Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as a new class of potent antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2009.09.092

Tetrahydroneotanshinlactone (TNT) and tetrahydronaphthalene-1-ol (TNO) derivatives were designed, synthesized, and evaluated for cytotoxic activity. The TNO derivatives were found to be a promising novel class of in vitro antitumor agents. The cyclohexene

Full text of DOI:10.1016/j.bmcl.2009.09.092

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6289–6292
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as
a new class of potent antitumor agents
a
a
a
a
b
Yizhou Dong , Qian Shi , Kyoko Nakagawa-Goto , Pei-Chi Wu , Kenneth F. Bastow ,
a
a,
*
Susan L. Morris-Natschke , Kuo-Hsiung Lee
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States
a
b
Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrahydroneotanshinlactone (TNT) and tetrahydronaphthalene-1-ol (TNO) derivatives were designed,
synthesized, and evaluated for cytotoxic activity. The TNO derivatives were found to be a promising novel
class of in vitro antitumor agents. The cyclohexene ring-A could dramatically affect the antitumor activity
and selectivity. Compound 20 showed the highest potency with ED50 values of 0.7 and 1.7 lM against SK-
BR-3 and ZR-75-1 breast cancer cell lines, respectively.
Received 26 August 2009
Revised 23 September 2009
Accepted 24 September 2009
Available online 29 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydronaphthalene-1-ol (TNO) analogs
Tetrahydroneotanshinlactone (TNT) analogs
Cytotoxicity
Breast cancer
O
C
O
O
O
Cancer is the second leading cause of death in the United States,
accounting for one-quarter of all deaths. Cancer incidence and
1
D
O
resultant mortality have increased by approximately 22% since
O
990,2 and 1,400,000 new cancer cases will be diagnosed in
A
B
1
2
3
009, according to estimates by the American Cancer Society. Nat-
ural products and natural product-derived compounds have pro-
vided more than two-third of the clinically used anticancer
agents, and thus, are important sources for drug discovery.
Tanshinone I (1)
Tanshinone IIA (2)
4
,5
Plant-based drug discovery has resulted particularly in the devel-
opment of new anticancer agents to by-pass multidrug resistance
and overcome side effects of current therapeutic medicines.
The above facts prompted us to focus on natural products and their
analogs in our anticancer drug program.
O
HOOC
OH
6
,7
O
O
O
Research on tanshinones (isolated from the Salvia genus) began
8
in the early 1930s. Tanshinone I (1) and tanshinone IIA (2) differ
Et
Me
structurally in the ring-A system: the former has an aromatic ring,
while the latter has a non-aromatic ring (Fig. 1). Compounds 1 and
Neo-tanshinlatone I (3)
4
2
have been studied extensively for their antitumor effects, and
8
display different activities and selectivities. Recent studies indi-
O
O
HOOC
OH
cated that 1 reduced metastasis and tumorigenesis by inhibition
9
10
of IL-8, while 2 induced cell differentiation and apoptosis. Neo-
1
1
tanshinlactone (3) (Fig. 1), reported by our group previously,
O
O
n
n
showed significant and selective in vitro anti-breast cancer activ-
ity. We further studied how the individual rings in 3 influence
the in vitro activity, and the results led to the discovery of a novel
R
R
5
6
*
Corresponding author. Tel.: +1 919 962 0066; fax: +1 919 966 3893.
E-mail address: khlee@unc.edu (K.-H. Lee).
Figure 1. Structures of tanshinone I (1), tanshinone IIA (2), neotanshinlactone (3),
analog 4, and two newly designed scaffolds 5–6.
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.092

6
290
Y. Dong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6289–6292
OMe
OMe
OH
Br
a
b
7
8
9
O
O
OH
O
O
c
OH
d
O
n
n
n
R
R
R
R
R
R
10, n=0, R=H
11, n=1, R=H
9, n=1, R= Me
12, n=0, R=H
15, n=0, R=H
13, n=1, R=H
16, n=1, R=H
14, n=1, R= Me
17, n=1, R= Me
HOOC
OH
HOOC
OMe
MeOOC
OMe
O
O
O
n
f
g
e
1
5-17
20
R R
1
1
2
8, n=0, R=H
21
22
9, n=1, R=H
0, n=1, R= Me
OH
OH
OH
OR
OR
MeO
O
O
O
h
i
1
7
g
2
6: R = Me
7: R = Et
2
2
4: R = Me
5: R = Et
2
3
2
k
28: R = Ac
Scheme 1. Reactions and conditions: (a) 4-methylpent-3-enylzinc(II) bromide, Pd(Cl
acid, PPA, 75 °C, 3 h; (d) chloroacetone, HOAc/NH OAc, toluene/EtOH, reflux, 24 h; (e) 5% NaOH (aq), reflux; (f) NaOH, 18-crown-6, MeI, CH
LiAlH , THF; (i) MeI or EtI, Cs CO , acetone, 50 °C; (g) MeI or EtI, NaH, THF, rt; (k) Ac O, Et N, DMAP, CH Cl
2
)(dppf), THF, reflux, 1 h; (b) (i) AlCl
3
, DCM, 0 °C, 15 min; (ii) BBr
3
, CH
2
Cl
2
; (c) malonic
4
3
CN, 90 °C; (g) SOCl
2
, MeOH, rt; (h)
4
2
3
2
3
2
2
.
class of potential anti-breast cancer agents, 2-(furan-2-yl)naphtha-
len-1-ol derivatives, such as analog 4. However, it remained un-
clear how ring-A affects the activity and selectivity of 3- and 4-
analogs. To answer this question, we designed derivatives with
two new scaffolds, tetrahydroneotanshinlactone (5, TNT) and tet-
rahydronaphthalene-1-ol (6, TNO). Like 2, both TNT and TNO deriv-
atives have a non-aromatic ring-A. Different ring sizes, including
five- and six-membered rings, were studied and 14 new analogs
were designed. This Letter reports the synthesis and biological
evaluation of 5- and 6-analogs.
Table 1
In vitro cytotoxic activity of 15–28
Compd SK-BR-
3
ZR-75-
1
MDA-MB-
231
A549 DU145 KB
KB-
vin
3
4
5
6
7
8
0.8
3.4
1.1
1.0
37.9
>37
>37
38.6
>37
44.6
73.5
24.7
>61
61.0
39.5
28.3
39.8
47.8
42.7
55.6
54.2
35.8
>37
58.3
29.4
>37
>37
30.7 23.6
>37 >37
>37
1
1
1
1
>60
5.1
35.8
30.2
32.4
0.7
25.5
27.1
21.3
23.7
9.9
18.5
19.8
14.0
>37
8.3
32.3
30.2
21.7
1.7
41.4
34.5
25.5
15.0
14.3
14.3
19.8
15.5
10.2
28.0
41.5
57.0
3.3
32.7
31.9
38.4
40.4
3.0
31.5 10.2
30.5 34.4
31.4 30.2
50.0 29.4
19
20
As shown in Scheme 1, compound 8 was synthesized by Negishi
cross-coupling reaction of compound 7 with 4-methylpent-3-enyl
4.7
4.7
2
2
2
2
1
2
3
4
53.5
61.0
24.5
23.3
22.9
19.4
22.9
28.7
34.1
33.5
22.7
21.7
17.5
17.5
17.7
16.7
43.3 47.8
53.4 52.1
22.0 19.9
25.3 21.7
16.9 15.3
11.5 20.1
21.6 16.5
25.4 24.9
12,13
zinc(II) bromide in 96% yield.
3
Treatment of 8 with AlCl fol-
lowed by demethylation gave 9 in 84% yield.13 Compounds 10
and 11, with five- and six-membered rings, respectively, are com-
mercially available. Compounds 9–11 underwent the previously
reported two-step ring closure reactions to afford furochromenon-
es 15–17, which were hydrolyzed by using sodium hydroxide to
give ring-opened compounds 18–20. Compound 20, with gem-di-
methyl substitution on ring-A, showed significant cytotoxic activ-
ity (Table 1), and was chosen for further modification to study
the functions of the hydroxyl and carboxylic acid groups (21–28).
The selective methylation of the hydroxy group on 20 was
25
2
2
2
6
7
8
Mean ED50
(lM), standard error of independent determinations was less than 5%.
achieved by the addition of MeI and 18-crown-6 ether to the crude
hydrolysis mixture of 17 without work-up. The resulting carbox-
ylic acid 21 was converted to methyl ester 22 with thionyl chloride
1
4

Y. Dong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6289–6292
6291
and MeOH at room temperature. Meanwhile, the reduction of 17
with lithium aluminum hydride afforded diol 23, which was trea-
ted with iodomethane and iodoethane in the presence of Cs CO to
2 3
generate ethers 24 and 25, respectively. The remaining primary
alcohol of 24 was alkylated with iodomethane and iodoethane in
the presence of NaH to obtain 26 and 27, respectively. Acetate 28
Further SAR and mechanism of action studies are ongoing and pro-
gress will be reported in due course. In summary, 20 is a promising
new lead compound with a novel skeleton for further development
toward a new potential clinical trials candidate.
Acknowledgment
2
was obtained by acetylation of 24 with Ac O.
The newly synthesized analogs 15–2815 were tested for in vitro
cytotoxic activity against a panel of human tumor cell lines accord-
ing to previously published methods.16 Cell lines include: SK-BR-3
This work was supported by NIH Grant CA-17625 from the Na-
tional Cancer Institute, awarded to K. H. Lee.
(
estrogen receptor negative, HER2 over-expressing breast cancer),
ZR-75-1 (estrogen receptor positive breast cancer), MDA-MB-231
estrogen receptor negative breast cancer), A549 (non-small cell
References and notes
(
1. Balunas, M. J.; Kinghorn, A. D. Life Sci. 2005, 78, 431.
lung cancer), DU145 (prostate cancer cell line), KB (nasopharyngeal
carcinoma), and KB-vin (vincristine-resistant MDR KB subline).
Among the three tetrahydroneotanshinlactone (TNT) deriva-
tives, 15 showed no activity against any tumor cell line tested,
which suggested that the five-membered ring-A was not favored.
Compound 16 was 3–7-fold more potent than 17 against SK-BR-
2. Parkin, D. M. Lancet Oncol. 2001, 2, 533.
3. Cancer Facts & Figures. American Cancer Society, 2009.
4.
5.
6.
Tan, G.; Gyllenhaal, C.; Soejarto, D. D. Curr. Drug Targets 2006, 7, 265.
Paterson, I.; Anderson Edward, A. Science 2005, 310, 451.
Rishton, G. M. Am. J. Cardiol. 2008, 101, 43D.
7. Saklani, A.; Kutty, S. K. Drug Discovery Today 2008, 13, 161.
8
9
.
.
Wang, X.; Morris-Natschke, S. L.; Lee, K. H. Med. Res. Rev. 2007, 27, 133.
Lee, C.-Y.; Sher, H.-F.; Chen, H.-W.; Liu, C.-C.; Chen, C.-H.; Lin, C.-S.; Yang, P.-C.;
Tsay, H.-S.; Chen, J. J. W. Mol. Cancer Ther. 2008, 7, 3527.
3
, ZR-75-1, A549, and KB-vin cell lines. However, while 16 was less
potent compared with 3 against SK-BR-3 and ZR-75-1 breast can-
cer cell lines, it also showed a broader antitumor spectrum, with
greatly enhanced potency against A549 and KB-vin. The results
suggested that ring-A could affect the potency and tumor-tissue
type selectivity dramatically.
Among tetrahydronaphthalene-1-ol (TNO) derivatives, com-
pounds 18 and 19 displayed only marginal antitumor activity,
while 20 showed potent and broad antitumor activity against all
10. Sung, H. J.; Choi, S. M.; Yoon, Y.; An, K. S. Exp. Mol. Med. 1999, 31, 174.
11. Wang, X.; Bastow, K. F.; Sun, C. M.; Lin, Y. L.; Yu, H. J.; Don, M. J.; Wu, T. S.;
Nakamura, S.; Lee, K. H. J. Med. Chem. 2004, 47, 5816.
12. Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594.
13. Danheiser, R. L.; Casebier, D. S.; Firooznia, F. J. Org. Chem. 1995, 60, 8341.
14. Glover, S. A.; Golding, S. L.; Goosen, A.; McCleland, C. W. J. Chem. Soc., Perkin
Trans. 1 1981, 842.
15. Spectroscopic
data:
1-Methyl-7,8-dihydrocyclopenta[h]furo[3,2-c]chromen-
10(6H)-one (15): 1H NMR (300 MHz, CDCl , ppm): d 2.19 (p, J = 7.5 Hz, 2H,
3
CH
.14 (t, J = 7.5 Hz, 2H, CH
J = 1.2 Hz, 1H, OCH), 7.63 (d, J = 8.1 Hz, 1H, aromatic); HRMS calcd for C15
(M+H ): 241.0859, found: 241.0858. 1-Methyl-8,9-dihydro-6H-benzo[h]furo[3,2-
c]chromen-11(7H)-one (16): H NMR (300 MHz, CDCl
H, CH CH CH CH ), 2.35 (d, J = 1.2 Hz, 3H, CH ), 2.84 (t, J = 5.7 Hz, 2H,
CH CH CH CH ), 2.94 (t, J = 6.0 Hz, 2H, CH CH CH CH ), 7.01 (d, J = 8.4 Hz, 1H,
aromatic), 7.34 (d, J = 0.9 Hz, 1H, OCH), 7.51 (d, J = 8.1 Hz, 1H, aromatic); HRMS
2
CH
2
CH
2
), 2.36 (d, J = 1.5 Hz, 3H, CH
3 2 2 2
), 3.04 (t, J = 7.5 Hz, 2H, CH CH CH ),
3
2
CH CH ), 7.19 (d, J = 7.8 Hz, 1H, aromatic), 7.36 (q,
2
2
tumor cell lines tested (ED50 0.7 lM against SK-BR-3; 1.7 lM
13 3
H O
against ZR-75-1). Thus, a non-aromatic six-membered ring-A with
gem-dimethyl substitution was favored for cytotoxic activity, in
comparison with unsubstituted five- and six-membered rings. As
to the tumor-tissue type selectivity, 20 was significantly active
against all tumor cell lines tested, except MDA-MB-231, while 3
and 4 were active against only two of the breast cancer cell lines.
In contrast to 20, compounds 3 and 4 lack the gem-dimethyls,
and are essentially planar. These results demonstrated that, by
changing the molecular conformation and orientation, introduc-
tion of a non-aromatic ring-A could greatly influence the antitumor
activity against all cell types. In our prior SAR studies of neotan-
shinlactone (3) and the ring-opened analog 4, the presence of
two functional groups from the opened lactone ring-C was critical
for antitumor activity, which encouraged us to study comparable
derivatives of 20 with ether and ester groups of various sizes. As
seen in Table 1, 21–28 showed only moderate to marginal activity
against all tumor cell lines tested, but interestingly, still displayed
low sensitivity against MDA-MB-231 compared with other tumor
cell lines. For example, 25 and 28 showed fourfold higher potency
against SK-BR-3 than MDA-MB-231. In summary, the current SAR
study indicated that the optimal substituents on the phenyl and
furanyl rings are hydroxy and carboxylic acid groups. The preli-
minary results indicated that the identities of the ring-A, hydroxy,
and carboxylic acid groups are important to antitumor activity and
selectivity. More analogs will be synthesized and evaluated to
establish detailed structure–activity relationships (SAR) of this
new series of compounds.
+
1
3
, ppm): d 1.80–1.86 (m,
4
2
2
2
2
3
2
2
2
2
2
2
2
2
+
calcd for C16
15 3
H O (M+H ): 255.1016, found: 255.1012. 1,6,6-Trimethyl-8,9-
dihydro-6H-benzo[h]furo[3,2-c]chromen-11(7H)-one (17): 38% Yield; mp 101–
1
1
2
03 °C; H NMR (300 MHz, CDCl
H, CCH CH CH ), 1.84–1.88 (m, 2H, CCH
CH CH ), 7.32 (d, J = 8.4 Hz, 1H, aromatic), 7.35 (q,
J = 1.2 Hz, 1H, OCH), 7.61 (d, J = 8.7 Hz, 1H, aromatic); HRMS calcd for C18
3
, ppm): d 1.33 (s, 6H, C(CH
3
)
2
), 1.67–1.71 (m,
2
2
2
2
CH CH ), 2.35 (d, J = 1.2 Hz, 3H, CH
2
2
3
),
2.97 (t, J = 6.3 Hz, 2H, CCH
2
2
2
H
19
O
3
+
(
4
M+H ): 283.1329, found: 283.1315. 2-(4-Hydroxy-2,3-dihydro-1H-inden-5-yl)-
-methylfuran-3-carboxylic acid (18): 1H NMR (300 MHz, CD
3
OD, ppm): d 2.06
(p, J = 7.5 Hz, 2H, CH CH CH ), 2.20 (d, J = 0.9 Hz, 3H, CH ), 2.89 (q, J = 7.5 Hz,
2
2
2
3
4
H, CH
J = 7.8 Hz, 1H, aromatic), 7.30 (d, J = 0.9 Hz, 1H, OCH); MS: m/z 257 (MÀH ). 2-
1-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methylfuran-3-carboxylic acid
2 2 2
CH CH ), 4.94 (s, 1H, OH), 6.83 (d, J = 7.8 Hz, 1H, aromatic), 7.14 (d,
+
(
1
(19): H NMR (300 MHz, CD COCD , ppm): d 1.75–1.77 (m, 4H, CH ), 2.20 (d,
3
3
2
J = 1.2 Hz, 3H, CH
3
), 2.69–2.75 (m, 4H, CH
2
) 6.67 (d, J = 8.4 Hz, 1H, aromatic),
7
.10 (d, J = 8.4 Hz, 1H, aromatic), 7.43 (s, 1H, OCH); HRMS calcd for C16H O
15 4
+
(
MÀH ): 271.0970, found: 271.0971. 2-(1-Hydroxy-5,5-dimethyl-5,6,7,8-
tetrahydronaphthalen-2-yl)-4-methylfuran-3-carboxylic acid (20): NMR
(300 MHz, CD OD, ppm): d 1.28 (s, 6H, C(CH ), 1.62–1.66 (m, 2H, CH
.78–1.82 (m, 2H, CH ), 2.21(d, J = 1.5 Hz, 3H, CH ), 2.70 (t, J = 6.3 Hz, 2H, CH
1
H
3
3
)
2
2
2
),
),
1
6
2
3
.96 (d, J = 8.4 Hz, 1H, aromatic), 7.13 (d, J = 8.4 Hz, 1H, aromatic), 7.33 (d,
+
J = 1.2 Hz, 1H, OCH); HRMS calcd for C18
301.1425. 2-(1-Methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-
methylfuran-3-carboxylic acid (21): H NMR (300 MHz, CDCl
H
19
O
4
(MÀH ): 301.1434, found:
1
3
, ppm): d 1.30 (s,
6
2
H, (CH
.36 (d, J = 0.9 Hz, 3H, CH
3
)
2
), 1.63–1.67 (m, 2H, CCH
2
CH
2
CH
2
), 1.77–1.83 (m, 2H, CCH CH CH ),
), 2.76 (t, J = 6.3 Hz, 1H, CCH CH CH ), 3.52 (s, 3H,
3
), 7.16 (d, J = 8.4 Hz, 1H, aromatic), 7.23 (d, J = 8.4 Hz, 1H, aromatic), 7.29
2
2
2
3
2
2
2
OCH
d, J = 1.5 Hz, 1H, OCH); MS: m/z 315 (M+H ). Methyl 2-(1-methoxy-5,5-
dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methylfuran-3-carboxylate (22):
+
(
1
3 3 2
H NMR (300 MHz, CDCl , ppm): d 1.30 (s, 6H, (CH ) ), 1.63–1.67 (m, 2H,
CCH CH CH ), 1.77–1.83 (m, 2H, CCH CH CH ), 2.20 (d, J = 1.2 Hz, 3H, CH ),
2
2
2
2
2
2
3
2
7
.75 (t, J = 6.3 Hz, 1H, CCH
.14 (d, J = 8.1 Hz, 1H, aromatic), 7.23 (d, J = 8.1 Hz, 1H, aromatic),7.27 (d,
2
CH
2
CH
2
), 3.46 (s, 3H, OCH
3
), 3.72 (s, 3H, COOCH
3
),
In conclusion, tetrahydroneotanshinlactone (TNT) and tetrahy-
dronaphthalene (TNO) derivatives were prepared in order to inves-
tigate the effect of the non-aromatic ring-A on in vitro antitumor
activity. The results indicated that a non-aromatic ring-A could
dramatically affect both activity and tumor cell line selectivity,
particularly the non-breast cell lines that were studied. Based on
this study, a novel class of antitumor agents, TNO derivatives,
was discovered and developed. Compound 20 was the most potent
+
J = 0.9 Hz, 1H, OCH); MS: m/z 329 (M+H ). 2-(3-(Hydroxymethyl)-4-
1
methylfuran-2-yl)-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-1-ol (23):
NMR (300 MHz, CDCl , ppm): d 1.30 (s, 6H, (CH ), 1.63–1.67 (m, 2H,
CCH CH CH ), 1.80–1.84 (m, 2H, CCH CH CH ), 2.11 (d, J = 0.9 Hz, 3H, CH ),
.71 (t, J = 6.3 Hz, 2H, CCH CH CH ), 4.58 (s, 1H, CH OH), 6.97 (d, J = 8.4 Hz, 1H,
H
3
3 2
)
2
2
2
2
2
2
3
2
2
2
2
2
aromatic), 7.20 (d, J = 8.4 Hz, 1H, aromatic), 7.28 (d, J = 0.9 Hz, 1H, OCH); MS:
+
m/z 385 (MÀH ). (2-(1-Methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)-4-methylfuran-3-yl)methanol (24): 1H NMR (300 MHz, CDCl
3
, ppm): d 1.30
(
s, 6H, (CH
CCH CH CH ), 2.12 (d, J = 0.9 Hz, 3H, CH
2.77 (t, J = 6.3 Hz, 2H, CCH CH CH ), 3.46 (s, 3H, OCH
3
3
)
2
), 1.64–1.68 (m, 2H, CCH
), 2.69 (t, J = 6.3 Hz, 1H, CH
), 4.41 (d, J = 5.7 Hz, 2H,
2
CH
2
CH
2
), 1.77–1.83 (m, 2H,
analog with an ED50 value of 0.7
lM against the SK-BR-3 cell line,
2
2
2
3
2
OH),
and showed broader antitumor activity compared with 3 and 4.
2
2
2

6
292
Y. Dong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6289–6292
CH
M+Na ).
methylfuran-3-yl)methanol (25): H NMR (300 MHz, CDCl
J = 7.2 Hz, 3H, CH CH ), 1.30 (s, 6H, (CH ), 1.64–1.68 (m, 2H, CCH
.77–1.83 (m, 2H, CCH CH CH ), 2.12 (d, J = 0.9 Hz, 3H, CH ), 2.76 (t, J = 6.3 Hz,
H, CCH CH CH ), 2.87 (br, 1H, CH OH), 3.58 (q, J = 7.2 Hz, 2H, CH CH ), 4.39 (s,
H, CH OH), 7.18 (s, 2H, aromatic), 7.26 (d, J = 0.3 Hz, 1H, OCH); MS: m/z 313
2
OH), 7.16–7.22 (m, 2H, aromatic), 7.27 (d, J = 0.9 Hz, 1H, OCH); MS: m/z 323
4-methylfuran (27): 1H NMR (300 MHz, CDCl
CH CH ), 1.30 (s, 6H, (CH ), 1.64–1.67 (m, 2H, CCH
2H, CCH CH CH ), 2.09 (d, J = 0.9 Hz, 3H, CH ), 2.77 (t, J = 6.3 Hz, 1H,
CCH CH CH ), 3.32 (s, 3H, CH OCH ), 3.59 (q, J = 6.9 Hz, 2H, CH CH ), 4.32 (s,
2H, CH OCH ), 7.16 (dd, J = 8.1 Hz, 2H, aromatic), 7.26 (d, J = 0.9 Hz, 1H, OCH);
MS: m/z 329 (M+H ). (2-(1-Methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)-4-methylfuran-3-yl)methyl acetate (28): 1H NMR (300 MHz, CDCl
, ppm):
d 1.30 (s, 6H, (CH ), 1.63–1.67 (m, 2H, CCH CH CH ), 1.77–1.83 (m, 2H,
CCH CH CH ), 2.06 (s, 3H, CH OCOCH ), 2.06 (d, J = 0.9 Hz, 3H, CH ), 2.76 (t,
J = 6.3 Hz, 1H, CCH CH CH ), 3.48 (s, 3H, OCH ), 5.01 (s, 2H, CH OCOCH ), 7.13–
3
, ppm): d 1.19 (t, J = 7.2 Hz, 3H,
CH CH ), 1.77–1.83 (m,
+
(
(2-(1-Ethoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-
2
3
3
)
2
2
2
2
1
3
, ppm): d 1.18 (t,
CH CH ),
2
2
2
3
2
3
)
3 2
2
2
2
2
2
2
2
3
2
3
1
1
2
2
2
2
3
2
3
+
2
2
2
2
2
3
2
+
3
(
(
MÀH ).
methoxymethyl)-4-methylfuran (26). 44% yield; H NMR (300 MHz, CDCl
), 1.64–1.67 (m, 2H, CCH CH CH ), 1.77–1.83 (m, 2H,
), 2.10 (d, J = 1.2 Hz, 3H, CH ), 2.77 (t, J = 6.3 Hz, 1H, CCH CH CH ),
.33 (s, 3H, CH OCH ), 3.49 (s, 3H, OCH ), 4.32 (s, 2H, CH OCH ), 7.17 (dd,
J = 8.4 Hz, 2H, aromatic), 7.28 (d, J = 1.2 Hz, 1H, OCH); MS: m/z 315 (M+H ). 2-
1-Ethoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(methoxymethyl)-
2-(1-Methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-
3
)
2
2
2
2
1
3
,
2
2
2
2
3
3
ppm): d 1.30 (s, 6H, (CH
CCH CH CH
3
)
2
2
2
2
2
2
2
3
2
3
+
2
2
2
3
2
2
2
7.19 (m, 2H, aromatic), 7.30 (d, J = 1.2 Hz, 1H, OCH); MS: m/z 365 (M+Na ).
16. Wang, X.; Nakagawa-Goto, K.; Bastow, K. F.; Don, M. J.; Lin, Y. L.; Wu, T. S.; Lee,
K. H. J. Med. Chem. 2006, 49, 5631.
3
2
3
3
2
3
+
(