 (2C), 127.0, 121.5, 120.6, 118.7, 116.6,

71.3, 69.0, 64.7, 21.2. MS (ESI): 427.0 [M＋Na].

HRMS (ESI): Calcd for C₂₄H₂₀O₆Na [M ＋ Na]:

427.1158, found 427.1133.

6-(2-(Benzyloxy)-6-(hydroxymethyl)phenoxy)-3-for-

myl-2-methoxybenzoic acid (13a): To a solution of 12a

(0.655 g, 1.55 mmol) in MeOH (12 mL) was added

TsOH•H₂O (55 mg, 0.32 mmol), and the resulting mix-

ture was stirred at r.t. for 1 h. Then NaOH tablets (0.722

g, 18.5 mmol) were added, and the mixture was refluxed

overnight. After cooling, the MeOH was evaporated, the

mixture was acidified with aq. 3 N HCl to adjust pH＝3

－4. The mixture was extracted with AcOEt (30 mL×4)

and the combined extracts were concentrated to give a

colorless oil 13a (837 mg, almost quantitative yield),

which was used in next step without further purification.

13b, 13c, 13f, 13g were prepared according to the

above operation except for different substrates used.

The spetral data of 13b are presented as an example: ¹H

NMR (DMSO, 400 MHz) δ: 10.11 (s, 1H, CHO), 7.67

(d, J＝8.8 Hz, 1H, ArH), 7.25－7.18 (m, 5H, ArH),

7.03 (s, 1H, ArH), 6.98 (s, 1H, ArH), 6.38 (d, J＝8.8 Hz,

1H, ArH), 5.08 (s, 2H, CH₂), 4.37 (s, 2H, CH₂), 3.97 (s,

3H, OCH₃), 2.34 (s, 3H, CH₃). MS (ESI): 421.0 [M−H].

11-(Benzyloxy)-4-methoxy-5-oxo-5,7-dihydrodiben-

zo[b,g][1,5]dioxocine-3-carbaldehyde (14a): To a solu-

tion of 2-chloro-1-methylpyridinium iodide (1.42 g,

5.57 mmol) in dry MeCN (40 mL) was added a solution

of the above crude 13a (0.568 g, 1.39 mmol) in dry

MeCN (10 mL) and Et₃N (4.4 mL, 31.6 mmol) at 80 ℃

by a syringe pump within 5 h. The resulting mixture

was refluxed for another 8 h. After cooling to r.t., the

mixture was concentrated, the residue was dissolved in

CH₂Cl₂(30 mL) and filtered through a pad of SiO₂, the

filter cake was washed with CH₂Cl₂(10 mL×5). The

filtrate was washed with H₂O (30 mL×3), dried over

MgSO₄, and concentrated. The residue was subjected to

column chromatography (SiO₂, CH₂Cl₂) to give a white

solid 14a (0.261 g, 55% based on 12a). m.p. 123－124

11-(Benzyloxy)-4-methoxy-9-(4-methoxyphenyl)-5-

oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocine-3-carbalde-

hyde (14c): Prepared according to the procedure for 14a

except that a different substrate 13c was used, a yellow-

ish oil 14c (18% based on 12c). TLC (petroleum

1

ether/AcOEt＝2∶1): R_f0.58. H NMR (CDCl₃, 400

MHz) δ: 10.37 (s, 1H, CHO), 8.02 (d, J＝8.7 Hz, 1H,

ArH), 7.54－7.51 (m, 2H, ArH), 7.45－7.36 (m, 5H,

ArH), 7.23 (d, J＝2.0 Hz, 1H, ArH), 7.08 (dd, J＝8.7,

0.8 Hz, 1H, ArH), 6.97－6.94 (m, 2H, ArH), 6.83 (d,

J＝2.0 Hz, 1H, ArH), 5.28 (s, 2H, CH₂), 5.23 (s, 2H,

CH₂), 4.14 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃); ¹³C

NMR (CDCl₃, 100 MHz) δ: 187.8, 166.0, 161.2, 159.5,

157.7, 150.8, 144.2, 138.3, 136.4, 133.4, 132.2, 128.7

(2C), 128.2, 128.0 (2C), 127.8, 127.4 (2C), 127.1, 120.6,

119.4, 118.8, 114.4, 114.3 (2C), 71.5, 69.1, 64.7, 55.3.

HRMS (APCI): Calcd for C₃₀H₂₅O₇[M＋H]: 497.1600,

found 497.1599.

11-(Benzyloxy)-4-methoxy-9-(methylthio)-5-oxo-

5,7-dihydrodibenzo[b,g][1,5]dioxocine-3-carbaldehyde

(14f): Prepared according to the procedure for 14a ex-

cept that a different substrate 13f was used, a yellowish

solid 14f (67% based on 12f). m.p. 99－100 ℃; TLC

(petroleum ether/AcOEt＝2∶1): R_f0.61. ¹H NMR (400

MHz, CDCl₃) δ: 10.33 (s, 1H), 7.98 (d, J＝8.5 Hz, 1H),

7.55－7.30 (m, 5H), 7.02 (d, J＝8.5 Hz, 1H), 6.96 (d,

J＝2.1 Hz, 1H), 6.54 (d, J＝2.1 Hz, 1H), 5.20 (s, 2H),

5.13 (s, 2H), 4.11 (s, 3H), 2.41 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 187.8, 165.9, 161.2, 157.7, 150.8,

143.1, 136.2, 135.6, 133.4, 128.8, 128.3, 128.2, 127.4

(2C), 127.2, 120.5, 119.1, 118.7, 114.5, 71.5, 68.8, 64.7,

16.4. MS (ESI): 436.9 [M＋H]. HRMS (ESI): Calcd for

C₂₄H₂₁O₆S [M＋H]: 437.1059, found 437.1066.

1

℃; TLC (petroleum ether/AcOEt＝2∶1): R_f0.67. H

NMR (CDCl₃, 400 MHz) δ: 10.35 (s, 1H, CHO), 7.99 (d,

J＝8.6 Hz, 1H, ArH), 7.50－7.34 (m, 5H, ArH), 7.08－

7.01 (m, 3H, ArH), 6.67 (d, J＝7.1 Hz, 1H, ArH), 5.22

(s, 2H, CH₂), 5.18 (s, 2H, CH₂), 4.12 (s, 3H, OCH₃); ¹³C

NMR (CDCl₃, 100 MHz) δ: 187.7, 166.0, 161.2, 157.6,

150.7, 145.2, 136.4, 133.3, 128.7 (2C), 128.1, 127.8,

127.2 (2C), 127.1, 125.2, 121.1, 120.5, 118.7, 115.9,

71.2, 68.9, 64.6. MS (ESI): 391.2 [M＋H]. HRMS (ESI):

Calcd for C₂₃H₁₈O₆Na [M ＋ Na]: 413.1001, found

413.0987.

11-(Benzyloxy)-9-(ethylthio)-4-methoxy-5-oxo-5,7-

dihydrodibenzo[b,g][1,5]dioxocine-3-carbaldehyde

(14g): Prepared according to the procedure for 14a ex-

cept that a different substrate 13g was used, a yellowish

solid 14g (56% based on 12g). m.p. 143－144 ℃; TLC

1

(petroleum ether/acetone＝4∶1): R_f0.30. H NMR

(400 MHz, CDCl₃) δ: 10.34 (s, 1H), 8.00 (d, J＝8.5 Hz,

1H), 7.48 (d, J＝7.3 Hz, 2H), 7.45－7.31 (m, 3H), 7.03

(d, J＝8.5 Hz, 2H), 6.63 (d, J＝1.7 Hz, 1H), 5.21 (s,

2H), 5.13 (s, 2H), 4.11 (s, 3H), 2.84 (q, J＝7.3 Hz, 2H),

1.23 (t, J＝7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ:

11-(Benzyloxy)-4-methoxy-9-methyl-5-oxo-5,7-dihy-

drodibenzo[b,g][1,5]dioxocine-3-carbaldehyde (14b):

Prepared according to the procedure for 14a except that

364

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

187.7, 165.9, 161.2, 157.6, 150.6, 143.6, 136.1, 133.5,

133.4, 128.7, 128.3, 128.0, 127.3, 127.1, 121.8, 120.4,

118.7, 116.8, 71.4, 68.8, 64.7, 28.2, 14.2. MS (ESI):

451.1 [M＋H]. HRMS (APCI): Calcd for C₂₅H₂₃O₆S [M

＋H]: 451.1215, found 451.1224.

methoxy-9-(4-methoxyphenyl)dibenzo[b,g][1,5]dioxo-

cin-5(7H)-one (15c): Prepared according to the proce-

dure for 15a except that a different substrate 14c was

used, a yellowish solid 15c, yield: 77%. m.p. 85－86

1

℃; TLC (petroleum ether/AcOEt＝5∶1): R_f0.30. H

11-(Benzyloxy)-3-(1-hydroxy-3,3-dimethylbutyl)-4-

methoxydibenzo[b,g][1,5]dioxocin-5(7H)-one (15a): A

dry flask was charged with fresh magnesium sheet (1.05

g, 44 mmol) and anhydrous ether (5.0 mL) and stirred at

r.t. under Ar atmosphere, then a grain of iodine was

added. After red color disappeared, a solution (1 mL) of

neopentyl bromide (5 mL) in anhydrous ether (10 mL)

was added dropwise to keep the reaction solution re-

fluxing, and the reaction mixture continued to reflux for

12 h. The solution was used directly in next step.

NMR (CDCl₃, 400 MHz) δ: 7.60 (d, J＝8.6 Hz, 1H,

ArH), 7.54－7.51 (m, 2H, ArH), 7.43－7.34 (m, 5H,

ArH), 7.19 (d, J＝1.6 Hz, 1H, ArH), 6.99 (d, J＝8.6 Hz,

1H, ArH), 6.95－6.92 (m, 2H, ArH), 6.80 (d, J＝1.6 Hz,

1H, ArH), 5.27 (s, 2H, CH₂), 5.20－5.10 (m, 2H), 5.18

(s, 2H), 3.99 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 1.93

(br s, 1H, OH), 1.70－1.55 (m, 2H, CH₂), 1.03 (s, 9H,

CMe₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 167.3, 159.3,

154.0, 152.0, 150.6, 145.2, 137.6, 137.5, 136.6, 132.3,

131.0, 128.6 (2C), 128.0, 127.9 (2C), 127.8, 127.3 (2C),

119.5, 119.3, 118.0, 114.4, 114.2 (2C), 71.5, 69.2, 66.4,

62.6, 55.3, 52.2, 30.7, 30.0 (3C). MS (ESI): 568.7 [M＋

H]. HRMS (APCI): Calcd for C₃₅H₃₇O₇[M ＋ H]:

569.2539, found 569.2534.

To a cold (－10 ℃) solution of 14a (0.150 g, 0.38

mmol) in dry THF (10 mL) was added a THF solution

(0.9 mL) of fresh-prepared neopentylmagnesium bro-

mide, and the mixture was stirred at －10 ℃ for 1 h.

After cautiously quenched with sat. aq. NH₄Cl, the

mixture was extracted with AcOEt (30 mL×3), the

combined extracts were washed with brine, dried over

Na₂SO₄, and concentrated. The residue was purified by

column chromatography (SiO₂, petroleum ether/AcOEt

＝4∶1) to give a white solid 15a (0.173 mg, 97%). m.p.

176－177 ℃; TLC (petroleum ether/AcOEt＝2∶1): R_f

11-(Benzyloxy)-3-(1-hydroxy-3,3-dimethylbutyl)-4-

methoxy-9-(methylthio)dibenzo[b,g][1,5]dioxocin-5(7H)-

one (15f): Prepared according to the procedure for 15a

except that a different substrate 14f was used, a white

solid 15f, yield: 83%. m.p. 155 － 156 ℃ ; TLC

1

(petroleum ether/CH₂Cl₂＝3∶1): R_f0.21. H NMR

(400 MHz, CDCl₃) δ: 7.58 (d, J＝8.5 Hz, 1H), 7.50 (s,

1H), 7.48 (s, 1H), 7.46－7.27 (m, 3H), 6.95－6.93 (m,

2H), 6.54 (d, J＝1.7 Hz, 1H), 5.20 (s, 2H), 5.19－5.13

(m, 1H), 5.09 (s, 2H), 3.97 (s, 3H), 2.40 (s, 3H), 1.99

(brs, 1H), 1.71－1.64 (m, 1H), 1.60－1.50 (m, 1H),

1.02 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 167.3,

154.0, 151.9, 150.7, 144.1, 137.7, 136.5, 134.4, 131.0,

128.7 (2C), 128.1 (2C), 127.3 (2C), 119.4, 119.2, 117.9,

114.7, 71.4, 68.8, 66.4, 62.6, 52.2, 30.7, 30.1 (3C), 16.5.

HRMS (ESI): Calcd for C₂₉H₃₂NaO₆S [M ＋ Na]:

531.1817, found 531.1828.

11-(Benzyloxy)-9-(ethylthio)-3-(1-hydroxy-3,3-dime-

thylbutyl)-4-methoxydibenzo[b,g][1,5]dioxocin-5(7H)-

one (15g): Prepared according to the procedure for 15a

except that a different substrate 14g was used, a yellow-

ish solid 15g, yield: 68%. m.p. 48－49 ℃; TLC

(petroleum ether/AcOEt＝2∶1): R_f0.66. ¹H NMR (400

MHz, CDCl₃) δ: 7.59 (d, J＝8.5 Hz, 1H), 7.49 (d, J＝

7.3 Hz, 2H), 7.44－7.30 (m, 3H), 7.01 (d, J＝2.0 Hz,

1H), 6.94 (d, J＝8.4 Hz, 1H), 6.63 (d, J＝2.0 Hz, 1H),

5.21 (s, 2H), 5.19－5.13 (m, 1H), 5.09 (s, 2H), 3.97 (s,

3H), 2.83 (q, J＝7.3 Hz, 2H), 1.96 (brs, 1H), 1.70－1.60

(m, 1H), 1.56 (dd, J＝14.5, 2.8 Hz, 1H), 1.21 (t, J＝7.3

Hz, 3H), 1.02 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ:

167.2, 154.1, 151.8, 150.6, 144.8, 137.8, 136.4 132.4,

131.0, 128.7 (2C), 128.1, 128.1, 127.3 (2C), 122.4,

119.2, 118.0, 117.3, 71.5, 68.8, 66.4, 62.7, 52.2, 30.7,

30.1 (3C), 28.5, 14.3. MS (ESI): 505.1 [M−OH]. HRMS

(ESI): Calcd for C₃₀H₃₄NaO₆S [M＋Na]: 545.1974,

found 545.1979.

1

0.5. H NMR (CDCl₃, 400 MHz) δ: 7.59 (d, J＝8.6 Hz,

1H, ArH), 7.51－7.48 (m, 2H, ArH), 7.42－7.33 (m, 3H,

ArH), 7.05－6.95 (m, 3H, ArH), 6.65 (d, J＝7.3 Hz, 1H,

ArH), 5.22 (s, 2H, CH₂), 5.19－5.16 (m, 1H, CH), 5.14

(s, 2H, CH₂), 3.98 (s, 3H, OCH₃), 1.87 (d, J＝4.8 Hz,

1H, OH), 1.69－1.59 (m, 2H, CH₂), 1.03 (s, 9H,

t-Bu-H); ¹³C NMR (CDCl₃, 100 MHz) δ: 167.3, 154.1,

152.0, 150.6, 146.3, 137.6, 136.7, 131.0, 128.6 (2C),

128.0, 127.8, 127.2 (2C), 124.5, 121.3, 119.4, 118.0,

116.0, 71.4, 69.0, 66.5, 62.7, 52.2, 30.7, 30.1 (3C). MS

(ESI): 463.1 [M＋H]. HRMS (ESI): Calcd for C₂₈H₂₉O₆

[M−H]: 461.1964, found 461.1966.

11-(Benzyloxy)-3-(1-hydroxy-3,3-dimethylbutyl)-4-

methoxy-9-methyldibenzo[b,g][1,5]dioxocin-5(7H)-one

(15b): Prepared according to the procedure for 15a ex-

cept that a different substrate 14b was used, a white

solid 15b, yield: 98%. m.p. 143 － 144 ℃ ; TLC

1

(petroleum ether/AcOEt＝3∶1): R_f0.44. H NMR

(CDCl₃, 400 MHz) δ: 7.57 (d, J＝8.2 Hz, 1H, ArH),

7.51－7.49 (m, 2H, ArH), 7.42－7.31 (m, 3H, ArH),

6.94 (d, J＝7.8 Hz, 1H, ArH), 6.85 (s, 1H, ArH), 6.44 (s,

1H, ArH), 5.19 (s, 2H, CH₂), 5.18－5.14 (m, 1H, CH),

5.08 (s, 2H, CH₂), 3.95 (s, 3H, OCH₃), 2.25 (s, 3H,

CH₃), 2.12 (br s, 1H, OH), 1.68－1.53 (m, 2H, CH₂),

1.02 (s, 9H, CMe₃); ¹³C NMR (CDCl₃, 100 MHz) δ:

167.5, 153.9, 152.0, 150.2, 144.0, 137.5, 136.7, 134.4,

130.9, 128.5 (2C), 127.9, 127.23, 127.16 (2C), 121.6,

119.3, 118.0, 116.5, 71.2, 69.0, 66.3, 62.5, 52.1, 30.6,

30.0 (3C), 21.0. MS (ESI): 477.2 [M＋H]. HRMS

(APCI): Calcd for C₂₉H₃₃O₆[M＋H]: 477.2277, found

477.2278.

11-(Benzyloxy)-3-(1-hydroxy-3,3-dimethylbutyl)-4-

methoxy-9-(methylsulfonyl)dibenzo[b,g][1,5]dioxocin-

5(7H)-one (15h): To a solution of 15f (0.152 g, 0.30

11-(Benzyloxy)-3-(1-hydroxy-3,3-dimethylbutyl)-4-

Chin. J. Chem. 2013, 31, 355—370

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365

Zhang et al.

FULL PAPER

mmol) in THF/H₂O (10 mL, V/V＝1∶2) was added

oxane (0.370 g, 0.40 mmol) in one portion at 0 ℃, and

stirred at r.t. for 3 h. Then water (10 mL) was added to

the reaction mixture, and the resulting mixture was ex-

tracted with AcOEt (30 mL×2). The combined extracts

were washed with brine, dried over Na₂SO₄, and con-

centrated. The residue was purified by column chroma-

tography (SiO₂, petroleum ether/acetone＝1.8∶1) to

give a yellowish solid 15h (0.152 mg, 94%). m.p. 127－

128 ℃; TLC (petroleum ether/acetone＝2∶1): R_f0.38.

¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J＝8.5 Hz, 1H),

7.58 (d, J＝2.0 Hz, 1H), 7.50 (d, J＝7.0 Hz, 2H), 7.45

－7.32 (m, 3H), 7.27 (d, J＝1.9 Hz, 1H), 6.90 (d, J＝

8.5 Hz, 1H), 5.26 (s, 2H), 5.21－5.10 (m, 3H), 3.95 (s,

3H), 2.99 (s, 3H), 1.63 (dd, J＝14.5, 8.7 Hz, 1H), 1.54

(dd, J＝14.5, 2.6 Hz, 1H), 1.02 (s, 9H); ¹³C NMR (100

MHz, CDCl₃) δ: 167.0, 154.4, 151.4, 151.0, 150.2,

139.1, 136.4, 135.7, 131.7, 129.1 (2C), 129.0, 128.8,

127.8 (2C), 121.1, 119.0, 118.1, 114.2, 71.8, 68.6, 66.5,

63.1, 52.5, 44.8, 31.0, 30.4 (3C). MS (ESI): 523.2

[M−OH]. HRMS (ESI): Calcd for C₂₉H₃₂NaO₈S [M＋

Na]: 563.1716, found 563.1721.

C₂₈H₂₉O₆[M＋H]: 461.1964, found 461.1979.

11-(Benzyloxy)-3-(1-hydroxypropyl)-4-methoxy-9-

methyldibenzo[b,g][1,5]dioxocin-5(7H)-one (15l): Pre-

pared according to the procedure for 15b except that a

different Grignard reagent (ethyl magnesium bromide)

was used, a white solid 15l, yield: 57%. m.p. 106－107

1

℃; TLC (petroleum ether/AcOEt＝2∶1): R_f0.37. H

NMR (400 MHz, CDCl₃) δ: 7.57－7.46 (m, 3H), 7.44－

7.29 (m, 3H), 6.95 (d, J＝8.4 Hz, 1H), 6.86 (s, 1H),

6.45 (s, 1H), 5.19 (s, 2H), 5.09 (s, 2H), 4.92 (t, J＝6.3

Hz, 1H), 3.95 (s, 3H), 2.25 (s, 3H), 2.21 (brs, 1H), 1.89

－1.64 (m, 2H), 0.95 (t, J＝7.4 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 167.5, 154.8, 152.3, 150.3, 144.0,

136.8, 135.5, 134.5, 131.2, 128.6 (2C), 128.0, 127.3,

127.2 (2C), 121.6, 119.4, 118.0, 116.6, 71.3, 69.8, 69.1,

62.8, 31, 21.1, 10.3. MS (ESI): 417.3 [M−OH]. HRMS

(ESI): Calcd for C₂₆H₂₆NaO₆[M ＋ Na]: 457.1627,

found 457.1614.

11-Hydroxy-3-(1-hydroxy-3,3-dimethylbutyl)-4-meth-

oxydibenzo[b,g][1,5]dioxocin-5(7H)-one (16a): To a

solution of 15a (42 mg, 0.09 mmol) in EtOH/AcOEt (10

mL, V/V＝1∶2) was added 10% Pd/C (4 mg), and the

resulting mixture was stirred under H₂(balloon) at r.t.

for 3 h (TLC monitoring). The mixture was diluted with

CH₂Cl₂(20 mL), then filtered through a pad of celite,

the filter cake was washed with AcOEt, and the com-

bined filtrate was concentrated. The residue was sub-

jected to column chromatography (SiO₂, petroleum

ether/AcOEt＝3∶1) to give a white solid 16a (29 mg,

85%). TLC (petroleum ether/AcOEt＝2∶1): R_f0.47.

¹H NMR (CDCl₃, 400 MHz) δ: 7.53 (d, J＝8.7 Hz, 1H,

ArH), 7.03 (d, J＝7.9 Hz, 1H, ArH), 6.97－6.93 (m, 1H,

ArH), 6.83 (d, J＝8.7 Hz, 1H, ArH), 6.82 (s, 1H, OH),

6.54 (d, J＝7.5 Hz, 1H, ArH), 5.15－5.12 (m, 3H), 3.97

(s, 3H, OCH₃), 2.28 (br s, 1H, OH), 1.64－1.51 (m, 2H,

CH₂), 1.01 (s, 9H, CMe₃); ¹³C NMR (CDCl₃, 100 MHz)

δ: 167.8, 153.7, 150.8, 147.9, 143.4, 138.1, 130.9, 126.1,

124.9, 120.2, 119.2, 117.6, 117.3, 69.1, 66.4, 62.4, 52.3,

30.7, 30.0 (3C). MS (ESI): 373.0 [M＋H]. HRMS (ESI):

Calcd for C₂₁H₂₄O₆Na [M ＋ Na]: 395.1471, found

395.1462.

11-(Benzyloxy)-9-(ethylsulfonyl)-3-(1-hydroxy-3,3-

dimethylbutyl)-4-methoxydibenzo[b,g][1,5]dioxocin-

5(7H)-one (15i): Prepared according to the procedure

for 15h except that a different substrate 15g was used, a

white solid 15i: 93%. m.p. 220 － 221 ℃ ; TLC

1

(petroleum ether/acetone＝2∶1): R_f0.36. H NMR

(400 MHz, CDCl₃) δ: 7.64 (d, J＝8.5 Hz, 1H), 7.52 (d,

J＝1.9 Hz, 1H), 7.49 (d, J＝7.2 Hz, 2H), 7.44－7.31 (m,

3H), 7.24 (d, J＝1.8 Hz, 1H), 6.93 (d, J＝8.5 Hz, 1H),

5.28 (s, 2H), 5.24－5.14 (m, 3H), 3.98 (s, 3H), 3.04 (q,

J＝7.4 Hz, 2H), 1.99 (d, J＝2.9 Hz, 1H), 1.70－1.60 (m,

1H), 1.56 (dd, J＝14.5, 2.6 Hz, 1H), 1.18 (t, J＝7.4 Hz,

3H), 1.03 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.6,

154.2, 151.0, 150.7, 150.0, 138.7, 135.4, 134.0, 131.3,

128.8 (2C), 128.6, 128.4, 127.4 (2C), 121.6, 118.8,

117.8, 114.9, 71.5, 68.4, 66.3, 62.8, 52.2, 50.7, 30.7,

30.1 (3C), 7.4. MS (ESI): 537.3 [M−OH]. HRMS (ESI):

Calcd for C₃₀H₃₄NaO₈S [M＋Na]: 577.1872, found

577.1868.

11-(Benzyloxy)-3-(1-hydroxy-3-methylbut-3-en-1-

yl)-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]-dioxo-

cin-5-one (15j): Prepared according to the procedure for

15a except that a different Grignard reagent (2-methyl-

prop-2-en-1-yl magnesium chloride) was used, a yel-

lowish solid 15j, yield: 82%. m.p. 55－56 ℃; TLC

11-Hydroxy-3-(1-hydroxy-3,3-dimethylbutyl)-4-

methoxy-9-methyldibenzo[b,g][1,5]dioxocin-5(7H)-one

(16b): Prepared according to the procedure for 16a ex-

cept that a different substrate 15b was used, a white

solid 16b, yield: 87%. m.p. 114 － 115 ℃ ; TLC

1

(petroleum ether/AcOEt＝2∶1): R_f0.42. H NMR

1

(petroleum ether/AcOEt＝2∶1): R_f0.50. H NMR

(CDCl₃, 400 MHz) δ: 7.52 (d, J＝8.7 Hz, 1H, ArH),

6.84 (s, 1H, ArH), 6.81 (d, J＝8.7 Hz, 1H, ArH), 6.76

(br s, 1H, OH), 6.34 (s, 1H, ArH), 5.15－5.04 (m, 3H),

3.96 (s, 3H, OCH₃), 2.31 (br s, 1H, OH), 2.23 (s, 3H,

CH₃), 1.64－1.50 (m, 2H, CH₂), 1.01 (s, 9H, CMe₃).

MS (ESI): 387.0 [M＋H].

11-Hydroxy-3-(1-hydroxy-3,3-dimethylbutyl)-4-me-

thoxy-9-(4-methoxyphenyl)dibenzo[b,g][1,5]dioxocin-

5(7H)-one (16c): Prepared according to the procedure

for 16a except that a different substrate 15c was used, a

white solid 16c, yield: 93%. TLC (petroleum ether/

(CDCl₃, 400 MHz) δ: 7.62 (d, J＝8.6 Hz, 1H), 7.60－

7.30 (m, 5H), 6.96 (d, J＝8.6 Hz, 1H), 6.86 (s, 1H),

6.46 (s, 1H), 5.19 (s, 2H), 5.08－5.14 (m, 3H), 4.93 (s,

1H), 4.84 (s, 1H), 3.98 (s, 3H), 2.47 (dd, J＝13.6, 3.2

Hz, 1H), 2.35－2.28 (m, 1H), 2.26 (s, 3H), 1.83 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ: 167.4, 154.5, 152.3,

150.2, 144.0, 142.3, 136.7, 135.0, 134.4, 130.9, 128.6

(2C), 127.9, 127.3, 127.2 (2C), 121.6, 119.3, 118.0,

116.5, 114.2, 71.3, 69.0, 65.5, 47.3, 29.6, 22.2, 21.0.

MS (ESI): 443.0 [M−OH]. HRMS(APCI): Calcd for

366

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Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

1

AcOEt＝2∶1): R_f0.24. ¹H NMR (CDCl₃, 400 MHz) δ:

7.55 (d, J＝8.2 Hz, 1H, ArH), 7.42－7.39 (m, 2H, ArH),

7.21 (d, J＝2.0 Hz, 1H, ArH), 6.95－6.92 (m, 2H, ArH),

6.87 (d, J＝8.2 Hz, 1H, ArH), 6.81 (br s, 1H, OH), 6.71

(d, J＝2.0 Hz, 1H, ArH), 5.17－5.14 (m, 3H), 3.98 (s,

3H, OCH₃), 3.83 (s, 3H, OCH₃), 2.24 (br s, 1H, OH),

1.66－1.52 (m, 2H, CH₂), 1.02 (s, 9H, CMe₃); ¹³C NMR

(CDCl₃, 100 MHz) δ: 167.8, 159.3, 153.8, 151.0, 147.9,

142.4, 138.1, 137.9, 132.1, 131.0, 127.9 (2C), 126.2,

119.2, 118.5, 117.6, 115.4, 114.2 (2C), 69.3, 66.4, 62.4,

55.3, 52.3, 30.7, 30.1 (3C). MS (ESI): 478.9 [M＋H].

HRMS (APCI): calcd for C₂₈H₃₁O₇[M＋H]: 479.2070,

found 479.2066.

11-Hydroxy-3-(1-hydroxy-3,3-dimethylbutyl)-4-meth-

oxy-9-(methylsulfonyl)dibenzo[b,g][1,5]dioxocin-5(7H)-

one (16h): Prepared according to the procedure for 16a

except that a different substrate 15h was used, a white

solid 16h, yield: 98%. TLC (petroleum ether/acetone＝

2∶1): R_f0.23. ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (brs,

1H), 7.62－7.49 (m, 2H), 7.15 (d, J＝1.8 Hz, 1H), 6.79

(d, J＝8.5 Hz, 1H), 5.23－4.91 (m, 3H), 3.94 (s, 3H),

3.02 (s, 3H), 2.69 (brs, 1H), 1.69－1.55 (m, 1H), 1.55－

1.45 (m, 1H), 1.01 (s, 9H); ¹³C NMR (100 MHz, CDCl₃)

δ: 167.6, 153.8, 149.7, 149.0, 147.4, 138.9, 136.51,

131.4, 127.4, 119.5, 118.2, 117.5, 116.7, 68.6, 66.3,

62.5, 52.2, 44.4, 30.7, 30.1 (3C). MS (ESI): 433.1

[M−OH]. HRMS (ESI): calcd for C₂₂H₂₆NaO₈S [M＋

Na]: 473.1246, found 473.1245.

9-(Ethylsulfonyl)-11-hydroxy-3-(1-hydroxy-3,3-di-

methylbutyl)-4-methoxydibenzo[b,g][1,5]dioxocin-

5(7H)-one (16i): Prepared according to the procedure

for 16a except that a different substrate 15i was used, a

white solid 16i, yield: 87%. TLC (petroleum ether/

acetone＝2∶1): R_f0.20. ¹H NMR (400 MHz, CDCl₃) δ:

7.80 (brs, 1H), 7.56 (d, J＝8.5 Hz, 1H), 7.49 (d, J＝2.0

Hz, 1H), 7.11 (d, J＝2.0 Hz, 1H), 6.80 (d, J＝8.5 Hz,

1H), 5.37－4.94 (m, 3H), 3.95 (s, 3H), 3.08 (q, J＝7.4

Hz, 2H), 1.66－1.58 (m, 1H), 1.56－1.44 (m, 1H), 1.25

(t, J＝7.4 Hz, 3H), 1.01 (s, 9H); ¹³C NMR (100 MHz,

CDCl₃) δ: 167.6, 153.8, 149.7, 148.9, 147.4, 138.9,

134.5, 131.4, 127.2, 120.3, 118.3, 117.5, 68.6, 66.2,

62.4, 52.3, 50.6, 30.7, 30.0 (3C), 7.4. MS (ESI): 447.1

[M−OH]. HRMS (ESI): Calcd for C₂₃H₂₈NaO₈S [M＋

Na]: 487.1403, found 487.1406.

ether/AcOEt＝2∶1): R_f0.46. H NMR (CDCl₃, 400

MHz) δ: 7.52 (d, J＝8.6 Hz, 1H), 6.84 (s, 1H), 6.83 (d,

J＝8.6 Hz, 1H), 6.64 (brs, 1H), 6.35 (s, 1H), 5.10－4.90

(m, 3H), 3.96 (s, 3H), 2.23 (s, 3H), 1.85－1.75 (m, 1H),

1.75－1.55 (m, 1H), 1.55－1.35 (m, 1H), 0.97 (d, J＝

6.8 Hz, 3H), 0.95 (d, J＝6.8 Hz, 3H); ¹³C NMR (CDCl₃,

100 MHz) δ: 167.9, 154.3, 151.2, 147.5, 141.3, 136.9,

135.0, 131.1, 125.7, 120.7, 119.3, 117.8, 117.7, 69.2,

66.6, 62.7, 47.6, 24.9, 23.4, 21.8, 20.8. MS (ESI): 355.0

[M−OH]. HRMS (APCI): Calcd for C₂₁H₂₅O₆[M＋H]:

373.1651, found 373.1654. 16m: TLC (petroleum ether/

AcOEt＝1∶2): R_f0.46. ¹H NMR (400 MHz, CDCl₃) δ:

7.30－7.25 (m, 1H), 6.85－6.70 (m, 2H), 6.37 (s, 1H),

6.26 (s, 1H), 5.06 (s, 2H), 3.94 (s, 3H), 2.70－2.50 (m,

2H), 2.23 (s, 3H), 1.70－1.50 (m, 1H), 1.50－1.40 (m,

2H), 0.94 (d, J＝6.6 Hz, 6H); ¹³C NMR (100 MHz,

CDCl₃) δ: 168.0, 155.8, 150.4, 147.6, 141.7, 135.5,

135.1, 134.1, 126.1, 121.11, 120.6, 117.7, 117.6, 69.3,

62.9, 40.0, 28.3, 27.6, 22.8 (2C), 21.2. MS (ESI): 357.2

[M＋H]. HRMS (APCI): Calcd for C₂₁H₂₅O₅[M＋H]:

357.1702, found 357.1709.

11-Hydroxy-3-(1-hydroxypropyl)-4-methoxy-9-meth-

yldibenzo[b,g][1,5]dioxocin-5(7H)-one (16l): Prepared

according to the procedure for 16a except that a differ-

ent substrate 15l was used. The crude product was used

directly in next step for 17l.

9-(1-Hydroxy-3,3-dimethylbutyl)-8-methoxy-7-oxo-

5,7-dihydrodibenzo[b,g][1,5]dioxocin-1-yl 7-methylbi-

cyclo[2.2.1]heptane-7-carboxylate (17a): To a solution

of 7-methylbicyclo[2.2.1]heptane-7-carboxylic acid^[18]

(500 mg, 3.24 mmol) in CH₂Cl₂(4.0 mL) was added a

drop of dry DMF at 0 ℃, followed by oxalyl dichloride

(0.34 mL, 3.9 mmol). The resulting solution was stirred

at r.t. for 1 h, then evaporated in vacuo and diluted with

anhydrous THF (64 mL), giving the acyl chloride solu-

－

1

tion (ca. 0.05 mol•L ) for the next step.

A dry flask was charged with NaH (60%, 8 mg,

0.172 mmol) under Ar atmosphere, a solution of 16a

(58 mg, 0.156 mmol) in dry THF (4 mL) was added,

and the resulting mixture was stirred at r.t. for 1 h. Then

the acyl chloride solution (4 mL, about 0.20 mmol) was

added dropwise. The reaction mixture was stirred at r.t.

overnight. After evaporation, the residue was purified

by preparative TLC (petroleum ether/AcOEt＝3∶1),

giving a white solid 17a (46 mg, 58%). m.p. 156－157

11-Hydroxy-3-(1-hydroxy-3-methylbutyl)-4-methoxy-

1

9-methyldibenzo[b,g][1,5]dioxocin-5(7H)-one

(16k)

℃; TLC (petroleum ether/AcOEt＝3∶1): R_f0.42. H

and 11-hydroxy-3-isopentyl-4-methoxy-9-methyldiben-

zo[b,g][1,5]dioxocin-5(7H)-one (16m): To a solution of

15j (202 mg, 0.44 mmol) in MeOH/AcOEt (6 mL, V/V

＝5∶1) was added 10% Pd/C (20 mg), the resulting

mixture was stirred under H₂(balloon) at r.t. for 3 h

(TLC monitoring). After addition of CH₂Cl₂(20 mL),

the mixture was filtered through a pad of celite, the fil-

ter cake was washed with AcOEt, the combined filtrates

were concentrated, and the residue was subjected to

column chromatography (SiO₂, petroleum ether/AcOEt

＝2∶5) to give a white solid 16k (106 mg, 65%) and a

white solid 16m (54 mg, 35%). 16k: TLC (petroleum

NMR (CDCl₃, 400 MHz) δ: 7.61 (d, J＝8.2 Hz, 1H,

ArH), 7.09－7.07 (m, 2H, ArH), 7.00 (d, J＝8.6 Hz, 1H,

ArH), 6.96－6.92 (m, 1H, ArH), 5.18－5.11 (m, 3H),

3.98 (s, 3H, OCH₃), 2.40－2.25 (m, 2H), 1.97－1.84 (m,

5H), 1.70－1.55 (m, 2H, CH₂), 1.45 (s, 3H, CH₃), 1.34

13

－1.32 (m, 4H), 1.03 (s, 9H, CMe₃); C NMR (CDCl₃,

100 MHz) δ: 175.3, 167.1, 153.9, 151.2, 148.4, 142.3,

138.3, 131.1, 127.6, 127.2, 124.5, 124.2, 119.6, 118.3,

69.1, 66.4, 63.0, 58.6, 52.3, 42.0, 30.7, 30.1, 29.4, 27.8,

17.1. HRMS (APCI): Calcd for C₃₀H₃₅O₇[M−H]:

507.2383, found 507.2375.

9-(1-Hydroxy-3,3-dimethylbutyl)-8-methoxy-3-meth-

Chin. J. Chem. 2013, 31, 355—370

www.cjc.wiley-vch.de

367

Zhang et al.

FULL PAPER

yl-7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-1-yl 7-

methylbicyclo[2.2.1]heptane-7-carboxylate (17b): Pre-

pared according to the procedure for 17a except that a

different substrate 16b was used, a white solid 17b,

yield: 89%. m.p. 175－176 ℃; TLC (petroleum ether/

AcOEt＝2∶1): R_f0.64. ¹H NMR (400 MHz, CDCl₃) δ:

7.60 (d, J＝8.5 Hz, 1H), 6.99 (d, J＝8.5 Hz, 1H), 6.88

(d, J＝1.5 Hz, 1H), 6.74 (s, 1H), 5.24－5.11 (m, 1H),

5.07 (s, 2H), 3.97 (s, 3H), 2.33 (s, 2H), 2.28 (s, 3H),

2.01－1.79 (m, 5H), 1.67 (dd, J＝14.5, 8.7 Hz, 1H),

1.62－1.49 (m, 1H), 1.45 (s, 3H), 1.40－1.20 (m, 4H),

1.02 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 175.4,

167.2, 153.9, 151.4, 146.1, 141.8, 138.0, 134.2, 131.1,

127.6, 127.1, 124.7, 119.7, 118.3, 69.1, 66.4, 62.9, 58.6,

52.2, 41.96, 41.95, 30.7, 30.1, 29.4, 27.8, 20.5, 17.1.

MS (ESI): 505.3 [M−OH]. HRMS (ESI): Calcd for

C₃₁H₃₈NaO₇[M＋Na]: 545.2515, found 545.2516.

9-(1-Hydroxy-3,3-dimethylbutyl)-8-methoxy-3-(4-

methoxyphenyl)-7-oxo-5,7-dihydrodibenzo[b,g][1,5]di-

oxocin-1-yl 7-methylbicyclo[2.2.1]heptane-7-carboxylate

(17c): Prepared according to the procedure for 17a ex-

cept that a different substrate 16c was used, a yellowish

oil 17c, yield: 72%. TLC (petroleum ether/AcOEt＝3∶

1): R_f0.37. ¹H NMR (CDCl₃, 400 MHz) δ: 7.63 (d, J＝

8.6 Hz, 1H, ArH), 7.43－7.40 (m, 2H, ArH), 7.20 (s, 1H,

ArH), 7.08 (s, 1H, ArH), 7.04 (d, J＝8.6 Hz, 1H, ArH),

6.95－6.93 (d, J＝8.6 Hz, 2H, ArH), 5.19－5.16 (m,

3H), 3.99 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 2.35 (s,

2H), 2.00－1.85 (m, 5H), 1.71－1.56 (m, 2H, CH₂),

1.48 (s, 3H, CH₃), 1.35－1.33 (m, 4H), 1.03 (s, 9H,

CMe₃); ¹³C NMR (CDCl₃, 100 MHz) δ: 191.0, 175.3,

167.1, 159.5, 153.9, 151.3, 147.2, 142.4, 138.3, 137.4,

131.4, 131.2, 128.0, 127.6, 125.3, 122.4, 118.4, 114.3,

69.3, 66.4, 63.0, 58.6, 55.3, 52.3, 42.0, 30.7, 30.1, 29.4,

27.8, 17.2. HRMS (APCI): Calcd for C₃₇H₄₁O₈[M−H]:

613.2802, found 613.2816.

9-(1-Hydroxy-3,3-dimethylbutyl)-8-methoxy-3-(meth-

ylsulfonyl)-7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-

1-yl 7-methylbicyclo[2.2.1]heptane-7-carboxylate (17h):

Prepared according to the procedure for 17a except that

a different substrate 16h was used, a white solid 17h,

yield: 89%. m.p. 188－189 ℃; TLC (petroleum ether/

AcOEt＝1∶1): R_f0.40. ¹H NMR (400 MHz, CDCl₃) δ:

7.75－7.63 (m, 2H), 7.59 (d, J＝2.0 Hz, 1H), 6.99 (d,

J＝8.5 Hz, 1H), 5.29－4.94 (m, 3H), 3.98 (s, 3H), 3.07

(s, 3H), 2.33 (s, 2H), 1.98 (d, J＝4.4 Hz, 1H), 1.93－

1.86 (m, 4H), 1.68－1.61 (m, 1H), 1.57 (dd, J＝14.5,

2.3 Hz, 1H), 1.46 (s, 3H), 1.40－1.20 (m, 4H), 1.03 (s,

9H); ¹³C NMR (100 MHz, CDCl₃) δ: 174.7, 166.2,

154.1, 152.7, 150.0, 142.9, 139.4, 135.9, 131.5, 128.8,

126.9, 124.1, 119.0, 118.0, 68.4, 66.2, 63.1, 58.6, 52.3,

44.7, 42.02, 42.01, 30.7, 30.1 (3C), 29.3, 27.7, 17.1. MS

(ESI): 569.2 [M−OH]. HRMS (ESI): Calcd for

C₃₁H₃₈NaO₉S [M＋Na]: 609.2134, found 609.2123.

3-(Ethylsulfonyl)-9-(1-hydroxy-3,3-dimethylbutyl)-

8-methoxy-7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-

1-yl 7-methylbicyclo[2.2.1]heptane-7-carboxylate (17i):

Prepared according to the procedure for 17a except that

a different substrate 16i was used, a white solid 17i,

yield: 87%. m.p. 125－126 ℃; TLC (petroleum ether/

AcOEt＝1∶1): R_f0.71. ¹H NMR (400 MHz, CDCl₃) δ:

7.67 (d, J＝8.5 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.00

(d, J＝8.5 Hz, 1H), 5.20－5.10 (m, 3H), 3.98 (s, 3H),

3.13 (q, J＝7.4 Hz, 2H), 2.33 (s, 2H), 2.01 (d, J＝4.3

Hz, 1H), 1.93 (d, J＝8.0 Hz, 2H), 1.86 (d, J＝8.1 Hz,

2H), 1.74－1.52 (m, 2H), 1.46 (s, 3H), 1.39－1.24 (m,

7H), 1.03 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 174.6,

166.2, 154.0, 152.6, 150.0, 142.8, 139.3, 133.9, 131.4,

128.6, 127.5, 124.8, 118.9, 117.9, 68.3, 66.1, 63.0, 58.5,

52.2, 50.7, 41.9, 30.6, 30.0 (3C), 29.2, 27.6, 17.0, 7.3.

MS (ESI): 583.3 [M−OH]. HRMS (ESI): Calcd for

C₃₂H₄₀NaO₉S [M＋Na]: 623.2291, found 623.2297.

9-(1-Hydroxy-3-methylbutyl)-8-methoxy-3-methyl-

7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-1-yl 7-me-

thylbicyclo[2.2.1]heptane-7-carboxylate (17k): Prepared

according to the procedure for 17a except that a differ-

ent substrate 16k was used, a white solid 17k, yield:

86%. TLC (petroleum ether/AcOEt＝3∶1): R_f0.33. ¹H

NMR (400 MHz, CDCl₃) δ: 7.58 (d, J＝8.6 Hz, 1H),

7.00 (d, J＝8.5 Hz, 1H), 6.88 (d, J＝1.6 Hz, 1H), 6.74

(d, J＝1.5 Hz, 1H), 5.09－5.07 (m, 3H), 3.97 (s, 3H),

2.32 (s, 2H), 2.28 (s, 3H), 2.03 (d, J＝4.1 Hz, 1H), 1.97

(d, J＝8.5 Hz, 2H), 1.85 (d, J＝9.7 Hz, 2H), 1.79 (dd,

J＝13.6, 7.0 Hz, 1H), 1.75－1.65 (m, 1H), 1.60－1.50

(m, 1H), 1.45 (s, 3H), 1.40－1.20 (m, 4H), 0.97 (dd, J＝

9.2, 6.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 175.6,

167.4, 154.6, 151.7, 146.3, 142.0, 137.1, 134.5, 131.3,

127.8, 127.3, 125.0, 120.0, 118.6, 69.3, 66.8, 63.3, 58.8,

47.7, 42.2, 42.1, 29.6, 28.0, 25.1, 23.6, 22.0, 20.8, 17.3.

MS (ESI): 531.2 [M＋Na]. HRMS (ESI): Calcd for

C₃₀H₃₆NaO₇[M＋Na]: 531.2359, found 531.2342.

9-(1-Hydroxypropyl)-8-methoxy-3-methyl-7-oxo-5,7-

dihydrodibenzo[b,g][1,5]dioxocin-1-yl 7-methylbicyclo-

[2.2.1]heptane-7-carboxylate (17l): Prepared according

to the procedure for 17a except that a different substrate

16l was used, a yellowish oil 17l, yield: 76%. TLC

(petroleum ether/AcOEt＝2∶1): R_f0.34. ¹H NMR (400

MHz, CDCl₃) δ: 7.56 (d, J＝8.5 Hz, 1H), 7.00 (d, J＝

8.5 Hz, 1H), 6.88 (d, J＝1.5 Hz, 1H), 6.74 (d, J＝1.4 Hz,

1H), 5.06 (s, 2H), 4.92 (dd, J＝10.0, 6.6 Hz, 1H), 3.96

(s, 3H), 2.32 (s, 2H), 2.28 (s, 3H), 2.17 (d, J＝4.0 Hz,

1H), 2.00－1.95 (m, 2H), 1.90－1.80 (m, 2H), 1.81－

1.72 (m, 2H), 1.45 (s, 3H), 1.37－1.28 (m, 4H), 0.96 (t,

13

J＝7.4 Hz, 3H); C NMR (100 MHz, CDCl₃) δ: 175.4,

167.2, 154.7, 151.5, 146.1, 141.8, 136.1, 134.3, 131.3,

127.6, 127.1, 124.8, 119.8, 118.3, 69.7, 69.1, 63.1, 58.6,

42.0, 41.9, 31.0, 29.4, 27.8, 20.5, 17.1, 10.3. MS (ESI):

503.2 [M＋Na]. HRMS (ESI): Calcd for C₂₈H₃₂NaO₇

[M＋Na]: 503.2046, found 503.2049.

9-Isopentyl-8-methoxy-3-methyl-7-oxo-5,7-dihydro-

dibenzo[b,g][1,5]dioxocin-1-yl 7-methylbicyclo[2.2.1]-

heptane-7-carboxylate (17m): Prepared according to the

procedure for 17a except that a different substrate 16m

was used, a white solid 17m, yield: 87%. m.p. 186－

187 ℃; TLC (petroleum ether/AcOEt＝4∶1): R_f0.75.

¹H NMR (400 MHz, CDCl₃) δ: 7.29 (d, J＝8.4 Hz, 1H),

368

www.cjc.wiley-vch.de

Chin. J. Chem. 2013, 31, 355—370

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

6.92 (d, J＝8.4 Hz, 1H), 6.87 (d, J＝1.6 Hz, 1H), 6.73

(d, J＝1.5 Hz, 1H), 5.05 (s, 2H), 3.93 (s, 3H), 2.62 (t,

J＝8.0 Hz, 2H), 2.40－2.20 (m, 2H), 2.28 (s, 3H), 1.98

(d, J＝8.4 Hz, 2H), 1.90－1.75 (m, 2H), 1.65－1.55 (m,

1H), 1.45 (s, 3H), 1.38－1.21 (m, 6H), 0.95 (d, J＝6.6

Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 175.6, 167.6,

155.6, 150.4, 146.5, 142.0, 135.2, 134.2, 134.1, 127.9,

127.4, 124.8, 120.6, 118.3, 69.3, 63.1, 58.8, 42.2, 41.8,

40.0, 29.6, 29.5, 28.2, 28.0, 27.9, 27.4, 22.6, 20.7, 17.3.

MS (ESI): 493.3 [M＋H]. HRMS (APCI): Calcd for

C₃₀H₃₇O₆[M＋H]: 493.2590, found 493.2602.

611.2098.

Assay of CETP inhibition

After preincubation with compounds diluted in

DMSO for 4 h at 37 ℃, aliquots of plasma were mixed

with [³H]CE-HDL (8 µg/mL) and LDL (60 µg/mL) in a

total volume of 200 µL buffer containing 50 mmol•L^－

1

Tris-HCl (pH 7.4), 150 mmol•L^－NaCl, 1 mmol•L^－

1

EDTA and 1% bovine serum albumin. The mixture was

kept in incubator for 16 h at 37 ℃. Then 20 µL of pre-

cipitating reagent (dextran sulfate/MgCl₂＝0.45%/0.23

－

1

9-(1-Fluoro-3,3-dimethylbutyl)-8-methoxy-3-methyl-

7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-1-yl 7-me-

thylbicyclo[2.2.1]heptane-7-carboxylate (17n): To a

solution of 17b (0.102 g, 0.19 mmol) in CH₂Cl₂(2.0 mL)

was added dropwise DAST (52 µL, 0.24 mmol) at －78

℃. The resulting mixture was stirred at this temperature

for 1 h. The reaction was quenched with sat. aq. Na-

HCO₃(5 mL), the mixture was extracted with AcOEt

(30 mL×3), and the combined organic phases were

washed with brine (30 mL), dried over Na₂SO₄, and

evaporated. The residue was subjected to column chro-

matography (SiO₂, petroleum ether/AcOEt ＝ 9 ∶ 1),

giving a white solid 17n (74 mg, 74%). m.p. 152－153

mol•L ) was added and the mixture was centrifuged at

1000 g for 15 min at 4 ℃. Half of the supernatant was

collected and its radioactivity was measured in a liquid

scintillation counter. The inhibition rate was determined

according to the following equation:

%inhibition

1

(CPM

CPM )/(CPM

－

test blank

＝－

) 100%

×

－

blank

CPM_control

‘Test’ samples contained plasma with inhibitor

compounds diluted by DMSO, while ‘Control’ samples

contained plasma with DMSO. ‘Blank’ samples were

prepared as ‘control’ samples but incubated at 4 ℃

instead of 37 ℃ for 16 h.

1

℃; TLC (petroleum ether/AcOEt＝3∶1): R_f0.80. H

NMR (400 MHz, CDCl₃) δ: 7.56 (d, J＝8.5 Hz, 1H),

7.02 (d, J＝8.5 Hz, 1H), 6.88 (d, J＝1.6 Hz, 1H), 6.74

(d, J＝1.4 Hz, 1H), 6.00－5.80 (m, 1H), 5.05 (d, J＝

13.9 Hz, 2H), 3.97 (s, 3H), 2.33 (s, 2H), 2.29 (s, 3H),

2.02－1.77 (m, 5H), 1.65－1.55 (m, 1H), 1.45 (s, 3H),

1.39－1.29 (m, 4H), 1.04 (s, 9H); ¹³C NMR (100 MHz,

CDCl₃) δ: 175.4, 167.0, 153.8 (d, J＝5.4 Hz), 152.2,

146.1, 141.9, 134.4, 133.8 (d, J＝21.6 Hz), 130.8, 130.7,

127.7, 127.1, 124.9 118.4, 87.3 (d, J＝170.3 Hz), 77.4,

77.0, 76.7, 69.2, 62.9, 58.6, 50.4 (d, J＝22.4 Hz), 42.0,

31.6, 30.5, 29.8, 29.4, 27.8, 22.7, 20.6, 17.2, 14.1; ¹⁹F

NMR (376 MHz, CDCl₃) δ: －176.57 (s). MS (ESI):

547.3 [M＋Na]. HRMS (ESI): Calcd for C₃₁H₃₇FO₆Na

[M＋Na]: 547.2466, found 547.2460.

9-(1-Fluoro-3,3-dimethylbutyl)-8-methoxy-3-(meth-

ylsulfonyl)-7-oxo-5,7-dihydrodibenzo[b,g][1,5]dioxocin-

1-yl 7-methylbicyclo[2.2.1]heptane-7-carboxylate (17o):

Prepared according to the procedure for 17n except that

a different substrate 17h was used, a white solid 17o,

yield: 80%. m.p. 207－208 ℃; TLC (petroleum ether/

AcOEt＝1∶1): R_f0.70. ¹H NMR (400 MHz, CDCl₃) δ:

7.68 (d, J＝2.2 Hz, 1H), 7.65－7.53 (m, 2H), 7.03 (d,

J＝8.5 Hz, 1H), 5.90 (dd, J＝48.6, 8.7 Hz, 1H), 5.15 (d,

J＝13.7 Hz, 2H), 3.98 (s, 3H), 3.07 (s, 3H), 2.33 (s, 2H),

2.01－1.76 (m, 5H), 1.65－1.50 (m, 1H), 1.46 (s, 3H),

1.40－1.30 (m, 4H), 1.05 (s, 9H); ¹³C NMR (100 MHz,

CDCl₃) δ: 174.8, 166.0, 154.03 (d, J＝5.4 Hz), 152.6,

150.8, 143.0, 136.2, 135.1 (d, J＝22.0 Hz), 131.1, 131.0,

128.8, 126.9, 124.3, 118.1, 87.2 (d, J＝171.1 Hz), 68.4,

63.2, 58.7, 50.4 (d, J＝22.3 Hz), 44.7, 42.1, 30.5, 29.8,

29.4, 27.8, 17.2. ¹⁹F NMR (376 MHz, CDCl₃) δ:

−177.57 (s). MS (ESI): 589.3 [M＋H]. HRMS (ESI):

Calcd for C₃₁H₃₇FNaO₈S [M＋Na]: 611.2091, found

Acknowledgement

We thank the National Natural Science Foundation

of China (20872019) for the research financial support

and we are grateful to Fudan University and Shanghai

Institute of Organic Chemistry for recording EI-MS or

1

ESI-MS, HRMS, H NMR, and ¹³C NMR spectra. We

are also grateful to Dr. Hanqing Dong (OSI Pharma-

ceuticals, USA) for his help in revising the manuscript.

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Synthesis and evaluation of the analogues of penicillide against cholesterol ester transfer protein

DOI: 10.1002/cjoc.201200977

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