Monastrol analogs: A synthesis of pyrazolopyridine, benzopyranopyrazolopyridine, and oxygen-bridged azolopyrimidine derivatives and their biological screening

Article abstract of DOI:10.1016/j.bmcl.2010.05.085

A synthesis of novel pyrazolopyridine, benzopyranopyrazolopyridine, and oxygen-bridged pyrazolo-, tetrazolo-, benzimidazo-, and thiazolopyrimidines via Hantzsch- and Biginelli-like condensations has been developed. The ability of these compounds to inhibit Eg5 activity has been examined. The results indicate that synthetic manipulations in the monastrol thiourea moiety are inefficient.

Full text of DOI:10.1016/j.bmcl.2010.05.085

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4073–4076
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Monastrol analogs: A synthesis of pyrazolopyridine, benzopyranopyrazolopyri-
dine, and oxygen-bridged azolopyrimidine derivatives
and their biological screening
a
b
b
Jan Svetlik a, , Lucia Veizerová , Thomas U. Mayer , Mario Catarinella
*
a Department of Pharmaceutical Analysis and Nuclear Pharmacy, Comenius University, Odbojarov 10, SK-832 32 Bratislava, Slovak Republic
b Department of Molecular Genetics, University of Konstanz, 78457 Konstanz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of novel pyrazolopyridine, benzopyranopyrazolopyridine, and oxygen-bridged pyrazolo-, tet-
razolo-, benzimidazo-, and thiazolopyrimidines via Hantzsch- and Biginelli-like condensations has been
developed. The ability of these compounds to inhibit Eg5 activity has been examined. The results indicate
that synthetic manipulations in the monastrol thiourea moiety are inefficient.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 April 2010
Revised 18 May 2010
Accepted 19 May 2010
Available online 26 May 2010
Keywords:
Biginelli reaction
Hantzsch reaction
Oxygen-bridged nitrogen heterocycles
Monastrol analogs
Monastrol ( )-1 (Fig. 1) is a simple low molecular weight mol-
ecule that was discovered a decade ago to be a cell-permeable
kinesin Eg5 inhibitor1; this discovery initiated a further stage in
Biginelli 3,4-dihydropyrimidine-2(1H)-one chemistry. The new
era in the long time history of this heterocyclic family2 has been
started in Squibb laboratories by detailed investigations3 of its
earlier recognized antihypertensive properties. In addition to the
targeted Ca2+ channel blockers, research was independently set
off that was oriented toward dihydropyrimidine selective a1A
adrenergic receptor antagonists for treatment of benign prostatic
hyperplasia.3 Convergently, the close resemblance to the 1,4-dihy-
dropyridine core plays a crucial role in both goals. 3,4-Dihydropyri-
midinone-5-carboxylate scaffold has also emerged as an integral
backbone of some neuropeptide Y (NPY) antagonists.3 Further-
more, recent pharmacological evaluations of Biginelli compounds
disclosed that these derivatives also functioned as melanin concen-
trating hormone receptor (MCH1-R) antagonists,4 chemical modu-
lators of heat shock protein 70 (Hsp 70),5 hepatitis B replication
inhibitors,6 and inhibitors of the fatty acid transporters.7 In partic-
ular, a simple 4-aryldihydropyrimidine derivative was recently dis-
covered to be highly effective against methicillin-resistant strain of
Staphylococcus aureus (MRSA).8
Diverse structures that effectively inhibit bipolar mitotic spindle
assembly have been found.9 Abiding interest in compound 1 has
led to conformative skeleton modifications of the parent ring by
annelation across the C-5–C-6 bond to provide more potent ana-
logs,10 such as dimethylenastron 2 and quinazoline-2(1H)-thione
3 (Fig. 1). Considerable work has also been devoted to gaining in-
sight into the structure–activity relationship in the monastrol
derivative series.11 However, C-6 substitution has not been ex-
plored. In order to probe the effect of methyl functionalization in
position 6 on the ability to inhibit Eg5 activity, we have recently
synthesized analogous Biginelli compounds 4 bearing methyl ace-
tate unit at C-6.12 The conformationally restricted dihydropyrimi-
dine prototype12 5 completed our trial set (Fig. 2). Some of
screened samples exhibited in vitro inhibitory effect at concentra-
tions of 100–200
lM in semi-quantitative assays; summing up the
In recent years, a significant progress has been reported in the
new class of promising anticancer agents led by monastrol 1.
* Corresponding author.
E-mail address: svetlik@fpharm.uniba.sk (J. Svetlik).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.085

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J. Svetlik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4073–4076
However, when salicylaldehyde was employed, a bicyclic anne-
lation accompanied by lactonization took place to yield tetracyclic
product 11. A small quantity of oxidized form 12 in a second crop
indicated that 1,4-dihydropyridine ring was partially oxidized in
air. Therefore, the reaction was carried out under nitrogen which
decreased the 12:11 ratio to 1:24 (Scheme 2).
To exploit the synthetic potential of amine 8, we used our meth-
odology16 based upon 4-(2-hydroxyphenyl)but-3-en-2-one 13 for
the preparation of conformationally restricted heterocycles having
the aromatic ring fixed by an oxygen-bridge. In this case, harsher
reaction conditions were necessary (reflux in DMF, 1 h) to achieve
heterocyclization (?14, Scheme 3). Apparently, of the three nucle-
ophilic nitrogen centers capable of attacking the olefinic enone
b-carbon, the sp3 N-1 atom of pyrazole tautomer 8 triggers the
multistep sequence. Michael addition forms the pyrazolopyrimi-
dine skeleton which is followed by subsequent O-bridge formation.
Detailed 1H and 13C NMR analysis was performed using 2D-corre-
lation techniques (COSY, HSQC, and HMBC). Moreover, close spatial
proximities for 5-Me–NH and NH–pyrazole-H, established from
1D-NOESY measurements, clearly pointed to a linear arrangement
of both nitrogen rings in tetracyclic molecule 14. An interesting
feature was found in the aliphatic region of the 1H NMR spectrum.
The CH2CH moiety and NH constitute a four spin system (ABMX) as
a result due to a planar long-range coupling of the W type between
the amine and equatorial diastereotopic methylene protons.
Accordingly, one of the two CH2 signals which appears at a higher
field as a doublet with a fine triplet splitting pattern could be as-
signed to H-13 equiv.
Figure 2.
testing, pyrimidine preparates were at least 10 times less active
than the monastrol standard.13
Based on the reported remarkable data for simple pyrazoles as
kinesin spindle protein (KSP) inhibitors,9a we directed our studies
at monastrol-related fused heteroanalogs. As a structural modifica-
tion we chose to integrate the monastrol key building block,
pyrimidine nucleus, and the five-membered nitrogen ring system
into a common, single heterocyclic molecule. Here we wish to de-
scribe the synthesis of novel condensed azolopyridines and azolo-
pyrimidines of pharmacological interest. The biological evaluation
of the prepared derivatives toward inhibition of KSP enzymatic
activity is also briefly described.
First, we examined a three-component reaction of 3-hydroxy-
benzaldehyde 6 with methyl acetoacetate 7 and 5-amino-3-
methyl-1H-pyrazole 8 adopting Quiroga’s protocol.14 Refluxing
the reactants in EtOH for 1.5 h afforded product 9 whose 1H NMR
spectrum lacked characteristic14b,15 singlet for the pyrazole
methine near 6.0 ppm. This revealed a cyclization mode leading
to pyrazolopyridine 9 and ruled out the pyrazolopyrimidine alter-
native 90 (Scheme 1). A similar behavior of the aminopyrazole has
been already reported.14
To further extend our set for activity screening, we employed
some other heterocyclic amines for the above cyclocondensation.
Upon refluxing enone template 13 with an equimolar amount of
5-amino-1H-tetrazole monohydrate in DMF for 2 h the expected
polyazaheterocycle 15 was obtained. Likewise, treatment of
Scheme 1.
Scheme 2.

J. Svetlik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4073–4076
4075
Acknowledgments
This work was supported by a Grant of Pharmaceutical Faculty
(#FaF UK/14/2009). The NMR experimental part of this work was
facilitated by the support of Slovak National Research and Develop-
ment Program No. 2003SP200280203.
References and notes
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2000, 33, 879.
Scheme 3.
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J.; Iyengar, R.; Vasudevan, A.; Kym, P. R.; Hancock, A. A.; Rueter, L. E. Eur. J.
Pharmacol. 2006, 540, 115.
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6. Deres, K.; Schröder, C. H.; Paessens, A.; Goldmann, S.; Hacker, H. J.; Weber, O.;
Krämer, T.; Niewöhner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
Masantschek, R. N. A.; Reimann, A.; Jaeger, R.; Groß, R.; Beckermann, B.;
Schlemmer, K.-H.; Haebich, D.; Rübsamen-Wagmann, H. Science 2003, 299, 893.
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S.; Ye, Y.; Gimeno, R. E.; Punreddy, S.; Sun, Y.; Wu, H.; Hubbard, B.; Kaushik, V.;
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9. (a) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.;
Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.;
Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D.
Bioorg. Med. Chem. Lett. 2007, 17, 2697; (b) DeBonis, S.; Skoufias, D. A.; Indorato,
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2008, 51, 1115; (c) Tarby, C. M.; Kaltenbach, R. F.; Huynh, T.; Pudzianowski, A.;
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Fairchild, C. R.; Vaccaro, W.; Chen, Z.; Borzilleri, R. M.; Naglich, J.; Lombardo, L.
J.; Gottardis, M.; Trainor, G. L.; Roussell, D. L. Bioorg. Med. Chem. Lett. 2006, 16,
2095; (d) Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.;
Huemmer, S.; Mayer, T. U.; Surrey, T.; Giannis, A. Bioorg. Med. Chem. 2005, 13,
6094; (e) Kim, K. S.; Lu, S.; Cornelius, L. A.; Lombardo, L. J.; Borzilleri, R. M.;
Schroeder, G. M.; Sheng, C.; Rovnyak, G.; Crews, D.; Schmidt, R. J.; Williams, D.
K.; Bhide, R. S.; Traeger, S. C.; McDonnell, P. A.; Mueller, L.; Sheriff, S.; Newitt, J.
A.; Pudzianowski, A. T.; Yang, Z.; Wild, R.; Lee, F. Y.; Batorsky, R.; Ryder, J. S.;
Ortega-Nanos, M.; Shen, H.; Gottardis, M.; Roussell, D. L. Bioorg. Med. Chem. Lett.
2006, 16, 3937; (f) Sakowicz, R.; Finer, J. T.; Beraud, C.; Crompton, A.; Lewis, E.;
Fritsch, A.; Lee, Y.; Mak, J.; Moody, R.; Turincio, R.; Chabala, J. C.; Gonzales, P.;
Roth, S.; Weitman, S.; Wood, K. V. Cancer Res. 2004, 64, 3276; (g) Matsuno, K.;
Sawada, J.; Sugimoto, M.; Ogo, N.; Asai, A. Bioorg. Med. Chem. Lett. 2009, 19,
1058.
10. (a) Gartner, M.; Sunder-Plassmann, N.; Seiler, J.; Utz, M.; Vernos, I.; Surrey, T.;
Giannis, A. ChemBioChem 2005, 6, 1173; (b) Sarli, V.; Huemmer, S.; Sunder-
Plassmann, N.; Mayer, T. U.; Giannis, A. ChemBioChem 2005, 6, 2005.
11. Klein, E.; DeBonis, S.; Thiede, B.; Skoufias, D. A.; Kozielski, F.; Lebeau, L. Bioorg.
Med. Chem. 2007, 15, 6474.
12. Svetlik, J.; Veizerova, L.; Kettmann, V. Tetrahedron Lett. 2008, 49, 3520.
13. Mayer, T. U. Unpublished results.
14. (a) Quiroga, J.; Insuasty, B.; Hormaza, A.; Saitz, C.; Jullian, C. J. Heterocycl. Chem.
1998, 35, 575; (b) Quiroga, J.; Mejia, D.; Insuasty, B.; Abonia, R.; Nogueras, M.;
Sanchez, A.; Cobo, J.; Low, J. N. Tetrahedron 2001, 57, 6947.
butenone 13 with 2-aminobenzimidazole gave rise to pentacyclic
product 16 in a good yield (Fig. 3). Full assignment of the 1H and
13C NMR signals for 16 has been established and additional NMR
data concerning benzimidazole chemical shifts were invoked17 to
support our analysis. The oxygen-bridged fused ring system with
nitrogen at the bridgehead position (16) represents, to our knowl-
edge, a new class of condensed heterocyclic compounds. Although
pyrazolo- and tetrazolobenzoxadiazocine heterocyclic families such
as 14 and 15 have been described,18 our approach has opened an
alternative route to
these derivatives.
Finally, thia-
zolobenzoxadiazocine 17 possessing a thiourea structural motif
was likewise synthesized using 2-amino-2-thiazoline to enlarge
the tested group (Fig. 3). It should be noted that a hydrobromide salt
of 17 was already prepared by us via cyclization of an oxygen-
bridged thioxopyrimidine with 1,2-dibromoethane.19 Furthermore,
we recently described a single-crystal X-ray analysis of 17.20
All the compounds prepared here21 as monastrol mimics were
tested for their ability to inhibit KSP enzymatic activity by using
an in vitro ATPase assay and an in vivo cell-based assay inducing
mitotic arrest in HeLa cells according to a method described in
Ref. 10b. Unfortunately, it followed from the biological screening
that none of the investigated compounds has shown any signifi-
cant inhibitory effect in vitro or monoastral spindle phenotype
in vivo. Moreover, benzimidazole derivative 16 appears to be toxic
15. Quiroga, J.; Insuasty, B.; Rincon, R.; Larrahondo, M.; Hanold, N.; Meier, H. J.
Heterocycl. Chem. 1994, 31, 1333.
16. (a) Svetlik, J.; Turecek, F.; Hanus, V. J. Chem. Soc., Perkin Trans. 1 1988, 2053; (b)
Svetlik, J.; Hanus, V.; Bella, J. Liebigs Ann. Chem. 1989, 91; (c) Svetlik, J.; Turecek,
F.; Hanus, V. J. Chem. Soc., Perkin Trans. 1 1990, 1315.
to BSC-1 and HeLa cell lines at 100 lM. It can be concluded that
structural modification of monastrol in the thiourea moiety by fu-
sion with additional rings results in a pronounced negative effect
on the inhibition potency against KSP. In view of these findings,
annelation of parent monastrol on left-hand side as reported by
Mayer and Giannis proved to be a rational step in further develop-
ment of effective analogs.10
In summary, we described syntheses of novel monastrol ana-
logs based on Hantzsch- and Biginelli-like reactions. The new ser-
ies consisted of pyridine and pyrimidine derivatives modified by
fusion with azoles and also by additional conformative bridging
through the phenol oxygen atom. Although the new compounds
have been found to be inactive against Eg5 mitotic kinesin, the re-
ported results contribute toward deeper insight into structure–
activity relationship.
17. (a) Papadopoulos, E. P.; Hollstein, U. Org. Magn. Reson. 1982, 19, 188; (b)
Lopyrev, V. A.; Larina, L. I.; Vakulskaya, T. I.; Shibanova, E. F.; Titova, I. A.;
Voronkov, M. G.; Liepinsh, E. E. Org. Magn. Reson. 1982, 20, 212; (c) Claramunt,
R. M.; Elguero, J.; Meco, T. J. Heterocycl. Chem. 1983, 20, 1245.
18. Bartashevich, E. V.; Plekhanov, P. V.; Rusinov, G. L.; Potemkin, V. A.; Belik, A. V.;
Chupakhin, O. N. Izv. Akad. Nauk SSSR Ser. Khim. 1999, 1573.
19. Svetlik, J.; Hanus, V.; Bella, J. J. Chem. Res., Synop. 1991, 4.
20. Kettmann, V.; Svetlik, J.; Veizerova, L. Acta Crystallogr., Sect. E 2009, 65, 2967.
21. Methyl 4-(3-hydroxyphenyl)-3,6-dimethyl-4,7-dihydro-2H-pyrazolo[3,4-b]-
pyridine-5-carboxylate (9): Mp 268–269 °C (MeOH), yield 36%; IR (KBr): mmax
3372, 3272, 1667, 1541, 1508, 1233, 1101 cmꢀ1 1H NMR (DMSO-d6) d 1.91 (s,
;
3H, Me-3), 2.31 (s, 3H, Me-6), 3.41 (s, 3H, OMe), 4.87 (s, 1H, H-4), 6.45 (dd, 1H,
J = 7.8 and 1.8 Hz, H-40), 6.50 (s, 1H, H-20), 6.58 (d, 1H, J = 7.8 Hz, H-60), 6.97 (t,
1H, J = 7.8 Hz, H-50), 9.10 (s, 1H, OH/NH), 9.31 (s, 1H, NH/OH)), 11.63 (s, 1H,
NH-2). 1,5-Dimethyl-4,11b-dihydro-[1]benzopyrano[4,3-d]pyrazolo[3,4-b]pyri-
din-6(2H)-one (11): Mp >300 °C (EtOH), yield 89%; IR (KBr): mmax 3287, 1695,
1596, 1546, 1503, 1199 cmꢀ1 1H NMR (DMSO-d6) d 2.15 (s, 3H, Me-1), 2.24 (s,
;
3H, Me-5), 4.86 (s, 1H, H-11b), 6.94 (d, 1H, J = 7.5 Hz, H-8), 7.06 (d, 1H, J = 7.5 Hz,

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J. Svetlik et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4073–4076
H-11), 7.10 (t, 1H, J = 7.5 Hz, H-10), 7.23 (t, 1H, J = 7.5 Hz, H-9), 9.76 (s, 1H, NH),
1.8 Hz, H-10), 9.19 (s, 1H, NH); 13C NMR (DMSO-d6) d 25.7 (Me), 31.0 (CH2), 48.5
(CH-11), 82.4 (C-5), 116.6 (CH-7), 120.6 (CH-9), 120.8 (C-10a), 128.6 (CH-10),
130.3 (CH-8), 152.1 (C-3a), 152.2 (C-6a); (6R*,14R*)-( )-6-Methyl-6,7-dihydro-
14H-6,14-methanobenzimidazo[2,1-d][1,3,5]benzoxadiazocine (16): Mp 264–
266 °C (EtOH), yield 64%; IR (KBr): mmax 3215, 1641, 1604, 1578, 1460, 1255,
12.10 (s, 1H, NH). 1,5-Dimethyl-[1]benzopyrano[4,3-d]pyrazolo[3,4-b]pyridin-
6(3H)-one (12): Mp >300 °C (EtOH), yield 4%; IR (KBr): mmax 1735, 1611, 1542,
1250 cmꢀ1 1H NMR (DMSO-d6) d 2.78 (s, 3H, Me-1), 2.94 (s, 3H, Me-5), 7.44 (d,
;
1H, J = 7.8 Hz, H-8), 7.48 (t, 1H, J = 7.8 Hz, H-10), 7.71 (t, 1H, J = 7.8 Hz, H-9), 8. 36
(d, 1H, J = 7.8 Hz, H-11), 13.8 (br s, 1H, NH). (5R*,11R*)-( )-2,5-Dimethyl-4,5-
dihydro-11H-5,11-methanopyrazolo[5,1-d][1,3,5]benzoxadiazocine (14): Mp
208–210 °C (MeCN), yield 43%; IR (KBr): mmax 3421, 1609, 1589, 1578,
1189, 1138, 1073, 754 cmꢀ1 1H NMR (DMSO-d6) d 1.81 (s, 3H, Me), 2.46 (dd, 1H,
;
J = 13.2 and 2.4 Hz, H-15 equiv), 2.52 (dd, 1H, J = 13.2 and 3.6 Hz, H-15ax), 5.68
(t, 1H, J = 3.0 Hz, H-14), 6.79 (t, 1H, J = 7.2 Hz, H-2), 6.80 (d, 1H, J = 7.9 Hz, H-4),
6.96 (m, 2H, H-10 + H-11), 7.14 (t, 1H, J = 7.2 Hz, H-3), 7.15 (m, 1H, H-9), 7.45 (d,
1H, J = 7.2 Hz, H-1), 7.62 (m, 1H, H-12), 8.75 (br s, 1H, NH); 13C NMR (DMSO-d6) d
26.4 (Me), 31.8 (CH2), 45.1 (CH-14), 82.1 (C-6), 107.9 (CH-12), 115.4 (CH-9),
116.3 (CH-4), 118.6 (CH-11), 119.9 (CH-2), 120.8 (CH-10), 122.5 (C-14a), 128.5
(CH-1), 129.5 (CH-3), 131.7 (C-12a), 142.7 (C-8a), 150.4 (C-7a), 152.3 (C-4a);
1461,1256, 1068, 843, 753, 729 cmꢀ1 1H NMR (DMSO-d6) d 1.71 (s, 3H, Me-5),
;
1.94 (s, 3H, Me-2), 2.26 (quasi dt, 1H, J = 13.2 Hz, H-13 equiv), 2.38 (dd, 1H,
J = 13.2 and 3.0 Hz, H-13ax), 4.97 (s, 1H, H-3), 5.17 (quasi t, 1H, J = 2.8 Hz, H-11),
6.74 (dd, 1H, J = 8.4 and 1.2 Hz, H-7), 6.79 (dt, 1H, J = 7.8 and 1.8 Hz, H-9), 7.12
(dt, 1H, J = 7.8 and 1.8 Hz, H-8), 7.25 (dd, 1H, 1H, J = 7.5 and 1.2 Hz, H-10), 7.50 (s,
1H, NH); 13C NMR (DMSO-d6) d 13.8 (Me-2), 26.7 (Me-5), 32.5 (CH2), 49.9 (CH-
11), 81.9 (C-5), 85.2 (CH-3), 115.8 (CH-7), 119.5 (CH-9), 123.1 (C-10a), 128.6 (CH-
10), 129.1 (CH-8), 142.4 (C-3a), 146.3 (C-2), 153.8 (C-6a); EI MS (m/z) 241 (M+).
(5R*,11R*)-( )-5-Methyl-4,5-dihydro-11H-5,11-methanotetrazolo[5,1-d][1,3,5]-
*
*
(5R ,11R )-( )-5-Methyl-1,2-dihydro-5H,11H-5,11-methano[1,3]thiazolo[2,3-d]-
[1,3,5]benzoxadiazocine (17): Mp 240–241 °C (MeCN), yield 64%; IR (KBr): mmax
1588, 1481, 1253, 1174, 1139, 879, 762 cmꢀ1 1H NMR (DMSO-d6) d 1.55 (s, 3H,
;
Me), 2.07 (dd, 1H, J = 13.2 and 3.0 Hz, H-13), 2.14 (dd, 1H, J = 13.2 and 3.0 Hz, H-
130), 3.08 (m, 1H, H-2), 3.18 (m, 2H, H-20 + H-1), 3.72 (m, 1H, H-10), 4.47 (t, 1H,
J = 3.0 Hz, H-11), 6.79 (d, 1H, J = 7.2 Hz, H-7), 6.85 (t, J = 7.2 Hz, H-9), 7.19 (m, 2H,
H-8 + H-10); 13C NMR (DMSO-d6) d 26.0 (CH2-2), 28.4 (Me), 31.2 (CH2-13), 49.1
(CH-11), 51.1 (CH2-1), 82.9 (C-5), 116.4 (CH-7), 119.3 (CH-9), 120.6 (C-10a),
129.4 (CH-10), 129.5 (CH-8), 152.5 (C-6a), 164.6 (C-3a).
benzoxadiazocine (15): Mp 231–233 °C (MeOH), yield 34%; IR (KBr):
mmax 3233,
1624, 1485, 1252, 1113, 1081, 868, 761 cmꢀ1 1H NMR (DMSO-d6) d 1.81 (s, 3H,
;
Me), 2.48 (ddd, 1H, J = 13.8, 3.0 and 1.2 Hz, H-13 equiv), 2.50 (dd, 1H, J = 13.8 and
3.0 Hz, H-13ax), 6.01 (t, 1H, J = 3.0 Hz, H-11), 6.84 (d, 1H, J = 7.8 Hz, H-7), 6.89 (t,
1H, J = 7.8 Hz, H-9), 7.22 (dt, 1H, J = 8.2 and 1.8 Hz, H-8), 7.39 (dd, 1H, J = 7.8 and