A chemoenzymatic asymmetric synthesis of methyl (6S,13R)-6,13-dihydroxytetradeca-(2E,4E,8E)-trienoate, a component of Mycosphaerella rubella

Article abstract of DOI:10.1016/j.tetasy.2009.04.004

The first asymmetric synthesis of (6S,13R)-6,13-dihydroxytetradeca-(2E,4E,8E)-trienoate has been developed. The key steps of the synthesis were the use of an efficient lipase-catalyzed acylation, a chiral template-driven enantiocontrolled allylation for introducing the stereogenic centers, and a cross-metathesis for controlling the C-8 olefin geometry.

Full text of DOI:10.1016/j.tetasy.2009.04.004

Tetrahedron: Asymmetry 20 (2009) 1164–1167
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A chemoenzymatic asymmetric synthesis of methyl (6S,13R)-6,13-dihydroxy-
tetradeca-(2E,4E,8E)-trienoate, a component of Mycosphaerella rubella
*
Anubha Sharma , Sunita Gamre, Subrata Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric synthesis of (6S,13R)-6,13-dihydroxytetradeca-(2E,4E,8E)-trienoate has been devel-
oped. The key steps of the synthesis were the use of an efficient lipase-catalyzed acylation, a chiral tem-
plate-driven enantiocontrolled allylation for introducing the stereogenic centers, and a cross-metathesis
for controlling the C-8 olefin geometry.
Received 26 February 2009
Accepted 17 April 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Hydroxy acids and the macrolides derived from them are of
wide occurrence in various natural sources; several of these show
impressive biological activity. For example, the C18-hydroxy acids
with diverse oxygenation patterns have been reported to be cyto-
toxic against HeLa cells,1a and P388 mouse leukemic cells.1b Earlier,
the encouraging anti-cancer activity of a ketohydroxy acid, obtai-
ned1c from corn, prompted us to develop its enantioselective syn-
thesis.2 Likewise, the isolation of a new hydroxytetradecatrienoic
acid growth inhibitor from Valsa ambiens,3a and that of other anti-
viral hydroxylated unsaturated fatty acids from the Basidiomycete,
Filoboletus, have been described.3b The fungi in the genus Mycosp-
haerella includes many phytopathogenic species which are sources
of interesting metabolites; some of these compounds exhibit
interesting pharmacological activities.4 For example, the novel
anthraquinone metabolites of rubellins A–D,5a,b and a phenan-
threnequinone, biruloquinone5c have been isolated from Mycosp-
haerella rubella (the causal agent of a disease of Angelica sih,
estris). More recently, methyl (6S,13R)-6,13-dihydroxytetradeca-
(2E,4E,8E)-trienoate 14, and the corresponding hydroxy acid 15,
along with some other derivatives, have been isolated from the
ethyl acetate extracts of the same fungus.5d Compound 15 showed
For the synthesis, acetaldehyde was reacted with the Grignard
reagent prepared from 5-bromopentene to furnish ( )-2. For its
resolution, a lipase-catalyzed trans-acetylation appeared promis-
ing. Lipases are currently widely used in asymmetric organic syn-
thesis, since they do not require any cofactor, operate on a wide
range of substrates, retain good catalytic activity in different med-
ia, display good stereoselectivity, and are commercially available in
free form as well as in immobilized form.6a–c We were particularly
interested in the lipase preparation, Novozyme 435Ò which is inex-
pensive, robust, and effective in resolving racemic carbinols and
amines.6d Although the above lipase is generally effective in resolv-
ing linear secondary alcohols, the enantioselectivity is known to be
governed by reaction conditions such as solvent used and/or acyl
donor.7a–c
For our studies, we used the inexpensive acyl donor, vinyl
acetate and carried out the resolution in diisopropyl ether. True
to our expectation, alcohol 2 could be efficiently resolved under
these conditions to obtain (R)-acetate 3 (96% ee) and (S)-2 (87%
ee) after 44% conversion (cf. GC, 1 h). Alkaline hydrolysis of ace-
tate (R)-3 with KOH/MeOH furnished alcohol (R)-2. The resolved
alcohol (S)-2 could be enantiomerically enriched to 98% ee by a
second Novozyme 435Ò-catalyzed acetylation (10% conversion)
as described above. This was subsequently converted to its anti-
pode under Mitsunobu conditions (p-nitrobenzoic acid/Ph3P/
DEAD/THF, 92%).8 The enantiomeric excesses of the enantiomeric
alcohols (R)-2 and (S)-2 were determined from the relative
weak antibacterial activity (100 lg per disc) against Sarcina lutea,
Bacillus cereus, and Bacillus subtilis, but not against Escherichia coli
and Saccharomyces cerevisiae. For the past few years we have
extensively used the easily available (R)-cyclohexylideneglyceral-
dehyde for the syntheses of a diverse array of bioactive com-
pounds. Herein, we report the first synthesis of (6S,13R)-14 using
the same chiral pool material and invoking a lipase-catalyzed
asymmetric strategy for the generation of the C-13 stereogenic
center.
intensities of the methoxyl resonances of the corresponding
a-
methoxytrifluoromethyl phenyl acetates (MTPAs), prepared using
with (R)-MTPA chloride.9 The configurations of the alcohols were
assigned by converting a small aliquot of the respective alkenol
enantiomers into heptan-2-ol enantiomers and by comparing
their specific rotations with those reported for the authentic
samples.10
* Corresponding author. Tel.: +91 22 25590267; fax: + 91 22 25505151.
E-mail address: anubhas@barc.gov.in (A. Sharma).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.004

A. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 1164–1167
1165
Alcohol (R)-2 was silylated with tert-butyldiphenylsilyl chloride
3. Experimental
(TBDPSCl) in the presence of 4-dimethylaminopyridine (DMAP) to
furnish 4. This was subjected to a cross-metathesis reaction with
the known11 homoallylic alcohol 5, obtained by an enantioselective
Zn-mediated Barbier type allylation of (R)-cyclohexylideneglycer-
aldehyde. The reaction proceeded smoothly in the presence of
Grubbs–Hoveyda second generation catalyst to furnish the desired
alcohol 6 (63%) along with the homo-coupled products of the start-
ing olefins (together 24%). However, the Grubbs’ first and second
generation catalysts did not produce any product. The E-geometry
of the olefin 6 was ascertained from its 1H NMR spectrum. Gener-
ally, increasing steric bulk through the addition of a hydroxyl pro-
tection reduces the cross-metathesis reactivity of the alkenols.12a
Given that substrate 5 already contained a bulky cyclohexylidene
group adjacent to the carbinol functionality, we preferred to use
free alcohol 5 for the cross-metathesis reaction. Also, higher E-
selectivity has been reported when the cross-metathesis is carried
with olefinic alcohols.12b
Silylation of 6 with TBDPSCl/DMAP produced compound 7,
which on treatment with aqueous trifluoroacetic acid (TFA) fur-
nished diol 8. Cleavage of the diol function of 8 with NaIO4 afforded
aldehyde 9. The other required achiral unit 12 was prepared as fol-
lows. Bromination of E-crotonic acid 10 with N-bromosuccinimide
(NBS) followed by esterification gave the bromoester 11, which on
heating with triethyl phosphite furnished phosphonate 12. Its
base-catalyzed reaction with the aldehyde 9 produced the conju-
gated ester 13. This on desilylation with Bu4NF afforded the target
natural ester 14 (Scheme 1).
3.1. General experimental details
All chemicals (Fluka and Lancaster) were used as received.
Other reagents were of AR grade. All anhydrous reactions were car-
ried out under an Ar atmosphere using freshly dried solvents. Un-
less otherwise mentioned, the organic extracts were dried over
anhydrous Na2SO4. The IR spectra as thin films were scanned with
a Jasco model A-202 FT-IR spectrophotometer. The 1H NMR
(200 MHz) and 13C NMR (50 MHz) spectra were recorded with a
Bruker AC-200 spectrometer. The optical rotations were recorded
with a Jasco DIP 360 digital polarimeter.
3.2. ( )-6-Hepten-2-ol 2
To a stirred solution of the Grignard reagent prepared from 5-
bromo-1-pentene (15.92 g, 0.107 mol) and Mg (3.09 g, 0.128 mol)
in THF (80 mL), was added acetaldehyde (4.7 g, 0.107 mmol) in
THF (20 mL). After stirring for 3 h, the mixture was treated with
saturated aqueous NH4Cl, and the organic layer was separated
and the aqueous portion was extracted with Et2O. The combined
organic extracts were washed with water and brine, dried, and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, 0–10% Et2O/hexane) to afford pure 2. Yield:
9.15 g (75%); IR: 3373, 1642 cmꢀ1 1H NMR: d 1.18 (d, J = 6.4 Hz,
;
3H), 1.43–1.46 (m, 4H), 1.83 (br s, 1H), 2.04–2.07 (m, 2H), 3.75–
3.81 (m, 1H), 4.91–5.03 (m, 2H), 5.69–5.90 (m, 1H); 13C NMR: d
OR
OH
i
ii
CH3CHO
(S)-2
+
(R)-3 R = Ac
2
1
iii
2
(R)- R = H
4
iv
R = TBDPS
OTBDPS
i v
O
OTBDPS
O
v
O
O
+
OR
6 R = H
OH
4
5
7 R = TBDPS
OTBDPS
OTBDPS
OH
vii
vi
OH
OTBDPS
CO2Me
CHO
OTBDPS
9
8
O
viii
EtO
ix
Br
CO2H
P
CO2Me
EtO
10
11
12
OR1
x
CO2R2
OR1
13 R1 = TBDPS, R2 = Me
14
xi
R
1 = H, R2 = Me
15 R1 = R2 = H
Scheme 1. Reagents and conditions: (i) CH2@CH(CH2)3MgBr/THF/25 °C/3 h (75%); (ii) vinyl acetate/Novozyme 435/diisopropyl ether/25 °C/1 h (40%); (iii) KOH/MeOH/25 °C/
6 h (88%); (iv) TBDPSCl/imidazole/DMAP/CH2Cl2/25 °C (4: 83%; 7: 88%); (v) Grubbs–Hoveyda second generation catalyst/CH2Cl2/25 °C/4 h (63%); (vi) aqueous TFA/0 °C/3 h
(88%); (vii) NaIO4/CH3CN–H2O/2 h/2 h (91%); (viii) NBS/CCl4; MeOH/H2SO4/D; (ix) P(OEt)3/D; (x) NaH/THF/9/25 °C/18 h (79%); (xi) Bu4NF/THF/0 °C/12 h (87%).

1166
A. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 1164–1167
23.2, 24.9, 33.5, 38.5, 67.6, 114.3, 138.5. Anal. Calcd for C7H14O: C,
73.63; H, 12.36. Found: C, 73.59; H, 12.24.
3.7. (2R,3S,10R)-3,10-Di-(tert-butyldiphenylsilyloxy)-1,
2-cyclohexanedioxyundec-5E-ene (2R,3S,10R)-7
3.3. (R)-2-Acetoxyhept-6-ene (R)-3
As described earlier, the silylation of 6 (0.780 g, 1.46 mmol) with
TBDPSCl (0.44 mL, 1.96 mmol) in the presence of imidazole
(0.118 g, 1.04 mmol) and DMAP (catalytic) in CH2Cl2 (20 mL) fol-
lowed by purification (column chromatography, silica gel, 0–10%
EtOAc/hexane) furnished pure 7. Yield: 1.0 g (88%); colorless oil;
A mixture of ( )-2 (0.912 g, 8.0 mmol), vinyl acetate (0.90 mL,
9.6 mmol), and Novozyme 435Ò (0.05 g) in diisopropyl ether
(20 mL) was agitated on an orbital shaker at 110 rpm for 1 h. The
reaction mixture was filtered, and the solution was concentrated
in vacuo to get a residue, which on chromatography (silica gel,
0–10% EtOAc/hexane) gave pure (S)-2 and (R)-3. Compound (S)-2:
½
a 2D2
ꢁ
¼ þ24:6 (c 1.12, CHCl3); IR: 1660, 1461, 970 cmꢀ1; 1H NMR: d
1.12 (merged s and d, J = 6.4 Hz, 21H), 1.24–1.43 (m, 6H), 1.53–1.57
(m, 8H), 1.76–1.78 (m, 2H), 2.03–2.06 (m, 2H) 3.72–3.78 (m, 2H),
3.83–3.89 (m, 2H), 3.93–4.02 (m, 1H), 5.16–5.22 (m, 2H), 7.25–7.44
(m, 12H), 7.64–7.67 (m, 8H); 13C NMR: d 19.3, 19.5, 23.4, 24.0, 24.1,
25.4, 27.2, 33.2, 35.0, 36.3, 39.1, 65.9, 69.5, 73.5, 77.8, 109.3, 125.0,
127.6, 129.6, 129.8, 134.3, 134.6, 134.9, 135.9, 136.1. Anal. Calcd for
C49H66O4Si2: C, 75.92; H, 8.58. Found: C, 75.71; H, 8.39.
Yield: 0.401 g (44%); colorless oil; ½a D22
¼ þ6:2 (c 1.0, CHCl3). Com-
ꢁ
pound (R)-3: Yield: 0.500 g (40%); colorless oil; ½a D22
¼ ꢀ1:5 (c 1.58,
ꢁ
CHCl3); IR: 1736, 1243 cmꢀ1 1H NMR: d 1.22 (d, J = 7.0 Hz, 3H),
;
1.40–1.46 (m, 4H), 1.98–2.10 (m containing a s at d 2.0, 5H),
4.84–4.97 (m, 3H), 5.71–5.84 (m, 1H); 13C NMR: d 21.0, 37.8,
39.8, 73.6, 117.8, 138.8, 170.3. Anal. Calcd for C9H16O2: C, 69.19;
H, 10.32. Found: C, 69.05; H, 10.40.
3.8. (2R,3S,10R)-3,10-Di-(tert-butyldiphenylsilyloxy)undec-5E-
ene-1,2-diol (2R,3S,10R)-8
3.4. (R)-6-Hepten-2-ol (R)-2
Compound7 (1.0 g, 1.29 mmol)was mixedwith 80%aqueousTFA
(10 mL), stirred for 3 h at 0 °C, and diluted with CHCl3 and water. The
organic layer was separated, the aqueous layer was extracted with
CHCl3, and the combined organic layers were washed successively
with aqueous 2% NaHCO3, water, and brine, and dried. Solvent re-
moval in vacuo followed by column chromatography of the residue
(silica gel, 0–5% MeOH/CHCl3) furnished pure 8. Yield: 0.790 g (88%);
A mixture of (R)-3 (2.34 g, 15 mmol) and KOH (1.68 g, 30 mmol)
in MeOH (25 mL) was stirred at room temperature for 6 h. The
mixture was filtered, and concentrated in vacuo, after which water
was added to it, and extracted with EtOAc. The organic layer was
washed with water and brine, and dried. Removal of the solvent
in vacuo followed by column chromatography of the residue (silica
gel, 0–10% EtOAc/hexane) afforded pure (R)-2. Yield: 1.50 g (88%);
thick liquid; ½a D22
ꢁ
¼ þ13:1 (c 3.12, CHCl3); IR: 3438, 971 cmꢀ1
;
1H
colorless oil; ½a D22
¼ ꢀ6:8 (c 1.22, CHCl3).
ꢁ
NMR: d 1.14 (merged s and d, J = 6.8 Hz, 21H), 1.26–1.44 (m, 4H),
1.75 (br s, 2H), 2.14–2.27 (m, 4H), 3.62–3.81 (m, 4H), 4.05–4.15
(m, 1H), 5.15–5.25 (m, 2H), 7.25–7.40 (m, 12H), 7.66–7.74 (m, 8H);
13C NMR: d 19.3, 23.1, 24.7, 27.0, 32.4, 36.6, 38.8, 62.9, 69.3, 73.4,
75.4, 127.3, 128.3, 129.4, 129.9, 133.0, 133.6, 134.8, 135.3. Anal.
Calcd for C43H58O4Si2: C, 74.30; H, 8.41. Found: C, 74.14; H, 8.56.
3.5. (R)-2-(tert)-Butyldiphenylsilyloxy-6-heptene (R)-4
To a stirred and cooled (ꢀ30 °C) solution of a mixture of (R)-2
(1.20 g, 10.52 mmol), imidazole (0.857 g, 12.60 mmol), and DMAP
(catalytic) in CH2Cl2 (20 mL) was dropwise added TBDPSCl
(3.47 g, 12.60 mmol) in CH2Cl2 (15 mL). After stirring the mixture
for 7 h at room temperature, it was poured into ice-cold water.
The organic layer was separated and the aqueous portion was ex-
tracted with CHCl3. The combined organic extracts were washed
with water and brine, and dried. Removal of solvent in vacuo fol-
lowed by purification of the residue by column chromatography
(silica gel, 0–5% EtOAc/hexane) afforded pure 4. Yield: 3.07 g
3.9. (2S,9R)-2,9-Di-(tert-butyldiphenylsilyloxy)dec-4E-enal
(2S,9R)-9
To
a cooled (10 °C) and stirred solution of 8 (0.350 g,
0.50 mmol) in 60% aqueous acetonitrile (20 mL) was added NaIO4
(0.212 g, 1.0 mmol) in portions. After stirring for 2 h, the mixture
was filtered, and the filtrate was treated with 10% aqueous NaHSO3
and was extracted with CHCl3. The organic layer was washed with
water and brine, and was concentrated in vacuo to get a residue,
which on column chromatography (silica gel, 0–10% EtOAc/hex-
ane) furnished pure 9. Yield: 0.304 g (91%); thick liquid;
(83%); colorless oil;
½
a 2D2
ꢁ
¼ þ13:2 (c 1.14, CHCl3); IR: 3050,
1642 cmꢀ1 1H NMR: d 1.17 (merged s and d, J = 6.8 Hz, 12H),
;
1.26–1.49 (m, 4H), 1.93–1.96 (m, 2H), 3.81–3.86 (m, 1H), 4.87–
4.98 (m, 2H), 5.65–5.85 (m, 1H), 7.36–7.46 (m, 6H), 7.66–7.70
(m, 4H); 13C NMR: d 19.3, 23.2, 24.5, 27.1, 33.7, 38.9, 69.4, 114.3,
127.4, 127.5, 129.4, 134.4, 135.9, 138.9. Anal. Calcd for C23H32OSi:
C, 78.35; H, 9.15. Found: C, 78.51; H, 9.32.
½
a 2D2
ꢁ
¼ þ16:0 (c 0.861, CHCl3); IR: 1712, 989, 961 cmꢀ1
;
1H NMR:
d 1.06 (s, 18H), 1.12 (d, J = 6.4 Hz, 3H), 1.65–1.84 (m, 4H), 2.21–
2.32 (m, 4H), 3.79–3.89 (m, 1H), 3.99–4.02 (m, 1H), 5.28–5.32
(m, 2H), 7.19–7.36 (m, 12H), 7.63–7.67 (m, 8H), 9.52 (d,
J = 1.4 Hz, 1H); 13C NMR: d 19.1, 19.4, 24.5, 27.8, 36.2, 63.1, 75.7,
127.2, 128.4, 129.8, 129.5, 132.7, 133.7, 135.2, 135.7, 198.1. Anal.
Calcd for C42H54O3Si2: C, 76.08; H, 8.21. Found: C, 75.91; H, 8.09.
3.6. (2R,3S,10R)-10-(tert)-Butyldiphenylsilyloxy-1,
2-cyclohexanedioxyundec-5E-en-3-ol (2R,3S,10R)-6
A
mixture of 4 (0.680 g, 1.93 mmol), alcohol 5 (0.409 g,
1.93 mmol), and Grubbs–Hoveyda second generation catalyst
(5 mol %) in CH2Cl2 (10 mL) was stirred for 4 h. After concentrating
the mixture in vacuo, the residue was subjected to column chro-
matography (silica gel, 0–15% EtOAc/hexane) to give pure 6. Yield:
3.10. Methyl (6S,13R)-6,13-di-(tert-butyldiphenylsilyloxy)
tetradeca-(2E,4E,8E)-trienoate 13
0.651 g (63%); colorless oil; ½a D22
¼ þ18:8 (c 1.04, CHCl3); IR: 3307,
ꢁ
To
a stirred suspension of pentane-washed NaH (33 mg,
1642, 967 cmꢀ1 1H NMR: d 1.15 (merged s and d, J = 6.8 Hz, 12H),
;
0.68 mmol, 50% suspension in oil) in THF (5 mL) was added phos-
phonate 12 (0.160 g, 0.68 mmol) in THF (5 mL). After 15 min, when
the solution became clear, the mixture was cooled to 0 °C, and
aldehyde 9 (0.300 g, 0.46 mmol) in THF (5 mL) was dropwise added
to it. After stirring at room temperature for 18 h, the mixture was
poured into ice-cold water and extracted with Et2O. The ether layer
was washed with water and brine, dried, and concentrated in va-
cuo to give a residue, which on column chromatography (silica
1.38–1.48 (m, 6H), 1.58–1.61 (m, 8H), 1.99–1.95 (m, 2H), 2.14–2.22
(m, 2H), 3.68–3.71 (m, 1H), 3.80–3.88 (m, 2H), 3.93–4.00 (m, 2H),
5.33–5.51 (m, 2H), 7.25–7.44 (m, 6H), 7.64–7.73 (m, 4H); 13C NMR:
d 19.2, 23.2, 23.8, 24.0., 24.9, 27.0, 32.5, 34.8, 36.2, 38.9, 64.9, 69.3,
70.7, 78.1, 109.8, 125.0, 127.3, 127.4, 129.4, 134.0, 134.3, 135.5,
135.8. Anal. Calcd for C33H48O4Si: C, 73.83; H, 9.01. Found: C,
73.62; H, 8.78.

A. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 1164–1167
1167
gel, 0–10% Et2O/hexane) furnished pure 13. Yield: 0.265 g (79%);
References
colorless oil; ½a D22
ꢁ
¼ þ8:9 (c 0.842, CHCl3); IR: 1742 cmꢀ1
;
1H
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Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122,
58–71.
NMR: d 1.08 (s, 18H), 1.25–1.42 (m containing a d at d 1.21,
J = 6.4 Hz, 7H), 2.04–2.17 (m, 4H), 3.69–3.81 (m containing a s at
d 3.73, 4H), 4.18–4.21 (m, 1H), 5.21–5.23 (m, 2H), 5.75 (d,
J = 15.4 Hz, 1H), 6.05–6.09 (m, 2H), 7.18–7.22 (m, 1H), 7.25–7.41
(m, 12H), 7.61–7.76 (m, 8H); 13C NMR: d 19.3, 26.6, 27.1, 29.7,
38.5, 40.8, 51.2, 64.2, 67.0, 120.5, 124.7, 127.7, 129.5, 129.7,
134.8, 135.2, 135.9, 144.2, 144.4, 168.2. Anal. Calcd for
C47H60O4Si2: C, 75.76; H, 8.12. Found: C, 75.63; H, 8.36.
3.11. Methyl (6S,13R)-6,13-dihydroxytetradeca-(2E,4E,8E)-
trienoate 14
To
a cooled (0 °C) and stirred solution of 13 (0.265 g,
0.36 mmol) in THF (5 mL) was added Bu4NF (1.1 mL, 1.10 mmol,
1.0 M in THF). The reaction mixture was brought to room temper-
ature and was stirred until the reaction was complete (cf. TLC,
12 h). The mixture was poured into ice-cold water and was ex-
tracted with EtOAc. The organic extract was washed with water
and brine, and dried. Removal of the solvent followed by column
chromatography of the residue (silica gel, 0–15% EtOAc/hexane)
furnished 14. Yield: 0.083 g (87%); colorless oil; ½a D22
¼ þ14:8 (c
ꢁ
0.618, MeOH) (lit.5d
½ ꢁ ¼ þ15:2 (c 0.2, MeOH)); IR: 3412,
a D
1724 cmꢀ1 1H NMR: d 1.16 (t, J = 6.2 Hz, 3H), 1.29–1.58 (m, 4H),
;
2.03–2.08 (m, 2H), 2.21–2.33 (m, 2H), 3.72–3.98 (m containing a
s at d 3.73, 4H), 4.18–4.27 (m, 1H), 5.41–5.57 (m, 2H), 5.87 (d,
J = 15.8 Hz, 1H), 6.08–6.14 (m, 2H), 7.21–7.28 (m, 1H); 13C NMR:
d 24.2, 26.2, 30.7, 38.5, 40.7, 51.4, 67.7, 69.8, 120.5, 124.4, 127.4,
129.7, 134.9, 135.7, 144.2, 144.5, 168.3.