azirine. This comparative study between the two chiral
auxiliaries clearly showed the 8-phenylmenthol derivatized
azirine 1a to be the most promising substrate. To confirm the
usefulness of the reaction an additional set of dienes were
reacted with azirine 1a. The dienes chosen were Danishefsky’s
diene (5), cyclopentadiene (8a), cyclohexadiene (8b), and
2-(trimethylsilyloxy)-1,3-cyclohexadiene (8c) (Scheme 2).
All the dienes gave together with 1a in the presence of
MgBr2·OEt2 or ZnCl2·OEt2 products with good to excellent
diastereoselectivity and in useful yields (Table 2). Both Lewis
acids proved to function well together with Danishefsky’s diene
giving 6 in high to excellent selectivities (entries 2 and 3) albeit
the obtained yield after chromatography was unsatisfactory.
Hydrolysis of the TMSO-group before purification might
improve the overall yield. MgBr2·OEt2 promoted higher
selectivity than ZnCl2·OEt2 for the addition of 8a to give
9a:10a, although high yields were obtained in both cases
(entries 5 and 6). The reaction between 1a and diene 8b in the
presence of MgBr2·OEt2 gave no expected product despite
complete consumption of the azirine (entry 8). For this diene
ZnCl2·OEt2 was a valuable complement affording 9b:10b in 99
% yield and 80 % de (entry 9). On the other hand, the TMSO
substituted cyclohexadiene 8c afforded a 98.5+1.5 mixture of
9c:10c in 99% yield using MgBr2·OEt2 (entry 11). The result
obtained with ZnCl2·OEt2 was similar to that without any Lewis
acid (compare entries 12 and 10). It can be concluded that for all
dienes a substantial increase in diastereoselectivity was ob-
tained when performing the reactions in the presence of a Lewis
acid (compare entries 1 with 2 and 3, 4 with 5 and 6, 7 with 9,
10 with 11). It is also clear that MgBr2·OEt2 was more efficient
than ZnCl2·OEt2, with diene 8b being the only exception.
The aziridine moiety in 9a:10a was easily ring opened by
MgBr2·OEt2 to form compounds 11 and 12 (Scheme 3). The
major product 11 was recrystallized and the absolute configura-
Scheme 3
Fig. 1 X-Ray structure of compound 11.
tion then confirmed by X-ray crystallography. The major
isomers 3a, 6, 9b and 9c were assigned in analogy (Fig. 1).‡ The
result was in agreement with previously suggested stereo-
chemical models of the transition state of 8-phenylmenthol
derivatives.12 It is assumed that the carbonyl group is aligned
with the axial hydrogen on C1 in the 8-phenylmenthol group
and the phenyl ring oriented parallel to the azirine ring.
Chelation of the nitrogen and the carbonyl group by a Lewis
acid then rigidifies the structure with the Re-face of the azirine
being shielded by the phenyl group.
We are pleased to report herein the first successful stereo-
selective Diels–Alder reactions of enantiomerically pure 2H-
azirines and a variety of dienes in the presence of a Lewis acid.
Further investigations in this area are in progress and will be
reported in due course. The authors are grateful for the financial
support provided by the Swedish Research Council. We also
thank Mr Daniel Strand for helpful discussions.
Notes and references
† A typical procedure: the azirine 1a (67 µmol) and ZnCl2·OEt2 (134 µmol)
were stirred for 20 min at 2100 °C in 1.3 ml CH2Cl2 (freshly distilled over
CaH2) under nitrogen atmosphere before 1-methoxybutadiene (134 µmol)
was added. The reaction was followed by TLC and quenched by addition of
1 ml NaHCO3 (aq). The biphasic mixture was after vigorous stirring filtered
through an Extrelute® NT3 tube and then concentrated to give yellow oil.
Purification by chromatography on SiO2 with pentane–EtOAc gave 3a:4a
as pale yellow oil.
‡ Crystal data: C24H32BrNO2, M = 446.43, orthorhombic, a = 6.557(1), b
= 10.915(2), c = 30.422(5) Å, V = 2177.1(7) Å3 T = 100 K, space group
P212121 (No. 19), Z = 4, m(Mo–Ka) = 1.9 mm21, 17434 reflections
measured, 4969 unique reflections (Rint = 0.073) used in all calculations.
Friedel pairs were not merged before refinement. Hydrogen atoms were
placed at calculated positions and refined using a riding model. The final
wR(F2) was 0.093 (all data). Flack parameter x = 20.007(10). CCDC
graphic data in .cif or other electronic format.
Scheme 2
Table 2 Lewis acid catalyzed D–A reactions of 1a with dienes 4, 7c, d
and e
1 D. L. Boger and S. M. Weinreb Hetero Diels–Alder methodology in
organic synthesis, Academic Press, Inc, New York, 1987.
2 J. F. Bickley, T. L. Gilchrist and R. Mendonça, Arkivoc, 2002, 192.
3 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679.
4 For a review, see: T. L. Gilchrist, Aldrichim. Acta, 2001, 34, 51.
5 F. A. Davis, Y. Wu, H. Yan, K. R. Prasad and W. McCoull, Org. Lett.,
2001, 4, 655.
6 Y. S. P. Álvares, M. J. Alves, N. G. Azoia, J. F. Bickley and T. L.
Gilchrist, J. Chem. Soc., Perkin Trans. 1, 2002, 1911.
7 T. L. Gilchrist and R. Mendonça, Arkivoc, 2000, 1, 769.
8 C. A. Ray, E. Risberg and P. Somfai, Tetrahedron Lett., 2001, 42,
9289.
9 C. A. Ray, E. Risberg and P. Somfai, Tetrahedron, 2002, 58, 5983.
10 Y. Motoyama and H. Nishiyama, in Lewis Acids in Organic Synthesis,
Wiley-VCH, Weinheim, 2000, p. 59.
11 S. Fukuzumi and K. Ohkubo, J. Am. Chem. Soc., 2002, 124, 10270.
12 M. Yamauchi, Y. Honda, N. Matsuki, T. Watanabe, K. Date and H.
Hiramatsu, J. Org. Chem., 1996, 61, 2719.
Entry
Diene LA
T (°C)
Yield (%) dea (%)
1
2
3
4
5
6
7
8
9
5
—
275 to 240
2100
2100 to 290
278 to 240
2100
2100
RT
277
278
275 to 240
275
277
90b
56c
31c
99b
88c
99b
100b,d
–
30
96
87
8
85
58
20
–
5
5
MgBr2·OEt2
ZnCl2·OEt2
—
MgBr2·OEt2
ZnCl2·OEt2
—
MgBr2·OEt2
ZnCl2·OEt2
–
MgBr2·OEt2
ZnCl2·OEt2
8a
8a
8a
8b
8b
8b
8c
8c
8c
99c
80c
99b
99b
80
30
97
34
10
11
12
a Selectivity determined by 1H NMR. b Crude product. c After chromatog-
raphy. d Based on unreacted azirine.
CHEM. COMMUN., 2003, 1150–1151
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