An expedient synthesis of D-callipeltose

Article abstract of DOI:10.1016/S0957-4166(01)00146-X

Methyl D-callipeltose 12 and D-callipeltose 4 were synthesized from D-glucal 5 in 10 and 11 steps, respectively. The synthesis features an azide displacement reaction of an α-nosyloxy ketone 7 and a highly diastereoselective C-methylation of α-azido keton

Full text of DOI:10.1016/S0957-4166(01)00146-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 937–942
An expedient synthesis of
D-callipeltose
Ainoliisa J. Pihko,a,b K. C. Nicolaoua,* and Ari M. P. Koskinenb,*
aDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA and Department of Chemistry and Biochemistry,
University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
bLaboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology,
FIN-02015 HUT, Finland
Received 9 March 2001; accepted 19 March 2001
Abstract—Methyl
D-callipeltose 12 and D-callipeltose 4 were synthesized from D-glucal 5 in 10 and 11 steps, respectively. The
synthesis features an azide displacement reaction of an a-nosyloxy ketone 7 and a highly diastereoselective C-methylation of
a-azido ketone 8. © 2001 Elsevier Science Ltd. All rights reserved.
The deoxy amino sugar 4 contains an unusual five-
membered oxazolidinone ring fused to the sugar back-
bone at positions 3 and 4. Both enantiomers of 4 have
1. Introduction
Callipeltoside A 1 belongs to a new class of cyclodep-
sipeptides called callipeltins. The molecules were iso-
lated in 1996 from the shallow water lithistid sponge
Callipelta sp., a native of New Caledonia.1,2 They were
found to inhibit in vitro proliferation of KB and P338
cells and to protect cells infected with HIV. Struc-
turally, 1 consists of a macrocyclic lactone linked to a
unique dienyne cyclopropane side chain and the deoxy
amino sugar, callipeltose, 4 (Fig. 1). The absolute stereo-
chemistry of the molecule has not been established.
been synthesized—methyl
from
-rhamnose8 and methyl
from methyl
-mannose.9 Herein we report an expedi-
ent synthesis of a- -callipeltose 4 from -glucal 5.
L
-callipeltose in 10 steps
L
D
-callipeltose in 14 steps
D
D
D
2. Results and discussion
The a,b-unsaturated ketone 6 was synthesized from
D
-glucal in three steps (Scheme 1).10 A sequence of
12,13
There has been considerable synthetic interest in 1
tosylation (TsCl, pyr.)11 and reduction with LiAlH4
although no total synthesis has been reported to date.3–7
effected deoxygenation of the 6-position of
D
-glucal 5.
Figure 1. Structures of callipeltosides A–C, 1–3.
* Corresponding authors. Tel.: +1 858 784 2400; fax: +1 858 784 2103 (K.C.N.); tel.: +358 9 451 2527; fax: +358 9 451 2538 (A.M.P.K.); e-mail:
kcn@scripps.edu; ari.koskinen@hut.fi
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00146-X

938
A. J. Pihko et al. / Tetrahedron: Asymmetry 12 (2001) 937–942
O
O
O
O
O
HO
HO
e
f
a,b,c
d
HO
N3
NsO
N3
HO
O
O
OH
O
5
6
7
8
9
g
O
OH
OMe
O
OMe
OMe
O
OMe
OMe
O
OMe
OH
j
h,i
k
BocHN
N3
HN
O
HN
O
HO
HO
O
O
4: D-callipeltose
12: D-methyl callipeltose
11
10
Scheme 1. Synthesis of
D
-callipeltose. Reagents and conditions: (a) TsCl, py, CH2Cl2, 0°C“rt, 78%; (b) LiAlH4, THF, D, 59%;
(c) MnO2, CH2Cl2, rt, 66%; (d) NsCl, py, CH2Cl2, 0°C“rt, 80%; (e) n-Bu4NN3, CH2Cl2, 0°C“rt, 95%; (f) MeLi, THF, −100°C,
77%; (g) m-CPBA, NaHCO3, MeOH, 0°C“rt, 60%; (h) MeI, Ag2O, Et2O, D, 72%; (i) H2, 10% Pd/C, Boc2O, EtOAc, rt, 62%;
(j) t-BuOK, THF, 0°C“rt, 69%; (k) 2 M H2SO4 in 1:1 H2O/dioxane, 60–70°C, 48%. Rt=room temperature, NsCl=nosyl
chloride, py=pyridine, m-CPBA=m-chloroperbenzoic acid, Boc=t-butoxycarbonyl.
14
The resulting
D-rhamnal was oxidized with MnO2 to
Nu
give a,b-unsaturated ketone 6. The next task was to
introduce a nitrogen atom at the 4-position of the sugar
by azide displacement of a suitable leaving group.
N3
O
O
Me
For this purpose, several leaving groups, including
mesylate,15 triflate15 and imidazolyl sulfonate,16 were
examined, but only the nosylate group17 could be dis-
placed at an acceptable rate without decomposition.
The nosylate 7 was obtained by the action of nosyl
chloride and pyridine on 6 in 80% yield along with ca.
3–5% of its C-(4) epimer. Sodium azide was found to be
too basic for the displacement reaction; stirring 7
overnight in DMSO with NaN3 at room temperature
gave, in addition to recovered starting material, ca. 1:1
mixture of both epimers of 8, presumably due to
product enolization. However, tetra-n-butylammonium
azide18,19 furnished the desired azide 8 in 90% yield
along with 5–10% of its C-(4) epimer.20 The C-methyla-
tion with methyllithium in THF at −100°C gave the
Nu
H
Figure 2. Preferred approach of nucleophile in the conversion
of 8 to 9.
ence of Boc-anhydride, furnished amide 11,30 setting the
stage for the oxazolidinone ring closure. Thus, exposure
of the tertiary alcohol 11 to potassium t-butoxide in
THF, following the procedure of Davies et al., fur-
nished the methyl glycoside 12.31 Finally, the glycoside
was hydrolyzed with 2 M sulfuric acid in water/dioxane
(1:1) at 60°C,32,33 concluding the synthesis of
tose 4 in 11 steps from commercially available
D
-callipel-
-glucal
D
5.
tertiary alcohol
9
in 77% yield as
a
single
diastereomer.14,21 The observed selectivity is rational-
ized through a synergy of steric and stereoelectronic
considerations, as described in Fig. 2: the axially dis-
posed azide group prevents attack from the Re face of
the carbonyl, and the electronegativity of the nitrogen
favors attack from the opposite (Si ) face.
3. Conclusion
In conclusion, methyl
tose 4 were synthesized in a highly selective manner
starting from -glucal 5 in 10 and 11 steps, respectively.
D
-callipeltose 12 and
D-callipel-
D
Key features of this synthesis, the shortest reported to
date for 4, include: (i) readily available starting materi-
als; (ii) use of an a-nosyloxy ketone 7 en route to azide
8; and (iii) a highly diastereoselective C-methylation
rationalized in Fig. 2.
The next objective was to install the final two stereocen-
ters of the sugar. Epoxidation accompanied by con-
comitant stereo- and regioselective opening of the
epoxide is a useful method to functionalize the double
bond in glucals.22–28 Thus, reaction of 9 with m-CPBA
in methanol in the presence of NaHCO3 led to the
stereoselective formation of 10 in 60% yield. Methyla-
tion of the newly created alcohol with MeI and Ag2O29
cleanly alkylated the secondary hydroxyl group. Subse-
quent palladium-catalyzed hydrogenation reduced the
azide to the corresponding amine, which, in the pres-
4. Experimental
All reactions were carried out under an argon atmo-
sphere with dry solvents under anhydrous conditions, if

A. J. Pihko et al. / Tetrahedron: Asymmetry 12 (2001) 937–942
939
necessary. Anhydrous solvents were obtained by pass-
ing them through commercially available activated alu-
mina columns. Yields refer to chromatographically
and spectroscopically (1H NMR) homogeneous materi-
als, unless otherwise stated. All reagents were pur-
chased at highest commercial quality and used without
further purification, unless otherwise stated. All reac-
tions were monitored by thin-layer chromatography
carried out on 0.25 mm E. Merck silica gel plates
(60F-254) using UV light as visualizing agent and
acidic PMA (2.5% phosphomolybdic acid, 1.5% o-
phosphoric acid and 5% sulfuric acid in water) or 1%
aqueous potassium permanganate solution and heat as
developing agents. E. Merck silica gel (60, particle size
0.040–0.063 mm) was used for flash column chro-
matography. NMR spectra were recorded on Bruker
DRX-600, DRX-500 or AMX-400 instruments and
calibrated using residual undeuterated solvents as an
internal reference (CDCl3 7.26 ppm, MeOH 3.34
ppm). The following abbreviations are used to explain
the multiplicities: s=singlet; d=doublet; t=triplet;
q=quartet; m=multiplet; b=broad. IR spectra were
recorded on a Perkin–Elmer 1600 series FT-IR spec-
trometer. Optical rotations were recorded on a Perkin–
Elmer 241 polarimeter. High resolution mass spectra
(HRMS) were recorded on an IonSpec mass spectrom-
eter under MALDI-FTMS conditions with NBA or
DHB as the matrix. Low resolution mass spectra were
recorded on a Hewlett Packard 5971A benchtop GC/
MS. Melting points (mp) are uncorrected and were
recorded on a Thomas–Hoover Unimelt capillary
melting point apparatus.
After stirring the reaction for 1 h, the mixture was
cooled to 0°C and quenched slowly with H2O (1.5
mL), 15% NaOH (1.5 mL) and H2O (4.5 mL). The
resulting slurry was diluted with Et2O, filtered through
a pad of Celite (Et2O rinse) and concentrated. Purifi-
cation by dry-column flash chromatography34 (silica,
20–100% EtOAc/hexanes) provided
D-rhamnal as a
white solid (1.02 g, 59% yield). Rf 0.37 (EtOAc); mp
72–73°C (Et2O/hexanes) (lit.35 71–73°C (EtOAc/hex-
1
anes)); H NMR (500 MHz, CDCl3) l 6.32 (dd, J=
6.0, 1.6 Hz, 1H), 4.72 (dd, J=6.0, 2.2 Hz, 1H), 4.21
(app. d, J=6.3 Hz, 1H), 3.87 (dq, J=9.8, 6.3 Hz, 1H),
3.43 (app. t, J=8.6 Hz, 1H), 1.39 (d, J=6.3 Hz, 3H).
4.2. 1,5-Anhydro-2,6-dideoxy-
D
-erythro-hex-1-enit-ulose
6
To a stirred solution of
D-rhamnal (100 mg, 0.768
mmol) in CH2Cl2 (7.5 mL) at room temperature was
added MnO2 (200 mg, 2.30 mmol). After 3 h, more
MnO2 (200 mg, 2.30 mmol) was added and the stirring
was continued. After 15 h, the reaction mixture was
diluted with CH2Cl2 (10 mL), filtered through a pad of
Celite (EtOAc rinse) and concentrated. Purification by
flash chromatography (silica, 40–50% EtOAc/hexanes)
provided 65 mg of 6 as a white volatile solid (66%
yield). Rf 0.66 (EtOAc); mp 91–92°C (Et2O/hexanes)
1
(lit.36 92–93°C); H NMR (500 MHz, CDCl3) l 7.39
(app. d, J=5.7 Hz, 1H), 5.46 (d, J=5.7 Hz, 1H), 4.20
(dqd, J=12.9, 6.4, 0.7 Hz, 1H), 3.54 (s, 1H), 1.57 (d,
J=6.4 Hz, 3H).
4.1.
D
-Rhamnal
4.3. 1,5-Anhydro-2,6-dideoxy-4-O-nosyl- -erythro-hex-
D
1-enit-3-ulose 7
To a stirred solution of
D
-glucal 5 (2.50 g, 17.1 mmol)
in pyridine (42 mL) and CH2Cl2 (42 mL), cooled at
0°C, was added tosyl chloride (4.89 g, 25.7 mmol) and
the cooling bath was removed. After stirring for 2.5 h
at ambient temperature, the reaction mixture was
cooled again to 0°C, quenched with water (5 mL) and
stirred for 30 min. More water (20 mL) was added,
the organic layer was separated and washed with sat.
aq. CuSO4 (3×20 mL) and water (3×20 mL). The
combined aqueous phases (excluding the first water
layer) were extracted with CH2Cl2 (2×20 mL) and
those organic extracts were washed with water (2×10
mL). The combined organic extracts were washed with
brine (20 mL), dried (Na2SO4), filtered and concen-
To a stirred solution of 6 (0.212 g, 1.65 mmol) in
CH2Cl2 (8.0 mL) at 0°C were added pyridine (0.667
mL, 8.25 mmol) and nosyl chloride (0.733 g, 3.31
mmol). The reaction mixture was allowed to warm to
room temperature over 2 h, and after stirring the
mixture for a further 3 h more nosyl chloride (0.367 g,
1.66 mmol) and pyridine (0.667 mL, 8.25 mmol) were
added. After 12 h the reaction mixture was cooled to
0°C and water (2 mL) was added. After stirring for 30
min more water (10 mL) was added, the aqueous layer
was separated and extracted with CH2Cl2 (2×10 mL),
the combined organic layers were washed with brine (5
mL), dried (Na2SO4), filtered and concentrated. Purifi-
cation by dry-columm flash chromatography (silica,
15–30% EtOAc/hexanes) provided 7 as a yellow crys-
talline solid (0.411 g, 80% yield). Rf 0.60 (50% EtOAc/
hexanes); mp 93°C; [h]D +138.8 (c 1.07, CHCl3); IR
(film) 3108, 1695, 1598, 1533, 1353, 1256, 1188, 1026,
854, 780 cm−1; 1H NMR (500 MHz, CDCl3) l 8.39
(app. d, J=9.2 Hz, 2H), 8.19 (app. d, J=9.2 Hz, 2H),
7.35 (d, J=5.9 Hz, 1H), 5.37 (d, J=5.9 Hz, 1H), 5.02
(d, J=12.1 Hz, 1H), 4.54 (dq, J=12.1, 6.2 Hz, 1H),
1.63 (d, J=6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
l 180.0, 163.5, 150.8, 142.1, 129.7, 124.1, 105.0, 79.6,
77.4, 17.4; HRMS (MALDI) calcd for C12H11NO7S
(M+) m/z: 313.0256, found 313.0286.
trated to provide crude 6-O-tosyl-D-glucal as a yellow
oil (3.99 g, 78% yield). Rf 0.55 (EtOAc); 1H NMR
(400 MHz, CDCl3) l 7.81 (d, J=8.2 Hz, 2H), 7.36 (d,
J=8.2 Hz, 2H), 6.24 (dd, J=6.1, 1.6 Hz, 1H), 4.74
(dd, J=6.1, 2.1 Hz, 1H), 4.48 (dd, J=11.4, 3.8 Hz,
1H), 4.27 (app. d, J=11.4 Hz, 2H), 3.91 (ddd, J=
10.0, 3.8, 2.1 Hz, 1H), 3.77 (dd, J=10.0, 7.3 Hz, 1H),
2.45 (s, 3H).
To a stirred solution of 6-O-tosyl-D-glucal (3.99 g,
13.3 mmol) in THF (30 mL) at 0°C was added LiAlH4
(0.9 M solution in THF, 44.2 mL, 39.9 mmol) drop-
wise and the reaction mixture was heated to reflux.

940
A. J. Pihko et al. / Tetrahedron: Asymmetry 12 (2001) 937–942
1
4.4. 1,5-Anhydro-4-azido-2,6-dideoxy-
D
-threo-hex-1-
997, 944, 814 cm−1; H NMR (500 MHz, CDCl3) l 4.76
(s, 1H), 4.03 (qd, J=6.5, 1.2 Hz, 1H), 3.62 (br s, 1H),
3.36 (s, 3H), 3.30 (d, J=11.0 Hz, 1H), 3.24 (s, 1H), 2.71
(d, J=11.0 Hz, 1H), 1.39 (s, 3H), 1.34 (d, J=6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) l 102.0, 73.2, 70.0,
64.2, 55.5, 23.5, 18.1; HRMS (MALDI) calcd for
C8H15N3O4Na (M+Na+) m/z: 240.0955, found
240.0956.
enit-3-ulose 8
To a stirred solution of 7 (190 mg, 0.606 mmol) in
CH2Cl2 (3.3 mL) at 0°C was added n-Bu4NN3 (0.651 g,
2.29 mmol) [CAUTION]19 in CH2Cl2 (0.5 mL) via
cannula. The reaction mixture was allowed to warm to
room temperature over 1.5 h and stirred at that temper-
ature for 1 h. Water (5 mL) was added, the aqueous
layer was extracted with CH2Cl2 (2×10 mL), the com-
bined organic extracts were washed with brine (5 mL)
and dried (Na2SO4), filtered and concentrated. Purifica-
tion by dry-column flash chromatography (silica, 10–
20% EtOAc/hexanes) provided 8 as a yellow oil (88 mg,
95% yield). Rf 0.43 (33% EtOAc/hexanes); [h]D −78.0 (c
0.383, CHCl3); IR (film) 3378, 2919, 2106, 1675, 1593,
4.7. Methyl 4-azido-4,6-dideoxy-3-C,2-O-dimethyl-a-
talo-pyranoside
D-
To a stirred solution of 10 (70 mg, 0.322 mmol) in Et2O
(2.0 mL) at room temperature were added MeI (0.200
mL, 3.22 mmol) and freshly prepared Ag2O29 (0.224 g,
0.967 mmol). The reaction mixture was protected from
light and heated to reflux. After stirring under reflux for
5 h, the reaction was diluted with EtOAc (10 mL),
filtered through a pad of Celite (EtOAc rinse) and
concentrated. Purification by flash chromatography (sil-
ica, 5–15% EtOAc/hexanes) provided the azidomethyl
glycoside as an oil (53 mg, 72% yield). Rf 0.33 (33%
EtOAc/hexanes); [h]D +164.8 (c 0.708, CHCl3); IR
(film) 3483, 2931, 2105, 1455, 1349, 1102, 1055, 597
1
1414, 1274, 1050 cm−1; H NMR (500 MHz, CDCl3) l
7.37 (d, J=6.0 Hz, 1H), 5.49 (dd, J=6.0, 0.9 Hz, 1H),
4.53 (qd, J=6.6, 3.1 Hz, 1H), 3.81 (d, J=3.1 Hz, 1H),
1.48 (d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
l 187.1, 163.6, 104.9, 76.9, 63.8, 15.3; HRMS (MALDI)
+
calcd for C6H8NO2 (MH−N2 ) m/z: 126.0550, found
126.0554.
1
4.5. 1,5-Anhydro-4-azido-2,6-dideoxy-3-C-methyl-
lyxo-hex-1-enitol 9
D
-
cm−1; H NMR (400 MHz, CDCl3) l 4.79 (s, 1H), 4.00
(qd, J=6.5, 1.6 Hz, 1H), 3.72 (d, J=1.0 Hz, 1H), 3.49
(s, 3H), 3.36 (s, 3H), 3.11 (br s, 1H) 2.90 (s, 1H), 1.40
(d, J=1.0 Hz, 3H), 1.35 (d, J=6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) l 98.4, 82.0, 70.1, 69.6, 64.3, 59.8,
55.2, 24.5, 17.9; HRMS (MALDI) calcd for
C9H17N3O4Na (M+Na+) m/z: 254.1111, found
254.1112.
To a stirred solution of 8 (95 mg, 0.620 mmol) in THF
(3.1 mL) at −100°C was added MeLi (1.5 M solution in
Et2O, 0.500 mL, 0.744 mmol) dropwise. After 1.5 h, sat.
aq. NH4Cl (1.0 mL) was added and the reaction mix-
ture was allowed to warm to room temperature. The
aqueous layer was extracted with EtOAc (2×5 mL), the
combined organic extracts were washed with brine (5
mL), dried (Na2SO4), filtered and concentrated. Purifi-
cation by dry-column flash chromatography (silica, 10–
25% EtOAc/hexanes) provided 9 as a yellow oil (81 mg,
77% yield). Rf 0.15 (20% EtOAc/hexanes); [h]D +84.2 (c
0.483, CHCl3); IR (film) 3413, 2919, 2097, 1637, 1449,
4.8. Methyl 4-(tert-butoxycarbonylamino)-4,6-dideoxy-
3-C,2-O-dimethyl-a- -talo-pyranoside 11
D
To a stirred solution of the methyl glycoside (26 mg,
0.112 mmol) and Boc2O (49 mg, 0.225 mmol) in EtOAc
(0.50 mL) at room temperature under argon was care-
fully added Pd/C (10%, 2 mg). The reaction flask was
evacuated and placed under an H2 atmosphere. After 4
h more Pd/C (10%, 2 mg) was added. After stirring for
1 h the reaction flask was purged with argon, the
mixture was filtered through a pad of Celite and con-
centrated. Purification by flash chromatography (silica,
10–20% EtOAc/hexanes with 2% Et3N) provided 11 as
an oil (21 mg, 62% yield). Rf 0.28 (33% EtOAc/hex-
anes); [h]D +59.4 (c 0.500, CHCl3) IR (film) 3429, 2929,
1716, 1503, 1170, 1060 cm−1; 1H NMR (500 MHz,
CDCl3) l 5.30 (d, J=10.4 Hz, 1H), 4.73 (s, 1H), 4.01
(qd, J=6.4, 1.7 Hz, 1H), 3.49 (dd, J=10.4, 1.7 Hz,
1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.23 (s, 1H) 2.91 (s, 1H),
1.44 (s, 9H), 1.41 (s, 3H), 1.15 (d, J=6.4 Hz, 3H); 13C
NMR (150 MHz, CDCl3) l 156.5, 98.6, 83.0, 79.3, 68.0,
65.0, 59.4, 58.4, 55.2, 28.3, 23.8, 17.1; HRMS (MALDI)
calcd for C14H27NO6Na (M+Na+) m/z: 328.1730, found
328.1731.
1378, 1232, 1132, 1049, 944, 820, 750 cm−1; H NMR
1
(500 MHz, CDCl3) l 6.27 (d, J=6.3 Hz, 1H), 4.70 (dd,
J=6.3, 2.2 Hz, 1H), 4.19 (qd, J=6.5, 0.9 Hz, 1H), 3.34
(br s, 1H), 2.24 (br s, 1H) 1.45 (d, J=6.6 Hz, 3H), 1.43
(s, 3H); 13C NMR (100 MHz, CDCl3) l 143.6, 104.8,
72.1, 68.8, 68.4, 29.5, 18.0. Low resolution mass spec-
trum (GC/MS) calcd for C7H11N3O2 (M+) 169, found
169.
4.6. Methyl 4-azido-4,6-dideoxy-3-C-methyl-a- -talo-
pyranoside 10
D
To a stirred solution of 9 (100 mg, 0.591 mmol, 100
mol%) in MeOH (3.1 mL) at 0°C were added NaHCO3
(153 mg, 1.86 mmol, 315 mol%) and m-CBPA (55–60%,
0.321 g, 1.86 mmol, 315 mol%). After stirring for 1 h
sat. aq. NaHCO3 (2 mL) was added, the aqueous layer
was extracted with EtOAc (2×10 mL), the combined
organic extracts were washed with brine (5 mL) and
dried (Na2SO4), filtered and concentrated. Purification
by flash chromatography (silica, 20–30% EtOAc/hex-
anes) provided 10 as an oil (76 mg, 60% yield). Rf 0.28
(33% EtOAc/hexanes); [h]D +143.8 (c 0.417, CHCl3); IR
(film) 3449, 2921, 2109, 1449, 1343, 1261, 1126, 1061,
4.9. a-D-Methyl callipeltose 12
To a stirred solution of 11 (28 mg, 0.0917 mmol) in
THF (0.50 mL) at 0°C was added t-BuOK (0.9 M
solution in THF, 0.204 mL, 0.183 mmol) dropwise and

A. J. Pihko et al. / Tetrahedron: Asymmetry 12 (2001) 937–942
941
the cooling bath was removed. After 4 h at room
temperature more t-BuOK (0.051 mL, 0.46 mmol) was
added. After 1 h sat. aq. NH4Cl (1 mL) was added, the
aqueous layer was extracted with EtOAc (2×5 mL), the
combined organic extracts were washed with brine (5
mL) and dried (Na2SO4), filtered and concentrated.
Purification by flash chromatography (silica, 1–3%
MeOH/CH2Cl2) provided 15 mg of 12 as a white solid
(69% yield). Rf 0.28 (5% MeOH/CH2Cl2); mp 145–
146°C (hexanes) (lit.8 147–148°C); [h]D +91.6 (c 1.06,
CHCl3) (lit.9 [h]D +76 (c=1.0, CHCl3)); IR (film) 3295,
2. Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.
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1
2931, 1747, 1376, 1267, 1104, 1060, 670 cm−1; H NMR
9. Gurjar, M. K.; Reddy, R. Carbohydr. Lett. 1998, 3,
169–172.
(500 MHz, MeOH-d4) l 4.48 (d, J=6.1 Hz, 1H), 3.94
(qd, J=6.5, 2.0 Hz, 1H), 3.52 (s, 3H), 3.45 (d, J=2.0
Hz, 1H), 3.41 (s, 3H), 3.38 (d, J=6.1 Hz, 1H), 1.50 (s,
3H), 1.12 (d, J=6.5 Hz, 3H); 1H NMR (400 MHz,
CDCl3) l 6.69 (br s, 1H), 4.60 (d, J=5.6 Hz, 1H), 3.89
(qd, J=6.5, 2.0 Hz, 1H), 3.53 (s, 3H), 3.41 (s, 3H), 3.37
(d, J=2.0 Hz, 1H), 3.19 (d, J=5.6 Hz, 1H), 1.54 (s,
3H), 1.17 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) l 159.1, 101.6, 81.9, 81.1, 63.7, 61.4, 60.6, 55.0,
23.3, 15.6; HRMS (MALDI) calcd for C10H17NO5Na
(M+Na+) m/z: 254.0999, found 254.1001.
10. On a larger scale,
D-glucal can be prepared from tri-O-
acetyl- -glucal by saponification of the three acetyl
D
groups with K2CO3 in MeOH.
11. Brimacombe, J. S.; Da’aboul, I.; Tucker, L. C. N. Carbo-
hydr. Res. 1971, 19, 276–280.
12. Boivin, J.; Montagnac, A.; Monneret, C.; Pa¨ıs, M. Car-
bohydr. Res. 1980, 85, 223–242.
13. Fraser-Reid, B.; Kelly, D. R.; Tulshian, D. B.; Ravi, P. S.
J. Carbohydr. Chem. 1983, 2, 105–114.
14. Thiem, J.; Elvers, J. Chem. Ber. 1981, 114, 1442–1454.
15. Csuk, R.; Huegener, M.; Vasella, A. Helv. Chim. Acta
1988, 71, 609–618.
4.10. a-D-Callipeltose 4
16. Hanessian, S.; Vate`le, J.-M. Tetrahedron Lett. 1981, 22,
3579–3582.
17. Nicolaou, K. C.; Li, J.; Zenke, G. Helv. Chim. Acta 2000,
83, 1977–2006.
A solution of 12 (4.3 mg, 0.186 mmol) in H2SO4 (2 M
in H2O/1,4-dioxane (1:1), 0.20 mL) was heated to 60°C
for 30 h. Saturated aq. NaHCO3 (1 mL) was added, the
solution was saturated with NaCl and extracted with
25% EtOH/CHCl3 (20×1 mL). The combined organic
extracts were washed with brine and dried (Na2SO4),
filtered and concentrated. Purification by flash chro-
18. Preparation of tetra-n-butylammonium azide: Bra¨nd-
stro¨m, A.; Lamm, B.; Palmertz, I. Acta Chem. Scand. B
1974, 28, 699–701. Commercially available from TCI
America. The commercial material was used in this
synthesis.
19. Solutions of tetra-n-butylammonium azide in CH2Cl2 are
reported to form explosive products on storage. If stored
for longer times, the compound should be dissolved in
toluene, which gives a stable solution: Hansson, T. G.;
Kihlberg, J. O. J. Org. Chem. 1986, 51, 4490–4492.
20. b-Keto azides have been found to be prone to epimeriza-
tion: Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow,
R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030.
21. The C-(4) epimer was also removed at this stage.
22. Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. Soc.
1990, 112, 4085–4086.
matography (silica, 5% MeOH/CH2Cl2) afforded D-cal-
lipeltose 4 as a film (1.9 mg, 48% yield). Rf 0.13 (5%
MeOH/CH2Cl2); [h]D +25.3 (c 0.150, CHCl3); IR (film)
1
3313, 2924, 1737, 1449, 1273, 1261, 1061, 667 cm−1; H
NMR (500 MHz, CDCl3) l 5.56 (s, 1H), 5.13 (d, J=5.9
Hz, 1H), 4.06 (qd, J=6.5, 1.9 Hz, 1H), 3.60 (s, 3H),
3.38 (d, J=1.9 Hz, 1H), 3.24 (d, J=5.9 Hz, 1H), 2.99
(br s, 1H), 1.56 (s, 3H), 1.17 (d, J=6.5 Hz, 3H); 13C
NMR (150 MHz, CDCl3) l 158.3, 95.0, 81.9, 81.8, 63.6,
61.3, 60.8, 23.3, 15.8; HRMS (MALDI) calcd for
C9H15NO5Na (M+Na+) m/z: 240.0842, found 240.0843.
23. Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F. Tetra-
hedron Lett. 1991, 32, 959–962.
Acknowledgements
24. Bellucci, G.; Catelani, G.; Chiappe, C.; D’Andrea, F.
Tetrahedron Lett. 1994, 35, 8433–8436.
25. Upreti, M.; Vishwakarma, R. A. Tetrahedron Lett. 1999,
40, 2619–2622.
26. Saleh, T.; Rousseau, G. Synlett 1999, 617–619.
27. Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000,
2, 231–234.
28. Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem.
2001, 66, 1380–1386.
We thank Dr. D. H. Huang and Dr. G. Siuzdak for
NMR spectroscopic and mass spectrometric assistance,
respectively. Financial support for this work was pro-
vided by The Skaggs Institute for Chemical Biology,
The Ministry of Education Graduate School Program
(Finland) and the Emil Aaltonen Foundation (both to
A.J.P.).
29. Silver(I) oxide was prepared according to: Pearl, I. A.
Org. Syn. Coll. Vol. IV, 972–973, washed with MeOH
and Et2O and dried in vacuo.
30. Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetra-
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