A nature-inspired concise synthesis of (+)-ent-chromazonarol

Article abstract of DOI:10.1007/s11426-012-4826-0

A large number of sesquiterpene quinone/hydroquinone natural products including (+)-ent-chromazonarol have been isolated and received great attention from the synthetic community. Herein, we report a nature-inspired concise synthesis of (+)-ent-chromazonarol in 4 steps from a readily available starting material. The synthesis relied on a Lewis acid mediated cyclization which correctly installed two vicinal stereocenters in one step. This highly efficient synthetic route allows us to further prepare natural product congeners for further biological studies.

Full text of DOI:10.1007/s11426-012-4826-0

SCIENCE CHINA
Chemistry
March 2013 Vol.56 No.3: 349–353
doi: 10.1007/s11426-012-4826-0
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
A nature-inspired concise synthesis of (+)-ent-chromazonarol
HUANG JieHui1 & LEI XiaoGuang1, 2*
1College of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
2National Institute of Biological Sciences (NIBS), Beijing 102206, China
Received November 15, 2012; accepted December 12, 2012; published online January 7, 2013
A large number of sesquiterpene quinone/hydroquinone natural products including (+)-ent-chromazonarol have been isolated
and received great attention from the synthetic community. Herein, we report a nature-inspired concise synthesis of
(+)-ent-chromazonarol in 4 steps from a readily available starting material. The synthesis relied on a Lewis acid mediated cy-
clization which correctly installed two vicinal stereocenters in one step. This highly efficient synthetic route allows us to fur-
ther prepare natural product congeners for further biological studies.
sesquiterpene, hydroquinone, total synthesis, chromazonarol
co-workers [11b] reported an elegant synthesis of ()-
chromazonarol (9) through a biomimetic cyclization of
polyprenoid using Lewis acid-assisted chiral Brønsted acid.
Very recently, Baran and co-workers [11e] reported an effi-
cient synthesis of (+)-ent-chromazonarol (7) through a
versatile borono-sclareolide intermediate.
Biosynthetically, the generation of (+)-ent-chromazonarol
(7) presumably involves a stereoselective cyclization of
polyene (12) derived from the coupling between farnesyl
pyrophosphate (11) and hydroquinone, to generate the ter-
tiary carbocation (13). This carbocation intermediate could
then undergo a cyclization to afford (+)-ent-chromazonarol
(Scheme 1) [12]. Inspired by this biosynthetic pathway, we
envisioned that alkene 14 might be a desired synthon to
generate the required carbocation intermediate for the final
cyclization. Herein, we report a highly concise synthesis of
(+)-ent-chromazonarol based on this nature-inspired syn-
thetic strategy.
1 Introduction
A large number of sesquiterpene quinones/hydroquinones [1]
with a normal drimane (1) skeleton (Figure 1) or a rear-
ranged drimane skeleton have been isolated and received
great attention from the synthetic community due to their
abundance of structural diversities (compounds 2–10) as
well as a wide range of attractive biological activities [2],
including antitumor [3], anti-HIV [4], anti-inflammation [5],
and anti-microbial activities [6]. Within this family of natu-
ral products, (+)-ent-chromazonarol (7) and its natural con-
geners have the most challenging tetracyclic chemical
structures. (+)-ent-Chromazonarol (7) was isolated from
marine sponge dysidea pallescens [7], and its epimer,
8-epi-chromazonarol (8) was isolated from smenospongia
aurea and smenospongia echina [8]. In addition, two close-
ly related natural products ()-chromazonarol (9) and iso-
chromazonarol (10) were also isolated from marine sponge
[9] and algae [10], respectively.
2 Experimentals
The striking chemical structure and promising antitumor
activity of chromazonarol have prompted a number of re-
markable synthetic studies [3a, 11]. In 2004, Yamamoto and
2.1 General
Unless otherwise noted, all reagents were used as supplied
by Sigma-Aldrich, J&K and Alfa Aesar Chemicals. CH2Cl2
*Corresponding author (email: leixiaoguang@nibs.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com www.springerlink.com

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Huang JH, et al. Sci China Chem March (2013) Vol.56 No.3
Figure 1 Drimane and the representative members of the sesquiterpene quinone/hydroquinone natural products.
Scheme 1 Proposed biosynthesis of chromazonarol.
was distilled from calcium hydride, THF and Et2O were
distilled from sodium/benzophenone ketyl prior to use. All
reactions were carried out in oven-dried glassware under an
chromatography.
2.2 Synthesis of compound 18
1
argon atmosphere unless otherwise noted. H NMR spectra
To a solution of 16 (126 mg, 0.57 mmol) in Et2O (2 mL) at
78 °C was added t-BuLi (1.7 M in pentene, 0.87 mL, 1.14
mmol) dropwise. The reaction was stirred at 78 °C for 30
min and a solution of aldehyde 15 (210 mg, 0.93 mmol) in
anhydrous Et2O (2 mL) was added dropwise. The resultant
mixture was stirred at 78 °C for 30 min, then allowed to
warm to room temperature. The mixture was quenched with
saturated NH4Cl solution (15 mL) and extracted with Et2O
(3 × 15 mL). The organic phases were combined, dried over
MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc:PE =
1:50) to afford alcohol 17 (314mg) as a mixture of two dia-
were recorded on a Varian 400 MHz spectrometer at ambi-
ent temperature with CDCl3 as the solvent unless otherwise
stated. 13C NMR spectra were recorded on a Varian 100
MHz spectrometer (with complete proton decoupling) at
ambient temperature. Chemical shifts are reported in parts
per million relative to chloroform (1H,  7.26; 13C,  77.00).
1
Data for H NMR are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad). Infrared spectra were recorded
on a Thermo Fisher FT-IR200 spectrophotometer. High-
resolution mass spectra were obtained at Peking University
Mass Spectrometry Laboratory using a Bruker APEX Flash

Huang JH, et al. Sci China Chem March (2013) Vol.56 No.3
351
stereomers, which was directly used for the next step.
ford 14 as a white solid (21 mg, 87%). 1H NMR (400 MHz,
CDCl3)  0.84 (s, 3H), 0.85–0.88 (m, 1H), 0.90 (s, 3H), 0.99
(s, 3H), 0.93–1.10 (m, 1H), 1.05–1.14 (m, 1H), 1.21 (d, J =
2.4 Hz, 1H), 1.25 (t, J = 3.6 Hz, 1H), 1.28–1.37 (m, 1H),
1.55 (s, 3H), 1.45–1.60 (m, 2H), 1.70–1.75 (m, 1H),
2.052.22 (m, 2H), 3.31 (q, J = 17.2, 7.6 Hz, 2H), 4.70 (s,
1H, OH), 5.07 (s, 1H, OH), 6.51–6.55 (m, 2H), 6.62–6.64
(m, 1H); 13CNMR (100 MHz, CDCl3) δ 18.8, 19.0, 20.2,
20.2, 21.7, 27.8, 33.2, 33.3, 33.5, 36.1, 39.0, 41.5, 51.7,
112.8, 115.8, 116.1, 128.2, 130.0, 137.2, 147.7, 149.1;
HRMS (ESI) [M+] calculated for C21H30O2: 314.2240, found:
314.2242; IR (neat) max: 3311, 2925, 2358, 1186 cm1;
[]2D2 +103.0 (c 0.5, MeOH).
To a stirred mixture of liquid NH3 (20 mL) and anhy-
drous THF (10 mL) at 78 °C was added Li (39 mg, 5.6
mmol). After stirred for 15 min, a solution of 17 (314 mg,
crude from previous step) in THF (5 mL) was added. The
resulting solution was stirred at 78 °C for 15 min, then
quenched with solid NH4Cl (1.00 g) and the NH3 was al-
lowed to evaporate by warming to room temperature. The
resultant mixture was diluted with H2O (50 mL) and ex-
tracted with Et2O (3 × 15 mL). The organic phases were
combined, dried over MgSO4, filtered and concentrated in
vacuo. The crude product was purified by flash column
chromatography using PE to afford 18 as a colorless oil
(230 mg, 75% over two steps). 1H NMR (400 MHz, CDCl3)
 0.15 (s, 6H), 0.19 (s, 6H), 0.84 (s, 3H), 0.90 (s, 3H), 0.95
(s, 9H), 0.99 (s, 3H), 1.02 (s, 9H), 1.04–1.11 (m, 1H),
1.23–1.36 (m, 4H), 1.49 (s, 3H), 1.45–1.56 (m, 4H),
1.71–1.76 (m, 1H), 2.05–2.22 (m, 2H), 3.17 (d, J = 17.6 Hz,
1H), 3.32 (d, J = 17.6 Hz, 1H), 6.49–6.55 (m, 2H), 6.61 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)  4.28,
4.26, 4.14,4.11, 18.3, 18.3, 18.8, 19.2, 20.1, 20.3, 21.6,
25.8, 25.9, 27.6, 33.3, 33.5, 35.8, 38.8, 41.7, 52.0, 117.1,
118.7, 120.1, 128.6, 132.5, 137.7, 147.3, 149.4; HRMS (ESI)
[M+H+] calculated for C33H59O2Si2: 543.4048, found:
543.4051; IR (neat) max: 2928, 1487, 1251, 1203, 837, 777
cm1; []D21 +72.4 (c 0.49, CHCl3).
2.4 Synthesis of (+)-ent-chromazonarol (7)
To a solution of 14 (31 mg, 0.1 mmol) in CH2Cl2 (2 mL) at
20 °C was added BF3·Et2O (0.06 mL, 0.5 mmol). The re-
action mixture was stirred at 20 °C for 2 h, and then
quenched with saturated NH4Cl solution. The mixture was
then extracted with CH2Cl2 (15 mL). The organic phases
were combined, dried over MgSO4, filtered and concentrat-
ed in vacuo. The crude material was purified by flash col-
umn chromatography (EtOAc:PE = 1:7) to afford (+)-ent-
chromazonarol (7) as a white solid (30 mg, 95%). 1H NMR
(400 MHz, CDCl3) δ 0.84 (s, 3H), 0.87 (s, 3H), 0.90 (s, 3H),
0.93–0.98 (m, 1H), 1.02 (dd, J = 12.4, 2.4 Hz, 1H), 1.13–
1.20 (m, 1H), 1.17 (s, 3H), 1.25–1.49 (m, 3H), 1.61–1.62 (m,
1H), 1.63–1.70 (m, 3H), 1.72–1.78 (m, 1H), 2.04 (dt, J =
12.4, 2.8 Hz, 1H), 2.56–2.58 (m, 2H), 4.55 (s, 1H, OH),
6.55–6.58 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 14.8, 18.5, 19.7, 20.6, 21.6, 22.5, 33.1, 33.4,
36.7, 39.1, 41.1, 41.8, 52.0, 56.1, 76.7, 114.2, 115.8, 117.5,
123.3, 147.0, 148.5; HRMS (ESI) [M+] calculated for
C21H30O2: 314.2240, found: 314.2241; IR (neat) max: 3372,
2926, 2359, 1493 cm1; []D23 +42.0 (c 1.0, CHCl3).
2.3 Synthesis of compound 14
To a solution of 18 (43 mg, 0.08 mmol) in THF (1.5 mL)
was added TBAF (1 M in THF, 0.17 mL, 0.17 mmol) at
0 °C. The reaction was stirred at 0 °C for 20 min, then
quenched with water (5 mL) and extracted with Et2O (3 × 5
mL). The organic phases were combined, dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified
by flash column chromatography (EtOAc:PE = 1:5) to af-
Scheme 2 Retrosynthetic plan for (+)-ent-chromazonarol (7).

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Huang JH, et al. Sci China Chem March (2013) Vol.56 No.3
Deoxygenation of 17 under a reductive condition (Li/NH3)
3 Results and discussion
provided 18 in 75% yield over two steps. Deprotection of
TBS group with TBAF afforded compound 14 in good yield.
Finally, the cyclization of compound 14 was smoothly
promoted upon the treatment of BF3·Et2O at 20 °C to fur-
nish the desired natural product (+)-ent-chromazonarol (7)
in 95% yield as a single diastereomer. Comparing to the
previous work reported by Villamizar et al. using an exo-
methylene precursor for the final cyclization (Scheme 2)
[11c], our synthesis using the tetra-substituted alkene 14
proved to be more efficient to install the two vicinal stereo-
genic centers with desired stereochemistry.
The physical and spectroscopic data of synthetic
(+)-ent-chromazonarol (7) were identical with those previ-
ously reported [3a, 8, 11c, 11e], and the relative stereo-
chemistry of 7 was further confirmed by NOESY experi-
ment (Figure 2) [15].
Accordingly, our retrosynthetic analysis is shown in Scheme
2. (+)-ent-Chromazonarol (7) might be derived from the
aforementioned intermediate 14. Compound 14 should be
generated from aldehyde 15 through a similar synthetic
route reported previously by Villamizar and coworkers
[11c]. However, we envisioned that aldehyde 15 could be
prepared more efficiently from the commercially available
(+)-sclareolide rather than the previously used (+)-manool.
Our synthesis commenced with the readily available ,
-unsaturated aldehyde 15 which were efficiently prepared
from the commercially available (+)-sclareolide [13]. A
brief summary of this synthetic route is shown in Scheme 3.
1, 2-Addition of aldehyde 15 with an aryllithium species
derived from aryl bromide 16 [14] afforded the secondary
alcohol 17 as a mixture of two diastereomers (Scheme 4).
Scheme 3 Efficient synthesis of aldehyde 15 from (+)-sclareolide. Reagents and conditions: a) CH3Li, Et2O, r.t., 15 min, 63%; b) maleic anhydride,
(CH3CO)2O, 50% H2O2, CH2Cl2, H2O, 26 h, 72%; c) KOH, MeOH, 10 min, quant; d) (COCl)2, DMSO, Et3N, CH2Cl2, 78–0 °C, 1.5 h, 90%; e) p-toluene-
sulfonic acid cat., toluene, reflux, 2 h, 75%.
Scheme 4 Synthesis of (+)-ent-chromazonarol. Reagents and conditions: a) t-BuLi, Et2O, 78 °C to r.t., 1 h; b) Li, liq. NH3, THF, 78 °C, 10 min; 75%
two steps; c) TBAF, THF, 0 °C, 20 min, 87%; d) BF3·Et2O, CH2Cl2, 20 °C, 2 h, 95%.

Huang JH, et al. Sci China Chem March (2013) Vol.56 No.3
353
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