The first stereoselective total synthesis of a naturally occurring bioactive diarylheptanoid, (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-en-3-ol, through two different approaches

Article abstract of DOI:10.1002/hlca.201200084

The stereoselective total synthesis of a naturally occurring bioactive diarylheptanoid, (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-en-3-ol, has been accomplished starting from 4-hydroxybenzaldehyde through two different approaches involving Wittig olefination

Full text of DOI:10.1002/hlca.201200084

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Helvetica Chimica Acta – Vol. 95 (2012)
The First Stereoselective Total Synthesis of a Naturally Occurring Bioactive
Diarylheptanoid, (3R,6E)-1,7-Bis(4-hydroxyphenyl)hept-6-en-3-ol, through
Two Different Approaches1)
by Jajula Kashanna, Paramesh Jangili, Rathod Aravind Kumar, and Biswanath Das*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
The stereoselective total synthesis of a naturally occurring bioactive diarylheptanoid, (3R,6E)-1,7-
bis(4-hydroxyphenyl)hept-6-en-3-ol, has been accomplished starting from 4-hydroxybenzaldehyde
through two different approaches involving Wittig olefination, hydrolytic kinetic resolution of a racemic
epoxide, and olefin cross-metathesis reaction as the key steps.
Introduction. – Diarylheptanoids exhibit various important biological activities
including anticancer, anti-HIV, anti-inflammatory, and antioxidant properties [1]. A
large number of these compounds with different functionalities have been isolated
from natural sources [2]. Recently, a new diarylheptanoid, (3R,6E)-1,7-bis(4-hydroxy-
phenyl)hept-6-ene-3-ol (1) and its enantiomer have been isolated in very small
quantities from the rhizomes of Curcuma kwangrsiensis (Zingiberaceae) [3]. The
compound was evaluated for its inhibitory effect on NO production induced by
lipopolysaccharide-activated macrophages. The activity of the compound was found to
be close to that of indomethacin [3]. The total synthesis of the compound has not yet
been reported. In continuation of our work [4] on the construction of bioactive natural
products, we have accomplished the stereoselective total synthesis of 1, which we report
here.
Results and Discussion. – The retrosynthetic analysis (Scheme 1) revealed that 1
can be synthesized from the alkenes 2 and 3. The first one, 2, can be prepared from the
epoxide 4, which in turn can be synthesized from the aldehyde 5 generated from 4-
hydroxybenzaldehyde (6). The diarylheptanoid 1 can also be synthesized (Scheme 2)
from the aldehyde 7 and the phosphonium ylide 8. The aldehyde 7 can be prepared
from the triol 9, which can again be produced from the olefinic alcohol 2 obtained from
6.
1
)
Part 62 in the series, ꢂSynthetic Studies on Natural Productsꢃ.
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1. First Retrosynthetic Analysis of 1
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Scheme 2. Second Retrosynthetic Analysis of 1
The present synthesis of 1 was initiated (Scheme 3) by converting 4-hydroxybenz-
aldehyde (6) to its benzyl ether, which was subjected to Wittig olefination with
PPh3CHCOOEt and subsequent reduction with NaBH4/NiCl2 · 6 H2O, followed by
adding LiAlH4 to produce the alcohol 10 [5]. The latter was oxidized with PCC to yield
the corresponding aldehyde 5, which again underwent Wittig olefination with PPh3CH2
to furnish the olefin 11 [6]. Treatment of 11 with m-CPBA afforded the epoxide 12 [6],
which, on hydrolytic kinetic resolution [7] with (S,S)-Jacobsenꢃs catalyst (A),
generated the (S)-configured epoxide 4. The latter was then treated with allylmagne-
sium bromide in the presence of CuI to give the olefinic alcohol 2. Eventually, the cross-
coupling metathesis reaction [8] of 2 with 4-ethenylphenol (3) using Grubbsꢃ second-
generation catalyst, B, resulted in the formation of the heptanoid 13. Finally,
deprotection of the benzyl ether of 13 with TiCl4 gave the target molecule 1.
In a second approach, the chiral olefinic alcohol 2 was treated with OsO4 and 4-
methylmorpholine N-oxide (NMO) in aqueous acetone, and the resulting triol 9 was
treated with NaIO4 to form the aldehyde 7 (Scheme 4). The latter was directly
subjected to Wittig olefination with the phosphonium ylide 8 to produce 13 as the major
product along with its (Z)-isomer (isomeric ratio 8 :2). The product 13 was separated,
and subsequently its benzyl ether group was deprotected with TiCl4 to afford

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Scheme 3
a) Pyridinium chlorochromate (PCC), Celite, CH2Cl2, 08 to r.t, 2 h; 81%. b) BuLi, THF, Ph3P¼CH2,
ꢀ 788 to r.t, 4 h; 76%. c) meta-Chloroperbenzoic acid (m-CPBA), CH2Cl2, NaHCO3, 08 to r.t, 3 h; 86%.
d) ((S,S)-Salen)Co(OAc) (A), dist. H2O, THF, 08, 24 h; 45%. e) C3H3MgBr, CuI, THF, ꢀ 788, 4 h; 81%.
f) Grubbsꢃ second generation catalyst (B), CH2Cl2, 508, 4 h; 68%. g) TiCl4, CH2Cl2, 08, 3 h; 72%.
compound 1. The optical rotation and spectroscopic data of the latter were found to be
identical to those of the naturally occurring (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-
en-3-ol.
Conclusions. – In conclusion, we have developed the first stereoselective total
synthesis of the natural bioactive heptanoid, (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-
en-3-ol starting from commercially available 4-hydroxybenzaldehyde through two
different approaches, employing hydrolytic kinetic resolution of a racemic epoxide,
Wittig olefination, and olefin cross metathesis reaction as the key steps. Both of the

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Scheme 4
a) OsO4, NMO, aq. acetone, r.t, 4 h. b) NaIO4, NaHCO3, CH2Cl2, r.t, 2 h. c) BuLi, THF, ꢀ 788, 4 h, 67%.
d) TiCl4, CH2Cl2, 08, 3 h; 72%.
synthetic methods are simple and can be utilized for the generation of various analogs
of 1.
Experimental Part
General. Silica-gel F254 plates were used for TLC; the spots were examined under UV light and then
developed by an I2 vapor. Column chromatography (CC) was performed with silica gel (SiO2; BDH
100 – 200 mesh). Solvents were purified according to standard procedures. Org. extracts were dried over
anh. Na2SO4. Optical rotations: JASCO DIP 300 digital polarimeter, at 258. IR Spectra: Perkin-Elmer
RX FT-IR spectrophotometer. NMR Spectra: Varian Gemini 200- (1H) and 50-MHz (13C) spectrometer.
ESI-MS: VG-Autospec micromass.
1-(Benzyloxy)-4-(but-3-en-1-yl)benzene (11) [6]. To a stirred suspension of Celite (10.0 g) in dry
CH2Cl2 (30 ml), a soln. of 3-[4-(benzyloxy)phenyl]propan-1-ol (10; 12.5 g, 51.6 mmol) in dry CH2Cl2
(10 ml) at r.t. was added, followed by careful addition of PCC (22.1 g, 103.3 mmol). The mixture was
allowed to stir slowly at r.t. After stirring for 1 h, the mixture was filtered through sintered funnel with
CH2Cl2 (2 ꢁ 30 ml) The combined org. extracts were washed with brine, dried, and concentrated under
reduced pressure. The residue was purified by CC (hexane/AcOEt) to afford 3-[4-(benzyloxy)phenyl-
propanal (5; 10.41 g, 81%) as a colorless liquid.
To a stirred soln. of methylidene(triphenyl)phospine (50.05 g, 125.0 mmol) in dry THF (30 ml)
under N2 at ꢀ 788, BuLi (41.6 ml in 2.5m hexane) was added dropwise, and the mixture was stirred at that
temp. for a few min until the yellow color appeared. Then, 5 (10.0 g, 41.66 mmol) in THF (20 ml) was
added dropwise, and the mixture was stirred at that temp. for 3 h. The reaction was quenched with sat.
NH4Cl soln. (20 ml) at 08, and the mixture was extracted with AcOEt (2 ꢁ 50 ml). The combined org.
extracts were washed with brine, dried, and concentrated under reduced pressure. The residue was
purified by CC (hexane/AcOEt) to afford 11 (7.53 g, 76%). Pale yellow liquid. IR (neat): 2925, 2855,
1460, 1376, 1250. 1H-NMR (200 MHz, CDCl3): 7.20 – 7.11 (m, 5 H); 7.02 (d, J ¼ 8.0, 2 H); 6.82 (d, J ¼ 8.0,
2 H); 5.90 – 5.71 (m, 1 H); 5.02 – 4.95 (m, 2 H); 4.99 (s, 2 H); 2.62 (t, J ¼ 7.0, 2 H); 2.39 – 2.22 (m, 2 H).
13C-NMR (50 MHz, CDCl3): 157.8; 139.1; 138.6; 134.9; 130.0; 129.1; 127.5; 126.9; 115.2; 115.0; 70.0; 32.5;
31.4. ESI-MS: 239 ([M þ H]þ). Anal. calc. for C17H18O (238.32): C 85.67, H 7.61; found: C 85.77, H 7.63.
2-{2-[4-(Benzyloxy)phenyl]ethyl}oxirane (12) [6]. To a stirred soln. of 11 (7.0 g, 29.4 mmol) in dry
CH2Cl2 (10 ml) under N2 at 08 was added m-CPBA (6.07 g, 35.2 mmol) dissolved in dry CH2Cl2 (10 ml).
The mixture was stirred for 2 h. The reaction was quenched with sat. aq. NaHCO3 (6 ml), and the mixture

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was stirred further for 1 h and then extracted with CH2Cl2 (2 ꢁ 30 ml). The combined org. layers were
dried and concentrated in vacuo. The residue on purification by CC (hexane/AcOEt) afforded pure 12
(6.91 g, 86%). Pale yellow liquid.
(2S)-2-{2-[4-(Benzyloxy)phenyl]ethyl}oxirane (4). A soln. of 12 (6.0 g, 23.1 mmol) and ((S,S)-
Salen)Co(OAc) (A; 0.076 g, 0.12 mmol) in THF (30 ml) was stirred at 08 for 5 min, and then dist. H2O
(229 ml, 12.7 mmol) was added. After stirring for 24 h, this mixture was concentrated and purified by CC
(hexane/AcOEt) to afford 4 (2.3 g, 45%). Yellow liquid. [a]2D5 ¼ ꢀ4.6 (c ¼ 1.0, CHCl3). IR (neat): 3454,
2926, 2854, 1730, 1253. 1H-NMR (200 MHz, CDCl3): 7.42 – 7.12 (m, 5 H); 7.08 (d, J ¼ 8.0, 2 H); 6.82 (d,
J ¼ 8.0, 2 H); 5.02 (s, 2 H); 2.95 – 2.86 (m, 1 H); 2.80 – 2.60 (m, 2 H); 2.41 – 2.32 (m, 1 H); 2.29 – 2.20 (m,
1 H); 1.84 – 1.72 (m, 1 H); 1.60 – 1.56 (m, 1 H). 13C-NMR (50 MHz, CDCl3): 155.4; 137.5; 134.1; 129.8;
129.2; 127.6; 126.9; 115.2; 70.2; 51.3; 46.1; 34.8; 29.9. ESI-MS: 255 ([M þ H]þ). Anal. calc. for C17H18O2
(254.32): C 80.28, H 7.13; found: C 80.39, H 7.11.
(3R)-1-[4-(Benzyloxy)phenyl]hept-6-en-3-ol (2). A round-bottomed flask was charged with CuI
(0.28 g, 1.4 mmol), gently heated under vacuum, and then slowly cooled under a flow of N2. THF (10 ml)
was then added, and the resulting suspension was cooled to ꢀ 788, stirred, and allylmagnesium bromide
(9.4 ml in 1m THF) was added. A soln. of 4 (2.0 g, 7.8 mmol) in THF (10 ml) was added to the above
reagent, and the mixture was stirred at ꢀ 788 for 4 h. After consumption of starting material, the reaction
was quenched with sat. aq. NH4Cl. The H2O layer was extracted with AcOEt (50 ml), and the combined
org. layers were washed with brine, dried, and concentrated in vacuo. The residue on purification by CC
(hexane/AcOEt) afforded 2 (1.88 g, 81%). Yellow liquid. [a]2D5 ¼ þ10.3 (c ¼ 1.0, CHCl3). IR (neat): 3451,
2925, 2855, 1637, 1459. 1H-NMR (200 MHz, CDCl3): 7.41 – 7.20 (m, 5 H); 7.04 (d, J ¼ 8.0, 2 H); 6.82 (d,
J ¼ 8.0, 2 H); 5.93 – 5.78 (m, 1 H); 5.38 – 4.93 (m, 1 H); 5.00 (s, 2 H); 3.69 – 3.56 (m, 1 H); 2.75 – 2.52 (m,
2 H); 2.20 – 2.05 (m, 2 H); 1.80 – 1.61 (m, 4 H). 13C-NMR (50 MHz, CDCl3): 156.8; 138.7; 137.5; 134.8;
129.6; 128.5; 127.0; 126.6; 115.0; 114.8; 70.4; 69.8; 39.8; 36.2; 30.8; 30.1. ESI-MS: 297 ([M þ H]þ). Anal.
calc. for C20H24O2 (296.40): C 81.04, H 8.16; found: C 81.16, H 8.09.
4-{(1E,5R)-7-[4-(Benzyloxy)phenyl]-5-hydroxyhept-1-en-1-yl}phenol (13). A soln. of 2 (0.5 g,
1.68 mmol) and 3 (0.506 g, 4.22 mmol) in dry CH2Cl2 (50 ml) was first bubbled with N2 flow, after
which Grubbsꢃ second-generation catalyst (0.045 g, 0.054 mmol) was added at once, and the resulting
mixture was heated under N2 at 508 for 4 h. After cooling, the solvent was evaporated in vacuo. The
residue on purification by CC (hexane/AcOEt) afforded 13 (0.348 g, 68%). Yellow liquid. [a]2D5 ¼ þ2.9
(c ¼ 1.0, CHCl3). IR (near): 3427, 2926, 2856, 1250. 1H-NMR (200 MHz, CDCl3): 7.39 – 7.21 (m, 5 H); 7.20
(d, J ¼ 8.0, 2 H); 7.01 (d, J ¼ 8.0, 2 H); 6.82 (d, J ¼ 8.0, 2 H); 6.68 (d, J ¼ 8.0, 2 H); 6.56 (d, J ¼ 16.0,
1 H); 5.81 – 5.69 (m, 1 H); 4.99 (s, 2 H); 3.68 – 3.51 (m, 1 H); 2.58 (t, J ¼ 7.0, 2 H); 2.30 – 2.02 (m, 4 H);
1.78 – 1.58 (m, 2 H); 1.48 – 1.30 (m, 2 H). ESI-MS: 389 ([M þ H]þ). Anal. calc. for C26H28O3 (388.50): C
80.38, H 7.26; found: C 80.47, H 7.18.
4,4’-[(1E,5R)-5-Hydroxyhept-1-ene-1,7-diyl]diphenol (1). To a soln. of 13 (0.30 g, mmol) in dry
CH2Cl2 (5 ml) was added a soln. of TiCl4 (0.16 ml, 2.64 mmol) in dry CH2Cl2 (5 ml) under N2 at 08. The
reaction was monitored by TLC, until the starting material was consumed. H2O was added, and the
mixture was extracted with CH2Cl2. The combined org. extract was washed with brine and dried. The
solvent was removed under reduced pressure, and the crude mass was purified by CC (silica gel; hexane/
AcOEt) to afford pure 1 (0.22 g, 74%). Yellow liquid. [a]2D5 ¼ þ15.5 (c ¼ 3.0, CHCl3). IR (neat): 3423,
1608, 1510, 1453, 1233. 1H-NMR (200 MHz, CDCl3): 7.22 (d, J ¼ 8.0, 2 H); 7.02 (d, J ¼ 8.0, 2 H); 6.81 (d,
J ¼ 8.0, 2 H); 6.68 (d, J ¼ 8.0, 2 H); 6.58 (d, J ¼ 16.0, 1 H; 5.83 – 5.65 (m, 1 H); 3.64 – 3.53 (m, 1 H); 2.81 –
2.77 (m, 1 H); 2.65 – 2.45 (m, 1 H); 2.22 – 2.01 (m, 2 H); 1.79 – 1.61 (m, 2 H); 1.59 – 1.48 (m, 2 H).
13C-NMR (50 MHz, CDCl3): 159.2; 156.7; 135.8; 134.6; 129.5; 128.8; 127.5; 126.4; 114.9; 114.1; 70.0; 39.6;
39.3; 30.8; 30.2. ESI-MS: 299 ([M þ H]þ). Anal. calc. for C19H22O3 (298.38): C 76.48, H 7.43; found: C
76.58, H 7.34.
(5S)-7-[4-(Benzyloxy)phenyl]heptane-1,2,5-triol (9). To stirred soln. of 2 (1.0 g, 3.37 mmol) in aq.
acetone (10 ml) was added NMO (1.2 g, 10.13 mmol), followed by OsO4 (2.5 weight-% in iBuOH). The
mixture was stirred for 3 h. After completion of reaction, the reaction was quenched with sat. NaHSO3
(5 ml), and the mixture was stirred for 30 min and then extracted with AcOEt (3 ꢁ 20 ml). The combined
org. layers were washed with brine, dried, and concentrated in vacuo. The residue, 9, was directly used for
the next step.

Helvetica Chimica Acta – Vol. 95 (2012)
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(4S)-6-[4-(Benzyloxy)phenyl]-4-hydroxyhexanal (7). To a stirred soln. of 9 (0.9 g, 2.72 mmol) in dry
CH2Cl2 (10 ml) at 08, aq. NaHCO3 (5 ml) was added, followed by careful addition of NaIO4 (1.1 g,
5.45 mmol). The mixture was allowed slowly to warm to r.t. After stirring for 2 h, Na2SO4 (1.0 g) was
added, and the mixture was stirred vigorously for 30 min. The mixture was filtered through a sintered
funnel with CH2Cl2 (2 ꢁ 30 ml). The combined org. extracts were washed with brine, dried, and
concentrated under reduced pressure. The residue was purified by CC (hexane/AcOEt) to afford 7 as
Yellow liquid.
To a stirred soln. of [(4-hydroxyphenyl)methylidene]triphenylphosphine (8; 2.9 g, 6.03 mmol) in dry
THF (10 ml) under N2 at ꢀ 788 BuLi (2.0 ml in 2.5m hexane) was added dropwise and the mixture was
stirred at ꢀ 788 for few min, until a yellow color appeared. Then, 7 was added dropwise, and the mixture
was stirred at ꢀ 788 for 4 h. The reaction was quenched with sat. NH4Cl soln. (10 ml) at 08, and the
mixture was extracted with AcOEt (2 ꢁ 50 ml). The combined org. extracts were washed with brine,
dried, and concentrated under reduced pressure. The residue was purified by CC(hexane/AcOEt) to
afford 13 (0.673 g, 67%). Yellow liquid.
Compound 13 was deprotected as reported earlier to obtain 1. [a]2D5 ¼ þ15.5 (c ¼ 3.0, CHCl3). The
optical and spectral properties of the compounds 1 were identical to those of the naturally occurring
bioactive diarylheptanoid, 4,4’-[(1E,5R)-5-hydroxyhept-1-ene-1,7-diyl]diphenol [7].
The authors thank CSIR and UGC, New Delhi for financial support.
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Reveived February 22, 2012