An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol via Asymmetric Aldol Reaction

Article abstract of DOI:10.1002/hlca.201500189

An efficient stereoselective total synthesis of (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) is reported based on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight steps from commercially available trans-cinnamaldehyde.

Full text of DOI:10.1002/hlca.201500189

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Helv. Chim. Acta 2016, 99, 70 – 72
FULL PAPER
An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R)-1-(4-Hydroxyphenyl)-7-
phenylheptane-3,5-diol via Asymmetric Aldol Reaction
by Perla Ramesh*, Atla Raju, and Nitin W. Fadnavis
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India
(phone: þ 91-40-27191631; fax: þ 91-40-27160512; e-mail: perlaramesh@yahoo.co.in)
An efficient stereoselective total synthesis of (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) is reported based
on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight
steps from commercially available trans-cinnamaldehyde.
Introduction. – Diarylheptanoids are an important class
of biologically active natural products. They have been
shown to display promising biological activities including
antioxidant, anticancer, and anti-inflammatory activities
[1 – 7]. One such diarylheptanoid is (3R,5R)-1-(4-hy-
droxyphenyl)-7-phenylheptane-3,5-diol (1, Fig. 1), isolated
from Alpinia officinarum (Zingiberaceae), which exhibits
anti-emetic activity [8 – 10]. Recently, Reddy et al. reported
the first total synthesis of 1 using Sharpless kinetic
resolution and an asymmetric epoxidation as the key steps
from commercially available 4-hydroxybenzaldehyde [11].
This synthetic method suffers from a large number of
synthetic steps and a low overall yield. We herein report the
total synthesis of 1 through Mukaiyama aldol reaction in
simple eight steps with 30% overall yield.
Scheme 1. Retrosynthetic Analysis of Compound 1
Me4NBH(AcO)3 to give the desired anti-diol 5 exclusively,
isolated in 80% yield (syn/anti 1:19) [15][16]. The diol
was protected as acetonide using 2,2-dimethoxypropane
(DMP) and a catalytic amount of PPTS. The relative
configuration of acetonide anti-6 was confirmed by
13C-NMR according to Rychnovskyꢀs method [17][18]. In
the 13C-NMR spectrum of 6, the C-atoms of the acetonide
Fig. 1. Structure of the diarylheptanoid 1
Results and Discussion. – The retrosynthetic plan of the Me groups were observed at 24.6 and 25.2 ppm and that of
target molecule 1 is illustrated in Scheme 1. Compound 1 the quaternary C-atom at 100.6 ppm, confirming the
could be obtained by Grignard reaction and acetonide presence of the anti-acetonide 6 [13] (Fig. 2).
deprotection followed by Pd/C reduction of primary
Then, the protected anti-diol ester 6 was reduced to the
alcohol 7. The latter could be derived from 4 by a successive corresponding primary alcohol by treatment with LiAlH4
implementation of diastereoselective reduction and aceto- in dry THF at 08 for 30 min. The primary OH group of 7
nide protection. d-Hydroxy-b-keto ester 4 can be easily was reacted with TsCl in the presence of Et3N and DMAP
prepared via asymmetric Mukaiyama aldol reaction be- (cat.) in CH2Cl2 to obtain crude compound 8, which was
tween Chanꢀs diene 3 and trans-cinnamaldehyde 2.
To begin the synthesis, the commercially available
trans-cinnamaldehyde 2 was subjected to the stereoselec-
tive Mukaiyama aldol reaction with Chanꢀs diene 3 in the
presence of catalytic amounts of Ti(iPrO)4/(S)-BINOL
complex (2 mol-%) to furnish aldol product 4 [12][13] in
94% yield with > 97% ee as determined by chiral HPLC
[14]. anti-Selective reduction of 4 was performed with
Fig. 2. Key 13C-NMR data of compound 6
DOI: 10.1002/hlca.201500189
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Helv. Chim. Acta 2016, 99, 70 – 72
Scheme 2. Synthesis of Compound 1
71
used in the next step without further purification. The
crude 8 was subjected to the coupling reaction with the
Grignard reagent 4-(benzyloxy)phenylmagnesium bro-
mide to afford the desired product 9 [11] in 84% yield
[19]. Finally the target molecule 1 was obtained from 9 by
acetonide deprotection using TsOH in MeOH, followed by
hydrogenation over Pd/C in 69% yield [11] (Scheme 2).
The spectroscopic data of synthetic compound 1 were in
agreement with those reported for the natural one [11].
In conclusion, an efficient stereoselective total syn-
thesis of (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-
3,5-diol (1) was accomplished via the Mukaiyama aldol
reaction and an anti selective reduction as key steps. The
present approach reduces the number of steps and
increases the overall yield of compound 1 to 30%.
dried (MgSO4), and concentrated under reduced pressure to obtain
crude silylated product. The crude silylated adduct was dissolved in
MeOH (20 ml), pyridinium p-toluenesulfonate (10 mg) was added, and
the mixture was stirred for 2 h at r.t. After completion of the reaction
(monitored by TLC), the volatiles were removed in vacuo, and the
crude product was purified by CC to obtain adduct 4 [12] (1.86 g, 94%)
as pale yellow oil. [a]2D5 ¼ À14.1 (c ¼ 1.0, CHCl3). IR (neat): 3452, 2991,
1732, 1716, 1032, 976, 748. 1H-NMR (500 MHz, CDCl3): 7.38 – 7.23 (m,
5 H); 6.64 (d, J ¼ 16.0, 1 H); 6.20 (dd, J ¼ 16.0, 6.1, 1 H); 4.81 – 4.77 (m,
1 H); 4.20 (q, J ¼ 14.3, 7.1, 2 H); 3.50 (s, 2 H); 2.87 (d, J ¼ 6.1, 2 H); 2.84
(br, d, J ¼ 3.3, 1 H); 1.28 (t, J ¼ 7.1, 3 H). 13C-NMR (75 MHz, CDCl3):
202.6; 166.8; 136.3; 130.6; 129.7; 128.5 (2 C); 127.7; 126.4 (2 C); 68.3;
61.5; 49.9; 49.5; 14.0. ESI-MS: 263 ([M þ H]þ), 285 ([M þ Na]þ).
Ethyl {(4S,6S)-2,2-Dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-
4-yl}acetate (6) [13]. Me4NBH(AcO)3 (1.506 g, 5.724 mmol) was added
to a mixture of dry MeCN (5 ml) and glacial AcOH (5 ml). The
resulting mixture was stirred at r.t. for 30 min. The mixture was cooled
to À 408 and a soln. of 4 (1.0 g, 3.816 mmol) in MeCN (2 ml) was added
drop-wise. The mixture was stirred at the same temp. for 3 h. 1n
Potassium sodium tartrate (5 ml) and Et2O (30 ml) were added to
the mixture, followed by aq. sat. Na2CO3 soln. (10 ml). The aq. phase
was extracted with Et2O (4 Â 10 ml). The combined org. phases were
dried (MgSO4), and concentrated under vacuum. The residue was
chromatographed over SiO2 (2 :1 hexane/AcOEt) to give 5 as a
colorless oil (901 mg, 80% yield).
The authors thank CSIR and UGC, New Delhi for financial
assistance.
Experimental Part
General. All solvents and reagents were purified by standard
techniques. Anal. TLC: precoated SiO2 60 F254 (0.5 mm) glass plates;
visualization of the spots on TLC plates was achieved either by
exposure to I2 vapor or UV light. Column chromatography (CC): silica
gel (SiO2, 60 – 120, 100 – 200 mesh). Optical rotations: JASCO DIP-370
digital polarimeter. IR Spectra: PerkinÀElmer infrared spectropho-
tometer with NaCl optics; n˜ in cmÀ1. 1H- and 13C-NMR spectra: Varian
Gemini 500 and Bruker Avance 300 instrument; in CDCl3; d in ppm rel.
to Me4Si as internal standard, J in Hz. MS: Micro Mass VG-7070 H
mass spectrometer for ESI and VG Auto spec M mass spectrometer for
FAB-MS; in m/z.
Ethyl (5S,6E)-5-Hydroxy-3-oxo-7-phenylhept-6-enoate (4) [12]. A
mixture of Ti(iPrO)4 (430 mg, 1.51 mmol), (S)-BINOL (433 mg,
1.51 mmol), and LiCl (128 mg, 3.0 mmol) in dry THF (20 ml) was
stirred at r.t. under inert atmosphere for 1 h. After cooling the mixture
to À 788, the trans-cinnamaldehyde 2 (1 g, 7.57 mmol) was added
dropwise, followed, after 30 min, by silyloxydiene 3 [20] (2.8 g,
15.15 mmol) in THF (10 ml). The resulting soln. was stirred at the
same temp. for 2 h. After warming to r.t., the mixture was stirred
overnight (12 h). After completion of the reaction as indicated by TLC,
the reaction was quenched with a sat. aq. soln. of NaHCO3 (5 ml) and
extracted with Et2O. The combined extracts were washed with brine,
To a stirred soln. of 5 (901 mg, 3.41 mmol), in CH2Cl2 (10 ml) was
added dimethoxypropane (0.84 ml, 6.82 mmol) and PPTS (10 mg,
0.4 mmol). The mixture was stirred at r.t. for 4 h. The mixture was
diluted with CH2Cl2 (10 ml) and washed with aq. sat. NaHCO3. The
combined org. phases were dried (MgSO4), and the solvent was
evaporated in vacuo. The crude product was purified by CC (10 :1
hexane/AcOEt) to afford 6 as a colorless oil (933 mg, 90% yield).
[a]2D5 ¼ þ19.2 (c ¼ 1.0, CHCl3). IR (neat): 3040, 2921, 1734, 1582, 1494,
1378, 1312, 1199, 1024, 967, 747. 1H-NMR (500 MHz, CDCl3): 7.39 – 7.20
(m, 5 H); 6.56 (d, J ¼ 16.0, 1 H); 6.23 (dd, J ¼ 16.0, 6.4, 1 H); 4.49 – 4.60
(m, 1 H); 4.42 – 4.32 (m, 1 H); 4.15 (m, 2 H); 2.58 (dd, J ¼ 15.4, 8.0,
1 H); 2.48 (dd, J ¼ 15.4, 5.4, 1 H); 1.99 – 1.93 (m, 1 H); 1.83 – 1.77 (m,
1 H); 1.43 (s, 3 H); 1.41 (s, 3 H); 1.26 (t, J ¼ 7.1, 3 H). 13C-NMR
(125 MHz, CDCl3): 170.7; 136.5; 130.5; 129.4; 128.4 (2 C); 127.6; 126.4
(2 C); 100.6; 67.5; 63.2; 60.4; 40.8; 37.2; 25.2; 24.6; 14.1. ESI-MS: 305
([M þ H]þ), 327 ([M þ Na]þ).
2-{(4R,6S)-2,2-Dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-
yl}ethanol (7). To a stirred suspension of LiAlH4 (62 mg, 1.64 mmol) in
dry THF (20 ml) was added drop-wise a soln. of 6 (500 mg,
1.644 mmol) in dry THF (5 ml) at 08. The mixture was allowed to
warm to r.t. and stirred for 30 min. The reaction was quenched by drop-
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Helv. Chim. Acta 2016, 99, 70 – 72
wise addition of sat. aq. Na2SO4 soln. (2 ml). The solid material was
filtered through a Celite pad and washed thoroughly with hot AcOEt
(4 Â 20 ml). The combined org. layers were dried (MgSO4). The
solvent was removed in vacuo and the crude residue was subjected to
(d, J ¼ 8.1, 2 H); 6.70 (d, J ¼ 8.0, 2 H); 4.01 – 3.89 (m, 2 H); 2.80 – 2.49
(m, 4 H); 1.90 – 1.67 (m, 4 H); 1.61 (t, J ¼ 5.2, 2 H). 13C-NMR (75 MHz,
CDCl3): 154.0; 141.8; 133.4; 129.4 (2 C); 128.4 (2 C); 128.3 (2 C); 125.9;
115.4 (2 C); 69.0; 68.9; 42.4; 39.0; 38.9; 32.1; 31.1. ESI-MS: 323 ([M þ
Na]þ).
CC to obtain pure alcohol 7 (366 mg, 85%) as colorless oil. [a]D25
¼
À21.2 (c ¼ 1.2, CHCl3). IR (neat): 3442, 2991, 1021, 915, 712.
1H-NMR (500 MHz, CDCl3): 7.39 – 7.22 (m, 5 H); 6.57 (d, J ¼ 16.0,
1 H); 6.23 (dd, J ¼ 16.0, 6.4, 1 H); 4.57 – 4.52 (m, 1 H); 4.19 – 4.13 (m,
1 H); 3.82 – 3.76 (m, 2 H); 1.92 – 1.75 (m, 4 H); 1.45 (s, 3 H); 1.43 (s,
3 H). 13C-NMR (75 MHz, CDCl3): 136.5; 130.5; 129.4; 128.4 (2C);
127.6; 126.4 (2 C); 100.5; 67.7; 66.4; 60.8; 37.7 (2 C); 25.4; 24.8. ESI-MS:
263 ([M þ H]þ).
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(3R,5R)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol (1) [11].
To a stirred soln. of 9 (200 mg, 0.46 mmol) in MeOH (5 ml) was added
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Received July 22, 2015
Accepted October 2, 2015
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