A new route toward 2-acetamido-4-O-methyl-2-deoxy-d-mannopyranose from a Ferrier derivative of tri-O-acetyl-d-glucal, which contributes to aldolase-catalyzed synthesis of laninamivir (CS-8958)

Article abstract of DOI:10.1016/j.tet.2013.07.018

A new route toward 2-acetamido-4-O-methyl-2-deoxy-d-mannopyranose (4-O-methylManNAc), the chemo-enzymatic precursor of 7-O-methylsialic acid and laninamivir, was established. Known p-methoxyphenyl 6-O-(tert- butyldimethylsilyl)-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside was the starting material, and it was derived via Ferrier reaction from tri-O-acetyl-d-glucal. The total yield was 43% over six steps from the starting material. As the key steps, Payne oxidation provided a syn-epoxy alcohol, and the inversion from an aziridine to an oxazoline proceeded stereoselectively. Although the ring opening reaction of the epoxide with an azide gave both the 2- and 3-azido regioisomers, they could be merged into the desired aziridine via independent routes.

Full text of DOI:10.1016/j.tet.2013.07.018

Tetrahedron 69 (2013) 7931e7935
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new route toward 2-acetamido-4-O-methyl-2-deoxy-
D-
mannopyranose from a Ferrier derivative of tri-O-acetyl-
D
-glucal,
which contributes to aldolase-catalyzed synthesis of laninamivir
(CS-8958)
*
Hayato Okazaki, Kengo Hanaya, Mitsuru Shoji, Noriyasu Hada, Takeshi Sugai
Department of Pharmaceutical Science, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2013
Received in revised form 5 July 2013
Accepted 7 July 2013
Available online 12 July 2013
A new route toward 2-acetamido-4-O-methyl-2-deoxy-D-mannopyranose (4-O-methylManNAc), the
chemo-enzymatic precursor of 7-O-methylsialic acid and laninamivir, was established. Known p-me-
thoxyphenyl 6-O-(tert-butyldimethylsilyl)-2,3-dideoxy- -erythro-hex-2-enopyranoside was the start-
ing material, and it was derived via Ferrier reaction from tri-O-acetyl- -glucal. The total yield was 43%
a-D
D
over six steps from the starting material. As the key steps, Payne oxidation provided a syn-epoxy alcohol,
and the inversion from an aziridine to an oxazoline proceeded stereoselectively. Although the ring
opening reaction of the epoxide with an azide gave both the 2- and 3-azido regioisomers, they could be
merged into the desired aziridine via independent routes.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2-Acetamido-4-O-methyl-2-deoxy-D-mannopyranose
(1a,
Scheme 1) is a simple derivative of N-acetyl-D-mannosamine
(ManNAc, 1b) and a very important aminosugar. Honda and co-
workers reported 1a as the starting material for the chemo-
enzymatic synthesis of laninamivir (CS-8958, 2a), whose corre-
sponding octanoate (inavir) is a potent neuraminidase inhibitor
used as a flu medicine similar to zanamivir (2b) as shown in
Scheme 1.1 Sialic acid aldolase has been known to transform 1a into
3a,2,3 which was the synthetic precursor of 2a, in 88% yield. In the
original report, the preparation of 1a required 17 steps from D-
glucose.2 Therefore, the starting material was later changed to
ManNAc (1b), via regioselective ring opening of an epoxide in a 1,6-
anhydrosugar intermediate1 or methylation after regioselective
protection of alcohols at C-4 and C-6,3 respectively. Since the
availability of ManNAc is scarce from natural resources, the con-
version of GlcNAc to ManNAc has been developed.4
We have so far exploited the chemo-enzymatic route from tri-O-
acetyl-D-glucal as shown in Scheme 2. The regio- and stereoselective
introduction of a nitrogen functional group on C-2 with the desired
manno-configurationwas the key transformation to convert 4 into 5.
However, a large molar excess of very expensive rhodium acetate
Scheme 1. Aldolase-catalyzed synthesis of sialic acid derivative 3, which are pre-
cursors for laninamivir 2a and zanamivir 2b; (a) sialic acid aldolase, CH3COCO2Na.
was required.5 In order to overcome this low cost-efficiency, we
propose a new route via oxazoline 6, based on the double regiose-
lective ring opening of three-membered ring intermediates in-
volving aziridine 7 and epoxide 8a as illustrated in Scheme 2.
2. Results and discussion
Substrate 9a6 for the epoxidation was prepared by Ferrier re-
* Corresponding author. Tel./fax: þ81 3 5400 2695; e-mail address: sugai-tk@
pha.keio.ac.jp (T. Sugai).
action7 of tri-O-acetyl-
D-glucal with p-methoxyphenol, solvolysis of
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.018

7932
H. Okazaki et al. / Tetrahedron 69 (2013) 7931e7935
Scheme 2. Our previous synthesis of 2-acetamido-4-O-methyl-2-deoxy-D-mannopyr-
anose (1a) and the proposed new transformation; (a) PhI(OCOt-Bu)2, Rh2(OAc)4, t-
BuOH, ClCH2CH2Cl; (b) Ref. 5 (three steps).
theacetates,8 andselective protection of theresulting primaryalcohol
at C-6 with a TBS group in good overall yield up to 88%. In our first
trials, the epoxidation did not proceed with conventional reagents,
such as m-chloroperoxybenzoic acid (m-CPBA) or magnesium mono-
peroxyphthalate (MMPP). The desired reaction could only be per-
formed by applying a less sterically hindered iminohydroperoxide,
which was generated in situ under Payne oxidation conditions9 with
alkaline H2O2 in acetonitrile (Scheme 3). The ratio between syn-8b
(syn-epoxy alcohol) and diastereomeric anti-8b (anti-epoxy alcohol)
was estimated to be 64:36 (see Experimental, Section 4.3). Undesired
b
-epoxidation occurred to a certain extent, although
was expected by hydrogen bond formation between the oxidant and
the -oriented allylic alcohol. It was supposed that the -oriented p-
a-epoxidation
Scheme 3. Synthesis of 6 from 9 via regio- and stereoselective ring opening of the
aziridine 7; (a) ureaehydrogen peroxide complex (UHP), KHCO3, CH3CN; (b) CH3I,
Ag2O, DMF; (c) NaN3, NH4Cl, aq MeOH; (d) Ac2O, pyridine, CH2Cl2; (e) MsCl, Et3N,
CH2Cl2; (f) Ph3P, (i-Pr)2NEt, aq CH3CN; then Ac2O, pyridine; (g) PPh3, toluene; then
a
a
methoxyphenyl group at C-1, and hydrogen bond formation between
the allylic hydroxy group and surrounding water under the aqueous
Payne oxidation conditions interfered with the access of the oxidant
Ac2O, pyridine; (h) NaI, N,N-dimethylacetamide (DMA); (i)
2 M HCl, THF; (j)
(NH4)2[Ce(NO3)6], NaHCO3, aq CH3CN.
from the a-orientation. In order to avoid the influence of the latter
effect, aqueous hydrogenperoxidewas replaced with ureaehydrogen
peroxide complex (UHP),10 which improved the ratio to 87:13. The
major syn-8b was recovered by silica gel column chromatographic
separation of the diastereomers (72% yield, 82% based on the con-
sumed starting material). An attempt at reagent-based control of
stereochemistry in the epoxidation of 9a under Sharpless’ asym-
After the methylation of the resulting free hydroxy group in syn-
8b to form 8a (96%), the opening of the epoxide ring in 8a with
nitrogen-containing nucleophiles, such as azide, acetamide, and
isocyanate was attempted. Among them, only the azide could open
the epoxide ring, giving a regioisomeric mixture of 10a and 11 in
a ratio of 74:26 in 82% combined yield. The regio- and stereo-
chemistry of 10a was determined after conversion to the corre-
sponding acetate 10b, whose downfield chemical shift of H-2 and
coupling constants (J1,2¼3.4 Hz, J2,3¼10.7 Hz) indicated a free hy-
metric epoxidation conditions [t-BuOOH, Ti(OiPr)4, and diethyl
(ꢀ)-tartrate]11 resulted in no reaction.
D-
At this stage, we compared another substrate for epoxidation,
9b with a free hydroxy group at C-6. The selectivity between syn-8c
and anti-8c was 64:36 under aqueous Payne oxidation conditions
and 83:17 with UHP, which was similar to that using TBS ether 9a.
Since the handling of epoxy alcohol 8b was easier than that of 8c,
TBS ether 9a was chosen as the substrate for epoxidation.
droxy group at C-2 with a-configuration. With this assignment, the
stereochemistry in syn-8b was also unambiguously confirmed as
depicted in Scheme 3. The free hydroxy group at C-2 in 10a was
mesylated to 10c, and the product was cyclized by the action of

H. Okazaki et al. / Tetrahedron 69 (2013) 7931e7935
7933
triphenylphosphine by Staudinger reaction. Subsequent acetylation
furnished aziridine 7 in 75% yield. The regioisomer 11, which had
been produced at the stage of the epoxide opening reaction was
effectively merged into the same 7 in 81% yield.
The regio- and stereoselective transformation at C-3 was in-
spired by the work of El Shafei and Guthrie.12 Aziridine 7, which
was activated by the introduction of an electron-withdrawing
acetyl group, was treated with iodide to give intermediate 12,
CH3CN (2.0 mL) and 30% H2O2 (3.5 mL), and the mixture was still
further stirred for 20 h. The progress of the reaction was checked by
silica gel TLC, developed with hexane/EtOAc (2:1), Rf for syn-8b:
0.33; anti-8b: 0.65. The reaction was quenched with Na2S2O3 aq
solution and organic materials were extracted with EtOAc three
times. The combined extract was washed with brine and dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
charged on a silica gel column (100 mL). Elution with hexane/EtOAc
(5:1) furnished syn-8b (1.13 g, 35%) as a colorless solid, along with
an inseparable mixture of anti-8b and the unreacted starting ma-
terial, 9a (1.98 g, 63%; anti-8b:9a¼33:67, judged by its 1H NMR
spectrum). The ratio between syn-8b (syn-epoxy alcohol) and di-
astereomeric anti-8b (anti-epoxy alcohol) was estimated to be
64:36 by the comparison of 1H NMR spectrum of the crude mixture.
which has an a-oriented iodine atom at C-3 with inversion of ste-
reochemistry. The reaction mixture was further heated to allow re-
cyclization by the oxygen atom of N-acetamide to give oxazoline 6
in 87% yield. Formation of the oxazoline functionality was con-
firmed by the 13C NMR chemical shift of the oxazoline sp2 carbon (
d
165.68), which matched that of the reported one (168.3).13 Through
this step, the double inversion at C-3 with retention at C-2 occurred
to furnish the correct stereochemistry. The stereochemical identi-
ties of 6 and mannosamine were further confirmed by spectral data
in the course of its conversion to 1a via 1c, through deprotection
and ring opening of the oxazoline.12,13
syn-8b: mp 77 ꢁC; [
a
]
D
22 þ89.6 (c 0.60, CHCl3); IR nmax 3473, 2951,
2927, 2856, 1506, 1464, 1250, 1217, 1146, 1099, 1003, 922, 829, 773,
665 cmꢀ1; 1H NMR (CDCl3)
d
: 7.04 (dd, J¼3.1, 9.2 Hz, 1H), 7.03 (dd,
J¼3.1, 9.2 Hz, 1H), 6.80 (dd, J¼3.1, 9.1 Hz, 1H), 6.79 (dd, J¼3.1, 9.1 Hz,
1H), 5.50 (d, J¼2.9 Hz, 1H), 4.02 (ddd, J¼ 1.8, 6.0, 10.6 Hz, 1H), 3.75
(s, 3H), 3.78e3.90 (m, 2H), 3.72 (dd, J¼5.0, 10.3 Hz, 1H), 3.68 (dd,
J¼2.9, 4.1 Hz, 1H), 3.54 (dd, J¼1.8, 4.1 Hz, 1H), 2.68 (d, J¼6.0 Hz, 1H),
3. Conclusion
0.86 (s, 9H), 0.05 (d, J¼2.7 Hz, 6H); 13C NMR (CDCl3)
d: 155.13,
We accomplished a new route for 4-O-methylated mannos-
amine in its oxazoline form (6) in 43% yield over six steps, starting
from known 9a. The total yield of 7-O-methylsialic acid from
150.96, 118.76 (ꢂ2), 114.44 (ꢂ2), 93.40, 68.77, 67.56, 63.93, 55.60,
55.12, 53.97, 25.81 (ꢂ3), 18.25, ꢀ5.50, ꢀ5.56. Anal. Calcd for
C19H30O6Si: C, 59.66; H, 7.90. Found: C, 59.44; H, 7.88.
commercially available tri-O-acetyl-
D-glucal was estimated to be
anti-8b: 1H NMR (CDCl3)
d
: 6.99 (dd, J¼3.0, 9.0 Hz, 1H), 6.98 (dd,
15%. In the present synthesis, the
a-oriented p-methoxyphenyl
J¼3.0, 9.0 Hz, 1H), 6.82 (dd, J¼3.0, 9.0 Hz, 1H), 6.81 (dd, J¼3.0,
9.0 Hz, 1H), 5.51 (s, 1H), 3.85 (d, J¼8.6 Hz, 1H), 3.76 (s, 3H),
3.68e3.80 (m, 2H), 3.60 (dd, J¼8.6, 8.0 Hz, 1H), 3.37 (d, J¼3.7 Hz,
1H), 3.30 (d, J¼3.7 Hz, 1H), 3.19 (d, J¼2.0 Hz, 1H), 0.86 (s, 9H), 0.05
(s, 6H).
group installed by a stereoselective Ferrier reaction, effectively
worked to suppress the undesired side reaction, that is, the ring
opening of the aziridine from the wrong direction at C-2 in 7. All
operation could be performed at a lower cost, compared to the
previous synthesis based on rhodium nitrenoid-mediated regio-
and stereoselective cyclization to introduce the key mannosamine
functionality.
Alternative procedure byapplying UHP is as follows. To a solution
of 9a (1.53 g, 4.17 mmol) in CH3CN (21 mL) were added KHCO3
(5.84 g, 58.3 mmol) and UHP (4.21 g, 44.8 mmol). The mixture was
stirred at 40 ꢁC. After 17.5, 45.5, 65.5 h, KHCO3 and UHP were sup-
plemented. First portion: 2.92 g (29.2 mmol) and 2.10 g (22.3 mmol);
second portion: 2.92 g (29.2 mmol) and 2.10 g (22.3 mmol); third
portion: 2.92 g (29.2 mmol) and 2.10 g (22.3 mmol), and after the
final addition, the mixture was further stirred for 5.0 h. The workup
and purification were performed in the same manner as above, to
give syn-8b (1.15 g, 72%) and the mixture of anti-8b and 9a (351 mg,
23%; anti-8b:9a¼48:52).
4. Experimental
4.1. Material and methods
Merck silica gel 60 F254 thin-layer plates (1.05744, 0.5 mm
thickness) and silica gel 60 (spherical and neutral; 100e210 mm,
37558e79) from Kanto Chemical Co. were used for preparative
thin-layer chromatography and column chromatography,
respectively.
4.4. p-Methoxyphenyl 2,3-anhydro-
a
-D-allopyranoside (syn-
8c) and p-methoxyphenyl 2,3-anhydro-
(anti-8c)
a-D-mannopyranoside
4.2. Analytical methods
All mps are uncorrected. IR spectra were measured by ATR on
a Jeol FT-IR SPX60 spectrometer. 1H and 13C NMR spectra were
measured at 400 or 100 MHz on an Agilent 400-MR, or at 500 or
125 MHz on an INOVA-500 spectrometer, respectively. High reso-
lution mass spectra were recorded on a Jeol JMS-700 MStation
spectrometer at 70 eV. Optical rotation values were recorded on
a Jasco P-1010 polarimeter.
To a solution of 9b (300 mg, 1.19 mmol) in CH3CN (6.0 mL) were
added KHCO3 (596 mg, 5.95 mmol) and 30% H2O2 (1.96 mL). The
mixture was stirred for 4 h at room temperature. The progress of
the reaction was checked by silica gel TLC, developed with EtOAc, Rf
for syn-8c: 0.37; anti-8c: 0.63. The reaction was quenched by
adding catalytic amount of PtO2 and the mixture was filtered
through a short column of CeliteÒ. Organic materials were extrac-
ted with EtOAc five times from the solid residue. The combined
extract was washed with brine and dried over anhydrous Na2SO4,
and concentrated in vacuo. The ratio of the products was as follows:
syn-8c:anti-8c:9b¼1:0.57:0.69, judged from 1H NMR of the mixture
4.3. p-Methoxyphenyl 2,3-anhydro-6-O-(tert-butyldime-
thylsilyl)-a-D-allopyranoside (syn-8b) and p-methoxyphenyl
2,3-anhydro-6-O-(tert-butyldimethylsilyl)-a-D-mannopyrano-
side (anti-8b)
[d: 3.56 (dd, H-3 for syn-8c), 3.43 (d, H-3 for anti-8c), 3.34 (d, H-2
for anti-8c), 5.93 (ddd, H-3 for 9b), 6.10 (ddd, H-2 for 9b)]. This
To a solution of 9a (3.10 g, 8.45 mmol) in CH3CN/MeOH (1:1,
8.5 mL) were added KHCO3 (4.20 g, 42.0 mmol) and 30% H2O2
(7.0 mL). The mixture was stirred for 13 h at room temperature. To
the reaction mixture were added another portion of CH3CN
(2.0 mL) and 30% H2O2 (3.5 mL), and the mixture was further stirred
for 5 h. To the reaction mixture were added still another portion of
residue was charged on a silica gel column (15 mL). Elution with
CHCl3 furnished syn-8c (75 mg, 24%) as a colorless solid.
26
syn-8c: Mp 126 ꢁC; [
a]
þ181.6 (c 0.44, CH3OH); IR nmax 3367,
D
3005, 2933, 2837, 1799, 1639, 1502, 1464, 1443, 1213, 993, 918, 829,
771 cmꢀ1; 1H NMR (CDCl3)
: 7.04 (dd, J¼3.1, 9.2 Hz, 1H), 7.03 (dd,
J¼3.1, 9.2 Hz, 1H), 6.80 (dd, J¼3.1, 9.1 Hz, 1H), 6.79 (dd, J¼3.1, 9.1 Hz,
d

7934
H. Okazaki et al. / Tetrahedron 69 (2013) 7931e7935
1H), 5.55 (d, J¼3.1 Hz, 1H), 4.00e4.07 (br, 1H), 3.76e3.90 (m, 3H),
3.75 (s, 3H), 3.73 (dd, J¼3.1, 4.1 Hz, 1H), 3.56 (dd, J¼1.8, 4.1 Hz, 1H).
HRMS (FAB): calcd for C13H16O6: [M]þ: 268.0947; found: 268.0958.
Further purification of the small amount of less polar fractions
by preparative TLC provided an analytical sample of anti-8c: 1H
progress of the reaction was checked by silica gel TLC, developed
with hexane/EtOAc (2:1), Rf for 10a: 0.70 and 11: 0.51. After con-
sumption of starting material, the reaction was diluted H2O and
organic materials were extracted with EtOAc three times. The
combined extract was washed with brine and dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was charged on
a silica gel column (30 mL). Elution with hexane/EtOAc (5:1) fur-
nished 10a (495 mg, 61%) and 11 (169 mg, 21%), respectively.
NMR (CDCl3)
d
: 7.00 (dd, J¼3.1, 9.0 Hz, 1H), 6.99 (dd, J¼3.1, 9.0 Hz,
1H), 6.83 (dd, J¼3.1, 9.0 Hz, 1H), 6.82 (dd, J¼3.1, 9.0 Hz, 1H), 5.57 (s,
1H), 3.96 (dd, J¼5.2, 8.4 Hz, 1H), 3.68e3.76 (m, 3H), 3.76 (s, 3H),
3.41 (d, J¼3.6, 1H), 3.33 (d, J¼3.6 Hz, 1H), 2.38 (d, J¼5.2, 1H), 1.71
(s, 1H).
Compound 10a: colorless oil; [
a
]
21 þ169.4 (c 0.85, CHCl3); IR nmax
D
3437, 2949, 2929, 2856, 2835, 2104, 1506, 1464, 1250, 1213, 1126,
The epoxidation of 9b (70 mg, 0.28 mmol) with UHP was carried
out in the similar manner as described for 9a. The ratio between
syn-8c:anti-8c:9b was 22:4:74. Chromatographic purification pro-
vided pure syn-8c (9.8 mg, 13%).
1076, 1024, 825, 777 cmꢀ1 1H NMR (CDCl3)
; d: 6.97e7.03 (m, 2H),
6.78e6.84 (m, 2H), 5.35 (d, J¼3.7 Hz,1H), 3.76 (s, 3H), 3.64e3.83 (m,
4H), 3.57 (s, 3H), 3.52e3.62 (m, 1H), 3.24 (dd, J¼9.5, 9.8 Hz, 1H),
0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3)
d: 155.41, 150.33, 118.15
(ꢂ2), 114.70 (ꢂ2), 97.49, 77.78, 72.26, 71.35, 66.97, 61.68, 60.38,
55.64, 25.85 (ꢂ3),18.29, ꢀ5.21, ꢀ5.43. Anal. Calcd for C20H33N3O6Si:
C, 54.65; H, 7.57; N 9.56. Found: C, 54.47; H, 7.67; N, 9.11.
4.5. p-Methoxyphenyl 2,3-anhydro-6-O-(tert-butyldime-
thylsilyl)-a-D-allopyranoside (syn-8b)
The regiochemistry of 10a was confirmed after conversion to the
To a solution of syn-8c (10 mg, 0.037 mmol) in CH2Cl2 (186
m
L)
corresponding acetate 10b in a conventional manner. 1H NMR
were added imidazole (3.0 mg, 0.044 mmol) and TBSCl (5.6 mg,
0.037 mmol). The solution was stirred for 4 h at 0 ꢁC. The progress
of the reaction was checked by silica gel TLC, developed with
hexane/EtOAc (2:1), Rf for syn-8b: 0.33. After consumption of
starting material, the reaction was diluted H2O and organic mate-
rials were extracted with EtOAc three times. The combined extract
was washed with brine and dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was charged on a silica gel
column (2.0 mL). Elution with hexane/EtOAc (5:1) furnished syn-8b
(13 mg, 93%) as a colorless solid. The physicochemical properties
and the spectral data of the present syn-8b were identical with
those reported in Section 4.3.
(CDCl3)
d
: 6.92e6.98 (m, 2H), 6.76e6.84 (m, 2H), 5.47 (d, J¼3.4 Hz,
1H), 4.69 (dd, J¼3.4, 10.7 Hz, 1H), 4.05 (dd, J¼9.8, 10.7 Hz, 1H), 3.80
(dd J¼3.5, 10.5 Hz, 1H) 3.75 (s, 3H), 3.66e3.77 (m, 2H), 3.58 (s, 3H),
3.31 (dd, J¼9.8, 10.5 Hz, 1H), 2.13 (s, 3H) 0.88 (s, 9H), 0.042 (s, 6H).
The enhancement of signal (5.5%) for H-2 was observed by a nuclear
Overhauser effect, when H-1 was irradiated.
Compound 11: 1H NMR (CDCl3)
d: 7.03 (dd, J¼3.1, 9.2 Hz, 1H),
7.02 (dd, J¼3.1, 9.2 Hz, 1H), 6.80 (dd, J¼3.1, 9.2 Hz, 1H), 6.79 (dd,
J¼3.1, 9.2 Hz,1H), 5.27 (d, J¼4.3 Hz,1H), 4.02e4.12 (m, 2H), 3.87 (dd,
J¼4.3, 7.0 Hz, 1H), 3.83 (dd, J¼3.3, 11.3 Hz, 1H), 3.78 (dd, J¼4.5,
11.3 Hz, 1H), 3.75 (s, 3H), 3.57 (dd, J¼3.7, 6.0 Hz, 1H), 3.45 (s, 3H),
2.83 (d, J¼8.4 Hz, 1H), 0.87 (s, 9H), 0.05 (s, 6H).
4.6. p-Methoxyphenyl 2,3-anhydro-6-O-(tert-butyldime-
4.8. p-Methoxyphenyl 2,3-(acetylepimino)-6-O-(tert-butyldi-
thylsilyl)-4-O-methyl-
a
-D
-allopyranoside (8a)
methylsilyl)-4-O-methyl-2,3-dideoxy-a-D-glucopyranoside (7)
To a solution of syn-8b (1.09 g, 2.83 mmol) in anhydrous DMF
(14 mL) was added CH3I (1.33 mL, 21.3 mmol) and Ag2O (3.95 g,
14.2 mmol). The solution was stirred for 23 h at room temperature
under an argon atmosphere. The progress of the reaction was
checked by silica gel TLC, developed with hexane/EtOAc (2:1), Rf for
8a: 0.55. After consumption of starting material, the mixture was
filtered through a short column of CeliteÒ and the filtrate was di-
luted with EtOAc. The organic layer was washed sequentially with
brine, H2O four times, and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was charged on a silica gel
To the solution of 10a (663 mg, 1.51 mmol) in anhydrous CH2Cl2
(7.5 mL) was added Et3N (315 L, 2.26 mmol) and MsCl (141 L,
m
m
1.82 mmol), and the mixture was stirred for 40 min at 0 ꢁC under an
argon atmosphere. The reaction was quenched with phosphate
buffer solution and organic materials were extracted with EtOAc
three times. The combined extract was washed with brine and
dried over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude mesylate 10c was employed for the next step
without further purification.
To the solution of the above-mentioned 10c in CH3CN (10 mL)
was added Ph3P (396 mg, 1.51 mmol), and the mixture was stirred
column (50 mL). Elution with hexane/EtOAc (5:1) furnished 8a
22
(1.08 g, 96%) as a colorless solid; mp 58 ꢁC; [
a
]
þ135.1 (c 0.84,
0
ꢁC under an argon atmosphere. After 10 min, to the resultant
D
CHCl3); IR nmax 2953, 2931, 2856, 2833, 1506, 1462, 1248, 1217, 1146,
mixture, H2O (2.0 mL) was added and the mixture was stirred for
11 h. To the solution was added DIPEA (789 L, 4.5 mmol) and the
1109, 1092, 991, 922, 827, 775, 667 cmꢀ1 1H NMR (CDCl3)
;
d
: 7.05
m
(dd, J¼3.1, 9.0 Hz, 1H), 7.04 (dd, J¼3.1, 9.0 Hz, 1H), 6.79 (dd, J¼3.1,
9.0 Hz, 1H), 6.78 (dd, J¼3.1, 9.0 Hz, 1H), 5.49 (d, J¼3.1 Hz, 1H), 3.89
(ddd, J¼2.2, 3.5, 9.4 Hz, 1H), 3.75 (s, 3H), 3.69e3.81 (m, 3H), 3.65
(dd, J¼3.1, 4.1), 3.61 (dd, J¼1.4, 4.1 Hz, 1H), 3.52 (s 3H), 0.86 (s, 9H),
mixture was allowed to warm to reflux and further stirred for 4.0 h.
To the resultant mixture was cooled to 0 ꢁC and added pyridine
(0.4 mL, 5.0 mmol) and Ac2O (0.3 mL, 3.2 mmol) and the mixture
was stirred for 20 min. The progress of the reaction was checked by
silica gel TLC, developed with hexane/EtOAc (2:1), Rf for 7: 0.43.
After consumption of starting material, the reaction was diluted
H2O and organic materials were extracted with EtOAc three times.
The combined extract was washed with brine and dried over an-
hydrous Na2SO4, and concentrated in vacuo. The residue was
0.025 (s, 6H); 13C NMR (CDCl3)
d
: 155.09, 151.18, 118.83 (ꢂ2), 114.44
(ꢂ2), 93.60, 73.28, 68.70, 62.20, 57.25, 55.65, 54.62, 51.23, 25.92
(ꢂ3), 18.40, ꢀ5.30, ꢀ5.40. Anal. Calcd for C20H32O6Si: C, 60.58; H,
8.13. Found: C, 60.44; H, 8.11.
4.7. p-Methoxyphenyl 6-O-(tert-butyldimethylsilyl)-4-O-
charged on a silica gel column (20 mL). Elution with hexane/EtOAc
21
methyl-3-deoxy-3-azido-
methoxyphenyl 6-O-(tert-butyldimethylsilyl)-4-O-methyl-2-
deoxy-2-azido- -altropyranoside (11)
a-
D-glucopyranoside (10a) and p-
(10:1) furnished 7 (496 mg, 75% in two steps) as a colorless oil; [
a]
D
þ100.7 (c 0.52, CHCl3); IR nmax 2953, 2929, 2856, 2833, 1705, 1504,
a
-D
1464, 1441, 1431, 1362, 1252, 1213, 1200, 1107, 1012, 987, 829, 775,
725, 665, 609 cmꢀ1; 1H NMR (CDCl3)
d
: 7.05 (dd, J¼3.1, 9.0 Hz, 1H),
To a solution of 8a (735 mg, 1.85 mmol) in MeOH/H2O (8:1,
12 mL) was added NH4Cl (198 mg, 3.70 mmol) and NaN3 (964 mg,
14.8 mmol), and the mixture was stirred at 80 ꢁC for 3 days. The
7.04 (dd, J¼3.1, 9.0 Hz, 1H), 6.80 (dd, J¼3.1, 9.0 Hz, 1H), 6.79 (dd,
J¼3.1, 9.0 Hz, 1H), 5.54 (s, 1H), 3.75 (s, 3H), 3.64e3.72 (m, 3H), 3.51
(s, 3H), 3.39 (d, J¼8.4 Hz, 1H), 2.96 (d, J¼5.7 Hz, 1H), 2.87 (d,

H. Okazaki et al. / Tetrahedron 69 (2013) 7931e7935
7935
J¼5.7 Hz, 1H), 2.18 (s, 3H), 0.83 (s, 9H), ꢀ0.004 (s, 6H); 13C NMR
Next, above-mentioned crude product was dissolved in a mix-
ture of CH3CN/H2O (4:1, 15 mL). After cooling to 0 ꢁC, to the mixture
was added NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture
was stirred for 36 h at room temperature, to remove the contam-
inant. During this operation, the less polar component disappeared
probably by hydrolysis. Then, to the mixture, (NH4)2[Ce(NO3)6]
(340 mg, 0.62 mmol) was added. The mixture was stirred for 15 min
at 0 ꢁC. The progress of the reaction was checked by silica gel TLC,
developed with EtOAc/EtOH (4:1), Rf for 1a: 0.31. The reaction was
(CDCl3)
d
: 181.59, 155.05, 118.27 (ꢂ2), 114.49 (ꢂ2), 94.31, 71.14,
69.31, 62.86, 57.27, 55.58, 37.53, 35.62, 25.86 (ꢂ3), 23.38, 18.34,
ꢀ5.40, ꢀ5.42. Anal. Calcd for C22H35NO6Si: C, 60.38; H, 8.06, N, 3.20.
Found: C, 60.19; H, 8.08, N, 3.06.
The regioisomer 11 was merged to 7 as follows. To the solution
of 11 (280 mg, 0.64 mmol) in toluene (3.2 mL) was added Ph3P
(167 mg, 0.64 mmol), and the mixture was stirred 0 ꢁC under an
argon atmosphere. After 20 min, the mixture was allowed to warm
to reflux and further stirred for 12 h. After cooling to 0 ꢁC, pyridine
quenched with 1,2,4-trimethoxybenzene (100 mL). The mixture was
(154
m
L, 1.91 mmol) and Ac2O (121
m
L, 1.28 mmol) were added and
partitioned with toluene and water. The organic phase was
extracted with H2O twice. The combined water layer was concen-
trated in vacuo. The residue was charged on a silica gel column
(10 mL). Elution with CHCl3/MeOH (20:1) furnished 1a (59 mg); 1H
the mixture was stirred for 40 min. The workup and purification
were performed in the same manner for the cyclization of 10c, to
give 7 (226 mg, 81%).
NMR (D2O, 3:2 mixture of
a
- and
b
-anomers)
d
: 5.09 (d, J¼1.6 Hz,
4.9. 2-Methyl-10-O-methoxyphenyl-40-O-methyl-60-O-(tert-
1H), 4.99 (d, J¼1.6 Hz, 0.7H), 4.42 (dd, J¼1.5, 4.5 Hz, 0.7H), 4.31 (dd,
J¼1.6, 4.5 Hz, 1H), 4.11 (dd, J¼4.5, 9.8 Hz, 1H), 3.91 (dd, J¼4.5, 9.8 Hz,
0.7H), 3.77e3.90 (m, 3.3H), 3.55 (s, 3H), 3.54 (s, 2H), 3.34e3.43 (m,
2.3H), 3.29 (dd, J¼9.7, 9.8 Hz, 1H), 2.10 (s, 2H), 2.06 (s, 3H); 13C NMR
butyldimethylsilyl)-a-D D2-oxazoline (6)
-mannopyrano[20,30]-
To a solution of 7 (354 mg, 0.81 mmol) in anhydrous DMA
(4.0 mL) was added NaI (243 mg, 1.62 mmol), and the mixture was
stirred at 120 ꢁC for 46 h under an argon atmosphere. The progress
of the reaction was checked by silica gel TLC, developed with CHCl3/
MeOH (50:1), Rf for 6: 0.58. The reaction was diluted H2O and or-
ganic materials were extracted with Et2O three times. The com-
bined organic phases were washed with brine and dried over
anhydrous Na2SO4, then concentrated in vacuo. The residue was
charged on a silica gel column (20 mL). Elution with hexane/EtOAc
(D2O, d: 1.7 for CH3CN as an internal standard) d: 176.5, 175.5, 93.4,
93.4, 77.4, 77.0, 75.8, 72.4, 71.6 (ꢂ2), 69.3, 60.8, 60.7, 60.6, 54.8, 53.9,
22.6, 22.5. Its 1H and 13C NMR spectra were in good accordance with
those previously reported.5 The yield (46%) in this two-step
transformation was estimated by comparing the integration of
signals of in 1H NMR of 1a with those of methyl
b-D-glucopyrano-
side, which was added as the internal standard.4
(5:1) furnished 6 (307 mg, 87%) as a yellow oil; [
a
]
23 þ55.5 (c 0.33,
D
CHCl3); IR nmax 2949, 2929, 2854, 2831, 1672, 1506, 1387, 1217, 1119,
Acknowledgements
1097, 1036, 997, 982, 831, 775 cmꢀ1 1H NMR (CDCl3)
; d: 6.99 (dd,
J¼3.2, 9.2 Hz, 1H), 6.98 (dd, J¼3.2, 9.2 Hz, 1H), 6.79 (dd, J¼3.2,
9.2 Hz, 1H), 6.78 (dd, J¼3.2, 9.2 Hz, 1H), 5.72 (s, 1H), 4.77 (dd, J¼6.2,
9.4 Hz, 1H), 4.26 (d, J¼9.4 Hz, 1H), 3.74 (s, 3H), 3.74 (dd, J¼4.1,
11.1 Hz, 1H). 3.71 (dd, J¼2.3, 11.1 Hz, 1H). 3.66 (ddd, J¼2.3, 4.1,
10.0 Hz, 1H), 3.48 (s, 3H), 3.27 (dd, J¼6.2, 10.0 Hz, 1H), 2.02 (d,
J¼2.0 Hz, 3H), 0.84 (s, 9H), 0.001 (d, J¼2.0 Hz, 6H); 13C NMR (CDCl3)
This paper is dedicated to Professor Teruaki Mukaiyama in cel-
ebration of the 40th anniversary of the Mukaiyama aldol reaction.
The authors thank Mr. Nobuyuki Chishima and Dr. Eriko Suzuki of
this lab, for their help in the early phase of this study, and Mr. Sho
Inomata for discussion. This work was supported both by a Grant-
in-Aid for Scientific Research (No. 23580152) and MEXT-supported
program for the strategic research foundation at private universi-
ties (centers of excellence for research) in ‘molecular nanotech-
nology for green innovation’, FY 2012-2016 and acknowledged with
thanks.
d
: 165.68, 154.85, 150.37, 117.86 (ꢂ2), 114.56 (ꢂ2), 97.64, 82.15,
77.25, 68.98, 68.91, 62.50, 58.66, 55.63, 25.88 (ꢂ3), 18.34, 14.17,
ꢀ5.31, ꢀ5.43. Anal. Calcd for C22H35NO6Si: C, 60.38; H, 8.06, N, 3.20.
Found: C, 60.19; H, 8.14, N, 3.04.
4.10. Confirmation of the regio- and stereochemistry of 6
A solution of 6 (68 mg, 0.16 mmol) in a mixture of THF (1.4 mL)
References and notes
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L) was stirred for 1 h at 0 ꢁC. The reaction was
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ꢀ
ꢀ
2. Auge, C.; David, S.; Gautheron, C.; Malleron, A.; Cavaye, B. New J. Chem. 1988, 12,
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deprotected form 1c; 1H NMR (CDCl3)
d
: 6.93 (dd, J¼3.0, 9.0 Hz, 1H),
6.92 (dd, J¼3.0, 9.0 Hz, 1H), 6.79 (dd, J¼3.0, 9.0 Hz, 1H), 6.78 (dd,
J¼3.0, 9.0 Hz, 1H), 6.00 (d, J¼7.7 Hz, 1H), 5.39 (d, J¼1.7 Hz, 1H), 4.54
(ddd, J¼1.5, 4.7, 7.7 Hz, 1H), 4.34 (dd, J¼4.7, 9.5 Hz, 1H), 3.74e3.82
(m, 2H), 3.74 (s, 3H), 3.71 (ddd, J¼3.0, 4.1, 9.7), 3.59 (s, 3H), 3.38 (dd,
J¼9.5, 9.7 Hz, 1H), 2.07 (s, 3H). The contamination of 2-amino-3-O-
acetyl derivative caused by another mode of oxazoline ring opening
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was suggested,
d
: 5.41 (dd, J¼3.9, 9.0 Hz, 1H), 5.13 (d, J¼1.7 Hz, 1H),
2.18 (s 3H). This byproduct was related to the less polar spot of two
[CHCl3/MeOH (4:1), Rf 0.67 and 0.57] on silica gel TLC analysis of the
crude mixture.