Catalytic route to a concise stereoselective synthesis of cytotoxic (3S,5S)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol and its (3R,5S)-isomer

Article abstract of DOI:10.1055/s-0030-1260183

Maruoka asymmetric allylation using bis[(R)-2,2-binaphthoxy)(isopropoxy) titanium] oxide, and Jacobsens hydrolytic kinetic resolution (HKR) using (R,R)-salen-Co(OAc) catalyst were used as key steps for the construction of syn- and anti-1,3-diol systems in

Full text of DOI:10.1055/s-0030-1260183

3180
PAPER
Catalytic Route to a Concise Stereoselective Synthesis of Cytotoxic (3S,5S)-1-
(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol and Its (3R,5S)-Isomer
Stereoselectiv
.
e
S
ynthesis
o
P
f
syn
-
and ant
u-1,3-Diols rushotham Reddy, K. Ashalatha, D. Kumar Reddy, B. Chinna Babu, Y. Venkateswarlu*
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: luchem@iict.res.in
Received 31 May 2011; revised 9 July 2011
OH OH
Abstract: Maruoka asymmetric allylation using bis[(R)-2,2¢-bi-
naphthoxy)(isopropoxy)titanium] oxide, and Jacobsen’s hydrolytic
kinetic resolution (HKR) using (R,R)-salen-Co(OAc) catalyst were
used as key steps for the construction of syn- and anti-1,3-diol sys-
tems in the synthesis of cytotoxic (3S,5S)-1-(4-hydroxyphenyl)-7-
phenylheptane-3,5-diol and its (3R,5S)-isomer.
OH
1a
OH OH
Key words: diarylheptanoids, cytotoxic, Maruoka asymmetric al-
lylation, Jacobsen’s hydrolytic kinetic resolution
OH
1b
OH OH
OMe
Diarylheptanoids having a 1,3-diol system are natural
plant metabolites that exhibit good medicinal properties
such as cytotoxic, anti-oxidative, hepatoprotective, anti-
inflammatory, and anti-emitic activities.1 A characteristic
feature of these compounds is the presence of two aromat-
ic rings tethered by a linear seven-carbon chain.2,3 We
evaluated cytotoxic properties of such diarylheptanoids
1a, 1b and their analogues 1c–f (Figure 1) against human
cancer cell lines, which were synthesized from carbohy-
drate D-mannitol.4 Recently Shinde et al.5a and Bhuniya et
al.5b reported the synthesis of diarylheptanoids and syn-di-
arylheptanoids, respectively, from D-glucose. Among
these compounds, 1a and 1b showed significant cytotoxic
activity against cancer cell lines THP-1 (12.82 0.89 mg/
mL for 1a, 12.62 0.69 mg/mL for 1b), U-937 (leukemia)
(31.09 8.07 mg/mL for 1a, 32.99 5.03 mg/mL for 1b),
and A-375 (melanoma) (56.30 3.88 mg/mL for 1a, 57.78
5.02 mg/mL for 1b).4 This prompted us to establish a
concise catalytic synthetic route for the synthesis of com-
pounds 1a and 1b employing the Maruoka asymmetric al-
lylation and Jacobsen’s resolution to obtain the required
chiral centers for the construction of the syn- and anti-1,3-
diol systems in diarylheptanoids 1a and 1b. By using this
strategy other diarylheptanoid analogues can also be pre-
pared.
OH
OH OH
1c
OMe
OH
1d
OH OH
1e
OH OH
1f
Figure
1
(3S,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol
(1a), (3R,5S)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1b),
(3S,5S)-1-(4-hydroxy-3-methoxyphenyl)-7-phenylheptane-3,5-diol
(1c), (3R,5S)-1-(4-hydroxy-3-methoxyphenyl)-7-phenylheptane-3,5-
diol (1d), (3S,5S)-1,7-diphenylheptane-3,5-diol (1e), (3R,5S)-1,7-
diphenylheptane-3,5-diol (1f).
OH OH
OH
OTPS
O
1a
From the retrosynthetic analysis (Scheme 1), we envis-
aged that the target molecules can be obtained from the in-
termediate epoxide 5 via opening of kinetically resolved
epoxide 6a with Grignard reagent, in turn intermediate
epoxide 5 prepared from 3-phenylpropanal (2) via the
Maruoka asymmetric allylation, tert-butyldiphenylsilyl
(TPS) protection, and m-chloroperoxybenzoic acid epoxi-
dation.
+
OH OH
5
OH
1b
O
H
2
SYNTHESIS 2011, No. 19, pp 3180–3184
x
x.
x
x
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2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1260183; Art ID: Z55511SS
Scheme 1 Retrosynthetic analysis
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Synthesis of syn- and anti-1,3-Diols
3181
OTPS
O
OH
a
c
b
H
2
3
4
OTPS
OTPS
OTPS
OH
O
O
OH
d
+
5
6a
7
OR1
OH
e
6a
OR2
8a R1 = TPS, R2 = Bn
1a R1 = R2 = H
f
Scheme 2 Reagents and conditions: (a) (R,R)-I (10 mol%), allyltributyltin, CH2Cl2, –15 to 0 °C, 24 h, 83%; (b) TPSCl, imidazole, dry CH2Cl2,
4 h, 87%; (c) MCPBA, CH2Cl2, r.t., 4 h, 95%; (d) (R,R)-Salen-Co(OAc) (0.5 mol%), distd H2O (0.55 equiv), 0 °C, 14 h, (46% for 6a, 42% for
7); (e) 1. Mg, 4-(benzyloxy)benzyl bromide, CuI, THF, –20 °C to r.t. 0.5 h, 2. 6a, 0 °C to r.t., 1 h, 88%; (f) TiCl4, anhyd CH2Cl2, 0 °C, 2 h, 73%.
The readily commercially available 3-phenylpropanal (2) compound 8a, which on one-pot deprotection of tert-bu-
was subjected to Maruoka asymmetric allylation6 with ti- tyldiphenylsilyl and benzyl groups with titanium(IV)
tanium complex (R,R)-I (Figure 2) to furnish (S)-homoal- chloride in dichloromethane afforded (3S,5S)-1-(4-hy-
lylic alcohol 3 in 83% yield with 97% ee. The secondary droxyphenyl)-7-phenylheptane-3,5-diol (1a) (Scheme 2).
hydroxy group in 3 was protected as its TPS ether using The physical and spectral data of synthetically prepared
tert-butyldiphenylsilyl chloride and imidazole in dry compound 1a (1H and 13C NMR) were found to be in
dichloromethane to yield 4, which was subjected to epoxi- agreement with those of reported product4 {[a]D25 –2.1 (c
dation using m-chloroperoxybenzoic acid in dichlo- 0.25, EtOH), Lit.4 [a]D25 –2.8 (c 1, EtOH)}.
romethane to afford a diastereomeric mixture of epoxide
5.
Our next concern was the construction of another stereo-
isomer (3R,5S)-1-(4-hydroxyphenyl)-7-phenylheptane-
3,5-diol (1b). Jacobsen’s resolved diol 7 was monotosy-
lated using tosyl chloride/triethylamine to afford monoto-
syl compound 9 which was reacted with potassium
carbonate in methanol to afford (S)-epoxide 6b.8 The (S)-
epoxide 6b was subjected to the same sequence of reac-
tions followed in Scheme 2 to afford (3R,5S)-1-(4-hy-
droxyphenyl)-7-phenylheptane-3,5-diol (1b) (Scheme 3).
The physical and spectral data of synthetically prepared
compound 1b (1H and 13C NMR) were found to be in
Oi-Pr
O
O
Ti
O
Ti
i-PrO
O
O
(R,R)-I
25
agreement the reported product4 {[a]D –1.1(c 0.5,
EtOH), Lit.4 [a]D25 –1.9 (c 1, EtOH)}. Utilizing the same
strategy one can prepare other diarylheptanoid analogues.
H
H
N
N
OTPS OH
OTPS OH
Co
OTs
OH
O
t-Bu
t-Bu
O
a
b
OAc
t-Bu
t-Bu
9
7
(R,R)-salen-Co(III)-OAc complex
OR1 OH
OTPS
O
Figure 2
c
OR2
The epoxide compound 5 was subjected to Jacobsen’s hy-
drolytic kinetic resolution7 using (R,R)-salen-Co(OAc)
catalyst (Figure 2) to afford chiral epoxide 6a {[a]D
6b
8b R1 = TPS, R2 = Bn
1b R1 = H, R2 = H
d
25
+30.64 (c 1.55, CHCl3)}, as a single isomer, and (S,S)-diol
7 {[a]D25 +39.7 (c 1.7, CHCl3)}; which were separated by
column chromatography. Chiral epoxide 6a was reacted
with 4-(benzyloxy)benzylmagnesium bromide to afford
Scheme 3 Reagents and conditions: (a) TsCl, Bu2SnO, Et3N, 0 °C
to r.t., 4 h, 89%; (b) K2CO3, MeOH, r.t., 1 h, 89%; (c) 1. Mg, 4-(ben-
zyloxy)benzyl bromide, CuI, THF, r.t. 0.5 h, 2. 6a, 0 °C to r.t., 1 h,
85%; (d) TiCl4, anhyd CH2Cl2, 0 °C, 2 h, 87%.
Synthesis 2011, No. 19, 3180–3184 © Thieme Stuttgart · New York

3182
S. Purushotham Reddy et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.74–7.60 (m, 5 H), 7.47–6.89 (m,
10 H), 5.81–5.63 (m, 1 H), 5.01–4.89 (m, 2 H), 3.87–3.73 (m, 1 H),
2.63–2.45 (m, 2 H), 2.35–2.15 (m, 2 H), 2.80–1.63 (m, 2 H), 1.07
(s, 9 H).
13C NMR (75 MHz, CDCl3): d = 142.3, 136.0 (4 C), 134.6, 134.4,
129.6 (2 C), 128.3 (4 C), 127.6 (2 C), 127.5 (2 C), 125.6 (2 C),
117.2, 72.4, 41.1, 37.9, 31.3, 27.2 (3 C), 19.6.
In conclusion, synthesis of cytotoxic anti-(3S,5S)-1-(4-
hydroxyphenyl)-7-phenylheptane-3,5-diol (1a) achieved
in six steps with 25% overall yield and its (3R,5S)-stereo-
isomer 1b achieved in ten steps with 16% overall yield by
combination of the Maruoka asymmetric allylation,
Jacobsen’s hydrolytic kinetic resolution (HKR) as key
steps. Using this method one can synthesize other ana-
logues.
HRMS (ESI): m/z [M + Na]+ calcd for C28H34ONaSi: 437.2271;
found: 437.2289.
2-[(S)-2-(tert-Butyldiphenylsiloxy)-4-phenylbutyl]oxirane (5)
A soln of 4 (3 g, 7.14 mmol) in CH2Cl2 (8 mL) was added to a mix-
ture of MCPBA (1.62 g, 9.42 mmol) in CH2Cl2 (10 mL). After stir-
ring at r.t. for 4 h, the mixture was cooled to –20 °C, filtered through
Celite, and washed with cold CH2Cl2. The filtrate was washed with
sat. aq Na2S2O3 and sat. aq NaHCO3 and dried (anhyd MgSO4).
Evaporation of the solvent afforded the oxirane as a colorless oil,
which was purified by column chromatography (silica gel, EtOAc–
hexane, 1:9) to afford pure 5 (2.9 g, 95%) as clear liquid.
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel 60–120 mesh. FT-IR spectra were measured with a Thermo
Nicolet Nexus 670 spectrophotometer. Optical rotations recorded
on Horiba high-sensitivity polarimeter, in a 10-mm cell. 1H and 13
C
NMR spectra were recorded in CDCl3 soln on a Varian Gemini 500
and Brucker Avance 300 with respect to internal TMS. Mass spectra
were acquired on a Micro mass Quattro microTM API (Waters) and
HRMS acquired on QSTARXL Hybrid MS/MS system (applied
Biosystems US) mass spectrometers.
[a]D25 +28.3 (c 0.75, CHCl3).
(S)-1-Phenylhex-5-en-3-ol (3)
IR (neat): 3048, 2928, 2856, 1427, 1108, 1062 cm–1.
To a stirred soln of TiCl4 (0.136 g, 0.75 mmol) in CH2Cl2 (5 mL)
was added Ti(Oi-Pr)4 (0.6 g, 2.23 mmol) at 0 °C under N2. The soln
was allowed to warm to r.t.. After 1 h, Ag2O (0.34 g, 1.49 mmol)
was added at r.t., and the mixture was stirred for 5 h in the absence
of light. The mixture was diluted with CH2Cl2 (5 mL) and treated
with (R)-2,2¢-binaphthol (0.85 g, 2.98 mmol) at r.t. for 2 h to furnish
chiral bis-Ti(IV) oxide (R,R)-I. Chiral bis-Ti(IV) oxide (R,R)-I was
cooled to –15 °C, aldehyde 2 (2 g, 14.92 mmol) and allyltributyltin
(7.41 g, 1.5 mmol) were sequentially added at same temperature and
the mixture was stirred at 0 °C for 24 h. The mixture quenched with
sat. NaHCO3 and extracted with Et2O. The combined organic ex-
tracts were dried (Na2SO4) and concentrated under vacuum to fur-
nish the crude residue, which was purified by column
chromatography (silica gel, EtOAc–hexane, 2:8) to afford pure 3
(2.24 g, 83%) as a clear liquid.
1H NMR (300 MHz, CDCl3): d = 7.73–7.58 (m, 4 H), 7.49–6.86 (m,
11 H), 4.04–3.89 (m, 1 H), 2.92 (m, 1 H), 2.70–2.42 (m, 3 H), 2.37–
2.21 (m, 1 H), 1.90–1.59 (m, 4 H), 1.06 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H34O2NaSi: 453.222;
found: 453.223.
(R)-2-[(S)-2-(tert-Butyldiphenylsiloxy)-4-phenylbutyl]oxirane
(6a) and (2S,4S)-4-(tert-Butyldiphenylsiloxy)-6-phenylhexane-
1,2-diol (7)
A mixture of (R,R)-Salen-Co(OAc) (63 mg, 0.10 mmol) in toluene
(2 mL) and AcOH (0.205 mmol) was stirred while open to the air at
r.t. for 1 h. The mixture was concentrated under reduced pressure
and the brown residue was dried under vacuum. The racemic ep-
oxide 5 (2.2 g, 5.12 mmol) was added in one portion at 0 °C, and
H2O (2.81 mmol) was added dropwise over 5 min. The mixture was
allowed to warm to r.t. and stirred for 14 h. The mixture was con-
centrated to give a residue, which was purified by column chroma-
tography [silica gel, EtOAc–hexane, 1:9 (for 6a) and EtOAc–
hexane, 3:7 (for 7)] to give pure epoxide 6a (1.01 g, 46%) and pure
diol 7 (0.96 g, 42%) both as clear liquids.
The enantiomeric purity was determined by chiral HPLC on a
CHIRALCEL-OJ-H column (250 × 4.6 mm, 5 mm) eluting with i-
PrOH–hexane (3:97) at 1 mL/min. tR: 14.149 min, 97% ee.
[a]D25 –19.0 (c 2.8, CHCl3).
IR (neat): 3379, 3070, 3026, 2927, 2857, 1640, 1453, 916, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.15 (m, 5 H), 5.87–5.77 (m,
1 H), 5.20–5.10 (m, 2 H), 3.71–3.63 (m, 1 H), 2.87–2.76 (m, 1 H),
2.75–2.65 (m, 1 H), 2.37–2.27 (m, 1 H), 2.24–2.14 (m, 1 H), 1.88–
1.71 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 141.9, 134.5, 128.3 (d) (4 C),
125.7, 118.2, 69.8, 41.9, 38.3, 31.9.
Oxirane 6a
[a]D25 +30.64 (c 1.55, CHCl3).
IR (neat): 3048, 2932, 2858, 1427, 1108, 1063, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71–7.61 (m, 4 H), 7.43–7.31 (m,
6 H), 7.21–7.05 (m, 3 H), 6.97–6.89 (m, 2 H), 4.17–3.98 (m, 1 H),
2.97–2.83 (m, 1 H), 2.71–2.63 (m, 1 H), 2.60–2.51 (m, 2 H), 2.34–
2.30 (m, 1 H), 1.82–1.63 (m, 4 H), 1.09 (s, 9 H).
MS (ESIMS): m/z = 199 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 142.0, 135.8 (4 C), 134.1, 134.0,
129.6 (2 C), 128.2 (4 C), 127.5 (4 C), 125.6, 71.2, 49.6, 47.4, 39.7,
38.9, 31.1, 27.0 (3 C), 19.4.
HRMS (ESI): m/z [M + Na]+ calcd for C28H34O2NaSi: 453.2220;
found: 453.2226.
(S)-4-(tert-Butyldiphenylsiloxy)-6-phenylhex-1-ene (4)
To a stirred, cooled (0 °C) soln of 3 (2 g, 11.36 mmol) and imidazole
(1.5 g, 22.723 mmol) in anhyd CH2Cl2 (10 mL) was added TPSCl
(3.73 g, 13.61 mmol) dropwise; stirring was continued for 4 h. After
the completion of the reaction, the mixture was diluted with H2O
(10 mL) and extracted into CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were washed with brine soln (10 mL), dried (Na2SO4),
and concentrated under vacuum to furnish the crude residue, which
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 5:95) to afford pure 4 (4.1 g, 87%) as a clear liquid.
Diol 7
[a]D25 +39.7 (c 1.7, CHCl3).
IR (neat): 3359, 3068, 3024, 2932, 2858, 1456, 1427, 1108, 1061,
702 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.62 (m, 4 H), 7.49–7.32 (m,
6 H), 7.19–7.02 (m, 3 H), 6.89–6.81 (m, 2 H), 4.19–3.91 (m, 1 H),
3.89–3.75 (m, 1 H), 3.51–3.41 (m, 1 H), 3.38–3.22 (m, 1 H), 2.50–
2.30 (m, 2 H), 1.9–1.61 (m, 4 H), 1.11 (s, 9 H).
[a]D25 +13.75 (c 0.8, CHCl3).
IR (neat): 3069, 3026, 2931, 2857, 1639, 1569, 1402, 1464, 1108,
1059, 998, 702 cm–1.
Synthesis 2011, No. 19, 3180–3184 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of syn- and anti-1,3-Diols
3183
13C NMR (75 MHz, CDCl3): d = 135.9 (4 C), 133.6, 129.9, 128.3,
128.1 (2 C), 127.8 (4 C), 125.8 (4 C), 125.7, 71.7, 68.7, 67.0, 37.7,
37.4, 31.7, 27.1 (3 C), 19.3.
HRMS (ESI): m/z [M + Na]+ calcd for C28H36O3NaSi: 471.2326;
found: 471.2366.
with H2O, and extracted with Et2O (3 × 20 mL). The combined or-
ganic layers were dried (anhyd Na2SO4) and concentrated to give
the crude product, which was purified by column chromatography
(silica gel, EtOAc–hexane, 1:9) to afford pure 6b (0.514 g, 89%) as
a clear liquid.
[a]D25 +5.6 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.72–7.61 (m, 4 H), 7.46–7.31 (m,
6 H), 7.20–6.90 (m, 5 H), 4.06–3.91 (m, 1 H), 3.01 (br s), 2.68–2.48
(m, 2 H), 2.35–2.25 (m, 1 H), 1.93–1.60 (m, 4 H), 1.09 (s, 9 H).
(3S,5S)-1-[4-(Benzyloxy)phenyl]-5-(tert-butyldiphenylsiloxy)-7-
phenylheptan-3-ol (8a); Typical Procedure
To a suspension of Mg (0.18 g, 7.62 mmol) in anhyd THF (15 mL)
at r.t. equipped with condenser (cool water circulation) was added
4-(benzyloxy)benzyl bromide (0.542 mL, 7.62 mmol) in a dropwise
manner followed by CuI (17.12 mg, 0.19 mmol) and the mixture
was allowed to stir for 0.5 h. Then the mixture was cooled to –20 °C
and enantiomerically pure (S,R)-epoxide 6a (0.22 g, 0.51 mmol) in
THF (3 mL) was added. The reaction was warmed to r.t. and stirred
at r.t. for 1 h. On completion the reaction was quenched with sat.
NH4Cl soln (15 mL) and extracted into EtOAc (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure to yield crude
product, which was purified by column chromatography (silica gel,
EtOAc–hexane, 2:8) to afford pure 8a (0.287 g, 88%) as a clear liq-
uid.
13C NMR (75 MHz, CDCl3): d = 142.0, 135.8 (4 C), 134.1. 134.0,
129.6 (2 C), 128.2 (4 C), 127.5 (4 C), 125.6 71.2, 50.5, 47.6, 39.7,
38.6, 31.1, 27.0 (3 C), 19.4.
MS (ESIMS): m/z = 453 [M + Na]+.
(3R,5S)-1-[4-(Benzyloxy)phenyl]-5-(tert-butyldiphenylsiloxy)-
7-phenylheptan-3-ol (8b)
Following the typical for procedure for 8a using: 1. Mg (0.135 g,
5.67 mmol), anhyd THF (15 mL), 4-(benzyloxy)benzyl bromide
(0.40 mL, 5.17 mmol), and CuI (12.84 mg, 0.142 mmol); and 2.
enantiomerically pure (S,S)-epoxide 6b (0.165 g, 0.38 mmol) in
THF (3 mL) afforded pure 8b (0.24 g, 85%) as a clear liquid.
[a]D25 –9.2 (c 1, CHCl3).
[a]D25 –5.6 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.71–7.62 (m, 5 H), 7.61–7.31 (m,
11 H), 7.21–6.91 (m, 5 H), 6.86–6.15 (m, 4 H), 5.2 (s, 2 H), 4.1–4.0
(m, 1 H), 3.9–3.72 (m, 1 H), 2.90 (br s, OH), 2.71–2.30 (m, 4 H),
1.72–1.55 (m, 6 H), 1.05 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 157.0, 141.7, 137.3, 136.0 (4 C),
134.5, 134.2, 133.7, 133.4, 129.9, 129.8, 129.4 (2 C), 128.6 (2 C),
128.3 (2 C), 128.2 (2 C), 127.8 (2 C), 127.7 (2 C), 127.4 (2 C),
125.7, 114.8 (2 C), 73.1, 71.9, 70.0, 69.3, 67.3, 43.6, 41.8, 38.8,
37.8, 31.7, 31.3, 30.9, 27.2 (3 C), 19.5.
IR (neat): 3077, 2922, 2854, 1720, 1644, 1430, 1387, 1249, 1042,
921 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71–7.62 (m, 5 H), 7.61–7.31 (m,
11 H), 7.21–6.71 (m, 9 H), 5.2 (s, 2 H), 4.1–3.9 (m, 2 H), 2.71–2.30
(m, 4 H), 1.90–1.51 (m, 6 H), 1.05 (s, 9 H).
13 CNMR (75 MHz, CDCl3): d = 157.0, 141.6, 137.3, 136.0 (4 C),
134.5, 133.6, 133.3, 129.9, 129.4 (2 C), 128.6 (2 C), 128.3 (2 C),
128.2 (2 C), 127.9 (2 C), 127.8 (2 C), 127.7 (2 C), 127.5 (2 C),
125.8, 114.8 (2 C), 72.1, 70.0, 76.5, 41.4, 39.6, 37.6, 31.7, 31.0,
27.1 (3 C), 19.3.
MS (EIMS): m/z = 628 [M]+.
MS (EIMS): m/z = 628 [M]+.
(3S,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol (1a);
Typical Procedure
(2S,4S)-4-(tert-Butyldiphenylsiloxy)-6-phenyl-1-(tosyloxy)hex-
an-2-ol (9)
To a soln of 8a (120 mg, 0.19 mmol) in anhyd CH2Cl2 (5 mL) was
added a soln of TiCl4 (0.1 mL, 0.94 mmol) in anhyd CH2Cl2 (5 mL)
under N2 at 0 °C and the mixture was stirred at this temperature for
2 h. On completion (TLC), the mixture was diluted with H2O (50
mL) and extracted into CH2Cl2 (2 × 20 mL). The combined organic
extracts were washed with NaHCO3 soln and dried (anhyd Na2SO4),
and solvent was removed under reduced pressure. The crude com-
pound was purified by column chromatography (EtOAc–hexane,
3:8) to afford pure 1a (46 mg, 73%) as a viscous liquid.
To a cooled (0 °C) soln of (S,S)-diol 7 (0.9 g, 2.00 mmol), Bu2SnO
(cat. 5 mg), and Et3N (0.40 g, 4.01) in CH2Cl2 (10 mL) was added
dropwise a soln of TsCl (0.34 g, 2.00 mmol) in CH2Cl2 (5 mL) and
the mixture was stirred at r.t. for 4 h. On completion, the mixture
was diluted with H2O and extracted into CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine soln, dried (anhyd
Na2SO4), and concentrated under reduced pressure to give the crude
residue, which was purified by column chromatography (silica gel,
EtOAc–hexane, 2:8) to afford pure 9 (1.07 g, 89%) as a clear liquid.
[a]D25 –2.1 (c 0.25, EtOH).
IR (neat): 3379, 3067, 2933, 2858, 1718, 1117, 1032, 1006, 818,
702 cm–1.
IR (neat): 3353, 3024, 2939, 2858, 1514, 1450, 1236, 1060, 830
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.83–7.73 (m, 2 H), 7.71–7.63 (m,
4 H), 7.43–7.30 (m, 8 H), 7.22–7.09 (m, 3 H), 6.92–6.83 (m, 2 H),
4.04–3.96 (m, 1 H), 3.95–3.86 (m, 2 H), 3.82–3.74 (m, 1 H), 2.47–
2.44 (m, 4 H), 1.85–1.52 (m, 2 H), 1.90–1.51 (m, 3 H), 1.06–1.11
(m, 9 H).
13 CNMR (75 MHz, CDCl3): d = 144.8, 141.4, 135.8, 133.7 (4 C),
133.4, 133.1, 132.7, 129.8 (6 C), 128.2 (4 C), 127.9, 127.7 (2 C),
125.6, 73.5, 71.0, 67.3, 38.6, 37.7, 31.3 (3 C), 26.9, 19.2, 14.1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.22 (m, 2 H), 7.17–7.12 (m,
3 H), 6.94 (d, J = 7.7 Hz, 2 H), 6.70 (d, J = 7.9 Hz, 2 H), 3.98–3.90
(m, 2 H), 2.78–2.47 (m, 4 H), 1.88–1.59 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.2, 142.0, 133.6, 129.6 (2 C),
128.6 (2 C), 128.5 (2 C), 126.1, 115.6 (2 C), 69.2, 69.1, 42.5, 39.26,
39.21, 32.3, 31.3.
MS (ESIMS): m/z = 323 [M + Na]+.
MS (ESIMS): m/z = 625 [M + Na]+.
(3R,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol (1b)
Following the typical procedure for 8a using 8b (90 mg, 0.14 mmol)
in anhyd CH2Cl2 (5 mL) and TiCl4 (0.08 mL, 0.70 mmol) in anhyd
CH2Cl2 (5 mL) to afford pure 1b (37 mg, 87%) as a viscous liquid.
(S)-2-[(S)-2-(tert-Butyldiphenylsiloxy)-4-phenylbutyl]oxirane
(6b)
To a soln of tosyl compound 9 (0.8 g, 1.33 mmol) in MeOH (10 mL)
was added K2CO3 (0.36 g, 2.65 mmol) and the mixture was stirred
at 25 °C for 1 h. On completion, the solvent was evaporated, diluted
[a]D25 –1.1 (c 0.5, EtOH).
IR (neat): 3353, 3024, 2939, 2858, 1514, 1450, 1236, 1060, 830
cm–1.
Synthesis 2011, No. 19, 3180–3184 © Thieme Stuttgart · New York

3184
S. Purushotham Reddy et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.34 (br s, 1 H), 7.25–7.20 (m, 2
H), 7.16–7.11 (m, 3 H), 6.93 (d, J = 8.3 Hz, 2 H), 6.72 (d, J = 8.3
Hz, 2 H), 3.90–3.78 (m, 2 H, 2-OH), 2.75–2.47 (m, 4 H), 1.79–1.52
(m, 6 H).
(2) Hashimoto, T.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull.
1986, 34, 1846.
(3) Shin, D.; Kinoshita, K.; Koyama, K.; Takahashi, K. J. Nat.
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(4) Narasimhulu, M.; Srikanth Reddy, T.; Chinni Mahesh, K.;
Sai Krishna, A.; VenkateswaraRao, J.; Venkateswarlu, Y.
Bioorg. Med. Chem. Lett. 2009, 19, 3125.
(5) (a) Pawar, V. U.; Shinde, V. S. Tetrahedron: Asymmetry
2011, 22, 8. (b) Bhosale, S.; Vyavahare, V. P.; Prasad, U.
V.; Palle, V. P.; Bhuniya, D. Tetrahedron Lett. 2011, 52,
3397.
(6) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 1708.
(7) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307.
13C NMR (75 MHz, CDCl3): d = 154.08, 141.7, 133.2, 129.3 (2 C),
128.37 (2 C), 128.34 (2 C), 125.8, 115.4 (2 C), 72.3 (2 C), 42.4,
39.6, 39.4, 31.5, 30.6.
MS (ESIMS): m/z = 323 [M + Na]+.
Acknowledgment
The authors are thankful to CSIR, New Delhi, India for financial
support and Dr. J. S. Yadav, Director, Indian Institute of Chemical
Technology (IICT), for his encouragement.
(b) Kumar Reddy, D.; Shekhar, V.; Prabhakar, P.;
Chanti Babu, D.; Ramesh, D.; Siddhardha, B.; Murthy, U. S.
N.; Venkateswarlu, Y. Bioorg. Med. Chem. Lett. 2011, 21,
997.
References
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Synthesis 2011, No. 19, 3180–3184 © Thieme Stuttgart · New York