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F. Wang et al. / Tetrahedron: Asymmetry 14 (2003) 2189–2193
Table 1. Eliminative ring-opening of 4a by Lewis acida
erated from reduction of 6, tosylation of the 2-hydroxy
group, cyclization and epoxidation. When 8 was treated
with AlEt3 in THF, it was converted to terminal a-
hydroxy olefin 9 efficiently in a high enantiomeric
purity (ee >99%), indicating that the eliminative ring-
opening is highly stereoselective. The results were listed
in Table 3.
Entry
Lewis acid
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
AlMe3
AlEt3
Zr(i-PrO)4
Al(i-PrO)3
Ti(i-PrO)2Cl2
TiCl4
SmI2
SnCl4
AlCl3
ZnMe2
ZnEt2
12
24
36
24
90
96
87
70
40
25
–
–
–
–
–
20
To determine the stereoselectivity of the rearrangement,
we studied the stereochemistry of the epoxy function in
4k and the hydroxy group in 5k (entry 11, Table 2)
using 2D NMR spectrum. The 2D NMR spectra
showed the epoxy function in 4k and the hydroxy
group in 5k both are a-oriented (trans to the b-oriented
methyl group), implying this AlEt3-promoted elimina-
tive ring-opening proceeds with retention of configura-
tion. The absolute configuration of the newly generated
stereogenic center in 9c was assigned as R by Mosher’s
method,8 indicating that the absolute configuration of
the epoxy function in 8c is (1R,2R). We tentatively
assume the hydroxy-directed m-CPBA epoxidation of 7
has the same face selectivity regardless of R1 and R2.
Based on this assumption, we tentatively assigned the
absolute configurations of 8 and 9 as shown in Table 3.
A possible mechanism is outlined in Scheme 3. Reac-
tion of AlEt3 with the hydroxyl group and subsequent
coordination to the epoxy function converts 8 to a
six-membered intermediate a; the epoxy group is thus
activated by the coordination leading to an eliminative
ring-opening with the formation of aluminium allylic
hydroxide b; hydrolysis of b finishes the transformation
with the release of a terminal a-hydroxy olefin and an
aldehyde. This mechanism is supported by the follow-
ing observations. (a) GC–MS analysis of the reaction
mixtures from 4d and 4g proved the presence of benz-
aldehyde; (b) no eliminative ring-opening occurred
when the hydroxy function in 8 was blocked by acetyl
group.
0.5
CPb
CP
NRc
NR
NR
NR
NR
9
10
11
12
13
ZnBr2
Ti(i-PrO)4
–
–
a Reaction condition: THF at 40°C.
b CP: complex products.
c NR: no reaction.
tion, even at refluxing temperatures. On the basis of
these results, we then expanded the scope of this trans-
formation to a series of b-hydroxy epoxides using AlEt3
as the Lewis acid and THF as the solvent, and the
results were summarized in Table 2.
As expected, all the b-hydroxy epoxides were trans-
formed to terminal a-hydroxy olefins in high yields.
The best results were obtained when excess AlEt3 (5
equiv.) was used. Use of a catalytic amount of AlEt3
only led to a partial conversion. It is noteworthy that
both of the diastereomers of b-hydroxy epoxide were
converted to the same terminal a-hydroxy olefin
(entries 6, 9, 10 and 13, Table 2). This reaction is
applicable to a wide range of b-hydroxy epoxides bear-
ing various R1, R2 and R3 substitutent. For example,
R1 and R2 could be two aliphatic (entries 1 and 2), one
aliphatic and one aromatic (entries 3–5 and 12) or
linked cyclic groups (entries 6–11), whereas R3 could be
an aliphatic (entries 1–3, 6 and 9–14) or an aromatic
substituent (entries 4 and 7), or a hydrogen (entries 5
and 8).
3. Conclusion
We have discovered a AlEt3-mediated eliminative ring-
opening reaction of b-hydroxy epoxides. This elimina-
tive ring-opening has been demonstrated to be a highly
stereoselective asymmetric synthesis for terminal a-
hydroxy olefins. Further studies on the application of
this methodology in the synthesis of natural products
are in progress.
With these successful results in hand, we then turned
our attention to the non-racemic version of such an
eliminative ring-opening. Enantiomerically pure b-
hydroxy epoxides were prepared from the cheap and
naturally abundant (S)-(−)-ethyl lactate 6, as shown in
Scheme 2. Reduction of 6 with NaBH4/AlCl3 followed
by tosylation of the primary hydroxyl group and
cyclization with BuLi afforded (S)-propylene oxide.
Reaction of (S)-propylene oxide with an in situ pre-
pared vinyl lithium reagent from ketone 1 at −15°C
gave homochiral b-hydroxy olefin 7. Epoxidation of 7
with m-CPBA yielded homochiral epoxide 8 (8a–d) as
one isomer. It should be mentioned that a highly
stereoselective epoxidation of 8c and 8d required a low
temperature (−780°C). These results indicated that
the b-hydroxy function could effectively direct the
epoxidation of a trisubstituented b-hydroxy olefin in
terms of face selectivity. 8e–h, enantiomers of 8a–d,
were similarly prepared from (R)-propylene oxide gen-
4. Experimental
4.1. General
THF was freshly distilled from a deep-blue solution of
sodium-benzophenone ketyl under argon. Column
1
chromatography was performed on silica cartridges. H
and 13C NMR spectra were recorded on an Avance
DRX-200 MHz (1H: 100 MHz, 13C: 50 MHz) or a
Bruker AM 400 MHz (1H: 400 MHz, 13C 100 MHz)
instrument with TMS as internal standard. MS data
were measured with EI (70 eV) and HRMS data were