The first total synthesis of a 12-membered macrolide balticolid

Article abstract of DOI:10.1016/j.tetlet.2012.10.027

Herein the first total synthesis of balticolid, a 12-membered macrolide is described.

Full text of DOI:10.1016/j.tetlet.2012.10.027

Tetrahedron Letters 53 (2012) 6843–6845
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The first total synthesis of a 12-membered macrolide balticolid
⇑
Palakodety Radha Krishna , Sunchu Prabhakar, D. Venkata Ramana
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein the first total synthesis of balticolid, a 12-membered macrolide is described.
Received 22 August 2012
Revised 5 October 2012
Accepted 6 October 2012
Available online 13 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Balticolid
12-Membered macrolide
Anti-HSV activity
Ring-closing metathesis
Many novel pharmacologically active secondary metabolites
have been isolated from marine microorganisms.1 Several
12-membered macrolides have been isolated from fungal metabo-
lites (for e.g. cladospolides,2 pandangolides3). Balticolid 1, a new
12-membered macrolide was isolated by Shushni et al,4 from the
marine fungus belonging to the Ascomycetous species. The struc-
ture was determined as (4R,5E,9E,12R)-4-hydroxy-12-methyloxa-
cyclododeca-5,9-diene-2,8-dione possessing an antiviral activity
was undertaken (Scheme 2). Accordingly, base induced ring-open-
ing reaction of (R)-propylene oxide with protected propargyl alco-
hol resulted in the corresponding alkylated propargylic alcohol
which on reported5a transformations gave the allylic alcohol 8.
Compound 8 on oxidation (IBX/DMSO/EtOAc/rt/3 h) afforded the
aldehyde (85%), which was further converted to 9 on Barbier ally-
lation (Zn/allylbromide/satd. NH4Cl/THF/0 °C to rt/12 h) followed
by the protection of the ensuing alcohol as its silyl-ether (TBS-Cl/
imidazole/DMAP/CH2Cl2/0 °C to rt/1 h). Furthermore compound 9
on PMB-deprotection (DDQ conditions7) furnished the requisite
alcohol 6 (80%).
Next, the synthesis of the acid component 7 (Scheme 3) was
taken up. Accordingly, allylic alcohol 10 was identified as an
important precursor and hence synthesis of 10 was accomplished
by adopting a literature inspired procedure.5c Further, compound
10 was converted into its MOM-ether (MOM-Cl/DIPEA/CH2Cl2/
0 °C to rt/12 h) to afford compound 11 (90%). The silyl group in
compound 11 was deprotected under conventional conditions
(TBAF/THF/0 °C to rt/2 h) to afford the corresponding primary alco-
hol that was oxidized8a {TEMPO/BIAB/CH2Cl2:H2O (1:1)/0 °C to rt/
2 h} to the desired acid 7 (91% over two steps).8b
(anti-HSV) with an IC50 value of 0.45 lM. Structurally, balticolid
attracted our attention due to its differently positioned functional
groups than related macrolides. For instance, the presence of a
sensitive methylene at C7 flanked by the vinyl ketone (C8–C10)
and allylic alcohol (C4–C6) moieties along with the two E-olefinic
bonds at C5–C6 and C9–C10 makes this molecule synthetically
interesting (Fig. 1). As a part of our interest in the synthesis of such
biologically active macrolides,5 herein we describe the total syn-
thesis of balticolid 1.
Ever since the discovery of Grubbs catalyst, metathesis6 based
synthetic strategies of natural products not only influenced the
way synthetic chemists think but also shortened the sequences
en route. Our synthetic plan (Scheme 1) involved RCM of the ester
5 that could be accessed from intermediates 6 and 7, to furnish
macrocycle 4a. Alcohol 6 and acid 7 were synthesized indepen-
dently. Subsequent transformations of macrocycle 4a resulted in
target compound 1.
7
6
O
O
8
9
Thus, the synthesis of balticolid 1 primarily involved the syn-
thesis of two key fragments 6 and 7 followed by their transforma-
tions into the target. Firstly, synthesis of alcohol intermediate 6
5
OH
OH
O
10
11
O
4
12
O
2
O
3
1
OH
O
O
OH
OH
Cladospolide B 2 Pandangolide 3
Balticolid 1
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
Figure 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.027

6844
P. Radha Krishna et al. / Tetrahedron Letters 53 (2012) 6843–6845
TBSO
OMOM
O
O
HO
OH
OMOM
OH
O
OMOM
OTBS
7
+
O
OTBS
O
O
O
O
4a
5
6
Balticolid 1
Scheme 1. Retrosynthesis.
Synthesis of alcohol fragment 6
OPMB
center as a single geometric isomer. However, no efforts were made
to separate the isomers because the epimeric carbon eventually
transforms into a ketone functionality in further steps. Thus, the
epimeric mixture of macrolides 4 on desilylation (TBAF/THF/0 °C
to rt/2 h) followed by oxidation (Dess–Martin periodinane/CH2Cl2/
0 °C to rt/2 h) gave macrocylic vinyl ketone 12 (82%), which on fur-
ther deprotection (PMB-silica/neat/rt/0.5 h) of MOM-group gave
the presumable target macrolide in 95% yield as an exclusive geo-
metric isomer. This compound was characterized from its spectral
data.9 The spectral data of the synthetic sample did not match with
the reported one. For instance, its 1H NMR spectrum revealed the
characteristic allylic olefinic proton (H4) appearing at d 4.35–
4.27 ppm as a multiplet and H5 proton and H6 appearing at d
5.53–5.47 as a multiplet, while the same proton (H4) reportedly res-
onated at d 4.54 ppm as a multiplet and H5 proton at d 5.73 as a dd
(J = 15.9, 2.8 Hz) and H6 at d 5.75 as a multiplet. The 13C NMR spec-
trum too revealed certain discrepancies: for instance C4 appeared at
OPMB
OTBS
O
a
Ref. 5a
OH
8
9
OH
OTBS
b
6
Scheme 2. Reagents and conditions: (a) (i) IBX, DMSO, EtOAc, rt, 3 h, 85%; (ii) Zn,
allylbromide, THF, satd. NH4Cl, 0 °C to rt, 12 h, 85%; (iii) TBS-Cl, imidazole, cat.
DMAP, CH2Cl2, 0 °C to rt, 1 h, 95%, (b) DDQ, CH2Cl2:H2O (18:1), 0 °C to rt, 1 h, 80%.
Having the requisite fragments 6 and 7 in hand, esterification
(DCC/DMAP/CH2Cl2/0 °C to rt, Scheme 4) between them furnished
ester 5 (79%). Next, the crucial RCM of ester 5 (G-II/CH2Cl2/reflux/
12 h) resulted in chromatographically inseparable diastereomeric
macrolides 4 (1:1 ratio in 75% combined yield), epimeric at C8
Synthesis of acid fragment 7
HO
b
TBSO
a
Ref. 5c
TBSO
OTBS
O
OMOM
OMOM
11
10
OH
7
Scheme 3. Reagents and conditions: (a) MOM-Cl, DIPEA, CH2Cl2, 0 °C to rt, 12 h, 90%, (b) (i) TBAF, THF, 0 °C to rt, 2 h, 91%; (ii) TEMPO, BAIB, CH2Cl2: H2O (1:1), 0 °C to rt, 2 h,
91%.
O
O
TBSO
OMOM
OTBS
O
d
c
b
O
a
6
+
7
OMOM
OH
O
O
OMOM
O
O
O
O
O
5
12
4
Z-I
e
TBSO
O
OMOM
OMOM
OH
f
g
O
O
O
O
O
O
1
4a
12a
Mes
Mes
Mes
Mes
Ph
Cl
Cl
Cl
Cl
Ru
O
Ru
P(Cy)3
Grubbs catalyst 2nd
generation
Hoveyda-Grubbs
catalyst 2ndgeneration
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to rt, 12 h, 79%, (b) G-II (10 mol %), CH2Cl2, reflux, 12 h; 75%, (c) (i) TBAF, THF, 0 °C to rt, 2 h, 80%;
(ii) Dess–Martin periodinane, CH2Cl2, 0 °C to rt, 2 h, 82%, (d) PMB-silica, neat, 0.5 h, 95%, (e) HG-II (10 mol %), toluene, reflux, 12 h, 70%, (f) (i) TBAF, THF, 0 °C to rt, 2 h, 82%; (ii)
Dess–Martin periodinane, CH2Cl2, 0 °C to rt, 2 h, 83%, (g) PMB-silica, neat, 0.5 h, 93%.

P. Radha Krishna et al. / Tetrahedron Letters 53 (2012) 6843–6845
6845
s, 9H), 0.04 (br s, 6H); 13C NMR (75 MHz, CDCl3): d 138.2, 117.0, 93.8, 74.2, 59.2,
55.3, 38.2, 25.8, ꢁ5.3; HRMS: m/z calcd for C13H28O3NaSi [M+Na]+: 283.1699;
d 71.5 ppm in contrast to the reported value at d 69.1 ppm while C6
appeared at d 128.6 ppm instead of at d 125.2 ppm. Also, the specific
found: 283.1704. Compound 7: Pale yellow liquid. ½a D25
ꢀ
+193.4 (c 0.25, CHCl3); 1
H
rotation value did not match with the reported value {½a D25
ꢀ
+195.2 (c
NMR (500 MHz, CDCl3): d 5.77–5.63 (m, 1H), 5.34–5.22 (m, 2H), 4.65 (d, 1H,
J = 6.7 Hz), 4.54–4.44 (m, 2H), 3.33 (br s, 3H), 2.70–2.44 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 176.3, 136.3, 118.3, 93.9, 73.5, 55.5, 40.7; HRMS: m/z calcd for
C7H12O4Na [M+Na]+: 183.0627; found: 183.0631. Compound 9: Colorless liquid.
0.25, MeOH); Lit.4 ½a D25
ꢀ
+135.2 (c 0.35, MeOH)}. Based on the above
data, the geometry of the newly formed double bond was tenta-
tively assigned as Z and the compound was christened as Z-1.9
Hence, ester 5 on RCM under Hoveyda-Grubbs II conditions
(Scheme 4, conditions e10) gave a mixture of separable macrolides
4 and 4a (1:3 ratio, 70% combined yield) as respective epimers.
Each macrolide set was separated and characterized indepen-
dently.9 The less polar minor macrolide set was found to have com-
parable data with the macrolide-4 that was obtained earlier under
G-II conditions and matched when a co-tlc was run. Since macro-
lide 4 was already shown to afford isomeric target molecule (Z-
1), it was decided that the rest of the synthetic sequence be carried
out on macrolide 4a. Thus, compound 4a, which was thought to be
different due to its E-geometry around the newly formed double
bond, was taken up next. Accordingly, epimeric mixture of macro-
lide 4a on desilylation (TBAF/THF/0 °C to rt/2 h) followed by oxida-
tion (Dess–Martin periodinane/CH2Cl2/0 °C to rt/2 h) furnished
macrocylic vinyl ketone 12a (83%), which on further deprotection
of MOM-group, under similar conditions as mentioned above, gave
balticolid 1 (93%). Compound 1 was characterized by its spectral
data. The spectral data of the synthetic sample matched with the
reported data and hence assigned as 1.4,9 For instance, the 1H
NMR spectrum of 1 revealed the characteristic the allylic olefinic
proton (C4) at d 4.50 ppm as a broad singlet and C5 proton and
C6 appearing at d 5.74–5.65 as a multiplet. The 13C NMR spectrum
of 1 displayed C4 at d 69.0 ppm while C6 appeared at d 125.1 ppm.
½
a 2D5
ꢀ
ꢁ11.76 (c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.18 (d, 2H, J = 8.3 Hz),
6.79 (d, 2H, J = 8.3 Hz), 5.80–5.60 (m, 1H), 5.59–5.40 (m, 2H), 5.02–4.96 (m, 2H),
4.40 (dd, 2H, J = 18.8, 11.3 Hz), 4.06 (q, 1H, J = 12.0, 6.0 Hz), 3.78 (br s, 3H), 3.54–
3.46 (m, 1H), 2.38–2.09 (m, 4H), 1.13 (d, 3H, J = 6.0 Hz), 0.87 (br s, 9H), 0.02 (d, 6H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d 158.9, 135.3, 135.1, 130.9, 129.0, 126.3,
116.5, 113.6, 74.3, 73.2, 69.9, 55.1, 43.0, 39.1, 39.0, 25.8, 19.4, 18.2, ꢁ4.7, ꢁ4.2;
HRMS: m/z calcd for
C
23H38O3NaSi [M+Na]+: 413.2482; found: 413.2491.
Compound 6: Yellow oil. ½a D25
ꢀ
ꢁ3.07 (c 0.15, CHCl3); 1H NMR (500 MHz, CDCl3):
d 5.82–5.68 (m, 1H), 5.59–5.46 (m, 2H), 5.01 (br d, J = 15.5 Hz), 4.16–4.09 (m, 1H),
3.80–3.73 (m, 1H), 2.29–2.16 (m, 3H), 2.16–2.05 (m, 1H), 1.17 (d, 3H, J = 6.0 Hz),
0.89 (s, 9H), 0.03 (d, 6H, J = 11.0 Hz); 13C NMR (75 MHz, CDCl3): d 136.7, 134.9,
125.9, 116.8, 72.7, 66.9, 43.0, 41.9, 25.7, 22.5, 18.1, ꢁ4.8; HRMS: m/z calcd for
C
15H30O2NaSi [M+Na]+: 293.1907; found: 293.1910. Compound 5: Yellow oil.
½ ꢀ
a 2D5 +138.2 (c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3): d 5.76–5.64 (m, 2H),
5.48–5.45 (m, 2H), 5.30 (d, 1H, J = 17.1 Hz), 5.19 (d, 1H, J = 9.9 Hz), 5.01–4.98 (m,
2H), 4.92–4.86 (m, 1H), 4.63 (d, 1H, J = 6.6 Hz), 4.50 (d, 1H, J = 6.6 Hz), 4.43 (m,
1H), 4.08–4.07 (m, 1H), 3.80 (br s, 3H), 2.60–2.54 (m, 1H), 2.42–2.38 (m, 1H),
2.31–2.16 (m, 3H), 1.19 (d, 3H, J = 6.0 Hz), 0.87 (br s, 9H), 0.01 (d, 6H, J = 12.1 Hz);
13C NMR (75 MHz, CDCl3): d 170.1, 136.8, 134.9, 124.7, 117.9, 116.7, 94.1, 73.9,
72.9, 70.6, 60.3, 55.5, 43.0, 41.1, 38.4, 29.6, 25.8, 20.9, 19.3, 18.2, 14.1, ꢁ4.7;
HRMS: m/z calcd for
Compound 4: Pale yellow liquid.
(500 MHz, CDCl3): 5.44–5.36 (m, 1H), 5.21–5.12 (m, 4H), 4.69 (d, 1H,
C
22H40O5NaSi [M+Na]+: 435.2548; found: 435.2675.
½ ꢀ
a 2D5 +202.5 (c 0.35, CHCl3); 1H NMR
d
J = 6.4 Hz), 4.52 (d, 1H, J = 6.4 Hz), 4.36–4.29 (m, 1H), 4.01–3.94 (m, 1H), 3.35
(s, 3H), 2.72 (dd, 1H, J = 12.8, 3.9 Hz), 2.48–2.38 (m, 2H), 1.23 (d, 3H, J = 6.4 Hz),
0.86 (s, 9H), 0.02 (d, 6H, J = 10.3 Hz); 13C NMR (300 MHz, CDCl3): d 169.8, 135.8,
132.0, 128.1, 93.4, 74.6, 73.9, 68.6, 55.4, 42.0, 40.7, 25.8, 20.7, ꢁ4.3; HRMS: m/z
calcd for C20H36O5NaSi [M+Na]+: 407.2224; found: 407.2231. Compound 4a:
Yellow oil. ½a 2D5
ꢀ
+ 171.9 (c 0.17, CHCl3); 1H NMR (75 MHz, CDCl3): d 5.67–5.53 (m,
1H), 5.39–5.12 (m, 3H), 5.09–5.00 (m, 1H), 4.69 (br s, 2H), 4.44–4.36(m, 1H),
4.19–4.10 (m, 1H), 3.41 (s, 3H), 2.75–2.63 (m, 1H), 2.56 (dd, 1H, J = 13.7, 3.5 Hz),
2.48–2.30 (m, 2H), 2.24–2.05 (m, 2H), 1.24 (d, 3H J = 7.9 Hz), 0.89 (s, 9H), 0.04 (d,
6H, J = 5.4 Hz); 13C NMR (75 MHz, CDCl3): d 169.4, 143.0, 136.0, 131.1, 128.3,
126.4, 94.3, 72.8, 71.9, 69.4, 55.4, 41.1, 40.4, 39.1, 25.8, 20.2, 18.2, ꢁ4.5; HRMS:
m/z calcd for C20H36O5NaSi [M+Na]+: 407.2224; found: 407.2221. Compound 12:
The specific rotation was found to be ½a D25
ꢀ
+141.2 (c 0.38, MeOH)
{Lit.4
½
a 2D5
+135.2 (c 0.35, MeOH)}. HRMS spectrum of 1 displayed
ꢀ
the [M+Na]+ at 247.0934 while calculated gave 247.0940 for the
molecular formula C21H26O3Na as an additional support.
In summary, synthesis of balticolid 1 was accomplished via
Hoveyda-Grubbs II catalyst assisted RCM of ester 5 in good yields
and selectivity. The key intermediates 6 and 7 were accessed from
common and inexpensive starting materials. Alongside, isomeric
balticolid Z-1 was also synthesized.
Yellow oil. ½a 2D5
ꢀ
+130.6 (c 0.15, CHCl3); 1H NMR (500 MHz, CDCl3): d 6.59–6.53 (m,
1H), 5.94 (d, 1H, J = 16.1 Hz), 5.72–5.66 (m, 1H), 5.45–5.34 (m, 1H), 5.24–5.17 (m,
1H), 4.66 (d, 1H, J = 6.4 Hz), 4.52 (d, 1H, J = 6.8 Hz), 4.41–4.36 (m, 1H), 3.38–3.30
(m, 4H), 3.18 (dd, 1H, J = 13.7, 4.0 Hz), 2.82 (dd, 1H, J = 12.5, 4.0 Hz), 2.47 (br t, 1H,
J = 12.1 Hz), 2.39–2.28 (m, 2H), 1.30 (d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3):
d 198.8, 169.3, 144.6, 134.0, 131.9, 129.9, 93.7, 74.4, 69.6, 55.3, 45.1, 41.9, 38.7,
20.8; HRMS: m/z calcd for C14H20O5Na [M+Na]+: 291.1208; found: 291.1202.
Compound 12a: Pale yellow oil. ½a D25
ꢀ
+110.4 (c 0.25, CHCl3); 1H NMR (500 MHz,
CDCl3): d 6.67–6.56 (m, 1H), 5.91 (d, 1H, J = 16.2 Hz), 5.87–5.77 (m, 1H), 5.48 (dd,
1H, J = 15.8, 4.9 Hz), 5.14–5.03 (m, 1H), 4.68 (dd, 2H, J = 14.5, 6.9 Hz), 4.47–4.45
(m, 1H), 3.40 (br s, 3H), 3.26 (d, 2H, J = 6.6 Hz), 2.76 (dd, 1H, J = 13.4, 4.5 Hz), 2.52
(dd, 1H, J = 13.4, 3.9 Hz), 2.49–2.28 (m, 1H), 1.30 (d, 3H, J = 6.2 Hz); 13C NMR
(75 MHz, CDCl3): d 197.3, 169.1, 144.9, 134.0, 131.9, 126.0, 122.1, 94.5, 71.8, 55.5,
51.9, 50.8, 50.6, 40.8, 38.4, 20.5; HRMS: m/z calcd for C14H20O5Na [M+Na]+:
Acknowledgments
Two of the authors (S.P. and D.V.R.) thank the CSIR, New Delhi
for the financial support in the form of fellowships.
291.1208; found: 291.1199. Balticolid Z-1: Yellow oil. ½a D25
ꢀ
+195.0 (c 0.25, MeOH);
1H NMR (75 MHz, CD3OD): d 6.60 (m, 1H), 5.87 (d, 1H, J = 16.2 Hz), 5.53–5.47 (m,
2H), 5.09 (m, 1H), 4.28 (m, 1H), 3.36–3.29 (m, 1H), 3.0 (dd, 1H, J = 14.3, 3.3 Hz),
2.63 (dd, 1H, J = 12.4, 4.7 Hz), 2.40–2.17 (m, 3H), 1.21 (d, 3H, J = 6.2 Hz); 13C NMR
(75 MHz, CD3OD): d 202.0, 171.8, 147.5, 138.1, 132.8, 128.6, 72.1, 71.5, 45.9, 44.8,
References and notes
39.7, 21.1; HRMS: m/z calcd for
C
12H16O4Na [M+Na]+: 247.0940; found:
247.0948. Balticolid 1: Pale yellow oil. ½a D25
ꢀ
+142.5(c 0.38, MeOH); 1H NMR
1. (a) Liberra, K.; Lindequist, U. Pharmazie 1995, 50, 583–588; (b) Blunt, J. W.;
Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2011,
28, 196–268.
2. Hirota, A.; Sakai, H.; Isogai, A. Agric. Biol. Chem. 1985, 49, 731–735.
3. Jadulco, R.; Proksch, P.; Wray, V.; Sudarsono; Berg, A.; Grafe, U. J. Nat. Prod.
2001, 64, 527–530.
(500 MHz, CD3OD): d 6.76–6.68 (m, 1H), 5.95 (d, 1H, J = 16.3 Hz), 5.74–5.64 (m,
2H), 5.11–5.03 (m, 1H), 4.50–4.49 (m, 1H), 3.37 (dd,1H, J = 13.2, 6.6 Hz), 3.19–
3.15 (m, 1H), 2.63 (dd, 1H, J = 13.5, 4.6 Hz), 2.58 (dd, 1H, J = 13.2, 3.4 Hz), 2.50–
2.45 (m, 1H), 2.36–2.28 (m, 1H), 1.28 (d, 3H, J = 6.2 Hz); 13C NMR (75 MHz,
CD3OD): d 202.5, 171.8, 148.0, 138.2, 132.6, 125.0, 72.0, 69.0, 45.6, 43.2, 39.5,
21.0; HRMS: m/z calcd for C12H16O4Na [M+Na]+: 247.0940; found: 247.0934.
10. The authors are thankful to the referees for asking us to describe all the RCM
reactions performed. The set of RCM reactions used are as follows: firstly the
RCM of compound 5 was conducted in reflux methylene chloride under G-II
catalyst which resulted in macrocyle as an exclusive Z-isomer with complete
consumption of starting material. Next, in order to check if temperature plays a
role in altering the double bond geometry, the same reaction was conducted in
reflux toluene. Yet, the macrocycle obtained was again Z-isomer. Hence, when
the RCM was performed with Hoveyda-Grubbs II catalyst in reflux methylene
chloride, two macrocyclic products (Z:E = 1:1 based on tlc) were formed though
no complete conversion of the started material 5 was observed. However, for the
same reaction when conducted at elevated temperature in toluene, complete
conversion was observed to result in macrocylic products with altered geometric
ratio in favor of E-isomer (Z:E = 1:3 based on tlc). It maybe deduced that while
the conversion (RCM under HG-II conditions) was dependent on temperature,
the double bond geometry was dependent both on the catalyst and the
temperature.
4. Shushni, M. A. M.; Singh, R.; Mentel, R.; Lindequist, U. Mar. Drugs 2011, 9, 844–
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(b) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 250, 243–251; (c)
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9. Spectral data of some selected compounds. Compound 11: Pale yellow liquid. ½a D25
ꢀ
+141.1 (c 0.75, CHCl3); 1H NMR (500 MHz, CDCl3): d 5.71–5.64 (m, 1H), 5.22–5.10
(m, 2H), 4.66 (d, 1H, J = 7.0 Hz), 4.50 (d, 1H, J = 6.5 Hz), 4.14 (q, 1H, J = 7.0 Hz),
3.73–3.63 (m, 2H), 3.34 (br s, 3H), 1.84–1.76 (m, 1H), 1.70–1.64 (m, 1H), 0.89 (br