The stereoselective synthesis of nopinone based triazole ketones

Article abstract of DOI:10.1016/j.tetasy.2004.10.020

The aldol reaction of nopinone 1 with triazole aldehydes followed by reduction with Zn/ZnCl₂ furnished isomers 2a-d in satisfactory overall yields and excellent diastereoselectivities (ca 94% de).

Full text of DOI:10.1016/j.tetasy.2004.10.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3719–3722
The stereoselective synthesis of nopinone based triazole ketones
Ronaldo C. da Silva Junior, V ´ı tor F. Ferreira and Sergio Pinheiro*
Departamento de Qu ı´ mica Org aˆ nica, Instituto de Qu ı´ mica, Universidade Federal Fluminense, CEG, Centro, 24020-150 Niter o´ i,
RJ, Brazil
Received 1 October 2004; accepted 19 October 2004
Abstract—The aldol reaction of nopinone 1 with triazole aldehydes followed by reduction with Zn/ZnCl furnished isomers 2a–d in
2
satisfactory overall yields and excellent diastereoselectivities (ca 94% de).
Ó 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
the lithium enolate of 1 with alkyl halides under kinetic
conditions was reported to furnish isomers 3 in excellent
diastereoselectivities.
9
Triazoles represent an interesting class of compounds
1
having a wide spectrum of biological properties.
Among them, some triazole substituted ketones are
attractive target molecules because of their importance
Herein we report that, in contrast to the literature prec-
9
a,b
edent,
the kinetic alkylation of the lithium enolate of
2
3
such as antifungal agents, germicides and antibacteri-
1 with triazole bromide 4 gives product 2, which was ob-
tained in excellent diastereoselectivities from the aldol
pathway.
4
5
als including activities against tuberculosis. The asym-
metric synthesis of triazole substituted ketone merits
attention since the absolute configuration of the alpha
position to the carbonyl plays an important role for
2
a
the antifungal activity.
2. Results and discussion
Due to our continuing interest on the use of pinenes in
6
The 1,2,3-triazole bromide 4 was prepared from alde-
hyde 5, a readily available derivative of D-(+)-glucose
asymmetric synthesis, we focused on the stereoselective
synthesis of novel (+)-nopinone based triazole ketones
with potential biological activities.
1
0
(Scheme 2). Reduction of 5 with NaBH furnished
4
1
1
alcohol 6, which upon treatment with PBr in ethyl
3
1
2
ether gave 4.
The alkylation of the enolate of (+)-nopinone 1 with
alkyl halides is reported to lead to a mixture of 2 and
OHC
N
a
N
N
b
N
N
HO
Br
3
usually favouring the thermodynamic diastereomer 2
7
N Ph
N Ph
N Ph
(Scheme 1), which was obtained in one case as the sole
product by an aldol reaction of 1 with PhCHO followed
N
5
6
4
8
by hydrogenation. Conversely the monoalkylation of
Scheme 2. Reagents and conditions: (a) NaBH
4
, MeOH, 10min, 94%;
(
b) PBr , Et O, 24h, 90%.
3
2
R
H
H
R
In contrast to that described in the literature for the use
9
1
. base
a,b
+
of alkyl halides,
13
the kinetic alkylation of the lithium
enolate of 1 with triazole bromide 4 at ꢀ45°C in the
2. R-X
O
O
O
1
2
3
presence of HMPA as additive following the typical
a,b
9
experimental procedure
was obtained in poor yields and stereoselectivity (Table
1
led to product 2a, which
Scheme 1. Thermodynamic and kinetic alkylations of (+)-nopinone 1.
1
4
, entry 1). At higher temperatures, compound 2a was
*
Corresponding author. Fax: +5521 26292129; e-mail: spin@
rmn.uff.br
produced in similar yield and in better diastereoselectiv-
ity (entry 2).
0
957-4166/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.020

3720
R. C. da Silva Junior et al. / Tetrahedron: Asymmetry 15 (2004) 3719–3722
8
Table 1. Stereoselectivities in the alkylation of 1 with the bromide 4
9. Reduction of 8 with Zn/ZnCl gave 9 in an exo/
2
endo = 97:3 ratio. The specific rotation of 9 thus ob-
tained was compared with the product reported by
hydrogenation of 8, showing that these methodologies
occur with the same stereochemical sense (Scheme 4).
8
10
8
N
Ph
Ph
+
H3
alkylation
N
N N
8
N
H3
2a
N
1
1
10
O
O
O
1
3a
a
b
Entry
1
Reaction and conditions
%
2a/3a
Ph
a
b or c
Ph
LDA, THF, ꢀ10°C then 4,
NaI, HMPA, ꢀ45°C, 4h
LDA, THF, ꢀ10°C then 4,
NaI, HMPA, 0°C, 1h
18
2487:13
76:24
H
O
O
O
2
1
8
9
a
2
Scheme 4. Reagents and conditions: (a) see Ref. 8; (b) see Ref. 8: H ,
Yields for the purified mixture of products 2a and 3a by flash chro-
20
Pd/C, AcOEt, 95%, ½aŠ ¼ ꢀ56:4 (c 1.6, EtOH); (c) Zn, ZnCl
2
, EtOH,
matography on silica gel.
D
20
b
1
reflux, 2h, 93%, ½aŠ ¼ ꢀ50 (c 1.6, EtOH).
Ratios determined from the signals of both H
NMR spectra (300MHz).
8
and H10 in the
H
D
In order to verify the scope of this stereochemical course
producing mainly isomers 2, the already known triazole
aldehydes 10–12 were employed in the aldol pathway
(Scheme 5). Thus, the aldol reactions of 1 with 10–12
furnished the corresponding enones 7b–d as single iso-
The 2a/3a ratios were determined from the signals due to
the hydrogens H , H10 and H12 in the H NMR spectra
at 300MHz of these crude mixtures. The stereochemical
assignment of the newly created stereogenic centre in the
main isomer 2a was made on the basis of NOE NMR
1
18
8
1
9–21
mers,
in EtOH to the respective compounds 2b–d in good
which were reduced with the Zn/ZnCl system
2
spectrum as already described in the literature for a re-
8
2
2–24
yields and diastereoselectivities (exo/endo = 97:3).
Also here the epimeric 2b–d/3b–d ratios at the 3-position
were obtained from the signals of H and H in the
crude H NMR spectra while the absolute configura-
tions at the 3-position were made from NOE spectra
as reported for the alkylation of 1.
lated compound. Indeed, starting from H , significant
8
NOE was observed with H4b (2.3%). Also observed were
NOEs of H4a with H (7.7%) and of H with H (4.6%),
8
12
3
3
7a
1
which implies a syn relationship between the methylene-
triazole appendage and the gem-dimethylene bridge of
the pinane moiety. Also noteworthy, the NOE between
H and H was not observed while a strong NOE of
8
10
H with H (9.1%) suggests for isomer 2a a preferred
3
10
conformation in which the hydrogens H and H are
8
not close together.
Cl
10
OHC
OHC
OHC
N
N
N
F
N
N
N
N
N
N
The aldol pathway proved to be a very attractive route
to isomer 2a in high diastereoselectivity (Scheme 3).
The aldol condensation of 1 with aldehyde 5 was carried
10
11
12
8
Ar
10
Ar
H
H
8
a
b
out following the typical procedure giving enone 7a as a
Ar
+
1
5
single geometric isomer. The assignment of the config-
uration of the double bond was made on the basis of
NOE NMR spectrum. Neither H4a nor H4b gave NOE
with H . However H showed a strong NOE with H
12
O
O
7b-d
O
2b-d
O
3b-d
1
(
2b-d: 3b-d = 97: 3)
1
0
4
(
8.4%) allowing us to define the geometry of the double
Scheme 5. Reagents and conditions: (a) 10 or 11 or 12 (1equiv), aq
KOH, reflux, 20h (7b: 55%, 7c: 58%, 7d: 59%); (b) Zn, ZnCl , EtOH,
reflux, 2h (2b: 75%, 2c: 70%, 2d: 80%).
bond. Since hydrogenation of 7a in Pd/C and in Pt
failed, this compound was converted to 2a upon treat-
ment with the system Zn/ZnCl2.
ratio was obtained from the signals of H , H and
H12 in the crude H NMR spectrum while the stereo-
chemistry at the 3-position was determined on the basis
of NOE experiments, as reported above for the alkyla-
tion of 1.
2
1
6,17
The 2a/3a = 97:3
8
10
1
3. Conclusion
In summary, the aldol pathway for the introduction of
methylenetriazole moieties in nopinone 1 furnishing
the isomers 2a–d in high stereoselectivities (ca 94% de),
is an attractive and complementary protocol to the
already reported kinetic alpha alkylation of the lithium
N
Ph
12
N
9
a,b
N
enolate of 1,
the alkylation with triazole bromide 4.
which was shown to be inefficient for
N
Ph
N
a
b
4
10
N
H
1
O
O
O
1
7a
2a
Acknowledgements
Scheme 3. Reagents and conditions: (a) 5 (1equiv), aq KOH, reflux,
0h, 56%; (b) Zn, ZnCl , EtOH, reflux, 2h, 92%.
2
2
The authors thank CNPq for financial support and are
indebted to Dr. Maria Cec ´ı lia B. V. de Souza as well
as to Dr. Katia Z. Leal (UFF) for NMR spectra; to
Dr. Marcos Eberlin (Unicamp) for mass spectra and
The catalytic hydrogenation of enone 8 derived from 1
was reported to furnish stereoselectively the exo-isomer

R. C. da Silva Junior et al. / Tetrahedron: Asymmetry 15 (2004) 3719–3722
3721
to Dr. Jos e´ O. Previatto (UFRJ) for specific rotation
measurements. R.C.S.J. and V.F.F. are grateful to
CNPq for research fellowships.
1.2Hz, H-14), 7.66 (s, H-12 of 2a), 7.62 (s, H-12 of 3a),
7
1
4
.46 (ddd, 7.5, 7.2, 1.8Hz, H-15), 7.32 (tt, 7.5, 1.2Hz, H-
6), 3.52 (dd, 15.0, 4.2Hz, H-10 of 2a), 3.41 (dd, 13.5,
.5Hz, H-10 of 3a), 3.10–3.00 (m, H-3 of 2a), 2.89–2.81
(
(
m, H-3 of 3a), 2.94(dd, 16.5, 4. 5Hz, H-10 of 3a), 2.72
dd, 15.0, 9.6Hz, H-10 of 2a), 2.66 (dd, 5.4, 5.1Hz, H-1),
References
2.59-2.53 (m, H-7b of 3a), 2.52–2.45 (m, H-7b of 2a), 2.33
ddd, 13.2, 10.2, 4.8Hz, H-4a), 2.27 (ddd, 5.4, 5.1, 4.8Hz,
(
1
. See references cited in: (a) Collin, X.; Sauleau, A.; Coulon,
J. Bioorg. Med. Chem. Lett. 2003, 13, 2601–2605; (b)
Kritsanida, M.; Mouroutsou, A.; Marakos, P.; Pouli, N.;
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H-5), 1.76 (d, 10.5Hz, H-7a), 1.71–1.64(m, H-4 b), 1.34(s,
H-9 of 2a), 1.33 (s, H-9 of 3a), 0.94(s, H-8 of 3a), 0.75 (s,
H-8 of 2a). C NMR (CDCl , ppm): 215.0 (C-2), 148.0
3
(C-11), 139.8 (C-13), 134.8 (C-12), 129.6 (C-15), 126.8 (C-
16), 118.4(C-1 4) , 58.5 (C-1 of 3a), 57.6 (C-1 of 2a), 43.2
(C-6), 42.4 (C-3), 41.6 (C-5), 31.5 (C-4 of 3a), 28.6 (C-4
and C-7 of 2a), 28.2 (C-7 of 3a), 25.9 (C-10 of 3a), 25.4(C-
10 of 2a), 26.1 (C-9), 21.9 (C-8).
1
3
1
05, 111–115.
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. (a) Ogata, M.; Matsumoto, H.; Takahashi, K.; Shimizu,
S.; Kida, S.; Murabayashi, A.; Shiro, M.; Tawara, K. J.
Med. Chem. 1987, 30, 1054–1068; (b) Ogata, M.; Matsu-
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Grushetskaya, G. N.; Panasenko, A. A.; Krimer, M. Z.
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R.; Joshi, V. Indian J. Chem. 1999, 38B, 192–196.
15. Compound 7a: White solid after flash chromatography on
silica gel (10% AcOEt in hexane as eluant), mp 63–64°C.
2
5
ꢀ1
2 2
Cl ). IR (KBr, cm ): 3084, 2932,
½aŠ ¼ ꢀ1:8 (c 2.65, CH
D
1698, 1624, 1597, 1499, 1463, 1213, 1198, 1063, 965, 756,
1
690, 666. H NMR (300MHz, CDCl , ppm): 8.13 (ddd,
3
7.2, 3.0, 1.3Hz, Harom), 7.97 (s, H-12), 7.76 (t, 2.6Hz, H-
10), 7.51 (ddd, 7.5, 7.2, 1.8Hz, Harom), 7.38 (tt, 7.5, 1.2Hz,
3
. Xiao, Y. D.; Wei, L. H.; Wang, J. T.; Zhang, J. B.; Lin, S.
F.; Zhou Chemometr. Intell. Lab. Syst. 1999, 45, 277–280.
. Soliman, F. M. A. J. Serb. Chem. Soc. 1995, 60, 9–14.
Harom), 3.15 (ddd, 18.0, 2.7, 2.4Hz, H-4a), 3.05 (dddd,
18.0, 2.4, 2.3, 2.1Hz, H-4b), 2.75 (dd, 5.7, 5.6Hz, H-1),
4
5
2.69 (dddd, 10.2, 6.0, 5.6, 2.1Hz, H-7b), 2.46–2.40 (m, H-
1
3
¨
. Dabak, K.; Sezer, O.; Akar, A.; Anac, O. Eur. J. Med.
Chem. 2003, 38, 215–218.
5), 1.55 (d, 10.2Hz, H-7a), 1.41 (s, H-9), 0.94 (s, H-8).
C
NMR (CDCl , ppm): 198.0 (C-2), 140.4 (C-11), 135.2 (C-
3
6
. (a) Pinheiro, S.; Pedraza, S. F.; Peralta, M. A.; Teixeira,
R. C.; Farias, F. M. C.; Ferreira, V. F.; Costa, P. R. R.
Tetrahedron: Asymmetry 2002, 13, 2513–2517; (b) Pinhe-
iro, S.; Gon c¸ alves, C. B. S. S.; Lima, M. B.; Farias, F. M.
C. Tetrahedron: Asymmetry 2000, 11, 3495–3502; (c)
Pinheiro, S.; Pedraza, S. F.; Farias, F. M. C.; Gon c¸ alves,
A. S. Tetrahedron: Asymmetry 2000, 11, 3845–3848; (d)
Costa, P. R. R.; Ferreira, V. F.; Ara u´ joFilho, H. C.;
Pinheiro, S. J. Braz. Chem. Soc. 1996, 7, 67–73.
13), 132.7 (C-12), 131.2 (C-3), 124.8 (C-15), 123.4 (C-16),
118.0 (C-10), 114.3 (C-14), 51.7 (C-1), 36.4 (C-6), 34.6 (C-
5), 27.0 (C-4), 23.3 (C-7), 21.8 (C-9), 17.2 (C-8). MS
(70eV, m/z): 294(M + 1, 16), 293 (M , 77), 278 (41), 250
+
(100), 91 (29), 77 (36). HREIMS calcd for C H N O
3
1
8
19
+
(M ): 293.1528. Found: 293.1506.
16. Toda, F.; Iida, K. Chem. Lett. 1976, 695–696.
17. Compound 2a in a 94% de: pale yellow oil by flash
chromatography on silica gel (3% AcOEt in hexane as
2
5
ꢀ1
7
8
9
. Kato, M.; Watanabe, M.; Vogler, B.; Awen, B. Z.;
Masuda, Y.; Tooyama, Y.; Yoshikoshi, A. J. Org. Chem.
eluant). ½aŠ ¼ ꢀ46:0 (c 0.76, CH
Cl ). IR (neat, cm ):
2 2
D
3053, 2927, 2870, 1705, 1598, 1519, 1500, 1463, 1348, 1201,
1
1038, 1024, 965, 852, 757, 691, 665. H NMR (300MHz,
1
991, 56, 7071–7076.
. Dumas, F.; Alencar, K.; Mahuteau, J.; Barbero, M. J. L.;
Miet, C.; G e´ rard, F.; Vasconcellos, M. L. A. A.; Costa, P.
R. R. Tetrahedron: Asymmetry 1997, 8, 579–583.
. (a) Campos, K. R.; Journet, M.; Cai, D.; Kowal, J. J.; Lee,
S.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2003, 68,
3
CDCl , ppm): 8.03 (ddd, 7.2, 3.0, 1.2Hz, H-14), 7.66 (s, H-
12), 7.46 (ddd, 7.5, 7.2, 1.8Hz, H-15), 7.32 (tt, 7.5, 1.2Hz,
H-16), 3.52 (dd, 15.0, 4.2Hz, H-10), 3.10–3.00 (m, H-3),
2.72 (dd, 15.0, 9.6Hz, H-10), 2.66 (dd, 5.4, 5.1Hz, H-1),
2.52–2.45 (m, H-7b), 2.33 (ddd, 13.2, 10.2, 4.8Hz, H-4a),
2.27 (ddd, 5.4, 5.1, 4.8Hz, H-5), 1.76 (d, 10.5Hz, H-7a),
2
338–2342; (b) Campos, K. R.; Lee, S.; Journet, M.;
1
3
Kowal, J. J.; Cai, D.; Larsen, R. D.; Reider, P. J.
Tetrahedron Lett. 2002, 43, 6957–6959; (c) Konopelski, J.
P.; Djerassi, C. J. Org. Chem. 1980, 45, 2297–2301.
1.71–1.64(m, H-4 b), 1.34(s, H-9), 0.75 (s, H-8). C NMR
(CDCl , ppm): 215.0 (C-2), 148.0 (C-11), 139.8 (C-13),
3
134.8 (C-12), 129.6 (C-15), 126.8 (C-16), 118.4 (C-14), 57.6
(C-1), 43.2 (C-6), 42.4 (C-3), 41.6 (C-5), 28.6 (C-4 and C-
7), 25.4(C-10), 26.1 (C-9), 21.9 (C-8). MS (70eV, m/z): 297
1
1
0. Hann, M. R.; Hudson, C. S. J. Am. Chem. Soc. 1944, 66,
35–738.
1. Alcohol 6: White solid, mp 64–65°C. IR (KBr, cm ):
7
ꢀ
1
+
(M + 2, 14), 296 (M + 1, 66), 295 (M , 100), 254(25), 226
3
9
8
7
5
317, 3232, 2943, 1595, 1489, 1414, 1353, 1306, 1050, 1014,
64, 849, 760, 730. H NMR (300MHz, CDCl , ppm):
.05 (ddd, 7.2, 3.0, 1.2Hz, CH), 7.80 (s, CH), 7.48 (ddd,
.5, 7.2, 1.8Hz, CH), 7.35 (tt, 7.5, 1.2Hz, CH), 4.88 (d,
(94), 185 (36), 171 (28), 159 (84), 158 (47), 137 (29), 103
(33), 95 (30), 91 (62), 83 (56), 77 (53), 55 (32). HREIMS
calcd for C H N O (M ): 295.0366. Found: 295.0351.
1
3
+
1
8
21
3
18. Cunha, A. C.; Figueiredo, J. M.; Tributino, J. L. M.;
Miranda, A. L. P.; Castro, H. C.; Zingali, R. B.; Fraga, C.
A. M.; Souza, M. C. B. V.; Ferreira, V. F.; Barreiro, E. J.
Bioorg. Med. Chem. 2003, 11, 2051–2059.
2
.6Hz, CH ), 1.98 (t, 5.6Hz, OH).
1
2. Compound 4: White solid after flash chromatography on
silica gel (10% AcOEt in hexane as eluant), mp 44-45°C.
IR (KBr, cm ): 3036, 1594, 1498, 1487, 1341, 1333, 1212,
ꢀ
1
19. Compound 7b: White solid after flash chromatography
on silica gel (10% AcOEt in hexane as eluant), mp 168–
1
1
034, 966, 859, 760, 737, 711. H NMR (300MHz, CDCl
3
,
2
5
ꢀ1
ppm): 8.07 (ddd, 7.3, 3.2, 1.2Hz, CH), 7.82 (s, CH), 7.46
169°C. ½aŠ ¼ þ5:5 (c 2.3, CH Cl ). IR (KBr, cm ):
D
3175, 3001, 2963, 2929, 1691, 1613, 1597, 1500, 1467, 1369,
2
2
(
(
ddd, 7.5, 7.3, 1.6Hz, CH), 7.36 (tt, 7.5, 1.2Hz, CH), 4.61
s, CH ).
1
1305, 1215, 1200, 1059, 1045, 983, 808, 759, 688. H NMR
2
1
1
3. (+)-Nopinone is available from Aldrich Chem. Co.
4. Mixture of isomers 2a and 3a: Pale yellow oil after flash
chromatography on silica gel (1% AcOEt in hexane as
(300MHz, CDCl , ppm): 8.14(s, H-12), 7.78 (ddd, 7.2,
3
3.0, 1.2Hz, Harom), 7.81 (t, 2.4Hz, H-10), 7.56 (ddd, 7.5,
7.2, 1.8Hz, Harom), 7.48 (tt, 7.2, 1.2Hz, Harom), 3.16 (ddd,
18.0, 2.6, 2.4Hz, H-4a), 3.06 (dddd, 18.0, 2.6, 2.4, 2.1Hz,
H-4b), 2.73 (dd, 5.7, 5.6Hz, H-1), 2.68 (dddd, 10.2, 6.1,
2
5
eluant). ½aŠ ¼ ꢀ27:0 (c 0.63, CH
2 2
Cl ) for 2a/3a = 76:24.
D
H NMR (300MHz, CDCl , ppm): 8.03 (ddd, 7.2, 3.0,
1
3

3722
R. C. da Silva Junior et al. / Tetrahedron: Asymmetry 15 (2004) 3719–3722
5
7
2
.7, 2.1Hz, H-7b), 2.44–2.38 (m, H-5), 1.55 (d, 10.2Hz, H-
2.51-2.44 (m, H-7b), 2.37 (ddd, 13.2, 10.0, 4.6Hz, H-4a),
2.29–2.21 (m, H-5), 1.76 (d, 10.5Hz, H-7a), 1.72 (dd, 13.2,
7.8Hz, H-4b), 1.34(s, H-9 of 2b), 1.33 (s, H-9 of 3b), 0.94
1
3
a), 1.40 (s, H-9), 0.93 (s, H-8). C NMR (CDCl
02.2 (C-2), 144.6 (C-11), 136.4 (C-13), 134.0 (C-3), 129.8
3
, ppm):
1
3
(
C-15), 128.9 (C-16), 122.6 (C-10), 122.4(C-12), 120.4(C-
3
(s, H-8 of 3b), 0.70 (s, H-8 of 2b). C NMR (CDCl ,
1
7
2
4), 55.9 (C-1), 41.0 (C-6), 39.3 (C-5), 31.2 (C-4), 27.8 (C-
), 26.1 (C-9), 21.7 (C-8). MS (70eV, m/z): 293 (M , 3),
50 (10), 222 (43), 104 (38), 91 (17), 77 (100), 51 (29).
ppm): 215.0 (C-2), 146.8 (C-11), 137.2 (C-13), 129.6 (C-
15), 128.2 (C-16), 120.2 (C-12 and C-14), 57.6 (C-1), 43.2
(C-10), 42.4 (C-3), 41.6 (C-5), 39.8 (C-6), 28.6 (C-4),
26.1 (C-9), 25.4(C-7), 21.9 (C-8). MS (70eV, m/z): 295
+
+
HREIMS calcd for C18
93.1481.
0. Compound 7c: White solid after flash chromatography
on silica gel (10% AcOEt in hexane as eluant), mp 143–
H
19
N
3
O (M ): 293.1528. Found:
+
2
(M , 3), 198 (23), 130 (100), 104(59), 77 (93), 55 (22).
HREIMS calcd for C H N O (M ): 295.0476. Found:
+
2
1
8
21
3
295.0498.
23. Compound 2c (2c/3c = 97:3): White solid after flash
chromatography on silica gel (3% AcOEt in hexane as
2
D
5
ꢀ1
1
3
1
44°C. ½aŠ ¼ þ2:5 (c 2.29, CH
2
Cl
2
). IR (KBr, cm ):
132, 2948, 1690, 1625, 1594, 1489, 1370, 1310, 1263, 1199,
1
055, 1043, 984, 882, 797, 780, 678. H NMR (300MHz,
25
eluant), mp 81–82°C. ½aŠ ¼ ꢀ11:1 (c 0.99, CH Cl ). IR
D
(neat, cm ): 3131, 3064, 2924, 2870, 1706, 1595, 1496,
2
2
ꢀ
1
CDCl
2.4Hz, Harom), 7.70 (dt, 7.8, 1.8Hz, Harom), 7.50 (t, 8.1Hz,
3
, ppm): 8.14(s, H-12), 7.81 (t, 2.0Hz, H-10), 7.79 (t,
1
1440, 1225, 1199, 1078, 1042, 804, 781, 770, 686. H NMR
H
arom), 7.45 (ddd, 8.1, 1.8, 1.6Hz, Harom), 3.13 (ddd, 18.0,
3
(300MHz, CDCl , ppm): 7.88 (s, H-12 of 2c), 7.80 (s, H-12
2
2
2
1
.7, 2.4Hz, H-4a), 3.03 (dddd, 18.0, 2.4, 2.3, 2.1Hz, H-4b),
.74(dd, 5.8, 5.6Hz, H-1), 2.67 (dddd, 10.2, 6.0, 5.8,
.1Hz, H-7b), 2.44-2.39 (m, H-5), 1.54 (d, 10.2Hz, H-7a),
of 3c), 7.78 (dd, 2.1, 1.9Hz, H-14), 7.63 (ddd, 7.8, 2.1,
1.5Hz, H-18), 7.45 (t, 7.8Hz, H-17), 7.41 (ddd, 7.8, 2.1,
1.5Hz, H-16), 3.44 (dd, 15.0, 5.1Hz, H-10 of 2c), 3.37 (dd,
15.0, 6.0Hz, H-10 of 3c), 3.16–3.03 (m, H-3), 2.90 (dd,
15.0, 5.8Hz, H-10 of 3c), 2.81 (dd, 15.0, 7.9Hz, H-10 of
2c), 2.63 (t, 5.1Hz, H-1), 2.52–2.44 (m, H-7b), 2.37 (ddd,
13.0, 10.0, 4.8Hz, H-4a), 2.30–2.22 (m, H-5), 1.76 (d,
10.5Hz, H-7a), 1.71 (dd, 13.0, 7.8Hz, H-4b), 1.34(s, H-9
of 2c), 1.33 (s, H-9 of 3c), 0.93 (s, H-8 of 3c), 0.70 (s, H-8
1
3
.41 (s, H-9), 0.93 (s, H-8). C NMR (CDCl , ppm): 202.0
3
(
C-2), 144.8 (C-11), 137.6 (C-15), 135.6 (C-13), 134.4 (C-
3
1
5
), 131.0 (C-17), 129.0 (C-16), 122.6 (C-14), 122.2 (C-12),
20.8 (C-10), 118.4(C-18), 56.0 (C-1), 41 .1 (C-6), 39.2 (C-
), 31.2 (C-4), 27.7 (C-7), 26.2 (C-9), 21.8 (C-8). MS
+
(70eV, m/z): 329 (M + 2, 3), 327 (M , 18), 299 (25), 298
(24), 264 (23), 258 (33), 256 (100), 228 (22), 193 (20), 154
(30), 138 (75), 111 (74), 91 (35), 75 (30), 55 (50). HREIMS
1
3
3
of 2c). C NMR (CDCl , ppm): 214.9 (C-2), 147.0 (C-11),
137.8 (C-15), 135.3 (C-13), 130.6 (C-17), 128.4(C-16),
120.4(C-1 4) , 120.2 (C-12), 118.1 (C-18), 58.2 (C-1 of 3c),
57.5 (C-1 of 2c), 43.3 (C-6), 42.4 (C-3), 40.6 (C-5 of 2c),
40.0 (C-5 of 3c), 28.6 (C-4of 2c), 28.2 (C-4of 3c), 26.2 (C-
9 of 2c), 26.0 (C-9 of 3c), 25.2 (C-7), 25.1 (C-10), 21.7 (C-
+
calcd for C H N ClO (M ): 327.1138. Found: 327.1129.
1
8
18
3
2
1. Compound 7d: White solid after flash chromatography on
silica gel (10% AcOEt in hexane as eluant), mp 164–
2
5
ꢀ1
1
3
1
65°C. ½aŠ ¼ þ11:2 (c 2.09, CH Cl ). IR (KBr, cm ):
1
060, 1046, 984, 840, 819, 770, 612. H NMR (300MHz,
D
168, 2934, 1734, 1688, 1610, 1518, 1368, 1310, 1234, 1198,
2
2
+
8). MS (70eV, m/z): 329 (M , 2), 232 (20), 164(100), 138
(64), 111 (68), 75 (30), 55 (36). HREIMS calcd for
+
ClO (M ): 329.1646. Found: 329.1672.
CDCl , ppm): 8.11 (s, H-12), 7.79 (t, 2.4Hz, H-10), 7.76
(ddd, 9.3, 4.5, 2.1Hz, H-14), 7.26 (ddd, 9.3, 8.1, 2.1Hz, H-
3
C
24. Compound 2d (2d/3d = 97:3): White solid after flash
18
H
20
N
3
1
2
5), 3.14(ddd, 18.0, 2.7, 2.4Hz, H-4 a), 3.04(dddd, 18.0,
.4, 2.3, 2.1Hz, H-4b), 2.72 (dd, 5.7, 5.6Hz, H-1), 2.68
chromatography on silica gel (3% AcOEt in hexane as
2
5
eluant), mp 82–83°C. ½aŠ ¼ ꢀ9:7 (c 1.03, CH
1
1456, 1227, 1047, 839, 817. H NMR (300MHz, CDCl ,
2 2
Cl ). IR
D
(neat, cm ): 3131, 3080, 2971, 2937, 2872, 1700, 1517,
ꢀ
1
(
dddd, 10.2, 6.0, 5.7, 2.1Hz, H-7b), 2.44–2.38 (m, H-5),
1
3
1
.54(d, 10.2Hz, H-7 a), 1.41 (s, H-9), 0.93 (s, H-8).
, ppm): 202.1 (C-2), 164.2 (C-11), 161.0 (C-
6), 145.0 (C-13), 134.0 (C-3), 124.4 (C-10 and C-14),
C
3
NMR (CDCl
3
ppm): 7.85 (s, H-12 of 2d), 7.80 (s, H-12 of 3d), 7.70 (ddd,
6.8, 4.5, 2.4Hz, H-14), 7.22 (ddd, 8.1, 6.8, 2.4Hz, H-15),
3.44 (dd, 15.0, 5.1Hz, H-10 of 2d), 3.37 (dd, 15.0, 6.0Hz,
H-10 of 3d), 3.18–3.03 (m, H-3), 2.91 (dd, 9.0, 4.5Hz, H-10
of 3d), 2.83 (dd, 15.0, 7.9Hz, H-10 of 2d), 2.63 (t, 5.1Hz,
H-1), 2.52-2.44 (m, H-7b), 2.39 (ddd, 13.2, 10.2, 4.8Hz, H-
4a), 2.29–2.23 (m, H-5), 1.77 (d, 10.5Hz, H-7a), 1.72 (dd,
13.2, 7.8Hz, H-4b), 1.34(s, H-9 of 2d), 1.33 (s, H-9 of 3d),
1
1
5
22.3 (C-12), 116.9 (C-15), 56.0 (C-1), 41.0 (C-6), 39.3 (C-
), 31.2 (C-4), 27.8 (C-7), 26.1 (C-9), 21.7 (C-8). MS
+
(70eV, m/z): 311 (M , 7), 283 (36), 268 (31), 240 (95), 212
(28), 172 (31), 122 (100), 95 (99), 91 (38), 55 (32).
+
HREIMS calcd for C H N FO (M ): 311.1434. Found:
8
1
18
3
311.1432.
1
3
2
2. Compound 2b (2b/3b = 97:3): White solid after flash
chromatography on silica gel (3% AcOEt in hexane as
3
0.94(s, H-8 of 3d), 0.69 (s, H-8 of 2d). C NMR (CDCl ,
ppm): 215.0 (C-2), 163.7 (C-11), 160.4(C-16), 1 46 .8 (C-
13), 122.2 (C-14of 2d), 122.1 (C-14of 3d), 120.4(C-12 of
2
5
eluant), mp 85–86°C. ½aŠ ¼ ꢀ10:8 (c 1.11, CH Cl ). IR
D
KBr, cm ): 3131, 3086, 2950, 2925, 2870, 1706, 1599,
2
2
ꢀ
1
(
2d), 120.3 (C-12 of 3d), 116.6 (C-15 of 3d), 116.3 (C-15 of
2d), 58.1 (C-1 of 3d), 57.5 (C-1 of 2d), 43.2 (C-3 of 3d), 42.4
(C-3 of 2d), 40.7 (C-5 of 3d), 40.6 (C-5 of 2d), 28.6 (C-4of
2d), 28.2 (C-4of 3d), 26.2 (C-9 of 2d), 26.0 (C-9 of 3d), 25.2
(C-7), 25.1 (C-10), 21.8 (C-8 of 3d), 21.7 (C-8 of 2d). MS
1
1
503, 1226, 1198, 1047, 768, 695. H NMR (300MHz,
CDCl , ppm): 7.88 (s, H-12 of 2b), 7.80 (s, H-12 of 3b),
.72 (ddd, 7.2, 3.0, 1.2Hz, H-14), 7.51 (ddd, 7.5, 7.2,
3
7
1
4
3
.8Hz, H-15), 7.42 (tt, 7.5, 1.2Hz, H-16), 3.46 (dd, 15.0,
.2Hz, H-10 of 2b), 3.38 (dd, 14.3, 4.0Hz, H-10 of 3b),
.17–3.03 (m, H-3), 2.91 (dd, 9.9, 4.2Hz, H-10 of 3b), 2.81
+
(70eV, m/z): 314(M + 1, 1), 313 (M , 2), 216 (20), 149
(51), 148 (100), 122 (51), 95 (33). HREIMS calcd for
+
C H N FO (M ): 313.3512. Found: 313.3506.
(
dd, 15.0, 9.6Hz, H-10 of 2b), 2.63 (dd, 5.3, 5.1Hz, H-1),
1
8
20
3