Lewis acid-promoted rearrangement of 2,3-epoxy alcohol derivatives: Stereochemical control and selective formation of two types of chiral quaternary carbon centers from the single carbon skeleton

Article abstract of DOI:10.1021/jo0604080

The Lewis acid-promoted rearrangement of 2,2,3,3-tetrasubstituted 2,3-epoxy alcohols with several kinds of protecting groups was investigated. When SnCl₄ is used as a Lewis acid, the reaction proceeds in a regio- and stereo-controlled manner to

Full text of DOI:10.1021/jo0604080

Lewis Acid-Promoted Rearrangement of 2,3-Epoxy Alcohol
Derivatives: Stereochemical Control and Selective Formation of
Two Types of Chiral Quaternary Carbon Centers from the Single
Carbon Skeleton
Yasuyuki Kita,* Satoshi Matsuda, Ryoko Inoguchi, Jnaneshwara K. Ganesh, and
Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, Yamadaoka 1-6,
Suita, Osaka 565-0871, Japan
kita@phs.osaka-u.ac.jp
ReceiVed February 27, 2006
The Lewis acid-promoted rearrangement of 2,2,3,3-tetrasubstituted 2,3-epoxy alcohols with several kinds
of protecting groups was investigated. When SnCl4 is used as a Lewis acid, the reaction proceeds in a
regio- and stereo-controlled manner to afford two types of carbonyl compounds selectively from a single
2,3-epoxy alcohol only by changing the protecting group of the alcohol. The method was then applied
to the formation of two types of acyclic and cyclic quaternary carbon centers from the single compound
in optically active forms.
SCHEME 1. Considerable Pathways in the Rearrangement
of Epoxide
Introduction
The rearrangement of epoxides and their derivatives with a
Lewis acid (LA) is one of the most valuable tools for
constructing carbonyl compounds.1 In particular, much attention
has been paid to the rearrangement of 2,3-epoxy alcohols and
their derivatives.2,3 This method is also useful for the asymmetric
synthesis of natural products because of the easy availability
of optically active 2,3-epoxy alcohols.4,5 To make the reactions
practical, it is necessary to solve two issues, that is, control of
the regiochemistry and control of stereochemistry (Scheme 1).
As for the control of the regiochemistry, many studies have
already been reported.1-3 However, most of the studies reported
to date are restricted to the 2,3-disubstituted, 2,2,3- or 2,3,3-
trisubstituted epoxides, and the reaction occurs through the
* Corresponding author. Tel.: +81 6-6879-8225. Fax: +81 6-6879-8229.
(1) For reviews of the Lewis acid-mediated rearrangement of epoxides,
see: (a) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737-799. (b)
Rickborn, B. In ComprehensiVe Organic Synthesis, Carbon-Carbon Bond
Formation; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; Vol. 3,
Chapter 3.3, pp 733-775.
carbocations on the more substituted carbons if the epoxides
do not have electron-stabilizing substituents such as a phenyl
or vinyl group. On the other hand, to the best of our knowledge,
the rearrangements of the 2,2,3,3-tetrasubstituted 2,3-epoxy
10.1021/jo0604080 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/09/2006
J. Org. Chem. 2006, 71, 5191-5197
5191

Kita et al.
SCHEME 2
alcohol derivatives are comparatively few.6 We have been
interested in the rearrangements of the 2,2,3,3-tetrasubstituted
2,3-epoxy alcohol derivatives in which the C2- and C3-
carbocations have a similar stability. Recently, we succeeded
in controlling the regiochemistry of the rearrangements of
2,2,3,3-tetrasubstituted 2,3-epoxy alcohol derivatives using acyl
and sulfonyl groups,4 which are known as strong electron-
withdrawing groups, as the protecting group of the alcohol. By
using this method, several desirable chiral quaternary carbon
centers and chiral spiro centers have been synthesized in
optically active forms, and the asymmetric syntheses of several
biologically active natural products have been achieved.4
We next planned to solve the problem of controlling the
stereochemistry of the rearrangements of the 2,2,3,3-tetrasub-
stituted 2,3-epoxy alcohol derivatives, in other words, controlling
the migrating groups of the rearrangements. Reports on the
control of the stereochemistry during the rearrangements of the
epoxy alcohol derivatives are few, and to the best of our
knowledge, only two groups have reported their studies on this
issue. Maruoka and Yamamoto used silylated epoxy alcohol
derivatives, and the stereocontrol of the reaction was achieved
by changing the type of LA.2f Recently, Suda and Takanami
reported controlling the stereochemistry of the rearrangement
by changing the metal in the porphyrin complex.2a They
succeeded in controlling the stereochemistry by changing the
type of the LAs. On the other hand, we communicated the
control of the stereochemistry by the combination of the
protecting group of the alcohol and the LA. The most interesting
result was the control of the stereochemistry using the single
LA, SnCl4.7 The method was then applied to the formation of
two types of quaternary carbon centers from the single
compound in optically active forms (Scheme 2). We now report
the full details of a new method for the control of the
rearrangements of the 2,2,3,3-tetrasubstituted 2,3-epoxy alcohol
derivatives and its application by a combination of a LA and
the protecting group of the alcohol (Scheme 2).
(2) For examples, see: (a) Suda, K.; Kikkawa, T.; Nakajima, S.;
Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554-9555. (b) Jeon, S.; Walsh,
P. J. Am. Chem. Soc. 2003, 125, 9544-9545. (c) Marson, C. M.; Walker,
A. J.; Pickering, J.; Hobson, A. D. J. Org. Chem. 1993, 58, 5944-5951.
(d) Marson, C. M.; Khan, A.; Porter, R. A.; Cobb, A. J. A. Tetrahedron
Lett. 2002, 43, 6637-6640. (e) Marson, C. M.; Oare, C. A.; McGregor, J.;
Walsgrove, T.; Grinter, T. J.; Adams, H. Tetrahedron Lett. 2003, 44, 141-
143. (f) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H.
Tetrahedron 1994, 50, 3663-3672. (g) Jung, M. E.; Lee, W. S.; Sun, D.
Org. Lett. 1999, 1, 307-310. (h) Jung, M. E.; Heuvel, A. V. D. Tetrahedron
Lett. 2002, 43, 8169-8172. (i) Jung, M. E.; Hoffmann, B.; Rausch, B.;
Contreras, J. M. Org. Lett. 2003, 5, 3159-3161. (j) Zhu, Y.; Shu, L.; Tu,
Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818-1826. (k) Ranu, B. C.; Jana, U.
J. Org. Chem. 1998, 63, 8212-8216. (l) Bhatia, K. A.; Eash, K. J.; Leonard,
N. M.; Oswald, M. C.; Mohan, R. S. Tetrahedron Lett. 2001, 42, 8129-
8132. (m) Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc.,
Perkin Trans. 1 2000, 3791-3794.
(3) (a) Maruoka, K.; Hasegawa, H.; Yamamoto, H.; Suzuki, K.; Shi-
mazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827-3829.
(b) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111,
6431-6432. (c) Maruoka, K.; Sato, J.; Yamamoto, H. J. Am. Chem. Soc.
1991, 113, 5449-5450. (d) Suzuki, K.; Miyazawa, M.; Tsuchihashi, G.
Tetrahedron Lett. 1987, 28, 3515-3518. (e) Shimazaki, M.; Hara, H.;
Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891-5894. (f)
Nakagawa, T.; Taya, M.; Kitamura, M.; Suzuki, K. J. Am. Chem. Soc. 1996,
118, 8949-8950. (g) Maruoka, K.; Sato, J.; Yamamoto, H. Tetrahedron
1992, 48, 3749-3762.
(4) For recent examples, see: (a) Fujioka, H.; Kitagaki, S.; Imai, R.;
Kondo, M..; Okamoto, S.; Yoshida, Y.; Akai, S.; Kita, Y. Tetrahedron Lett.
1995, 36, 3219-3222. (b) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.;
Fang, D.-F.; Fujioka, H. Tetrahedron Lett. 1997, 38, 1061-1064. (c) Kita,
Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Kondo, M.; Okamoto,
S.; Imai, R.; Akai, S.; Fujioka, H. J. Org. Chem. 1997, 62, 4991-4997. (d)
Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka H. J.
Org. Chem. 2003, 68, 5917-5924. (e) Fujioka, H.; Yoshida, Y.; Kita, Y.
J. Synth. Org. Chem., Jpn. 2003, 61, 133-143. (f) Kita, Y.; Futamura, J.;
Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. Tetrahedron Lett. 2003,
44, 411-413.
Results and Discussion
As shown in Scheme 1, once the regiochemistry is controlled,
the remaining problem is the control of the stereochemistry.
We then chose the 2,3-epoxy-1-alcohol derivatives because the
control of their regiochemistry had already been solved.4 To
control the stereochemistry of the rearrangement reactions, we
paid attention to the two lone pairs of the oxygen atom on the
oxiran ring, which occupy the opposite sides of the oxygen atom.
When the reaction proceeds in a stereoselective manner, the
migrating groups of the rearrangements depend on the attacking
course of the LA (Scheme 3). If the protecting group has a
nucleophilic ability, that is, the protecting group prefers to
chelate to the LA, the LA approaches the lone pair of the oxygen
from the same side of the alcohol, and the alkyl group would
preferably migrate (route a). On the contrary, when the
protecting group repels the LA, the LA approaches the lone
pair of the oxygen from the opposite side of the alcohol, and
the hydroxy alkyl group would preferably migrate (route b).
Rearrangement of Cyclic 2,3-Epoxy Alcohols. First of all,
we selected the six-membered ring 2,3-epoxy alcohol derivatives
as the substrates and examined the influence of the type of LA
and the protecting group of the alcohol. These results are
(5) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (c) Erickson,
T. J. J. Org. Chem. 1986, 51, 934-935.
(6) There is only one example for practical use, except for our work (ref
4), see: Abad, A.; Agullo´, C.; Arno´, M.; Cunˇat, A. C.; Zaragoza´, R. J.
Synlett 1993, 895-896.
(7) Part of this study was published as a preliminary communication:
Kita, Y.; Matsuda, S.; Inoguchi, R.; Ganesh, J. K.; Fujioka, H. Tetrahedron
Lett. 2005, 46, 89-91.
5192 J. Org. Chem., Vol. 71, No. 14, 2006

Lewis Acid-Promoted Rearrangement of 2,3-Epoxy Alcohol
SCHEME 3. Concept for the Control of Stereochemistry
TABLE 1. Rearrangement of Cyclic 2,3-Epoxy Alcohol Derivatives
product (yield, %)a
entry
R
1
X
Lewis acid
2
3
ratiob (2:3)
1
2
3
4
5
6
7
8
9
10
11
12
13
Et
1a
1b
1c
1d
1e
1f
1g
1h
1a
1b
1c
1g
1h
H
H
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
3a; X ) H (69)
3b; X ) H (98)
3c; X ) Bn (44)
3d; X ) Me (59)
3 only
3 only
1:2.2
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Et
Bu
Bu
Bu
Bu
Bn
Me
Me3Si
Et3Si
t-BuMe2Si
PNB
2c; X ) Bn (20)
2d; X ) Me (8)
2b; X ) H (39)
2b; X ) H (71)
2b; X ) H (94)
2h; X ) PNB (26)
2a; X ) H (75)
2b; X ) H (47)
2c; X ) Bn (81)
2b; X ) H (34)
2h; X ) PNB (24)
1:7.3
2 only
2 only
2 only
1:1.8
2 only
2 only
2 only
2 only
1:1.4
3h; X ) PNB (46)
3h; X ) PNB (34)
H
H
Bn
t-BuMe2Si
PNB
a Isolated yields. b The ratios were determined by the isolation of each product.
SCHEME 4. Plausible Mechanism for the Difference
between BF3‚OEt2 and SnCl4 in Cyclic 2,3-Epoxy Alcohols
coordinates with the two oxygen atoms of the alcohol and
oxirane ring. In particular, BF3‚OEt2 coordinates with one of
the two lone pairs of the oxirane ring, which is outside of the
six-membered ring for steric repulsion. The C1-C2 bond then
migrates to the C3 carbocation to give the ring-contracted five-
membered ring â-hydroxy ketones 2. We next examined several
kinds of protecting groups of the alcohol in the presence of
SnCl4 and BF3‚OEt2. In the case of SnCl4, a clear difference
depending on the protecting groups was observed. The trialkyl-
silyl ether exclusively afforded 2 (entries 5-7), and tert-butyl-
dimethylsilyl (TBS) ether 1g gave the best result compared with
trimethylsilyl ether 1e and triethylsilyl ether 1f. The benzyl and
methyl ether 1c,d preferentially afforded 3c and 3d (entries 3
and 4) like that of the alcohols 1a,b (entries 1 and 2). However,
the p-nitrobenzoyl (PNB) ester 1h did not show such tendency
(entry 8). On the other hand, in the case of BF3‚OEt2, â-hydroxy
ketones 2 were preferentially obtained even when the alcohol
was protected with the benzyl group and TBS group (entries
11 and 12). When the alcohol was converted to the PNB ester
1h, both the R-hydroxy ketone 2h and â-hydroxy ketone 3h
were obtained in the ratio of 1:1.4 (entry 13). These results show
that SnCl4 is the best LA for the selective rearrangement. A
plausible mechanism for the selectivity depending on the
protecting groups of the alcohol will be discussed later
(Scheme 5).
summarized in Table 1. Initially, we examined the reaction of
the cyclic six-membered ring 2,3-epoxy alcohol as the substrate,
with SnCl4 as the representative LA, which causes chelation,
and BF3‚OEt2 as the representative LA, which does not cause
chelation. As shown in Table 1, in the case of SnCl4, six-
membered ring R-hydroxy ketones 3a and 3b were exclusively
obtained (entries 1 and 2). On the other hand, in the case of
BF3‚OEt2, five-membered ring â-hydroxy ketones 2a and 2b
were obtained (entries 9 and 10). These interesting phenomena
are explained by Scheme 4. In the case of SnCl4, the tin atom
coordinates with both the alcohol and the oxirane ring in a
chelation manner. As a result, the oxirane ring and alcohol unit
are fixed, and the C2 alkyl group migrates to the C3 carbocation
to give the six-membered ring R-hydroxy ketones 3. On the
other hand, in the case of BF3‚OEt2, BF3‚OEt2 separately
Rearrangement of Acyclic 2,3-Epoxy Alcohols. Next we
tried to apply this method to the acyclic 2,3-epoxy alcohol
derivatives, and the effect of the protecting group of the alcohol
J. Org. Chem, Vol. 71, No. 14, 2006 5193

Kita et al.
TABLE 2. Rearrangements of Acyclic 2,3-Epoxy Alcohol Derivatives
product (yield, %)a
entry
R
4
X
Lewis acid
5
6
ratiob (5:6)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Et
Et
Me
Me
cis-4a
trans-4a
cis-4b
trans-4b
cis-4c
trans-4c
cis-4d
trans-4d
cis-4e
trans-4e
cis-4f
trans-4f
cis-4a
trans-4a
cis-4d
H
H
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
6a; X ) H (76)
6a; X ) H (56)
6b; X ) Bn (94)
6b; X ) Bn (55)
6 only
1:2.1
5a; X ) H (27)
Bn
Bn
TBS
TBS
H
6 only
6 only
5 only
5 only
10.3:1
5 only
6 only
6 only
5 only
5 only
0.92:1
1:2.2
5a; X ) H (65)
5a; X ) H (47)
5d; X ) H (31)
5d; X ) H (60)
6d; X ) H (3)
H
Bn
Bn
TBS
TBS
H
H
H
H
6e; X ) Bn (91)
6e; X ) Bn (76)
5d; X ) H (90)
5d; X ) H (100)
5a; X ) H (46)
5a; X ) H (31)
5d; X ) H (58)
6a; X ) H (50)
6a; X ) H (67)
6d; X ) H (14)
6d; X ) H (100)
4.1:1
6 only
trans-4d
a Isolated yields. b The ratios were determined by the isolation of each product.
TABLE 3. Rearrangement of Acyclic 2,3-Epoxy Alcohol
Derivatives with C3 Phenyl Group
preferentially obtained (entries 7 and 8). This is the opposite
tendency compared with the case of 4a (R ) Et, X ) H; entries
1 and 2). This is probably due to the low migration ability of
the methyl group, which is often reported in the literature.2l-n
For the trialkylsilyloxy compounds, every reaction afforded the
â-hydroxy ketones possibly obtained by the desilylation after
the rearrangement because the products are completely different
from those derived from the epoxy alcohols without protecting
groups. On the other hand, for the reactions by BF3‚OEt2, no
regular reaction was observed (entries 13-16).
Rearrangements of Acyclic 2,3-Epoxy Alcohols with C3
Phenyl Group. Next we examined the reactivity of the 2,3-
epoxy alcohol derivatives with the phenyl group at the C3
position (Table 3). The rearrangement reaction of the substrate
must proceed via the more stable C3 carbocation. In these cases,
control of the stereochemistry was also achieved to give the
â-hydroxy ketones 8 and R-hydroxy ketones 9, depending on
the protecting group. Thus, the effect of the protecting group
in this SnCl4-promoted rearrangement of the epoxy alcohol
derivatives was also observed in the acyclic system bearing a
cation stabilizing group, such as the phenyl group. However,
the selectivity of two kinds of carbonyl groups in the case of
XdH, Bn (entries 1-4) was slightly lower than that observed
in Table 2. These results suggest some participation of the
stepwise reaction process as a result of the cation stabilizing
ability of the phenyl group at the C3 position.
Consideration of the Reaction Mechanism: As shown
above, especially in the use of the SnCl4, selective formation
of two types of hydroxyl ketones was possible. Thus, the epoxy
silyl ethers afforded the â-hydroxy ketones as major products,
whereas the epoxy alcohols and the epoxy alkyl ethers produced
R-hydroxy ketones as the major products. These results are
rationalized by the nonchelation and chelation controls. The
epoxy silyl ethers form nonchelation intermediates. The hy-
product (yield, %)a
ratiob
entry
7
X
8
9
(8:9)
1
2
3
4
5
6
cis-7a
trans-7a
cis-7b
trans-7b Bn
cis-7c
H
H
Bn
8a; X ) H (39)
8a; X ) H (42)
9a; X ) H (52)
9a; X ) H (53)
1:1.3
1:1.3
8b; X ) Bn (13) 9b; X ) Bn (68) 1:5.2
8b; X ) Bn (11) 9b; X ) Bn (80) 1:7.3
TBS 8a; X ) H (78)
trans-7c TBS 8a; X ) H (89)
8 only
8 only
a Isolated yields. b The ratios were determined by the isolation of each
product.
was examined. These results are shown in Table 2. SnCl4 had
almost the same reactivity in the acyclic system as in the cyclic
system. The epoxy alcohol itself 4a or the benzyl ethers 4b,e
afforded the R-hydroxy ketone 6a or R-benzyloxy ketones 6b,e
as the major products by migration of the R group via the C3
carbocation (entries 1-4, 9, and 10). In contrast, the TBS ethers
4c,f afforded the â-hydroxy ketones 5a,d as a single product
by migration of the siloxymethyl group and successive cleavage
of the O-Si bond (entries 5, 6, 11, and 12). Furthermore, this
tendency was observed in both the cis- and trans-isomers of
the 2,3-epoxy alcohol derivatives. However, in the case of 4d
(R ) Me and X ) H), the â-hydroxy ketone 5d was
5194 J. Org. Chem., Vol. 71, No. 14, 2006

Lewis Acid-Promoted Rearrangement of 2,3-Epoxy Alcohol
SCHEME 5. Plausible Reaction Mechanism
SCHEME 6. Asymmetric Synthesis of Two Quaternary Carbon Centers in Acyclic System
droxyl or alkyl ether compounds can form the bidentate
chelation transition state between two oxygen atoms and the
Sn metal. This decreases the migratory aptitude of the alkoxym-
ethyl group, and then the C2 alkyl group, opposite to the
alkoxymethyl group, selectively migrates to produce the R-hy-
droxy ketones. On the other hand, the bulky trialkylsilyl group
inhibits the formation of the chelation transition state and makes
the LA attack the opposite-side lone pair of the oxygen atom
of the oxiran ring. The stereoselective rearrangement of the
trialkylsilyloxy group in the anti-periplanar position followed
by the cleavage of the O-Si bond then occurs to give the
â-hydroxy ketones (Scheme 5).
Selective Construction of Optically Active Two Chiral
Quaternary Carbon Centers from the Single Isomer. Because
many biologically active natural products have chiral quaternary
carbon centers, the construction of such structural subunits is
one of the important issues in synthetic organic chemistry and
has been widely studied.8 We then tried to apply our method to
the asymmetric synthesis of carbonyl compounds bearing chiral
quaternary carbon centers. As shown in Scheme 6, we prepared
the chiral nonracemic 2,3-epoxy alcohol (-)-trans-4a using the
Katsuki and Sharpless asymmetric epoxidation protocol.5 This
alcohol was protected with the benzyl and TBS group to give
(+)-trans-4b and (-)-trans-4c, respectively. They were then
treated with SnCl4. In the case of the benzyl group (+)-trans-
4b, the reaction proceeded through a chelation intermediate to
give the R-benzyloxy ketone (+)-6b in good yield without
racemization. On the other hand, when the TBS ether (-)-trans-
4c was treated with SnCl4 at 0 °C, the â-hydroxy ketone 5a
was obtained by deprotection of the TBS ether of the rearranged
product under acidic reaction conditions. This compound 5a
was benzoylated and found to be 35% ee, determined by the
HPLC analysis of its benzoylated compound (-)-12. This is
probably due to the partial racemization through a retro-aldol
and aldol mechanism.9 When the reaction was performed at -78
°C and quenched at the same temperature, the racemization was
partly suppressed, and the product was found to be 76% ee after
benzoylation (Scheme 6). We already observed the remarkable
effect of the reaction temperature on the enantiomeric excess
of the â-hydroxy ketone derivatives under basic conditions.10
Scheme 7 shows our other application of the method for the
selective formation of two types of optically active quaternary
carbon centers in the cyclic system. That is, the known R,â-
(9) Racemization through a retro-aldol-type reaction, see: Kimura, T.;
Yamamoto, N.; Suzuki, Y.; Kawano, K.; Norimine, Y.; Ito, K.; Nagato, S.;
Iimura, Y.; Yonaga, M. J. Org. Chem. 2002, 67, 6228-6231.
(10) Akai, S.; Tsujino, T.; Fukuda, N.; Iio, K.; Takeda, Y.; Kawaguchi,
K.; Naka, T.; Higuchi, K.; Akiyama, E.; Fujioka, H.; Kita, Y. Chem.sEur.
J. 2005, 11, 6286-6297.
(8) (a) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-401.
J. Org. Chem, Vol. 71, No. 14, 2006 5195

Kita et al.
SCHEME 7. Selective Synthesis of Optically Active Five-Membered and Six-Membered Ring Skeletons
unsaturated ketone 1311 was converted to the epoxy alcohol (+)-
1b by asymmetric reduction using the method of Corey et al.,12
followed by cis-selective epoxidation by the Sharpless and
Michaelson procedure.13 The protection of the hydroxyl function
of (+)-1b with TBDPS, a stable protecting group under acidic
conditions, and the benzyl group afforded the optically active
epoxy alcohol derivatives (+)-15 and (-)-1c in good yields,
respectively. Three different types of optically active 2,3-epoxy
alcohol derivatives (+)-15, (-)-1c, and (+)-1b were then treated
with SnCl4. As we already described above, the six-membered
ring product (-)-3b was exclusively obtained in the case of
the 2,3-epoxy alcohol (+)-1b without the protecting group. The
ee value of (-)-3b, 94% ee, was deduced by the HPLC analysis
of its benzoate (-)-3h. In contrast, the five-membered ring
product (-)-16 was exclusively obtained in the case of the
TBDPS ether (+)-15, whereas the benzyl ether (-)-1c afforded
a 1:2 mixture of the five-membered ring product (-)-2c and
six-membered ring one (+)-3c. No racemization occurred in
every rearranged product. This fact also indicates that our
method is applicable to the construction of the quaternary
asymmetric carbon centers of cyclic systems as well as acyclic
systems.
by changing the type of protecting group of the alcohol. Thus,
we have succeeded in selectively producing two types of
rearranged products from the single carbon skeleton. A detailed
mechanistic investigation and applications of this method
including natural product synthesis are now in progress in our
laboratory.
Experimental Section
General Procedure for the Rearrangement Reaction of 2,3-
Epoxy Alcohol Derivatives using BF3‚Et2O or SnCl4: BF3‚Et2O
or SnCl4 (1.1 mmol) was added to a stirred solution of the 2,3-
epoxy alcohol derivatives (1.0 mmol) in CH2Cl2 (10 mL) at 0 °C
or -78 °C under N2, and the mixture was gradually warmed to rt.
After the completion of the reaction (TLC check), saturated aqueous
NaHCO3 was added to the solution, and the resulting mixture was
extracted with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 column chromatography using hexane/AcOEt (2/
1∼20/1) as the eluent to give the rearranged product.
(1RS,3RS)-2-Methyl-2-pentanoylcyclopentanol (2b; Entry 10
in Table 1): BF3‚Et2O (47 µL, 0.37 mmol) was added to a stirred
solution of 1b (61.8 mg, 0.34 mmol) in CH2Cl2 (3.4 mL) at 0 °C
under N2, and the mixture was gradually warmed to rt. After the
completion of the reaction (TLC check), saturated aqueous NaHCO3
was added to the solution, and the resulting mixture was extracted
with CH2Cl2. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by SiO2
column chromatography using hexane/AcOEt (7/1) as the eluent
to give 2b (29.1 mg, 47%) as a colorless oil. IR (KBr): 3441, 1693
cm-1. 1H NMR (CDCl3): δ 0.91 (t, 3H, J ) 6.9 Hz), 1.16 (s, 3H),
1.20-1.36 (m, 2H), 1.49-2.02 (m, 8H), 2.16 (br s, 1H), 2.41-
2.56 (m, 2H), 4.29 (t, 1H, J ) 8.1 Hz). 13C NMR (CDCl3): δ 13.9,
16.7, 18.3, 22.3, 25.7, 30.2, 32.8, 37.7, 57.1, 75.5, 216.7. Anal.
Calcd for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.47; H, 10.83.
(1RS,3RS)-3-Butyl-3-methyl-2-oxacyclohexanol (3b; Entry 2
in Table 1): SnCl4 (1.0 M in CH2Cl2, 0.22 mL, 0.22 mmol) was
added to a stirred solution of 1b (36.0 mg, 0.20 mmol) in CH2Cl2
(2.0 mL) at 0 °C under N2, and the mixture was gradually warmed
to rt. After the completion of the reaction (TLC check), saturated
Conclusion
We have found that the LA-promoted rearrangement of
2,2,3,3-tetrasubstituted 2,3-epoxy alcohol derivatives, which are
supposed to have only a slight difference in the stability of
carbocation at the C2 and the C3 positions, proceeds through
the C3 carbocation. Moreover, when we used SnCl4 as a LA,
control of the stereochemistry of the rearranged products was
achieved via the chelation or nonchelation transition state only
(11) Doris, E.; Dechoux, L.; Mioskowski, C. J. Am. Chem. Soc. 1995,
117, 12700-12704.
(12) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925-7926.
(13) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136-6137.
5196 J. Org. Chem., Vol. 71, No. 14, 2006

Lewis Acid-Promoted Rearrangement of 2,3-Epoxy Alcohol
aqueous NaHCO3 was added to the solution, and the resulting
mixture was extracted with CH2Cl2. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2 column chromatography using hexane/AcOEt
(7/1) as the eluent to give 3b (35.3 mg, 98%) as a colorless oil. IR
H, 9.55. Found: C, 78.74; H, 9.60. HPLC analysis: 94% ee (Daicel
Chiralpak OD-H; hexane only, 0.5 mL/min, 20 °C).
(-)-(2S)-1-(tert-Butyldimethylsilanyloxy)-2-cyclohexyl-2-methyl-
pentan-3-one ((-)-11) and (-)-(1S)-2-Cyclohexyl-2-methyl-3-
oxo pentyl benzoate ((-)-12). The crude rearranged products
obtained from (-)-trans-4a (1 mmol) were subjected to benzoy-
lation using benzoic anhydride (2 mmol), triethylamine (2 mmol),
and a catalytic amount of 4-(dimethylamino)pyridine in CH2CH2
(10 mL) at 0 °C under N2. After being stirred for 16 h, H2O was
added to the reaction mixture, and the solution was extracted with
CH2Cl2. The combined organic layer was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified
by SiO2 column chromatography using hexane/AcOEt (9/1) as the
eluent to give (-)-11 and (-)-12 in the yield shown in Scheme 3.
(-)-11: Colorless oil. IR (KBr): 1705, 1450, 1256, 1084, 839
cm-1. 1H NMR (CDCl3): δ 0.00 (s, 6H), 0.85 (s, 9H), 1.00 (t, 3H,
J ) 7.2 Hz), 1.05 (s, 3H), 1.07-1.31 (m, 6H), 1.47-1.80 (m, 5H),
2.43-2.51 (m, 2H), 3.47 (A in ABq, 1H, J ) 9.3 Hz), 3.79 (B in
1
(KBr): 3479, 1705 cm-1. H NMR (CDCl3): δ 0.88 (t, 3H, J )
7.2 Hz), 0.92-1.00 (m, 2H), 1.09 (s, 3H), 1.21-1.94 (m, 9H),
2.38-2.45 (m, 1H), 3.77 (d, 1H, J ) 3.6 Hz), 4.28-4.36 (m, 1H).
13C NMR (CDCl3): δ 13.9, 18.9, 22.0, 23.2, 26.0, 37.2, 37.3, 40.7,
48.4, 72.4, 215.8. HRMS (FAB) calcd for C11H20O2Li [M + Li]+,
191.1624; found, 191.1622.
(+)-3-Cyclohexyl-3-methyl-2-oxo-1-benzyloxypentane ((+)-
6b): Colorless oil; [R]25D +2.51 (c 0.47, CHCl3). IR (KBr): 1712
1
cm-1. H NMR (CDCl3): δ 0.75 (t, 3H, J ) 7.5 Hz), 0.87-1.74
(m, 13H), 2.17 (s, 3H), 4.23 (d, 2H, J ) 2.5 Hz), 4.61 (s, 2H),
7.29-7.34 (m, 5H). 13C NMR (CDCl3): δ 8.8, 14.7, 26.5, 26.7,
26.8 (2C), 28.5, 29.6, 45.1, 53.5, 71.9, 73.0, 127.6, 127.7 (2C),
128.2 (2C), 137.3, 211.5. Anal. Calcd for C19H28O2: C, 79.12; H,
9.78. Found: C, 78.99; H, 9.67.
ABq, 1H, J ) 9.3 Hz). [R]25 - 9.93 (c 0.38, CHCl3). 13C NMR
D
(-)-(1S,2R)-(1-[2-(tert-Butyldiphenylsilanyloxy)-1-methyl-cy-
(CDCl3): δ -5.7 (2C), 7.8, 14.2, 18.1, 25.8 (3C), 26.5, 26.8, 26.9,
27.4, 28.4, 32.2, 42.2, 56.2, 69.0, 215.8. HRMS (FAB) calcd for
C18H37O2Si [M + H]+, 313.2563; found, 313.2569. (-)-12:
clopentyl]-pentan-1-one ((-)-16): Colorless oil; [R]25 -11.9 (c
D
0.91, CHCl3). IR (KBr): 1703, 1427 cm-1. H NMR (CDCl3): δ
1
1
Colorless oil. IR (KBr): 1722, 1450, 1269, 1113, 712 cm-1. H
0.85 (t, 3H, J ) 7.2 Hz), 1.09 (s, 9H), 1.15-1.24 (m, 2H), 1.26 (s,
3H), 1.31-1.70 (m, 7H), 1.88-1.94 (m, 1H), 2.25-2.34 (m, 2H),
4.42 (t, 1H, J ) 6.6 Hz), 7.32-7.46 (m, 6H), 7.61-7.68 (m, 4H).
13C NMR (CDCl3): δ 13.9, 17.9, 19.3, 20.3, 22.3, 26.0, 27.0 (3C),
33.3, 34.4, 37.6, 59.1, 78.0, 127.4 (2C), 127.5 (2C), 129.5, 129.6,
133.6, 134.6, 135.9 (4C), 214.5. Anal. Calcd for C27H38O2Si: C,
76.72; H, 9.06. Found: C, 76.42; H, 9.15. HPLC analysis: 94%
ee (Daicel Chiralpak OD-H; hexane only, 0.5 mL/min, 20 °C).
(-)-(1R,2S)-(1-Benzyloxy-2-methyl-2-pentanoylcyclopen-
NMR (CDCl3): δ 0.80-1.44 (m, 4H), 1.05 (t, 3H, J ) 7.2 Hz),
1.21 (s, 3H), 1.48-1.87 (m, 6H), 2.44-2.62 (m, 2H), 4.38 (A in
ABq, 1H, J ) 10.9 Hz), 4.50 (B in ABq, 1H, J ) 10.9 Hz), 7.42
(t, 2H, J ) 7.5 Hz), 7.56 (t, 2H, J ) 7.5 Hz), 7.94 (d, 2H, J ) 6.9
Hz). [R ]25 -9.01 (c 0.50, CHCl3). 13C NMR (CDCl3): δ 8.0,
D
15.1, 26.4, 26.7, 26.8, 27.7, 28.0, 31.4, 43.0, 54.4, 69.8, 128.5 (2C),
129.5 (2C), 129.9, 133.1, 166.3, 213.8. HRMS (FAB) calcd for
C19H27O3 [M + H]+, 303.1960; found, 303.1960. HPLC analysis
(Daicel Chiralpak AD-H; hexane/i-PrOH ) 99/1, 0.4 mL/min, 20
°C).
tane ((-)-2c). Colorless oil; [R]25 -54.1 (c 0.94, CHCl3). IR
D
(KBr): 1703 cm-1. 1H NMR (CDCl3): δ 0.89 (t, 3H, J ) 7.5 Hz),
1.20-1.34 (m, 2H), 1.23 (s, 3H), 1.48-1.75 (m, 6H), 1.92-2.04
(m, 2H), 2.39-2.57 (m, 2H), 4.14 (t, 1H, J ) 6.6 Hz), 4.42 (A in
ABq, 1H, J ) 12.0 Hz), 4.53 (B in ABq, 1H, J ) 12.0 Hz), 7.25-
7.33 (m, 5H). 13C NMR (CDCl3): δ 13.9, 17.6, 20.3, 22.4, 26.1,
30.1, 35.0, 37.5, 58.1, 71.7, 82.8, 127.4, 127.5 (2C), 128.3 (2C),
138.8, 214.7. Anal. Calcd for C18H26O2: C, 78.79; H, 9.55.
Found: C, 78.64; H, 9.68. HPLC analysis: 94% ee (Daicel
Chiralpak OD-H; hexane only, 0.5 mL/min, 20 °C).
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research (S) from Japan Society for the
Promotion of Science and by Grant-in-Aid for Scientific
Research on Priority Areas (17035047) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Full experimental details
(+)-(1RS,3RS)-1-Benzyloxy-3-butyl-3-methyl-2-oxocyclohex-
1
including the physical data and H and 13C NMR spectra of 1d,
ane ((+)-3c): Colorless oil; [R]26 +45.8 (c 1.98, CHCl3). IR
D
1e, 1f, 2d, 3a, 3b, 3d, cis-4d, 6a, 8b, 9a, 10, (-)-trans-4a, (+)-
trans-4b, (+)-6b, (-)-trans-4c, (-)-11, (-)-12, (+)-14, (+)-1b,
(+)-15, (-)-16, (-)-1c, (-)-2c, (+)-3c, (-)-3b, and (-)-3h. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(KBr): 1717 cm-1. 1H NMR (CDCl3): δ 0.86 (t, 3H, J ) 7.5 Hz),
1.05 (s, 3H), 1.19-1.90 (m, 11H), 2.23-2.30 (m, 1H), 4.12 (dd,
1H, J ) 6.9, 11.3 Hz), 4.45 (d, 1H, J ) 12.3 Hz), 4.80 (d, 1H, J
) 12.3 Hz), 7.26-7.40 (m, 5H). 13C NMR (CDCl3): δ 13.9, 19.5,
22.1, 23.2, 26.1, 34.9, 37.2, 40.4, 49.6, 71.7, 78.9, 127.7, 127.9
(2C), 128.4 (2C), 138.1, 213.3. Anal. Calcd for C18H26O2: C, 78.79;
JO0604080
J. Org. Chem, Vol. 71, No. 14, 2006 5197