B. Porte6in et al. / Tetrahedron Letters 44 (2003) 9263–9265
9265
menialdisine could also be envisioned using this
synthetic pathway.
esters 6 and 7 were prepared by reacting aldisine with
diethyl malonate (DEM) in the presence of TiCl4
(Scheme 3).
References
Starting from pyrrole, we chose to prepare aldisine 2
using the procedure described by Cho (Scheme 4).5
1. (a) Curman, D.; Cinel, B.; Williams, D. E.; Rundle, N.;
Block, W. D.; Goodarzi, A. A.; Hutchins, J. R.; Clarke, P.
R.; Zhou, B.-B.; Lees-Miller, S. P.; Andersen, R. J.; Roberge,
M. J. Biol. Chem. 2001, 276, 17914–17919; (b) Tasdemir, D.;
Mallon, R.; Greenstein, M.; Feldberg, L. R.; Kim, S. C.;
Collins, K.; Wojciechowicz, D.; Mangalindan, G. C.; Con-
cepcion, G. P.; Harper, M. K.; Ireland, C. M. J. Med. Chem.
2002, 45, 529–532; (c) Meijer, L.; Thunissen, A. M.; White,
A. W.; Garnier, M.; Nikolic, M.; Tsai, L. H.; Walter, J.;
Cleverley, K. E.; Salinas, P. C.; Wu, Y. Z.; Mandelkow, E.
M.; Kim, S. H.; Pettit, G. R. Chem. Biol. 2000, 7, 51–63.
2. Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36,
413–416.
Pyrrole was reacted with diphosgene in the presence of
dimethylaniline to give the acid chloride. Then a solu-
tion of ethyl 3-aminopropionate (or b-alanine ethyl
ester) was added in one-pot to give ester 8 in 74% yield
for the two steps. Saponification (70%) was followed by
cyclisation in polyphosphoric acid (PPA) in the pres-
ence of a small amount of P2O5 to produce aldisine 2 in
56% yield on a 30 g scale. Aldisine was reacted with
thiohydantoin in the presence of TiCl4 and pyridine,
but the intermediate 9 was only detected in trace
amounts. Replacement of TiCl4 with BF3·Et2O in the
presence of triethylamine6 gave 9 after chromatography
in an unoptimized 31% yield. Finally, DBH was
obtained after chromatography in 74% yield by reacting
9 with aqueous ammonia in the presence of tert-
butylhydroperoxide.7
3. (a) Xu, Y.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997,
62, 456–464; (b) Barrios Sosa, A. C.; Yakushijin, K.; Horne,
D. A. J. Org. Chem. 2000, 65, 610–611.
4. Prager, R. H.; Tsopelas, C. Aust. J. Chem. 1992, 45,
1771–1777.
5. Cho, H.; Matsuki, S.; Mizuno, A.; Annoura, H.; Tatsuoka,
T. J. Heterocycl. Chem. 1997, 34, 87–91.
6. Niigata, K.; Okada, M.; Yoneda, T. Australian patent 1987,
AU-A-67401/87, 138-9.
7. Lindel, T.; Hoffmann, H. Tetrahedron Lett. 1997, 38,
8935–8938.
In summary, starting from earlier investigations, we
have developed a very simple synthesis that allows the
preparation of multigram quantities of DBH. Although
several steps deserve further optimisation, the prepara-
tion of analogs such as hymenialdisine and dibromohy-