Oxidation of bicyclic oxazolines: Applications to glycomimetics and novel saccharide derivatives

Article abstract of DOI:10.1016/S0040-4039(01)02161-X

A general procedure is reported for the oxidation of substituted oxazolines to α-acyloxyketoximes and the derived α-acyloxyketones. In the case of oxazolines derived from 2-acetamido-2-deoxyhexoses, the resulting 2-oximinoesters can be converted to 2-nitr

Full text of DOI:10.1016/S0040-4039(01)02161-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 347–349
Oxidation of bicyclic oxazolines: applications to glycomimetics
and novel saccharide derivatives
Matthew A. Clark, Qunzhao Wang and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 6 November 2001; accepted 13 November 2001
Abstract—A general procedure is reported for the oxidation of substituted oxazolines to a-acyloxyketoximes and the derived
a-acyloxyketones. In the case of oxazolines derived from 2-acetamido-2-deoxyhexoses, the resulting 2-oximinoesters can be
converted to 2-nitroglycals. © 2002 Elsevier Science Ltd. All rights reserved.
Substituted oxazolines are important synthetic interme-
diates,1 and have also been found in natural products
and enzyme inhibitors.2 As part of our continuing
interest in new glycomimetic frameworks, we recently
investigated the photolysis of pyridinium and pyrylium
salts 1 and 5, respectively, at 254 nm in acetonitrile–
water. In that process, solvent capture of the valence
bond isomer led, by a stereocontrolled Ritter reaction
and subsequent ring opening of the derived aziridine or
epoxide, to highly functionalized oxazolines 3 and 7
(Scheme 1).3 Attempted peracid epoxidation of N-
acetylated 3 and 7 unexpectedly formed a-acetoxy
oximes 4 and 8, respectively.
synthetic utility of this methodology is demonstrated by
the preparation of highly substituted cyclopentenones
and novel monosaccharide derivatives.
Prior studies on the oxidation of oxazolines have
achieved varying results. While investigating the peracid
oxidation of iminoethers, Aue and Thomas found that
2-methyloxazoline reacted with m-chloroperoxybenzoic
acid (MCPBA, 1 equiv.) to form mixtures of starting
material and the corresponding oxaziridine.4 Attempts
to achieve complete conversion using more MCPBA
resulted in overoxidation to 2-acetoxyacetaldoxime,
which was only detected after distillation (Eq. (1)). The
intermediacy of an oxaziridine-N-oxide was suggested,
although no detailed mechanism was presented. Keana
and Lee later reported that the oxidation of 4,4-
dimethyl-2-pentyloxazoline with MCPBA afforded an
isolable oxaziridine that, upon silica gel chromatogra-
phy, isomerized to the corresponding nitrone (Eq. (2)).5
Here we present several examples illustrating the scope
and generality of this oxazoline oxidation, and further
show that the first-formed oxime products can be con-
verted to the corresponding ketones without epimeriza-
tion or hydrolysis of other sensitive functionality. The
H3C
OAc
O
H
N CH3
O
hν
HON
NHAc
N
NHCH3
N
N
CH3
1
CH3CN
H2O
X
H
4
3
2
OH
OH
H
O
hν
H
HON
N
N
CH3CN
H2O
O
H3C
O
AcO
X
O
6
7
5
8
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02161-X

348
M. A. Clark et al. / Tetrahedron Letters 43 (2002) 347–349
CH3
O
O
N
O
N
O
N
[O]
[O]
CH3
O
CH3
O
CH3
O
N
(1)
(2)
O
OH
O
O
O
SiO2
[O]
C5H11
C5H11
C5H11
CH3
CH
CH3
CH3
CH3
N
3O
N
N
O
CH3
To better understand the mechanism of oxidation,
exploratory studies were conducted using the known
bicyclic oxazoline 9, which is readily prepared from
cyclohexene by a published method.6 When oxidations
were conducted at rt in either CH2Cl2 or CH3CN using
MCPBA (2.5 equiv., Aldrich, 85%), azoxy dimer 13,
was isolated in 65–70% yield (Scheme 2). A plausible
mechanism for the formation of 13 involves stepwise
oxidation of 9 to the oxaziridine 10, and then to
oxaziridine N-oxide 11. Rearrangement of 11 would
afford the nitroso intermediate 12, which can undergo
well-precedented dimerization to the corresponding
azoxy compound 13. Consistent with the product distil-
lation step carried out by Aue and Thomas in Eq. (1),
heating the isolated dimer 13 in toluene at reflux fur-
nished the acetoxyoxime 14 in high yield.
Based on these observations, an optimized method was
developed for transforming 9 directly to 14 by stirring
with MCPBA (2.1 equiv.) at rt, then at reflux. The two
stage, one-pot procedure bypassed the need for a radi-
cal inhibitor to prevent thermal decomposition of the
peracid.7
To extend the utility of this oxazoline oxidation, it was
of interest to determine whether the oxime group in 14
O
N
O
N
OAc
N=O
O
N
[O]
[O]
rt
CH3
CH3
CH3
O
O
O
9
10
11
12
OAc
OAc
OAc
toluene
reflux
2 h
O
N
O
N
O
N
OH
AcO
13
65-70%
14
85%
15
74%
Scheme 2.
OCOPh
O
OCOPh
O
[O]
Ph
N
N
OH
16
17
18
51%
86%
AcO
AcO
AcO
O
AcO
AcO
[O]
O
O
[O]
AcO
AcO
AcO
AcO
N
O
HON
NO2
OAc
H C
3
19
20
21
55%
52%
AcO
AcO
AcO
AcO
AcO
AcO
O
[O]
O
O
[O]
AcO
AcO
AcO
N
O
HON
NO2
OAc
24
61%
H3C
23
50%
22
Scheme 3.

M. A. Clark et al. / Tetrahedron Letters 43 (2002) 347–349
349
might be transformed to the corresponding ketone
Acknowledgements
without disturbing the adjacent acyloxy group. After
screening a variety of deoximation procedures, the pro-
cess of acid-catalyzed transoximation using excess acet-
aldehyde,8 which avoids both hydrolytic and
nucleophilic conditions, smoothly transformed 14 to
acetoxyketone 15 in 74% yield.
We thank the US National Institutes of Health (DK
55823) for financial support. The Cornell NMR Facility
is supported by the National Science Foundation (CHE
7904825, PGM 8018643) and NIH (RR02002).
Three additional oxazolines (Scheme 3) were synthe-
sized to test the scope and generality of this new
methodology. Like 9, the previously prepared6 phenyl-
substituted bicyclic oxazoline 16 was smoothly oxidized
(50°C, 24 h) and rearranged (reflux, 1.5 h) in one
operation to 17, which could be deprotected using
acetaldehyde to the known9 2-benzoyloxycyclohex-
anone 18.
References
1. Review: Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50,
2297–2360.
2. Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.;
Takahashi, S.; Haruyama, H.; Okuma, Y.; Kinoshita, Y.;
Enokita, R. J. Antibiot. 1991, 44, 1165–1168.
3. Clark, M. A.; Schoenfeld, R. C.; Ganem, B. J. Am.
Chem. Soc. 2001, 123, 10425–10426.
Saccharide-derived oxazolines 19 and 22 were prepared
from 2-acetamido-2-deoxy-d-glucose and 2-acetamido-
4. Aue, D. H.; Thomas, D. J. Org. Chem. 1974, 39, 3855–
3862.
2-deoxy-d-galactose, respectively, by
a
known
5. (a) Keana, J. F. W.; Lee, T. D. J. Am. Chem. Soc. 1975,
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method.10 Oxazolines 19 and 22 were oxidized
(CH3CN, rt, 9–48 h) and the intermediate azoxy dimers
were rearranged in situ (50°C, 12–15 h) to the corre-
sponding acetoxyoximes 2011 and 23, respectively.
However, both 20 and 23 were prone to decomposition
under the acidic transoximation conditions. Interest-
ingly, a recently reported oxidative deoximation proce-
dure using the Dess–Martin periodinane12 transformed
20 and 23 to the 2-nitroglucal and galactal derivatives
21 and 24, respectively.13 A related oxidative elimina-
tion of a-haloketoximes to a-nitroolefins has been
reported.14
11. Lemieux, R. U.; Nagabushan, T. L.; Gunner, S. W. Can.
J. Chem. 1968, 46, 405–411.
In summary, a general procedure has been devised for
the oxidation of substituted oxazolines to a-
acyloxyketoximes and the derived a-acyloxyketones. In
the case of oxazolines derived from 2-acetamido-2-
deoxyhexoses, the resulting oximes can be converted to
nitroglycals, which are novel monosaccharide deriva-
tives of potential use in the assembly of di- and
oligosaccharides.15
12. (a) Chaurhuri, S. S.; Akamanchi, K. G. Tetrahedron Lett.
1998, 39, 3209–3212; (b) Chaurhuri, S. S.; Akamanchi, K.
G. Synthesis 1999, 760–764.
1
13. For 21: H NMR l (300 MHz, CDCl3) 8.32 (s, 1H), 5.99
(m, 1H), 5.23 (t, 1H, J=2 Hz), 4.70–4.75 (m, 1H), 4.46
(dd, 1H, J=12, 8 Hz), 4.16 (dd, 1H, J=12, 4 Hz), 2.11 (s,
6H), 2.1 (s, 3H); 13C NMR 170.4, 109.2 (2), 155.6, 128.3,
76.3, 65.7, 61.5, 60.5, 21.0, 20.9, 20.8.
For 24: 1H NMR l 8.22 (s, 1H), 6.30 (m, 1H), 5.47 (t,
1H, J=4.3 Hz), 4.57–4.62 (m, 1H), 4.46 (dd, 1H, J=12.4,
9.1 Hz), 4.32 (dd, 1H, J=12.4, 3.2 Hz), 2.12 (s, 6H), 2.09
(s, 3H); 13C NMR 170.7, 169.7, 169.4, 155.6, 129.2, 75.4,
64.2, 60.9, 60.6, 21.0, 20.7 (2).
Representative procedure: To a solution of 19 (0.71 g,
2.2 mmol) in CH3CN (70 mL) was added MCPBA
(1.03 g, 80–85% pure). The solution was stirred at rt for
9 h, then heated at 50°C for 12 h. After cooling and
concentration in vacuo, the residue was dissolved in
EtOAc (80 mL), washed with sat NaHSO3, satd
NaHCO3, and satd NaCl. The organic phase was dried
(Na2SO4) and concentrated. Flash chromatography (2:3
EtOAc:hexanes) afforded 0.43 g (55%) of pure 20.
14. Sakakibara, T.; Ikeda, Y.; Sudoh, R. Bull. Chem. Soc.
Jpn. 1982, 55, 635–636.
15. See for example: Sakakibara, T.; Tachimori, Y.; Sudoh,
R. Carbohydr. Res. 1984, 131, 197–208.