Enantioselective syntheses of (+)- and (-)-brazilin

Article abstract of DOI:10.1016/j.tetasy.2014.08.009

Two enantiomers of brazilin were prepared in 9 steps from 7-hydroxychroman-4-one using the AD-mix-α and AD-mix-β-directed enantioselective dihydroxylation of 3-(4-hydroxy-3-methoxyphenyl)-2H-chromen-7-ol as a key step.

Full text of DOI:10.1016/j.tetasy.2014.08.009

Tetrahedron: Asymmetry 25 (2014) 1270–1274
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective syntheses of (+)- and (ꢀ)-brazilin
Umair Javed a, Moinul Karim a, Katherine C. Jahng b, Jae-Gyu Park c, Yurngdong Jahng a,
⇑
a College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
b Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA
c Pohang Techno-Park, Pohang 790-834, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2014
Accepted 10 August 2014
Two enantiomers of brazilin were prepared in 9 steps from 7-hydroxychroman-4-one using the
AD-mix- and AD-mix-b-directed enantioselective dihydroxylation of 3-(4-hydroxy-3-methoxy-
phenyl)-2H-chromen-7-ol as a key step.
a
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
The metal [especially Fe(III) or Al(III)] complexes of brazilin and
hematoxylin are commonly used to stain sections of animal tissues
for microscopic examination,15 and hematoxylin is one of the most
commonly used histologic stains. Brazilin also has a variety of bio-
logical properties, such as hepatoprotective,16 immunomodula-
tory,17 hypoglycemic,18 anticonvulsant,19 antiinflammatory,20 and
(+)-Brazilin 1a was first isolated as a crystalline solid by
Chevreul in 1808 from the brazilwood tree which belongs to the
species Caesalpinia.1 However, its molecular formula and structure
remained controversial until Libermann and Burg determined a
molecular formula of C16H14O5 and a partial structure of three
phenolic hydroxyl groups and an alcoholic hydroxyl group.2 A ser-
ies of elegant chemical degradations and syntheses by Perkin et al.
revealed a 6,6a,7,11b-tetrahydrobenzindeno[2,1-c]pyran as the
basic skeleton.3–5 Subsequent spectroscopic6 and synthetic stud-
ies7,8 finally led to assignments of the four hydroxyl-groups and
the cis geometry of the B/C ring junction, which were later con-
firmed by X-ray crystallography of O-trimethylbrazilin 1d.9 In
addition, the absolute configuration of brazilin was later confirmed
using Horeau’s partial resolution method and from chemical
correlations.10,11
antioxidant (IC50 = 8.8
reported to inhibit aldose reductase (IC50 = 100
polysaccharide-induced NO production (IC50 = 24.3
l
M)21 activities. In addition, it has been
M)22 and lipo-
M).23 Brazilin
l
l
also showed strong antibacterial activity against antibiotic-
resistant bacteria, such as methicillin-resistant Staphylococcus aur-
eus (MRSA, MIC = 16 lg/mL) and vancomycin-resistant enterococci
#222 (VRE #222, MIC = 16
l
g/mL), and multidrug resistant
Burkholderia cepacia (MIC = 64
lg/mL) as well as against other bac-
teria at MICs of 4–32 l
g/mL.24 Furthermore, it has been recently
reported to have anti-cervical activity (IC50 = 0.28
l
g/mL),25 and
The brazilin analogs, (+)-hematoxylin 1b and (+)-30-O-meth-
ylbrazilin 1c were additionally isolated from Haematoxylon campe-
thianum11 and Caesalpinia sappan,12 respectively, whereas
O-trimethylbrazilin 1d was prepared by reacting brazilin with
methyl iodide in the presence of NaOCH3.13,14
DNA nicking activity.26
Such biological properties and its unique structure have led
researchers to develop several synthetic procedures for brazilin
including a couple of enantioselective routes.7,8,12,27,28 However,
most of the procedures suffer from low chemical yield and long
reaction sequences, and required expensive chiral catalysts.
Herein we describe a new enantioselective synthesis of the (+)
OR4
9
8
R3O
10
11
and (ꢀ)-brazilin from resorcinol by the AD-mix-
a and AD-mix-
1a
1b
D
R
R
1 = R2 = R3 = R4 = H [(+)-Brazilin]
1 = R3 = R4 = H, R2 = OH [(+)-Haematoxylin]
b-directed enantioselective dihydroxylation of 3-(4-hydroxy-3-
1
H
C
1c R1 = R2 = R3 = H, R4 = CH3 (3'-O-Methylbrazilin)
1d R1 = R3 = R4 = CH3, R2 = H (O-Trimethylbrazilin)
7
2
methoxyphenyl)-2H-chromen-7-ol as a key step.
A
B
O
OH
R1O
3
6
4
R2
2. Results and discussion
The enantioselective synthetic scheme for brazilin is quite
straightforward as shown below. The classical acid-catalyzed
Claisen–Schmidt reaction of 7-hydroxychroman-4-one 229 with
⇑
Corresponding author. Tel.: +82 53 810 2821; fax: +82 53 810 4654.
E-mail address: ydjahng@ynu.ac.kr (Y. Jahng).
http://dx.doi.org/10.1016/j.tetasy.2014.08.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

U. Javed et al. / Tetrahedron: Asymmetry 25 (2014) 1270–1274
1271
4-hydroxy-3-methoxybenzaldehyde 3 in absolute EtOH saturated
with HCl (g) afforded the corresponding chalcone 4 in 95% yields,
whereas a reaction under basic condition afforded the correspond-
ing chalcone 4 in a somewhat lower yield (56–62%). Catalytic
hydrogenation of 4 in EtOH in the presence of a catalytic amount
of 5% Pd/C under a H2 atmosphere (50 psi) afforded the corre-
sponding ketone 5 in 98% yield. To address the inactivity of 5a
toward reduction by NaBH4 and LiAlH4, two phenolic hydroxyl
groups were protected by benzylation to the corresponding diben-
zyl ether 6, which was then reduced with NaBH4 to the corre-
sponding alcohol 7 in 88% yield as a 1:1 diastereomeric mixture.
Although these diastereomers were separable, vide infra, the
diastereomeric mixture was dehydrated by p-TsOH-mediated
dehydration to yield the 2H-chromene derivative 8 in 70% yield.
The resulting 8 was then subjected to AD-mix-mediated enantiose-
lective dihydroxylation.30 More specifically, reaction of 8 with
benzyl)chroman-3,4,7-triol (83%, 67% ee), followed by concd
HCl-catalyzed cyclization, and deprotection by AlCl3 in 47% yield.
3. Conclusion
Both the (+)- and (ꢀ)-brazilin were prepared in 9 steps from
7-hydroxychroman-4-one via the AD-mix-a- and AD-mix-b-direc-
ted enantioselective dihydroxylation of 3-(4-hydroxy-3-methoxy-
phenyl)-2H-chromen-7-ol as a key step. Structural modifications
of brazilin using the synthetic procedure described and biological
studies on the products obtained are in progress.
4. Experimental
4.1. General
an equimolar amount of AD-mix-
a afforded the (3R,4S)-3-
Melting points were determined using a Fischer-Jones melting
point apparatus and are not corrected. IR spectra were obtained
using a Perkin-Elmer 1330 spectrophotometer. NMR spectra were
obtained using a Bruker-250 spectrometer 250 MHz or 600 MHz
for 1H NMR and 62.5 MHz for 13C NMR and are reported as parts
per million (ppm) from the internal standard tetramethylsilane
(TMS). Chemicals and solvents were commercial reagent grade
and used without further purification. TLC was performed on pre-
coated Silica gel 60 F254 plates (0.25 mm thickness, Merck) and
the spots were visualized by UV irradiation (254 nm). Electrospray
ionization (ESI) mass spectrometry (MS) were performed on a LCQ
advantage-trap mass spectrometer (Thermo Finnigan, San Jose, CA,
USA). Specific rotations were measured with a JASCO DIP-181 dig-
ital polarimeter. The starting 7-hydroxychroman-4-one 2 was pre-
(4-hydroxy-3-methoxybenzyl)chroman-3,4,7-triol 9, and the
enantiomeric excess, as determined by chiral HPLC, was 63% ee.
Acid-catalyzed cyclization of 9 yielded protected brazilin 10 in
92% yield, and this was then subjected to hydrogenolysis to 30-O-
methylbrazilin in quantitative yield. Subsequent AlCl3-catalyzed
demethylation yielded (+)-brazilin 1 in 69% yield. Note that the
BBr3-catalyzed demethylation of (+)-1,3,8-O-trimethylbrazilin
afforded a complex product mixture28a and pyridine-HCl-catalyzed
processes resulted in low yields (36%) even under harsh reaction
condition (190–200 °C, 3 h),27d either stepwise or direct deprotec-
tion of (+)-10 proceeded smoothly to yield (+)-1a.
The absolute configurations of diols 8 and 30-O-methylbrazilins
9 were determined by comparing their specific rotations with that
of brazilin finally obtained from the reaction sequence described
above, which reflected the stereochemistries of 9 and 10 and liter-
ature values of (+)-brazilin.31 Accordingly, the absolute stereo-
pared from resorcinol by employing
a previously reported
method.29
chemistries at C-3 and C-4 of 9 prepared using an AD-mix-
a are
4.2. (E)-3-(4-Hydroxy-3-methoxybenzylidene)-7-hydroxychro-
man-4-one 4
(3S,4R), that is, is (3R,4S)-3-(4-hydroxy-3-methoxybenzyl)
9
chroman-3,4,7-triol and 30-O-methylbrazilin 10b is (6aS,11bR), or
more accurately, (6aS,11bR)-9-methoxy-6,6a,7,11b-tetrahydroin-
deno[2,1-c]chromene-3,6a,10-triol, as shown in Scheme 1.
The same procedure described for (+)-1a was applied to 8 using
an AD-mix-b to afford (ꢀ)-1a via (3S,4R)-3-(4-hydroxy-3-methoxy-
Method A: A mixture of 7-hydroxychroman-4-one (2, 1.64 g,
10 mmol) and the 4-hydroxy-3-methoxybenzaldehyde (3, vanillin,
1.67 g, 11 mmol) in dry EtOH (25 mL) was saturated with dry HCl
gas under cooling and then stirred at room temperature. After
O
OCH3
H
O
O
O
O
O
OH
H2
OCH3
OH
OCH3
OR
3
HCl (g)
Pd-C
EtOH
HO
HO
RO
O
EtOH (95%)
2
5 (R = H, 98%)
6 (R = Bn, 67%)
4
BnCl/K2CO3
OH
OCH3
OBn
p-TsOH
NaBH4
(88%)
AD-mix-α
(65%)
OCH3
OBn
benzene
(70%)
BnO
O
BnO
OH
O
8
7
OCH3
RO
OH
c. HCl
AlCl3
OCH3
OBn
(+)-1a
H
CH3OH
(85%)
CH2Cl2
(79%)
BnO
O
OH
RO
O
9
(+)-10a (R = Bn)
b (R = H)
H2/Pd-C
(83%)
Scheme 1. Enantioselective synthesis of (+)-brazilin.

1272
U. Javed et al. / Tetrahedron: Asymmetry 25 (2014) 1270–1274
20 h, the mixture was poured into water (100 mL), and 1 N NaOH
aq (20 mL) was added. The mixture was stirred at room tempera-
ture for 5 h, and the precipitate was filtered off, washed sufficiently
with H2O, and dried over P2O5 to give compound 4 (2.26 g, 76%).
The filtrate was chromatographed on silica gel eluting with CH2Cl2/
EtOAc (9:1) (Rf = 0.35) to give an additional product (0.57 g, 19%):
mp 248–250 °C. 1H NMR (DMSO-d6) d 10.63 (s, 1H, OH), 9.68 (s,
1H, OH), 7.73 (d, 1H, J = 7.6 Hz, H-5), 7.61 (br s, 1H, vinylic H),
7.02 (s, 1H), 6.87 (s, 2H, H50 and H60), 6.54 (1H, dd, J = 7.6, 2.2 Hz,
H-6), 6.31 (1H, d, J = 2.2 Hz, H-8), 5.39 (2H, d, J = 1.8 Hz, H-2),
3.82 (s, 3H). 13C NMR (DMDO-d6) d 180.4, 165.4, 163.3, 149.3,
148.5, 136.9, 130.2, 128.9, 126.3, 125.0, 116.5, 115.5, 115.2,
111.9, 103.3, 68.5, 56.6. MS (ESI) m/z: 300 [M+H]+. Anal. Calcd
For C17H14O5: C, 68.45; H, 4.73. Found: C, 68.71; H, 4.72.
Method B: To a mixture of 7-hydroxychroman-4-one (2, 1.64 g,
10 mmol) and 4-hydroxy-3-methoxybenzaldehyde (3, vanillin,
1.67 g, 11 mmol) in a mixture of H2O/EtOH (1:2, 25 mL) was added
KOH (300 mg). The resulting mixture refluxed for 8 h and extracted
with EtOAc (100 mL ꢁ 3). The organic layers were combined and
washed with water and dried over MgSO4. Evaporation of the
solvent afforded a solid material which was chromatographed on
silica gel eluting with CH2Cl2/EtOAc (10:1) (Rf = 0.35) to give the
product and additional product (1.71 g, 57%): mp 240–242 °C.
The spectroscopic data were identical to those obtained from
Method A.
192.6, 165.2, 163.6, 150.0, 147.2, 137.4, 136.1, 131.75, 129.37,
128.8, 128.6, 127.651, 127.614, 127.612, 127.3, 121.3, 114.8,
114.6, 113.0, 110.7, 101.9, 71.4, 70.4, 69.9, 56.2, 47.6, 32.4. Anal.
Calcd For C31H28O5: C, 77.48; H, 5.87. Found: C, 76.75; H, 5.86.
4.5. 3-(4-Benzyloxy-3-methoxybenzyl)-7-benzyloxy-3,4-dihy-
dro-2H-chromen-4-ol 7
To a solution of 6 (1.78 g, 3.7 mmol) in THF (20 mL) was added a
solution of NaBH4 (15 mg, 3.7 mmol) in ethanol (10 mL). The
resulting mixture was stirred at room temperature for 5 h. Evapo-
ration of the solvent gave a solid material (off white in color) which
was then re-dissolved in CH2Cl2 (20 mL). To the mixture was added
water (5 mL) and the CH2Cl2 layer was separated and dried over
MgSO4. A thick viscous liquid (1.57 g, 88%) was obtained, and chro-
matographed on silica gel eluting with hexane/EtOAc (7:3). cis-Iso-
mer 7a: Pale yellow oil (45%). Rf = 0.45 [hexane/EtOAc (7:3)]. 1H
NMR (CDCl3, 250 MHz) d 7.33–7.26 (m, 10 H), 7.09 (1H, d,
J = 8.5 Hz, H5), 6.84 (1H, d, J = 8.3 Hz, H50), 6.80 (1H, d, J = 1.8 Hz,
H20), 6.72 (1H, dd, J = 8.0, 1.8 Hz, H60), 6.55 (1H, dd, J = 8.5,
2.5 Hz, H6), 6.45 (1H, d, J = 2.5 Hz, H8), 5.13 (s, 2H), 5.01 (s, 2H),
4.45 (br. s, 1H, H4), 4.04 (d, 2H, J = 6.8 Hz, H2), 3.87 (s, 3H), 2.80
(1H, dd, J = 13.8, 7.5 Hz, H9A), 2.50 (1H, dd, J = 13.8, 7.5 Hz, H9B),
2.15 (1H, m, H3). 13C NMR (CDCl3) d 180.3, 155.6, 150.0, 147.0,
137.6, 137.0, 132.6, 131.1, 128.8, 128.7, 128.1, 128.0, 127.6,
127.5, 121.3, 117.4, 114.6, 113.2, 108.6, 102.5, 71.5, 70.2, 65.2,
64.7, 56.2, 40.4, 32.7. Anal. Calcd For C31H30O5: C, 77.16; H, 6.27.
Found: C, 76.99; H, 6.29. trans-Isomer 7b: Pale yellow oil (43%).
Rf = 0.31 [hexane/EtOAc (7:3)]. 1H NMR (CDCl3, 250 MHz) d 7.38–
7.28 (m, 10H), 7.18 (1H, d, J = 8.5 Hz, H5), 6.81 (1H, d, J = 8.4 Hz,
H50), 6.70 (1H, d, J = 1.8 Hz, H20), 6.63 (1H, dd, J = 7.3, 1.8 Hz, H6),
6.60 (1H, dd, J = 8.4, 1.8 Hz, H8), 6.49 (d, 1H, J = 2.5 Hz, H), 5.11
(s, 2H), 5.02 (s, 2H), 4.41 (d, 1H, J = 3.3 Hz, H4), 4.19 (d, 1H,
J = 11.1, 2.5 Hz, H2A), 3.94 (d, 1H, J = 11.1, 2.5 Hz, H2B), 3.84 (s,
3H), 2.60 (1H, dd, J = 13.8, 6.7 Hz, H9A), 2.44 (1H, dd, J = 13.8,
6.7 Hz, H9B), 2.78 (1H, m, H3). 13C NMR (CDCl3) d 180.3, 155.6,
150.0, 147.0, 137.6, 137.0, 132.6, 131.1, 128.8, 128.7, 128.1,
128.0, 127.6, 127.5, 121.3, 117.4, 114.6, 113.2, 108.6, 102.5, 71.5,
70.2, 65.2, 64.7, 56.2, 40.4, 32.7. Anal. Calcd For C31H30O5: C,
77.16; H, 6.27. Found: C, 77.42; H, 6.29.
4.3. (E)-3-(4-Hydroxy-3-methoxybenzyl)-7-hydroxychroman-4-
one 5
A mixture of 4 (2.98 g, 0.01 mol) and 5% Pd/C (100 mg) in EtOH
(60 mL) was hydrogenated under a H2 atmosphere (50 psi) for 6 h.
Filtration of the reaction mixture through CeliteÒgave an oily mate-
rial which was chromatographed on silica gel eluting with CH2Cl2/
EtOAc (10:1). The early fractions (Rf = 0.35) afforded a white pow-
der (CH3OH) (2.94 g, 98%): mp 178–179 °C. 1H NMR (DMSO-d6,
250 MHz) d 10.51 (br. s, 1H, OH), 8.72 (br. s, 1H, OH), 7.65 (1H, d,
J = 8.7 Hz, H5), 6.79 (1H, d, J = 1.5 Hz, H50), 6.68 (1H, d, J = 8.0 Hz,
H20), 6.59 (1H, dd, J = 8.0, 2.0 Hz, H60), 6.50 (1H, dd, J = 8.7,
2.0 Hz, H6), 6.30 (1H, d, J = 2.0 Hz, H8), 4.29 (1H, dd, J = 11.5,
4.6 Hz, H2A), 4.10 (1H, dd, J = 11.0, 9.0 Hz, H2B), 3.75 (s, 3H),
3.02 (dd, J = 13.7, 4.8 Hz, H9A), 2.87 (1H, m, H3), 2.50 (1H, dd,
J = 13.7, 4.8 Hz, H9B). 13C NMR (acetone-d6) d 191.5, 164.4, 163.0,
147.5, 144.9, 129.2, 128.8, 121.1, 115.3, 113.1, 112.9, 110.6,
102.2, 69.4, 55.5, 46.3, 31.4. Anal. Calcd For C17H16O5: C, 67.99;
H, 5.37. Found: C, 70.23; H, 5.35.
4.6. 3-(4-Benzyloxy-3-methoxybenzyl)-7-benzyloxy-2H-chro-
mene 8
Method A: A mixture of 7 (1.78 g, 3.7 mmol) and p-TsOH (30 mg,
0.17 mmol) in benzene (40 mL) was refluxed for 40 min. The reac-
tion mixture was cooled to room temperature and then washed
with saturated NaHCO3 (3 ꢁ 20 mL), then water (2 ꢁ 20 mL). The
organic layers were dried over MgSO4. The benzene was evapo-
rated and thick viscous liquid was obtained, which was chromato-
graphed on silica gel eluting with hexane/EtOAc (4:1) to give the
desired product [Rf = 0.39, hexane/EtOAc (4:1)] (1.2 g, 70%) as off-
white crystals: mp 129–131 °C. 1H NMR (CD3COCD3, 250 MHz) d
7.48–7.32 (m, 10H), 6.79 (d, 1H, J = 8.1 Hz, H5), 6.75 (d, 1H,
J = 8.0 Hz, H50), 6.72 (d, 1H, J = 2.1 Hz, H20), 6.57 (dd, 1H, J = 8.0,
2.1 Hz, H60), 6.33 (dd, 1H, J = 8.1, 2.6 Hz, H6), 6.22 (d, 1H,
J = 2.6 Hz, H8), 6.14 (br. s, 1H, H4), 4.54 (s, 2H, H2), 3.79 (s, 3H),
3.27 (s, 2H). 13C NMR (CD3COCD3, 62.5 MHz) d 159.5, 154.3,
150.1, 147.2, 137.5, 137.2, 131.33, 131.11, 128.752, 128.713,
128.534, 128.116, 127.990, 127.617, 127.504, 126.9, 121.2, 120.0,
116.4, 114.6, 112.9, 108.0, 102.6, 71.4, 70.3, 68.4, 56.3, 39.6. Anal.
Calcd For C31H28O4: C, 80.15; H, 6.08. Found: C, 79.98; H, 6.07.
Method B: A solution of 7 (300 mg, 0.62 mmol) in dry pyridine
(10 mL) was cooled in an ice bath, to which freshly distilled POCl3
(1.39 mL, 14.86 mmol) was added dropwise. The reaction mixture
was allowed to stir at room temperature for 24 h. To the resulting
4.4. 3-(4-Benzyloxy-3-methoxybenzyl)-7-benzyloxychroman-4-
one 6
To a stirring solution of 5 (3.00 g, 10.0 mmol) in THF (20 mL),
K2CO3 (4.00 g, 28.9 mmol), and NaI (200 mg) was slowly added
benzyl chloride (3.30 g, 27.0 mmol) and the resulting mixture
was stirred at room temperature for 2 h. Evaporation of the solvent
gave a solid material which was then re-dissolved in CH2Cl2
(80 mL) and washed with water (20 mL ꢁ 3), brine, and dried over
MgSO4. Evaporation of the solvent under reduced pressure
afforded a solid material which was chromatographed on silica
gel eluting with hexane/EtOAc (4:1, Rf = 0.36) to give 3.2 g (67%)
of the desired product as light orange needles: mp 77–79 °C. 1H
NMR (CDCl3, 250 MHz) d 7.88 (d, 1H, J = 7.5 Hz, H5), 7.42–7.29
(m, 10H), 6.83 (1H, d, J = 7.5 Hz, H40), 6.79 (1H, d, J = 2.5 Hz, H8),
6.70 (1H, dd, J = 7.5, 2.5 Hz, H5), 6.68 (1H, dd, J = 7.5, 2.5 Hz, H6),
6.49 (1H, d, J = 2.5 Hz, H20), 5.12 (s, 2H), 5.07 (s, 2H), 4.34 (dd,
1H, J = 11.3, 5.0 Hz, H2A), 4.14 (dd, 1H, J = 11.3, 7.5 Hz, H2B), 3.87
(s, 3H), 3.19 (dd, 1H, J = 13.8, 1.8 Hz, H9A), 2.87–2.76 (m, 1H,
H3), 2.50 (1H, dd, J = 13.8, 10.0 Hz, H9B), 13C NMR (CDCl3) d

U. Javed et al. / Tetrahedron: Asymmetry 25 (2014) 1270–1274
1273
red brown mixture, water was added carefully to hydrolyze the
excess POCl3. The reaction mixture was extracted with ether
(3 ꢁ 30 mL). The ethereal layers were washed with 10% HCl, water,
brine, and dried over MgSO4. The solvent was evaporated to give an
oily material which was purified as described above in Method A.
All spectroscopic data were identical to those obtained above for
Method A.
3.93 (dd, 1H, J = 11.6, 2.0 Hz, H6A), 3.77 (s, 3H), 3.70 (d, 1H,
J = 11.6 Hz, H6B), 3.06 (d, 1H, J = 16.0 Hz, H7A), 2.88 (d, 1H,
J = 16.0 Hz, H7B). 13C NMR (CD3OD, 62.5 MHz) d 159.9, 155.9,
151.2, 148.9, 138.96, 138.92, 138.3, 133.8, 132.2, 129.6, 129.5,
129.0, 128.9, 128.6, 116.9, 113.1, 110.8, 110.2, 104.2, 78.4, 72.9,
71.2, 71.1, 56.9, 51.6, 43.3. Anal. Calcd For C31H28O5: C, 77.48; H,
5.87. Found: C, 77.43; H, 5.89.
4.7. (3R,4S)-3-(4-Benzyloxy-3-methoxybenzyl)-7-benzyloxy-3,4-
dihydro-2H-chromene-3,4-diol (+)-9
4.10. (6aR,11bS)-3,10-Bis(benzyloxy)-6,6a,7,11b-tetrahydro-9-
methoxyindeno[2,1-c]chromen-6a-ol (ꢀ)-10a
To a solution of CH3CN (15 mL) and H2O (15 mL) was added
The same procedure described above for (+)-10a was applied to
(ꢀ)-9 (50 mg, 0.10 mmol) to afford (ꢀ)-10a (40 mg, 83%). White
crystalline solid: mp 130–132 °C. 1H NMR (CD3OD, 250 MHz) d
7.34–7.24 M, 10H), 7.18 (d, 1H, J = 8.5 Hz, H1), 6.88 (s, 1H, H11),
6.80 (s, 1H, H8), 6.64 (dd, 1H, J = 8.4, 2.5 Hz, H2), 6.47 (d, 1H,
J = 2.5 Hz, H5), 5.00 (s, 2H), 4.98 (s, 2H), 3.97 (br s, 1H, C6a-OH),
3.94 (dd, 1H, J = 11.6, 2.0 Hz, H6A), 3.76 (s, 3H), 3.70 (d, 1H,
J = 11.6 Hz, H6B), 3.07 (d, 1H, J = 16.0 Hz, H7A), 2.89 (d, 1H,
J = 16.0 Hz, H7B). 13C NMR (CD3OD, 62.5 MHz) d 159.9, 155.9,
151.2, 148.9, 138.96, 138.92, 138.3, 133.8, 132.2, 129.6, 129.5,
129.0, 128.9, 128.6, 116.9, 113.1, 110.8, 110.2, 104.2, 78.4, 72.9,
71.2, 71.1, 56.9, 51.6, 43.3. Anal. Calcd For C31H28O5: C, 77.48; H,
5.87. Found: C, 77.39; H, 5.89.
dropwise AD-mix-
perature, then methanesulfonamide (80 mg) was added. The
resulting mixture was cooled to 0 °C, to which (0.34 g,
a (1.85 g, 0.17 mmol) with stirring at room tem-
8
0.73 mmol) was added and then the heterogeneous slurry was stir-
red vigorously at 0 °C for 48 h. While the mixture was stirred at
0 °C, solid sodium sulfite (1.30 g) was added and the resulting
mixture was allowed to warm to room temperature and stirred
for an additional hour. The reaction mixture was extracted with
EtOAc (20 mL ꢁ 3). The organic layers were combined and washed
with water (50 mL ꢁ 3), brine, and dried over MgSO4. Evaporation
of the solvent afforded a pale yellow solid, which was chromato-
graphed on silica gel eluting with hexanes/EtOAc (7:3) to afford
(+)-9 as pale yellow needles (0.55 g, 65%, Rf = 0.14 (hexane/
EtOAc = 7:3)], [
a]
25 = +75.7 (c 0.038, CHCl3), ee 63%. 1H NMR
4.11. (+)-9-Methoxybrazilin [30-O-methoxylbrazilin, (6aS,11bR)-
9-methoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]-chromene-3,6a,
10-triol, (+)-10b]
D
(CD3CN, 250 MHz) d 7.46–7.34 (m, 10H), 7.22 (d, 1H, J = 8.8 Hz,
H20), 6.90 (d, 1H, J = 8.0 Hz, H50), 6.79 (d, 1H, J = 1.9 Hz, H60), 6.68
(dd, 1H, J = 8.1, 2.0 Hz, H6), 6.62 (dd, 1H, J = 8.5, 2.5 Hz, H8), 6.45
(d, 1H, J = 2.4 Hz, H8), 5.07 (s, 2H), 5.06 (s, 2H), 4.25 (d, 1H,
J = 3.9 Hz, H4), 3.86 (d, 1H, J = 10.8 Hz, H2A), 3.78 (s, 3H), 3.70 (d,
1H, J = 10.8 Hz, H2B), 2.69 (AB quartet, 2H, H9). 13C NMR
(62.5 MHz, CD3OD) d 161.3, 156.1, 150.6, 148.3, 139.1, 138.8,
133.0, 131.1, 129.94, 129.88, 129.3, 129.1, 124.2, 118.7, 116.4,
115.1, 109.9, 103.2, 97.0, 72.1, 71.1, 70.8, 69.7, 68.9, 56.9, 41.4.
Anal. Calcd For C31H30O6: C, 74.68; H, 6.07. Found: C, 74.39; H, 6.09.
To a solution of (+)-10a (10 mg, 0.021 mmol) in EtOAc (1 mL)
and EtOH (2 mL) was added Pd/C (1 mg) under nitrogen. The nitro-
gen line was replaced by a hydrogen balloon and the reaction mix-
ture was stirred for 48 h. Filtration through Celite and evaporation
of the solvent gave the debenzylated product (+)-10b (5 mg, 83%).
Spectroscopic data were identical to those reported previously.12,32
4.12. (ꢀ)-9-Methoxybrazilin [30-O-methoxylbrazilin, (6aR,11bS)-
9-methoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]-chromene-3,6a,
10-triol, (ꢀ)-10b)
4.8. (3S,4R)-3-(4-Benzyloxy-3-methoxybenzyl)-7-benzyloxy-3,4-
dihydro-2H-chromene-3,4-diol (ꢀ)-9
The same procedure as described above for (+)-9 was employed
for 8 using AD-mix-b and afforded (ꢀ)-9 (64%). White powder:
To a solution of (ꢀ)-10a (30 mg, 0.06 mmol) in EtOAc (3 mL)
and EtOH (6 mL) was added Pd/C (1 mg) under nitrogen. The nitro-
gen line was replaced by a hydrogen balloon and the reaction mix-
ture was stirred for 48 h. Filtration through Celite and evaporation
of the solvent gave the debenzylated product (ꢀ)-10b (16 mg,
85%). 1H NMR (CD3OD, 250 MHz) d 7.23 (d, 1H, J = 8.4 Hz, H1),
6.87 (s, 1H, H11), 6.80 (s, 1H, H8), 6.64 (dd, 1H, J = 8.4, 2.5 Hz,
H2), 6.48 (d, 1H, J = 2.5 Hz, H5), 5.00 (s, 2H), 4.98 (s, 2H), 3.98 (br
s, 1H, C6a-OH), 3.94 (dd, 1H, J = 11.8, 2.0 Hz, H6A), 3.78 (s, 3H),
3.69 (d, 1H, J = 11.8 Hz, H6B), 3.06 (d, 1H, J = 16.0 Hz, H7A), 2.87
(d, 1H, J = 16.0 Hz, H7B). 13C NMR (CD3OD, 62.5 MHz) d 158.7,
156.2, 148.7, 147.0, 139.0, 132.4, 132.1, 116.5, 112.7, 110.0,
109.9, 78.7, 71.6, 56.9, 52.0, 43.6. MS (ESI) for C16H15O5 [M+H]+
301.
mp 129–131 °C, [
a
]
D
25 = ꢀ92.7 (c 0.038, CHCl3), ee 67%. 1H NMR
(CD3CN, 250 MHz) d 7.45–7.34 (m, 10H), 7.22 (d, 1H, J = 8.8 Hz,
H20), 6.90 (d, 1H, J = 8.0 Hz, H50), 6.79 (d, 1H, J = 1.9 Hz, H60), 6.68
(dd, 1H, J = 8.1, 2.0 Hz, H6), 6.62 (dd, 1H, J = 8.5, 2.5 Hz, H8), 6.45
(d, 1H, J = 2.4 Hz, H8), 5.07 (s, 2H), 5.06 (s, 2H), 4.25 (d, 1H,
J = 3.9 Hz, H4), 3.86 (d, 1H, J = 10.8 Hz, H2A), 3.78 (s, 3H), 3.70 (d,
1H, J = 10.8 Hz, H2B), 2.69 (AB quartet, 2H, H9). 13C NMR
(62.5 MHz, CD3CN) d 161.1, 155.9, 150.3, 148.2, 138.9, 138.6,
132.8, 130.8, 129.84, 129.79, 129.2, 129.0, 124.0, 117.8, 116.1,
114.7, 109.7, 103.0, 96.7, 71.8, 71.0, 70.6, 69.5, 68.7, 56.7, 41.2.
Anal. Calcd For C31H30O6: C, 74.68; H, 6.07. Found: C, 74.42; H, 6.09.
4.9. (6aS,11bR)-3,10-Bis(benzyloxy)-6,6a,7,11b-tetrahydro-9-meth-
oxyindeno[2,1-c]chromen-6a-ol (+)-10a
4.13. (+)-Brazilin [(6aS,11bR)-3,6a,9,10-tetrahydroxy-6a,11b-dihy-
dro-7H-indeno[2,1-c]chromene, (+)-1a]
To a solution of (+)-9 (30 mg, 0.06 mmol) in methanol (10 mL)
was added 5 drops of concd HCl. The reaction mixture was refluxed
for 2 h. Evaporation of the solvent lead to a thick liquid which was
chromatographed on silica gel eluting with CH2Cl2/EtOAc (9:1).
The early fractions afforded (+)-10 (25 mg, 85%), as a white crystal-
line solid: mp 130–132 °C. 1H NMR (CD3OD, 250 MHz) d 7.36–
7.23 M, 10H), 7.18 (d, 1H, J = 8.5 Hz, H1), 6.88 (s, 1H, H11), 6.80
(s, 1H, H8), 6.63 (dd, 1H, J = 8.5, 2.5 Hz, H2), 6.47 (d, 1H,
J = 2.5 Hz, H5), 4.99 (s, 2H), 4.98 (s, 2H), 4.00 (br s, 1H, C6a-OH),
A solution of (+)-10b (300 mg, 1 mmol) and AlCl3 (500 mg) in
CH2Cl2 (30 mL) was stirred for 2 h and poured into ice-cold dilute
HCl to form a solid material which was chromatographed on silica
gel eluting with CHCl3/CH3OH (9:1). The early fractions (Rf = 0.3)
afforded (+)-1 as a yellow powder (225 mg, 79%): mp 248–250 °C
(lit.25mp 249–250 °C) [ 25 = +125.6 (c 0.61, CH3OH). 1H NMR (ace-
a]
D
tone-d6, 250 MHz) d 7.35 (d, 1H, J = 8.3 Hz, H1), 6.92 (s, 1H, H8),
6.80 (s, 1H, H11), 6.66 (dd, 1H, J = 8.3, 2.5 Hz, H2), 6.45 (d, 1H,

1274
U. Javed et al. / Tetrahedron: Asymmetry 25 (2014) 1270–1274
J = 2.5 Hz, H4), 4.12 (s, 1H, H12), 4.10 (d, 1H, 2J = 11.0 Hz, H6A),
3.87 (d, 1H, 2J = 11.0 Hz, H6B), 3.18 (d, 1H, 2J = 15.8 Hz, H7A),
2.98 (d, 1H, 2J = 15.8 Hz, H7B). 13C NMR (acetone-d6, 62.5 MHz) d
157.9, 155.8, 145.4, 145.1, 137.6, 132.3, 131.7, 115.8, 113.0,
112.6, 110.0, 104.3, 78.2, 70.9, 51.4, 43.2. MS (ESI) for C16H15O5
[M+H]+ 287.
9. Gupta, M. P.; Gupta, N. P. Curr. Sci. 1968, 37, 250 [Chem. Abstr. 1968, 69,
39531y].
10. Horeau, A. Stereochemistry In Determination of Configurations by Chemical
Methods; Kagan, H. B., Ed.; Georg Thieme Publishers: Stuttgart, 1977; Vol. 3, pp
51–94.
11. Chevreul, M. Ann. Chim. Phys., [ii] 1810, 82, 53.
12. Namikashi, M.; Nakata, H.; Yamada, H.; Nagai, M.; Saitoh, T. Chem. Pharm. Bull.
1987, 35, 2761.
13. Schall, C.; Dralle, G. Ber. 1888, 21, 3009.
14. Gilbody, A. W.; Perkin, W. H., Jr.; Yates, J. J. Chem. Soc., Trans. 1901, 79, 1396.
15. Hickson, S. J. Q. J. Microscopy. Sci. 1901, 469.
16. Moon, C.-K.; Park, K. S.; Kim, S. G.; Won, H. S.; Chung, J. H. Drug Chem. Toxicol.
1992, 15, 81.
4.14. (ꢀ)-Brazilin [(6aR,11bS)-3,6a,9,10-tetrahydroxy-6a,11b-dihy-
dro-7H-indeno[2,1-c]chromene, (ꢀ)-1a]
17. Choi, S. Y.; Yang, K. M.; Jeon, S. D.; Kim, J. H.; Khil, L. Y.; Chang, T. S.; Moon, C.-K.
Planta Med. 1997, 63, 405.
18. Kim, Y. M.; Kim, S. G.; Khil, L. Y.; Moon, C. K. Planta Med. 1995, 61, 297.
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Res. 2000, 23, 344.
20. Hikino, H.; Taguchi, T.; Fujimura, H.; Hiramatsu, Y. Planta Med. 1977, 31, 214.
21. Batubara, I.; Mitsunaga, T.; Ohashi, H. J. Wood Sci. 2010, 56, 77.
22. Moon, C. K.; Yun, Y. P.; Lee, J. H.; Wager, H.; Shin, Y. H. Planta Med. 1985, 47, 66.
23. Bae, I.-K.; Min, H.-Y.; Han, A.-R.; Seo, E.-K.; Lee, S. K. Eur. J. Pharmacol. 2005, 513,
237.
The same procedure described above for (+)-brazilin was
applied to (ꢀ)-10a (240 mg, 0.5 mmol) with AlCl3 (300 mg) to yield
(ꢀ)-brazilin (134 mg, 89%). [
a]
25 = ꢀ94.0 (c 1.45, CH3OH). 1H NMR
D
(acetone-d6, 250 MHz) d 7.36 (d, 1H, J = 8.3 Hz, H1), 6.93 (s, 1H,
H8), 6.80 (s, 1H, H11), 6.67 (dd, 1H, J = 8.3, 2.5 Hz, H2), 6.46 (d,
1H, J = 2.5 Hz, H4), 4.13 (s, 1H, H12), 4.09 (d, 1H, 2J = 11.0 Hz,
H6A), 3.87 (d, 1H, 2J = 11.0 Hz, H6B), 3.19 (d, 1H, 2J = 15.8 Hz,
H7A), 2.97 (d, 1H, 2J = 15.8 Hz, H7B). 13C NMR (acetone-d6,
62.5 MHz) d 157.8, 155.8, 145.6, 145.3, 137.3, 132.4, 131.5, 115.6,
113.1, 112.7, 109.9, 104.4, 78.5, 71.1, 51.6, 43.6. MS (ESI) for
24. Xu, H.-X.; Lee, S. F. Phytother. Res. 2004, 18, 647.
25. Kitdamrongtham, W.; Manosroi, A.; Akazawa, H.; Gidado, A.; Stienrut, P.;
Manosroi, W.; Lohcharoenkal, W.; Akihisa, T.; Manosroi, J. J. Ethnopharmacol.
2013, 149, 288.
26. Mar, W.; Lee, H.-T.; Je, K.-H.; Choi, H.-Y.; Seo, E.-K. Arch. Pharm. Res. 2003, 26,
147.
C
16H15O5 [M+H]+ 287.
27. (a) Pfeiffer, P.; Oberlin, H.; Konermann, E. Ber. 1947, 1925, 58; (b) Gregory, R. A.;
Tomlinson, M. L. J. Chem. Soc. 1956, 795; (c) Morsingh, F.; Robinson, R.
Tetrahedron 1970, 26, 281; (d) Huang, Y.; Zhang, J.; Pettus, R. R. Org. Lett. 2005,
7, 5841; (e) Yen, C.-T.; Nakagawa-Goto, K.; Hwang, T.-L.; Wu, P.-C.;
Morris-Natscheke, S. L.; Lai, W.-C.; Bastow, K. F.; Chang, F.-R.; Wu, Y.-C.; Lee,
K.-H. Bioorg. Med. Chem. Lett. 2010, 20, 1037; (f) Li, L.-Q.; Li, M.-M.; Wang, K.;
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Acknowledgements
Financial support from Yeungnam University, Korea is
gratefully acknowledged.
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