9598
G. A. Kraus, N. Zhang / Tetrahedron Letters 43 (2002) 9597–9599
Scheme 2.
References
cially available 2,4,5-trimethoxybenzoic acid. The
reaction of 3 with orcinol dimethyl ether required 1
equiv. of trifluoroacetic acid and generated two insep-
arable isomers (Scheme 2). The mixture of isomers
was methylated (Me2SO4, K2CO3, acetone, 60°C) to
give biphenyls 10 and 11 as an 8:1 ratio of separable
isomers. Initially, we attempted to reduce 10 to alde-
hyde 12 using DIBAL. Despite modifications of tem-
perature (−78 to 25°C) and stoichiometry (1–3 equiv.
DIBAL/10), we recovered mostly unreacted starting
material. Fortunately, the ester could be reduced in
92% yield using LAH in ether at 0°C. Attempted
oxidation (Swern, DDQ12) led to recovered starting
material. This is consistent with molecular modeling
experiments, which show that the benzylic alcohol is
not very accessible. However, reaction of the alcohol
with MnO2 in boiling toluene at 110°C afforded alde-
hyde 12 in 65% yield from 10. The reaction of 12
with P4-tBu (benzene, 100°C, 8 h) followed by oxida-
tion gave quinone 14 (in 60% yield from 12) whose
NMR was identical to that reported by Krohn.13
Selective demethylation using the conditions of Krohn
(TMSI, CH2Cl2, rt) provided denbinobin in 52%
yield.
1. (a) Tezuka, Y.; Yoshida, Y.; Kikuchi, T.; Xu, G. J.
Chem. Pharm. Bull. 1993, 41, 1346–1349; (b) Lin, T.-
H.; Chang, S.-J.; Chen, C.-C.; Wang, J.-P.; Tsao, L.-T.
J. Nat. Prod. 2001, 64, 1084–1086; (c) Talapatra, B.;
Mukhopadhyay, P.; Chaudhury, P.; Talapatra, 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. Synthesis Krohn, K.; Loock, U.; Paavilainen, K.;
Hausen, B.; Schmalle, H. W.; Kiesele, H. ARKIVOC
[online computer file] 2001, 2, 973–1003.
5. Kraus, G. A.; Zhang, N.; Verkade, J. G.; Nagarajan,
M.; Kisanga, P. B. Org. Lett. 2000, 2, 2409–2410.
6. Bruce, J. M.; Heatley, F.; Ryles, R. G.; Scrivens, J. H.
J. Chem. Soc., Perkin 2 1980, 860.
7. Parker, K. A.; Spero, D. M.; Koziski, K. A. J. Org.
Chem. 1987, 52, 183–188.
8. Kraus, G. A.; Hoover, K.; Zhang, N. Tetrahedron Lett.
2002, 43, 5319–5321.
9. Kraus, G. A.; Wu, Y. Tetrahedron Lett. 1991, 32, 3803.
10. Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972,
94, 227.
Denbinobin has been synthesized in seven steps from
quinone 3. This route is direct enough to permit the
synthesis of quantities of 1 sufficient for extensive
biological evaluation. The testing of intermediates 7, 8
and 14 will be reported in due course.
11. Farina, F.; Molina, M. T.; Paredes, C. Synth. Commun.
1986, 16, 1015–1017.
12. Becker, H.; Bjork, A.; Alder, E. J. Org. Chem. 1980,
45, 1596–1600.
13. Compound 12: 1H NMR (CDCl3): l 1.98 (s, 3H), 3.46
(s, 3H), 3.67 (s, 3H), 3.84 (s, 3H), 3.96 (s, 3H), 3.98 (s,
3H), 6.36–6.37 (d, 1H, J=2.1 Hz), 6.43–6.44 (d, 1H,
J=2.1 Hz), 6.54 (s, 1H), 9.70 (s, 1H). 13C NMR
(CDCl3): l 20.6, 55.5, 55.8, 56.1, 56.3, 60.6, 95.7, 96.0,
106.5, 115.6, 116.8, 137.0, 138.9, 140.6, 157.9, 158.3,
158.9, 160.4, 190.5. HRMS: found 346.1422, calcd
346.1416. Mp=141–142°C.
Acknowledgements
We thank Iowa State University for partial support of
this research.