8104
Y.-C. Wang et al. / Tetrahedron Letters 46 (2005) 8103–8104
P+Ph3
Br
a
Br-
OCH3
97%
H3CO
OCH3
H3CO
OCH3
c
84%
Br
H3CO
3,5-dimethoxybenzyl
bromide (6)
7
OCH3
+
RO
H3CO
OCH3
H3CO
Br
OR
CHO
Br
CHO
9
4
b
trans (E) 9 : cis (Z) 4 = 3 : 5
H3CO
H3CO
Br
98%
R = TBDMS (
)
Si
OR
OH
TBDMS = tert-butyldimethylsilyl
2-Bromoisovanillin (5)
8
O
O
d
g
f
82%
H3CO
RO
H3CO
74%
H3CO
64%
H3CO
OCH3
O
O
H3CO
OCH3
HO
OCH3
10 : R = TBDMS
3 : R = H
e
2
Denbinobin (1)
Scheme 1. Reagents and conditions: (a) PPh3, toluene; (b) (i-Pr)2NEt, TBDMSCl, THF; (c) n-BuLi, THF, À78 °C; (d) AIBN, Bu3SnH, benzene; (e)
TBAF, THF; (f) FremyÕs salt, NaOAc, DMF, MeOH; (g) TMSI, CH2Cl2, rt.
2-bromisovanillin (8) and (3,5-dimethoxy-benzyl)-tri-
phenyl-phosphonium bromide (7) as reactants.
References and notes
1. (a) Tezuka, Y.; Yoshida, Y.; Kikuchi, T.; Xu, G. J. Chem.
Pharm. Bull. 1993, 41, 1346–1349; (b) See, Ref. 3; (c)
Talapatra, B.; Mukhopadhyay, P.; Chaudhury, P.; Tala-
patra, S. K. Indian J. Chem. 1982, 21B, 386–387.
2. Lee, Y. H.; Park, J. D.; Baek, N. I.; Kim, S. I.; Ahn, B. Z.
Planta Med. 1995, 61, 178–180.
3. Lin, T. H.; Chang, S. J.; Chen, C. C.; Wang, J. P.; Tsao,
L. T. J. Nat. Prod. 2001, 64, 1084–1086.
4. Krohn, K.; Loock, U.; Paavilainen, K.; Hausen, B.;
Schmalle, H. W.; Kiesele, H. ARKIVOC 2001, 1, 88–130.
5. Kraus, G. A.; Zhang, N. Tetrahedron Lett. 2002, 43, 9597–
9599.
The reaction conditions for Wittig reaction with n-BuLi
as base in THF at À78 °C gave the trans isomer 9 and
cis isomer 4 by chromatography in a ratio of 3:5 in
84% yield. The cis-olefin 4 was subjected to AIBN/
Bu3SnH-bearing free radical cyclization6 to afford the
desired phenanthrene 10 in 74% yield. The silyl-pro-
tected 10 was treated with tetra-n-butylammonium fluo-
ride (TBAF) to give phenol 37 in quantitative yield
which is critical, as the phenolic group can be used to
facilitate the oxidation forming the related quinone
functionality. We tried PIFA, CAN, and FremyÕs salt-
mediated oxidation to make the quinone functional
group. FremyÕs salt8 could convert the desired quinone
29 in a yield of 82%, which was converted to denbinobin
(1, 97 mg) under the conditions reported by Krohn
et al.4 by selective demethylation in 64% yield.
6. (a) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R.
Tetrahedron Lett. 2002, 43, 3185–3187; (b) Hoarau, C.;
Couture, A.; Deniau, E.; Grandclaudon, P. Eur. J. Org.
Chem. 2001, 2559–2567.
7. Compound 3: mp 121–123 °C. 1H NMR (500 MHz,
CDCl3): d 3.95 (s, 3H), 4.03 (s, 3H), 4.08 (s, 3H), 6.84 (d,
1H, J = 2.4 Hz), 6.97 (d, 1H, J = 2.4 Hz), 7.29 (d, 1H,
J = 8.5 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.39 (d, 1H,
J = 8.5 Hz), 7.55 (d, 1H, J = 8.7 Hz), 9.80 (s, 1H). 13C
NMR (75 MHz, CDCl3): d 55.5, 56.6, 57.0, 101.1, 104.0,
111.9, 114.0, 118.4, 119.2, 124.1, 127.8, 129.1, 136.4, 143.2,
148.1, 155.3, 158.3.
In summary, the total synthesis of denbinobin (1) has
been accomplished in seven steps from commercially
available 2-bromisovanillin and 3,5-dimethoxybenzyl
bromide. This facile methodology will be applied to syn-
thesize denbinobin derivatives to extensively evaluate
the structure–activity relationships of this class of
compounds.
8. Kongkathip, N.; Luangkamin, S.; Kongkathip, B.;
Sangma, C. C.; Grigg, R.; Kongsaeree, P.; Prabpai, S.;
Pradidphol, N.; Piyaviriyagul, S.; Siripong, P. J. Med.
Chem. 2004, 47, 4427–4438.
9. Compound 2: mp 179–180 °C. 1H NMR (500 MHz,
CDCl3): d 3.93 (s, 3H), 3.93 (s, 3H,), 3.94 (s, 3H), 6.00 (s,
1H), 6.70 (d, 1H, J = 2.1 Hz), 6.77 (d, 1H, J = 2.1 Hz), 7.88
(d, 1H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz). 13C NMR
(75 MHz, CDCl3): d 55.5, 55.9, 56.5, 99.1, 101.9, 106.2,
116.9, 122.6, 130.7, 132.3, 132.8, 139.0, 158.1, 160.8, 162.9,
181.0, 184.3. HRMS: found 298.0835, calcd 298.0842.
Acknowledgements
This research was supported by the Taipei Medical
University under Grant No. TMU 93-AE1-B-03.