A convergent approach to dibenzodioxocinones: Synthesis of racemic penicillide

Article abstract of DOI:10.1002/hlca.201100405

A convergent approach to dibenzodioxocinones was explored, thereby racemic penicillide ((±)-1a) could be obtained in 13 steps in 4.2% overall yield, based on 5-amino-2-methylphenol (5) (Schemes 2-4).

Full text of DOI:10.1002/hlca.201100405

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A Convergent Approach to Dibenzodioxocinones: Synthesis of Racemic
Penicillide
by Chun-Lin Denga), Qiao Zhangb), Lisong Fanga), Xinsheng Lei*a), and Guoqiang Lin*a)c)
a) School of Pharmacy, Fudan University, ZhangHeng Road 826, Shanghai 201203, P. R. China
(phone/fax: þ 86-21-54237756; e-mail: leixs@fudan.edu.cn)
b) Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University,
Zhengzhou 450001, P. R. China
c) Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032,
P. R. China
A convergent approach to dibenzodioxocinones was explored, thereby racemic penicillide ((ꢀ)-1a)
could be obtained in 13 steps in 4.2% overall yield, based on 5-amino-2-methylphenol (5) (Schemes 2 –4).
Introduction. – Penicillide (¼11-hydroxy-3-[(1S)-1-hydroxy-3-methylbutyl]-4-me-
thoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one; 1a; Fig.) is a metabolite
produced by a filamentous fungus (Penicillium sp.), which was isolated and identified
by Sassa, Udagawa, and co-workers [1][2]. Since then, a number of its derivatives, i.e.,
1 – 3 (see Fig.), have been isolated and demonstrated to possess versatile biological
activities such as ACTC inhibitory activity, oxytocin antagonism, and antihypertensive
potential [3 – 5]. Recently, the modified penicillide compound 4a has been disclosed by
a research group of Bayer company [6] as a potent inhibitor against cholesterol ester
transfer protein (CETP), which is one potential target relative to coronary heart
disease [7]. It is noteworthy that the drug discovery aiming at more potent CETP
inhibitors mainly focused on derivatization of penicillide, which provided a preliminary
structureꢁactivity relationship (SAR). For example, the SAR of the alkyl side chain
(R1 in 4a, Fig.) was rather steep, and only the neopentyl (¼2,2-dimethylpropyl) group
showed a slight improvement of activity. The derivatization of the phenolic OH group
in the ꢀlowerꢁ aromatic ring (R4 in 4a) by etherification, esterification, or formation of a
carbamate showed that an a-branched bicyclic aliphatic C¼O residue was necessary to
obtain an improved activity with a longer half-time; and the exploration of substitution
at the ꢀlowerꢁ aromatic ring (R2 and R3 in 4a) caused a substantial increase of the in
vitro activity. Despite the above achievements, it remains desirable to get more
extensive SARs of the penicillide skeleton. To this end, it is pre-required to explore a
synthetic approach to the penicillide scaffold, particularly in a convergent manner.
However, to the best of our knowledge, racemic or enantiomerically pure penicillide
has not been synthesized so far. Herein, we report the first synthesis of racemic
penicillide ((ꢀ)-1a) in the context of our preliminary program on CETP inhibitors.
Results and Discussion. – Our retrosynthetic route for (ꢀ)-penicillide ((ꢀ)-1a) is
outlined in Scheme 1. According to the designed route, (ꢀ)-1a will be prepared from
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Figure. Penicillide (1a) and natural products derived from 1a
aldehyde 24 through nucleophilic addition of organometallics. Aldehyde 24 could be
constructed from aryl bromide 12 and the corresponding phenol 20 in a convergent
manner, which could be accomplished by an Ullmann coupling reaction and
lactonization. In turn, 12 and 20 could be obtained from the commercially available
starting materials 5 and 13, respectively through multistep functional-group trans-
formation. By this approach, not only (ꢀ)-penicillide ((ꢀ)-1a) might be obtained but
also structural modifications of the parent (ꢀ)-penicillide might be conveniently
achieved, thus allowing to perform subsequently structureꢁactivity-relationship
studies.
Scheme 1. Restrosynthetic Route for (ꢀ)-Penicillide ((ꢀ)-1a)

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Thus, the commercially available 5-amino-2-methylphenol (5) was first selectively
protected with the pivaloyl (¼2,2-dimethylpropanyl) group (!6), followed by
methylation of the phenolic OH group to give compound 7 in a two-step yield of
91% (Scheme 2). Then, 7 was regio-selectively lithiated with BuLi at ꢁ 208, and
subsequently CO2 gas was bubbled through the solution to give the carboxylic acid 8 in
90% yield. Via esterification and deprotection, compound 8 was converted into 9 in a
one-pot reaction in 80% yield. By the Sandmeyer reaction, the NH2 group of 9 was
successfully replaced by a Br-atom (!10, 79% yield), and subsquent treatment with N-
bromosuccinimide (NBS) (!11) followed by hydrolysis with H2SO4 provided the
target intermediate 12 in a yield of 86%.
Scheme 2. Preparation of Intermediate 12 (Piv ¼ Me3CCO)
a) 2,2-Dimethylpropanoyl chloride (PivCl), NaHCO3, AcOEt/H2O, r.t., 1 h; 97%. b) MeI, K2CO3,
DMF, r.t., 4 h; 94%. c) BuLi, THF, ꢁ 208, 2 h; CO2 (gas), 2 h; 90%. d) (MeO)3CH, H2SO4 (conc.),
MeOH, reflux, 3 d; 80%. e) NaNO2, aq. HBr soln., ꢁ 208, 1 h; CuBr, aq. HBr soln., r.t., until no gas
evolved; 808, overnight; 79%. f) N-Bromosuccinimide (NBS), 2,2’-azobis[2-propanenitrile] (AIBN;
cat.), CCl4, reflux, 12 h; 94%. g) H2SO4 (aq.), r.t., 1 h; 92%.
On the other hand, starting from commercially available 2,3-dihydroxybenzalde-
hyde (13), the OH group at C(3) was at first selectively benzylated with benzyl
bromide in the presence of NaH (2.0 equiv.) to obtain compound 14 in 73% yield
according to the known method [8] (Scheme 3). Subsequent bromination with NBS in
the presence of AcONH4 in MeCN at room temperature for 4 h, according to the
method of Das and co-workers [9], gave the bromo derivative 15 in 85% yield. Then,
the OH group of 15 was protected with the tBuMe2Si group to afford compound 16a in
95% yield. Treatment of 16a with Me2Zn in the presence of [Pd(dppf)Cl2] (dppf ¼ [1,1’-
bis(diphenylphosphino-kP)ferrocene] in refluxing anhydrous dioxane for 1 h afforded
the coupling product 17 in 82% yield via Negishi reaction [10]. Notably, under the same
coupling conditions, the corresponding Me coupling product could not be obtained in
reasonable yields from either 15 or 16b (16b was derived from 15 in two steps). Then,
aldehyde 17 was reduced to the benzyl alcohol 18 in 91% yield with NaBH4 in MeOH at
t
room temperature for 4 h. After removal of the BuMe2Si group of 18 with Bu4NF · x
H2O in THF (!19) and protection of the benzylic OH group with 3,4-dihydro-2H-
pyran in the presence of TsOH, the target intermediate 20 was obtained in 79% yield
over two steps.

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Scheme 3. Preparation for Intermediate 20
629
a) NaH (2.0 equiv.), r.t., 1 h; BnBr/THF, r.t., 4 h; 73%. b) NBS, AcONH4, MeCN, r.t., 4 h, 85%. c)
tBuMe2 · SiCl, (iPr)2NEt, DMF, r.t., 1 h; 95%. d) Me2Zn, [1,1’-bis(diphenylphosphino-kP)ferrocene]di-
chloropalladium ([Pd(dppf)Cl2]; cat.), 1,4-dioxane, reflux, 1 h; 82%. e) NaBH4, MeOH, r.t., 4 h; 91%. f)
Bu4NF · x H2O, THF, r.t., 30 min; 94%. g) 3,4-Dihydro-2H-pyran, TsOH · H2O (cat.), CH2Cl2, 08, 1 h;
84%.
With 12 and 20 in hand, we performed the Ullmann coupling reaction (Scheme 4).
After having tested several typical coupling conditions including Cu2O/Pyridine [11],
CuI/Me2CHCO2H/Cs2CO3/DMF [12], and CuBr/tBuCOCH2COtBu/Cs2CO3/1-methyl-
pyrrolidin-2-one (NMP) [13], we could not get satisfying results. Fortunately, the
coupling product 21 could be obtained in 60% yield in the presence of activated Cu
powder and copper oxide black in refluxing MeCN after 12 h [14]. Then, removal of the
terahydro-2H-pyran-2-yl (THP) group in 21 under acidic conditions led to 22 in 93%
yield. The formyl group of 22 was protected as its dimethyl acetal by treatment with
MeOH in the presence of a catalytic amount of TsOH · H2O; then the ester group in the
resulting dimethyl acetal was saponified with KOH in refluxing MeOH for 12 h, to give
acid 23 in 98% overall yield. Tremendous efforts to achieve the lactonization of 23
failed to give 24 in acceptable yields, such as TsOH · H2O-catalyzed lactonization,
intramolecular Mitsunobu reaction and Yamagushi reaction. Fortunately, the problem
could be solved by treatment of 23 in the presence of Et3N with Mukaiyamaꢁs reagent
[15] in refluxing MeCN for 12 h, affording the desired lactone 24 in a satisfactory yield
of 51% based on 22. Attempts to obtain (ꢀ)-1a from 24 by a direct nucleophilic
addition of 2-methylpropyl Grignard reagent or (2-methylpropyl)lithium to the formyl
group were unsuccessful, resulting mainly in the corresponding benzyl alcohol due to
reduction of the formyl group. Therefore, an indirect approach was adopted instead,
and nucleophilic addition of a 2-methylprop-2-en-1-yl Grignard reagent to the formyl
group of 24 was performed in anhydrous THF at ꢁ 108 for 1 h, giving 25 in 82% yield.
Finally, hydrogenation of 25 was carefully performed with H2 gas in the presence of
10% Pd/C in AcOEt/MeOH at room temperature for 3 h which saturated the C¼C
bond and removed the protective benzyl group, resulting in (ꢀ)-1a with a yield of 65%.

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Scheme 4. Synthesis of (ꢀ)-1a
a) Cu, CuO, N,N-dimethylpyridin-4-amine (DMAP), MeCN, reflux, 12 h; 60%. b) TsOH · H2O, iPrOH/
H2O, reflux, 12 h; 93%. c) TsOH · H2O, MeOH, 1 h; KOH, reflux, 12 h. d) Et3N, 2-chloro-1-
methylpyridinium iodide (Mukaiyamaꢁs reagent), MeCN, reflux; 51% over two steps. e) (2-Methyl-
prop-2-en-1-yl)magnesium chloride (0.5m in THF), THF, ꢁ 108, 1 h; 82%. f) 10% Pd/C, H2 (1 atm),
MeOH/AcOEt, r.t., 3 h; 65%.
Conclusions. – In summary, we have developed a convergent approach to
dibenzodioxocinones, by which racemic penicillide ((ꢀ)-1a) was synthesized through
13 steps in 4.2% overall yield based on 5-amino-2-methylphenol (5). The asymmetric
syntheses of penicillide and derivatives thereof are under way.
We thank the National Natural Foundation of China (20872019) and Fudan University for the
financial support of our research, and we are grateful to the Shanghai Institute of Organic Chemistry for
recording EI- or ESI-MS, HR-MS, and 1H-, and 13C-NMR spectra.
Experimental Part
General. Solvents were distilled from the appropriate drying agents before use. All the reagents were
purchased from Acros, Alfa Aesar, and National Chemical Reagents Group Co., Ltd., P. R. China.
Column chromatography (CC): commercial silica gel (SiO2, 300 – 400 mesh; Qingdao Haiyang Chemical
Group Co.). TLC: TLC plates GF254 (Yantai Jiangyou Silica R&D Co., Ltd., P. R. China), detection
under UV light or with I2. 1H- and 13C-NMR Spectra: Varian-Mercury-Plus spectrometer; at 300 or 400
(1H) and 100 MHz (13C); d in ppm, with residual CHCl3 (d(H) 7.26; d(C) 77.0) as internal standard, J in
Hz. EI-, ESI-, HR-APCI-, and HR-ESI-MS: Finnigan-Mat-95 mass spectrometer(APCI ¼ atmospheric-
pressure chemical ionization); in m/z.
N-(3-Hydroxy-4-methylphenyl)-2,2-dimethylpropanamide (6). To a heterogeneous mixture of 5-
amino-2-methylphenol (5; 1.00 g, 8.13 mmol), Na2CO3 (2.05 g, 24.4 mmol), AcOEt (28 ml), and H2O

Helvetica Chimica Acta – Vol. 95 (2012)
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(33 ml) was added 2,2-dimethylpropanoyl chloride (1.05 ml, 8.54 mmol). The two-phased system was
stirred for 1 h. Then the org. phase was washed with 1n HCl (30 ml), dried (Na2SO4), and concentrated.
Crystallization of the residue afforded 6 (1.84 g, 97%). TLC (petroleum ether/AcOEt 2 :1): Rf 0.75.
1H-NMR (CDCl3, 400 MHz): 8.57 (s, 1 H); 7.89 (s, 1 H); 7.38 (s, 1 H); 6.99 (d, J ¼ 7.8, 1 H); 6.39 (d, J ¼
7.8, 1 H); 2.19 (s, 3 H); 1.32 (s, 9 H). 13C-NMR (CDCl3, 100 MHz): 177.6; 155.6; 136.0; 130.3; 121.0; 110.2;
107.4; 39.6; 27.5 (3 C); 15.6. ESI-MS: 208.0 ([M þ H]þ). HR-APCI-MS: 208.1349 ([M þ H]þ,
C12H18NOþ2 ; calc.208.1338).
N-(3-Methoxy-4-methylphenyl)-2,2-dimethylpropanamide (7).
A stirred soln. of 6 (1.00g,
4.83 mmol) and K2CO3 (1.67 g, 12.1 mmol) in DMF (10 ml) was treated at r.t. with MeI (0.36 ml,
5.8 mmol) in small portions. The mixture was stirred at r.t. for 4 h, then dil. with H2O (10 ml) and
extracted with AcOEt (3 ꢂ 20 ml). The combined extracts was washed with H2O (2 ꢂ 50 ml), dried
(MgSO4), and concentrated, and the residue subjected to CC (SiO2, AcOEt/petroleum ether 1:6): 7
(1.00 g, 94%). TLC (petroleum ether/AcOEt 4 :1): Rf 0.69. 1H-NMR (CDCl3, 300 MHz): 7.49 (s, 1 H);
7.27 (br. s, 1 H); 7.03 (d, J ¼ 8.1, 1 H); 6.71 (dd, J ¼ 1.5, 7.8, 1 H); 3.84 (s, 3 H); 2.17 (s, 3 H); 1.32 (s, 9 H).
ESI-MS: 222.2 ([M þ H]þ).
6-[(2,2-Dimethyl-1-oxopropyl)amino]-2-methoxy-3-methylbenzoic Acid (8). To a soln. of 7 (0.50 g,
2.26 mmol) in dry THF (10 ml) at ꢁ 208 was added dropwise 1.6m Buli in hexane (4.5 ml, 7.24 mmol), and
the mixture was stirred for 2 h. Then CO2 was bubbled continuously through the mixture for an
additional 2 h. To the resulting yellow soln. was added H2O (30 ml). The mixture was extracted with
AcOEt (20 ml) and the aq. phase acidified with HCl to pH 1. The aq. phase was extracted with AcOEt
(4 ꢂ 30 ml) and the combined the org. extract washed with brine, dried (Na2SO4), and concentrated:
crude 8 (0.54 g, 90%). Red oil which was used for the next step without further purification. TLC
(petroleum ether/AcOEt 4 :1): Rf 0.24. 1H-NMR (CDCl3, 300 MHz): 11.72 (s, 1 H); 8.63 (d, J ¼ 8.7, 1 H);
7.40 (d, J ¼ 8.4, 1 H); 3.92 (s, 3 H); 2.32 (s, 3 H); 1.34 (s, 9 H). EI-MS: 265 (Mþ).
Methyl 6-Amino-2-methoxy-3-methylbenzoate (9). To a soln. of 8 (12.6 g, 47.6 mmol) in MeOH
(50 ml), conc. H2SO4 soln. (5.7 ml), and trimethoxymethane (5.7 ml, 52.4 mmol) were added dropwise,
and the mixture was refluxed for 3 d. Then the mixture was cooled and 1n HCl added. After dilution with
CH2Cl2 (30 ml), the pH of the aq. phase was adjusted to pH 13 by adding 3n NaOH. Then the aq. phase
was, extracted with CH2Cl2 (3 ꢂ 50 ml) and the combined extract dried (MgSO4) and concentrated;
crude 9 (7.41 g, 80%) which was used for the next step without further purification. TLC (petroleum
ether/AcOEt 3 :1): Rf 0.64. 1H-NMR (CDCl3, 300 MHz): 7.03 (d, J ¼ 8.4, 1 H); 6.40 (d, J ¼ 8.7, 1 H); 5.01
(br. s, 2 H); 3.93 (s, 3 H); 3.74 (s, 3 H); 2.16 (s, 3 H). ESI-MS: 196.1 ([M þ H]þ).
Methyl 6-Bromo-2-methoxy-3-methylbenzoate (10) [16]. To a soln. of 9 (7.41 g, 38 mmol) in 80 ml
H2O, aq. HBr soln. (21 ml) was added. The resulting mixture was cooled to ꢁ 208 and a soln. of NaNO2
(2.86 g, 41.4 mmol) in H2O was added dropwise. The mixture was stirred for 1 h, and then a soln. of CuBr
(7.77 g, 54.3 mmol) in aq. HBr soln. (10 ml), was added dropwise. The resulting mixture was stirred until
no gas was generated. Then the mixture was stirred at 808 overnight. After cooling and extraction with
CH2Cl2 (3 ꢂ 100 ml), the combined org. extract was washed with sat. Na2CO3 soln. and brine, dried
(Na2SO4), and concentrated and the residue subjected to CC (SiO2, AcOEt/petroleum ether 1:100): 10
(7.76 g, 79%). Green oil which was used for the next step without further purification. TLC (petrolium
1
ether/AcOEt 20 :1): Rf 0.62. H-NMR (CDCl3, 300 MHz): 7.23 (d, J ¼ 8.4, 1 H); 7.09 (d, J ¼ 8.1, 1 H);
3.96 (s, 3 H); 3.79 (s, 3 H); 2.26 (s, 3 H). ESI-MS: 259.0, 261.1 ([M þ H]þ).
Methyl 6-Bromo-3-(dibromomethyl)-2-methoxybenzoate (11). To a flame-dried flask was added
NBS (0.50 g, 2.81 mmol), AIBN (0.028 g, 0.18 mmol), and a soln. of 10 (0.228 g, 0.88 mmol) in CCl4
(10 ml), and the suspension was refluxed in the dark. After 12 h, the mixture was cooled to r.t. and
concentrated. The residue was subjected to CC (SiO2, AcOEt/petroleum ether 1:100): pure 11 (0.344 g,
94%). TLC (petroleum ether/AcOEt 50 :1): Rf 0.38. 1H-NMR (CDCl3, 400 MHz): 7.82 (d, J ¼ 8.4, 1 H);
7.45 (d, J ¼ 8.4, 1 H); 6.97 (s, 1 H), 3.98 (s, 3 H); 3.92 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 165.9; 151.7;
135.1; 132.6; 130.2; 129.3; 121.3; 63.2; 53.0; 32.5. EI-MS: 415, 417 (Mþ).
Methyl 6-Bromo-3-formyl-2-methoxybenzoate (12) [16]. To a flame-dried flask was added 11
(0.344 g, 0.83 mmol) and conc. H2SO4 soln. (5 ml). The mixture was stirred at r.t. for 1 h (TLC
monitoring) and then poured into ice water with stirring. The mixture was extracted with AcOEt (3 ꢂ
10 ml), the extract washed with Na2CO3 soln. and H2O, dried (Na2SO4), and concentrated, and the

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residue subjected to CC (SiO2/AcOEt/petroleum ether 1:40): 12 (208 mg, 92%). TLC (petroleum ether/
AcOEt 50 :1): Rf 0.17. 1H-NMR (CDCl3, 300 MHz): 10.30 (s, J ¼ 8.4, 1 H); 7.76 (d, J ¼ 7.2, 1 H); 7.47 (d,
J ¼ 7.2, 1 H); 3.99 (s, 3 H); 3.98 (s, 3 H); data well in accordance with those of [16]. ESI-MS: 272.9, 274.9
([M þ H]þ).
3-(Benzyloxy)-2-hydroxybenzaldehyde (14). To a suspension of 60% NaH (5.8 g, 144 mmol) in dry
THF (150 ml), a soln. of 13 (10.0 g, 72 mmol) in dry THF was added in dropwise under stirring. The
suspension was stirred at r.t. for 1 h. Then benzyl bromide (12.3 g, 72 mmol) was added dropwise at 258
and stirring continued for 24 h. After addition of H2O (300 ml), the mixture was acidified with HCl until
the pH of the aq. layer was 2 and extracted with CH2Cl2 (3 ꢂ 100 ml). The combined org. phase was
washed with 1n HCl, dried (MgSO4), and concentrated and the residue subjected to CC (short SiO2
column, AcOEt/petroleum ether 1:20) to give the crude product, which was purified by recrystallization
from EtOH: 14 (10.7g, 65%). TLC (petroleum ether/AcOEt 10 :1): Rf 0.42. 1H-NMR (CDCl3,
300 MHz): 11.12 (s, 1 H); 9.92 (s, 1 H); 7.47 – 7.32 (m, 5 H); 7.20 (dd, J ¼ 7.8, 1.4, 1 H); 7.13 (dd, J ¼ 7.8, 1.4,
1 H); 6.90 (t, J ¼ 7.8, 1 H); 5.20 (s, 2 H); data well in accordance with those of [8b]. ESI-MS: 229.1 ([M þ
H]þ)
3-(Benzyloxy)-5-bromo-2-hydroxybenzaldehyde (15). To a soln. of 14 (4.00 g, 17.5 mmol) in MeCN
(90 ml), AcONH4 (137 mg, 1.75 mmol) and NBS (3.28 g, 18.4 mmol) were added. The mixture was
stirred for 4 h at r.t. and then concentrated. H2O (100 ml) was added to the residue, the mixture extracted
with AcOEt (3 ꢂ 30ml), the combined org. extract dried (MgSO4) and concentrated, and the residue
subjected to CC (SiO2 AcOEt/petroleum ether 1:20): 15 (4.59 g, 85%). TLC (petroleum ether/CH2Cl2
2 :1): Rf 0.35. 1H-NMR (CDCl3, 400 MHz): 10.96 (s, 1 H); 9.86 (s, 1 H); 7.46 – 7.35 (m, 5 H); 7.33 (d, J ¼ 2,
1 H); 7.23 (d, J ¼ 2, 1 H); 5.16 (s, 2 H); data well in accordance with those of [17]. ESI-MS: 329.0, 331.1
([M þ Na]þ).
3-(Benzyloxy)-5-bromo-2-{[(tert-butyl)dimethylsilyl]oxy}benzaldehyde (16a). To a soln. of 15
(307 mg, 1 mmol) in DMF (1 ml), N,N-diisopropylethylamine (0.35 ml, 2 mmol) was added and the
mixture stirred for 10 min at r.t. Then tBuMe2Si (301 mg, 2 mmol) was added and the mixture stirred for
1 h at r.t. The reaction was quenched with H2O (50 ml), the mixture extracted with AcOEt (3 ꢂ 50 ml),
the combined org. extract washed with H2O and brine, dried (MgSO4), and concentrated, and the residue
subjected to CC (SiO2, AcOEt/petroleum ether 1:100): 16 (401 mg, 95%). TLC (petroleum ether/AcOEt
15 :1): Rf 0.78. 1H-NMR (CDCl3, 400 MHz): 10.40 (s, 1 H); 7.52 (d, J ¼ 2.4, 1 H); 7.42 – 7.41 (m, 5 H); 7.21
(d, J ¼ 2.4, 1 H); 5.03 (s, 2 H); 0.92 (s, 9 H); 0.07 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 188.7; 151.3;
148.5; 135.0; 128.9; 128.7 (2 C); 128.4 (2 C); 121.9; 121.1; 113.7; 71.4; 25.7 (3 C); 18.7; ꢁ 4.3 (2 C). ESI-
MS: 421.1, 423.1([M þ H]þ).
3-(Benzyloxy)-2-{[(tert-butyl)dimethylsilyl]oxy}-5-methylbenzaldehyde (17). To a flame-dried flask
was added 16 (2.21 g, 5.24 mmol), [Pd(dppf)Cl2] (58 mg, 0.08 mmol), 1.2m dimethylzinc in toluene
(5.2 ml, 6.29 mmol) and dry 1,4-dioxane (15 ml), and the suspension was heated at 1108 for 1 h. After
cooling, the mixture was quenched with 1n HCl (50 ml) and extracted with AcOEt (2 ꢂ 50 ml), the
extract washed with H2O and brine, dried (MgSO4), and concentrated, and the residue subjected to CC
(SiO2, AcOEt/petroleum ether 1:40): 17 (1.53 g, 82%). TLC (petroleum ether/AcOEt 15 :1): Rf 0.57.
1H-NMR (CDCl3, 400 MHz): 10.46 (s, 1 H); 7.44 – 7.35 (m, 5 H); 7.21 (d, 1 H); 6.94 (d, 1 H); 5.05 (s, 2 H);
2.28 (s, 3 H); 0.94 (s, 9 H); 0.08 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 190.5; 150.1; 147.2; 136.0; 130.9;
128.6 (2 C); 128.3; 128.2 (2 C); 127.7; 119.7; 119.2; 71.0; 25.8 (3 C); 21.0; 18.8; ꢁ 4.3 (2 C). ESI-MS: 357.2
([M þ H]þ).
(3-(Benzyloxy)-2-{[(tert-butyl)dimethylsilyl]oxy}-5-methylbenzene)methanol
(18).
NaBH4
(378 mg, 10.0 mmol) was added in portions to a stirred soln. of 17 (891 mg, 2.5 mmol) in MeOH
(200 ml) at 08. The resulting mixture was stirred for 4 h at r.t. and then concentrated. The residue was
dissolved in 3n HCl (50ml), the soln. extracted with CH2Cl2 (3 ꢂ 20 ml), and the combined CH2Cl2
ectract washed with H2O (3 ꢂ 50 ml), dried (Na2SO4), and concentrated: 18 (812 mg, 91%). TLC
(petroleum ether/AcOEt 10 :1): Rf 0.41. 1H-NMR (CDCl3, 400 MHz): 7.42 – 7.30 (m, 5 H); 6.75 (s, 1 H);
6.68 (s, 1 H); 5.02 (s, 2 H); 4.67 (s, 2 H); 2.26 (s, 3 H); 2.23 (s, 1 H); 0.94 (s, 9 H); 0.06 (s, 6 H). 13C-NMR
(CDCl3, 100 MHz): 148.9; 140.1; 136.5; 132.0; 130.7; 128.4 (2 C); 128.2 (2 C); 128.0; 121.0; 113.1; 70.6;
61.7; 25.9 (3 C); 21.0; 18.6; ꢁ 4.0 (2 C). ESI-MS: 381.2 ([M þ Na]þ).

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633
3-(Benzyloxy)-2-(hydroxy)-5-methylbenzenemethanol (19). To a cold (08) soln. of 18 (323 mg,
0.90 mmol) in dry THF (9 ml), Bu4NF · x H2O (471 mg, 1.8 mmol) added, the mixture was stirred for
0.5 h at r.t. H2O (20 ml) was added, the mixture was extracted with AcOEt (3 ꢂ 20 ml), the combined
org. extract washed with H2O and brine, dried (Na2SO4), and concentrated, and the residue purified by
CC (SiO2, AcOEt/petroleum ether 1:4): 19 (206 mg, 94%). TLC (petroleum ether/AcOEt 3 :1): Rf 0.26.
1H-NMR (CDCl3, 400 MHz): 7.43 – 7.37 (m, 5 H); 6.73 (s, 1 H); 6.70 (s, 1 H); 5.91 (s, 1 H); 5.09 (s, 2 H);
4.70 (s, 2 H); 2.36 (s, 1 H); 2.28 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 145.4; 141.5; 136.3; 129.2; 128.7
(2 C); 128.3; 127.8 (2 C); 126.3; 121.5; 112.6; 71.1; 61.8; 21.0. ESI-MS: 267.1 ([M þ Na]þ).
2-(Benzyloxy)-4-methyl-6-{[(tetrahydro-2H-pyran-2-yl)oxy]methyl}phenol (20). To a cold (ꢁ208)
soln. of 19 (0.892 g, 3.66 mmol) in dry CH2Cl2 (20 ml), TsOH · H2O (0.07g, 0.37 mmol) was added, and
the mixture was stirred at ꢁ208 for 15 min. Then 3,4-dihydro-2H-pyran (0.35 ml, 3.84 mmol) was added
dropwise and the soln. stirred for 1 h. The reaction was quenched with Et3N (1 ml), the mixture washed
with brine and dried (MgSO4), the solvent evaporated, and the residue subjected to CC (SiO2, AcOEt/
petroleum ether 1:20) 20 (1.01 g, 84%). TLC (petroleum ether/AcOEt 4 :1): Rf 0.67. 1H-NMR (CDCl3,
400 MHz): 7.44 – 7.34 (m, 5 H); 6.74 (s, 1 H); 6.71 (s, 1 H); 6.23 (s, 1 H); 5.08 (s, 2 H); 4.82 (d, J ¼ 12, 1 H);
4.75 (t, J ¼ 3.3, 1 H); 4.58 (d, J ¼ 12, 1 H); 3.97 (m, 1 H); 3.57 (m, 1 H); 2.26 (s, 3 H); 1.88 – 1.53 (m, 6 H).
ESI-MS: 351.1 ([M þ Na]þ).
Methyl 6-{2-(Benzyloxy)-4-methyl-6-{[(tetrahydro-2H-pyran-2-yl)oxy]methyl}phenoxy}-3-formyl-2-
methoxybenzoate (21). To a flame-dried flask was added 12 (1.11 g, 4.08 mmol), 20 (1.61 g, 4.89 mmol),
activated Cu powder (0.653 g, 10.2 mmol), CuO black (0.816 g, 10.2 mmol), DMAP (1.49 g, 12.2 mmol)
and dry MeCN (30 ml), and the suspension was refluxed for 12 h. After cooling, the mixture was diluted
with CH2Cl2 (20 ml) and filtered over a pad of Celiteꢄ, the filter cake washed with CH2Cl2 (3 ꢂ 10 ml), the
filtrate was concentrated, and the residue subjected to CC (SiO2, AcOEt/petroleum ether 6 :1): 21
(1.27 g, 60%). Light yellow oil. TLC (petroleum ether/AcOEt 10 :1): Rf 0.1. 1H-NMR (CDCl3,
400 MHz): 10.22 (s, 1 H); 7.76 (d, J ¼ 8.7, 1 H); 7.28 – 7.16 (m, 5 H); 6.94 (s, 1 H); 6.83 (s, 1 H); 6.46 (d, J ¼
9.1, 1 H); 5.00 (s, 2 H); 4.69 (d, J ¼ 12, 1 H); 4.68 (s, 1 H); 4.43 (d, J ¼ 12, 1 H); 3.99 (s, 3 H); 3.95 (s, 3 H);
3.79 (m, 1 H); 3.49 (m, 1 H); 2.36 (s, 3 H); 1.66 – 1.41 (m, 6 H). 13C-NMR (CDCl3, 100 MHz): 187.7;
165.3; 161.7; 161.5; 150.1; 138.3; 136.5; 136.4; 132;2; 131.0; 128.2 (2 C); 127.6; 126.7 (2 C); 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. ESI-MS: 543.4 ([M þ Na]þ).
HR-ESI-MS: 543.1968 ([M þ Na]þ, C30H32NaOþ8 ; calc. 543.1995).
Methyl 6-[2-(Benzyloxy)-6-(hydroxymethyl)-4-methylphenoxy]-3-formyl-2-methoxybenzoate (22).
To a flame-dried flask was added 21 (1.23 g, 2.37 mmol), TsOH · H2O (3 mg), iPrOH (10 ml), and H2O
(3 ml), and the soln. was refluxed overnight. After cooling, the mixture was extracted with AcOEt (3 ꢂ
30 ml), the extract washed with H2O and brine, dried (Na2SO4), and concentrated, and the residue
subjected to CC (SiO2, AcOEt/petroleum ether 1:3): 22 (0.96 g, 93%). Colorless amorphous solid. TLC
(petroleum ether/AcOEt 3 :1): Rf 0.20. 1H-NMR (CDCl3, 400 MHz): 10.22 (s, 1 H); 7.74 (d, J ¼ 9.0, 1 H);
7.26 – 7.16 (m, 5 H); 6.88 (s, 1 H); 6.83 (s, 1 H); 6.46 (d, J ¼ 9.0, 1 H); 5.02 (s, 2 H); 4.56 (s, 2 H); 3.40 (s,
3 H); 3.96 (s, 3 H); 2.78 (br. s, 1 H); 2.35 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 187.7; 165.6; 161.9; 160.9;
150.2; 138.0; 136.8; 136.3; 134.6; 131.6; 128.3 (2 C); 127.7; 126.7 (2 C); 123.3; 121.9; 117.4; 114.7; 109.9;
70.5; 64.7; 60.7; 52.9; 21.4. ESI-MS: 459.3 ([M þ Na]þ). HR-ESI-MS: 459.1409 ([M þ Na]þ,
C25H24NaOþ7 ; calc. 459.1420).
6-[2-(Benzyloxy)-6-(hydroxymethyl)-4-methylphenoxy}-3-formyl-2-methoxybenzoic Acid (23). To a
soln. of 22 (912 mg, 2.09 mmol) in MeOH (12 ml), TsOH · H2O (80 mg, 0.42 mmol) was added, and the
soln. was stirred for 1 h. Then NaOH tablets (0.94 g, 23.5 mmol) were added, and the mixture was
refluxed overnight. After cooling, the MeOH was evaporated, and 3n HCl was added to the residue until
pH 3 was reached. The mixture was extracted with AcOEt (4 ꢂ 30 ml) and the combined extract
concentrated: crude 23 (837 mg, 98%), which was used for the next step without further purification.
1
TLC (CH2Cl2/MeOH 5 :1): Rf 0.4. H-NMR (DMSO, 400 MHz): 10.11 (s, 1 H); 7.67 (d, J ¼ 8.8, 1 H);
7.25 – 7.18 (m, 5 H); 7.03 (s, 1 H); 6.98 (s, 1 H); 6.38 (d, J ¼ 8.8, 1 H); 5.08 (s, 2 H); 4.37 (s, 2 H); 3.97 (s,
3 H); 2.34 (s, 3 H). ESI-MS: 421.0 ([M ꢁ H]ꢁ).
11-(Benzyloxy)-4-methoxy-9-methyl-5-oxo-5H,7H-dibenzo[b,g][1,5]dioxocin-3-carboxaldehyde
(24). To a soln. of 2-chloro-1-methylpyridinium iodide (4.04 g, 16 mmol) in dry MeCN (300 ml), a soln.
of crude 23 (1.67 g, 4 mmol) in dry MeCN (40 ml) and Et3N (4.4 ml, 31.6 mmol) was added at 808 by a

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Helvetica Chimica Acta – Vol. 95 (2012)
syringe pump within 5 h, and the mixture was stirred for another 8 h. After cooling to r.t., the mixture was
concentrated, the residue redissolved in CH2Cl2 (30 ml), the soln. filtered over a pad of SiO2, the filter
cake washed with CH2Cl2 (5 ꢂ 10 ml), the filterate washed with H2O (3 ꢂ 30 ml), dried MgSO4, and
concentrated, and the residue subjected to CC (SiO2, CH2Cl2): 24 (814 mg, 51% over two steps). TLC
(petroleum ether/AcOEt 2 :1): Rf 0.8. 1H-NMR (CDCl3, 400 MHz): 10.35 (d, J ¼ 0.6, 1 H); 7.98 (d, J ¼
8.6, 1 H); 7.50 – 7.35 (m, 5 H); 7.03 (dd, J ¼ 0.6, J ¼ 8.6, 1 H); 6.89 (d, J ¼ 1.5, 1 H); 6.48 (d, J ¼ 1.2, 1 H);
5.20 (s, 2 H); 5.13 (s, 2 H); 4.12 (s, 3 H); 2.28 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 187.8; 166.1; 161.2;
158.0; 150.4; 143.2; 136.5; 135.3; 133.3; 128.7 (2 C); 128.1; 127.32; 127.27 (2 C); 127.0; 121.5; 120.6; 118.7;
116.6; 71.3; 69.0; 64.7; 21.2. ESI-MS: 427.0 ([M þ Na]þ). HR-ESI-MS: 427.1133([M þ Na]þ,
C24H20NaOþ6 ;calc. 427.1158).
11-(Benzyloxy)-3-(1-hydroxy-3-methylbut-3-en-1-yl)-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]-
dioxocin-5-one (25). To a cold (ꢁ108) soln. of 24 (404 mg, 0.25 mmol) in dry THF (15 ml), 0.5m 2-
methylprop-2-en-1-ylmagnesium chloride in THF (5 ml, 2.5 mmol) was added, and the mixture was
stirred at ꢁ108 for 1 h. After cautious quenching with sat. aq. NH4Cl soln., the mixture was extracted
with AcOEt (3 ꢂ 30 ml), the extract washed with brine, dried (Na2SO4), and concentrated, and the
residue purified by CC (SiO2, AcOEt/petroleum ether 1:4): 25 (379 mg, 82%). White amorphous
powder. TLC (petroleum ether/AcOEt 2 :1): Rf 0.5. 1H-NMR (CDCl3, 400 MHz): 7.62 (d, J ¼ 8.6, 1 H);
7.60 – 7.30 (m, 5 H); 6.86 (s, 1 H); 6.46 (s, 1 H); 5.19 (s, 2 H); 5.08 – 5.14 (m, 3 H); 4.93 (s, 1 H); 4.84 (s,
1 H); 3.98 (s, 3 H); 2.47 (dd, J ¼ 13.6, 3.2, 1 H); 2.32 (m, 1 H); 2.26 (s, 3 H); 1.83 (s, 3 H). 13C-NMR
(CDCl3, 100 MHz): 167.4; 154.5; 152.3; 150.2; 144.0; 142.3; 136.7; 135.0; 134.4; 130.9; 128.6 (2 C); 127.9;
127.3; 127.2 (2 C); 121.6; 119.3; 118.0; 116.5; 114.2; 71.3; 69.0; 65.5; 47.3; 29.6; 22.2; 21.0. ESI-MS: 443.0
([M ꢁ OH]þ). HR-APCI-MS: 461.1979 ([M þ H]þ, C28H29Oþ6 ; calc. 461.1964).
rac-11-Hydroxy-3-(1-hydroxy-3-methylbutyl)-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxo-
cin-5(7H)-one (ꢀ)-(1a). To the soln. of 25 (202 mg, 0.44 mmol) in MeOH/ AcOEt 5 :1) (6 ml) was added
10% Pd/C (20 mg), and the mixture was stirred under H2 (balloon) at r.t. for ca. 3 h (TLC monitoring).
After addition of CH2Cl2 (20 ml), the mixture was filtered over a pad of Celiteꢄ, the filter cake washed
with AcOEt, the combined filterate concentrated, and the residue subjected to CC (SiO2, AcOEt/
petroleum ether 5 :2): (ꢀ)-1a (106 mg, 65%). Light yellow amorphous powder. TLC (petroleum ether/
1
AcOEt 1:2): Rf 0.46. H-NMR (CDCl3, 400 MHz): 7.52 (d, J ¼ 8.6, 1 H); 6.84 (s, 1 H); 6.83 (d, J ¼ 8.6,
1 H); 6.64 (br. s, 1 H); 6.35 (s, 1 H); 5.06 (m, 3 H); 3.96 (s, 3 H); 2.23 (s, 3 H); 1.78 (m, 1 H); 1.66 (m,
1 H); 1.45 (m, 1 H); 0.97 (d, J ¼ 6.8, 3 H); 0.95 (d, J ¼ 6.8, 3 H). 13C-NMR (CDCl3, 100 MHz): 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. ESI-MS: 355.0 ([M ꢁ OH]þ). HR-APCI-MS: 373.1654 ([M þ H]þ, C21H25Oþ6 ; calc.
373.1651).
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Received October 18, 2011