Synthesis of tetrahydrofurans by regio- and stereoselective cyclization of epoxyalcohols using magnesium halide

Article abstract of DOI:10.1016/S0040-4039(02)00042-4

A novel synthetic method for several tetrahydrofuran derivatives by intramolecular cyclization of epoxyalcohols is described. The presence of a catalytic amount of magnesium halide altered the regio- and stereoselectivity of the cyclization reaction.

Full text of DOI:10.1016/S0040-4039(02)00042-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1495–1498
Synthesis of tetrahydrofurans by regio- and stereoselective
cyclization of epoxyalcohols using magnesium halide
Michinori Karikomi,* Shigeru Watanabe, Yukino Kimura and Tadao Uyehara
Department of Applied Chemistry, Faculty of Engineering, Utsunomiya University, Yoto 7-1-2, Utsunomiya 321-8585, Japan
Received 30 November 2001; revised 19 December 2001; accepted 21 December 2001
Abstract—A novel synthetic method for several tetrahydrofuran derivatives by intramolecular cyclization of epoxyalcohols is
described. The presence of a catalytic amount of magnesium halide altered the regio- and stereoselectivity of the cyclization
reaction. © 2002 Elsevier Science Ltd. All rights reserved.
Intramolecular cyclization of epoxyalcohols is a useful
reaction for the construction of oxygen-containing hete-
rocycles. Actually, many natural compounds and
related biologically active compounds have been syn-
spiro-tetrahydrofuran derivatives (2a) were obtained in
69% yield. Formation of an oxethane derivative was
not observed (Table 1, entry 1). The three possible
transition states are depicted in Fig. 1. Cyclization by
aqueous sodium hydroxide proceeds via the transition
state A (4-exo-tet ring closure) exclusively. The transi-
tion state B (5-endo-tet ring closure) is not preferable
because the angle h, which consists of the leaving
oxygen of the oxirane, the reaction carbon center and
the nucleophilic oxygen anion, is not allowed to take a
linear arrangement in its conformation in the transition
state. On the contrary, our method will take the transi-
tion state C (5-exo-tet ring closure), which has no
difficulties to take the linear arrangement in the transi-
tion state. To explain the high regioselectivity, we
assumed that the existing of the equilibrium between
the starting epoxyalcohols and the halohydrin interme-
diates. The unpreferable regioisomeric halohydrin inter-
mediate could not form the oxetanes caused by the ring
strain. Only the other preferable halohydrin intermedi-
ate could form the tetrahydrofurans. Another possibil-
ity could point out that the high regioselective
bromination was achieved by the chelation mechanism.
However, we could not find out further evidences of the
1
thesized according to this strategy. As an epoxy ring
possesses two reactive carbons, different membered het-
erocycles are formed depending on its regioselective
nature. Therefore, the regioselectivity of the cyclization
2
has been paid considerable attention. Previously, we
have reported a novel synthesis of 3-hydroxyazetidines
by intramolecular cyclization of 2,3-epoxyamines using
3
magnesium halide. Our results show that the presence
of a catalytic amount of magnesium halide alters a both
the regio- and stereoselectivity compared with the
results of the known reactions. Consequently, we
expected this method would be applicable to the syn-
thesis of oxygen-containing heterocyclic systems. In this
letter we described a novel regio- and stereoselective
synthesis of tetrahydrofurans.
Epoxyalcohol cyclizations are known to prefer the exo
mode of ring closure over the endo mode, in accord
4
with Baldwin’s rules. For example, it is reported that
1
-(2,3-epoxypropyl)cyclohexane-1-ol (1a) with aqueous
sodium hydroxide gives only spiro-oxethane derivatives
6
5
existing of the chelate intermediate.
(
3).
As for the stereoselectivity, the intramolecular cycliza-
tion of epoxy alcohols proceeds with inversion accord-
Initially, we attempted a method for the intramolecular
cyclization of 1a. A mixture of 1a with 10 mol% of
magnesium bromide in THF was refluxed for 20 h. The
ing to an S 2 mechanism (Scheme 1, Eq. (1)). On the
N
other hand, our method would proceed with retention
caused by double inversion (Eq. (2)). The initial step of
this reaction proceeds with ring-opening of epoxide by
the halide anion. Then, the ring closure process would
take place with the substitution of the halogen by the
intramolecular hydroxyl group. Therefore, the stereo-
Keywords: epoxyalcohols; cyclization; magnesium halides, epoxides;
furans.
*
Corresponding author. Tel.: +0081 28 689 6148; fax: +0081 28 689
009; e-mail: karikomi@cc.utsunomiya-u.ac.jp
6
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00042-4

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496
M. Karikomi et al. / Tetrahedron Letters 43 (2002) 1495–1498
a
Table 1. Synthesis of cyclic ether by reaction of epoxyalcohol with magnesium halide
b
c
Entry
1
MgX2
Products/Yield% (ratio)
Substrate
OH
Solvent
Time/h
HO
HO
O
O
O
2a
1a
3
MgBr2
69 (>98 : 2)
THF
20
HO
Ph
HO
O
2
OH
Ph
O
Ph
O
1b
2b
2c
MgBr2-Et2O
MgI2
7days
73 (76 : 24)
84 (85 : 15)
70 (54 : 46)
THF
3
4
THF
40
5
MgI2
Dioxane
Ph
O
OH
OH
5
MgI2
65 ( 4 : 96)
1
c
THF
65
HO
Et
HO
Et
Et
O
6
7
O
O
1
d
2d
2e
MgI2
60 ( 2 : >98)
THF
THF
72
24
Me
OH
Me
OH
Me
O
OH
O
O
2g
1e
2f
MgI2
73 (65 : 35)
a
b
c
All reactions were performed at reflux with 10 mol% MgX2.
Combined yield of diastereoisomers.
Determined by 1H NMR. The indication >98:2 means that a single diastereoisomer was observed.
O
O
X
OH
α
α
α
>
O
O
O
MgX
A
B
C
4-exo-tet ring closure
5-endo-tet ring closure
5-exo-tet ring closure
Base catalized TS
Figure 1. Transition states for the cyclization of 3,4-epoxyalcohols.
MgX2 catalized TS

M. Karikomi et al. / Tetrahedron Letters 43 (2002) 1495–1498
1497
HO
R
Acid or Base
(
1)
(inversion)
O
O
R
OH
O
OH
HO
R
MgX2
-MgX2
R
-
+
O Mg X
(2)
(inversion)
(inversion)
X
MX = MgBr , MgI
2
2
2
Scheme 1.
chemical outcome of Eqs. (1) and (2) will give opposite
results.
Acknowledgements
The research was financially supported by the
Sasakawa Scientific Research Grant from The Japan
Science Society.
Phenyl- and ethyl-substituted 3,4-epoxyalcohols (1b–d)
were then subjected to several experiments directed
towered a cyclization reaction. Epoxyalcohol 1b gave a
mixture of stereoisomeric tetrahydrofuran derivatives in
76% combined yield (2b:2c=76:24, entry 2).
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