Synthesis and biological activity of 22-oxa CD-ring modified analogues of 1α,25-dihydroxyvitamin D3: Spiro[5.5]undecane CF-ring analogues

Article abstract of DOI:10.1016/j.bmcl.2004.05.058

The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1α,25-dihydroxyvitamin D₃, lacking the D-ring and featuring a connection between C-18 and C-21 (spiro[5.5]undecane CF-ring analogues), is described. The central

Full text of DOI:10.1016/j.bmcl.2004.05.058

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3889–3892
Synthesis and biological activity of 22-oxa CD-ring modified
analogues of 1a,25-dihydroxyvitamin D3: spiro[5.5]undecane
CF-ring analogues
Wim Schepens,a Dirk Van Haver,a Maurits Vandewalle,a Pierre J. De Clercq,a,*
Roger Bouillonb and Annemieke Verstuyf b
aDepartment of Organic Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Gent, Belgium
bLaboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven,
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
Received 6 April 2004; accepted 25 May 2004
Available online 17 June 2004
Abstract—The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1a,25-dihydroxyvitamin D3, lacking
the D-ring and featuring a connection between C-18 and C-21 (spiro[5.5]undecane CF-ring analogues), is described. The central ring
system is conveniently synthesised from an achiral intermediate. The analogues have marginal binding affinity for the nVDR and
possess low to moderate genomic activity.
Ó 2004 Elsevier Ltd. All rights reserved.
Over the last decade there has been a continuous interest
in the development of analogues of 1a,25(OH)2D3 (2;
calcitriol), the hormonally active metabolite of vitamin
D3 (1; cholecalciferol), with the purpose of separating
calcemic and prodifferentiating and/or antiproliferative
activities.1 In this context we wish to report here on the
synthesis and biological activity of spirocyclic analogues
such as 3 and 4. Among the various structural modifi-
cations that have been introduced in the parent com-
pound,2 a few are of special interest in view of the
present work. The 22-oxa modification in the side chain
led tothe first analogue ( 5, OCT) that showed dissoci-
ation in activities.3 Epimerisation at C-20 (cf. 6,
MC1288) often generates derivatives with enhanced
biological activity.4 And removal of C-19 is usually
accompanied by a reduction in calcemic activity.5
Whereas the above modifications are located in the
flexible parts of the molecule, that is the side chain or A-
ring, our laboratories have rather focused on structural
changes within the central CD-ring skeleton of the
molecule,6 the part that is, from a synthetic point of
view, the least accessible one.7 In this context several
series of analogues have been developed that show the
desired separation of activities, including ones charac-
terised by ring deletions.8
22
O
21
18
22
20
21
F
25
18
R
20
OH
17a
16
C
C
D
17
15
H
a
b
20α-substitution
20β-substitution
19
R
A
1
HO
R
HO
OH
R = H,H
1
2
R = H (cholecalciferol)
R = OH (calcitriol)
3
4
R = CH
2
O
OH
OH
H
H
HO
OH
HO
OH
5
(OCT)
6 (MC1288)
In the accompanying paper bicyclic CE-ring analogues
o f a1,25(OH)2D3 (2) are described. In this work the
central ring system consists of a spiro[5.5]undecane
* Corresponding author. Tel.: +32-9-2644463; fax: +32-9-2644998;
e-mail: pierre.declercq@UGent.be
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.058

3890
W. Schepens et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3889–3892
bicyclic moiety, featuring the deletion of C-15 and of C-
16, and a connection between C-18 and C-21 (CF-ring
system).9 The choice of a six-membered F-ring with a
22-oxa side chain at C-20 allows for a synthetic scheme
with the epimeric alcohols 11a and 11b as achiral
intermediates, so that the enantioselectivity of the syn-
thesis of the CF-ring system is not an issue.
NOE
H
H
H
17a
H
18
OH
OH
O
14
17
21
14
H
H
NOE
12a
O
12b
Figure 1. 1H NMR NOE measurements of 12a and 12b.
The synthesis of 11a and 11b is shown in Scheme 1.
Their spirocyclic skeleton results from the known cat-
ionic p cyclisation of allylic alcohol rac-7 in formic acid
leading toformate rac-8 in 92% yield.10 The precursor
alcohol is readily obtained from 3-ethoxy-2-cyclohexen-
1-one via a sequence involving: (i) addition of the
Grignard derivative of 5-bromo-1-pentene; (ii) acid
hydrolysis to 3-(4-pentenyl)-2-cyclohexen-1-one (85%
yield); (iii) reduction with lithium aluminum hydride
(99% yield).10 The further conversion of formate rac-8 to
enone rac-10 involves the reductive removal of the for-
mate ester group with lithium aluminum hydride (95%
yield), followed by Swern oxidation of the resulting
alcohols to rac-9 (93% yield). After protection of the
carbonyl group as ethylene ketal (96% yield), allylic
oxidation with pyridinium dichromate and tert-butyl-
hydroperoxide leads to rac-10 (64% yield). The catalytic
hydrogenation of rac-10 (Pd/C in MeOH) affords a
mixture of the achiral alcohols 11a and 11b, which is
separated by chromatography (52% and 45% isolated
yield, respectively). The stereochemical assignment of
alkoxides derived from 11 (NaH) with 4-bromo-2-
methyl-2-butene in the presence of tetrabutylammonium
iodide (DMF, 25 °C), followed by mercuric acetate
assisted water addition and treatment with sodium
borohydride (NaOH), led after acid hydrolysis to
ketones 13 (overall yield: a: 61%; b: 53%).
In view of the expected problems related to vitamin–
previtamin equilibration (see accompanying paper), it
was decided to first synthesise the 19-nor analogues 3a
and 3b. The appendage of the A-ring was achieved using
the reliable Wittig–Horner based procedure developed
11a
11b
a, b, c
a, b, c
O
O
OH
OH
1
both isomers follows from H NMR COSY and NOE
O
O
measurements that were performed on the correspond-
ing ketones 12a and 12b, obtained by acid hydrolysis
(Fig. 1). The final transformation of 11a and 11b into
the corresponding stereoisomeric analogues 3a, 4a and
3b, 4b involves the consecutive introduction of the
flexible parts of the molecule, that is the side chain and
the seco-B,A-ring portion (Scheme 2). Alkylation of the
13a
13b
OPPh
2
R
d or e, f
e, f
TBDMSO
OTBDMS
14 R = H,H
15 R = CH
2
a
OH
( )
3
O
O
OCHO
OH
OH
b, c
( )-7
( )-8
8
8
7
O
7
+
6
6
d, e
R
R
O
O
O
HO
OH
HO
OH
O
a
b
20α-substitution
20β-substitution
f
3
4
R = H,H
R = CH
16 R = H,H
17 R = CH
( )-9
( )-10
2
2
OH
OH
O
OH
25 °C
HO
+
4a
O
O
O
25 : 75
18a
HO
11a
11b
Scheme 2. Reagents and conditions: (a) (i) NaH, DMF, rt; (ii)
Me2C@CHCH2Br, n-Bu4NI, rt (a: 83%; b: 71%); (b) (i) Hg(OAc)2,
THF–H2O, rt; (ii) NaBH4, NaOH, rt (a: 86%; b: 90%); (c) TsOH,
Me2CO, H2O, rt (a: 85%; b: 83%); (d) 14, n-BuLi, THF, )78 °C (a:
47%; b: 72%); (e) 15, n-BuLi, THF, )78 °C (59%); (f) TBAF, THF, rt
(80–86%).
Scheme 1. Reagents and conditions: (a) HCOOH, rt (92%); (b)
LiAlH4, THF, 0 °C (95%); (c) (COCl)2, Et3N, DMSO, CH2Cl2, )60 °C
(93%); (d) HO(CH2)2OH, TsOH, toluene, reflux (96%); (e) PDC,
t-BuOOH, Celite, PhH, rt (64%); (f) H2, Pd/C, MeOH, rt (a: 52%; b:
45%).

W. Schepens et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3889–3892
3891
Table 1. Biological activity of CF-ring 22-oxa-1a,25(OH)2D3 ana-
loguesa
O
O
OH
OH
VDRb
(pig)
HL-60c
MCF-7d
Ca serume
(mice)
9
14
9
14
H
H
H
H
H
H
NOE
6
6
7
7
H
H
H
H
NOE
2
100
100
8
100
60
7
100
3af
3b
16b
4a
<0.1
<0.1
<0.1
0.5
<0.25
<0.25
<0.25
<0.25
H
H
4
10
4 10
6
HO
OH
HO
OH
<1
—
0
10
Figure 2. 1H NMR COSY (left) and NOE studies (right) of 3a and 3b.
a The activities are presented as relative values, the reference value of
1a,25(OH)2D3 (2) being defined as 100.
b Binding affinity for the nuclear vitamin D receptor.
c Prodifferentiating activity on human leukemia HL-60 cells.
d Antiproliferative activity on human breast cancer MCF-7 cells.
e Effect on Ca level in blood serum.
by Lythgoe and co-workers.11 Attachment of the 19-nor
A-ring toketnoe
13a was realised using the known
derivative 14.12 After fluoride-induced silyl ether de-
protection, a mixture of dienes 3a and 16a (ratio8:2)
was obtained, which could not be separated by chro-
matography. The identification of the major isomer as
the (E)-derivative 3a rests on 1H NMR COSY and NOE
measurements of the mixture (Fig. 2). When the same
sequence was applied tothe epimeric ketone 13b, again a
mixture of dienes 3b and 16b (ratio8:2) was obtained
from which now, however, analogue 3b could be isol-
ated in pure form by HPLC. The (E)-stereochemistry of
3b was alsoconfirmed by 1H NMR analysis (Fig. 2).
f Contaminated with 20% of 16a.
effects. The lack of affinity for the VDR is presumably
due to the rigidity of the central hydrophobic part of the
molecule. Future work will be directed towards estab-
lishing more flexible spirocyclic systems in which at least
one of the central rings will consist of a five-membered
ring.
Given the Z-contaminant in the 19-nor a series, the
Wittig–Horner reaction was as yet carried out using the
natural A-ring in order to obtain analogue 4a. The
sequence was performed on ketone 13a using the known
phosphine oxide 15,13 which after removal of the
TBDMS protective groups (tetrabutylammonium
fluoride) led to a separable mixture of isomeric (E)- and
(Z)-trienes 4a and 17a, in favour of the desired (E)-
derivative 4a (ratio85:15). Somewhat unexpected (see
accompanying paper) 4a was found to be rather stable
with regard to the equilibration towards the previtamin
form 18a (Scheme 2).14 The stereochemical assignment
of the (E)-7,8-double bond in 4a follows from 1H NMR
NOE difference experiments that were performed on the
mixture of the TBDMS protected derivatives (Fig. 3).
Analytical and spectral data consistent with the depicted
structures were obtained for all compounds.15
Acknowledgements
Financial assistance of the FWO-Vlaanderen (projects
G.0150.02 and G.0036.00) is gratefully acknowledged.
W.S. thanks the IWT and the FWO-Vlaanderen for a
scholarship.
References and notes
1. (a) Vitamin D; Feldman, D., Glorieux, F. H., Eds.;
Academic Press: San Diego, USA, 1997; 1285 pp; (b)
Proceedings of the Eleventh Workshop on Vitamin D;
Norman, A. W., Bouillon, R., Thomasset, M., Eds.;
University of California: Riverside, USA, 2000; pp 1–992,
and the previous 10 volumes in this series.
2. Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr.
Rev. 1995, 16, 200–257.
The results of the biological evaluation of 3a (contami-
nated with 16a), 3b, 16b and 4a are given in Table 1.
Inspection of the table learns that: (i) the binding affinity
for the VDR of all derivatives is very low, (ii) Z-isomer
16b is inactive, so that the moderate activity of impure
3a probably originates from the major E-isomer, (iii) all
derivatives possess low calcemic activity, (iv) impure 3a
shows the aimed at separation of calcemic and genomic
3. (a) Murayama, E.; Miyamoto, K.; Kubodera, M.; Mori,
T.; Matsunaga, I. Chem. Pharm. Bull. (Tokyo) 1986, 34,
4410–4413; (b) Abe, J.; Morikawa, M.; Miyamoto, K.;
Kaiko, S.; Fukushima, M.; Miyaura, C.; Abe, E.; Suda,
T.; Nishii, Y. FEBS Lett. 1987, 226, 58–62; (c) Nishii, Y.;
Okano, T. Steroids 2001, 66, 137–146.
4. Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.;
Calverley, M.; Hansen, K. Biochem. Pharmacol. 1991,
42, 1569–1575.
5. Perlman, K. L.; Sicinski, R. R.; Schnoes, H. K.; DeLuca,
H. F. Tetrahedron Lett. 1990, 31, 1823–1824.
O
OH
6. Bouillon R.; De Clercq P.; Pirson P.; Vandewalle M. Novel
Structural Analogues of Vitamin D, Patent PCT/EP
93,202037,3, 1993; Chem. Abstr. 1996, 122, 314933m.
7. (a) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95,
1877–1952; (b) Posner, G. H.; Kahraman, M. Eur. J. Org.
Chem. 2000, 3889–3895.
9
6
14
7
H
H
H
H
NOE
NOE
H
CH
2
19
4
8. (a) Sabbe, K.; D’Halleweyn, C.; De Clercq, P.; Vande-
walle, M.; Bouillon, R.; Verstuyf, A. Bioorg. Med. Chem.
Lett. 1996, 6, 1697–1702; (b) Chen, Y.-J.; Gao, L. J.;
TBDMSO
OTBDMS
Figure 3. 1H NMR NOE measurements of TBDMS protected 4a.

3892
W. Schepens et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3889–3892
Murad, I.; Verstuyf, A.; Verlinden, L.; Verboven, C.;
(s, 6H) ppm. For E/Z-mixture 3a/16a (ratio8:2): 1H NMR
(500 MHz, CD2Cl2) d 6.22 (AB, J ¼ 11:3 Hz, 1H of E-
isomer), 6.20 (AB, J ¼ 11:3 Hz, 1H of Z-isomer), 6.10
(AB, J ¼ 11:3 Hz, 1H of Z-isomer), 5.95 (AB,
J ¼ 11:3 Hz, 1H of E-isomer), 4.03 (br s, 2H), 3.68 (t,
J ¼ 5:8 Hz, 2H), 3.54 (s, 1H), 3.30 (tt, J ¼ 8:3, 4.1 Hz,
1H), 2.60 (dd, J ¼ 13:3, 3.8 Hz, 1H), 2.45 (dd, J ¼ 13:3,
3.6 Hz, 1H), 2.29–2.21 (m, 2H), 2.17–2.12 (m, 2H), 1.96 (s,
2H), 1.87–1.70 (m, 4H), 1.71 (t, J ¼ 5:8 Hz, 2H), 1.61 (br s,
2H), 1.55–1.40 (m, 8H), 1.19 (s, 6H), 1.15–1.10 (m,
2H) ppm. For 3b: 1H NMR (500 MHz, CDCl3) d 6.24
(AB, J ¼ 11:3 Hz, 1H), 5.94 (AB, J ¼ 11:3 Hz, 1H), 4.12–
4.07 (m, 2H), 3.79 (br s, 1H), 3.72 (t, J ¼ 5:7 Hz, 2H), 3.27
(tt, J ¼ 8:9, 3.9 Hz, 1H), 2.63 (dd, J ¼ 13:4, 3.6 Hz, 1H),
2.49 (dd, J ¼ 13:2, 3.6 Hz, 1H), 2.32–2.16 (m, 4H), 2.06
(AB, J ¼ 13:3 Hz, 1H), 2.02 (AB, J ¼ 13:3 Hz, 1H), 1.92–
1.82 (m, 2H), 1.76 (t, J ¼ 5:7 Hz, 2H), 1.75–1.72 (m, 10H),
1.58–1.42 (m, 2H), 1.25 (s, 6H), 1.11–1.07 (m, 2H) ppm.
For 16b: 1H NMR (500 MHz, CD2Cl2) d 6.23 (AB,
J ¼ 11:2 Hz, 1H), 6.11 (AB, J ¼ 11:2 Hz, 1H), 4.05–4.01
(m, 2H), 3.70 (t, J ¼ 5:8 Hz, 2H), 3.60 (br s, 1H), 3.26 (tt,
J ¼ 9:1, 4.1 Hz, 1H), 2.59 (dd, J ¼ 13:3, 3.8 Hz, 1H), 2.46
(dd, J ¼ 13:1, 3.6 Hz, 1H), 2.26 (dd, J ¼ 13:3, 7.4 Hz, 1H),
2.23 (AB, J ¼ 13:2 Hz, 1H), 2.18 (AB, J ¼ 13:2 Hz, 1H),
2.16 (dd, J ¼ 13:2, 7.1 Hz, 1H), 2.14–2.11 (m, 2H), 1.86–
1.73 (m, 4H), 1.73 (t, J ¼ 5:8 Hz, 2H), 1.58–1.54 (m, 5H),
1.50–1.42 (m, 3H), 1.40–1.38 (m, 2H), 1.21 (s, 6H), 1.16–
1.09 (m, 2H) ppm. For 4a: 1H NMR (500 MHz, CDCl3) d
6.31 (AB, J ¼ 11:2 Hz, 1H), 6.05 (AB, J ¼ 11:2 Hz, 1H),
5.32 (s, 1H), 4.98 (s, 1H), 4.43 (br s, 1H), 4.23–4.19 (br m,
1H), 3.80 (br s, 1H), 3.69 (t, J ¼ 5:7 Hz, 2H), 3.29 (tt,
J ¼ 7:9, 3.9 Hz, 1H), 2.60 (dd, J ¼ 13:1, 3.6 Hz, 1H), 2.31–
2.22 (m, 3H), 1.96 (t, J ¼ 5:6 Hz, 2H), 1.91 (s, 2H), 1.74 (t,
J ¼ 5:7 Hz, 2H), 1.71–1.69 (m, 2H), 1.59 (br s, 2H), 1.54–
1.43 (m, 8H), 1.24 (s, 6H), 1.13–1.08 (m, 2H) ppm. For
17a: 1H NMR (500 MHz, CDCl3) d 6.27 (AB, J ¼ 11:3 Hz,
1H), 6.19 (AB, J ¼ 11:3 Hz, 1H), 5.32 (s, 1H), 5.00 (s, 1H),
4.42 (br s, 1H), 4.21 (br m, 1H), 3.77 (br s, 1H), 3.70 (t,
J ¼ 5:8 Hz, 2H), 3.31 (tt, J ¼ 8:6, 3.6 Hz, 1H), 2.59 (dd,
J ¼ 13:1, 3.7 Hz, 1H), 2.28 (dd, J ¼ 13:0, 7.4 Hz, 1H), 2.09
(s, 2H), 2.08 (t, J ¼ 6:2 Hz, 2H), 1.98–1.94 (m, 2H), 1.75 (t,
J ¼ 5:8 Hz, 2H), 1.76–1.74 (m, 2H), 1.59–1.43 (m, 10H),
Bouillon, R.; Viterbo, D.; Milanesio, M.; Van Haver, D.;
Vandewalle, M.; De Clercq, P. J. Org. Biomol. Chem.
2003, 1, 257–267, and references cited therein.
9. For bridged 1a,25(OH)2D3 analogues with an intact D-
ring, but a connection between positions 18 and 20, see: (a)
ꢀ
Cornella, I.; Perez Sestelo, J.; Mourino, A.; Sarandeses, L.
A. J. Org. Chem. 2002, 67, 4707–4714; (b) Varela, C.;
~
~
Nilsson, K.; Torneiro, M.; Mourino, A. Helv. Chim. Acta
2002, 85, 3251–3261.
10. Harding, K. E.; Cooper, J. L.; Puckett, P. M. J. Org.
Chem. 1979, 44, 2834–2838.
11. Kociensky, P. J.; Lythgoe, B.; Waterhouse, I. J. Chem.
Soc., Perkin Trans. 1 1980, 1045–1050.
12. Perlman, K. L.; Swenson, R. E.; Paaren, H. E.; Schnoes,
H. K.; DeLuca, H. F. Tetrahedron Lett. 1991, 32, 7663–
7666.
13. Baggiolini, E. G.; Iacobelli, J. A.; Hennesy, B. M.;
Uskokovic, M. R. J. Am. Chem. Soc. 1982, 104, 2945–
2948.
14. The vitamin–previtamin equilibrium 4a–18a (Scheme 2)
was investigated (CDCl3, rt). Starting from the vitamin as
well as the previtamin the same equilibrium composition
was reached and was found to be in favour of previtamin
18a (25:75), but the equilibration was very slow (about
90 days starting from 4a).
15. Spectral data, for rac-9: 1H NMR (500 MHz, CDCl3) d
5.64 (dt, J ¼ 10:1, 3.7 Hz, 1H), 5.42 (br d, J ¼ 10:1 Hz,
1H), 2.32–2.26 (m, 2H), 2.21 (AB, J ¼ 13:9 Hz, 2H), 1.95–
1.82 (m, 4H), 1.72 (m, 1H), 1.63–1.52 (m, 3H), 1.51–1.40
1
(m, 2H) ppm. For rac-10: H NMR (500 MHz, CDCl3) d
7.05 (d, J ¼ 10:3 Hz, 1H), 5.86 (d, J ¼ 10:3 Hz, 1H), 3.95–
3.87 (m, 4H), 2.42 (t, J ¼ 6:8 Hz, 2H), 2.01 (dt, J ¼ 13:4,
6.6 Hz, 1H), 1.89 (dt, J ¼ 13:5, 6.9 Hz, 1H), 1.77–1.57 (m,
7H), 1.44 (m, 1H) ppm. For 11a: 1H NMR (500 MHz,
CDCl3) d 3.88 (s, 4H), 3.59 (m, 1H), 1.72–1.67 (m, 5H),
1.56–1.55 (m, 4H), 1.43–1.37 (m, 6H), 1.19 (m, 2H) ppm.
For 11b: 1H NMR (500 MHz, CDCl3) d 3.95–3.89 (m,
4H), 3.63 (m, 1H), 1.80–1.73 (m, 4H), 1.63–1.56 (m, 6H),
1.47–1.40 (m, 3H), 1.26 (m, 2H), 1.14 (m, 2H) ppm. For
13a: 1H NMR (500 MHz, CDCl3) d 3.69 (t, J ¼ 5:8 Hz,
2H), 3.62 (s, 1H), 3.33 (tt, J ¼ 7:9, 3.9 Hz, 1H), 2.29 (t,
J ¼ 6:8 Hz, 2H), 2.17 (s, 2H), 1.84 (m, 2H), 1.75 (t,
J ¼ 5:6 Hz, 2H), 1.74 (m, 2H), 1.68 (dd, J ¼ 6:1, 6.1 Hz,
2H), 1.58 (s, 1H), 1.58–1.49 (m, 4H), 1.24 (s, 6H), 1.22 (m,
1
1.24 (s, 6H), 1.15–1.11 (m, 2H) ppm. For 18a: H NMR
(500 MHz, CDCl3) d 5.87 (AB, J ¼ 12:4 Hz, 1H), 5.70
(AB, J ¼ 12:4 Hz, 1H), 5.64 (br s, 1H), 4.19 (br s, 1H),
4.14–4.09 (m, 1H), 3.79 (br s, 1H), 3.70 (t, J ¼ 5:7 Hz, 2H),
3.32 (tt, J ¼ 8:0, 4.0 Hz, 1H), 2.44 (dd, J ¼ 16:7, 4.7 Hz,
1H), 2.08–2.03 (m, 3H), 1.86 (AB, J ¼ 16:9 Hz, 1H), 1.82
(AB, J ¼ 16:9 Hz, 1H), 1.72 (s, 3H), 1.76–1.41 (m, 14H),
1.24 (s, 6H), 1.14–0.90 (m, 2H) ppm.
1
2H) ppm. For 13b: H NMR (500 MHz, CDCl3) d 3.68 (t,
J ¼ 5:8 Hz, 2H), 3.30 (tt, J ¼ 8:2, 4.0 Hz, 1H), 3.60 (s,
1H), 2.29 (t, J ¼ 6:8 Hz, 2H), 2.26 (s, 2H), 1.86 (m, 2H),
1.76 (m, 2H), 1.75 (t, J ¼ 5:8 Hz, 2H), 1.61 (dd, J ¼ 6:1,
6.1 Hz, 2H), 1.55 (m, 2H), 1.49 (m, 2H), 1.24 (m, 2H), 1.23