468
Scheme 5. Synthesis of (±)-geodin [(±)-2]. (a) n-BuLi, THF, −78°C; 5, −78°C→rt, 86%; (b) Dess–Martin periodinane,
CH2Cl2, rt, 98%; (c) H2 (1 atm), 10% Pd–C, EtOH, rt, 79%; (d) Dess–Martin periodinane, CH2Cl2, rt, 95%; (e) NaClO2,
NaH2PO4, 2-methyl-2-butene, THF–tert-BuOH–H2O, rt; (f) CH2N2, Et2O, 90% (two steps); (g) p-TsOH, MeOH, reflux, 81%;
(h) DDQ, CH2,Cl2–EtOH, rt, 57%
References
1. Chu, M.; Mierzwa, R.; Truummes, I.; King, A.; Sapidou, E.; Barrabee, E.; Terracciano, J.; Patel, M. G.; Gullo, V. P.; Burrier,
R.; Das, P. R.; Mittelmann, S.; Paur, M. S. Tetrahedron Lett. 1997, 38, 6111–6114.
2. It is noteworthy that Sch 202596 (1) is the only small molecule to date shown to inhibit [125I]-galanin binding to GalR1-
containing membranes prepared from human melanoma cells using a radioligand competition assay (IC50=1.7 µM).1
3. So far, three galanin receptor subtypes, GalR1, GalR2, and GalR3, have been cloned and characterized. For a recent review
on the galanin receptors as novel therapeutic targets, see: Wang, S.; Gustafson, E. L. Drug News Perspect. 1998, 11, 458–468.
4. (a) Crawley, J. N.; Robinson, J. K.; Langel, Ü.; Bartfai, T. Brain Res. 1993, 600, 268–272. (b) Rowland, N. E.; Kalra, S. P.
CNS Drugs 1997, 419–426. (c) Kask, K.; Berthold, M.; Bartfai, T. Life Sci. 1997, 60, 1523–1533.
5. Fathi, Z.; Church, W. B.; Lismaa, T. P. Annu. Rep. Med. Chem. 1998, 33, 41–50.
6. Structurally, 1 belongs to the griseofluvin family of compounds. Therefore, the absolute stereochemistry of the
spirocoumaranone moiety in 1 was determined by comparing its circular dichroic (CD) spectrum with that of griseofluvin.
The relative stereochemistry of the cyclohexene ring of 1 was revealed by analysis of 2D NMR spectra (COSY, NOESY,
HETCOR, and HMBC experiments); however, its absolute stereochemistry has not been established.
7. Barton, D. H. R.; Scott, A. I. J. Chem. Soc. 1958, 1767–1772.
8. Related biogenetic-type phenolic coupling reactions for the construction of the spirocoumaranone ring system have been
reported, see: (a) Taub, D.; Kuo, C. H.; Slates, H. L.; Wendler, N. L. Tetrahedron 1963, 19, 1–17. (b) Day, A. C.; Nobney,
J.; Scott, A. I. J. Chem. Soc. 1961, 4067–4074. (c) Scott, A. I. Proc. Chem. Soc. 1958, 195.
9. The biosynthetic pathway of (+)-geodin (2) has been well studied at the enzyme and molecular genetic level, see: (a) Huang,
K.; Fujii, I.; Ebizuka, Y.; Gomi, K.; Sankawa, U. J. Biol. Chem. 1995, 270, 21495–21502. (b) Huang, K.; Yoshida, Y.;
Mikawa, K.; Fujii, I.; Ebizuka, Y.; Sankawa, U. Biol. Pharm. Bull. 1996, 19, 42–46, and references cited therein.
10. (a) Srivastava, R. P.; Zhu, X.; Walker, L. A.; Sindelar, R. D. Bioorg. Med. Chem. Lett. 1995, 5, 2429–2434. (b) Hollinshead,
S. P.; Nichols, J.; Wilson, J. W. J. Org. Chem. 1994, 59, 6703–6709. (c) Duffley, R. P.; Handrick, G. R.; Uliss, D. B.; Lambert,
G.; Dalzell, H. G.; Razdan, R. K. Synthesis 1980, 733–736.
11. In this reaction, reactivity of the hydroxy group adjacent to the formyl group in 14 would be precluded by the formation of
an intramolecular hydrogen bond.
12. (a) Smith Jr, C. R. J. Org. Chem. 1960, 25, 588–591. (b) Natori, S. Yakugaku Zasshi 1951, 71, 371–373.
13. When the aryl aldehyde i (prepared from 7 by sequential formylation, selective MOM protection, and O-methylation) was
used as a substrate for the coupling reaction with the aryl lithium ii (prepared in situ from 6), none of the desired coupling
product iv was obtained and the starting material i and the protonation product iii were recovered. This unsuccessful result
might be attributable to the very low electrophilicity of the formyl group and/or steric hindrance of the methoxycarbonyl
group in i.