SnCl4-promoted rearrangement of 2,3-epoxy alcohol derivatives: Stereochemical control of the reaction

Article abstract of DOI:10.1016/j.tetlet.2004.11.018

The SnCl₄-promoted rearrangement of 2,2,3,3-tetrasubstituted-2, 3-epoxy-1-alcohol derivatives proceeded in a regio- and stereo-controlled manner to selectively give two types of rearranged products from a single isomer by changing the protectin

Full text of DOI:10.1016/j.tetlet.2004.11.018

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 89–91
SnCl4-promoted rearrangement of 2,3-epoxy alcohol derivatives:
stereochemical control of the reaction
Yasuyuki Kita,* Satoshi Matsuda, Ryoko Inoguchi, Jnaneshwara K. Ganesh and
Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 4 October 2004; revised 29 October 2004; accepted 4 November 2004
Abstract—The SnCl4-promoted rearrangement of 2,2,3,3-tetrasubstituted-2,3-epoxy-1-alcohol derivatives proceeded in a regio- and
stereo-controlled manner to selectively give two types of rearranged products from a single isomer by changing the protecting group
of the alcohol.
Ó 2004 Elsevier Ltd. All rights reserved.
The rearrangements of epoxides with a Lewis acid (LA)
are powerful transformations of carbon skeletons, and
have been broadly studied.1 The structures of the rear-
ranged products depend on the course of the rearrange-
ment, in other words, the stereochemistry of the
reactions. The control of the stereochemistry is then very
important. The oxygen atom of the oxiran ring has two
lone pairs, lone pair a and lone pair b. When the reac-
tion proceeds in a stereoselective manner, the different
attacking course of LA to the lone pair gives the differ-
ent products, product A from the lone pair a attack and
product B from the lone pair b attack (Scheme 1). We
present here such examples, that is, remarkable control
of the stereochemistry of the rearrangement, for the
reactions of the SnCl4–mediated rearrangement of
2,2,3,3-tetrasubstituted-2,3-epoxy-1-alcohols by only
changing the protecting group of the alcohol.
The rearrangement of 2,3-epoxy-1-alcohols and their
derivatives is one of the most valuable tools for con-
structing a- or b-hydroxy ketones, via the C3- or the
C2-cleavage of the oxiran rings. Most of them are 2,3-
disubstituted and 2,2,3- or 2,3,3-trisubstituted epoxides,
and the reactions occur via more stable carbocation
intermediates.2 In other words, the reaction occurs
through the carbocations on the more substituted car-
bons, 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 rearrange-
ments of 2,2,3,3-tetrasubstituted epoxy alcohol deriva-
tives are comparatively few.3 Recently, we studied the
rearrangement of 2,2,3,3-tetrasubstituted-2,3-epoxy-1-
acylates and 2,2,3,3-tetrasubstituted-2,3-epoxy-1-sulfo-
nates, and succeeded in controlling the regiochemistry
of the rearrangements.4 As an extension of the study,
O
LA attack on lone pair a and
R4
R3
concerted rearrangement
b
a
(R1 migration)
R2
R1
O
A
2
+
LA
R1
R2
1
O
R4
R3
R4
R3
R1
LA attack on lone pair b and
concerted rearrangement
(R2 migration)
The reaction via
C1—O cleavage
R2
B
Scheme 1.
Keywords: SnCl4-promoted rearrangement; Tetrasubstituted-2,3-epoxy alcohol; Stereocontrol; a-Alkoxy ketone; b-Hydroxy ketone.
*
Corresponding author. Tel.: +81 668798225; fax: +81 668798229; e-mail: kita@phs.osaka-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.018

90
Y. Kita et al. / Tetrahedron Letters 46 (2005) 89–91
we next aimed to control the stereochemistry of the rear-
rangement. To examine the concept in Scheme 1, we
chose six-membered and acyclic 2,2,3,3-tetrasubsti-
tuted-2,3-epoxy-1-alcohols and their derivatives for the
following reasons: (1) tetrasubstituted epoxides can
avoid the difference in the stability of the carbocations
on the C2- and C3-carbons, (2) conformationally more
flexible substrates, that is, the six-membered rings for
cyclic system and acyclic system, have little affect on
the two rearrangement courses, and (3) the oxygen atom
of the alcohol function can proceed via the chelation
transition state by the bidentate LA. We chose BF3Æ
Et2O, as the representative monodentate LA, and SnCl4,
as the representative bidentate LA.
unit makes the C2-carbocation unstable. When an acyl
function (PNB: p-nitrobenzoyl) was used as a protecting
group of the alcohol, the difference in the ratio of the
two products depending on the kind of LA (SnCl4 and
BF3ÆEt2O) was not observed (entries 1 and 8). However,
SnCl4 tended to afford the products in two ways. In the
reactions of epoxy alcohols and alkyl ether derivatives,
the six-membered a-hydroxy ketones 3 were obtained
as major products (entries 2–4). On the other hand,
the compounds with the trialkylsilyl group gave the
ring-contracted five-membered products 2 in good yields
(entries 5–7). These phenomena might be rationalized by
a chelation and nonchelation transition state as will be
discussed later (Scheme 2). However, for the reactions
using BF3ÆEt2O, a monodentate LA, every epoxy alco-
hol derivative gave the ring-contracted five-membered
product 2 without depending on the protecting group
(entries 8–11).
In the first place, we studied the reaction of the cyclic
six-membered compounds 1 (Table 1). Every reaction
proceeded via the C3-carbocation intermediate. Since
we already concluded the reason for the reactions of
epoxy acylates via the C3-carbocation intermediates
due to destabilization of the C2-carbocation by the elec-
tron-withdrawing nature of the acyloxy group,4 the re-
sult can be rationalized by the fact that the electron-
withdrawing nature of the LA-coordinated alcohol
For the bidentate LA, SnCl4 also showed a similar reac-
tivity in acyclic systems (Table 2). Treatment of the
epoxy alcohols (cis- and trans-4a) with SnCl4 generated
the bidentate chelation transition state between Sn metal
and two oxygen atoms (hydroxy and epoxide oxygens),
which selectively led to the formation of the a-hydroxy
ketone 6a. Similarly, the epoxy benzyl ethers, cis-4b,c,
and trans-4b,c selectively afforded the a-benzyloxy ke-
tones 6b,c by the migration of the alkyl groups via the
C3-carbocation intermediate (entries 2 and 3 for cis-iso-
mer and entries 7 and 8 for trans-one).5 On the other
hand, the epoxy tert-butyldimethylsilyl (TBS) ethers,
cis-4d,e, and trans-4d,e, gave the b-hydroxy ketones,
cis-5d,e by the migration of silyloxymethyl groups via
the C3-carbocation (entries 4 and 5 for cis-isomer and
entries 9 and 10 for trans-one).
Table 1.
OR'
OR'
OR'
O
LA (1.1 eq.)
O
Bu
O
and / or
Bu
2
3
Bu
CH2Cl2
0 °C
1
2
3
Entry
1
R0
LA
Yield (%)
2
3
The above results are rationalized as follows: the alkyl
ether compounds can form the bidentate chelation tran-
sition state between two oxygen atoms and Sn metal.
This decreases the migratory aptitude of the alkyloxy
methyl group, and then the alkyl group opposite to
the benzyloxy methyl group selectively migrates to pro-
duce the a-alkoxy ketones. On the other hand, the bulky
trialkylsilyl group inhibits the formation of the chelation
intermediate and makes the LA attack opposite-side
lone pair of the oxygen atom. A stereoselective rear-
rangement of the trialkylsilyloxy group in the anti-peri-
planer position then occurs. For the trialkylsilyloxy
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
PNB
H
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
26
––
8
46
98
59
44
––
––
––
Me
Bn
20
94a
71a
39a
t-BuMe2Si
Et3Si
Me3Si
1g
8
1a
1b
1d
1e
PNB
BF3ÆEt2O
BF3ÆEt2O
BF3ÆEt2O
BF3ÆEt2O
24
47
81
34a
34
––
––
––
9
H
Bn
10
11
t-BuMe2Si
a Hydroxy compound (R0 = H) was obtained.
Cl3Sn
OR' R4
O
R4
R3
R2
R'=Me, Bn, H
R'
R3
R2
O
R1
R1
R2
O
O
R3
Chelation
OR'
α-Alkoxy (or α-Hydroxy)
R4
R1
ketone
SnCl4
O
R3
SnCl4
O
R2
R4
R1
C3-Cleavage
R3
R2
OSiR''3
O-Si
R4
OH
R1
R'=SiR''3
cleavage
β-Hydroxy ketone
non-Chelation
Scheme 2.

Y. Kita et al. / Tetrahedron Letters 46 (2005) 89–91
91
Table 2.
Table 3.
O
O
O
O
R
Et
Et
R
OR'
OR'
OR'
cis-4a—e
SnCl4
(1.1 eq.)
OR'
OR'
SnCl4
(1.1 eq.)
5a—e
8
cis-7
O
and/or
O
CH2Cl2
—78 °C ~ r.t.
CH2Cl2
0 °C
O
O
OR'
OR'
OR'
and/or
R
R
Et
trans-7
Et
trans-4a—e
6a—e
9
Entry
4
R
R0
Yield (%)
Entry
Substrate
Yield (%)
5
6
8
9
1
2
3
4
5
cis-4a
cis-4b
cis-4c
cis-4d
cis-4e
Et
R0 = H
––
––
––
76
91
94
––
––
1
2
3
4
cis-7a (R0 = Bn)
13
68
80
––
––
Me
Et
R0 = Bn
R0 = Bn
R0 = TBS
R0 = TBS
trans-7a (R0 = Bn)
cis-7b (R0 = TBS)
trans-7b (R0 = TBS)
11
78a
89a
Me
Et
90a
65a
a Hydroxy ketone (8: R0 = H) was obtained.
6
trans-4a
trans-4b
trans-4c
trans-4d
trans-4e
Et
R0 = H
27
11
56
76
55
––
––
7
Me
Et
R0 = Bn
R0 = Bn
R0 = TBS
R0 = TBS
8
––
Lewis acid, SnCl4, which can be a very useful tool in
the organic synthetic field.
9
10
Me
Et
100a
47a
a Hydroxy ketone (5: R0 = H) was obtained.
References and notes
compounds, every reaction afforded the b-hydroxy
ketone possibly obtained by desilylation after the
rearrangement because the products are completely dif-
ferent from those derived from epoxy alcohols without
protecting group.
1. For reviews on the Lewis acid-mediated rearrangement of
epoxides, see: (a) Parker, R. E.; Isaacs, N. S. Chem. Rev.
1959, 59, 737; (b) Rickborn, B. In Comprehensive Organic
Synthesis, Carbon–Carbon-Bond Formation; Pattenden, G.,
Ed.; Pergamon: Oxford, 1991; Vol. 3, Chapter 3.3, p 733.
2. For examples, see: (a) Suda, K.; Kikkawa, T.; Nakajima,
S.; Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554; (b)
Jeon, S.; Walsh, P. J. Am. Chem. Soc. 2003, 125, 9544; (c)
Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.
J. Org. Chem. 1993, 58, 5944; (d) Marson, C. M.; Harper,
S.; Oare, A. J. Org. Chem. 1998, 63, 3798; (e) Marson, C.
M.; Khan, A.; Porter, R. A.; Cobb, A. J. A. Tetrahedron
Lett. 2002, 43, 6637; (f) Marson, C. M.; Oare, C. A.;
McGregor, J.; Walsgrove, T.; Grinter, T. J.; Adams, H.
Tetrahedron Lett. 2003, 44, 141; (g) Maruoka, K.; Murase,
N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron 1994,
50, 3663; (h) Jung, M. E.; Lee, W. S.; Sun, D. Org. Lett.
1999, 1, 307; (i) Jung, M. E.; Heuvel, A. V. D. Tetrahedron
Lett. 2002, 43, 8169; (j) Jung, M. E.; Hoffmann, B.; Rausch,
B.; Contreras, J. M. Org. Lett. 2003, 5, 3159; (k) Zhu, Y.;
Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818; (l)
Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212; (m)
Bhatia, K. A.; Eash, K. J.; Leonard, N. M.; Oswald, M. C.;
Mohan, R. S. Tetrahedron Lett. 2001, 42, 8129.
The above phenomenon was also observed in the reac-
tions of the compounds with the C3–phenyl group 7.
The rearrangement reactions of 7 must proceed via the
more stable C3-carbocation than those of compounds
1 and 4. In these cases, the control of the stereochemis-
try was also achieved to give the b-hydroxy ketones 8
and the a-benzyloxy ketones 9 depending on the protect-
ing group. These results are also rationalized as shown
in Scheme 2. This result shows that the concept in
Scheme 1 has a generality for conformationally flexible
compounds (Tables 2 and 3).
In conclusion, we have found that the Lewis acid pro-
moted rearrangement reaction of the 2,2,3,3-tetrasubsti-
tuted-2,3-epoxy-1-alcohol derivatives, which are
supposed to have only a slight difference in the stability
between the C2- and C3-carbocation, proceed via the
C3-carbocation, and furthermore, the reactions using
SnCl4 as a Lewis acid can proceed in a stereoselective
manner by controlling the chelation and nonchelation
transition state only by changing the protecting group.
This method could produce two types of rearranged
products from the single carbon skeleton. Studies on
the stereocontrol of the rearrangement reactions of
epoxy alcohol derivatives are rare. Only two papers, to
the best of our knowledge, have reported this matter
using trisubstituted epoxides and rather special Lewis
acids such as high-valent metalloporphyrin complex,2a
MABR and SbF5.2g Our method here uses a common
3. There is only one example for practical level except our
´
work (Ref. 4), see: Abad, A.; Agullo, C.; Arno, M.; Cun˜at,
A. C.; Zaragoza, R. J. Synlett 1993, 895.
´
´
4. For recent examples, see: (a) Kita, Y.; Furukawa, A.;
Futamura, J.; Ueda, K.; Sawama, Y.; Hamamoto, H.;
Fujioka, H. J. Org. Chem. 2001, 66, 8779; (b) Kita, Y.;
Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.;
Fujioka, H. J. Org. Chem. 2003, 68, 5917; (c) Fujioka, H.;
Yoshida, Y.; Kita, Y. J. Synth. Org. Chem. Jpn. 2003, 61,
133; (d) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.;
Ganesh, J. K.; Fujioka, H. Tetrahedron Lett. 2003, 44,
411.
5. Benzyl ether was chosen because of its easier deprotection
than that of methyl ether.