sugar 1218 derived from D-xylose was treated with methyl-
enetriphenylphosphorane19 to give the alkene 13, and the
resulting secondary alcohol was transformed to O-mesylate
14. After ozonolysis of the terminal alkene, the aldehyde 15
with a leaving group was obtained. Treatment of the
4-mesylate-aldehyde 15 with hydroxylamine under basic
conditions produced the cyclic nitrone 9 possibly through
the formation of a geminal bis(hydroxylamino) sugar, then
cyclization and subsequent elimination of the second hy-
droxylamine unit.20 During nitrone formation, although
pyridine was inefficient as a base, triethylamine, diethyl-
amine, sodium bicarbonate, and sodium carbonate all work
well for mediating this process. This synthetic approach
possesses obvious merits in that (1) one-pot reactions can
be effected from 13 to the final product 9 and (2) the
sequence is capable of multigram scale synthesis.
Scheme 3. Synthesis of 4′-Deoxyradicamine B (18)
selective bromination of benzene at the para position of the
methoxyl group using AcOH as solvent.24 Debenzoylation
of 21 was unsuccessful with potassium carbonate in EtOH.
However, the phenol hydroxyl group was released easily after
treatment of 21 with sodium hydroxide in EtOH, followed
by bubbling in carbon dioxide. The benzylation of 4-bro-
moguaiacol 22 was accomplished to afford the desired
bromide 23 according to the reported procedures.25
Unlike phenylmagnesium bromide, the preparation of
Grinard reagent 10 required heating the bromide 23 and
magnesium turnings in refluxing THF for 1-3 h (Scheme
4). Similarly, reaction of the Grignard reagent 10 with nitrone
We next investigated the model addition of phenylmag-
nesium bromide 16 to nitrone 9. Thus, treatment of 9 with
phenylmagnesium bromide 16 afforded the desired product,
the benzyl-protected N-hydroxylpyrrolidine 17, in 90%
isolated yield. The gratifyingly high stereoselectivity might
be ascribed to a Felkin-Anh transition-state model which
could be invoked.21 Catalytic hydrogenation of 17 furnished
coumpound 18, 4′-deoxyradicamine B, in 85% isolated
yield.22 The configuration of the newly created stereocenter
was confirmed to be (S) through the strong nOe effects
1
between C(4)-H and C(2′,6′)-H in the 600 MHz H NMR
spectrum of 18.
Scheme 4. Preparation of Grignard Reagent 10
Following the successful model reaction, we turned our
attention to the synthesis of radicamine A. According to our
retrosynthesis (Scheme 1), Grignard reagent 10 was required.
Starting with guaiacol, we revised the preparation of
substituted phenyl bromide 2323 as depicted in Scheme 3.
Guaiacol was treated with benzoyl chloride in aqueous
sodium hydroxide to give the benzoate 20. The electron-
withdrawing property of benzoyl group leads to the regio-
(15) (a) Cardona, F.; Goti, A. Angew. Chem., Int. Ed. 2005, 44, 7832-
7835. (b) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem., Int.
Ed. 2003, 42, 2265-2268.
(16) For recent work on polyhydroxylated cyclic nitrones, see: (a)
Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337-1342. (b)Duff,
F. J.; Vivien, V.; Wightman, R. H. Chem. Commun. 2000, 2127-2128. (c)
Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344-1346. (d) Cardona,
F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003,
44, 2315-2318. (e) Carmona, A. T.; Wightman, R. H.; Robina, I.; Vogel,
P. HelV. Chim. Acta 2003, 86, 3066-3073. (f) Desvergnes, S.; Py, S; Valle´e,
Y. J. Org. Chem. 2005, 70, 1459-1462. (g) Cicchi, S.; Marradi, M.; Vogel,
P.; Goti, A. J. Org. Chem. 2006, 71, 1614-1619.
(17) (a) Alibe´s, R.; Blanco, P.; de March, P.; Figueredo, M.; Font, J.;
AÄ lvarez-Larena, AÄ .; Piniella, J. F. Tetrahedron Lett. 2003, 44, 523-525.
(b) Berge, J. M.; Copley, R. C. B.; Eggleston, D. S.; Hamprecht, D. W.;
Jarvest, R. L.; Mensah, L. M.; O’Hanlon, P. J.; Pope, A. J. Bioorg. Med.
Chem. Lett. 2000, 10, 1811-1814.
(18) (a) Barker, R.; Fletcher, H. G. J. Org. Chem. 1961, 26, 4605-
4609. (b) Tejima, S.; Fletcher, H. G. J. Org. Chem. 1963, 28, 2999-3004.
(19) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770-
1771.
(20) Peer, A.; Vasella, A. HelV. Chim. Acta 1999, 82, 1044-1065.
(21) Merino, P.; Revuelta, J.; Tejero, T.; Cicchi, S. and Goti; A. Eur. J.
Org. Chem. 2004, 776-782.
9 in THF afforded the desired benzyl-protected N-hydroxy-
lpyrrolidine 24 in 89% isolated yield. After catalytic hydro-
genation of 24, compound 1 was readily obtained in 87%
isolated yield (Scheme 5).
The 600 MHz NOESY spectrum (D2O) supported the
assigned stereochemistry based on the strong NOE effects
seen between the C(4)-H and C(2′)-H as well as between
the C(5)-H and C(6′)-H. 1H and 13C NMR spectra of
compound 1 were identical with those reported for the natural
(22) It is noteworthy that the N-hydroxylamine was unstable and turned
deeply colored both in solution and solid state. Thus, the compounds were
purified by chromatography (silica gel) quickly and then used immediately
for debenzylation in acidic aqueous methanol.
(23) Chaffee, A. L.; Cooke, R. G.; Dagley, I. J.; Perlmutter, P.; Thomas,
R. L. Aust. J. Chem. 1981, 34; 587-598.
(24) (a) Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903-3906.
(b) Diaz, A.; Siro, J. G.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-Builla,
J. Synthesis 1997, 559-562.
(25) Yu, Y.; Singh, S. K.; Liu, A.; Li, T.-K.; Liu, L. F.; LaVoie, E. J.
Bioorg. Med. Chem. 2003, 11, 1475-1491.
Org. Lett., Vol. 8, No. 14, 2006
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