Stereoselective total synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol

Article abstract of DOI:10.1016/j.tetlet.2013.12.056

A stereoselective total synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl) phenol has been accomplished in two different synthetic approaches. In the first approach, Prins cyclization has been successfully utilized to produce the anti-1,3-diol unit, which wa

Full text of DOI:10.1016/j.tetlet.2013.12.056

Tetrahedron Letters 55 (2014) 1395–1397
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis
of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol
a
a
a
a
J. S. Yadav a, , P. Adi Narayana Reddy , A. Suman Kumar , A. R. Prasad , B. V. Subba Reddy ,
⇑
Ahmad Alkhazim Al Ghamdi b
a Centre for SemioChemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol has been accomplished in
two different synthetic approaches. In the first approach, Prins cyclization has been successfully utilized
to produce the anti-1,3-diol unit, which was further converted into a required syn-1,3-diol through Mits-
unobu reaction. The side chain was constructed through cross metathesis and hydrogenation sequence.
In the second approach, the chiral syn-1,3-diol was prepared by a sequence of reactions such as alkylation
of 1,3-dithane with (R)-epichlorohydrin, ring opening of the epoxide with vinylmagnesium bromide, and
1,3-syn-reduction of the b-hydroxyketone with NaBH4 in the presence of diethylmethoxyborane.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 27 November 2013
Revised 12 December 2013
Accepted 14 December 2013
Available online 21 December 2013
Keywords:
Prins cyclization
Cross metathesis
1,3-syn Reduction
The gingerols are known to exhibit potent antioxidant proper-
ties.1 They are also used in the traditional medicine as anti-inflam-
matory, antitumor and chemopreventive,2 bactereostatic,3 and
nematocida agents.4 Recently, a novel class of 4-((3S,5R)-3,5-
dihydroxynonadecyl)phenol (1) was isolated from the resinous
exudates of Chilean desert plants (Fig. 1).5 It also shows a promis-
ing anti-oxidant behavior. The absolute stereochemistry of (1) was
determined by Gao and co-workers6 through its total synthesis.
Inspired by its fascinating structural features and biological
activity, we attempted the total synthesis of (1) employing our
own strategy to construct the 1,3-diol system.7 Following our
interest on the total synthesis of biologically active natural prod-
ucts,8 we herein report the total synthesis of 4-((3S,5R)-3,5-dihydr-
oxynonadecyl)phenol (1) in two different synthetic approaches
(Scheme 1).
from tetrahydropyranyl derivative 3. In our second strategy, the
syn-1,3-diol 2 was proposed to be obtained from b-hydroxy ketone
OH OH
1
11
3
5
18
OH
1
(
)
OH OH
2
NO2
OMe
O
O
HO
S
S
In the first strategy, we assumed that the target molecule (1)
could be synthesized from syn-1,3-diol 2, which can be accessed
TsO
6
O
OMe
3
OMe
OMe
19
11
OH OH
1
O
3
5
+
S
S
OMe
+
HO
OH
OH
OHC
7
8
5
Cl
4
Figure 1. Naturally occurring 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol (1).
Strategy 1
Strategy 2
⇑
Corresponding author. Tel.: +91 40 27193737; fax: +91 40 27160512.
E-mail address: yadavpub@gmail.com (J.S. Yadav).
Scheme 1. Retrosynthetic analysis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol
(1).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.056

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J. S. Yadav et al. / Tetrahedron Letters 55 (2014) 1395–1397
6, which in turn could be prepared by alkylation of 1,3-dithane 8
with (R)-epichlorohydrin 7 (Scheme 1).
a
S
H
S
b
HO
O
According to our first strategy, the (S)-homoallyl alcohol 49 was
treated with p-methoxyhydrocinnamaldehyde 510 in the presence
of TFA in DCM. The resulting trifluoroacetate was then hydrolyzed
with K2CO3 in MeOH to afford the tetrahydropyranol 9.11 Tosyla-
tion of the primary alcohol of 9 with 1.1 equiv of tosyl chloride
in the presence of TEA in DCM gave the corresponding primary tos-
ylate 10. Mitsunobu inversion12 of the secondary hydroxyl group of
10 using DEAD, TPP, and p-nitrobenzoic acid in THF afforded the
corresponding benzoate 3 in 94% yield. Further treatment of 3 with
NaI in refluxing acetone gave the corresponding iodide derivative,
which was then subjected to reductive elimination using zinc me-
tal in refluxing EtOH to furnish the homoallylic benzoate 11 in 85%
yield (over two steps). Cleavage of the benzoate 11 with K2CO3 in
methanol gave the required syn-1,3-diol 213 in 92% yield.
Cross-metathesis of the terminal olefin 2 with a readily available
tridec-1-ene, using Grubb’s 2nd generation catalyst in DCM under
reflux conditions afforded the olefinic derivative 12 in 85% yield.14
Reduction of the olefin 12 using palladium on carbon in ethyl ace-
tate under hydrogen atmosphere gave the saturated syn-1,3-diol
13 in 94% yield. Finally, the demethylation of 13 using sodium hy-
dride in the presence of ethanethiol and AlCl3 in DCM afforded the
target molecule (1) in 95% yield (28% overall yield) (Scheme 2). The
OMe
OMe
14
8
HO
S
S
S
S
c
6
15
OMe
OMe
OH
O
d
e
16
OMe
OH OH
2
f,g,h
(1)
OMe
Scheme 3. Umpolung route for the synthesis of 4-((3S,5R)-3,5-dihydroxynonade-
cyl)phenol (1). Reagents and conditions: (a) (i) IBX/DMSO, (ii) 1,3-ethane dithiol,
BF3.OEt2, DCM, 0 °C to rt, 3 h, 90%; (b) n-BuLi, (R)-epichlorohydrin, THF, À78 °C, 4 h,
80%; (c) vinylmagnesium bromide, CuCN, À78 °C to À40 °C, 84%; (d) CuCl2/CuO,
Acetone (99% aqueous), 82%; (e) diethyl(methoxy)borane, THF/MeOH (4:1), NaBH4,
À78 °C, 5h, 80%; (f) tridec-1-ene (10 equiv), Grubbs 2 catalyst (5 mol %), DCM,
reflux, 12 h, 85%; (g) 10% Pd/C, EtOAc, H2, rt, 3 h, 94%; (h) AlCl3, EtSH, DCM, 0 °C to
rt, 1 h, 95%.
OH
OMe
a
b
spectral data of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol (1) are
in good agreement with the reported values.15
+
HO
O
9
HO
OH
5
As per our second strategy, the readily available alcohol 14 was
treated with 2-iodoxybenzoic acid (IBX) to give the corresponding
aldehyde, which was then protected with 1,3-propanedithiol using
a catalytic amount of boron trifluoride–diethyl ether at room tem-
perature to furnish the 1,3-dithiane 8 in 90% overall yield in two
steps. Alkylation of the dithiane 8 with (R)-epichlorohydrin 7 using
n-BuLi in THF at À78 °C gave the epoxy dithiane 15 in 80% yield.16
Ring opening of the epoxide 15 with vinylmagnesium bromide in
THF using a catalytic amount of CuCN gave the homoallylic alcohol
6 in 84% yield. Removal of the dithiane group with CuCl2/CuO in
aqueous acetone furnished the b-hydroxyl ketone 16 in 82% yield.
Treatment of the b-hydroxy ketone 16 with NaBH4 in the presence
of diethyl(methoxy)borane in THF/MeOH afforded the syn-1,3-diol
2 in 80% yield (Scheme 3).17 The remaining transformations were
similar to Scheme 2. The spectral data of the molecule (1) are in
good agreement with the reported values.15
OHC
4
OMe
O
OH
O
NO2
c
d
TsO
O
TsO
O
3
10
OMe
OMe
NH2
OH OH
O
O
OH
e
f
2
11
OMe
OMe
In conclusion, we have demonstrated a stereoselective total
synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol (1)
employing two alternative strategies. The first route involves
Prins cyclization as a key step affording the desired molecule in
28% overall yield whereas the second strategy involves mainly
1,3-syn reduction of the b-hydroxy ketone with an overall yield
of 30%.
OH OH
OH OH
g
13
12
OMe
OMe
Acknowledgments
h
OH OH
P.A.N.R. and A.S. thank CSIR, New Delhi for the award of
fellowships. J.S.Y. thanks CSIR for the award of Bhatnagar
Fellowship.
(1)
OH
Scheme 2. Synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol (1) through
Prins cyclization. Reagents and conditions: (a) (i) TFA, DCM, 6 h, (ii) K2CO3, MeOH,
3 h, 60% over two steps; (b) Et3N, TsCl, DCM, 0 °C to rt, 6h, 90%; (c) DEAD, TPP, p-
NO2ÀC6H4CO2H, THF, 0 °C to rt, 5 h, 88%; (d) (i) acetone, NaI, reflux, 24 h (ii) zinc
dust, EtOH, reflux, 2 h, 85% over two steps; (e) K2CO3, MeOH, rt, 3 h, 92%; f)
tridecene (10 equiv), Grubbs-II catalyst (5 mol %), DCM, reflux, 12 h, 85%; (g) 10%
Pd/C, EtOAc, H2, rt, 3 h, 94%; (h) AlCl3, EtSH, DCM, 0 °C to rt, 1 h, 93%.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
056.

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