smoothly and allylic sulfonamides 15a-d and 16a-c were
generated in 58-85% yield. For aziridine cis-13, TBME was
the preferred solvent as it generally gave a ∼10% improve-
ment in yield (Table 1, compare entries 1/2, 3/4, and 5/6).
In general, reactions using PhLi gave lower yields compared
with those using primary and secondary alkyllithium reagents
(Table 1, compare entries 1/3/5/7 and 9-11). In all of the
thus been the subject of several recent synthetic studies.1,16
As outlined in Scheme 4, we envisaged that azaspirocycle
21 could be obtained from allylic sulfonamide 22 by two
cyclization processes (including N-Ts deprotection). To
prepare allylic sulfonamide 22, reaction of aziridine cis-13
with excess functionalized aryllithium 23 (obtained by
lithium-bromine exchange) was to be explored.
1
examples shown in Table 1, we saw no evidence in the H
NMR spectra of the crude products of intramolecular
cyclopropanation of the aziridines, even though such a
process is well established for certain lithiated epoxides and
aziridines equipped with a pendent alkene.13
Scheme 4
With allylic sulfonamides 15a-d and 16a-c in hand, we
were ready to investigate a two-step conversion into the
desired azaspirocycles. First of all, chemo- and regioselective
hydroboration of the terminal alkene was achieved using
9-BBN14 to give alcohols 17a-d and 18a-c in 35-86%
yield (Table 2). Then, cyclization under Mitsunobu condi-
tions15 using DEAD or DIAD and PPh3 gave azaspirocycles
19a-d and 20a-c in 61-87% yield (Table 2). Thus, a
simple, three-step route from â-methoxy aziridines cis-13
and cis-14 to azaspirocycles 19a-d and 20a-c has been
established. Azaspirocycles 20a-c correspond to the spiro-
cyclic substucture of halichlorine, and Me3SiCH2-substituted
allylic sulfonamide 20b could be elaborated toward this
natural product.
To investigate the viability of using functionalized aryl-
lithium reagents in combination with â-methoxy aziridines,
reactions between the aryllithiums derived from either
bromobenzene or bromides 25-2717 and aziridines cis-27 and
cis-13 were studied (Table 3). Lithium-bromine exchange18
of bromobenzene or 24 was accomplished using n-BuLi, and
Table 3. Transformation of â-Methoxy Aziridines into
Substituted Allylic Sulfonamides Using Functionalized
Aryllithium Reagents
Table 2. Hydroboration-Mitsunobu Cyclization of Allylic
Sulfonamides 15 and 16
entry
SM
R
prod, % yielda
prod, % yielda
1
2
3
4
5
6
7
15a
15b
15c
15d
16a
16b
16c
nBu
17a, 35
17b, 86
17c, 79
17d, 60b
18a, 64
18b, 71
18c, 69
19a, 65
19b, 76
19c, 61
19d, 71b
20a, 79
20b, 87
20c, 76
Me3SiCH2
Ph
sBu
nBu
Me3SiCH2
Ph
entry
SM
ArBr
solvent
product
% yielda
1
2
3
4
5
6
7
cis-2
cis-2
PhBr
25
26
26
26
Et2O
Et2O
Et2O
TBME
Et2O
Et2O
TBME
24ab
24bb
15e
15e
15e
15f
46c
46
64
54
44d
43
37
a Isolated yield after chromatography. b Obtained as a 1:1 mixture of
diastereoisomers.
cis-13
cis-13
cis-13
cis-13
cis-13
27
27
15f
Our next aim was to utilize this azaspirocycle synthetic
methodology for the preparation of azaspirocycle 21, a
potential intermediate for cephalotaxine synthesis. Naturally
ocurring esters derived from cephalotaxine (e.g., deoxyhar-
ringtonine) show pronounced antileukemic activity and have
a Isolated yield after chromatography. b Reaction carried out using 2.5
equiv of ArLi. c 69% yield of 24a using a commercial solution of PhLi in
nBu2O. d Reaction carried out using 1.5 equiv of 26 and 3 equiv of nBuLi.
(13) (a) Dechoux, L.; Agami, C.; Doris, E.; Mioskowski, C. Tetrahedron
2003, 59, 9701. (b) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am.
Chem. Soc. 2004, 126, 8664. (c) Hodgson, D. M.; Humphreys, P. G.; Ward,
J. G. Org. Lett. 2006, 8, 995.
(14) Riber, D.; Hazell, R.; Skrydstrup, T. J. Org. Chem. 2000, 65, 5382.
(15) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Davis
Harris, G.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(16) For selected recent examples, see: (a) Eckelbarger, J. D.; Wilmot,
J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370. (b) Zhao, Z.; Mariano,
P. S. Tetrahedron 2006, 62, 7266. (c) Li, W.-D. Z.; Ma, B.-C. J. Org. Chem.
2005, 70, 3277. (d) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem.
2004, 69, 3087. (e) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121,
10264.
Org. Lett., Vol. 8, No. 22, 2006
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