TIPSOTf-promoted tandem reaction through rearrangement of epoxides into aldehydes with selective alkyl migration followed by prins-type cyclization to cyclopentanes

Article abstract of DOI:10.1055/s-0031-1290324

The tandem reaction of trisubstituted epoxides to cyclopentanes promoted by TIPSOTf in nitromethane has been found. It consists of stereospecific rearrangement of epoxides into aldehydes accompanied with selective alkyl migration and subsequent Prins-type cyclization of the aldehydes generated to cyclopentanes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290324

458
LETTER
TIPSOTf-Promoted Tandem Reaction through Rearrangement of Epoxides
into Aldehydes with Selective Alkyl Migration Followed by Prins-Type
Cyclization to Cyclopentanes
T
IPSO
T
f-Prom
a
otedTande
k
m
R
eactiono
e
f
E
poxides
s
toCyclop
h
entanes i Kodama, Shingo Harada, Takeshi Tanaka, Yoshimitsu Tachi, Yoshiki Morimoto*
Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan
Fax +81(6)66052522; E-mail: morimoto@sci.osaka-cu.ac.jp
Received 14 November 2011
that in nonpolar dichloromethane the cleavage of C6–O
Abstract: The tandem reaction of trisubstituted epoxides to cyclo-
pentanes promoted by TIPSOTf in nitromethane has been found. It
consists of stereospecific rearrangement of epoxides into aldehydes
accompanied with selective alkyl migration and subsequent Prins-
type cyclization of the aldehydes generated to cyclopentanes.
bond would be slower than that in polar nitromethane;
therefore, during the cleavage of C6–O bond the hydroxy
group suffered from silylation to produce epoxy silyl ether
11. Since the oxygen of the silylated ether loses nucleo-
philicity, the epoxide would open into the allylic silyl
ethers 10a (like in E2 elimination). To demonstrate this
we prepared the epoxy silyl ether 7b (R1 = TMS) which
was subjected to the same condition as that of entry 2 in
Table 1 to give 10a (R2 = TMS) in a similar ratio and yield
according to our expectation (entry 4, Table 1).
Key words: cyclization, epoxides, rearrangement, steric hindrance,
tandem reaction
Lewis acid promoted rearrangement of epoxides into car-
bonyl compounds is one of the most useful tools in organ-
ic synthesis.1 The rearrangement has widely been applied
to the synthesis of various biologically active natural and
non-natural products;2 however, it is well known that the
yield and regio- and stereoselectivity of these rearrange-
ments markedly depend on the mode of substituents on
the ring and the reaction conditions.3 The rearrangement
of trisubstituted epoxide 1 takes place with hydrogen
(path a) or alkyl (path b) migration to produce the corre-
a
R2
R3
O
H
R2
R3
O
alkyl
hydrogen
migration
R2
R3
H
O
migration
R1
R1
R1
path b
path a
H
3
b
1
2
R1
O
R2
H
O
OH
R1
R2
alkyl
migration
Prins-type
cyclization
H
R1
R2
sponding ketone
3
or aldehyde 2, respectively
(Scheme 1). Although considerable efforts have been de-
voted to the development of efficient reagents and cata-
lysts which allow access to ketone 3,4 only a few examples
are documented on alkyl migration that allows access to
aldehyde 2.5,6 On the other hand, tandem reactions are cur-
rently of great interest because they offer a convenient and
economical way to prepare desired organic molecules.7
Recently, we fortuitously encountered the tandem reac-
tion that is thought to proceed via the TIPSOTf-promoted
rearrangement of epoxide 4 into aldehyde 5 with selective
alkyl migration followed by Prins-type cyclization to five-
membered ring 6. Such tandem reaction has never been
reported to our knowledge. In this paper, we report the
course of the findings and the results examined with some
substrates.
6
5
4
H
Scheme 1 The mode of rearrangement of epoxide 1 and our tandem
reaction of epoxide 4 to five-membered ring 6
At that time we also tried treating the epoxy silyl ether 7b
(R1 = TMS) under the condition of the 6-endo cyclization,
and it was found that five-membered ring products 12a
and 12b are unexpectedly formed in a ratio of 3.2:1 (entry
5).9 The relative stereochemistry of the cyclopentanes 12a
and 12b was unambiguously determined by diagnostic
NOEs observed between the protons shown by arrows in
the NOESY spectra.
The production of cyclopentanes 12a and 12b from ep-
oxide 7b (R1 = TMS) might be rationalized as shown in
Scheme 2. First, as soon as TIPSOTf coordinates to the
epoxide oxygen, the C6–O bond begins cleaving in polar
nitromethane and the epoxide rearrangement would oc-
cur. Then the alkyl group would migrate instead of hydro-
gen so as to avoid steric repulsion with the bulky Lewis
acid.5 Further, the generated aldehyde could undergo a nu-
cleophilic attack under the condition by the intramolecu-
lar p-bond at an appropriate position to provide cyclized
products. The major product 12a might be produced by
way of the most stable transition state B without such ster-
Previously, we developed the regioselective 6-endo cy-
clization of bishomoepoxy alcohol 7a (R1 = H) to THP 8
promoted by TIPSOTf in the presence of 2,6-lutidine in
nitromethane (entry 1 in Table 1).8 This reaction is sus-
ceptible to solvents, and so treatment of 7a (R1 = H) with
R2OTf in dichloromethane afforded allylic silyl ethers
10a as the major product (entries 2 and 3). We guessed
SYNLETT 2012, 23, 458–462
x
x.
x
x.
2
0
1
2
Advanced online publication: 27.01.2012
DOI: 10.1055/s-0031-1290324; Art ID: U66511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
TIPSOTf-Promoted Tandem Reaction of Epoxides to Cyclopentanes
459
Table 1 Reactions of Epoxides 7 Promoted by R2OTf in the Pres-
ence of 2,6-Lutidine under Various Conditions
steric repulsion
OTMS
5
OTf
O
Si
OTIPS
R2OTf
2,6-lutidine
H
2
••
OR1
6
O
O
solvent
0 °C
6
7
8
O
H
9
silylation
7b (R1 = TMS)
OTIPS
R2OTf
O
steric
repulsion
OR2
epoxide-
opening
H
7
X
CH3
6
CH3
O
R2
H
H
H
OR2
O+
6'
O+
10a = Δ6,7; 10b = Δ6,6'
12a
Si
11
Si
base
H
H
H
NOE
TMSO
TIPSO
H
TMSO
TIPSO
H
B
A
steric
repulsion
H
steric
repulsion
TMSO
TMSO
CH3
12a
12b
CH3
antiperiplanar
H
H
Entry 7 (R1)
R2OTf
Solvent Product (ratio),a yieldb
MeNO2 8/9 (15:1), 83%
CH2Cl2 10a/10b (9:1), 70%
H
12b
O+
1c
2c
3c
7a (H)
7a (H)
7a (H)
R2 = TIPS
R2 = TMS
R2 = TIPS
Si
O+
Si
OTMS
OTMS
D
C
CH2Cl2 10a, 38%;
8/9 (2.7:1), 34%
Scheme 2 Possible transition states B and C leading to 12a and
12b, respectively
4
5
7b (TMS)d R2 = TMS
7b (TMS)d R2 = TIPS
CH2Cl2 10a/10b (10:1), 65%
MeNO2 12a/12b (3.2:1), 64%
Next, we examined the chirality transfer ability of the ep-
oxide rearrangement using an optically active substrate.
The known optically active epoxide 15 (84% ee)5 was
subjected to the tandem reaction to afford diastereomeric
cyclopentanes 16a {[a]D21 –6.35 (c = 0.97, CHCl3)}, and
16b {[a]D29 –4.09 (c = 0.33, CHCl3)}11 with virtually the
same optical purity12 as that of the starting material in a ra-
tio of 5.3:1 (Scheme 3). The relative configuration of 16a
and 16b was elucidated on the basis of such NOE experi-
ments as shown in 12. The absolute configuration of 16a
and 16b was determined by comparing their optical rota-
tions with those of cyclopentanes 16a and 16b obtained in
a similar ratio of 5.6:1 from the known S-aldehyde 17 re-
ported by Yamamoto and co-workers.5a,b Thus, it has been
found that in the tandem reaction the first epoxide rear-
a The ratio was determined by integration of the 1H NMR spectra of
the mixture.
b Isolated yield.
c These data are cited from ref. 8.
d Epoxide 7b (R1 = TMS) was prepared by silylation of 7a (R1 = H)
(TMSCl, Et3N, CH2Cl2, 0 °C to r.t., 16 h, 83%).
ic repulsion as exists in other transition states A, C, and D.
The minor product 12b might be formed through only one
acyclic extended transition state C having antiperiplanar
p-bonds.10
To evidence the intermediacy of aldehyde in the tandem
reaction, we tried to trap the rearrangement product alde-
hyde such as 5. When saturated epoxide 13, which was
prepared by hydrogenation of 7b (R1 = TMS; H2, Pd/C,
THF, r.t., 2.5 h, 76%), was treated under the condition of
the tandem reaction, alkyl-migrated aldehyde 14 could be
isolated (Equation 1).
TIPSOTf
2,6-lutidine
TIPSO
TBSO
TIPSO
TBSO
TBSO
MeNO2
0 °C, 1 h
S
S
O
OTMS
16a
16b
(9.5%, 84% ee)
15 (84% ee)
(50.5%, 84% ee)
TIPSOTf
2,6-lutidine
OHC
16a (68%)
O
MeNO2, 0 °C
15 min, 65%
refs.
5a,b
TIPSOTf
[α]D29 –6.34 (c = 1.00, CHCl3)
2,6-lutidine
15
OTMS
OHC
17
S
MeNO2
0 °C, 15 min
16b (12%)
13
14
[α]D29 –3.23 (c = 0.21, CHCl3)
Equation 1
OTBS
Scheme 3 The tandem reaction of optically active epoxide 15 to
five-membered rings 16a and 16b with integrity of the optical purity
© Thieme Stuttgart · New York
Synlett 2012, 23, 458–462

460
T. Kodama et al.
LETTER
Table 2 The TIPSOTf-Promoted Tandem Reaction of Some Ep-
rangement takes place accompanying inversion of config-
uration at the quaternary carbon of the epoxide without
any loss of optical purity, and the second cyclization
should indeed proceed from an aldehyde intermediate to
form cyclopentanes.
oxidesa (continued)
Entry Epoxide
Time, Productb (ratio),c yieldd
The TIPSOTf-promoted tandem reaction was further ex-
amined for some epoxides (Table 2). Epoxides 18 and
19,5b,c,12 diastereomeric to 7b (R1 = TMS) and 15, similar-
ly underwent the tandem reaction providing 12a, 12b and
ent-16a, ent-16b in moderate yields, respectively (entries
1 and 2). This indicates that in the first epoxide rearrange-
ment alkyl groups selectively migrate irrespective of the
relative stereochemistry of the epoxide.5
0 °C, 1 h, then reflux, 20 h,
recovered 28, 82%
7
O
28
CHO
8
Table 2 The TIPSOTf-Promoted Tandem Reaction of Some Ep-
O
oxidesa
Time, Productb (ratio),c yieldd
29
30
Entry Epoxide
30 min, 78%
OMe
MeO
OMe
OTIPS
TMSO
1
1 h, 12a/12b (3.6:1), 54%
O
9
MeO
18
O
32
15 min, 36%
TBSO
TIPSO
TBSO
TIPSO
TBSO
31
2
a The reaction was performed at 0 °C for the indicated time under a
nitrogen atmosphere by treating the starting epoxide in the presence
of 2,6-lutidine in MeNO2 with TIPSOTf, unless otherwise noted.
b The stereochemistry of the product was determined by NOE exper-
iments.
O
ent-16a
ent-16b
15 min, ent-16a (74% ee),
41.7%; ent-16b, 8.3%
19 (74% ee)
c The ratio was determined by integration of the 1H NMR spectra of
the mixture except for entry 2.
TIPSO
TIPSO
d Isolated yield.
3
4
5
O
21a
21b
Vinyl-substituted epoxide 20 afforded products 21a and
21b in a relatively good yield, probably due to higher mi-
grating ability of a vinyl group compared to other alkyl
groups (entry 3).4j,13 To our surprise, epoxide 22, diastereo-
meric to 20, did not give predictable cyclopentanes such
as 21 but a different type of cyclopentanes 23a and 23b
that were directly cyclized at the allylic carbon of the ep-
oxide (entry 4). In the case of epoxide 22 with hydrogen
syn to the attacking p-bond, the direct cyclization might
occur because the p-bond can more easily approach the re-
active allylic carbon than in the case of epoxide 20 with
the syn vinyl group as shown in Scheme 4.
20
30 min, 21a/21b (2.8:1), 80%
TIPSO
23a
TIPSO
23b
O
22
1 h, 23a/23b (1.3:1), 78%
TIPSO
TIPSO
O
25a
25b
steric
repulsion
24
1 h, 25a/25b (1.5:1), 55%
H
O
H
O
TIPSO
TIPSO
H
H
O
O
6
20a
20b
22a
22b
O
27a
27b
Scheme 4 Conformation of vinyl epoxides 20 and 22
15 h, 27a/27b (1.3:1), 53%;
recovered 26, 22%
26
Synlett 2012, 23, 458–462
© Thieme Stuttgart · New York

LETTER
TIPSOTf-Promoted Tandem Reaction of Epoxides to Cyclopentanes
461
Nakajima, S.; Takanami, T. Chem. Commun. 2002, 2570.
(j) Deng, X.-M.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2005,
70, 6537.
Although tandem reaction products 25a, 25b and 27a, 27b
were also obtained from epoxides 24 and 26, respectively,
in the reaction of 26 the starting material was recovered in
22% yield after 15 hours (entries 5 and 6). Furthermore,
epoxide 28 was recovered in 82% yield, even after the re-
action was carried out at 0 °C for one hour and then under
reflux for 20 hours (entry 7). These results indicate that
the first epoxide rearrangement promoted by bulky
TIPSOTf is subtly influenced by steric circumstances
around the epoxide function. Next, aromatic rings were
investigated in place of double bonds as the intramolecu-
lar nucleophile. Although epoxide 29 was only rearranged
into aldehyde 30 (entry 8), epoxide 31 bearing a more nu-
cleophilic dimethoxyphenyl group provided a tandem re-
action product 32, demonstrating that the second
cyclization can form not only five-membered rings but
also a six-membered ring (entry 9).
(5) (a) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc.
1989, 111, 6431. (b) Maruoka, K.; Ooi, T.; Nagahara, S.;
Yamamoto, H. Tetrahedron 1991, 47, 6983. (c) Suda, K.;
Kikkawa, T.; Nakajima, S.; Takanami, T. J. Am. Chem. Soc.
2004, 126, 9554. (d) Suda, K.; Nakajima, S.; Satoh, Y.;
Takanami, T. Chem. Commun. 2009, 1255.
(6) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117,
7379.
(7) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem. Int. Ed. 2006, 45, 7134. (b) Tietze, L. F.; Brasche,
G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006, 672. (c) Ho, T.-L. Tandem
Organic Reactions; Wiley: New York, 1992, 502.
(8) Morimoto, Y.; Nishikawa, Y.; Ueba, C.; Tanaka, T. Angew.
Chem. Int. Ed. 2006, 45, 810.
(9) Typical Procedure for the Tandem Reaction: To a
solution of epoxide 7b (R1 = TMS, 30.0 mg, 0.100 mmol),
prepared from 7a (R1 = H, ref. 8) according to footnote d in
Table 1, in nitromethane (1.0 mL) were successively added
dropwise 2,6-lutidine (92 mL, 0.703 mmol) and triisopropyl-
silyl triflate (0.135 mL, 0.502 mmol) under a nitrogen
atmosphere at 0 °C, and the mixture was stirred at the same
temperature for 45 min. H2O was added to the solution, and
the aqueous layer was extracted with hexane. The organic
layer was washed with brine, dried over anhyd Na2SO4, and
concentrated under reduced pressure. The residue was
purified by flash column chromatography (hexane–benzene,
98:2) on silica gel to afford a mixture of cyclopentanes 12a
and 12b (29.4 mg, 64% yield) in a ratio of 3.2:1 as a colorless
oil; Rf 0.58 (hexane–benzene, 95:5). 1H NMR (400 MHz,
CDCl3): d = 4.77 (s, 1 H), 4.71 (s, 1 H), 3.88 (d, J = 6.6 Hz,
0.24 H), 3.82 (d, J = 7.3 Hz, 0.76 H), 2.53–2.64 (m, 1 H),
1.14–1.93 (m, 8 H), 1.72 (s, 3 H), 1.22 (s, 1.44 H), 1.20 (s,
4.56 H), 0.97–1.12 (m, 21 H), 0.94 (s, 0.72 H), 0.90 (s, 2.28
H), 0.10 (s, 9 H). 13C NMR (75 MHz, CDCl3): d = 147.3,
147.2, 111.1, 110.7, 84.1, 77.2, 74.0, 54.8, 53.7, 45.6, 45.4,
39.9, 39.4, 35.3, 34.8, 34.2, 29.8, 26.7, 24.1, 20.0, 19.7, 18.6,
18.5, 18.4, 13.4, 13.3, 2.7, 2.6. IR (neat): 3076, 1641, 1462,
1378, 1107, 882 cm–1. HRMS (FAB): m/z [M – H+] calcd for
C26H53O2Si2: 453.3584; found: 453.3591.
In conclusion, we have demonstrated that the TIPSOTf-
promoted tandem reaction via stereospecific rearrange-
ment of trisubstituted epoxides into aldehydes followed
by the electrophilic cyclization of the aldehydes generated
five- and six-membered ring compounds. Further scope
and limitations of the tandem reaction and its application
to biologically important natural products are under inves-
tigation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was financially supported by the Asahi Glass Foundation
and Grants-in-Aid for Scientific Research on Basic Research (B)
and (C) from the Japan Society for the Promotion of Science.
References and Notes
(10) (a) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc.
1980, 102, 3248. (b) Noyori, R.; Murata, S.; Suzuki, M.
Tetrahedron 1981, 37, 3899.
(1) For reviews, see: (a) Parker, R. E.; Issacs, N. S. Chem. Rev.
1959, 59, 737. (b) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G.
Tetrahedron 1983, 39, 2323. (c) Smith, J. G. Synthesis
1984, 629.
(11) Compound 16a: Rf = 0.62 (hexane). 1H NMR (400 MHz,
CDCl3): d = 4.77–4.81 (m, 1 H), 4.68–4.72 (m, 1 H), 4.24 (d,
J = 7.3 Hz, 1 H), 3.44 (d, J = 9.5 Hz, 1 H), 3.30 (d, J = 9.8
Hz, 1 H), 2.59 (dt, J = 9.9, 7.1 Hz, 1 H), 1.82–1.93 (m, 1 H),
1.74 (dt, J = 12.2, 8.4 Hz, 1 H), 1.72 (s, 3 H), 1.32–1.42 (m,
1 H), 1.27 (ddd, J = 12.4, 7.9, 4.6 Hz, 1 H), 1.00–1.09 (m, 21
H), 0.90 (s, 9 H), 0.88 (s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 147.3, 111.0, 77.3, 67.6,
54.2, 48.0, 32.6, 26.8, 25.9, 19.6, 18.4, 18.3, 17.9, 13.3, –5.5,
–5.6. IR (neat): 3079, 1644, 1463, 1254, 1087, 835 cm–1.
HRMS (FAB): m/z [M+] calcd for C25H52O2Si2: 440.3506;
found: 440.3515.
(2) For a review, see: Silva, L. F. Jr. Tetrahedron 2002, 58,
9137.
(3) For a review, see: Rickborn, B. Acid-Catalyzed
Rearrangements of Epoxides, In Comprehensive Organic
Synthesis, Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, Chap. 3.3, 733.
(4) (a) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.;
Yamamoto, H. Tetrahedron 1994, 50, 3663.
(b) Kulasegaram, S.; Kulawiec, R. J. J. Org. Chem. 1994, 59,
7195. (c) Takanami, T.; Hirabe, R.; Ueno, M.; Hino, F.;
Suda, K. Chem. Lett. 1996, 25, 1031. (d) Sudha, R.;
Narashimhan, K. M.; Saraswathy, V. G.; Sankararaman, S.
J. Org. Chem. 1996, 61, 1877. (e) Ranu, B. C.; Jana, U.
J. Org. Chem. 1998, 63, 8212. (f) Suda, K.; Baba, K.;
Nakajima, S.; Takanami, T. Tetrahedron Lett. 1999, 40,
7243. (g) Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne,
B. J.; Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527.
(h) Martínez, F.; Campo, C.; Llama, E. F. J. Chem. Soc.,
Perkin Trans. 1 2000, 1749. (i) Suda, K.; Baba, K.;
Compound 16b: Rf 0.51 (hexane). 1H NMR (400 MHz,
CDCl3): d = 4.74–4.78 (m, 1 H), 4.70–4.74 (m, 1 H), 3.97 (d,
J = 7.1 Hz, 1 H), 3.63 (d, J = 10.0 Hz, 1 H), 3.50 (d, J = 10.0
Hz, 1 H), 2.63 (dt, J = 9.3, 7.0 Hz, 1 H), 1.81–1.94 (m, 2 H),
1.72 (s, 3 H), 1.32–1.44 (m, 1 H), 1.18–1.31 (m, 1 H), 0.97–
1.10 (m, 21 H), 1.02 (s, 3 H), 0.90 (s, 9 H), 0.04 (s, 3 H), 0.03
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 147.2, 110.9, 83.9,
66.5, 55.3, 48.0, 33.1, 27.3, 26.0, 22.9, 19.9, 18.39, 18.37,
18.32, 13.2, –5.45, –5.49. IR (neat): 3079, 1642, 1463, 1086,
© Thieme Stuttgart · New York
Synlett 2012, 23, 458–462

462
T. Kodama et al.
LETTER
835 cm–1. HRMS (FAB): m/z [M – H+] calcd for
C25H51O2Si2: 439.3427; found: 439.3422.
spectra, respectively: Dale, J. A.; Dull, D. L.; Mosher, H. S.
J. Org. Chem. 1969, 34, 2543. (b) The optical purities of
16a, 16b, and ent-16a were determined to be 84% ee, 84%
ee, and 74%ee, respectively, by derivatization of desilylated
diols in 16a, 16b, and ent-16a to their di(R)-MTPA esters
and integration of the 1H NMR (16a and 16b) and 19F NMR
(ent-16a) spectra.
(12) (a) The optical purities of 15 and 19 were determined to be
84% ee and 74% ee by derivatization of epoxy alcohols,
which were prepared from geraniol and nerol by Sharpless
asymmetric epoxidation using diethyl L-(+)-tartrate (ref. 5),
to their (R)-a-methoxy-a-trifluoromethylphenylacetyl
(MTPA) esters and integration of the 1H NMR and 19F NMR
(13) Jung, M. E.; Anderson, K. L. Tetrahedron Lett. 1997, 38,
2605.
Synlett 2012, 23, 458–462
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