First asymmetric synthesis of the oxylipin, (6S,9R,10S)-6,9,10- trihydroxyoctadeca-7E-enoic acid

Article abstract of DOI:10.1016/j.tetasy.2011.02.008

A brief and facile synthesis of the title compound has been developed using cyclohexylideneglyceraldehyde as a chiral template. The key steps in the synthesis were: (i) two highly diastereoselective organometallic addition reactions to the aldehyde to furnish the required synthons with the appropriate stereogenic centers, and (ii) their cross metathesis to give the E-olefin geometry of the target compound.

Full text of DOI:10.1016/j.tetasy.2011.02.008

Tetrahedron: Asymmetry 22 (2011) 367–372
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First asymmetric synthesis of the oxylipin,
(6S,9R,10S)-6,9,10-trihydroxyoctadeca-7E-enoic acid
⇑
Sucheta Chatterjee, Seema V. Kanojia, Subrata Chattopadhyay, Anubha Sharma
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A brief and facile synthesis of the title compound has been developed using cyclohexylideneglyceralde-
hyde as a chiral template. The key steps in the synthesis were: (i) two highly diastereoselective organo-
metallic addition reactions to the aldehyde to furnish the required synthons with the appropriate
stereogenic centers, and (ii) their cross metathesis to give the E-olefin geometry of the target compound.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 January 2011
Accepted 10 February 2011
Available online 14 March 2011
1. Introduction
the reported immunomodulatory activity of 1d was very attractive
because many such agents show impressive anti-ulcer, anti-
Araceae is one of the most dominant tropical families amongst
herbs and vines, and many of the species are used as traditional
remedies or food. The plant, Dracontium loretense Engl., which be-
longs to this family (subfamily Lasioideae), is widely distributed in
the Peruvian Amazon, where it is known as ‘jergón sacha’. There
are various preparations of jergón sacha such as dried powder,
tincture, alcoholic, and its aqueous-alcoholic extracts, which are
popular amongst current Peruvian herbal medicines. The infusion
of its corms is considered an immune-booster in Peruvian folk
medicine. The combination of the extracts of D. loretense and
Uncaria tomentosa is also used by AIDS patients to reinforce the im-
mune system.1a–c Very recently, four novel oxylipins 1a–d (Fig. 1)
were isolated from the n-butanol extract of D. loretense corms
and their structures were elucidated by extensive spectrocopy.2
The absolute configurations of the three stereogenic carbinol
centers of 1d remain unresolved, although the relative stereo-
chemistry of the C-9 and C-10 centers was ascertained by NMR
spectrometry. The n-butanol extract and some of its fractions
inflammatory, and anti-neoplastic properties. Similar polyhydroxy
acids and the macrolides derived from them are of wide occurrence
in various natural sources and show diverse biological proper-
ties.4a–c These factors and the lack of any synthesis of 1d prompted
us to develop the first asymmetric synthesis of the (6S,9R,10S)-ste-
reomer of compound 1d.
2. Results and discussion
For the past several years, we have been involved in devising
simple and efficient asymmetric syntheses of various bioactive tar-
get compounds. To this end, we have found the inexpensive and
easily available aldehyde 2 to be a versatile chiral template for
the synthesis of a diverse array of natural compounds.5 The alde-
hyde 2 is amenable to various diastereoselective transformations
using commonly available, inexpensive reagents.6 Herein, a con-
vergent strategy toward the synthesis of the C18 fatty acid 1d
was conceived using a cross metathesis reaction between the chi-
ral building blocks, ‘A’ and ‘B’ that would also provide the desired
7E-olefin function of the target oxylipin (Fig. 1). Different versions
of the olefin metathesis reaction have turned out to be promising
strategies for the construction of C–C bonds.7 We have also suc-
cessfully utilized the cross metathesis of terminal alkenes to for-
mulate efficient syntheses of three hydroxy fatty acids.8a–c It was
envisaged that the building blocks, ‘A’ and ‘B’ can be constructed
by carrying out diastereoselective additions of alkyl/allyl organo-
metallic reagents to aldehyde 2. This would provide the required
stereogenic diol/carbinol moieties of the ‘A’ and ‘B’ units, while
the cyclohexylidenedioxy group can be suitably functionalized to
provide the terminal alkene functionality.
(10 lg/mL), as well as compound 1d (10 lM), showed potential
immunostimulatory effects as revealed by a 3H-thymidine incorpo-
ration assay with human peripheral blood mononuclear cells
(PBMCs). However, at a higher concentration, these were toxic to
the cells. Amongst the constituent oxylipins of D. loretense, only
compound 1d exhibited proliferation activity on the OKT3-
activated PBMCs, while its C-10 epimer 1c was inactive.2 This
emphasized the crucial role of the C-10 stereochemistry for biolog-
ical activity.
The primary motivation of the present work stems from our
own interest in aliphatic polyhydroxy acids as immunomodula-
tory, anti-inflammatory, and anti-neoplastic agents.3 In particular,
Very recently, we have found that the Ga-mediated crotylation
of aldehyde 2 at room temperature in the ionic liquid, [bmim][Br]
proceeded with excellent diastereoselectivity.9 For the synthesis
⇑
Corresponding author.
E-mail address: anubhas@barc.gov.in (A. Sharma).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.008

368
S. Chatterjee et al. / Tetrahedron: Asymmetry 22 (2011) 367–372
OH OH
OH OH
OH
CO2H
OH
OH
O
1b
1a
HO
HO
CO2H
CO2H
CH3(CH2)7
CH3(CH2)7
OH
OH
OH
OH
1d
1c
CO2R
HO
OPg
A
CO2H
CM
O
CH3(CH2)7
+
O
HO
CHO
OH
OH
2
CH3(CH2)7
(6S)-1d
OPg
B
Figure 1.
(Scheme 1) of the ‘A’ unit, a similar protocol was employed using
allyl bromide. This furnished the homoallylic alcohol 3 almost
exclusively (anti/syn = 95:5). The pure anti-isomer was easily
separated by column chromatography. This was silylated with
tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of
4-dimethylaminopyridine (DMAP) to furnish 4. The alkene func-
treatment with K2CO3 in MeOH. The reaction of the sulphorane,
generated by the base (n-BuLi)-catalyzed deprotonation of trim-
ethylsulphonium iodide (Me3SI) with epoxide 14 proceeded regio-
selectively at the C-1 position to afford allylic alcohol 15.
In the final sequence of reactions, alcohol 15 was subjected to a
cross-metathesis reaction with ester 10 in the presence of Grubbs’
2nd generation catalyst to furnish the desired alcohol 16 (63%,
based on 10) along with the unreacted substrates 10 and 15. The
homo-dimerized product of 10 was also obtained in 10–12% yields.
We used alcohol 15 in excess, as its dimerized product would pro-
duce a highly polar product, which can be easily separated from
alcohol 16. Generally, increasing the steric bulk via the addition
of a hydroxyl protection reduces the cross-metathesis reactivity
of the alkenols.7f Hence we used directly the unprotected alcohol
15 for the metathesis. Desilylation of the compound 16 with Bu4NF
afforded the ester 17, which on alkaline hydrolysis furnished the
title acid 1d.
tion of
4 was regioselectively hydroborated with BH3–Me2S
(BMS) and the resultant product oxidized with H2O2 to afford alco-
hol 5. This upon oxidation with pyridinium chlorochromate (PCC)
afforded the aldehyde 6. Its base-catalyzed Horner–Emmons reac-
tion with triethyl phosphonoacetate produced the conjugated ester
7. Although inconsequential to the present synthesis, the 2E-geom-
etry of the ester 7 can be easily confirmed from the 1H NMR spec-
trum. Catalytic hydrogenation of 7 gave the ester 8, which upon
treatment with aqueous trifluoroacetic acid (TFA) furnished the
diol ester 9. Its reaction with excess p-toluenesulphonyl chloride
(p-TsCl) in the presence of pyridine furnished the ditosylate, which
on heating with NaI and Zn-dust in DMF afforded the alkene ester
10 in an unusually clean manner.
3. Experimental
As per our synthetic plan, the synthesis of the other building
block 15 (B equivalent) required two key steps. For the synthesis
of the chiral diol segment of compound 15, we resorted to our
own methodology of alkyl lithium addition to aldehyde 2.5d The
cyclohexylidenedioxy moiety of the resultant product was then
converted to the one-carbon homologated allylic alcohol using sul-
fur-ylide chemistry. Despite its tremendous potential, the latter
reaction has not been utilized extensively in organic synthesis.
Thus, aldehyde 2 was reacted with CH3(CH2)7Li to furnish the
anti-triol derivative 11 almost exclusively (dr = 95:5). In contrast,
using the corresponding Grignard reagent produced a 29:71 mix-
ture of syn/anti isomers. The anti-compound 1110 could be easily
isolated as a pure enantiomer by column chromatography. The
anti-stereochemistry of 11 was confirmed from the 1H NMR reso-
nances of the carbinol protons that appeared at d 3.70–3.78 (1H)
and d 3.86–3.97 (m, 3H). For the corresponding syn-isomer, these
appear as 1:1:2 multiplets at d 3.46–3.48, d 3.68–3.72 and d
3.94–4.02.10 Silylation of alcohol 11 with TBDPSCl/DMAP in CH2Cl2
produced compound 12, which upon treatment with aqueous TFA
furnished diol 13. Its reaction with p-TsCl/pyridine proceeded
regioselectively at the primary carbinol function to furnish the cor-
responding monotosylate. This was converted to epoxide 14 by
3.1. General experimental details
Chemicals (Fluka and Lancaster) were used as received. Other
reagents were of AR grade. All anhydrous reactions were carried
out under an Ar atmosphere, using freshly dried solvents. The or-
ganic extracts were dried over anhydrous Na2SO4. The IR spectra
as thin films were scanned with a Jasco model A-202 FT-IR spec-
trometer. The 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra
were recorded with a Bruker AC-200 spectrometer in CDCl3. The
optical rotations were recorded with a Jasco DIP 360 digital
polarimeter.
3.1.1. (2R,3S)-3-tert-Butyldiphenylsilyloxy-1,2-cyclohexylidene-
dioxyhex-5-ene 4
To a stirred and cooled (ꢀ30 °C) solution of the mixture of 3
(1.48 g, 6.95 mmol), imidazole (0.80 g, 11.80 mmol) and DMAP
(catalytic) in CH2Cl2 (25 mL) was dropwise added TBDPSCl
(2.86 g, 10.4 mmol) in CH2Cl2 (10 mL). After stirring the mixture
for 10 h at room temperature, it was poured into ice-cold water
(25 mL). The organic layer was separated and the aqueous portion

S. Chatterjee et al. / Tetrahedron: Asymmetry 22 (2011) 367–372
369
O
O
O
i
iii
v
O
O
R
O
CO2Et
O
O
84%
93%
91%
CHO
OTBDPS
OTBDPS
OR
2
3 R = H
5 R = CH2OH
6 R =CHO
7
ii,88%
iv,81%
4 R =TBDPS
OH
O
vi
viii
CO2Et
HO
vii
81%
CO2Et
O
CO2Et
~quant.
75%
OTBDPS
OTBDPS
OTBDPS
9
10
8
O
OH
ix
(CH2)7CH3
O
vii
84%
x
2
HO
(CH2)7CH3
O
(CH2)7CH3
OTBDPS
14
86%
79%
OTBDPS
13
OR
11 R = H
ii,86%
12 R =TBDPS
HO
OH
CO2Et
CH3(CH2)7
xiii,87%
xii
(CH2)7CH3
xi
xiii
95%
(6S,9R,10S)-1d
OR
OR
81%
63%
OTBDPS
15
16 R = TBDPS
17 R =H
Scheme 1. Reagents and conditions: (i) Allyl bromide/Ga/[bmim][Br]/4 h; (ii) TBDPSCl/imidazole/DMAP/CH2Cl2/25 °C/10 h; (iii) BMS/THF/0 °C/3 h; aqueous NaOH/H2O2/0–
25 °C/15 h; (iv) PCC/NaOAc/CH2Cl2/0 °C/3 h; (v) NaH/THF/(EtO)2P(O)CH2CO2Et/0–25 °C/18 h; (vi) H2/10% Pd-C/EtOH/25 °C/22 h; (vii) aqueous 80% TFA/CH2Cl2/0 °C/3 h/25 °C/
18–24 h; (viii) PTSCl/pyridine/0–25 °C/24 h (89%); Zn/DMF/80 °C/4 h; (ix) CH3(CH2)7Li/THF/ꢀ78 °C to 25 °C/3 h; (x) PTSCl/pyridine/0 °C/18 h; K2CO3/MeOH/25 °C/3 h; (xi)
Me3SI/BuLi/THF/ꢀ40 °C/4 h/25 °C/12 h; (xii) 10/Grubbs’ 2nd generation catalyst (5 mol %)/CH2Cl2/25 °C/22 h; (xii) Bu4NF/THF/0 °C/3 h; (xiii) aqueous-ethanolic KOH/25 °C/
4 h.
extracted with CHCl3 (2 ꢁ 15 mL). The combined organic extracts
were washed with water (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and
dried. Removal of solvent in vacuo followed by purification of the
residue by column chromatography (silica gel, 0–5% EtOAc/
hexane) afforded pure 4. Yield: 2.75 g (88%); colorless oil;
3.1.3. (4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclohexylidene-
dioxyhexanal 6
To a cooled (0 °C) and stirred suspension of PCC (1.90 g,
8.82 mmol) and NaOAc (10 mol %) in CH2Cl2 (20 mL) was added
alcohol 5 (2.70 g, 5.77 mmol) in one portion. After stirring for 3 h,
the reaction mixture was diluted with Et2O (30 mL) and the super-
natant passed through a pad of silica gel (200 ꢁ 100). Removal of sol-
vent in vacuo followed by column chromatography of the residue
(silica gel, 0–10% EtOAc/hexane) furnished pure 6. Yield: 2.19 g
½
a 2D4
ꢂ
;
¼ þ16:8 (c 1.13, CHCl3); IR: 3070, 1639 cmꢀ1 1H NMR: d
1.07 (s, 9H), 1.38–1.44 (m, 2H), 1.50–1.64 (m, 8H), 2.12–2.21 (m,
2H), 3.68–3.79 (m, 1H), 3.89–3.96 (m, 2H), 4.04–4.09 (m, 1H),
4.87–4.99 (m, 2H), 5.74–5.78 (m, 1H), 7.36–7.44 (m, 6H), 7.67–
7.76 (m, 4H); 13C NMR: d 19.3, 23.8, 23.9, 25.2, 26.9, 34.8, 36.1,
38.7, 65.8, 73.1, 77.3, 109.2, 117.4, 127.4, 127.5, 129.6, 129.7,
133.5, 133.8, 133.9, 135.9. Anal. Calcd for C28H38O3Si: C, 74.62; H,
8.50. Found: C, 74.48; H, 8.36.
(81%); colorless oil;
½
a 2D4
ꢂ
¼ þ7:7 (c 1.24, CHCl3); IR: 2714,
1729 cmꢀ1 1H NMR: d 1.04 (s, 9H), 1.32–1.36 (m, 2H), 1.45–1.52
;
(m, 8H), 1.81–1.88 (m, 2H), 2.25–2.54 (m, 2H), 3.48–3.62 (m,
1H), 3.67–3.77 (m, 1H), 3.88–4.00 (m, 2H), 7.34–7.43 (m, 6H),
7.62–7.68 (m, 4H), 9.14 (t, J = 1.2 Hz, 1H); 13C NMR: d 19.4, 23.8,
25.1, 26.3, 26.9, 34.7, 36.1, 38.8, 67.2, 73.3, 77.6, 109.7, 127.7,
129.8, 133.3, 133.5, 135.9, 202.2. Anal. Calcd for C28H38O4Si: C,
72.06; H, 8.21. Found: C, 72.21; H, 8.18.
3.1.2. (4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclohexylidene-
dioxyhexan-1-ol 5
To a stirred and cooled (0 °C) solution of 4 (3.52 g, 7.82 mmol)
in THF (20 mL) was added BMS (0.52 mL, 5.2 mmol), and the mix-
ture stirred for 3 h at the same temperature. Aqueous 3 M NaOH
(3.13 mL) was then added, followed by H2O2 (30%, 3.13 mL) at
0 °C. After stirring for 3 h at 0 °C and 12 h at room temperature,
the mixture was extracted with EtOAc (3 ꢁ 15 mL). The combined
organic extracts were washed with H2O (2 ꢁ 10 mL), aqueous 10%
HCl (1 ꢁ 10 mL), H2O (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and dried.
Solvent removal followed by column chromatography (silica gel,
0–15% EtOAc/hexane) of the residue furnished 5. Yield: 3.39 g
3.1.4. Ethyl (6S,7R)-6-tert-butyldiphenylsilyloxy-7,8-cyclohexy-
lidenedioxyoct-2E-enoate 7
To a stirred suspension of pentane-washed NaH (0.444 g,
9.24 mmol, 50% suspension in oil) in THF (20 mL) was added
triethyl phosphonoacetate (1.85 mL, 9.24 mmol) in THF (5 mL).
After 15 min, when the solution became clear, the mixture was
cooled to 0 °C, and the aldehyde 6 (2.15 g, 4.61 mmol) in THF
(5 mL) was dropwise added into it. After stirring at room temper-
ature for 18 h, the mixture was poured into ice-water and
extracted with Et2O (3 ꢁ 20 mL). The ether layer was washed with
H2O (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), dried, and concentrated in
vacuo to give a residue, which upon column chromatography (sil-
ica gel, 0–10% Et2O/hexane) furnished pure 7. Yield: 2.25 g (91%);
(93%); colorless oil; ½a D25
ꢂ
¼ þ3:4 (c 1.13, CHCl3); IR: 3433 cmꢀ1
;
1H NMR: d 1.04 (s, 9H), 1.32–1.39 (m, 2H), 1.41–1.52 (m, 13H),
3.39 (t, J = 6.2 Hz, 2H), 3.64–3.72 (m, 1H), 3.78–3.83 (m, 1H),
3.92–4.13 (m, 2H) 7.32–7.47 (m, 6H), 7.64–7.77 (m, 4H); 13C
NMR: d 19.4, 23.8, 23.9, 25.1, 26.9, 27.2, 30.2, 34.8, 36.1, 60.4,
62.7, 66.8, 73.6, 109.5, 127.5, 129.7, 133.5, 133.9, 135.8, 135.9.
Anal. Calcd for C28H40O4Si: C, 71.75; H, 8.60. Found: C, 71.64; H,
8.78.
colorless oil; ½a D24
ꢂ
¼ þ12:7 (c 1.07, CHCl3); IR: 1716, 997 cmꢀ1
;
1H NMR: d 1.04 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H), 1.33–1.37 (m, 2H),
1.45–1.59 (m, 8H), 1.65–1.76 (m, 2H), 2.12–2.21 (m, 2H),

370
S. Chatterjee et al. / Tetrahedron: Asymmetry 22 (2011) 367–372
3.58–3.66 (m, 1H), 3.70–3.76 (m, 1H), 3.90–4.05 (m, 2H), 4.14 (q,
J = 7.2 Hz, 2H), 5.66 (d, J = 16.0 Hz, 1H), 6.71–6.79 (m, 1H), 7.32–
7.43 (m, 6H), 7.62–7.68 (m, 4H); 13C NMR: d 14.2, 19.3, 23.7,
23.8, 25.0, 26.9, 32.1, 34.7, 36.0, 59.9, 67.0, 73.5, 77.4, 109.5,
121.1, 127.5, 129.7, 133.3, 133.6, 135.7, 135.8, 148.7, 166.5. Anal.
Calcd for C32H44O5Si: C, 71.60; H, 8.26. Found: C, 71.44; H, 8.48.
successively with 10% aqueous Na2S2O3 (1 ꢁ 10 mL), H2O
(3 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and dried. Solvent removal fol-
lowed by column chromatography (silica gel, 0–10% Et2O/hexane)
of the residue gave pure 10. Yield: 0.565 g (84%); colorless oil;
½
a 2D4
ꢂ
;
¼ þ21:3 (c 1.01, CHCl3); IR: 1735, 997 cmꢀ1 1H NMR: d 1.05
(s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 1.39–1.58 (m, 6H), 2.16 (t,
J = 7.0 Hz, 2H), 4.08 (q, J = 7.2 Hz, 2H), 4.92–5.01 (m, 3H), 5.70–
5.80 (m, 1H), 7.33–7.38 (m, 6H), 7.61–7.68 (m, 4H); 13C NMR: d
14.2, 19.3, 23.9, 24.8, 26.9, 34.2, 37.0, 60.1, 74.3, 114.3, 127.3,
127.4, 129.4, 129.5, 134.1, 134.3, 135.8, 135.9, 140.6, 173.6. Anal.
Calcd for C26H36O3Si: C, 73.54; H, 8.54. Found: C, 73.78; H, 8.71.
3.1.5. Ethyl (6S,7R)-6-tert-butyldiphenylsilyloxy-7,8-cyclohexy-
lidenedioxyoctanoate 8
A mixture of 7 (1.3 g, 2.42 mmol) and 10% Pd/C (0.05 g) in EtOH
(10 mL) was magnetically stirred at 25 °C for 22 h under a positive
pressure of H2. The mixture was diluted with Et2O (30 mL) and
passed through a small pad of silica gel. Removal of solvent in va-
cuo furnished pure 8. Yield: 1.25 g (ꢃquant.); colorless oil;
3.1.8. (2R,3S)-1,2-Cyclohexylidenedioxyundecan-3-ol 11
To a cooled (ꢀ78 °C) and stirred solution of C8H17Li [prepared
from 1-bromooctane (11.60 g, 60.0 mmol) and Li (0.890 g,
127.1 mmol)] in THF (80 mL) was added 2 (5.10 g, 30.0 mmol) in
THF (20 mL). After stirring the mixture for 3 h at ꢀ78 °C, it was
gradually brought to room temperature and treated with aqueous
saturated NH4Cl. The supernatant was decanted and the residue
washed with Et2O (2 ꢁ 20 mL). The combined organic extracts
were washed with aqueous saturated NH4Cl (1 ꢁ 10 mL), dried,
and concentrated in vacuo to give a residue, which upon column
chromatography (silica gel, 0–15% EtOAc/hexane) furnished 11.
½
a 2D4
ꢂ
¼ þ7:7 (c 1.06, CHCl3); IR: 1735 cmꢀ1
;
1H NMR: d 1.04 (s,
9H), 1.23 (t, J = 7.2 Hz, 3H), 1.20–1.48 (m, 8H), 1.50–1.60 (m, 8H),
2.07–2.15 (m, 2H), 3.63–3.78 (m, 2H), 3.89–3.97 (m, 2H), 4.08 (q,
J = 7.2 Hz, 2H), 7.32–7.42 (m, 6H), 7.63–7.70 (m, 4H); 13C NMR: d
14.1, 19.3, 23.6, 23.7, 23.8, 24.8, 25.1, 26.9, 33.6, 34.1, 34.7, 36.0,
60.0, 66.5, 73.5, 77.5, 109.3, 127.5, 129.6, 133.5, 134.0, 135.8,
173.5. Anal. Calcd for C32H46O5Si: C, 71.33; H, 8.61. Found: C,
71.34; H, 8.47.
3.1.6. Ethyl (6S,7R)-6-tert-butyldiphenylsilyloxy-7,8-dihydroxy-
octanoate 9
Yield: 7.32 g (86%); colorless oil; ½a D24
¼ þ12:6 (c 1.02, CHCl3),
ꢂ
{lit.10
½
a 2D4
ꢂ
¼ þ6:2 (c 1.15, CHC13)}; IR: 3457 cmꢀ1
;
1H NMR: d
A mixture of 8 (1.20 g, 2.23 mmol) in CH2Cl2 (15 mL) and aque-
ous 80% TFA (8 mL) was stirred at 0 °C for 3 h and then at 25 °C un-
til completion of the reaction (TLC, 24 h). Most of the solvent was
removed in vacuo. The residue was diluted with H2O (30 mL) and
extracted with EtOAc (3 ꢁ 20 mL). The combined organic extracts
were washed successively with H2O (3 ꢁ 10 mL), aqueous 10%
NaHCO3 (2 ꢁ 10 mL), H2O (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and
dried. Solvent removal followed by column chromatography (silica
gel, 0–5% MeOH/CHCl3) of the residue gave pure 9. Yield: 0.830 g
0.86 (t, J = 6.4 Hz, 3H), 1.17–1.43 (m containing a s at d 1.21,
16H), 1.56–1.79 (m, 8H), 1.94 (br s, 1H), 3.70–3.78 (m, 1H), 3.86–
3.97 (m, 3H); 13C NMR: d 13.9, 22.5, 23.7, 23.9, 25.0, 25.7, 29.1,
29.4, 29.5, 31.7, 32.5, 34.8, 36.0, 63.9, 70.5, 78.2, 109.3. Anal. Calcd
for C17H32O3: C, 71.79; H, 11.34. Found: C, 71.94; H, 11.50.
3.1.9. (2R,3S)-3-tert-Butyldiphenylsilyloxy-1,2-cyclohexylidene-
dioxyundecane 12
As described earlier, silylation of 11 (2.87 g, 10.10 mmol) with
TBDPSCl (3.53 g, 12.85 mmol), imidazole (0.87 g, 12.85 mmol)
and DMAP (catalytic) in CH2Cl2 (40 mL), followed by work up
and column chromatography (silica gel, 0–5% EtOAc/hexane) affor-
(81%); colorless oil;
½
a 2D5
ꢂ
¼ þ26:5 (c 1.08, CHCl3); IR: 3455,
1731 cmꢀ1 1H NMR: d 1.06 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 1.32–
;
1.43 (m, 6H), 2.04–2.12 (m, 2H), 2.43 (br s, 2H), 3.63–3.72 (m,
3H), 3.80–3.84 (m, 1H), 4.07 (q, J = 7.2 Hz, 2H), 7.36–7.47 (m,
6H), 7.64–7.70 (m, 4H); 13C NMR: d 14.2, 19.4, 24.7, 27.0, 29.7,
32.5, 33.9, 60.2, 63.1, 73.4, 75.1, 127.6, 127.8, 129.9, 133.0, 133.5,
135.8, 173.6. Anal. Calcd for C26H38O5Si: C, 68.08; H, 8.35. Found:
C, 67.86; H, 8.53.
ded pure 12. Yield: 4.54 (86%); colorless oil; ½a D24
¼ þ15:5 (c 1.06,
ꢂ
CHCl3); IR: 3072, 3050 cmꢀ1 1H NMR: d 0.89 (t, J = 6.4 Hz, 3H),
;
1.14–1.38 (m containing a s at d 1.06, 25H), 1.48–1.72 (m, 8H),
3.66–3.75 (m, 2H), 3.80–3.87 (m, 1H), 3.93–4.10 (m, 1H), 7.34–
7.47 (m, 6H), 7.67–7.75 (m, 4H); 13C NMR: d 14.1, 19.4, 22.6,
23.8, 23.9, 24.2, 25.2, 26.9, 29.1, 29.3, 29.6, 31.8, 34.1, 34.8, 36.1,
66.4, 73.7, 77.7, 109.3, 127.4, 129.5, 133.8, 134.3, 135.8, 135.9.
Anal. Calcd for C33H50O3Si: C, 75.81; H, 9.64. Found: C, 75.74; H,
9.48.
3.1.7. Ethyl (6S)-6-tert-butyldiphenylsilyloxyoct-7-enoate 10
To a cooled (0 °C) and stirred solution of 9 (0.820 g, 1.79 mmol)
in pyridine (8 mL) was added p-TsCl (0.750 g, 3.94 mmol). The
reaction mixture was brought to room temperature and stirred
for 24 h. It was then poured onto ice-cold water (30 mL) and ex-
tracted with EtOAc (2 ꢁ 15 mL). The combined organic extracts
were washed successively with H2O (2 ꢁ 10 mL), aqueous 2 M
HCl (2 ꢁ 10 mL), H2O (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and dried.
Solvent removal followed by column chromatography (silica gel,
0–10% EtOAc/hexane) of the residue gave the pure ditosylate as a
mixture of rotamers. Yield: 1.22 g (89%); colorless oil;
3.1.10. (2R,3S)-3-tert-Butyldiphenylsilyloxyundecane-1,2-diol
13
As described earlier, compound 12 (2.87 g, 5.50 mmol) was
deacetalized in CH2Cl2 (20 mL) with aqueous 80% TFA (8.0 mL).
Usual work up and column chromatography (silica gel, 0–5%
MeOH/CHCl3) afforded pure 13. Yield: 2.0 g (84%); colorless oil;
½
a 2D4
ꢂ
¼ þ21:0 (c 1.04, CHCl3); IR: 3398 cmꢀ1
;
1H NMR: d 0.89 (t,
½
a 2D4
ꢂ
¼ þ20:9 (c 1.03, CHCl3); IR: 1370, 1177 cmꢀ1
;
1H NMR: d
J = 6.8 Hz, 3H), 1.09–1.35 (m containing a s at d 1.10, 21H), 1.45–
1.55 (br m, 4H), 3.65–3.72 (m, 3H), 3.78–3.89 (m, 1H), 7.35–7.49
(m, 6H), 7.68–7.75 (m, 4H); 13C NMR: d 14.1, 19.4, 22.6, 24.8,
27.0, 29.1, 29.2, 29.4, 31.7, 32.9, 63.1, 73.6, 75.5, 127.5, 127.7,
129.7, 129.8, 133.1, 133.7, 135.9. Anal. Calcd for C27H42O3Si: C,
73.25; H, 9.56. Found: C, 73.14; H, 9.72.
1.00 (m, 9H), 1.23–1.51 (m, 7H), 1.60–1.80 and 1.90–2.10 (m,
2H), 2.45 (s, 6H), 3.80–3.88 (m, 1H), 4.03–4.28 (m, 3H), 4.34–4.43
(m, 1H), 4.56–4.70 (m, 1H), 7.30–7.48 (m, 8H), 7.50–7.69 (m,
10H); 13C NMR: d 14.2, 19.3, 21.7, 24.3, 26.8, 33.5, 33.8, 60.2,
67.0, 73.7, 80.8, 127.5, 127.7, 127.9, 128.1, 129.9, 130.0, 135.7,
136.1, 144.9, 145.1, 172.7.
A mixture of the above compound (1.22 g, 1.59 mmol), NaI
(1.43 g, 9.53 mmol) and Zn-dust (0.650 g, 10.0 mmol) in DMF
(10 mL) was heated at 90 °C for 8 h (TLC). The mixture was brought
to room temperature, poured in H2O (30 mL) and extracted with
Et2O (3 ꢁ 15 mL). The combined organic extracts were washed
3.1.11. (2R,3S)-3-tert-Butyldiphenylsilyloxy-1,2-epoxyundecane
14
To a cooled (0 °C) stirred solution of 13 (1.10 g, 2.49 mmol) in
pyridine (8 mL) was added PTSCl (0.475 g, 2.49 mmol) in portions.
After stirring for 18 h at the same temperature, the mixture was

S. Chatterjee et al. / Tetrahedron: Asymmetry 22 (2011) 367–372
371
poured into ice-water and extracted with EtOAc (2 ꢁ 20 mL). The
combined organic extracts were washed with H2O (3 ꢁ 15 mL)
and brine (1 ꢁ 5 mL), dried, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, 0–10% EtOAc/
hexane) to furnish the monotosylate. Yield: 1.30 g (84%); colorless
134.1, 134.4, 135.5, 135.8, 135.9, 140.6, 173.6. Anal. Calcd for
52H74O5Si2: C, 74.77; H, 8.93. Found: C, 74.98; H, 9.09.
C
3.1.14. Ethyl (6S,9R,10S)-6,9,10-trihydroxyoctadeca-7E-enoate
17
oil; ½a 2D4
ꢂ
¼ þ19:5 (c 1.16, CHCl3); IR: 3528, 1362, 1177 cmꢀ1
;
1H
To a cooled (0 °C) and stirred solution of 16 (0.300 g,
NMR: d 0.86 (t, J = 6.8 Hz, 3H), 1.02 (s, 9H), 1.25–1.42 (m, 14H),
2.18 (br s, 1H), 2.45 (s, 3H), 3.75–3.87 (m, 2H), 3.98–4.04 (m,
1H), 4.21–4.27 (m, 1H), 7.31–7.45 (m, 8H), 7.61–7.66 (m, 4H),
7.78 (t, J = 8.0 Hz, 2H); 13C NMR: d 14.0, 19.3, 21.5, 22.5, 24.5,
26.9, 28.9, 29.2, 29.3, 31.7, 32.7, 71.3, 71.5, 74.2, 127.4, 127.6,
127.9, 129.8, 132.5, 132.9, 133.5, 135.7, 144.8.
0.36 mmol) in THF (5 mL) was added Bu4NF (0.57 mL, 1 M in
THF, 0.57 mmol). The reaction mixture was brought to room tem-
perature and stirred until the reaction was complete (TLC, 3 h). The
mixture was poured into ice-cold water (15 mL) and extracted
with EtOAc (2 ꢁ 10 mL). The organic extract was washed with
water (2 ꢁ 10 mL) and brine (1 ꢁ 5 mL), and dried. Removal of sol-
vent followed by column chromatography of the residue (silica gel,
0–15% EtOAc/hexane) furnished 17. Yield: 0.112 g (87%); colorless
A mixture of the above compound (1.20 g, 2.01 mmol) and
anhydrous K2CO3 (0.63 g, 4.58 mmol) in MeOH (10 mL) was stirred
for 3 h at room temperature. The supernatant was decanted, and
the solid residue washed with EtOAc (20 mL) and the combined or-
ganic extracts concentrated in vacuo. The residue was taken in
EtOAc (30 mL) washed with H2O (3 ꢁ 15 mL) and brine
(1 ꢁ 5 mL), dried, and concentrated in vacuo. Column chromatog-
raphy (silica gel, 0–5% EtOAc/hexane) of the residue gave pure
oil; ½a 2D4
ꢂ
¼ þ3:3 (c 1.22, CHCl3); IR: 3435, 1729 cmꢀ1
;
1H NMR: d
0.88 (t, J = 6.4 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.26–1.39 (m, 14H),
1.42–1.54 (m, 6H), 2.25 (t, J = 7.0 Hz, 2H), 2.50 (br s, 1H), 2.71 (br
s, 2H), 3.51–3.56 (m, 1H), 4.01–4.17 (m, 4H), 5.56–5.68 (m, 2H);
13C NMR: d 14.2, 18.9, 24.8, 26.2, 26.6, 31.2, 31.5, 34.2, 36.5, 37.2,
73.0, 74.2, 75.0, 78.3, 131.2, 137.1, 173.7. Anal. Calcd for
14. Yield: 0.770 g (90%); colorless oil; ½a D24
ꢂ
¼ þ20:2 (c 1.14, CHCl3);
C20H38O5: C, 67.00; H, 10.68. Found: C, 67.26; H, 10.88.
IR: 1110 cmꢀ1; 1H NMR: d 0.89 (t, J = 6.4 Hz, 3H), 1.08 (s, 9H), 1.22–
1.40 (m, 12H), 1.53–1.59 (m, 2H), 2.11–2.16 (m, 1H), 2.43–2.48 (m,
1H), 2.86–2.91 (m, 1H), 3.37–3.43 (m, 1H), 7.32–7.48 (m, 6H),
7.64–7.72 (m, 4H); 13C NMR: d 13.9, 19.2, 22.5, 24.1, 26.7, 29.0,
29.2, 29.5, 31.7, 35.2, 45.9, 54.1, 73.1, 127.3, 127.4, 129.4, 129.5,
133.6, 133.7, 135.7. Anal. Calcd for C27H40O2Si: C, 76.36; H, 9.49.
Found: C, 76.42; H, 9.27.
3.1.15. (6S,9R,10S)-6,9,10-Trihydroxyoctadeca-7E-enoic acid 1d
A solution of 17 (0.1 g, 0.28 mmol) in aqueous-ethanolic KOH
(2 M, 5 mL) was stirred at room temperature for 4 h. Most of the
solvent was removed in vacuo. The residue was taken in CHCl3
(10 mL), and the extract washed with water (2 ꢁ 5 mL) and brine
(1 ꢁ 5 mL), and dried. Removal of solvent followed by preparative
thin layer chromatography of the residue (silica gel, 5% MeOH/
CHCl3) furnished pure 1d. Yield: 0.087 g (95%); semi-solid;
3.1.12. (3R,4S)-4-tert-Butyldiphenylsilyloxydodec-1-en-3-ol 15
To a cooled (ꢀ40 °C) and stirred suspension of Me3SI (1.25 g,
6.13 mmol) in THF (20 mL) was added n-BuLi (3.0 mL, 1.5 M in
hexane, 4.91 mmol). After stirring for 1 h, compound 14 (0.522 g,
1.23 mmol) in THF (5.0 mL) was injected into the mixture and stir-
ring was continued at ꢀ40 °C for 3 h and at room temperature for
12 h. Next, H2O (15 mL) was added to the mixture. The organic
layer was separated, and the aqueous layer extracted with EtOAc
(2 ꢁ 10 mL). The combined organic extracts were washed with
H2O (1 ꢁ 10 mL), and brine (1 ꢁ 5 mL), and dried. Solvent removal
followed by column chromatography (silica gel, 0–15% EtOAc/hex-
ane) of the residue gave pure 15. Yield: 0.436 g (81%); colorless oil;
½
a 2D4
a 2D5
ꢂ
¼ þ5:7 (c, 0.831, CHCl3), ½a D24
ꢂ
¼ þ6:3 (c 0.980, MeOH) {lit.2
½
ꢂ
¼ ꢀ10:7 (c 0.15, MeOH) for natural 1d}; IR: 3630–3550,
3488, 1729 cmꢀ1
;
1H NMR (500 MHz): d 0.86 (t, J = 6.2 Hz, 3H),
1.22–1.39 (m, 14H), 1.40–1.61 (m, 6H), 2.25 (t, J = 6.8 Hz, 2H),
1.83 (br s, 1H), 2.41 (br s, 2H), 3.52–3.55 (m, 1H), 4.04–4.10 (m,
2H), 5.56 (dd, J = 15.4, 5.4 Hz, 1H), 5.67 (dd, J = 15.4, 5.4 Hz, 1H);
13C NMR: d 14.2, 23.8, 26.4, 26.9, 30.7, 30.8, 31.2, 33.9, 34.2, 37.7,
73.2, 75.0, 76.8, 130.8, 137.0, 177.2.
References
1. (a) Brack Egg, A. Diccionario Enciclopedico de Plantas utiles del Peru´; Centro de
Estudios Regionales Andinos Bartolome de las Casas: Cuzco, Peru, 1999. p 187;
(b) Miyake, M.; Sasaki, K.; Ide, K.; Matsukura, Y.; Shijima, K.; Fujiwara, D. J.
Immunol. 2006, 176, 5797–5804; (c) Lovera, A.; Bonilla, C.; Hidalgo, J. Rev. Peru´
Med. Exp. Salud Publica 2006, 23, 177–181.
2. Benavides, A.; Napolitano, A.; Bassarello, C.; Carbone, V.; Gazzerro, P.;
Malfitano, AM.; Saggese, P.; Bifulco, M.; Piacente, S.; Pizza, C. J. Nat. Prod.
2009, 72, 813–817.
3. (a) Vyavahare, V. P.; Chakraborty, C.; Maity, B.; Chattopadhyay, S.; Puranik, V.
G.; Dhavale, D. D. J. Med. Chem. 2007, 50, 5519–5523; (b) Maity, B.;
Chattopadhyay, S. Curr. Bioact. Compat. 2008, 4, 225–244; (c) Guha, P.; Dey,
A.; Sarkar, B.; Dhyani, M. V.; Chattopadhyay, S.; Bandyopadhyay, S. K. J. Exp.
Pharmacol. Ther. 2009, 328, 1–10; (d) Maity, B.; Banerjee, D.; Bandyopadhyay, S.
K.; Chattopadhyay, S. Int. Immunopharmacol. 2009, 9, 491–498; (e) Yadav, S. K.;
Adhikary, B.; Maity, B.; Bandyopadhyay, S. K.; Chattopadhyay, S. Eur. J.
Pharmacol. 2009, 614, 106–113; (f) Guha, P.; Dey, A.; Chatterjee, A.;
Chattopadhyay, S.; Bandyopadhyay, S. K. Br. J. Pharmacol. 2010, 159, 726–
734; (g) Patro, B. S.; Maity, B.; Chattopadhyay, S. Antioxid. Redox. Signal. 2010,
12, 945–960.
4. (a) Turner, W. B.; Aldridge, D. C. Fungal Metabolites II; Academic Press: London,
1983; (b) Gardner, H. W. J. Lipid Res. 1970, 11, 311–321; (c) Kawagishi, H.;
Ando, M.; Micno, T.; Yokota, H.; Konishi, S. Agric. Biol. Chem. 1990, 54, 1329–
1331; (d) Kuga, H.; Ejima, A.; Mitui, I.; Sato, K.; Ishihara, N.; Fukunda, K.; Saito,
F.; Uenaki, K. Biosci. Biotech. Biochem. 1993, 57, 1020–1021; (e) Simon, B.; Anke,
T.; Sterner, O. Phytochemistry 1994, 36, 815–816; (f) Nagai, T.; Kiyohara, H.;
Munakata, K.; Shirahata, T.; Sunazuka, T.; Harigaya, Y.; Yamada, H. Int.
Immunopharmacol. 2002, 2, 1183–1193.
½
a 2D4
ꢂ
¼ þ16:5 (c 1.08, CHCl3); IR: 3475, 997, 925 cmꢀ1
;
1H NMR: d
0.86 (t, J = 6.4 Hz, 3H), 1.08 (s, 9H), 1.14–1.39 (m, 14H), 1.96 (br
s, 1H), 3.48–3.52 (m, 1H), 4.01–4.07 (m, 1H), 4.93–5.23 (m, 2H),
5.74–5.95 (m, 1H), 7.34–7.43 (m, 6H), 7.61–7.65 (m, 4H); 13C
NMR: d 14.1, 19.3, 22.6, 25.4, 26.9, 29.1, 29.2, 29.4, 31.8, 31.9,
74.3, 77.9, 117.6, 127.4, 127.5, 127.6, 129.7, 129.8, 133.4, 133.6,
135.5, 135.7, 135.9, 136.4. Anal. Calcd for C28H42O2Si: C, 76.66; H,
9.65. Found: C, 76.84; H, 9.48.
3.1.13. Ethyl (6S,9R,10S)-6,10-di-tert-butyldiphenylsilyloxy-9-
hydroxyoctadeca-7E-enoate 16
A mixture of 10 (0.097 g, 0.23 mmol), 15 (0.153 g, 0.35 mmol)
and Grubbs’ 2nd generation catalyst (5 mol %) in CH2Cl2 (5 mL)
was stirred for 22 h. After concentrating the mixture in vacuo,
the residue was subjected to column chromatography (silica gel,
0–15% EtOAc/hexane) to give pure 16. Yield: 0.120 g (63% based
on 10); colorless oil; ½a D25
¼ þ16:3 (c 1.02, CHCl3); IR: 3583,
ꢂ
1736 cmꢀ1 1H NMR: d 0.86 (t, J = 6.8 Hz, 3H), 1.19–1.44 (m con-
;
taining a s at d 1.12, 36H), 1.48–1.74 (m, 6H), 2.16 (t, J = 7.2 Hz,
2H), 3.41–3.48 (m, 1H), 4.01–4.14 (m containing a q at d 4.07,
J = 7.2 Hz, 4H), 5.68–5.72 (m, 2H), 7.35–7.41 (m, 12H), 7.61–7.68
(m, 8H); 13C NMR: d 14.1, 14.2, 19.3, 22.6, 23.9, 24.8, 25.5, 26.9,
29.2, 29.4, 31.8, 31.9, 34.2, 37.0, 60.1, 74.2, 74.4, 78.0, 114.3,
127.3, 127.4, 127.6, 129.4, 129.5, 129.7, 129.8, 133.4, 133.7,
5. (a) Salaskar, A.; Mayekar, N. V.; Sharma, A.; Chattopadhyay, A.; Nayak, S. K.;
Chattopadhyay, S. Synthesis 2005, 2777–2781; (b) Salaskar, A.; Sharma, A.;
Chattopadhyay, S. Tetrahedron: Asymmetry 2006, 17, 325–329; (c) Roy, S.;
Sharma, A.; Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron Lett. 2006, 47,
7067–7069; (d) Sharma, A.; Gamre, S.; Chattopadhyay, S. Tetrahedron Lett.

372
S. Chatterjee et al. / Tetrahedron: Asymmetry 22 (2011) 367–372
2007, 48, 633–634; (e) Sharma, A.; Gamre, S.; Chattopadhyay, S. Tetrahedron
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (e) Blackwell, H. E.; O’Leary, D. J.;
Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58–71; (f) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370.
Lett. 2007, 48, 3705–3707; (f) Sharma, A.; Gamre, S.; Roy, S.; Goswami, D.;
Chattopadhyay, A.; Chattopadhyay, S. Tetrahedron Lett. 2008, 49, 3902–3905;
(g) Sharma, A.; Das, P.; Chattopadhyay, S. Tetrahedron: Asymmetry 2008, 19,
2167–2170.
8. (a) Sharma, A.; Mahato, S.; Chattopadhyay, S. Tetrahedron: Lett. 2009, 50, 4986–
4988; (b) Sharma, A.; Gamre, S.; Chattopadhyay, S. Tetrahedron: Asymmetry
2009, 20, 1164–1167; (c) Biswas, S.; Chattopadhyay, S.; Sharma, A. Tetrahedron:
Asymmetry 2010, 21, 27–32.
6. (a) Roy, S.; Sharma, A.; Mula, S.; Chattopadhyay, S. Chem. A Eur. J. 2009, 15,
1713–1722; (b) Roy, S.; Sharma, A.; Dhotare, B.; Vichare, P.; Chattopadhyay, A.;
Chattopadhyay, S. Synthesis 2007, 1082–1090.
7. For reviews on olefin metathesis, see: (a) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371–388; (b) Schrock, R. R. Tetrahedron 1999, 55, 8141–8153; (c)
Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (d) Trnka, T. M.;
9. Goswami, D.; Chattopadhyay, A.; Chattopadhyay, S. Tetrahedron: Asymmetry
2009, 20, 1957–1961.
10. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585–587.