Synthesis of ACAT inhibitors through substitution using allylic picolinate and copper reagent

Article abstract of DOI:10.1016/j.tetlet.2010.09.035

Amide of an octanoic acid possessing an aryl group at C3 position is a highly potent ACAT inhibitor. In this paper, we describe a synthetic access to this class of compounds as optically active forms. The key reaction is substitution of the allylic picoli

Full text of DOI:10.1016/j.tetlet.2010.09.035

Tetrahedron Letters 51 (2010) 6018–6021
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of ACAT inhibitors through substitution using allylic picolinate
and copper reagent
⇑
Yuichi Kobayashi , Paveena Lalitnorasate, Yuki Kaneko, Yohei Kiyotsuka, Yoshiki Endo
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Amide of an octanoic acid possessing an aryl group at C3 position is a highly potent ACAT inhibitor. In this
paper, we describe a synthetic access to this class of compounds as optically active forms. The key reac-
tion is substitution of the allylic picolinate of (S,Z)-8-(benzyloxy)oct-5-en-4-ol with a copper reagent
derived from (benzo[d][1,3]dioxol-4-yl)MgBr and CuBrꢀMe2S to produce anti SN20 product regio- and
stereo-selectively. The product was hydrogenated to afford (S)-3-benzo[d][1,3]dioxol-4-yloctan-1-ol,
which upon oxidation furnished the octanoic acid. Finally, the acid was converted with 2,6-(i-Pr)2
C6H3NH2 to the target amide via acid chloride. In a similar way, the one-carbon long homolog was
synthesized.
Received 6 August 2010
Revised 7 September 2010
Accepted 10 September 2010
Available online 16 September 2010
Keywords:
ACAT inhibitor
Octanoic acid derivative
Allylic substitution
Picolinate
Ó 2010 Elsevier Ltd. All rights reserved.
Copper reagent
Recently, we have reported allylic picolinates that are suited for
allylic substitution with organocopper reagents derived from Grig-
nard reagents and CuBrꢀMe2S to deliver anti SN20 products highly
efficiently in terms of yields and regio/stereoselectivity.1,2 One of
the significant advantages of using the picolinate is its compatibility
with a wide range of aryl copper reagents, whereas the previous
methods with aryl copper reagents had suffered from low selectiv-
ity3 except for specific substrates.4 The picolinate method was then
extended to organolithium-based copper reagents,5 which in the
presence of MgBr2 furnished anti SN20 products as well, thus
allowing us to use several preparations of organolithiums for the
substitution. With these results in mind we have interest in develop-
ing a synthesis of an optically active form of acylcoenzyme choles-
terol acyltransferase (ACAT) inhibitors of the general structure 1
shown in Figure 1.6 Among them, racemic octanoic acid derivative
rac-1a7 inhibits ACAT in human hepatoma cells (HepG2) with
duce anti SN20 product 4 as the key intermediate. Herein, we
present results of the investigation.
The requisite picolinate 2 was prepared by using a sequence of
reactions summarized in Scheme 2. 3-Butyn-1-ol (6) was converted
O
i-Pr
Ar1
O
O
O
Ar2
*
(CH2)n
Me(CH2)m
(CH2)n
N
H
N
H
i-Pr
1
rac-1a, (S)-1a, n = 1
rac-1b, (S)-1b, n = 2
Figure 1. The general structure for the ACAT inhibitors and targets we have chosen.
IC50 = 0.018 lM. Synthesis of rac-1a was accomplishedby amidefor-
O
O
mationofthecorrespondingacidchloride with2,6-(i-Pr)2C6H3NH2,6
and the acid was in turn prepared from the aryl aldehyde (Ar1CHO)
by constructing the octanoic acid structure on it through the nor-
acid.8 The method is, however, inconvenient in the preparation of
derivatives with varying aryl groups since the group is involved
in the synthesis from the beginning.
N
O
O
O
"Cu"
(3)
O
OBn
OBn
4
2
O
O
To avoid the strategic inconvenience, we envisioned a method
illustrated in Scheme 1, in which the aryl copper reagent is in-
stalled to the octanoic chain 2 by using allylic substitution to pro-
(S)-1a
CO2H
5
⇑
Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
Scheme 1. Strategy for synthesis of (S)-1a.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.035

Y. Kobayashi et al. / Tetrahedron Letters 51 (2010) 6018–6021
6019
O
OH
OH
Ru cat.a
1) NaH, BnBr
PCC
OH
2) n-BuLi
then PrCHO
i-PrOH
86%
82%
OBn
OBn
OBn
8
6
(S)-7
rac-7
98%
O
O
(2-Py)CO2H
[2-ClC5H4N]+I–
H2
Cu– M+
OCO(2-Py)
Lindlar cat.
H2, Pd/C
2
4
2
DMAP, Et 3N
96%
92%
OBn
3A, M = (MgBr)+ + MgBr2
97% ee
9
3B, M = Li+ • LiBr + 3 MgBr2
0 °C, 1 h
O
O
O
O
CrO3, H+
92%
2,6-(i-Pr)2C6H3NH2
72% from 5
(S)-1a
COX
OH
10
5, X = OH
11, X = Cl
SOCl2
DMF
57% yield with 3A, 64% CT
72% yield with 3B, 97% CT
Scheme 2. Synthesis of (S)-1a. aRu cat. = Ru[(S,S)-TsDPEN](p-cymene).
to ketone 8 in three steps using the standard reactions. Asymmetric
reduction of 8 with Ru[(S,S)-TsDPEN](p-cymene)9 as a catalyst in i-
PrOH gave (S)-7, which was transformed to the key picolinate 2 by
esterification with (2-Py)CO2H followed by Lindlar hydrogenation.
Enantiomeric excess (ee) of 2 was 97% by chiral HPLC analysis and
purity of the cis olefin was >99% by 1H NMR spectroscopy (d 2.49–
2.69 (m, 2 H) for 2; 2.32–2.43 (m, 2H) for the trans isomer10).
For preparation of the bromide 15 via bromocatechol 14 we fol-
lowed the literature protocol11 consisting of the ortho formylation
of bromophenol 12 using (CH2O)n, Et3N, and MgCl2 followed by the
Dakin oxidation of the resulting aldehyde with H2O2 in one-pot
(Scheme 3). However, a mixture of 14, 3-bromo-2-hydroxybenzyl
alcohol, and unidentified products were obtained in our hand.
The first-step was then re-examined to find that the reaction with
MgBr2 at 70 °C proceeded cleanly to afford aldehyde 13, whereas
the use of original MgCl2 gave a mixture of 13 and others. The Da-
kin oxidation of the aldehyde proceeded well to produce catechol
14 in 63% yield from 12.12 The yield was higher than that pub-
lished11 (55% yield). Finally, reaction with CH2Br2 gave 15 in 83%
yield.
O
O
CuBr·Me2S
(1 equiv)
Mg
15
MgBr
16A (2 equiv)
O
O
Cu–(MgBr)+ + MgBr2
2
3A
CuBr·Me2S
(1 equiv)
O
O
t-BuLi
15
Li
16B (2 equiv)
MgBr2
(3 equiv)
O
O
Cu–Li+ • LiBr + 3 MgBr2
The Grignard reagent 16A in THF was derived from bromide 15
and Mg turnings as usual and mixed with CuBrꢀMe2S in a 2:1 ratio
at 0 °C for 30 min to prepare the copper reagent 3A (Scheme 4),
which was subjected to reaction with allylic picolinate 2 at 0 °C
for 1 h to produce the desired product 4 and the residue(s) derived
2
3B
O
O
n-, s-, or t-BuLi
16B
17
OH
Br
OHC
OH
Br
(CH2O)n, Et3N, MgX2
THF, 70 °C, 16 h
Scheme 4. Preparation of copper reagents 3A and 3B.
12
13
MgX2 (X = Cl, Br), see the text for the result
from the reagent. Due to the close Rf values of the products on TLC,
the mixture was hydrogenated with 10% Pd/C under hydrogen to
afford the polar octanol derivative 10, which was isolated easily
by chromatography on silica gel. However, the yield was 57% and
chirality transfer (CT) determined by chiral HPLC analysis was
insufficiently 64%. The observed suspension of 16A in THF might
be responsible for the unsatisfactory result.13 We then investigated
substitution with a lithium-based copper reagent. Although ortho
lithiation14 of catechol derivative 17 with n-, s-, and t-BuLi was
unsuccessful,15 halogen–lithium exchange of 15 with t-BuLi
O
O
HO
OH
Br
H2O2, NaOH
rt, 16 h
CH2Br2, Cs2CO3
Br
DMF, 110 °C
83%
14
63% from 12
15
Scheme 3. Preparation of bromide 15.

6020
Y. Kobayashi et al. / Tetrahedron Letters 51 (2010) 6018–6021
(2-Py)CO2H
[2-ClC5H4N]– I+
OH
O
Ru cat.a
1) BnBr, NaH
OH
OBn
OBn
2) n-BuLi
then PrCHO
3) PCC
i-PrOH
83%
DMAP, Et 3N
95%
18
(S)-20
19
73%
O
O
H2
OCO(2-Py)
OCO(2-Py)
Lindlar cat.
3B
OBn
OBn
OBn
92%
0 °C, 1 h
22
21
23
95% ee
O
O
O
O
H2, Pd/C
CrO3, H+
63%
2,6-(i-Pr)2C6H3NH2
(S)-1b
OH
COX
70% from 25
24
25, X = OH
26, X = Cl
73% from 22
93% CT
SOCl2
DMF
Scheme 5. Synthesis of (S)-1b. aRu cat. = Ru[(S,S)-TsDPEN](p-cymene).
cleanly produced anion 16B,15 which was subsequently mixed
with CuBrꢀMe2S to afford the other copper reagent 3B. Substitution
of picolinate 2 with the reagent 3B (1 equiv) at 0 °C proceeded
cleanly in the presence of MgBr2 (5 equiv) to deliver anti SN20 prod-
uct 4, which was converted to alcohol 10 in 72% yield over two
steps with 97% CT.16 Jones oxidation furnished acid 5 in 92% yield.
Finally, the acid was transformed to (S)-1a in 72% yield through the
acid chloride 11.17,18
To show flexibility of the method, we then targeted the homolog
(S)-1b. As shown in Scheme 5, allylic picolinate 22 was prepared
from 18 in a similar manner to picolinate 2. Briefly, ketone 19 was
prepared from alcohol 18 in 73% yield and reduced with Ru[(S,S)-
TsDPEN](p-cymene) in i-PrOH to afford alcohol (S)-20, which upon
esterification with (2-Py)CO2H and reduction with Lindlar catalyst
delivered picolinate 22 with 95% ee by chiral HPLC analysis. Allylic
substitution of 22 and 3B in the presence of MgBr2 proceeded
smoothly and subsequent hydrogenation gave alcohol 24 in 73%
yield from picolinate 22. Finally, Jones oxidation followed by amide
formation of the resulting acid 2517 with 2,6-(i-Pr)2C6H3NH2
afforded (S)-1b in good yield.
3. (a) Fujii, N.; Habashita, H.; Shigemori, N.; Otaka, A.; Ibuka, T.; Tanaka, M.;
Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4969–4972; (b) Torneiro, M.; Fall, Y.;
Castedo, L.; Mouriño, A. J. Org. Chem. 1997, 62, 6344–6352; (c) Habashita, H.;
Kawasaki, T.; Takemoto, Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 2392–
2396; (d) Borthwick, S.; Dohle, W.; Hirst, P. R.; Booker-Milburn, K. I.
Tetrahedron Lett. 2006, 47, 7205–7208.
4. (a) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett. 1997, 38, 6705–
6708; (b) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998, 120, 11832–11833; (c)
Belelie, J. L.; Chong, J. M. J. Org. Chem. 2002, 67, 3000–3006; (d) Perrone, S.;
Knochel, P. Org. Lett. 2007, 9, 1041–1044.
5. (a) Kiyotsuka, Y.; Kobayashi, Y. Tetrahedron Lett. 2008, 49, 7256–7259; (b)
Kiyotsuka, Y.; Kobayashi, Y. Tetrahedron 2010, 66, 676–684.
6. Jikihara, T.; Shirasaka, T.; Suzuki, K.; Suzuki, H.; Taniguchi, M.; Inoue, S. Eur. Pat.
Appl. 1994, EP 0591830 A1 19940413; Chem. Abstr. 1995, 123, 9465.
7. (S)-1a was also synthesized via the nor-acid, which was obtained by optical
resolution in 39% yield, whereas the potency of (S)-1a is not reported.
8. Sekiya, T.; Inoue, S.; Shirasaka, T.; Miyajima, C.; Okushima, H.; Suzuki, K.;
Kawai, M.; Mitsuka, M.; Umezu, K. Chem. Pharm. Bull. 1994, 42, 586–591.
9. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738–8739.
10. The trans isomer was prepared by reduction of rac-7 with LiAlH4 followed by
esterification with picolinic acid: 1H NMR (300 MHz, CDCl3) d (diagnostic
signals) 1.64–1.77 (m, 1H), 1.80–1.93 (m, 1H), 2.32–2.43 (m, 1H), 3.51 (t,
J = 7 Hz, 2H), 4.50 (s, 2H), 5.56 (q, J = 7 Hz, 1H), 5.66 (ddt, J = 15, 7.5, 1 Hz, 1H),
5.86 (dt, J = 15, 7 Hz, 1H).
11. Loriot, M.; Robin, J.-P.; Brown, E. Tetrahedron 1984, 40, 2529–2535.
12. Isolated yields of 13 from 12 and 14 from 13 in repeated reactions were 65%
and 80% yields, respectively.
13. In contrast, PhMgBr in THF was prepared (as a clean solution), and converted to
Ph2Cuꢁ(MgBr)+, which upon reaction with 2 successfully gave the product i
with 99% CT. The result suggests that purity of the reagent 3A is a likely reason
for the low efficiency of the reaction.
In summary, the potential ACAT inhibitor (S)-1a was synthe-
sized as an optically active form. Total yield from 6 in 11 steps
was 29%, whereas that of rac-1a calculated for the 12 steps from
benzo[d][1,3]dioxole-4-carbaldehyde in the literature is 6.7%.6,8
Furthermore, the flexibility of the method is demonstrated by syn-
thesis of the homolog (S)-1b.
Ph
Ph2Cu(MgBr)·MgBr2
2
OBn
THF, 0 °C, 1 h
Acknowledgment
i
73% yield, 99% CT
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
14. Snieckus, V. Chem. Rev. 1990, 90, 879–933.
15. Checked by addition reaction to p-MeOC6H4CHO.
16. To a solution of bromide 15 (58 mg, 0.288 mmol) in THF (1 mL) was added t-
BuLi (0.37 mL, 1.57 M in n-pentane, 0.581 mmol) dropwise at ꢁ78 °C. The
resulting mixture was stirred at ꢁ78 °C for 30 min, and added to an ice-cold
mixture of CuBrꢀMe2S (30 mg, 0.146 mmol) and a THF solution of MgBr2
(3.6 mL, 0.20 M, 0.720 mmol). After 30 min at 0 °C, a solution of picolinate 2
(49 mg, 0.144 mmol) in THF (1 mL) was added to the mixture. The reaction was
carried out at 0 °C for 1 h and quenched by addition of saturated NH4Cl. The
resulting mixture was extracted with EtOAc three times. The combined
extracts were washed with brine, dried over MgSO4, and concentrated to afford
4, which was passed through a short silica gel column for the next reaction. A
mixture of 4 prepared above and 10% Pd/C (30 mg) in MeOH (2 mL) was stirred
at rt overnight under hydrogen, diluted with EtOAc, and filtered through a pad
of Celite. The filtrate was concentrated and the residue was purified by
chromatography on silica gel with (hexane/EtOAc) to afford alcohol 10 (26 mg,
References and notes
1. (a) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi, Y. Org. Lett.
2008, 10, 1719–1722; (b) Kiyotsuka, Y.; Katayama, Y.; Acharya, H. P.; Hyodo, T.;
Kobayashi, Y. J. Org. Chem. 2009, 74, 1939–1951; (c) Kiyotsuka, Y.; Kobayashi, Y.
J. Org. Chem. 2009, 74, 7489–7495.
2. (a) Takashima, Y.; Kobayashi, Y. Tetrahedron Lett. 2008, 49, 5156–5158; (b)
Hyodo, T.; Kiyotsuka, Y.; Kobayashi, Y. Org. Lett. 2009, 11, 1103–1106; (c)
Hyodo, T.; Katayama, Y.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 3547–3549;
(d) Takashima, Y.; Kaneko, Y.; Kobayashi, Y. Tetrahedron 2010, 66, 197–207; (e)
Kaneko, Y.; Kiyotsuka, Y.; Acharya, H. P.; Kobayashi, Y. Chem. Commun. 2010,
46, 5482–5484.

Y. Kobayashi et al. / Tetrahedron Letters 51 (2010) 6018–6021
6021
72% over two steps from 2): ½a D24
ꢂ
+4.9 (c 0.72, CHCl3); 1H NMR (300 MHz,
(ꢁ), 38.8 (+), 42.0 (ꢁ), 100.6 (ꢁ), 107.1 (+), 122.0 (+), 122.1 (+), 123.4 (+), 125.8
(ꢁ), 128.4 (+), 131.0 (ꢁ), 145.1 (ꢁ), 146.3 (ꢁ), 147.4 (ꢁ), 171.2 (ꢁ). Alcohol 24:
CDCl3) d 0.84 (t, J = 7 Hz, 3 H), 1.10–1.32 (m, 4 H), 1.48 (br s, 1 H), 1.53–1.85 (m,
3 H), 1.88–2.01 (m, 1 H), 2.83–2.95 (m, 1 H), 3.45 (ddd, J = 11, 8, 6 Hz, 1H), 3.57
(dq, J = 11, 5 Hz, 1H), 5.91 (d, J = 1.5, 1H), 5.93 (d, J = 1.5, 1H), 6.66 (dd, J = 8,
1.5 Hz, 1H), 6.69 (dd J = 8, 1.5 Hz, 1H), 6.79 (dd, J = 8, 5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 14.1 (+), 22.6 (ꢁ), 27.3 (ꢁ), 31.9 (ꢁ), 35.1 (ꢁ), 36.4 (+), 38.4
(ꢁ), 61.2 (ꢁ), 100.4 (ꢁ), 106.5 (+), 120.8 (+), 121.9 (+), 126.6 (ꢁ), 145.5 (ꢁ),
147.0 (ꢁ).
½
a 2D6
ꢂ
ꢁ4 (c 0.811, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.84 (t, J = 6.5 Hz, 3H),
1.10–1.32 (m, 6H), 1.34–1.78 (m, 7H), 2.71 (dq, J = 7, 7 Hz, 1H), 3.59 (t,
J = 6.5 Hz, 2H), 5.91 (s, 2H), 6.64 (dd, J = 8, 1 Hz, 1H), 6.68 (dd, J = 8, 1 Hz, 1H),
6.77 (t, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.5 (+), 22.6 (ꢁ), 27.3 (ꢁ),
31.0 (ꢁ), 31.4 (ꢁ), 31.9 (ꢁ), 35.3 (ꢁ), 40.1 (+), 63.1 (ꢁ), 100.3 (ꢁ), 106.3 (+),
121.0 (+), 121.6 (+), 127.4 (ꢁ), 145.4 (ꢁ), 147.0 (ꢁ). Acid 25: ½a D26
ꢁ7 (c 0.21,
ꢂ
17. The 1H NMR spectra of 5, (S)-1a, and 25 were consistent with the data
reported.6
CHCl3); 1H NMR (300 MHz, CDCl3) d 0.83 (t, J = 6.5 Hz, 3H), 1.10–1.32 (m, 6H),
1.47–1.78 (m, 2H), 1.82–2.07 (m, 2 H), 2.22 (t, J = 6.5 Hz, 2H), 2.65–2.78 (m,
1H), 5.91 (s, 2 H), 6.62 (dd, J = 8, 1 Hz, 1H), 6.69 (dd, J = 8, 1 Hz, 1H), 6.77 (t,
J = 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.1 (+), 22.6 (ꢁ), 27.3 (ꢁ), 29.9 (ꢁ),
31.9 (ꢁ), 32.2 (ꢁ), 35.0 (ꢁ), 39.9 (+), 100.5 (ꢁ), 106.6 (+), 121.0 (+), 121.7 (+),
126.1 (ꢁ), 145.5 (ꢁ), 147.1 (ꢁ), 179.7 (ꢁ). Amide (S)-1b: 1H NMR (300 MHz,
CDCl3) d 0.84 (t, J = 7 Hz, 3H), 1.19 (d, J = 7 Hz, 12H), 1.00–1.32 (m, 8H), 1.49–
2.37 (m, 4H), 2.76–2.89 (m, 1H), 2.96–3.16 (m, 2H), 5.92 (d, J = 1.5 Hz, 1H), 5.93
(d, J = 1.5 Hz, 1H), 6.58 (br s, 1H), 6.69 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H),
6.82 (t, J = 8 Hz, 1H), 7.16 (d, J = 7 Hz, 2H), 7.25–7.33 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 14.1 (+), 22.6 (ꢁ), 23.8 (+), 27.3 (ꢁ), 28.8 (+), 31.3 (ꢁ), 31.9
(ꢁ), 35.0 (ꢁ), 35.3 (ꢁ), 40.2 (+), 100.4 (ꢁ), 106.7 (+), 121.2 (+), 121.9 (+), 123.5
(+), 126.6 (ꢁ), 128.4 (+), 131.2 (ꢁ), 145.5 (ꢁ), 146.4 (ꢁ), 147.1 (ꢁ), 172.4 (ꢁ).
18. Characterization data: acid 5: ½a D24
ꢂ
0 (c 0.38, CHCl3); 1H NMR (300 MHz, CDCl3)
d 0.83 (t, J = 7 Hz, 3H), 1.08–1.35 (m, 6 H), 1.54–1.76 (m, 2H), 2.66 (dd, J = 16,
8 Hz, 1H), 2.72 (dd, J = 16, 8 Hz, 1H), 3.11–3.24 (m, 1H), 5.92 (s, 2H), 6.65 (dd,
J = 7.5, 1.5 Hz, 1H), 6.69 (dd, J = 7.5, 1.2 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 14.1 (+), 22.6 (ꢁ), 27.1 (ꢁ), 31.7 (ꢁ), 34.4 (ꢁ), 37.2 (+), 39.5
(ꢁ), 100.6 (ꢁ), 106.9 (+), 121.4 (+), 121.6 (+), 125.6 (ꢁ), 145.2 (ꢁ), 147.3 (ꢁ),
178.4 (ꢁ). Amide (S)-1a: ½a D24
ꢂ
+26 (c 0.34, CHCl3); 1H NMR (300 MHz, CDCl3) d
0.84 (t, J = 7 Hz, 3 H), 1.08 (d, J = 7 Hz, 12H), 1.15–1.35 (m, 8 H), 1.62–1.80 (m, 2
H), 2.77 (dd, J = 14.5, 5.5 Hz, 1 H), 2.87 (dd, J = 14.5, 10.5 Hz, 1H), 3.29–3.37 (m,
1H), 5.94 (s, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.73–6.76 (m, 2H), 6.80 (dd, J = 9,
7 Hz, 1H), 7.09 (d, J = 7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 14.1 (+), 22.6 (ꢁ), 23.6 (+), 23.8 (+), 27.1 (ꢁ), 28.6 (+), 31.8 (ꢁ), 35.3