Asymmetrie desymmetrization of 4,5-epoxycyclohex-1-ene by enantioselective allylic oxidation

Article abstract of DOI:10.1021/ol901284v

Asymmetrie desymmetrization of allylic oxidation of 4,5-epoxycyclohex-1-ene (1) took place in the presence of 2.5 mol % of Cu(CH₃CN) ₄PF₆ and 3 mol % of chiral N,N-bidentate ligand (S)-2 to afford (3S,4S,5S)-3-benzoyloxy-4

Full text of DOI:10.1021/ol901284v

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3314-3317
Asymmetric Desymmetrization of
4,5-Epoxycyclohex-1-ene by
Enantioselective Allylic Oxidation
Qitao Tan†,‡ and Masahiko Hayashi*,‡
Department of Frontier Research and Technology, Headquarters for InnoVatiVe
Cooperation and DeVelopment, Kobe UniVersity, Nada, Kobe 657-8501, Japan, and
Department of Chemistry, Graduate School of Science, Kobe UniVersity,
Nada, Kobe 657-501, Japan
mhayashi@kobe-u.ac.jp
Received May 23, 2009
ABSTRACT
Asymmetric desymmetrization of allylic oxidation of 4,5-epoxycyclohex-1-ene (1) took place in the presence of 2.5 mol % of Cu(CH3CN)4PF6
and 3 mol % of chiral N,N-bidentate ligand (S)-2 to afford (3S,4S,5S)-3-benzoyloxy-4,5-epoxycyclohex-1-ene (3) in 84% ee, which was increased
up to >99% ee after recrystallization of 3-4′-nitrobenzoyloxy derivative 6. Optically pure 6 proved to be a key intermediate for enantioselective
synthesis of O-protected 2-deoxystreptamine (2-DOS) precursor 12.
There have been many reports on asymmetric allylic oxida-
tion of olefins with tert-butyl perbenzoate.1,2 However, these
reactions still have problems to be overcome such as sub-
strate limitations and poor reactivity.3 In practice, only some
simple cycloalkenes were suitable substrates for this oxidative
reaction. Olefins with other functional groups have only
rarely been explored as substrates presumably due to their
poor tolerance to the oxidative conditions.4 Recently, we
developed a chiral N,N-bidentate imine (Schiff base)-copper
catalyst for asymmetric allylic oxidation of simple cyclic
olefins which exhibited high reactivity as well as good
enantioselectivity.5 In this paper, we will disclose the first
example of allylic oxidation of a meso cyclic epoxyolefin,
which will lead to products with high potential toward further
transformations, especially considering the existence of the
double bond and epoxy group.
We first examined the effect of copper precursors com-
bined with chiral imine (Schiff base) 2 on reactivity and
enantioselectivity (Table 1).
With use of Cu(OTf)2, tert-butyl perbenzoate disappeared
in 5 h, but only trace amounts of products were detected
(entry 1). The Cu(OTf)2-PhNHNH2 system, which is an
effective copper source for simple cyclic olefins, gave
complicated products, although the perester disappeared in
3 h. The use of CuOTf·0.5C6H6 afforded a mixture of 3 and
4 in 40% yield after 15 h. The use of Cu(CH3CN)4PF6 was
found to be the best choice as the copper source and gave
higher yields and ee values. When 4,5-epoxycyclohex-1-ene
* To whom correspondence should be addressed.
† Department of Frontier Research and Technology, Headquarters for
Innovative Cooperation and Development, Kobe University.
‡ Department of Chemistry, Graduate School of Science, Kobe Univer-
sity.
(1) For reviews, see: (a) Eames, J.; Watkinson, M. Angew. Chem., Int.
Ed. 2001, 40, 3567–3571. (b) Andrus, M. B.; Lahley, J. C. Tetrahedron
2002, 58, 845–866
.
10.1021/ol901284v CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

Scheme 1
Table 1. Enantioselective Allylic Oxidation of 4,5-
Epoxycyclohex-1-ene (1)
with the solvent, affording 5 in 25% yield7,8 (Scheme 1).
When tert-butyl p-nitroperbenzoate2g was used instead of
tert-butyl perbenzoate, the desired trans isomer 3 was
obtained resulting in 82% ee and >99% ee after recrystal-
lization in only 15% yield. Furthermore, tert-butyl p-
nitroperbenzoate is not commercially abvailable, so we had
to prepare it according to the reported method.2g Therefore,
we selected the route as shown Scheme 2. It should be
ee of ee of
entry
Cu precursor
Cu(OTf)2
Cu(OTf)2-PhNHNH2
CuOTf·0.5C6H6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
time/h yield/%a 3/4
3b
4c
1
5
3
15
16
72
40
trace
trace
40
2
3
1/1 82
1/1 85
1/1 90
79
89
92
4
75
5d
6
46
32
>99/1 85
a Isolated yield of 3 and 4. b Determined by 1H NMR and HPLC.
c Determined by HPLC (Chiralpak AS). d The reaction was carried out at
0 °C.
Scheme 2
was treated with tert-butyl perbenzoate in the presence of 5
mol % of Cu(CH3CN)4PF6 and 6 mol % of chiral imine
(Schiff base) ligand 2 at 25 °C in acetone, trans-3-
benzoyloxy-4,5-epoxycyclohex-1-ene (3) and its cis isomer
4 were obtained nonselectively (75% yield), though the ee
values of both isomers were relatively high, i.e., 85% ee for
3 and 89% ee for 4. When the reaction was carried out at
0 °C, trans-3 and cis-4 were obtained in up to 90% ee and
92% ee, respectively. It should be mentioned that the reports
of asymmetric allylic oxidation of functionalized cyclic
olefins are only a few.6 It is interesting that a prolonged
reaction time (40 h) increased the trans/cis isomer ratio up
to >99/1, though the yield was lower. We confirmed that
the prolonged reaction time caused the cis isomer to react
mentioned that 1,3-dioxolane 5 was not observed when the
perester existed. It seemed that the valence state of copper
in the presence of the perester, proposed as Cu(III), did not
catalyze the transformation of 4 to 5. As for the structure of
4, we determined it as the cis isomer of 3. Judging from the
COSY spectrum of the 1,3-dioxolane 5 from the cis isomer
4, lack of correlation of the double bond protons and the
neighboring protons of the 1,3-dioxolane should exclude the
possibility of the regioisomeric compound (see the Support-
ing Information, p 8).
(2) For examples, see: (a) Gokhale, A. S.; Minidis, A. B. M.; Pfaltz, A.
Tetrahedron Lett. 1995, 36, 1831–1834. (b) Andrus, M. B.; Argade, A. B.;
Chen, X.; Pamment, M. G. Tetrahedron Lett. 1995, 36, 2945–2948. (c)
Kawasaki, K.; Tsumura, S.; Katsuki, T. Synlett 1995, 1245–1246. (d)
Andrus, M. B.; Asgari, D.; Sclafani, J. A. J. Org. Chem. 1997, 62, 9365–
9368. (e) Sekar, G.; Dattagupta, A.; Singh, V. K. J. Org. Chem. 1998, 63,
2961–2967. (f) Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org.
Lett. 2000, 2, 3047–3049. (g) Andrus, M. B.; Zhou, Z. J. Am. Chem. Soc.
2002, 124, 8806–8807. (h) Ginotra, S. K.; Singh, V. K. Org. Biomol. Chem.
2006, 4, 4370–4374. (i) Ramalingam, B.; Neuburger, M.; Pfaltz, A. Synthesis
2007, 572–582. (j) Hoang, V. D. M.; Reddy, P. A. N.; Kim, T. J.
Organometallics 2008, 27, 1026–1027. (k) Cheng, X. M.; Zheng, Z. B.;
Li, N.; Qin, Z. H.; Fu, B.; Wang, N. D. Tetrahedron: Asymmetry 2008, 19,
2159–2163. (l) Boyd, D. R.; Sharma, N. D.; Sbireea, L.; Murphy, D.;
Belhocine, T.; Malone, J. F.; James, S. L.; Allen, C. C. R.; Hamilton, J. T. G.
Chem. Commun. 2008, 5535–5537.
Optically active 3 was then transformed into its derivative
6, which had better crystallinity, in order to improve the
optical purity by recrystallization. It was possible to use a
lower load of catalyst (2.5 mol %) without a deleterious effect
on the enantioselectivity (84% ee). As expected, the ee of 6
was improved to >99% ee in 23% yield after recrystallization
(3) (a) Rawlinson, D. J.; Sosnovsky, G. Synthesis 1972, 1–28. (b)
Kawasaki, K.; Katsuki, T. Tetrahedron 1997, 53, 6337–6350. (c) Ginotra,
S. K.; Singh, V. K. Tetrahedron 2006, 62, 3573–3581.
(7) The stereochemistry of 1,3-dioxolane 5 is not determined at present.
We represented the 2D-NMR (COSY) spectrum of 1,3-dioxolane 5 in the
Supporting Information.
(4) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2000, 41, 3941–3945.
(5) Tan, Q. T.; Hayashi, M. AdV. Synth. Catal. 2008, 350, 2639–2644.
(6) (a) Clak, J. S.; Clarke, M.-R.; Clough, J.; Blake, A. J.; Wilson, C.
Tetrahedron Lett. 2004, 45, 9447–9450. See, also their original: Clark, J. S.;
Tolhurst, K. F.; Taylor, M.; Swallow, S. L. J. Chem. Soc., Perkin Trans.
1998, 1, 1167–1169. (b) Reference 4. (c) Reference 2b and references cited
therein.
(8) Formation of 1,3-dioxolanes from epoxides: (a) Benfatti, F.; Cardillo,
G.; Gentilucci, L.; Tolomelli, A.; Monari, M.; Piccinelli, F. AdV. Synth.
Catal. 2007, 349, 1256–2264. (b) Solladie-Cavallo, A.; Choucair, E.; Balaz,
M.; Lupattelli, P.; Bonini, C.; Di Blasio, N. Eur. J. Org. Chem. 2006, 3307–
3011. (c) Procopio, A.; Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Nardi,
M.; Russo, B. AdV. Synth. Catal. 2006, 348, 1447–1450. (d) Vyvyan, J. R.;
Meyer, J. A.; Meyer, K. D. J. Org. Chem. 2003, 68, 9144–9147
.
Org. Lett., Vol. 11, No. 15, 2009
3315

from compound 1 (three steps) (Scheme 2). This procedure
was successfully carried out on a 15-g scale.9
The relative configuration of 6 was determined by X-ray
analysis as shown in Figure 1. The absolute configuration
cently, 2-DOS and its analogues have attracted much interest
as the central scaffold of clinically important aminoglycoside
antibiotics, and the first generation of RNA-targeted ligands
has already been designed.12,13 From a synthetic perspective,
enantiopure 2-DOS derivatives pose an interesting synthetic
challenge due to the five contiguous stereogenic centers, thus
numerous attempts including chemical or enzymatic desym-
metrization of meso-2-deoxystreptamine,13a,14 degradation of
neomycin and kanamycin,15 and total synthesis from a chiral
pool16 have been made. Therefore, we applied our asym-
metric desymmetrization by allylic oxidation of 4,5-epoxy-
cyclohex-1-ene (1) giving enantiopure alcohol 7 to a
straightforward synthsis of O-protected 2-DOS precursor and
its regioisomer as the key step.
The synthesis of optically pure 4,5-O-protected 2-deoxy-
streptamine is summarized in Scheme 3. Treatment of 6 with
Scheme 3
Figure 1
probability.
. ORTEP diagram of 6 with ellipsoids set at 50%
of 6 was assigned as (3S,4S,5S) by conversion to a known
compound 14.10,11
Then we applied the present method to the synthsis of
O-protected 2-deoxystreptamine (2-DOS) precursor. Re-
(9) A typical experimental procedure is as follows: A solution of ligand
2 (0.61 g, 2.4 mmol) and Cu(CH3CN)4PF6 (0.76 g, 2.0 mmol) in acetone
(100 mL) was stirred at rt for 1 h. To this dark red solution was added the
epoxide 1 (15.4 g, 160 mmol), followed by dropwise addition of a solution
of PhCO3-t-Bu (15.6 g, 80.0 mmol) in acetone (20 mL) over 1 h. The
reaction was stirred at 25 °C until the cis isomer 4 completely disappeared,
which was judged by HPLC analysis. Then acetone was removed and the
residue was dissolved in EtOAc (200 mL). The solution was washed with
sat. NaHCO3 solution (2 × 30 mL) and dried with Na2SO4. After removal
of the solvent, the residue was passed through a short pad of silica, using
hexane/EtOAc (8:1) as eluent, to give crude 3 as an oil (12.5 g), which
was contaminated with the by-product 5. The crude oil was dissolved in
methanol (100 mL) and a NaOMe solution (prepared from Na (65 mg, 2.82
mmol) and methanol (6 mL)) was added. After 2 h, the reaction was
quenched with acetic acid (0.18 g, 3.0 mmol). After complete removal of
methanol, the residue was dissolved in CH2Cl2 (150 mL) and Et3N (10
mL, 71 mmol) and a solution of 4-nitrobenzoyl chloride (10.8 g, 58 mmol)
in CH2Cl2 (50 mL) was added dropwise over 30 min. The mixture was
stirred at rt overnight and sat. NaHCO3 solution was added to quench the
reaction. The organic layer was separated and the aqueous solution was
extracted with CH2Cl2 (2 × 30 mL). The combined organic layer was
washed with NaHCO3 solution and dried (Na2SO4). After removal of solvent,
the residue was passed through a short pad of silica gel to give a white
solid. The solid was recrystallized from hot hexane/EtOAc solution (120
mL/30 mL) to afford enantiopure 6 as a colorless slice (9.5 g, 23% for
0.05 equiv of NaOMe/methanol solution afforded enantiopure
alcohol 7 quantitatively. It should be mentioned that this is
the first report of an optically active form of 7.17 After MOM
protection, ring-opening of compound 8 with NaN3 afforded
(12) For a review of 2-DOS, see: Busscher, G. F.; Rutjes, F. P. J. T.;
van Delft, F. L. Chem. ReV. 2005, 105, 775–791
.
(13) For some recent representative reports, see: (a) Greenberg, W. A.;
Priestley, E. S.; Sears, P. S.; Alper, P. B.; Roenbohm, C.; Hendrix, M.;
Hung, S. C.; Wong, C. H. J. Am. Chem. Soc. 1999, 121, 6527–6541. (b)
Sucheck, S. J.; Wong, A. L.; Koeller, K. M.; Boehr, D. D.; Draker, K.;
Sears, P.; Wright, G. D.; Wong, C. H. J. J. Am. Chem. Soc. 2000, 122,
5230–5231. (c) Luedtke, N. W.; Baker, T. J.; Goodman, M.; Tor, Y. J. Am.
Chem. Soc. 2000, 122, 12035–12036. (d) Tok, J. B.-H.; Fenker, J. Bioorg.
Med. Chem. Lett. 2001, 11, 2987–2991. (e) Russell, R. J. M.; Murray, J. B.;
Lentzen, G.; Haddad, J.; Mobashery, S. J. Am. Chem. Soc. 2003, 125, 3410–
3411. (f) Hanessian, S.; Tremblay, M.; Swayze, E. E. Tetrahedron 2003,
59, 983–993. (g) Liu, X.; Thomas, J. R.; Hergenrother, P. J. J. Am. Chem.
Soc. 2004, 126, 9196–9197. (h) Yokoyama, K.; Numakura, M.; Kudo, F.;
three steps). Rf ) 0.30 (hexane/EtOAc ) 2/1); mp 125-127 °C; [R]21
D
+209 (c 0.5, CHCl3, 99.1% ee). The ee value was determined by HPLC on
a Chirapak AS column (hexane/2-propanol ) 90/10, 1.0 mL/min, tR of major
isomer (3S,4S,5S): 20.9 min; tR of major isomer (3R,4R,5R): 23.7 min).
(10) To confirm the absolute configuration of 6, we transformed 6 to
(1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol (14) in several steps.
[R]22D of synthetic sample was +110.5 (c 1.0, CHCl3); lit.15 [R]D (derived
from D-glucose in 13 steps) was [R]D +106.2 (c 1.16, CHCl3). The details
of the transformation of 3 to 14 will be published in a separate paper.
Ohmori, D.; Eguchi, T. J. Am. Chem. Soc. 2007, 129, 15147–15155
(14) Orsat, B.; Alper, P. B.; Moree, W.; Mak, C. P.; Wong, C. H. J. Am.
Chem. Soc. 1996, 118, 712–713
.
.
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1693–1696. (c) van den Broek, S. A. M. W.; Gruijters, B. W. T.; Rutjes,
F. P. J. T.; van Delft, F. L.; Blaauw, R. H. J. Org. Chem. 2007, 72, 3577–
3580. (d) Aslam, M. W.; Busscher, G. F.; Weiner, D. P.; de Gelder, R.;
Rutjes, F. P. J. T.; van Delft, F. L. J. Org. Chem. 2008, 73, 5131–5134.
(11) To´th, Z. G.; Pelyva´s, I. F.; Szegedi, C.; Benke, P.; Magyar, E.;
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.
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Org. Lett., Vol. 11, No. 15, 2009

9 regioselectively. Epoxidation of acetate-protected 10 with
m-CPBA followed by ring-opening of 11 gave a mixture of
1213c and its regioisomer 13 in 90% yield (12/13 ) 45/55),
which were readily separated by chromatography.
centers in one reaction utilizing an asymmetric desymmetric
reaction. We believe this method provides a useful protocol
for the asymmetric version of the Kharasch-Sosnovosky
allylic oxidation reaction of functionalized cycloalkenes.
In conclusion, we have revealed a straightforward enan-
tioselective synthesis of 4,5-O-protected 2-deoxystreptamine
based on asymmetric desymmetrization of 4,5-epoxycyclo-
hex-1-ene. Asymmetric allylic oxidation took place in the
presence of 2.5 mol % of Cu(CH3CN)4PF6 and 3 mol % of
chiral N,N-bidentate ligand 2 to afford 3-benzoyloxy-4,5-
epoxycyclohex-1-ene (3) in 84% ee, which was increased
to >99% ee after recrystallization of 4-nitrobenzoyloxy
derivative 6. This method generates three carbon stereogenic
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” and No.
B17340020 from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. The authors also thank Dr.
Eda and Mr. Kawamura of Kobe University for X-ray
analysis and Dr. Amii and Dr. Tanaka of Kobe University
for helpful discussions.
(16) (a) Baer, H. H.; Arai, I.; Radatus, B.; Rodwell, J.; Nguyen, C. Can.
J. Chem. 1987, 65, 1443–1451. (b) da Silva, E. T.; Le Hyaric, M.; Machado,
A. S.; Almeida, M. V. Tetrahedron Lett. 1998, 39, 6659–6662. (c) Almeida,
M. V.; Da Silva, E. T.; Le Hyaric, M.; Machado, A. S.; Souza, M. V. N.;
Santiaga, R. M. J. Carbohydr. Chem. 2003, 22, 733–742. (d) Buscher, G. F.;
Tutjes, F. P. J. T.; van Delft, F. L. Tetrahedron lett. 2004, 45, 3629–3632.
(17) For racemic synthesis of 7, Delft and his co-workers reported the
synthesis of racemic 7 starting from the Diels-Alder adduct of cyclopen-
tadiene and p-benzoquinone in six steps. See: Busscher, G. F.; Groothuys,
S.; Gelder, R.; Rutjes, F. P. J. T.; Delft, F. L. J. Org. Chem. 2004, 69,
4477–4481.
Supporting Information Available: Details of experi-
mental procedures and characterization data (1H, 13C, and
COSY NMR, IR, mass spectrometry, elementary analyses
for all new compounds, HPLC and GC profiles, and a CIF
file of 6). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL901284V
Org. Lett., Vol. 11, No. 15, 2009
3317