TBAT-mediated nitrone formation of ω-mesyloxy-O-tert-butyldiphenylsilyloximes: Facile synthesis of cyclic nitrones from hemiacetals

Article abstract of DOI:10.1055/s-2002-32988

Chiral and cyclic nitrones were synthesized by TBAT-mediated desilylative cyclization of ω-mesyloxy-O-tert-butyl-diphenylsilyloximes, readily prepared from sugar derivatives by a consecutive treatment with O-tert-butyldiphenylsilylhydroxylamine and with m

Full text of DOI:10.1055/s-2002-32988

1344
LETTER
TBAT-Mediated Nitrone Formation of -Mesyloxy-O-tert-butyldiphenylsilyl-
oximes: Facile Synthesis of Cyclic Nitrones from Hemiacetals
F
ormation of -M
s
esyloxy-
O
a
-tert -butyld
m
iphenylsilyloximesu Tamura,* Atsushi Toyao, Hiroyuki Ishibashi*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan
E-mail: tamura@mail.p.kanazawa-u.ac.jp
Received 22 May 2002
1b,10 1c, and 1d afforded -mesyloxyoximes 3b, 3c, and
3d in 89%, 92%, and 59% yields, respectively.
Abstract: Chiral and cyclic nitrones were synthesized by TBAT-
mediated desilylative cyclization of -mesyloxy-O-tert-butyl-
diphenylsilyloximes, readily prepared from sugar derivatives by a
consecutive treatment with O-tert-butyldiphenylsilylhydroxyl-
amine and with mesyl chloride. The method was applied to sequen-
tial nitrone formation and intramolecular cycloaddition.
With four mesylates 3a–d in hand, a fluoride ion-mediat-
ed nitrone formation reaction was next examined (Table
2). When compound 3a was treated with CsF in boiling
THF, desilylative cyclization occurred to give nitrone 4a
in 42% yield (entry 1). The use of TBAF as a fluoride ion-
source again gave low yields of 4a, probably due to the in-
stability of 4a under the basic conditions arising from
TBAF (entries 2 and 3). The most satisfactory result was
obtained by employing tetrabutylammonium triphenyldi-
fluorosiliconate (TBAT),11 known as a non-basic fluoride
Key words: carbohydrate-derived -mesyloxy-O-tert-butyldiphe-
nylsilyloxime, TBAT, cyclization, nitrone, intramolecular cycload-
dition
Chiral and cyclic nitrones are recognized as attractive syn-
thetic intermediates, especially for optically active alka-
loids and amino sugars.1 Therefore, there have been Table 1 Formation of -Mesyloxy-O-tert-butyldiphenyl-
silyl oximes 3.
intensive studies on the syntheses of such nitrones: oxida-
tion of secondary amines or hydroxylamines,1b,d,2 in-
X
RO
RO
O
H2NOTBDPS
RO
RO
OH
tramolecular
condensation
of
aldehydes
with
NOTBDPS
hydroxylamines,1i,j intramolecular Michael addition of ni-
trogen-atom of oximes,3 and intramolecular N-alkylation
of oximes having leaving groups in the molecule.1a,c,1e–g
Among them, the N-alkylation of oximes is the most at-
tractive because of the regio- and stereospecificity. In this
context, synthesis of (3R,4S)-3,4-isopropylidenedioxy-
pyrroline 1-oxide from 3,4-isopropylidene-D-erythrose
via 3,4-isopropylidene-4-mesyloxy-D-erythrose O-trime-
thylsilyloxime has recently been described.4 This report
prompted us to present results of our own work on a gen-
eral method for synthesis of chiral and cyclic nitrones us-
ing TBAT-mediated cyclization of -mesyloxy-O-tert-
butyldiphenylsilyloximes, readily prepared from chiral
hemiacetals such as sugars.5
PPTS, MgSO4
toluene, reflux
RO
1
RO
MsCl, Et3N
CH2Cl2, 0 °C
2: X = OH
3: X = OMs
Entry Sugar Derivative 1
O-TBDPS Oxime 2
Yield
(%)
1
98
O
MsO
NOTBDPS
OH
O
O
O
O
3a
1a
2
89
O
O
H
O
H
O
OMs
NOTBDPS
OH
Our investigation was initiated by preparation of intramo-
lecular-alkylation precursors 3a–d from the hemiacetals
1a–d (Table 1). Treatment of lactol 1a6 derived from
D-erythrose with O-tert-butyldiphenylsilylhydroxylamine
(H2NOTBDPS)7 in boiling toluene in the presence of 0.05
equiv. of PPTS and excess MgSO4 gave -hydroxyl-O-
tert-butyldiphenylsilyloxime 2a.8 The latent hydroxyl
group of the oxime group of 2a is effectively differentiat-
O
O
O
O
O
1b
3b
3
4
92
59
O
OH
MsO
NOTBDPS
OBn
BnO
OBn
BnO
ed from the primary -hydroxyl group, and hence the
-
OBn
OBn
hydroxyl group can be easily transformed into a leaving
group. Thus, treatment of 2a with mesyl chloride and
Et3N in CH2Cl2 at 0 °C afforded -mesyloxyoxime 3a in
98% yield from 1a (entry 1).9 Similar reactions of lactols
1c
3c
O
OH
MsO
NOTBDPS
OTBDPS
OTBDPS
O
O
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1344,1346,ftx,en;Y08002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
O
O
Ph
Ph
1d
3d

LETTER
Formation of -Mesyloxy-O-tert-butyldiphenylsilyloximes
1345
Ph
Ph
source. Thus, heating 3a with TBAT (1.0–1.05 equiv) and
MS 4Å in boiling THF rapidly caused desilylative cy-
clization to afford 4a in 70% yield (entry 4).12,13 Secon-
dary mesylate 3b and homologated mesylate 3c also
underwent nitrone-formation reactions under similar con-
ditions to give -substituted nitrone 4b and six-mem-
bered nitrone 4c in 67% and 71% yields, respectively
(entries 5 and 6). Since the present conditions are very
mild, an O-TBDPS group can be compatible through the
nitrone formation (entries 7 and 8).
O-
N+
Ph
O
O
N
N
+
H
H
toluene
reflux, 3 hr
89%
O
O
O
O
O
O
20:1
4a
5a
5b
Scheme 1
Me
CO2Me
N
tBuO2C
CO2Me
NHZ
tBuO2C
The nitrones obtained here were found to be very useful.
For example, nitrone 4a underwent 1,3-dipolar cycload-
dition with styrene to afford cycloadduct 5a in a highly
stereoselective manner, along with a small amount of 5b
(Scheme 1).
a, b, c
O
7
6
PMB
Me
O
Me
HO
O
OH
CO2Me
We next turned our attention to the application of the
present nitrone-formation reaction to a sequential nitrone
formation and intramolecular cycloaddition. The requisite
g, h
d, e, f
N
N
O
9
PMB
PMB
8
Scheme 2 a) 5% Pd/C, H2, MeOH; b) p-anisaldehyde, NaBH3CN,
EtOH, AcOH, H2O; c) (E)-ClCOCH=CHMe, aq NaHCO3, CH2Cl2,
92% from 6; d) TFA, CH2Cl2; e) i-BuOCOCl, Et3N; f) Zn(BH4)2,
THF, 78% from 7; g) TsOH, benzene, reflux; h) DIBAL-H, Et2O–
CH2Cl2, –78 °C, 93% from 8
Table 2 Desilylative Cyclization of -Mesyloxy-O-tert-butyldi-
phenylsilyloximes 3.
O–
OMs
+
RO
RO
N
RO
RO
NOTBDPS
MS 4Å
3
RO
4
hemiacetal 9 was prepared from readily available L-
glutamate derivative 6 in 67% overall yield (Scheme 2).
RO
Entry Oxime Conditions
Nitrone
Yield
(%)
Hemiacetal 9 was treated with NH2OTBDPS in the pres-
ence of MgSO4 and PPTS in boiling Et2O followed by ex-
posure to mesyl chloride and Et3N to give mesylate 10 in
96% yield (Scheme 3). Treatment of 10 with TBAT in the
presence of MS 4A in refluxing THF afforded cycload-
duct 11 in 84% yield via desilylation and intramolecular
cycloaddition of the resulting nitrone A. Hydrogenolysis
of the N-O bond of cycloadduct 11 followed by treatment
with benzyl chloroformate gave bicyclic alcohol 12. The
present sequence would be useful for synthesis of an alka-
loid laccarin (13) possessing phosphodiesterase inhibitory
activity.14
O–
N+
1
2
3
4
3a
3a
3a
3a
CsF, THF, reflux,
7 min
TBAF, THF, reflux,
7 min
TBAF, benzene,
reflux, 7 min
TBAT, THF, reflux,
7 min
42
37
34
70
O
O
4a
O–
N+
5
3b
TBAT, THF, reflux,
5 min
67
H
α'
O
O
OTBDPS
N
O–
N+
O
O
Me
O
Me
O
MsO
a, b
c
9
4b
N
N
O–
N+
6
3c
TBAT, THF, reflux,
5 min
71
PMB
10
PMB
A
BnO
OBn
O
Me
HO
N
Me
O
OBn
O
H
H
Me
O
H
Z
H
N
H
N
N
4c
H
d, e
O
O–
N+
7
8
3d
3d
TBAT, THF, reflux,
5 min
13
49
N
N
H
H
H
H
Me
laccarin (13)
PMB
PMB
TBAT, benzene, re-
flux, 5 min
11
12
OTBDPS
O
Scheme 3 a) NH2OTBDPS, cat. PPTS, MgSO4, Et2O, reflux;
b) MsCl, Et3N, CH2Cl2, 96% from 9; c) TBAT, MS 4A, THF, reflux,
30 min, 84%; d) Pd(OH)2, H2, MeOH; e) CbzCl, aq NaHCO3, 91%
from 11
O
Ph
4d
Synlett 2002, No. 8, 1344–1346 ISSN 0936-5214 © Thieme Stuttgart · New York

1346
O. Tamura et al.
LETTER
(9) In contrast, treatment of desilylated congener of 2a with
mesyl chloride (1 equiv) and Et3N (2 equiv) gave an
inseparable complex mixture.
(10) Mita, N.; Tamura, O.; Ishibashi, H.; Sakamoto, M. Org. Lett.
2002, 4, 1111.
In conclusion, we have developed a general method for
synthesis of chiral and cyclic nitrones from hemiacetals
such as sugar derivatives using TBAT-mediated desilyla-
tive cyclization of -mesyloxy-O-tert-butyldiphenylsilyl-
oximes. This synthetic sequence would be useful for poly-
hydroxylated alkaloids and aza-sugars.
(11) (a) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem.
Soc. 1995, 117, 5166. (b) Pilcher, A. S.; DeShong, P. J. Org.
Chem. 1996, 61, 6901.
(12) The reaction required a prolonged reaction time without MS
4Å.
Acknowledgement
(13) Typical procedure. Preparation of 4a from 1a: A mixture of
1a (500 mg, 3.12 mmol) and MgSO4 (1.5 g) in toluene (5
mL) was heated at reflux for 5 min. To this mixture were
added successively H2NOTBDPS (2.54 g, 9.36 mmol) and
PPTS (39.0 mg, 0.156 mmol) at the same temperature. After
further heating for 15 min, MgSO4 was filtered off, and the
filtrate was washed successively with an aqueous saturated
solution of NaHCO3 and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with n-
hexane–EtOAc (2:1) to give 2a. Compound 2a was
dissolved in CH2Cl2 (8 mL). Mesyl chloride (0.73 mL, 9.26
mmol) and Et3N (0.60 mL, 9.27 mmol) were added to the
stirred solution at 0 °C. After stirring for 15 min, water was
added to the mixture, and the whole was extracted with
CHCl3. The organic phase was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel with n-hexane–EtOAc (3:1) to afford a 65:35 mixture of
(E)-3a and (Z)-3a (1.51 g, 98% from 1a). (E)-3a: 1H NMR
(500 MHz, CDCl3) 1.09 (9 H, s), 1.36 (3 H, s), 1.53 (3 H,
s), 2.97 (3 H, s), 4.16 (1 H, dd, J = 6.8, 11.2 Hz), 4.20 (1 H,
dd, J = 4.5, 11.2 Hz), 4.46 (1 H, br dt, J = 4.5, 6.8 Hz), 4.79
(1 H, br t, J = 7.3 Hz), 7.39–7.41 (5 H, m), 7.64–7.69 (6 H,
m). (Z)-3a: 1.11 (9 H, s), 1.31 (3 H, s), 1.49 (3 H, s), 2.86 (3
H, s), 4.08 (1 H, dd, J = 5.5, 11.0 Hz), 4.27 (1 H, dd, J = 2.8,
11.0 Hz), 4.76 (1 H, br dt, J = 2.8, 7.3 Hz), 5.44 (1 H, br dd,
J = 3.7, 7.3 Hz), 7.19 (1 H, d, J = 3.7 Hz), 7.36–7.43 (5 H,
m), 7.61–7.68 (5 H, m). To a boiling suspension of 3a
obtained above (603 mg, 1.23 mmol) and MS 4A (powder,
2.5 g) in THF (50 mL) was added a solution of TBAT (682
mg, 1.23 mmol) in THF (3 mL), and the mixture was further
heated at the same temperature for 7 min. After cooling, MS
4A was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel with EtOAc–MeOH (1:0 to
8:1) to give 4a (135 mg, 70%), mp 110–112 °C (diisopropyl
ether), [ ]D26 –26.3 (c 0.50, CH2Cl2) [lit.4 mp 110–111 °C,
[ ]D20 –28.0 (c 0.46, CH2Cl2)]. 1H NMR (500 MHz, CDCl3)
1.38 (3 H, s), 1.47 (3 H, s), 4.05 (1 H, br d, J = 15.1 Hz),
4.14 (1 H, br dd, J = 4.4, 15.1 Hz), 4.92 (1 H, br t, J = 6.4
Hz), 5.31 (1 H, br d, J = 5.9 Hz), 6.89 (1 H, br s); 13C NMR
(125 MHz, CDCl3) 25.6, 27.1, 67.9, 73.5, 79.8, 112.1,
132.5. The 1H NMR spectral data are identical with those
previously reported.4
This work was supported by NOVARTIS Foundation (Japan) for
the Promotion of Science.
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(8) When H2NOTMS or H2NOTBDMS was used, a mixture of
the corresponding -hydroxy-O-silylated oxime and the
desilylated oxime was obtained. Use of azeotropic removal
of water instead of MgSO4, again gave a similar mixture.
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Synlett 2002, No. 8, 1344–1346 ISSN 0936-5214 © Thieme Stuttgart · New York