Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 2: Role of the alditol side chain stereochemistry

Article abstract of DOI:10.1016/j.bmc.2013.12.052

Five alditol analogs 1b-1f of a novel glycolipid acremomannolipin A (1a), the potential Ca²⁺ signal modulator isolated from Acremonium strictum, were synthesized by employing a stereoselective β-mannosylation of appropriately protected mannose with five hexitols with different stereochemistry, and their potential on modulating Ca²⁺ signaling were evaluated All these analogs were more potent compared to the original compound 1a, and proved that mannitol stereochemistry of 1a was not critical for the potent calcium signal modulating

Full text of DOI:10.1016/j.bmc.2013.12.052

Bioorganic & Medicinal Chemistry 22 (2014) 945–959
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structure–activity relationship studies on acremomannolipin A, the
potent calcium signal modulator with a novel glycolipid structure 2:
Role of the alditol side chain stereochemistry
Nozomi Tsutsui a, Genzoh Tanabe a, Genki Gotoh a, Nao Morita a, Naohisa Nomura a, Ayako Kita b,
Reiko Sugiura b, , Osamu Muraoka a,
⇑
⇑
a Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
b Laboratory of Molecular Pharmacogenomics, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Five alditol analogs 1b–1f of a novel glycolipid acremomannolipin A (1a), the potential Ca2+ signal mod-
ulator isolated from Acremonium strictum, were synthesized by employing a stereoselective b-mannosy-
lation of appropriately protected mannose with five hexitols with different stereochemistry, and their
potential on modulating Ca2+ signaling were evaluated. All these analogs were more potent compared
to the original compound 1a, and proved that mannitol stereochemistry of 1a was not critical for the
potent calcium signal modulating.
Article history:
Received 8 November 2013
Revised 20 December 2013
Accepted 21 December 2013
Available online 2 January 2014
Keywords:
Acremomannolipin A
Glycolipid
Ó 2014 Elsevier Ltd. All rights reserved.
Calcium signal modulator
Acremonium strictum
SAR study
1. Introduction
Calcium signaling pathways are known to be widely prolifer-
ated throughout the cell and participate in all basic cellular func-
Recently, we isolated a novel glycolipid, acremomannolipin A
(1a),1 from Acremonium strictum, as a potential calcium signal
modulator using a newly developed chemical-genetic method.2
tions.4 The ability to manipulate Ca2+ signaling pathways would
provide a powerful tool for applications in therapeutic and biotech-
nological settings. In the present work, as the second attempt to
examine the SAR of 1a with the activity, the contribution of the ste-
reochemistry of the hexitol moiety was examined. Thus, five
homologs (1b–1f) with diastereomeric hexitol-talis were synthe-
sized and their potential as calcium signal modulators were exam-
ined (Fig. 2).
The structure of 1a is quite unique, in which
D-mannopyranose is
connected to -mannitol through a b-glycoside linkage. All the
D
hydroxyls in the mannose are highly masked as peresters with ali-
phatic acids, and thus the moiety is hydrophobic, whereas the
mannitol part exhibits the highly hydrophilic property.1 The com-
pound (1a) was found to show quite characteristic bioactive prop-
erty, enabling calcineurin deletion cells to grow in the presence of
Clꢀ, which would be caused by calcium signal modulating. The
activity was so potent as to exert the effect at a concentration of
200 nM. The first total synthesis of this unique compound was
accomplished by us via stereoselective b-mannosylation as the
OCOC7H15
OH
OH
C5H11COO
C5H11COO
O
O
OH
OH
C H11COO
5
key reaction.3a Concurrently, it’s
a-isomer (epi-1a) was also syn-
HO
OCOC7H15
O
thesized, and the calcium modulating activity was evaluated. As
the result, the activity was reduced upon the inversion of the con-
figuration at the anomeric center, but remained to some extents.
Thus, the b-configuration was found not critical for onset of the
activity, but preferable for the activity (Fig. 1).3b
acremomannolipin A (1a)
OH
C5H11COO
C5H11COO
C H11COO
5
O
OH
epi-1a
OH
HO
⇑
OH
Corresponding authors. Tel.: +81 6 4307 3642 (R.S.), +81 6 4307 4015 (O.M.).
E-mail addresses: sugiurar@phar.kindai.ac.jp (R. Sugiura), muraoka@phar.
Figure 1. Acremomannolipin A (1a) and the
a-anomer (epi-1a).
kindai.ac.jp (O. Muraoka).
0968-0896/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.12.052

946
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
OCOC7H15
C5H11COO
O
C5H11COO
O
C5H11COO
R
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
5
3
R =
R =
R =
R =
R =
R =
HO
(6-
HO
(1-
OH
OH
HO
HO
HO
2
HO
4
OH
OH
OH
OH
acremomannolipin A (1a)
(1- -mannito)
1b
1c
1d
-glucito)
1e
1f
D
D
-galactito)
D
-galactito)
(6-
D
(1-
D
-glucito)
(1-
L
-glucito)
Figure 2. Structures of acremomannolipin A (1a) and analogs 1b–1f with diastereomeric hexitol-tails.
The preparation of the regio-isomeric galactitol acceptor 3c was
2. Results and discussion
achieved by the following sequence: D-galactose diethyl dithioace-
tal (9), prepared according to a literature,6 was treated with
2,2-dimethoxypropane in a manner similar to that used for the
acetalization of 5 to give bis-acetonides, 2,3:4,5-di-O-isopropyli-
2.1. Preparation of acceptors (3b–3e and ent-3e) for
mannosylation
dene-
D-galactose diethyl dithioacetal (10) as the main bis-acetonide
In the synthetic methodology especially for the sugar related
molecules, selection of the protecting groups is the most important
step. In the total synthesis of 1a, 4,6-benzylidene protected man-
nosyl sulfoxide (2) was proved to be an appropriate donor for the
stereoselective b-mannosylation with a mannitol as the acceptor.5
Therefore, the target glycolipids 1b–1f were synthesized by the
b-selective mannosylation of the donor 2 with suitably protected
hexitols (3b–3e and ent-3e) as acceptors (Scheme 1).
(72%) along with small amount of 2,3:5,6-di-O-isopropylidene-
D-
galactose diethyl dithioacetal (11, 17%), which was also converted
to 10 under acidic conditions. Compound 10 was then treated with
tert-butyldimethylsilyl (TBS) chloride to give 6-O-(tert-butyldi-
methylsilyl)-2,3:4,5-di-O-isopropylidene-D-galactose diethyl
dithioacetal (12) in 86% yield. The oxidative dethioacetalization
of 12 by NBS, and subsequent reduction of the resulting aldehyde
with NaBH4 gave the desired acceptor 3c in 91% yield.
The acceptors 3d and 3e were synthesyzed by the methods
analogous to those used for preparation of 3b and 3c. Thus,
Of the five acceptors 3b–3e and ent-3e, two
D
-galactito-hexitols,
-galactitol (3b)
6-O-tert-butyldimethylsilyl-2,3:4,5-di-O-isopropylidene-
2,3:4,5-di-O-isopropylidene-1-methoxymethyl-
D
and
D-
D
-glucose (D-13) was converted to the corresponding TBDPS ether,
6-O-(tert-butyldiphenylsilyl)- -glucitol (14) or its dithioacetal,
-glucose diethyl dithioacetal (18) in good yields. Upon acetoniza-
tion, 14 and 18 showed the different regioselectivity from 5 and 9,
giving 6-O-(tert-butyldiphenylsilyl)-1,2:3,4-di-O-isopropylidene-
galactitol (3c) were synthesized from
D-galactose (4) as the
D
common starting material. Thus, the primary hydroxyl in 4 was
selectively protected with tert-butyldiphenylsilyl (TBDPS) moiety,
and the resulting silyl ether was reduced with NaBH4 to give
D
6-O-(tert-butyldiphenylsilyl)-D-galactitol (5) in good yield. The
D
-glucitol (15, 77%) and 4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-
acetalization of 5 with 2,2-dimethoxypropane proceeded smoothly
to give 6-O-(tert-butyldiphenylsilyl)-2,3:4,5-di-O-isopropylidene-
O-isopropylidene- -glucose diethyl dithioacetal (19, 43%),
D
respectively, as the main bisacetonides, which were then con-
verted to 3d and 3e thtough the similar sequences to those used
for the preparation of 3b and 3c, respectively.
Finally, L-glucose (L-13) was exposed to the aforementioned
four step sequence to give the enantiomer (ent-3e) of 3e in good
D
-galactitol (6) and its regioisomer, 6-O-(tert-butyldiphenylsilyl)-
1,2:4,5-di-O-isopropylidene- -galactitol (7) in 81% and 11%,
D
respectively, via three steps from 4. These two regioisomers were
easily distinguishable with each other by the NMR spectral proper-
ties; the major isomer 6 showed a 1H NMR signal assignable to OH
at dH 2.35 as a doublet of doublets (J = 8.6 and 4.3 Hz), which cor-
responded to the primary alcoholic moiety, while the minor one 7
showed the OH signal as a doublet (J = 6.0 Hz) at dH 2.53 corre-
sponding to the secondary alcoholic moiety. In the 13C NMR spec-
tra, the carbinol carbon of the major isomer (6) resonated at dC
62.7, while the secondary carbinol carbon of the minor one (7)
shifted downfield up to dC 73.2. The minor isomer 7 could be isom-
erized to the major isomer 6 by subjecting 7 to the conditions em-
ployed for the acetalization of 5. The major isomer 6 was then
converted to the target acceptor 3b in 80% yield though meth-
oxymethylation and subsequent de-silylation of the resulting
MOM ether, 6-O-(tert-butyldiphenylsilyl)-2,3:4,5-di-O-isopropyli-
yield (Scheme 2).
2.2. Syntheses of heptitol diastereomers of acremomannolipin
A (1b–1f)
With 5 acceptors (3b–3e and ent-3e) in hand, the coupling reac-
tion of these 5 acceptors with mannosyl sulfoxide 2 in the presence
of trifluoromethanesulfonic anhydride (Tf2O) was examined. The
b-selectivity in the coupling reaction of 2 with acceptors 3b, 3c,
3d, 3e and ent-3e was excellent, giving corresponding b-manno-
sides 22b, 22c, 22d, 22e and 22f (b/a = >ca. 20/1) in 60, 69, 56,
69 and 59% yield, respectively (Scheme 3). The MOM protected
b-mannosides (22b and 22d) and the TBS protected b-mannosides
dene-1-methoxymethyl-D-galactitol (8) by action of TBAF.
OMOM
OTBS
O
O
O
O
HO
HO
O
O
OPMB
O
O
O
O
O
HO
O
HO
HO
O
O
Ph
O
O
+
1b 1f
O
O
BnO
O
OTBS
MOMO
OTBS
O
O
S
O
O
Ph
O
3b
-galactito)
3c
-galactito)
3d
-glucito)
3e
-glucito)
ent-3e
2
(6-
D
(1-D
(6-D
(1-D
(1-
L
-glucito)
Scheme 1. Retrosynthetic analysis of acremomannolipin A homologs 1b–1f.

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
947
iii
iii
OR
OH
2
OH
O
OH
O
2
TBDPSO
O
TBDPSO
O
1
1
1
1
O
O
O
O
OH
OH
O
OH
OH
O
O
TBDPSO
TBDPSO
TBDPSO
HO
TBDPSO
RO
iii
iii
2
2
6
6
+
4
4
+
3
5
3
5
4
4
5
3
OH
O
HO
O
O
OH
O
OH
O
5
6 : R = H
7
14
15 : R = H
16
iv
iv
8 : R = MOM
17 : R = MOM
i,ii
i,ii
6
6
v
v
HO
O
HO
O
3b
3d
OH
OH
OH
OH
1
1
HO
HO
OH
-galactose (
OH
-glucose (
D
D
-4)
D
D
-13)
iii
iii
vi
vi
OR
5
EtS
OH
O
OH
O
O
EtS
EtS
EtS
EtS
EtS
EtS
EtS 1
EtS
EtS 1
6
6
6
6
6
O
O
EtS
OH
O
OH
OH
O
O
5
iii
iii
EtS
1
5
5
1
1
1
+
+
3
2
4
3
3
3
O
2
4
2
OH
OH
OR
HO
HO
O
HO
O
O
O
OH
O
OH
O
O
9
10 : R = H
11
18
19 : R = H
20
vii
vii
12 : R = TBS
21 : R = TBS
viii
viii
3e
3c
HO
HO
O
OH
vi, iii, vii, viii
ent-3e
OH
OH
L
-glucose (L-13)
Scheme 2. Reagents and conditions: (i) TBDPSCl, imidazole, DMF, rt; (ii) NaBH4, MeOH, rt; (iii) 2,2-dimethoxypropane, concd H2SO4, acetone, rt; (iv) MOMCl, iPr2NEt, CH2Cl2,
rt; (v) TBAF, THF, rt; (vi) EtSH, concd HCl, 0 °C; (vii) TBSCl, Py, rt or TBSOTf, 2,6-lutidine, CH2Cl2, rt; (viii) NBS, acetone, ꢀ78 °C, then NaBH4, EtOH, rt.
(22c, 22e and 22f) showed their quasimolecular-ion [M+Na]+ peaks
at m/z 789 and 859, respectively. The NMR spectral properties of
these b-mannosides were similar with each other. For example,
in the 1H NMR spectrum of 22b–22f were shown signals due to
anomeric protons at d 4.50–4.57. The b-mannoside linkage was
confirmed by the NOE correlations between the signal due to the
anomeric proton at C10 and signals due to C30-H and C50-H.
Disruption of the calcineurin gene (ppb1+) in fission yeast re-
sulted in a Clꢀ-sensitive growth defect, thus calcineurin gene dele-
tion cells (Dppb1) grew in yeast extract peptone dextrose (YPD)
medium, but failed to grow in YPD medium containing 0.12 M
MgCl2 [see the filter paper disc containing DMSO (control) in
Figure 3A–C]. When a solution of acremomannolipin A (1a) in
DMSO was added onto the filter paper disc,
around the disc 1a (Fig. 3A–C). On the basis of the effect of 1a on
the growth of ppb1 cells in the presence of MgCl2, the activities
Dppb1 cells grew well
The selective removal of the PMB group at C20 in the coupled
products (22b–22f) were successfully conducted by DDQ to give
corresponding monoalcohols (23b–23f) in 79–92% yields, which
were then treated with octanoyl chloride to give the corresponding
octanoyl esters (24b–24f) in good yields. Simultaneous hydrogen-
olysis of both the benzyl and benzylidene moieties of 24b–24f over
palladium on carbon gave the desired trisalcohols (25b–25f),
which were then derived to the corresponding tetraesters (26b–
26f), by treating with hexanoic anhydride, in 63–86% yields in
two steps. Finally, the two acetonide moieties and the TBS or
MOM groups in 26b–26f were selectively removed without affect-
ing ester moieties under acidic conditions to give the target diaste-
reomers (1b–1f) of acremomannolipin A (1a) in 67–94% yields. All
the compounds showed quasimolecular-ion [M+Na]+ at m/z 787;
their molecular formula C38H68O15 were confirmed by the high res-
olution fast atom bombardment mass spectrometry (HRFABMS)
analysis. The 13C NMR spectroscopic properties of all the final
products were similar with those of 1a as shown in Table 1.
D
of homologs 1b–1f were relatively evaluated by comparison of
the size of colonies around the discs (the effect of 1a is estimated
to be +3). By addition of 1b–1f onto the filter paper discs, relatively
bigger colonies formed around the discs containing 1b (+5), 1c
(+3–+4), 1d (+4), 1e (+5) and 1f (+4) than that around the disc
containing 1a (Fig. 3A, B, C), proving that all homolog possessed
biological activity to affect cell integrity of fission yeast irrespec-
tive of the stereochemistry of the hexitol moiety. It is noteworthy
that, homologs 1b and 1e showed significant improvement for the
growth of
Dppb1 cells in the presence of MgCl2 (discs 1b and 1e).
Thus, the result indicated that they were better calcineurin modu-
lators than 1a and stereochemistry of the hexitol was found not
critical for the potent calcium signal modulating. Further studies
on SAR of 1a bearing the different side chains in length are in
progress.
3. Experimental
3.1. General
2.3. Bioassay of acremomannolipin A homologs (1b–1f)
The potencies of the synthesized homologs 1b–1f as calcium
signal modulators were examined according to the method devel-
oped by Sugiura and co-workers.2
Mps were determined on an AS ONE ATM-02 melting point
apparatus, and mps and bps are uncorrected. IR spectra were

948
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
OR
OCOC7H15
O
RO
RO
Ph
O
OMOM
O
O
OMOM
O
O
O
O
BnO
O
O
RO
iv
vi
H
1b
1c
H
H
O
O
NOE
O
O
22b : R = PMB
23b : R = H
25b : R = H
ii
iii
v
26b : R = COC5H11
24b : R = COC7H15
OR
OCOC7H15
O
O
RO
Ph
O
OTBS
O
OTBS
RO
RO
O
O
BnO
O
O
O
iv
O
vi
H
H
H
O
O
NOE
O
O
22c : R = PMB
23c : R = H
25c : R = H
ii
iii
v
26c : R = COC5H11
24c : R = COC7H15
OR
OCOC7H15
O
RO
Ph
O
O
O
O
O
O
RO
O
O
O
O
O
BnO
RO
iv
iv
iv
vi
vi
vi
i
H
2
1d
1e
H
H
MOMO
MOMO
O
NOE
O
22d : R = PMB
23d : R = H
25d : R = H
ii
iii
v
26d : R = COC5H11
24d : R = COC7H15
OR
OCOC7H15
O
RO
Ph
O
O
O
O
O
RO
O
O
O
O
O
O
BnO
RO
H
H
H
OTBS
OTBS
NOE
O
O
22e : R = PMB
23e : R = H
25e : R = H
ii
iii
v
26e : R = COC5H11
24e : R = COC7H15
OR
OCOC7H15
O
RO
Ph
O
O
O
O
O
RO
O
O
O
O
O
O
BnO
RO
1f
H
H
H
OTBS
OTBS
NOE
O
O
22f : R = PMB
23f : R = H
25f : R = H
26f : R = COC5H11
ii
iii
v
24f : R = COC7H15
Scheme 3. Reagents and conditions: (i) 3b–3e and ent-3e, Tf2O, DTBMP, CH2Cl2, ꢀ78 °C; (ii) DDQ, CH2Cl2, H2O, rt; (iii) CH3(CH2)6COCl, Py, DMAP, CH2Cl2, rt; (iv) H2, Pd–C,
AcOEt, rt; (v) [CH3(CH2)4CO]2O, Py, DMAP, CH2Cl2, rt; (vi) 90% TFA aq, 0 °C.
measured on a Shimadzu IRAffinity-1 spectrophotometer. NMR
spectra were recorded on a JEOL JNM-ECA 400 (400 MHz 1H,
Table 1
100 MHz 13C), a JEOL JNM-ECA 500 (500 MHz 1H, 125 MHz 13C),
13C NMR data for acremomannolipin A (1a) and diastereomers 1b–1f in CD3OD
JEOL JNM-ECA 700 (700 MHz 1H, 175 MHz 13C), or a JEOL JNM-
1aa
1bb
1ca
1da
1ea
1fc
ECA 800 (800 MHz 1H, 200 MHz 13C) spectrometer. Chemical shifts
(d) and coupling constants (J) are given in ppm and Hz, respec-
tively. Low-resolution and high-resolution mass spectra were re-
corded on a JEOL JMS-700T spectrometer. Optical rotations were
determined with a JASCO P-2200 polarimeter. Column chromatog-
raphy was effected over Fuji Silysia silica gel BW-200. All the or-
ganic extracts were dried over anhydrous sodium sulfate prior to
evaporation.
C1
C2
C3
C4
C5
C6
C10
C20
C30
C40
C50
C60
73.7
73.2
72.70
73.39
72.1
72.68
71.7
71.0
71.2
73.0
65.2
100.5
70.5
72.7
66.8
73.5
63.0
70.2
71.33
71.27
71.8
65.0
100.3
70.5
72.7
66.8
73.5
63.0
69.6
71.2
71.3
71.9
65.0
100.0
70.5
72.68
66.8
73.5
63.0
71.7
73.37
70.6
75.1
64.2
100.6
70.5
72.7
66.8
73.5
63.1
73.2
70.8
73.7
73.0
64.9
100.0
70.4
72.6
66.8
73.5
63.0
73.57
71.0
73.65
73.0
64.8
100.3
70.5
72.66
66.8
73.4
3.1.1. 6-O-(tert-Butyldiphenylsilyl)-2,3:4,5-di-O-isopropylidene-
63.0
D
-galactitol (6) and 6-O-(tert-butyldiphenylsilyl)-1,2:4,5-di-O-
isopropylidene- -galactitol (7)
To a suspension of -galactose (D-4) (1.00 g, 5.55 mmol) and
imidazole (757 mg, 11.1 mmol) in dimethylformamide (DMF,
a
b
c
D
Measured at 200 MHz.
Mesured at 175 MHz.
Measured at 125 MHz.
D

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
949
76.4 (C-2), 77.5 (C-4), 80.7 (C-5), 109.2/109.4 [C(CH3)2], 127.7
(4C)/129.71/129.75/135.7 (4C) (d, Ar), 133.08/133.11 (s, Ar). FAB-
MS m/z (%): 523 ([M+Na]+, 11), 135 (100). FABHRMS calcd for
C
28H40O6SiNa [M+Na]+: 523.2492; found: 523.2493.
3.1.2. 6-O-(tert-Butyldiphenylsilyl)-2,3:4,5-di-O-isopropylidene-
1-O-methoxymethyl- -galactitol (8)
D
To a solution of 6 (1.00 g, 2.00 mmol) in dichloromethane (CH2-
Cl2, 20 mL) were added N,N-diisopropylethylamine (1.02 mL,
6.00 mmol) and chloromethyl methyl ether (MOMCl, 0.45 mL,
6.00 mmol) at room temperature, and the mixture was stirred at
room temperature for 15 h. After being cooled with ice-water,
the reaction mixture was diluted with water, and the resulting
mixture was extracted with CH2Cl2. The extract was washed with
brine, and condensed in vacuo. The residue was purified by means
Figure 3. Suppression of the Clꢀ-sensitive growth defect of calcineurin deletion
cells by acremomannolipin A (1a) and the synthesized homologs 1b–1f. Calcineurin
of column chromatography (n-hexane–EtOAc, 8/1) to give
8
(902 mg, 83%) as a colorless oil. ½a D24
ꢁ
+0.75 (c 1.01, CHCl3). IR (neat)
deletion (
Filter paper containing DMSO (5
1e, and 1f contain 5 L of 100
D
ppb1) cells were spread onto the YPD medium containing 0.12 M MgCl2.
L) is used as a control. Filter papers 1a, 1b, 1c, 1d,
M DMSO solutions of 1a, 1b, 1c, 1d, 1e and 1f,
cmꢀ1: 1215, 1111, 1045. 1H NMR (400 MHz, CDCl3) d: 1.06 [s, 9H,
SiC(CH3)3], 1.35/1.39/1.40/1.43 [each s, 3H, C(CH3)2], 3.38 (s, 3H,
OCH3), 3.64 (dd, J = 10.8, 6.4 Hz, 1H, H-1a), 3.77–3.81 (m, 2H, H-3
and H-6a), 3.82 (dd, J = 10.8, 2.8 Hz, 1H, H-1b), 3.92 (dd, J = 10.8,
2.0 Hz, 1H, H-6b), 4.06–4.11 (m, 2H, H-4 and H-5), 4.21 (ddd,
J = 7.6, 6.4, 2.8 Hz, 1H, H-2), 4.68/4.70 (each d, J = 6.4 Hz, 1H,
OCH2O), 7.34–7.45 (m, 6H, Ar), 7.68–7.74 (m, 4H, Ar). 13C NMR
(100 MHz, CDCl3) d: 19.3 [SiC(CH3)3], 26.8 [3C, SiC(CH3)3], 26.96/
27.04/27.18/27.22 [C(CH3)2], 55.3 (OCH3), 63.6 (C-6), 68.0 (C-1),
77.5 (C-4), 78.4 (C-3), 79.6 (C-2), 81.3 (C-5), 96.7 (OCH2O), 109.7/
109.8 [C(CH3)2], 127.6 (4C)/129.59/129.62/135.6 (4C) (d, Ar),
133.3133.4 (s, Ar). FABMS m/z (%): 567 ([M+Na]+, 2), 99 (100). FAB-
l
l
l
respectively. Cells were grown at 27 °C for 3 days.
30 mL) was added dropwise a solution of TBDPSCl (1.59 mL,
6.11 mmol) in DMF (25 mL) at 0 °C. The mixture was stirred at
room temperature for 15 h. After being cooled with ice-water,
the reaction mixture was diluted with water. The resulting mixture
was washed with hexane, and the aqueous layer was extracted
with EtOAc. The extract was washed with brine and condensed
to give pale yellow oil (2.2 g). To a mixture of the oil (2.2 g) and
MeOH (160 mL) was added NaBH4 (420 mg, 11.1 mmol), and the
mixture was stirred at room temperature for 2 h. After the reaction
was quenched with acetone, the solvent was evaporated, and the
residue was dissolved in acetone (50 mL). To the solution were
added 2,2-dimethoxypropane (DMP, 6 mL) and concd sulfuric acid
(0.5 mL), and the mixture was stirred at room temperature for 2 h.
The reaction was quenched with Et3N, and the resulting mixture
was condensed in vacuo. The residue was purified by means of col-
umn chromatography (n-hexane–EtOAc, 15/1) to give 6 (2.26 g,
81% from D-4) and 7 (302 mg, 11% from D-4).
HRMS calcd for
567.2762.
C
30H44O7SiNa [M+Na]+): 567.2754; found:
3.1.3. 2,3:4,5-Di-O-isopropylidene-1-O-methoxymethyl-D-
galactitol (3b)
To a solution of 8 (841 mg, 1.54 mmol) in tetrahydrofuran (THF,
12.7 mL) was added 1 M solution of tetrabutylammonium fluoride
(TBAF) in THF (2.3 mL, 2.3 mmol) at room temperature. After being
stirred at room temperature for 5 h, the reaction mixture was di-
luted with water. The resulting mixture was extracted with EtOAc.
The extract was washed with brine, and condensed in vacuo. The
residue was purified by means of column chromatography (n-hex-
Compound 6: A colorless oil. ½a D24
ꢁ
+10.6 (c 1.00, CHCl3); IR (neat)
cmꢀ1: 3487, 1242, 1215, 1142, 1111, 1065. 1H NMR (500 MHz,
CDCl3) d: 1.06 [s, 9H, SiC(CH3)3], 1.34/1.38/1.41/1.45 [each s, 3H,
C(CH3)2], 2.35 (dd, J = 8.6, 4.3 Hz, 1H, OH), 3.76 (ddd, J = 11.5, 8.6,
4.0 Hz, 1H, H-1a), 3.79 (dd, J = 7.7, 7.7 Hz, 1H, H-3), 3.80 (dd,
J = 11.2, 3.5 Hz, 1H, H-6a), 3.82 (ddd, J = 11.5, 4.8, 4.3 Hz, 1H,
H-1b), 3.94 (dd, J = 11.2, 2.3 Hz, 1H, H-6b), 4.07 (ddd, J = 7.7, 4.8,
4.0 Hz, 1H, H-2), 4.08 (dd, J = 7.7, 7.7 Hz, 1H, H-4), 4.10 (ddd,
J = 7.7, 3.5, 2.3 Hz, 1H, H-5), 7.35–7.44 (m, 6H, Ar), 7.69–7.73 (m,
4H, Ar). 13C NMR (125 MHz, CDCl3) d: 19.3 [SiC(CH3)3], 26.8 [3C,
SiC(CH3)3], 26.86/26.95/27.2 (2C) [C(CH3)2], 62.7 (C-1), 63.3 (C-6),
77.1 (C-4), 79.5 (C-3), 81.0 (C-2), 81.7 (C-5), 109.6/109.9
[C(CH3)2], 127.6 (4C)/129.61/129.64/135.7 (4C) (d, Ar), 133.3/
133.4 (s, Ar). FABMS m/z (%): 523 ([M+Na]+, 36), 135 (100). FAB-
ane–EtOAc, 4/1) to give 3b (454 mg, 96%) as a colorless oil. ½a D24
ꢁ
ꢀ14.3 (c 1.07, CHCl3); IR (neat) cmꢀ1: 3499, 1215, 1045; 1H NMR
(500 MHz, CDCl3) d: 1.38/1.40/1.41/1.43 [each s, 3H, C(CH3)2],
2.30 (br dd-like, 1H, OH), 3.39 (s, 3H, OCH3), 3.65 (dd, J = 10.9,
6.3 Hz, 1H, H-1a), 3.73–3.79 (m, 3H, H-6a, H-3 and H-4),
3.81–3.84 (m, 1H, H-6b), 3.83 (dd, J = 10.9, 2.6 Hz, 1H, H-1b),
4.05 (ddd, J = 7.2, 4.3, 4.3 Hz, 1H, H-5), 4.19 (ddd, J = 6.9, 6.3,
2.6 Hz, 1H, H-2), 4.69/4.70 (each d, J = 6.6 Hz, 1H, OCH2O). 13C
NMR (125 MHz, CDCl3) d: 26.85/26.91/26.95/27.03 [C(CH3)2], 55.3
(OCH3), 62.6 (C-6), 67.6 (C-1), 77.9 (C-4), 79.2 (C-3), 80.3 (C-2),
81.1 (C-5), 96.7 (OCH2O), 109.8/110.2 [C(CH3)2]. FABMS m/z (%):
329 ([M+Na]+, 59), 291 (100). FABHRMS calcd for C14H26O7SiNa
[M+Na]+: 329.1576; found: 329.1578.
HRMS calcd for
523.2509.
C
28H40O6SiNa [M+Na]+: 523.2492; found:
7: A colorless oil. ½a D26
ꢁ
+11.4 (c 0.97, CHCl3). IR (neat) cmꢀ1
:
3.1.4.
D-Galactose diethyl dithioacetal (9)
3476, 1250, 1215, 1146, 1111, 1069. 1H NMR (500 MHz, CDCl3) d:
1.07 [s, 9H, SiC(CH3)3], 1.38 [s, 6H, C(CH3)2], 1.40/1.45 [each s,
3H, C(CH3)2], 2.53 (d, J = 6.0 Hz, 1H, OH), 3.50 (ddd, J = 8.3, 6.0,
4.3 Hz, 1H, H-3), 3.81 (dd, J = 10.9, 4.3 Hz, 1H, H-6a), 3.86 (dd,
J = 10.9, 4.3 Hz, 1H, H-6b), 3.92 (dd, J = 8.3, 6.8 Hz, 1H, H-1a), 3.98
(dd, J = 8.3, 7.4 Hz, 1H, H-4), 4.07 (dd, J = 8.3, 6.9 Hz, 1H, H-1b),
4.15 (ddd, J = 7.4, 4.3, 4.3 Hz, 1H, H-5), 4.25 (ddd, J = 6.9, 6.8,
4.3 Hz, 1H, H-2), 7.36–7.44 (m, 6H, Ar), 7.69–7.72 (m, 4H, Ar). 13C
NMR (125 MHz, CDCl3) d: 19.2 [SiC(CH3)3], 25.4/26.4/27.1 (2C)
[C(CH3)2], 26.8 [3C, SiC(CH3)3], 64.5 (C-6), 66.1 (C-1), 73.2 (C-3),
According to the literature,6 to a solution of
D
-galactose (D-4)
(10.0 g, 51.5 mmol) in concd hydrochloric acid (20.0 mL) was
added ethanethiol (8.6 mL, 117 mmol) at 0 °C. The mixture was
stirred at 0 °C for 1 h and at room temperature for another
20 min, during which the reaction mixture solidified. The solids
were collected by filtration, and successively washed with cold
water and ether to give a colorless solid (10.8 g, 73%), which was
pure enough for further reaction. For analytical purpose a small
portion was recrystallized from EtOH to give 9 as colorless needles.
Mp: 143–144 °C (lit.6a, 142–144 °C; lit.6b 142–143 °C). ½a 2D3
ꢁ
+13.1 (c

950
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
1.00, CH3OH) [lit.6b, ꢀ4.8 (c 1.09, H2O)]. IR (nujor) cmꢀ1: 3502,
3333, 1454, 1184, 1030; 1H NMR (400 MHz, CD3OD) d: 1.25/1.26
(each t, J = 7.6 Hz, 3H, SCH2CH3), 2.67/2.68/2.74/2.75 (each dq,
J = 12.4, 7.6 Hz, 1H, SCH2CH3), 3.63 (d, J = 6.4 Hz, 2H, H-6), 3.65
(dd, J = 9.2, 1.2 Hz, 1H, H-4), 3.87 (dd, J = 9.2, 1.2 Hz, 1H, H-3),
3.92 (td, J = 6.4, 1.2 Hz, 1H, H-5), 4.08 (d, J = 9.2 Hz, 1H, H-1), 4.13
(dd, J = 9.2, 1.2 Hz, 1H, H-2). 13C NMR (100 MHz, CD3OD) d: 14.8
(q), 14.9 (q), 25.3 (t, 2C), 56.0 (d), 65.0 (t), 71.0 (d), 71.7 (d), 71.8
(d), 72.7 (d). FABMS m/z (%): 309 ([M+Na]+, 21), 242 (100). FAB-
4.03 (d, J = 2.8 Hz, 1H, H-1), 4.05 (ddd, J = 7.6, 4.0, 2.8 Hz, 1H, H-
5), 4.14 (dd, J = 8.4, 7.2 Hz, 1H, H-3), 4.35 (dd, J = 7.2, 2.8 Hz, 1H,
H-2). 13C NMR (100 MHz, CDCl3) d: ꢀ5.4/ꢀ5.3 [Si(CH3)2], 14.3/
14.4 (SCH2CH3), 18.4 [SiC(CH3)3], 24.9/25.3 (SCH2CH3), 26.0 [3C,
SiC(CH3)3], 27.0/27.1/27.2/27.3 [C(CH3)2], 52.2 (C-1), 63.0 (C-6),
77.2 (C-4), 79.8 (C-3), 81.8 (C-5), 84.6 (C-2), 109.7/110.4
[C(CH3)2]. FABMS m/z (%): 503 ([M+Na]+, 4), 73 (100). FABHRMS
calcd for C22H44O5S2SiNa [M+Na]+: 503.2297; found: 503.2284.
HRMS calcd for
309.0813.
C
10H22O5S2Na [M+Na]+: 309.0806; found:
3.1.7. 6-O-(tert-Butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
D
-galactitol (3c)6
To a solution of 12 (501 mg, 1.00 mmol) in acetone (10 mL) was
3.1.5. 2,3:4,5-Di-O-isopropylidene-D-galactose diethyl
added N-bromosuccinimide (NBS, 392 mg, 2.20 mmol) at ꢀ78 °C.
After being stirred at ꢀ78 °C for 20 min, the reaction was quenched
with aqueous sodium thiosulfate–sodium bicarbonate. The result-
ing mixture was extracted with chloroform, and the extract was
washed with brine, and condensed in vacuo. The residue was dis-
solved in EtOH (10 mL). To the solution was added NaBH4
(75.7 mg, 2.00 mmol) at 0 °C, and the mixture was stirred at room
temperature for 1 h. The reaction was quenched with acetone, and
the solvent was evaporated. The residue was diluted with chloro-
form, and the resulting mixture was washed with brine, and was
condensed in vacuo. The residue was purified by means of column
chromatography (n-hexane–EtOAc, 6/1) to give 3c6 (332 mg, 88%
dithioacetal (10) and 2,3:5,6-di-O-isopropylidene-D-galactose
diethyl dithioacetal (11)
To a solution of 9 (3.00 g, 10.5 mmol) in acetone (105 mL) were
added DMP (12 mL) and concd sulfuric acid (0.1 mL), and the mix-
ture was stirred at room temperature for 30 min. The reaction was
quenched with Et3N, and the resulting mixture was condensed in
vacuo. The residue was purified by means of column chromatogra-
phy (n-hexane–EtOAc, 8/1) to give 10 (2.78 g, 72%) and 11 (657 mg,
17%).
Compound 10: A colorless oil. ½a D24
ꢀ60.7 (c 1.03, CHCl3). IR
ꢁ
(neat) cmꢀ1: 3499, 1454, 1373, 1238, 1219, 1061. 1H NMR
(800 MHz, CDCl3) d: 1.27/1.29 (each t, J = 7.6 Hz, 3H, SCH2CH3),
1.39 [s, 6H, C(CH3)2], 1.41/1.46 [each s, 3H, C(CH3)2], 2.27 (dd,
J = 9.0, 3.9 Hz, 1H, OH), 2.69/2.73/2.76/2.77 (each dq, J = 12.8,
7.3 Hz, 1H, SCH2CH3), 3.76 (ddd, J = 11.7, 9.0, 4.2 Hz, 1H, H-6a),
3.79 (dd, J = 8.7, 8.0 Hz, 1H, H-4), 3.83 (ddd, J = 11.7, 4.4, 3.9 Hz,
1H, H-6b), 4.04 (d, J = 2.3 Hz, 1H, H-1), 4.08 (ddd, J = 8.0, 4.4,
4.2 Hz, 1H, H-5), 4.15 (dd, J = 8.7, 7.4 Hz, 1H, H-3), 4.36 (dd,
J = 7.4, 2.3 Hz, 1H, H-2). 13C NMR (200 MHz, CD3OD) d: 14.3/14.5
(SCH2CH3), 25.0/25.3 (SCH2CH3), 26.9/26.98/27.01/27.2 [C(CH3)2],
51.8 (C-1), 62.5 (C-6), 79.1 (C-4), 79.2 (C-3), 81.1 (C-5), 84.9 (C-
2), 109.8/110.7 [C(CH3)2]. FABMS m/z (%): 389 ([M+Na]+, 29), 247
from 12) as a colorless oil. ½a D26
ꢁ
+9.49 (c 0.73, CHCl3). IR (neat)
cmꢀ1: 3499, 1254, 1215, 1146, 1092, 1069. 1H NMR (800 MHz,
CDCl3) d: 0.078/0.081 [each s, 3H, Si(CH3)2], 0.91 [s, 9H, SiC(CH3)3],
1.38/1.39/1.40/1.41 [each s, 3H, C(CH3)2], 2.34 (dd, J = 7.8, 2.3 Hz,
1H, OH), 3.74 (dd, J = 11.2, 4.2 Hz, 1H, H-6a), 3.74 (ddd, J = 11.2,
7.8, 4.4 Hz, 1H, H-1a), 3.79 (dd, J = 8.2, 7.8 Hz, 1H, H-3), 3.81
(ddd, J = 11.2, 4.6, 2.3 Hz, 1H, H-1b), 3.90 (dd, J = 11.2, 2.8 Hz, 1H,
H-6b), 3.92 (dd, J = 8.2, 7.6 Hz, 1H, H-4), 4.04 (ddd, J = 7.6, 4.2,
2.8 Hz, 1H, H-5), 4.06 (ddd, J = 7.8, 4.6, 4.4 Hz, 1H, H-2). 13C NMR
(200 MHz, CDCl3) d: ꢀ5.4/ꢀ5.3 [Si(CH3)2], 18.4 [SiC(CH3)3], 25.9
[3C, SiC(CH3)3], 26.9/26.96/27.03/27.1 [C(CH3)2], 62.7 (C-1), 62.9
(C-6), 77.0 (C-4), 79.5 (C-3), 80.9 (C-2), 81.8 (C-5), 109.6/109.9
[C(CH3)2]. FABMS m/z (%): 399 ([M+Na]+, 12), 73 (100). FABHRMS
calcd for C18H36O6SiNa (M+Na9+: 399.2179; found: 399.2189.
(100). FABHRMS calcd for
found: 389.1424.
C
16H30O5S2Na [M+Na]+: 389.1432;
Compound 11: A colorless oil. ½a D24
ꢀ59.8 (c 1.01, CHCl3), IR
ꢁ
(neat) cmꢀ1: 3476, 1454, 1373, 1242, 1215, 1057. 1H NMR
(800 MHz, CDCl3) d: 1.27/1.28 (each t, J = 7.6 Hz, 3H, SCH2CH3),
1.37/1.38/1.45/1.46 [each s, 3H, C(CH3)2], 2.44 (d, J = 5.8 Hz, 1H,
OH), 2.71/2.73/2.75/2.77 (each dq, J = 12.6, 7.6 Hz, 1H, SCH2CH3),
3.50 (ddd, J = 8.7, 5.8, 4.8 Hz, 1H, H-4), 3.91 (dd, J = 8.5, 6.7 Hz,
1H, H-6a), 4.07 (dd, J = 8.7, 6.9 Hz, 1H, H-3), 4.085 (d, J = 3.0 Hz,
1H, H-1), 4.091 (dd, J = 8.5, 6.7 Hz, 1H, H-6b), 4.25 (ddd, J = 6.7,
6.7, 4.8 Hz, 1H, H-5), 4.41 (dd, J = 6.9, 3.0 Hz, 1H, H-2). 13C NMR
(200 MHz, CDCl3) d: 14.39/14.43 (SCH2CH3), 25.17/25.19 (SCH2-
CH3), 25.4/26.5/27.2/27.3 [C(CH3)2], 53.1 (C-1), 66.3 (C-6), 73.7
(C-4), 76.6 (C-5), 78.8 (C-3), 84.2 (C-2), 109.3/110.3 [C(CH3)2]. FAB-
MS m/z (%): 389 ([M+Na]+, 11), 247 (100). FABHRMS calcd for C16-
H30O5S2Na [M+Na]+: 389.1432; found: 389.1431.
3.1.8. 6-O-(tert-Butyldiphenylsilyl)-1,2:3,4-di-O-isopropylidene-
D-glucitol (15) and 6-O-(tert-butyldiphenylsilyl)-2,3:4,5-di-O-
isopropylidene- -glucitol (16)
D
Following the method used for the preparation of 6, D-glucose
(D-13, 1.00 g, 5.55 mmol) was treated with TBDPSCl (1.59 mL,
6.11 mmol) to give 6-O-silylated
D-glucose (2.17 g), which on
NaBH4 reduction in MeOH gave the corresponding
D-glucitol deriv-
ative (2.85 g) as a colorless oil. The oil was then acetalized with
DMP in the presence of concd sulfuric acid. Work-up gave a pale
yellow oil (3.56 g), which on column chromatography (n-hexane–
EtOAc, 15/1) gave 15 (1.12 g, 40% from D-13) and 16 (456 mg,
16% from D-13).
Compound 15: A colorless oil. ½a D26
ꢁ
+5.81 (c 0.96, CHCl3). IR
3.1.6. 6-O-(tert-Butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
(neat) cmꢀ1: 3480, 1250, 1215, 1157, 1111, 1072. 1H NMR
(800 MHz, CDCl3) d: 1.07 [s, 9H, SiC(CH3)3], 1.31/1.388/1.394/1.44
[each s, 3H, C(CH3)2], 2.68 (d, J = 4.6 Hz, 1H, OH), 3.69 (dddd,
J = 8.3, 6.2, 4.6, 3.4 Hz, 1H, H-5), 3.75 (dd, J = 10.5, 6.2 Hz, 1H,
H-6a), 3.88 (dd, J = 10.5, 3.4 Hz, 1H, H-6b), 3.90 (dd, J = 8.3,
7.1 Hz, 1H, H-4), 3.94 (dd, J = 8.2, 7.5 Hz, 1H, H-1a), 4.03 (dd,
J = 8.2, 6.4 Hz, 1H, H-1b), 4.06 (dd, J = 7.1, 4.8 Hz, 1H, H-3), 4.23
(ddd, J = 7.5, 6.4, 4.8 Hz, 1H, H-2), 7.38–7.40 (m, 4H, Ar), 7.43–
7.45 (m, 2H, Ar), 7.66–7.68 (m, 4H, Ar). 13C NMR (200 MHz, CDCl3)
d: 19.3 [SiC(CH3)3], 25.7/26.3/27.0/27.2 [C(CH3)2], 26.8 [3C,
SiC(CH3)3], 65.3 (C-6), 66.1 (C-1), 73.4 (C-5), 76.3 (C-2), 76.7
(C-4), 80.1 (C-2), 109.5/109.8 [C(CH3)2], 127.77 (2C)/127.81 (2C)/
129.86/129.89/135.5 (2C)/135.6 (2C) (d, Ar), 132.9/133.0 (s, Ar).
D-galactose diethyl dithioacetal (12)
To a solution of 10 (500 mg, 1.36 mmol) in pyridine (13.6 mL)
was added TBSCl (308 mg, 2.05 mmol), and the mixture was stirred
at room temperature for 3 h. After the solvent was evaporated, the
residue was purified by means of column chromatography
(n-hexane–EtOAc, 30/1) to give 12 (561 mg, 86%) as a colorless
oil. ½a 2D5
ꢁ
ꢀ40.3 (c 1.01, CHCl3). IR (neat) cmꢀ1: 1458, 1373, 1250,
1215, 1146, 1092, 1061. 1H NMR (400 MHz, CDCl3) d: 0.075/0.078
[each s, 3H, Si(CH3)2], 0.91 [s, 9H, SiC(CH3)3], 1.27/1.28 (each t,
J = 7.2 Hz, 3H, CH3CH2), 1.37/1.38/1.39/1.45 [each s, 3H, C(CH3)2],
2.69/2.76 (eqch dq, J = 12.4, 7.2 Hz, 1H, SCH2CH3), 2.75 (q,
J = 7.2 Hz, 2H, SCH2CH3), 3.72 (dd, J = 11.6, 4.0 Hz, 1H, H-6a), 3.90
(dd, J = 11.6, 2.8 Hz, 1H, H-6b), 3.93 (dd, J = 8.4, 7.6 Hz, 1H, H-4),

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
951
FABMS m/z (%): 523 ([M+Na]+, 7), 135 (100); FABHRMS calcd for
117 mmol) in concd hydrochloric acid (10.0 mL) at 0 °C for
30 min, during which the reaction mixture solidified. Work-up
gave 18 as a colorless solid (8.02 g, 46%), which was pure enough
for further reaction. For analytical purpose a small portion was
recrystallized from EtOH to give title compound 18 as colorless
needles. Mp: 129–130 °C (lit.,7a 125–126 °C; lit.,7b 123–124 °C).
C
28H40O6SiNa [M+Na]+: 523.2492; found: 523.2502.
Compound 16: A colorless oil. ½a D26
ꢁ
–40.0 (c 0.75, CHCl3). IR
(neat) cmꢀ1: 3480, 1254, 1215, 1165, 1111, 1088. 1H NMR
(500 MHz, CDCl3) d: 1.05 [s, 9H, SiC(CH3)3], 1.33/1.36/1.41/1.47
[s, 3H, C(CH3)2], 1.81 (dd, J = 7.5, 4.8 Hz, 1H, OH), 3.61 (ddd,
J = 12.0, 7.5, 4.0 Hz, 1H, H-1a), 3.82 (ddd, J = 12.0, 4.8, 3.4 Hz, 1H,
H-1b), 3.97 (dd, J = 10.0, 5.5 Hz, 1H, H-6a), 4.05 (dd, J = 10.0,
8.3 Hz, 1H, H-6b), 4.12 (ddd, J = 8.9, 4.0, 3.4 Hz, 1H, H-2), 4.16
(dd, J = 8.9, 0.8 Hz, 1H, H-3), 4.19 (dd, J = 6.9, 0.8 Hz, 1H, H-4),
4.42 (ddd, J = 8.3, 6.9, 5.5 Hz, 1H, H-5), 7.35–7.44 (m, 6H, Ar),
7.64–7.68 (m, 4H, Ar). 13C NMR (125 MHz, CDCl3) d: 19.2
[SiC(CH3)3], 25.4/26.5/26.9/27.3 [C(CH3)2], 26.8 [3C, SiC(CH3)3],
61.4 (C-1), 62.9 (C-6), 74.8 (C-3 and C-4), 76.8 (C-5), 77.6 (C-2),
109.1/109.4 [C(CH3)2], 127.7 (4C)/129.72/129.74/135.5 (2C)/135.6
(2C) (d, Ar), 133.26/133.30 (s, Ar). FABMS m/z (%): 523 ([M+Na]+,
16), 135 (100). FABHRMS calcd for C28H40O6SiNa [M+Na]+:
523.2492; found: 523.2485.
½
a 2D2
ꢁ
ꢀ5.8 (c 0.97, CH3OH) [lit.,7a ꢀ28 (c 1.0, H2O)]. IR (nujor)
cmꢀ1: 3399, 3321, 1454, 1265, 1080, 1045. 1H NMR (400 MHz,
CD3OD) d: 1.25/1.26 (each t, J = 7.6 Hz, 3H, SCH2CH3), 2.677/
2.863/2.73/2.75 (each dq, J = 12.4, 7.6 Hz, 1H, SCH2CH3), 3.61 (dd,
J = 11.2, 6.0 Hz, 1H, H-6a), 3.62 (dd, J = 8.0, 2.4 Hz, 1H, H-4), 3.70
(ddd, J = 8.0, 6.0, 3.6 Hz, 1H, H-5), 3.77 (dd, J = 11.2, 3.6 Hz, 1H,
H-6b), 3.83 (dd, J = 6.8, 4.0 Hz, 1H, H-2), 4.06 (d, J = 6.8 Hz, 1H, H-
1), 4.23 (dd, J = 4.0, 2.4 Hz, 1H, H-3). 13C NMR (100 MHz, CD3OD)
d: 14.8 (q), 14.9 (q), 25.7 (t), 26.0 (t), 55.7 (d), 64.8 (t), 70.9 (d),
73.1 (d), 74.3 (d), 76.8 (d). FABMS m/z (%): 309 ([M+Na]+, 5), 57
(100). FABHRMS calcd for C10H22O5S2Na [M+Na]+: 309.0806;
found: 309.0801.
3.1.9. 6-O-(tert-Butyldiphenylsilyl)-1,2:3,4-di-O-isopropylidene-
3.1.12. 2,3:5,6-Di-O-isopropylidene-D-glucose diethyl
5-O-methoxymethyl-
D-glucitol (17)
dithioacetal (19) and 3,4:5,6-di-O-isopropylidene-D-glucose
Following the method used for the preparation of 8, 15 (650 mg,
1.30 mmol) was methoxymethylated with MOMCl (0.45 mL,
2.60 mmol). Work-up gave a colorless oil (747 mg), which on col-
umn chromatography (n-hexane–EtOAc, 5/1) gave Compound 17
diethyl dithioacetal (20)
Following the method used for the preparation of 10, 18 (3.00 g,
10.5 mmol) was acetalized with DMP in the presence of concd sul-
furic acid. Work-up gave a pale yellow oil (5.54 g), which on col-
umn chromatography (n-hexane–EtOAc, 15/1) gave 19 (2.96 g,
77%) and 20 (833 mg, 22%).
(680 mg, 99%) as a colorless oil. ½a D24
ꢀ5.37 (c 1.10, CHCl3). IR (neat)
ꢁ
cmꢀ1: 1369, 1250, 1215, 1111, 1065, 1034. 1H NMR (400 MHz,
CDCl3) d: 1.06 [s, 9H, SiC(CH3)3], 1.35/1.38/1.41/1.43 [each s, 3H,
C(CH3)2], 3.34 (s, 3H, OCH3), 3.77 (ddd, J = 10.0, 5.2, 3.2 Hz, 1H,
H-5), 3.78 (dd, J = 13.2, 5.2 Hz, 1H, H-6a), 3.89 (dd, J = 13.2,
3.2 Hz, 1H, H-6b), 3.91 (dd, J = 8.0, 7.6 Hz, 1H, H-1a), 4.00 (dd,
J = 8.0, 6.4 Hz, 1H, H-1b), 4.08 (dd, J = 7.2, 4.4 Hz, 1H, H-3), 4.13
(dd, J = 10.0, 7.2 Hz, 1H, H-4), 4.17 (ddd, J = 7.6, 6.4, 4.4 Hz, 1H,
H-2), 4.65/4.82 (each d, J = 6.4, Hz, 1H, OCH2O), 7.36–7.45 (m, 6H,
Ar), 7.67–7.68 (m, 4H, Ar). 13C NMR (100 MHz, CDCl3) d: 19.2
[SiC(CH3)3], 25.7/26.3/27.1/27.3 [C(CH3)2], 26.8 [3C, SiC(CH3)3],
55.9 (OCH3), 63.7 (C-6), 65.9 (C-1), 76.4 (C-2), 76.6 (C-4), 78.0 (C-
5), 78.6 (C-3), 96.4 (OCH2O), 109.6/109.8 [C(CH3)2], 127.67 (2C)/
127.69 (2C)/129.70/129.74/135.6 (4C) (d, Ar), 133.21/133.25 (s,
Ar). FABMS m/z (%): 567 ([M+Na]+, 10), 135 (100). FABHRMS calcd
for C30H44O7SiNa [M+Na]+: 567.2754; found: 567.2741.
Compound 19: A colorless oil. ½a D24
ꢀ38.2 (c 1.04, CHCl3). IR
ꢁ
(neat) cmꢀ1: 3480, 1454, 1373, 1253, 1215, 1065. 1H NMR
(800 MHz, CDCl3) d: 1.27/1.28 (each t, J = 7.6 Hz, 3H, SCH2CH3),
1.36/1.44/1.45/1.48 [each s, 3H, C(CH3)2], 2.19 (d, J = 9.2 Hz, 1H,
OH), 2.70/2.78 (each dq, J = 12.6, 7.4 Hz, 1H, SCH2CH3), 2.71/2.76
(each dq, J = 12.8, 7.4 Hz, 1H, SCH2CH3), 3.74 (br dd, J = 9.2,
7.8 Hz, 1H, H-4), 3.91–3.94 (m, 1H, H-1), 4.03 (ddd, J = 7.8, 6.4,
4.8 Hz, 1H, H-5), 4.08 (dd, J = 8.7, 4.8 Hz, 1H, H-6a), 4.10 (dd,
J = 8.7, 6.4 Hz, 1H, H-6b), 4.31–4.33 (m, 2H, H-2 and H-3). 13C
NMR (175 MHz, CDCl3) d: 14.3/14.4 (SCH2CH3), 24.9/25.30 (SCH2-
CH3), 25.31/26.9/27.15/27.20 [C(CH3)2], 53.3 (C-1), 66.9 (C-6),
71.1 (C-4), 76.6 (C-5), 79.2/79.4 (C-2 and C-3), 109.4/109.9
[C(CH3)2]. FABMS m/z (%): 389 ([M+Na]+, 34), 247 (100). FABHRMS
calcd for C16H30O5S2Na [M+Na]+: 389.1432; found: 389.1423.
Compound 20: A colorless oil. ½a D24
ꢁ
+21.4 (c 1.00, CHCl3). IR
3.1.10. 1,2:3,4-Di-O-isopropyliden-5-O-methoxymethyl-
D
-
(neat) cmꢀ1: 3476, 1454, 1373, 1246, 1215, 1069; 1H NMR
(800 MHz, CDCl3) d: 1.29 (t, J = 7.6 Hz, 6H, SCH2CH3), 1.34/1.39/
1.41/1.42 [each s, 3H, C(CH3)2], 2.68/2.69/2.72/2.73 (each dq,
J = 12.4, 7.4 Hz, 1H, SCH2CH3), 2.87 (d, J = 7.1 Hz, 1H, OH), 3.76
(ddd, J = 8.0, 7.1, 1.4 Hz, 1H, H-2), 3.96 (dd, J = 8.5, 5.1 Hz, 1H, H-
6a), 4.01 (dd, J = 8.5, 7.8 Hz, 1H, H-4), 4.02 (d, J = 8.0 Hz, 1H, H-1),
4.09 (ddd, J = 8.5, 6.2, 5.1 Hz, 1H, H-5), 4.14 (dd, J = 8.5, 6.2 Hz,
1H, H-6b), 4.49 (dd, J = 7.8, 1.4 Hz, 1H, H-3). 13C NMR (200 MHz,
CDCl3) d: 14.5 (2C, SCH2CH3), 24.4/25.0 (SCH2CH3), 25.3/26.7/
26.8/27.2 [C(CH3)2], 55.9 (C-1), 67.9 (C-6), 70.8 (C-2), 77.3 (C-5),
77.7 (C-4), 79.0 (C-3), 109.7/109.8 [C(CH3)2]. FABMS m/z (%): 389
([M+Na]+, 20), 143 (100); FABHRMS calcd for C16H30O5S2Na
[M+Na]+: 389.1432; found: 389.1432.
glucitol (3d)
Following the method used for the preparation of 3b, 17 (1.19 g,
2.24 mmol) was treated with 1 M TBAF solution in THF (3.4 mL,
3.36 mmol). Work-up gave a colorless oil (1.22 g), which on col-
umn chromatography (n-hexane–EtOAc, 2/1) gave 3d (572 mg,
83%) as a colorless oil. ½a D25
ꢁ
+49.4 (c 1.40, CHCl3). IR (neat) cmꢀ1
:
3480, 1373, 1250, 1215, 1160, 1061, 1034. 1H NMR (500 MHz,
CDCl3) d: 1.39/1.41 [each s, 3H, C(CH3)2], 1.44 [s, 6H, C(CH3)2],
3.03 (br t-like, 1H, OH), 3.44 (s, 3H, OCH3), 3.64 (ddd, J = 6.9, 6.0,
2.6 Hz, 1H, H-5), 3.65–3.70 (br m, 1H, H-6a), 3.83–3.89 (br m, 1H,
H-6b), 3.89 (dd, J = 8.3, 7.4 Hz, 1H, H-1a), 4.00 (dd, J = 6.9, 6.9 Hz,
1H, H-4), 4.01 (dd, J = 6.9, 4.3 Hz, 1H, H-3), 4.03 (dd, J = 8.3,
6.6 Hz, 1H, H-1b), 4.19 (ddd, J = 7.4, 6.6, 4.3 Hz, 1H, H-2), 4.71/
4.77 (each d, J = 6.9, Hz, 1H, OCH2O). 13C NMR (125 MHz, CDCl3)
d: 25.7/26.3/27.1/27.4 [C(CH3)2], 56.0 (OCH3), 63.0 (C-6), 66.0 (C-
1), 76.2 (C-2), 76.7 (C-4), 79.6 (C-3), 82.4 (C-5), 97.0 (OCH2O),
109.7/110.2 [C(CH3)2]. FABMS m/z (%): 329 ([M+Na]+, 34), 57
(100); FABHRMS calcd for C14H26O7Na [M+Na]+: 329.1576; found:
329.1560.
3.1.13. 4-O-(tert-Butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene-
D-glucose diethyl dithioacetal (21)
To a solution of 19 (500 mg, 1.36 mmol) in CH2Cl2 (13.6 mL)
were added 2,6-lutidine (0.32 mL, 2.73 mmol) and TBSOTf
(0.47 mL, 2.05 mmol), and the mixture was stirred at room temper-
ature for 1 h After the reaction was diluted with water, the result-
ing mixture was extracted with CH2Cl2. The extract was washed
with brine, and condensed in vacuo. The residue was purified by
means of column chromatography (n-hexane–EtOAc, 30/1) to
3.1.11.
Following the method used for the preparation of 9,
(D-13, 10.0 g, 51.5 mmol) was treated with ethanethiol (8.6 mL,
D-Glucose diethyl dithioacetal (18)
D-glucose
quantitatively give 21 (653 mg) as a colorless oil. ½a D25
ꢀ2.91 (c
ꢁ

952
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
1.04, CHCl3). IR (neat) cmꢀ1: 1458, 1377, 1253, 1215, 1161, 1076.
1H NMR (400 MHz, CDCl3) d: 0.15/0.16 [each s, 3H, Si(CH3)2], 0.91
[s, 9H, SiC(CH3)3], 1.270/1.273 (each t, J = 7.6 Hz, 3H, SCH2CH3),
1.34/1.40 [each s, 3H, C(CH3)2] 2.69/2.73/2.776/2.782 (each dq,
J = 12.4, 7.6 Hz, 1H, SCH2CH3), 3.92 (dd, J = 7.6, 6.8 Hz, 1H, H-6a),
3.94 (d, J = 5.2 Hz, 1H, H-1), 3.98 (dd, J = 5.2, 3.2 Hz, 1H, H-2),
4.01 (dd, J = 7.6, 6.4 Hz, 1H, H-6b), 4.15 (ddd, J = 6.8, 6.4, 4.8 Hz,
1H, H-5), 4.18 (dd, J = 7.2, 3.2 Hz, 1H, H-3), 4.29 (dd, J = 7.2,
4.8 Hz, 1H, H-4). 13C NMR (100 MHz, CDCl3) d: –4.1/–3.7 [Si(CH3)2],
14.3/14.5 (SCH2CH3), 18.4 [SiC(CH3)3], 25.09/26.5/27.1/27.4
[C(CH3)2], 25.11/25.5 (SCH2CH3), 26.1 [3C, SiC(CH3)3], 53.8 (C-1),
66.2 (C-6), 72.9 (C-4), 77.1 (C-5), 80.1/81.7 (C-2 and C-3), 108.5/
109.7 [C(CH3)2]. FABMS m/z (%): 503 ([M+Na]+, 2), 73 (100); FAB-
HRMS calcd for C22H44O5SiS2Na [M+Na]+: 503.2297; found:
503.2296.
with brine, and condensed in vacuo. The residue was purified by
means of column chromatography (n-hexane–EtOAc, 10/1) to give
2,3:4,5-di-O-isopropylidene-1-O-methoxymethyl-
D
-galactitol-6-yl 4,6-
-manno-
ꢀ49.1 (c 1.07,
O-benzylidene-3-O-benzyl-2-O-(p-methoxybenzyl)-b-
D
pyranoside (22b, 441 mg, 60%) as a colorless oil. ½a D25
ꢁ
CHCl3). IR (neat) cmꢀ1: 1250, 1096, 1041. 1H NMR (800 MHz,
CDCl3) d: 1.34/1.39/1.41/1.42 [each s, 3H, C(CH3)2], 3.32 (ddd,
J = 10.0, 9.8, 4.8 Hz, 1H, H-50), 3.39 (s, 3H, OCH3), 3.57 (dd, J = 9.8,
3.2 Hz, 1H, H-30), 3.58 (dd, J = 11.0, 7.6 Hz, 1H, H-6a), 3.64 (dd,
J = 10.8, 6.5 Hz, 1H, H-1a), 3.68 (dd, J = 8.0, 8.0 Hz, 1H, H-4), 3.77
(dd, J = 8.0, 7.8 Hz, 1H, H-3), 3.80 (s, 3H, OCH3), 3.82 (dd, J = 10.8,
2.5 Hz, 1H, H-1b), 3.95 (dd, J = 10.6, 10.0 Hz, 1H, H-60a), 4.00 (dd,
J = 3.2, 0.7 Hz, 1H, H-20), 4.15 (ddd, J = 7.8, 6.5, 2.5 Hz, 1H, H-2),
4.20 (dd, J = 9.8, 9.8 Hz, 1H, H-40), 4.21 (dd, J = 11.0, 2.5 Hz, 1H,
H-6b), 4.22 (ddd, J = 8.0, 7.6, 2.5 Hz, 1H, H-5), 4.30 (dd, J = 10.6,
4.8 Hz, 1H, H-60b), 4.56/4.66 (each d, J = 12.6 Hz, 1H, OCH2Ph),
4.57 (d, J = 0.7 Hz, 1H, H-10), 4.69/4.70 (each d, J = 6.4 Hz, 1H, OCH2-
O), 4.85/4.93 (each d, J = 11.9 Hz, 1H, OCH2C6H4OCH3), 5.61 (s, 1H,
CHPh), 6.85 (d, J = 8.7 Hz, 2H, Ar), 7.25–7.30 (m, 5H, Ar), 7.34–7.39
(m, 3H, Ar), 7.41 (d, J = 8.7 Hz, 2H, Ar), 7.49–7.51 (m, 2H, Ar). 13C
NMR (200 MHz, CDCl3) d: 26.99/27.02 (2C)/27.3 [C(CH3)2], 55.2
(OCH3), 55.3 (CH2OCH3), 67.6 (C-50), 67.8 (C-1), 68.6 (C-60), 70.6
(C-6), 72.3 (OCH2Ph), 74.3 (OCH2C6H4OCH3), 74.9 (C-20), 77.7 (C-
30), 78.0 (C-3), 78.4 (C-4), 78.6 (C-40), 80.0 (C-2), 80.3 (C-5), 96.7
(OCH2O), 101.4 (CHPh), 102.4 (C-10), 110.0/110.1 [C(CH3)2], 113.5
(2C)/126.0 (2C)/127.48 (2C)/127.51/128.2 (2C)/128.3 (2C)/128.8/
130.3 (2C) (d, Ar), 130.5/137.6/138.3/159.2 (s, Ar). FABMS m/z
(%): 789 ([M+Na]+, 5), 121 (100). FABHRMS calcd for C42H54O13SiNa
[M+Na]+: 789.3462; found: 789.3461.
3.1.14. 6-O-(tert-Butyldimethylsilyl)-2,3:4,5-di-O-
isopropylidene-D-glutitol (3e)
Following the method used for the preparation of 3c, 21
(500 mg, 1.04 mmol) was dethioketalized with NBS (407 mg,
2.29 mmol) to give the corresponding D-glucose derivative
(488 mg), which was then treated with NaBH4 (78.7 mg,
2.80 mmol) in EtOH. Work-up gave a colorless oil (685 mg), which
on column chromatography (n-hexane–EtOAc, 4/1) gave 3e
(879 mg, 44% from 21) as a colorless oil. ½a D26
ꢁ
+2.13 (c 0.84, CHCl3).
IR (neat) cmꢀ1: 3480, 1253, 1215, 1161, 1057. 1H NMR (800 MHz,
CDCl3) d: 0.11/0.13 [each s, 3H, Si(CH3)2], 0.90 [s, 9H, SiC(CH3)3],
1.33/1.40/1.406/1.413 [each s, 3H, C(CH3)2], 2.07 (dd, J = 7.8,
5.1 Hz, 1H, OH), 3.69 (ddd, J = 12.0, 7.8, 4.1 Hz 1H, H-1a), 3.81
(ddd, J = 12.0, 5.1, 4.1 Hz 1H, H-1b), 3.87 (dd, J = 5.0, 5.1 Hz, 1H,
H-4), 3.8890 (dd, J = 8.0, 7.6 Hz, 1H, H-6a), 3.8894 (dd, J = 8.0,
5.0 Hz, 1H, H-3), 4.02 (dd, J = 8.0, 6.4 Hz, 1H, H-6b), 4.08 (ddd,
J = 8.0, 4.1, 4.1 Hz, 1H, H-2), 4.11 (ddd, J = 7.6, 6.4, 5.1 Hz, 1H,
H-5). 13C NMR (100 MHz, CDCl3) d: ꢀ4.3/ꢀ4.0 [Si(CH3)2], 18.3
[SiC(CH3)3], 25.2/26.5/26.97/27.04 [C(CH3)2], 26.0 [3C, SiC(CH3)3],
62.4 (C-1), 66.5 (C-6), 73.0 (C-4), 76.5 (C-5), 77.1 (C-2), 79.6
(C-4), 108.6/108.8 [C(CH3)2]. FABMS m/z (%): 399 ([M+Na]+, 17),
73 (100), FABHRMS calcd for C18H36O6SiNa [M+Na]+: 399.2179;
found: 399.2186.
Following the method described above, 3c (231 mg,
0.613 mmol), 3d (320 mg, 1.02 mmol), 3e (770 mg, 1.87 mmol),
and ent-3e (384 mg, 1.02 mmol) were converted to the corre-
sponding coupled products, 6-O-(tert-butyldimethylsilyl)-2,3:4,5-
di-O-isopropylidene-
zyl-2-O-(p-methoxybenzyl)-b-
69%), 1,2:3,4-di-O-isopropylidene-5-O-methoxymethyl-
6-yl 3-O-benzyl-4,6-O-benzylidene-2-O-(p-methoxybenzyl)-b-
mannopyranoside (22d, 360 mg, 56%), 4-O-(tert-butyldimethylsi-
lyl)-2,3:5,6-di-O-isopropylidene- -glucitol-1-yl 3-O-benzyl-4,6-O-
benzylidene-2-O-(p-methoxybenzyl)-b- -mannopyranoside (22e,
1.03 g, 72%), and 4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-O-isopro-
pylidene- -glucitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-O-(p-
D
-galactitol-1-yl 4,6-O-benzylidene-3-O-ben-
-mannopyranoside (22c, 294 mg,
-glucitol-
D
D
D-
D
D
3.1.15. 4-O-(tert-Butyldimethylsilyl)-2,3:5,6-di-O-
isopropylidene-
Following the method used for the preparation of 3e,
(L-13, 3.00 g, 16.7 mmol) was first converted to 2,3:5,6-di-O-iso-
propylidene- -glucose diethyl dithioacetal [ent-18, 2.81 g, 46%,
+39.2 (c 0.94, CHCl3)], which on silylation with TBDPSCl gave
L
-glucitol (ent-3e)
L
L
-glucose
methoxybenzyl-b-D-mannopyranoside (22f, 424 mg, 59%),
respectively.
L
Compound 22c: A colorless oil. ½a D25
ꢀ52.9 (c 1.04, CHCl3). IR
ꢁ
½
a 2D5
ꢁ
(neat) cmꢀ1: 1250, 1095. 1H NMR (500 MHz, CDCl3) d: 0.078/
0.081 [each s, 3H, Si(CH3)2], 0.91 [s, 9H, SiC(CH3)3], 1.34/1.39 [eash
s, 3H, C(CH3)2], 1.37 [s, 6H, C(CH3)2], 3.32 (ddd, J = 10.0, 10.0,
4.8 Hz, 1H, H-50), 3.56 (dd, J = 10.0, 3.2 Hz, 1H, H-30), 3.73 (dd,
J = 11.2, 4.3 Hz, 1H, H-6a), 3.80 (s, 3H, OCH3), 3.86 (dd, J = 11.8,
2.6 Hz, 1H, H-1a), 3.89 (dd, J = 11.2, 2.8 Hz, 1H, H-6b), 3.93 (dd,
J = 5.7, 5.7 Hz, 2H, H-3 and H-4), 3.92 (dd, J = 10.3, 10.0 Hz, 1H,
H-60a), 3.96 (d, J = 3.2 Hz, 1H, H-20), 4.04 (dd, J = 11.8, 3.7 Hz, 1H,
H-1b), 4.05 (ddd, J = 5.7, 4.3, 2.8 Hz, 1H, H-5), 4.13 (ddd, J = 5.7,
3.7, 2.6 Hz, 1H, H-2), 4.19 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 4.29
(dd, J = 10.3, 4.8 Hz, 1H, H-60b), 4.570 (s, 1H, H-10), 4.572/4.68 (each
d, J = 12.6 Hz, 1H, OCH2Ph), 4.81/4.91 (each d, J = 11.7 Hz, 1H,
OCH2C6H4OCH3), 5.61 (s, 1H, CHPh), 6.85 (d, J = 8.4 Hz, 2H, Ar),
7.26–7.29 (m, 5H, Ar), 7.29 (d, J = 8.6 Hz, 2H, Ar), 7.35-7.40 (m,
3H, Ar), 7.48–7.50 (m, 2H, Ar). 13C NMR (125 MHz, CDCl3) d:
ꢀ5.4/ꢀ5.2 [Si(CH3)2], 18.4 [SiC(CH3)3], 25.9 [3C, SiC(CH3)3], 27.0/
27.1/27.2/27.3 [C(CH3)2], 55.2 (OCH3), 63.2 (C-6), 67.6 (C-50), 68.6
(2C, C-1 and C-60), 72.3 (OCH2Ph), 74.3 (OCH2C6H4OCH3), 75.3
(C-20), 77.6/77.68 (C-3 and C-4), 77.73 (C-30), 78.6 (C-40), 79.9
(C-2), 81.5 (C-5), 101.4 (CHPh), 102.6 (C-10), 109.6/109.8
[C(CH3)2], 113.5 (2C), 126.0 (2C)/127.5 (3C)/128.2 (2C)/128.3
4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene-
L
-glucose
diethyl dithioacetal [ent-19, 1.70 g, 46%, ½a D25
ꢁ
+13.3 (c 1.88, CHCl3)].
Oxidation of ent-19 with NBS (1.37 g, 7.68 mmol) followed by
NaBH4 reduction gave ent-3e [849 mg, 65% from ent-19, ½a D25
ꢁ
ꢀ6.35 (c 1.95, CHCl3)] as a colorless oil. The NMR spectroscopic
properties of ent-18, ent-19, ent-3e were in good accord with
those of the corresponding enantiomers 18, 19 and 3e,
respectively.
3.1.16. Coupling reaction between mannosyl sulfoxide (2) and
protected hexitols (3b–3e and ent-3e)
Under argon atomosphere, to
a
solution of 23 (500 mg,
0.852 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP,
350 mg, 1.70 mmol) in CH2Cl2 (8.5 mL) was added trifluorometh-
anesulfonic anhydride (Tf2O, 0.15 mL, 0.94 mmol) at ꢀ78 °C, and
the mixture was stirred at ꢀ78 °C for 10 min. A solution of 3b
(313 mg, 1.02 mmol) in CH2Cl2 (8.5 mL) was added to the mixture,
and the resulting mixture was stirred at ꢀ78 °C for another 1 h.
After addition of aqueous sodium hydrogen carbonate, the result-
ing mixture was extracted with CH2Cl2. The extract was washed

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
953
(2C)/128.8/130.2 (2C) (d, Ar), 130.5/137.6/138.3/159.2 (s, Ar). FAB-
MS m/z (%): 859 ([M+Na]+, 1), 121 (100). FABHRMS calcd for C46-
H64O12SiNa [M+Na]+: 859.4065; found: 859.4078.
(each d, J = 11.8 Hz, 1H, OCH2C6H4OCH3), 5.61 (s, 1H, CHPh), 6.84
(d, J = 8.6 Hz, 2H, Ar), 7.25–7.32 (m, 5H, Ar), 7.33–7.40 (m, 5H,
Ar), 7.49–7.51 (m, 2H, Ar). 13C NMR (125 MHz, CDCl3) d: ꢀ4.1/
ꢀ3.9 [Si(CH3)2], 18.3 [SiC(CH3)3], 25.1/26.5/26.9/27.3 [C(CH3)2],
26.0 [3C, SiC(CH3)3], 55.2 (OCH3), 66.1 (C-6), 67.7 (C-50), 68.5
(C-60), 70.9 (C-1), 72.22 (OCH2Ph), 72.24 (C-4), 74.3 (OCH2C6H4-
OCH3), 75.3 (C-20), 76.3 (C-2), 76.7 (C-5), 77.7 (C-30), 78.6 (C-40),
79.8 (C-3), 101.4 (CHPh), 102.4 (C-10), 108.5/109.3 [C(CH3)2],
113.5 (2C)/126.0 (2C)/127.50 (2C)/127.52/128.2 (2C)/128.3 (2C)/
128.8/130.1 (2C) (d, Ar), 130.6/137.5/138.3/159.1 (s, Ar). FABMS
m/z (%): 859 ([M+Na]+, 10), 73 (100). FABHRMS calcd for C46H64O12-
SiNa [M+Na]+: 859.4065; found: 859.4092.
Compound 22d: A colorless oil. ½a D24
ꢀ46.4 (c 0.88, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1373, 1250, 1215, 1153, 1096. 1H NMR (700 MHz,
CDCl3) d: 1.37/1.41[eash s, 3H, C(CH3)2], 1.44 [s, 6H, C(CH3)2],
3.33 (ddd, J = 10.2, 9.8, 4.8 Hz, 1H, H-50), 3.39 (s, 3H, OCH3),3.57
(dd, J = 10.0, 3.2 Hz, 1H, H-30), 3.63 (dd, J = 10.8, 6.0 Hz, 1H, H-6a),
3.80 (s, 3H, OCH3), 3.84 (ddd, J = 6.2, 6.0, 2.8 Hz, 1H, H-5), 3.912
(dd, J = 8.4, 7.4 Hz, 1H, H-1a), 3.914 (dd, J = 10.4, 10.2 Hz, 1H,
H-60a), 3.95 (dd, J = 3.2, 0.6 Hz, 1H, H-20), 4.01 (dd, J = 8.4, 6.6 Hz,
1H, H-1b), 4.05 (dd, J = 6.8, 4.2 Hz, 1H, H-3), 4.08 (dd, J = 6.8,
6.2 Hz, 1H, H-4), 4.19 (ddd, J = 7.4, 6.6, 4.2 Hz, 1H, H-2), 4.18 (dd,
J = 10.0, 9.8 Hz, 1H, H-40), 4.20 (dd, J = 10.8, 2.8 Hz, 1H, H-6b),
4.30 (dd, J = 10.4, 4.8 Hz, 1H, H-60b), 4.50 (d, J = 0.6 Hz 1H, H-10),
4.56/4.68 (each d, J = 12.4 Hz, 1H, OCH2Ph), 4.66/4.83 (each d,
J = 6.8 Hz, 1H, OCH2O), 4.79/4.89 (each d, J = 11.8 Hz, 1H, OCH2C6-
H4OCH3), 5.61 (s, 1H, CHPh), 6.84 (d, J = 8.6 Hz, 2H, Ar), 7.26–7.31
(m, 6H, Ar), 7.35–7.39 (m, 4H, Ar), 7.49–7.50 (m, 2H, Ar). 13C
NMR (175 MHz, CDCl3) d: 25.7/26.3/27.2/27.4 [C(CH3)2], 55.2
(OCH3), 56.0 (CH2OCH3), 65.9 (C-1), 67.7 (C-50), 68.6 (C-60), 69.8
(C-6), 72.4 (OCH2Ph), 74.4 (OCH2C6H4OCH3), 75.4 (C-20), 76.2
(C-2), 76.6 (C-4), 77.1 (C-5), 77.9 (C-30), 78.6 (C-40), 79.1 (C-3),
96.5 (OCH2O), 101.4 (CHPh), 102.7 (C-10), 109.6/110.2 [C(CH3)2],
113.6 (2C)/126.0 (2C)/127.5 (3C)/128.2 (2C)/128.3 (2C)/128.8/
130.2 (2C) (d, Ar), 130.5/137.6/138.3/159.2 (s, Ar). FABMS m/z
(%): 789 ([M+Na]+, 8), 121 (100). FABHRMS calcd for C42H54O13Na
[M+Na]+: 789.3462; found: 789.3468.
3.1.17. Deprotection of PMB group at C20 position in coupled
products (22b–22f)
To a mixture of 22b (369 mg, 0.482 mmol), CH2Cl2 (4.6 mL), and
H2O (200 lL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ, 160 mg, 0.674 mmol), and the mixture was stirred at room
temperature for 1 h. To the reaction mixture was added saturated
sodium hydrogen carbonate, and the resulting mixture was ex-
tracted with CH2Cl2. The extract was washed with brine, and con-
densed in vacuo. The residue was purified by means of column
chromatography (n-hexane–EtOAc, 5/1) to give 2,3:4,5-di-O-iso-
propylidene-1-methoxymethyl-D-galactitol-6-yl 4,6-O-benzyli-
dene-3-O-benzyl-b-D-mannopyranoside (23b, 246 mg, 79%) as a
colorless oil. ½a D25
ꢁ
ꢀ17.0 (c 1.05, CHCl3). IR (neat) cmꢀ1: 3483,
1215, 1096, 1045. 1H NMR (400 MHz, CDCl3) d: 1.37 [s, 6H,
C(CH3)2], 1.40/1.41 [eash s, 3H, C(CH3)2], 2.70 (br s, 1H, OH), 3.35
(ddd, J = 9.6, 9.6, 4.8 Hz, 1H, H-50), 3.39 (s, 3H, OCH3), 3.63 (dd,
J = 11.2, 6.8 Hz, 1H, H-6a), 3.65 (dd, J = 9.6, 2.8 Hz, 1H, H-30), 3.67
(dd, J = 8.0, 7.2 Hz, 1H, H-4), 3.68 (dd, J = 11.2, 7.2 Hz, 1H, H-1a),
3.77 (dd, J = 8.0, 8.0 Hz, 1H, H-3), 3.82 (dd, J = 11.2, 2.8 Hz, 1H, H-
1b), 3.90 (dd, J = 10.4, 9.6 Hz, 1H, H-60a), 4,147 (dd, J = 11.2,
3.2 Hz, 1H, H-6b), 4.148 (ddd, J = 8.0, 7.2, 2.8 Hz, 1H, H-2), 4.16
(dd, J = 9.6, 9.6 Hz, 1H, H-40), 4.20 (dd, J = 2.8, 0.8 Hz, 1H, H-20),
4.21 (ddd, J = 7.2, 6.8, 3.2 Hz, 1H, H-5), 4.32 (dd, J = 10.4, 4.8 Hz,
1H, H-60b), 4.63 (d, J = 0.8 Hz, 1H, H-10), 4.68/4.70 (each d,
J = 6.8 Hz, 1H, OCH2O), 4.78/4.86 (each d, J = 12.4 Hz, 1H, OCH2Ph),
Compound 22e: A colorless oil. ½a D25
ꢀ49.6 (c 0.53, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1373, 1250, 1215, 1169, 1142, 1096. 1H NMR
(700 MHz, CDCl3) d: 0.09/0.13 [each s, 3H, Si(CH3)2], 0.90 [s, 9H,
SiC(CH3)3], 1.32/1.34 [eash s, 3H, C(CH3)2], 1.39 [s, 6H, C(CH3)2],
3.32 (ddd, J = 10.2, 10.0, 4.8 Hz, 1H, H-50), 3.56 (dd, J = 10.0,
3.2 Hz, 1H, H-30), 3.80 (s, 3H, OCH3), 3.81 (dd, J = 12.0, 2.8 Hz, 1H,
H-1a), 3.84 (dd, J = 5.4, 4.6 Hz, 1H, H-4), 3.88 (dd, J = 8.2, 7.4 Hz,
1H, H-6a), 3.92 (dd, J = 10.2, 10.2 Hz, 1H, H-60a), 3.96 (d,
J = 3.2 Hz, 1H, H-20), 4.02 (dd, J = 8.2, 6.3 Hz, 1H, H-6b), 4.03 (dd,
J = 12.0, 3.0 Hz, 1H, H-1b), 4.08 (dd, J = 8.4, 4.6 Hz, 1H, H-3), 4.10
(ddd, J = 7.4, 6.3, 5.4 Hz, 1H, H-5), 4.15 (ddd, J = 8.4, 3.0, 2.8 Hz,
1H, H-2), 4.18 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 4.29 (dd, J = 10.2,
4.8 Hz, 1H, H-60b), 4.55 (s, 1H, H-10), 4.56/4.67 (each d,
J = 12.4 Hz, 1H, OCH2Ph), 4.80/ 4.90 (each d, J = 11.8 Hz, 1H, OCH2-
C6H4OCH3), 5.61 (s, 1H, CHPh), 6.85 (d, J = 8.8 Hz, 2H, Ar), 7.25–7.31
(m, 5H, Ar), 7.34–7.39 (m, 5H, Ar), 7.49–7.50 (m, 2H, Ar). 13C NMR
(175 MHz, CDCl3) d: ꢀ4.2/ꢀ3.9 [Si(CH3)2], 18.3 [SiC(CH3)3], 25.3/
26.5/27.0/27.2 [C(CH3)2], 26.0 [3C, SiC(CH3)3], 55.2 (OCH3), 66.5
(C-6), 67.7 (C-50), 68.2 (C-1), 68.6 (C-60), 72.3 (OCH2Ph), 72.8 (C-
4), 74.5 (OCH2C6H4OCH3), 75.5 (C-20), 75.9 (C-2), 76.7 (C-5), 77.8
(C-30), 78.6 (C-40), 78.7 (C-3), 101.4 (CHPh), 102.8 (C-10), 108.6/
108.7 [C(CH3)2], 113.6 (2C)/126.0 (2C)/127.5 (3C)/128.2 (2C)/
128.3 (2C)/128.8/130.2 (2C) (d, Ar), 130.5/137.6/138.3/159.2 (s,
Ar). FABMS m/z (%): 859 ([M+Na]+, 6), 73 (100). FABHRMS calcd
for C46H64O12SiNa [M+Na]+: 859.4065; found: 859.4079.
5.61 (s, 1H, CHPh), 7.27–7.42 (m, 8H, Ar), 7.49–7.52 (m, 2H, Ar). 13
C
NMR (100 MHz, CDCl3) d: 26.7 (3C)/27.1 [C(CH3)2], 55.3 (OCH3),
67.0 (C-50), 67.8 (C-1), 68.6 (C-60), 69.7 (C-20), 70.2 (C-6), 72.4
(OCH2Ph), 76.5 (C-30), 78.0 (C-3), 78.4 (C-40), 78.9 (C-4), 79.8/79.9
(C-2 and C-5), 96.7 (OCH2O), 100.3 (C-10), 101.5 (CHPh), 110.0/
110.3 [C(CH3)2], 126.0 (2C)/127.8/127.9 (2C)/128.2 (2C)/128.4
(2C)/128.9 (d, Ar), 137.4/138.0 (s, Ar). FABMS m/z (%): 669
([M+Na]+, 13), 91 (100). FABHRMS calcd for C34H46O12SiNa
[M+Na]+: 669.2887; found: 669.2879.
Following the method described above, 22c (279 mg,
0.333 mmol), 22d (340 mg, 0.452 mmol), 22e (860 mg, 1.03 mmol),
and 22f (402 mg, 0.480 mmol) were converted to 6-O-(tert-butyldi-
methylsilyl)-2,3:4,5-di-O-isopropylidene-
benzylidene-3-O-benzyl-b- -mannopyranoside (23b, 209 mg,
88%), 1,2:3,4-di-O-isopropylidene-5-O-methoxymethyl- -glucitol-
6-yl 3-O-benzyl-4,6-O-benzylidene-b- -mannopyranoside (23d,
266 mg, 92%), 4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-O-isopro-
pylidene- -glucitol-1-yl 3-O-benzyl-4,6-O-benzylidene-b- -man-
nopyranoside
butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene-
D-galactitol-1-yl 4,6-O-
D
D
Compound 22f: A colorless oil. ½a D25
ꢁ
–54.8 (c 1.13, CHCl3). IR
D
(neat) cmꢀ1: 1250, 1215, 1172, 1096. 1H NMR (500 MHz, CDCl3)
d: 0.12/0.13 [each s, 3H, Si(CH3)2], 0.91 [s, 9H, SiC(CH3)3], 1.33/
1.38/1.41/1.42 [eash s, 3H, C(CH3)2], 3.32 (ddd, J = 10.3, 9.8,
4.9 Hz, 1H, H-50), 3.58 (dd, J = 9.8, 3.2 Hz, 1H, H-30), 3.62 (dd,
J = 10.9, 7.2 Hz, 1H, H-1a), 3.79 (dd, J = 8.0, 4.0 Hz, 1H, H-3), 3.80
(s, 3H, OCH3), 3.901 (dd, J = 8.0, 7.4 Hz, 1H, H-6a), 3.900 (dd,
J = 4.6, 4.0 Hz, 1H, H-4), 3.92 (dd, J = 10.3, 10.3 Hz, 1H, H-60a),
3.99 (d, J = 3.2 Hz, 1H, H-20), 4.00 (dd, J = 8.0, 6.3 Hz, 1H, H-6b),
4.07 (dd, J = 10.9, 2.9 Hz, 1H, H-1b), 4.12 (ddd, J = 7.4, 6.3, 4.6 Hz,
1H, H-5), 4.19 (dd, J = 9.8, 9.8 Hz, 1H, H-40), 4.23 (ddd, J = 8.0, 7.2,
2.9 Hz, 1H, H-2), 4.29 (dd, J = 10.3, 4.9 Hz, 1H, H-60b), 4.572/4.67
(each d, J = 12.6 Hz, 1H, OCH2Ph), 4.574 (s, 1H, H-10), 4.81/4.90
D
D
(23e,
614 mg,
83%),
and
4-O-(tert-
L
-glucitol-1-yl
3-O-benzyl-4,6-O-benzylidene-b-
D
-mannopyranoside
(23f,
295 mg, 86%), respectively.
Compound 23c: A colorless oil. ½a D25
ꢁ
ꢀ15.3 (c 1.01, CHCl3). IR
(neat) cmꢀ1: 3499, 1254, 1215, 1096. 1H NMR (800 MHz, CDCl3)
d: 0.07/0.08 [each s, 3H, Si(CH3)2], 0.91 [s, 9H, SiC(CH3)3], 1.367/
1.39 [eash s, 3H, C(CH3)2], 1.371 [s, 6H, C(CH3)2], 2.64 (br s, 1H,
OH), 3.35 (ddd, J = 10.1, 10.0, 4.8 Hz, 1H, H-50), 3.63 (dd, J = 10.0,
3.2 Hz, 1H, H-30), 3.73 (dd, J = 11.2, 4.1 Hz, 1H, H-6a), 3.865 (dd,

954
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
J = 7.8, 7.8 Hz, 1H, H-3), 3.872 (dd, J = 11.3, 3.2 Hz, 1H, H-1a), 3.88
(dd, J = 11.2, 3.2 Hz, 1H, H-6b), 3.89 (dd, J = 10.3, 10.1 Hz, 1H, H-
60a), 3.92 (dd, J = 7.8, 7.3 Hz, 1H, H-4), 4.01 (dd, J = 11.3, 4.8 Hz,
1H, H-1b), 4.03 (ddd, J = 7.3, 4.1, 3.2 Hz, 1H, H-5), 4.15 (dd,
J = 3.2, 0.9 Hz, 1H, H-20), 4.16 (ddd, J = 7.8, 4.8, 3.2 Hz, 1H, H-2),
4.17 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 4.31 (dd, J = 10.3, 4.8 Hz, 1H,
H-60b), 4.61 (d, J = 0.9 Hz, 1H, H-10), 4.79/4.86 (each d, J = 12.4 Hz,
1H, OCH2Ph), 5.61 (s, 1H, CHPh), 7.27–7.30 (m, 1H, Ar), 7.31–7.34
(m, 2H, Ar), 7.35–7.40 (m, 5H, Ar), 7.50–7.51 (m, 2H, Ar). 13C
NMR (100 MHz, CDCl3) d: ꢀ5.4/ꢀ5.3 [Si(CH3)2], 18.4 [SiC(CH3)3],
25.9 [3C, SiC(CH3)3], 27.00/27.01/27.04/27.2 [C(CH3)2], 63.1 (C-6),
67.0 (C-50), 68.6 (C-60), 69.0 (C-1), 69.9 (C-20), 72.5 (OCH2Ph), 76.5
(C-30), 77.5 (C-3), 78.3 (C-4 and C-40), 79.5 (C-2), 81.4 (C-5), 100.6
(C-10), 101.5 (CHPh), 109.7/109.8 [C(CH3)2], 126.0 (2C)/127.8/
127.9 (2C)/128.2 (2C)/128.4 (2C)/128.9 (d, Ar), 137.4/138.0 (s,
Ar). FABMS m/z (%): 739 ([M+Na]+, 34), 91 (100). FABHRMS calcd
for C38H56O11SiNa [M+Na]+: 739.3490; found: 739.3489.
(ddd, J = 9.6, 9.6, 4.8 Hz, 1H, H-50), 3.64 (dd, J = 9.6, 3.2 Hz, 1H, H-
30), 3.68 (dd, J = 10.8, 7.2 Hz, 1H, H-1a), 3.74 (dd, J = 8.0, 4.4 Hz,
1H, H-3), 3.879 (dd, J = 10.0, 9.6 Hz, 1H, H-60a), 3.884 (dd, J = 8.0,
7.2 Hz, 1H, H-6a), 3.90 (dd, J = 4.8, 4.4 Hz, 1H, H-4), 4.00 (dd,
J = 8.0, 6.4 Hz, 1H, H-6b), 4.04 (dd, J = 10.8, 3.6 Hz, 1H, H-1b),
4.11 (ddd, J = 7.2, 6.4, 4.8 Hz, 1H, H-5), 4.16 (dd, J = 9.6, 9.6 Hz,
1H, H-40), 4.18 (dd, J = 3.2, 0.8 Hz, 1H, H-20), 4.20 (ddd, J = 8.0, 7.2,
3.6 Hz, 1H, H-2), 4.31 (dd, J = 10.0, 4.8 Hz, 1H, H-60b), 4.61 (d,
J = 0.8 Hz, 1H, H-10), 4.78/4.86 (each d, J = 12.4 Hz, 1H, OCH2Ph),
5.61 (s, 1H, CHPh), 7.24–7.41 (m, 8H, Ar), 7.49–7.51 (m, 2H, Ar).
13C NMR (100 MHz, CDCl3) d: ꢀ4.3/ꢀ4.0 [Si(CH3)2], 18.3
[SiC(CH3)3], 25.1/26.4/26.9/27.1 [C(CH3)2], 26.0 [3C, SiC(CH3)3],
66.1 (C-6), 67.0 (C-50), 68.6 (C-60), 69.7 (C-20), 70.7 (C-1), 72.4
(2C, C-4 and OCH2Ph), 76.0 (C-2), 76.5 (2C, C-5 and C-30), 78.4 (C-
40), 80.1 (C-3), 100.4 (C-10), 101.5 (CHPh), 108.6/109.3 [C(CH3)2],
126.0 (2C)/127.8/127.9 (2C)/128.2 (2C)/128.4 (2C)/128.9 (d, Ar),
137.4/138.0 (s, Ar). FABMS m/z (%): 739 ([M+Na]+, 100). FABHRMS
calcd for C38H56O11SiNa [M+Na]+: 739.3490; found: 739.3505.
Compound 23d: A colorless oil. ½a D24
ꢁ
+12.3 (c 1.10, CHCl3). IR
(neat) cmꢀ1: 3480, 1373, 1250, 1215, 1153, 1096, 1038. 1H NMR
(700 MHz, CDCl3) d: 1.40 [s, 6H, C(CH3)2], 1.43/1.44 [eash s, 3H,
C(CH3)2], 2.86 (br s, 1H, OH), 3.35 (ddd, J = 10.2, 9.6, 4.8 Hz, 1H,
H-50), 3.39 (s, 3H, OCH3), 3.64 (dd, J = 9.6, 3.2 Hz, 1H, H-30), 3.69
(dd, J = 10.8, 6.4 Hz, 1H, H-6a), 3.87 (dd, J = 10.2, 10.2 Hz, 1H,
H-60a), 3.88 (ddd, J = 6.4, 6.0, 3.2 Hz, 1H, H-5), 3.92 (dd, J = 8.2,
7.2 Hz, 1H, H-1a), 4.0315 (dd, J = 8.2, 6.4 Hz, 1H, H-1b), 4.0321
(dd, J = 7.0, 4.0 Hz, 1H, H-3), 4.06 (dd, J = 7.0, 6.0 Hz, 1H, H-4),
4.138 (dd, J = 3.2, 1.0 Hz, 1H, H-20), 4.140 (dd, J = 10.8, 3.2 Hz, 1H,
H-6b), 4.16 (dd, J = 9.6, 9.6 Hz, 1H, H-40), 4.19 (ddd, J = 7.2, 6.4,
4.0 Hz, 1H, H-2), 4.31 (dd, J = 10.2, 4.8 Hz, 1H, H-60b), 4.55 (d,
J = 1.0 Hz, 1H, H-10), 4.71/4.80 (each d, J = 6.8 Hz, 1H, OCH2O),
4.79/4.86 (each d, J = 12.4 Hz, 1H, OCH2Ph), 5.60 (s, 1H, CHPh),
7.27–7.30 (m, 1H, Ar), 7.31–7.34 (m, 2H, Ar), 7.36–7.40 (m, 5H,
Ar), 7.49–7.51 (m, 2H, Ar). 13C NMR (175 MHz, CDCl3) d: 25.6/
26.3/27.1/27.3 [C(CH3)2], 56.0 (OCH3), 65.9 (C-1), 67.0 (C-50), 68.6
(C-60), 69.4 (C-6), 69.8 (C-20), 72.5 (OCH2Ph), 75.9 (C-2), 76.5/76.6
(C-4 and C-30), 77.1 (C-5), 78.4 (C-40), 78.7 (C-3), 96.7 (OCH2O),
100.9 (C-10), 101.6 (CHPh), 109.7/110.0 [C(CH3)2], 126.0 (2C)/
127.8/127.9 (2C)/128.2 (2C)/128.4/128.9 (d, Ar), 137.4/138.0 (s,
Ar). FABMS m/z (%): 669 ([M+Na]+, 57), 91 (100). FABHRMS calcd
for C34H46O12Na [M+Na]+: 669.2887; found: 669.2866.
3.1.18. Esterification of monoalcohols (23b–23f)
To a solution of 23b (224 mg, 0.346 mmol) and N,N-dimethyl-
aminopyridine (DMAP, 84.6 mg, 0.692 mmol) in a mixture of
CH2Cl2 (3.5 mL) and pyridine (0.06 mL, 0.692 mmol) was added
n-octanoyl chloride (0.12 mL, 0.692 mmol), and the mixture was
stirred at room temperature for 20 h. After the reaction was
quenched with water, the resulting mixture was extracted with
CH2Cl2. The extract was successively washed with aqueous sodium
bicarbonate, water and brine, and condensed in vacuo. The residue
was purified by means of column chromatography (n-hexane–
EtOAc, 15/1) to quantitatively give 2,3:4,5-di-O-isopropylidene-1-
methoxymethyl-D-galactitol-6-yl 4,6-O-benzylidene-3-O-benzyl-
2-O-octanoyl-b-D-mannopyranoside (24b, 268 mg) as a colorless
oil. ½a 2D4
ꢁ
ꢀ51.5 (c 1.01, CHCl3). IR (neat) cmꢀ1: 1744, 1215, 1096,
1045. 1H NMR (400 MHz, CDCl3) d: 0.87 [t, J = 7.2 Hz, 3H, CO(CH2)6-
CH3], 1.20–1.34 [m, 8H, CO(CH2)2(CH2)4CH3], 1.36 [s, 6H, C(CH3)2],
1.37/1.41 [eash s, 3H, C(CH3)2], 1.65 [tt, J = 7.6, 7.6 Hz, 2H, COCH2-
CH2(CH2)4CH3], 2.46 [t, J = 7.6 Hz, 2H, COCH2(CH2)5CH3], 3.385
(s, 3H, OCH3), 3.389 (ddd, J = 10.0, 10.0, 4.8 Hz, 1H, H-50), 3.63
(dd, J = 10.8, 6.4 Hz, 1H, H-6a), 3.67 (dd, J = 10.8, 6.4 Hz, 1H,
H-1a), 3.72 (dd, J = 10.0, 7.2 Hz, 1H, H-3), 3.73 (dd, J = 10.0,
3.2 Hz, 1H, H-30), 3.74 (dd, J = 7.6, 7.6 Hz, 1H, H-4), 3.81 (dd,
J = 10.8, 2.8 Hz, 1H, H-1b), 3.91 (dd, J = 10.8, 10.0 Hz, 1H, H-60a),
4.00 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 4.10 (dd, J = 10.8, 2.4 Hz, 1H,
H-6b), 4.14 (ddd, J = 10.0, 6.4, 2.8 Hz, 1H, H-2), 4.16 (ddd, J = 7.6,
6.8, 2.4 Hz, 1H, H-5), 4.33 (dd, J = 10.8, 4.8 Hz, 1H, H-60b), 4.63/
4.74 (each d, J = 12.8 Hz, 1H, OCH2Ph), 4.68/4.70 (each
d, J = 6.8 Hz, 1H, OCH2O), 4.75 (d, J = 0.8 Hz, 1H, H-10), 5.61 (s, 1H,
CHPh), 5.71 (dd, J = 3.2, 0.8 Hz, 1H, H-20), 7.27–7.42 (m, 8H, Ar),
7.49–7.52 (m, 2H, Ar). 13C NMR (100 MHz, CDCl3) d: 14.1
[CO(CH2)6CH3], 22.6 [COCH2CH2(CH2)5CH3], 24.9 [CO(CH2)5CH2-
CH3], 26.97 (2C)/27.02 (2C) [C(CH3)2], 28.9/29.0 [CO(CH2)2(CH2)2
(CH2)2CH3], 31.6 [CO(CH2)4CH2CH2CH3], 34.1 [COCH2(CH2)5CH3],
55.3 (OCH3), 67.3 (C-50), 67.7 (C-1), 68.3 (C-20), 68.5 (C-60), 69.9
(C-6), 71.5 (OCH2Ph), 75.7 (C-30), 77.96 (2C)/78.01 (C-3, C-4 and
C-40), 79.9/80.1 (C-2 and C-5), 96.6 (OCH2O), 99.7 (C-10), 101.5
(CHPh), 110.0/110.1 [C(CH3)2], 126.0 (2C)/127.7 (3C)/128.2 (2C)/
128.3 (2C)/128.9 (d, Ar), 137.3/137.7 (s, Ar), 173.2 (OCOCH2).
FABMS m/z (%): 795 ([M+Na]+, 5), 91 (100). FABHRMS calcd for
Compound 23e: A colorless oil. ½a D24
ꢀ15.1 (c 1.36, CHCl3). IR
ꢁ
(neat) cmꢀ1: 3476, 1254, 1215, 1150, 1096. 1H NMR (400 MHz,
CDCl3) d: 0.09/0.12[each s, 3H, Si(CH3)2], 0.90 [s, 9H, SiC(CH3)3],
1.32/1.35/1.39/1.40 [eash s, 3H, C(CH3)2], 2.54 (br s, 1H, OH), 3.34
(ddd, J = 9.6, 9.6, 4.8 Hz, 1H, H-50), 3.63 (dd, J = 9.6, 3.2 Hz, 1H, H-
30), 3.83 (dd, J = 11.6, 3.6 Hz, 1H, H-1a), 3.84 (dd, J = 4.8, 4.8 Hz,
1H, H-4), 3.885 (dd, J = 8.0, 7.6 Hz, 1H, H-6a), 3.886 (dd, J = 10.4,
9.6 Hz, 1H, H-60a), 3.95 (dd, J = 8.0, 4.8 Hz, 1H, H-3), 4.008 (dd,
J = 8.0, 6.4 Hz, 1H, H-6b), 4.013 (dd, J = 11.6, 3.6 Hz, 1H, H-1b),
4.11 (ddd, J = 7.6, 6.4, 4.8 Hz, 1H, H-5), 4.14 (ddd, J = 8.0, 3.6,
3.6 Hz, 1H, H-2), 4.15 (d, J = 3.2 Hz, 1H, H-20), 4.16 (dd, J = 9.6,
9.6 Hz, 1H, H-40), 4.31 (dd, J = 10.4, 4.8 Hz, 1H, H-60b), 4.59 (s, 1H,
H-10), 4.78/4.87 (each d, J = 12.4 Hz, 1H, OCH2Ph), 5.61 (s, 1H,
CHPh), 7.28–7.42 (m, 8H, Ar), 7.49–7.51 (m, 2H, Ar). 13C NMR
(100 MHz, CDCl3) d: ꢀ4.3/ꢀ4.0 [Si(CH3)2], 18.3 [SiC(CH3)3], 25.2/
26.5/26.9 (2C) [C(CH3)2], 26.0 [3C, SiC(CH3)3], 66.3 (C-6), 67.0 (C-
50), 68.5 (C-60), 68.7 (C-1), 69.9 (C-20), 72.6 (OCH2Ph), 72.7 (C-4),
75.7 (C-2), 76.59/76.63 (C-5 and C-30), 78.3 (C-40), 79.3 (C-3),
100.8 (C-10), 101.5 (CHPh), 108.6/108.8 [C(CH3)2], 126.0 (2C)/
127.8/127.9 (2C)/128.2 (2C)/128.4 (2C)/128.9 (d, Ar), 137.4/137.9
(s, Ar). FABMS m/z (%): 739 ([M+Na]+, 59), 73 (100). FABHRMS calcd
for C38H56O11SiNa [M+Na]+: 739.3490; found: 739.3487.
C
42H60O13SiNa [M+Na]+): 795.3932; found: 795.3942.
Following the method described above, 23c (203 mg,
0.283 mmol), 23d (247 mg, 0.382 mmol), 23e (584 mg,
0.815 mmol), and 23f (275 mg, 0.384 mmol) were converted to
Compound 23f: A colorless oil. ½a D25
ꢁ
ꢀ12.8 (c 1.07, CHCl3). IR
6-O-(tert-butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
titol-1-yl 4,6-O-benzylidene-3-O-benzyl-2-O-octanoyl-b-
nopyranoside (24c, 218 mg, 91%), 1,2:3,4-di-O-isopropylidene-5-
O-methoxymethyl- -glucitol-6-yl 3-O-benzyl-4,6-O-benzylidene-
D
-galac-
(neat) cmꢀ1: 3483, 1254, 1215, 1153, 1096. 1H NMR (400 MHz,
CDCl3) d: 0.10/0.13 [each s, 3H, Si(CH3)2], 0.90 [s, 9H, SiC(CH3)3],
1.32/1.38/1.40/1.42 [eash s, 3H, C(CH3)2], 2.55 (br s, 1H, OH), 3.34
D-man-
D

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
955
2-O-octanoyl-b-
butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene-
O-benzyl-4,6-O-benzylidene-2-O-octanoyl-b- -mannopyranoside
(24e, 646 mg, 94%), and 4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-O-
isopropylidene- -glucitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-O-
D
-mannopyranoside (24d, 250 mg, 84%), 4-O-(tert-
(CH2)4CH3], 1.32/1.36/1.38/1.41 [eash s, 3H, C(CH3)2], 1.66 [tdd,
J = 7.2, 7.2, 7.2 Hz, 2H, COCH2CH2(CH2)4CH3], 2.43/2.47 [each dt,
J = 15.6, 7.2 Hz, 1H, COCH2(CH2)5CH3], 3.38 (ddd, J =10.4, 9.6,
4.8 Hz, 1H, H-50), 3.71 (dd, J = 9.6, 3.2 Hz, 1H, H-30), 3.80 (dd,
J = 11.6, 3.2 Hz, 1H, H-1a), 3.84 (dd, J = 4.8, 4.8 Hz, 1H, H-4), 3.88
(dd, J = 8.0, 7.6 Hz, 1H, H-6a), 3.90 (dd, J = 10.4, 10.4 Hz, 1H,
H-60a), 3.97 (dd, J = 8.4, 4.8 Hz, 1H, H-3), 3.98 (dd, J = 11.6, 3.2 Hz,
1H, H-1b), 3.99 (dd, J = 9.6, 9.6 Hz, 1H, H-40), 4.01 (dd, J = 8.0,
6.4 Hz, 1H, H-6b), 4.07 (ddd, J = 8.4, 3.2, 3.2 Hz, 1H, H-2), 4.09
(ddd, J = 7.6, 6.4, 4.8 Hz, 1H, H-5), 4.31 (dd, J = 10.4, 4.8 Hz, 1H,
H-60b), 4.62/4.73 (each d, J = 12.4 Hz, 1H, OCH2Ph), 4.68 (d,
J = 1.2 Hz, 1H, H-10), 5.61 (s, 1H, CHPh), 5.69 (dd, J = 3.2, 1.2 Hz,
1H, H-20), 7.25–7.42 (m, 8H, Ar), 7.48–7.52 (m, 2H, Ar). 13C NMR
(100 MHz, CDCl3) d: ꢀ4.2/ꢀ4.0 [Si(CH3)2], 14.1 [CO(CH2)6CH3],
18.3 [SiC(CH3)3], 22.6 [CO(CH2)5CH2CH3], 25.0 [COCH2CH2(CH2)5-
CH3], 25.3/26.5/26.8/27.0 [C(CH3)2], 26.0 [3C, SiC(CH3)3], 28.96/
29.04 [CO(CH2)2(CH2)2(CH2)2CH3], 31.7 [CO(CH2)4CH2CH2CH3],
34.1 [COCH2(CH2)5CH3], 66.3 (C-6), 67.3 (C-50), 68.3 (C-20), 68.5/
68.6 (C-1 and C-60), 71.6 (OCH2Ph), 72.5 (C-4), 75.6/75.7 (C-2 and
C-30), 76.7 (C-5), 77.9 (C-40), 78.7 (C-3), 100.2 (C-10), 101.5 (CHPh),
108.6/108.8 [C(CH3)2], 126.1 (2C)/127.71/127.75 (2C)/128.2 (2C)/
128.3 (2C)/129.0 (d, Ar), 137.3/137.6 (s, Ar), 173.0 (OCOCH2). FAB-
MS m/z (%): 865 ([M+Na]+, 3), 73 (100). FABHRMS calcd for C46H70-
O12SiNa [M+Na]+: 865.4534; found: 865.4537.
D
-glucitol-1-yl 3-
D
L
octanoyl-b-D-mannopyranoside (24f, 313 mg, 97%), respectively.
Compound 24c: A colorless oil. ½a D25
ꢀ47.2 (c 1.05, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1744, 1250, 1215, 1096. 1H NMR (800 MHz, CDCl3)
d: 0.088/0.090 [each s, 3H, Si(CH3)2], 0.88 [t, J = 7.1 Hz, 3H,
CO(CH2)6CH3], 0.92 [s, 9H, SiC(CH3)3], 1.23–1.35 [m, 8H, CO(CH2)2
(CH2)4CH3], 1.361/1.362/1.40 [eash s, 3H, C(CH3)2], 1.40 [s, 6H,
C(CH3)2], 1.64–1.70 [m, 2H, COCH2CH2(CH2)4CH3], 2.42/2.46 [each
dt, J = 15.8, 7.6 Hz, 1H, COCH2(CH2)5CH3], 3.39 (ddd, J = 10.0, 10.0,
4.8 Hz, 1H, H-50), 3.72 (dd, J = 10.0, 3.4 Hz, 1H, H-30), 3.73 (dd,
J = 11.3, 4.1 Hz, 1H, H-6a), 3.88 (dd, J = 11.3, 3.0 Hz, 1H, H-6b),
3.89 (dd, J = 7.4, 6.4 Hz, 1H, H-4), 3.90 (dd, J = 7.4, 6.4 Hz, 1H, H-
3), 3.909 (dd, J = 10.3, 10.0 Hz, 1H, H-60a), 3.913 (dd, J = 11.7,
2.5 Hz, 1H, H-1a), 3.99 (dd, J = 11.7, 3.6 Hz, 1H, H-1b), 4.01 (dd,
J = 10.0, 10.0 Hz, 1H, H-40), 4.05 (ddd, J = 6.4, 4.1, 3.0 Hz, 1H, H-5),
4.07 (ddd, J = 7.4, 3.6, 2.5 Hz, 1H, H-2), 4.32 (dd, J = 10.3, 4.8 Hz,
1H, H-60b), 4.64/4.74 (each d, J = 12.2 Hz, 1H, OCH2Ph), 4.73 (d,
J = 1.1 Hz, 1H, H-10), 5.62 (s, 1H, CHPh), 5.72 (dd, J = 3.4, 1.1 Hz,
1H, H-20), 7.27–7.29 (m, 1H, Ar), 7.31–7.33 (m, 2H, Ar), 7.36–7.41
(m, 5H, Ar), 7.51–7.52 (m, 2H, Ar). 13C NMR (100 MHz, CDCl3) d:
ꢀ5.4/ꢀ5.3 [Si(CH3)2], 14.1 [CO(CH2)6CH3], 18.4 [SiC(CH3)3], 22.6
[CO(CH2)5CH2CH3], 25.0 [COCH2CH2(CH2)5CH3], 25.9 [3C,
SiC(CH3)3], 26.9/27.0/27.1 (2C) [C(CH3)2], 28.9/29.0 [CO(CH2)2
(CH2)2(CH2)2CH3], 31.6 [CO(CH2)4CH2CH2CH3], 34.1 [COCH2(CH2)5-
CH3], 63.1 (C-6), 67.2 (C-50), 68.4 (C-20), 68.5/68.6 (C-1 and C-60),
71.6 (OCH2Ph), 75.5 (C-30), 77.3 (C-3), 77.6 (C-4), 78.0 (C-40), 79.9
(C-2), 81.5 (C-5), 100.1 (C-10), 101.5 (CHPh), 109.6/109.7
[C(CH3)2], 126.1 (2C)/127.70/127.75 (2C)/128.2 (2C)/128.3 (2C)/
128.9 (d, Ar), 137.3/137.7 (s, Ar), 173.1 (OCOCH2). FABMS m/z
(%): 865 ([M+Na]+, 1), 91 (100). FABHRMS calcd for C46H70O12SiNa
[M+Na]+: 865.4534; found: 865.4545.
Compound 24f: A colorless oil. ½a D24
ꢀ43.8 (c 0.97, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1744, 1254, 1215, 1157, 1096. 1H NMR (400 MHz,
CDCl3) d: 0.09/0.13 [each s, 3H, Si(CH3)2], 0.87 [t, J = 6.8 Hz, 3H,
CO(CH2)6CH3], 0.90 [s, 9H, SiC(CH3)3], 1.24–1.34 [m, 8H, CO(CH2)2
(CH2)4CH3], 1.32/1.34/1.39/1.41 [eash s, 3H, C(CH3)2], 1.66 [tt,
J = 7.6, 7.6 Hz, 2H, COCH2CH2(CH2)4CH3], 2.44 [t, J = 7.6 Hz, 2H,
COCH2(CH2)5CH3], 3.38 (ddd, J = 9.6, 9.6, 4.8 Hz, 1H, H-50), 3.69
(dd, J = 10.4, 5.6 Hz, 1H, H-1a), 3.72 (dd, J = 9.6, 3.2 Hz, 1H, H-30),
3.79 (dd, J = 8.0, 4.0 Hz, 1H, H-3), 3.86 (dd, J = 4.0, 4.0 Hz, 1H, H-
4), 3.89 (dd, J = 8.0, 7.2 Hz, 1H, H-6a), 3.90 (dd, J = 10.4, 9.6 Hz,
1H, H-60a), 3.97 (dd, J = 10.4, 3.6 Hz, 1H, H-1b), 3.98 (dd, J = 9.6,
9.6 Hz, 1H, H-40), 3.99 (dd, J = 8.0, 6.4 Hz, 1H, H-6b), 4.10 (ddd,
J = 7.2, 6.4, 4.0 Hz, 1H, H-5), 4.14 (ddd, J = 8.0, 5.6, 3.6 Hz, 1H, H-
2), 4.32 (dd, J = 10.4, 4.8 Hz, 1H, H-60b), 4.63/4.74 (each d,
J = 12.4 Hz, 1H, OCH2Ph), 4.71 (s, 1H, H-10), 5.61 (s, 1H, CHPh),
5.70 (d, J = 3.2 Hz, 1H, H-20), 7.27–7.41 (m, 8H, Ar), 7.49–7.52 (m,
Compound 24d: A colorless oil. ½a D25
ꢀ29.7 (c 1.14, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1744, 1373, 1250, 1215, 1157, 1096. 1H NMR
(400 MHz, CDCl3) d: 0.87 [t, J = 6.4 Hz, 3H, CO(CH2)6CH3], 1.24–
1.33 [m, 8H, CO(CH2)2(CH2)4CH3], 1.386/1.392/1.43/1.44 [eash s,
3H, C(CH3)2], 1.66 [tt, J = 7.6, 7.6 Hz, 2H, COCH2CH2(CH2)4CH3],
2.44 [t, J = 7.6 Hz, 2H, COCH2(CH2)5CH3], 3.37 (s, 3H, OCH3), 3.38
(ddd, J = 10.0, 10.0, 4.8 Hz, 1H, H-50), 3.63 (dd, J = 10.4, 6.8 Hz, 1H,
H-6a), 3.72 (dd, J = 10.0, 3.2 Hz, 1H, H-30), 3.81 (ddd, J = 6.8, 6.4,
2.4 Hz, 1H, H-5), 3.886 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 3.891 (dd,
J = 8.0, 7.6 Hz, 1H, H-1a), 3.96 (dd, J = 6.8, 6.4 Hz, 1H, H-4), 3.99
(dd, J = 10.0, 10.0 Hz, 1H, H-60a), 4.02 (dd, J = 8.0, 6.4 Hz, 1H, H-
1b), 4.03 (dd, J = 6.8, 4.0 Hz, 1H, H-3), 4.17 (dd, J = 10.4, 2.4 Hz,
1H, H-6b), 4.18 (ddd, J = 7.6, 6.4, 4.0 Hz, 1H, H-2), 4.33 (dd,
J = 10.0, 4.8 Hz, 1H, H-60b), 4.62 (s, 1H, H-10), 4.63/4.73 (each d,
J = 12.4 Hz, 1H, OCH2Ph), 4.65/4.78 (each d, J = 6.8 Hz, 1H, OCH2O),
5.61 (s, 1H, CHPh), 5.67 (d, J = 3.2 Hz, 1H, H-20), 7.28–7.41 (m, 8H,
Ar), 7.49–7.51 (m, 2H, Ar). 13C NMR (100 MHz, CDCl3) d: 14.0
[CO(CH2)6CH3], 22.6 [CO(CH2)5CH2CH3], 25.0 [COCH2CH2(CH2)5-
CH3], 25.7/26.3/27.2/27.4 [C(CH3)2], 28.95/29.02 [CO(CH2)2(CH2)2
(CH2)2CH3], 31.7 [CO(CH2)4CH2CH2CH3], 34.1 [COCH2(CH2)5CH3],
56.0 (OCH3), 65.9 (C-1), 67.3 (C-50), 68.4 (C-60), 68.5 (C-20), 70.8
(C-6), 71.7 (OCH2Ph), 75.6 (C-30), 76.2 (C-2), 76.7 (2C, C-4 and
C-5), 78.0 (C-40), 79.1 (C-3), 96.8 (OCH2O), 100.2 (C-10), 101.6
(CHPh), 109.6/110.2 [C(CH3)2], 126.1 (2C)/127.7 (3C)/128.2 (2C)/
128.3 (2C)/129.0 (d, Ar), 137.3/137.7 (s, Ar), 173.1 (OCOCH2).
FABMS m/z (%): 795 ([M+Na]+, 14), 91 (100). FABHRMS calcd for
2H, Ar).13
C
NMR (100 MHz, CDCl3) d: ꢀ4.2/ꢀ4.0 [Si(CH3)2],
14.1 [CO(CH2)6CH3], 18.3 [SiC(CH3)3], 22.6 [CO(CH2)5CH2CH3],
24.9 [COCH2CH2(CH2)5CH3], 25.1/26.5/26.9/27.0 [C(CH3)2], 26.0
[3C, SiC(CH3)3], 28.96/29.03 [CO(CH2)2(CH2)2(CH2)2CH3], 31.7
[CO(CH2)4CH2CH2CH3], 34.1 [COCH2(CH2)5CH3], 66.0 (C-6), 67.4
(C-50), 68.3 (C-20), 68.5 (C-60), 70.4 (C-1), 71.5 (OCH2Ph), 72.1 (C-
4), 75.7 (C-30), 75.9 (C-2), 76.8 (C-5), 77.9 (C-40), 79.9 (C-3), 99.7
(C-10), 101.5 (CHPh), 108.4/109.2 [C(CH3)2], 126.1 (2C)/127.67/
127.71 (2C)/128.2 (2C)/128.3 (2C)/128.9 (d, Ar), 137.3/137.7 (s,
Ar), 173.0 (OCOCH2). FABMS m/z (%): 865 ([M+Na]+, 12), 91 (100).
FABHRMS calcd for C46H70O12SiNa [M+Na]+: 865.4534; found:
865.4508.
3.1.19. Hydrogenolysis of octanoyl esters (24b–24f)
A suspension of 24b (263 mg, 0.341 mmol) and 10% palladium
on carbon (25 mg) in EtOAc (3.4 mL) was hydrogenated at room
temperature until the uptake of hydrogen ceased. The catalyst
was filtered off and washed with MeOH. The combined filtrate
and washings were condensed in vacuo. The residue was purified
by means of column chromatography (CHCl3–MeOH, 30/1) to give
2,3:4,5-di-O-isopropylidene-1-methoxymethyl-D-galactitol-6-yl 2-
C
42H60O13Na [M+Na]+: 795.3932; found: 795.3943.
O-octanoyl-b-D-mannopyranoside (25b, 184 mg, 91%) as a color-
Compound 24e: A colorless oil. ½a D23
ꢁ
ꢀ29.5 (c 0.73, CHCl3). IR
less amorphous. ½a D24
ꢁ
ꢀ25.0 (c 1.02, CHCl3). IR (neat) cmꢀ1: 3445,
(neat) cmꢀ1: 1744, 1254, 1215, 1161, 1096. 1H NMR (400 MHz,
CDCl3) d: 0.08/0.12 [each s, 3H, Si(CH3)2], 0.87 [t, J = 7.2 Hz, 3H,
CO(CH2)6CH3], 0.90 [s, 9H, SiC(CH3)3], 1.23–1.35 [m, 8H, CO(CH2)2
1744, 1215, 1161, 1069, 1042. 1H NMR (400 MHz, CD3OD) d: 0.90
[t, J = 7.2 Hz, 3H, CO(CH2)6CH3], 1.30–1.35 [m, 8H, CO(CH2)2(CH2)4
CH3], 1.35 [s, 6H, C(CH3)2], 1.37/1.39 [eash s, 3H, C(CH3)2], 1.62

956
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
[tdd, J = 7.6, 7.6, 7.6 Hz, 2H, COCH2CH2(CH2)4CH3], 2.36/2.40 [each
dt, J = 15.6, 7.6 Hz, 1H, COCH2(CH2)5CH3], 3.25 (ddd, J = 9.6, 6.4,
2.4 Hz, 1H, H-50), 3.35 (s, 3H, OCH3), 3.51 (dd, J = 9.6, 9.6 Hz, 1H,
H-40), 3.62 (dd, J = 9.6, 3.2 Hz, 1H, H-30), 3.63 (dd, J = 10.8, 5.6 Hz,
1H, H-6a), 3.68 (dd, J = 10.8, 5.6 Hz, 1H, H-1a), 3.70 (dd, J = 12.0,
6.4 Hz, 1H, H-60a), 3.76 (dd, J = 10.8, 2.8 Hz, 1H, H-1b), 3.85 (dd,
J = 7.2, 6.0 Hz, 1H, H-3), 3.87 (dd, J = 7.2, 6.0 Hz, 1H, H-4), 3.89
(dd, J = 12.0, 2.4 Hz, 1H, H-60b), 4.08 (ddd, J = 7.2, 5.6, 2.8 Hz, 1H,
H-5), 4.10 (dd, J = 10.8, 2.8 Hz, 1H, H-6b), 4.15 (ddd, J = 7.2, 5.6,
2.8 Hz, 1H, H-2), 4.64 (s, 2H, OCH2O), 4.70 (d, J = 1.2 Hz, 1H,
H-10), 5.35 (dd, J = 3.2, 1.2 Hz, 1H, H-20). 13C NMR (100 MHz, CD3-
OD) d: 14.4 [CO(CH2)6CH3], 23.7 [CO(CH2)5CH2CH3], 26.0 [COCH2-
CH2(CH2)5CH3], 27.28/27.31 (2C)/27.35 [C(CH3)2], 30.1/30.2
[CO(CH2)2(CH2)2(CH2)2CH3], 32.9 [CO(CH2)4CH2CH2CH3], 35.1
[COCH2(CH2)5CH3], 55.6 (OCH3), 62.9 (C-60), 68.7 (C-1), 68.8 (C-
40), 70.6 (C-6), 72.8 (C-20), 73.6 (C-30), 78.6 (C-50), 79.0 (C-3), 79.3
(C-4), 80.82/80.84 (C-2 and C-5), 97.7 (OCH2O), 100.7 (C-10),
111.0/111.1 [C(CH3)2], 175.0 (OCOCH2). FABMS m/z (%): 617
([M+Na]+, 100). FABHRMS calcd for C28H50O13SiNa [M+Na]+:
617.3149; found: 617.3148.
(ddd, J = 6.8, 6.0, 3.2 Hz, 1H, H-5), 3.88 (dd, J = 8.0, 7.2 Hz, 1H, H-
1a), 3.90 (dd, J = 12.0, 2.8 Hz, 1H, H-60b), 4.03 (dd, J = 6.8, 2.8 Hz,
1H, H-3), 4.040 (dd, J = 6.8, 6.8 Hz, 1H, H-4), 4.042 (dd, J = 8.0,
6.8 Hz, 1H, H-1b), 4.15 (dd, J = 10.4, 3.2 Hz, 1H, H-6b), 4.22 (ddd,
J = 7.2, 6.8, 2.8 Hz, 1H, H-2), 4.63/4.81 (each d, J = 6.8 Hz, 1H, OCH2-
O), 4.66 (d, J = 0.8 Hz, 1H, H-10), 5.34 (dd, J = 3.6, 0.8 Hz, 1H, H-20).
13C NMR (100 MHz, CD3OD) d: 14.4 [CO(CH2)6CH3], 23.7 [CO(CH2)5-
CH2CH3],
26.0
[COCH2CH2(CH2)5CH3],
26.1/26.6/27.5/27.7
[C(CH3)2], 30.2 [2C, CO(CH2)2(CH2)2(CH2)2CH3], 32.9 [CO(CH2)4CH2-
CH2CH3], 35.1 [COCH2(CH2)5CH3], 56.4 (OCH3), 63.0 (C-60), 67.0 (C-
1), 69.0 (C-40), 71.1 (C-6), 72.9 (C-20), 73.5 (C-30), 77.0 (C-2), 77.9/
78.0 (C-4 and C-5), 78.5 (C-50), 79.6 (C-3), 97.8 (OCH2O), 100.8
(C-10), 110.6/111.0 [C(CH3)2], 175.1 (OCOCH2). FABMS m/z (%):
617 ([M+Na]+, 33), 55 (100). FABHRMS calcd for C28H50O13Na
[M+Na]+: 617.3149; found: 617.3171.
Compound 25e: A colorless amorphous. ½a D23
ꢀ22.1 (c 2.11,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3418, 1744, 1254, 1219, 1161, 1072. 1H
NMR (800 MHz, CDCl3) d: 0.10/0.13 [each s, 3H, Si(CH3)2], 0.90 [t,
J = 7.1 Hz, 3H, CO(CH2)6CH3], 0.91 [s, 9H, SiC(CH3)3], 1.27–1.38
[m, 8H, CO(CH2)2(CH2)4CH3], 1.32/1.33/1.34/1.39 [eash s, 3H,
C(CH3)2], 1.63 [tdd, J = 7.6, 7.6, 7.6 Hz, 2H, COCH2CH2(CH2)4CH3],
2.36/2.40 [each dt, J = 15.8, 7.6 Hz, 1H, COCH2(CH2)5CH3],, 3.26
(ddd, J = 9.6, 6.2, 2.5 Hz, 1H, H-50), 3.51 (dd, J = 9.6, 9.6 Hz, 1H, H-
40), 3.63 (dd, J = 9.6, 3.2 Hz, 1H, H-30), 3.71 (dd, J = 11.7, 6.2 Hz,
1H, H-60a), 3.75 (dd, J = 11.2, 3.4 Hz, 1H, H-1a), 3.88 (dd, J = 8.0,
7.8 Hz, 1H, H-6a), 3.90 (dd, J = 11.7, 2.5 Hz, 1H, H-60b), 3.92 (dd,
J = 4.4, 4.1 Hz, 1H, H-4), 3.95 (dd, J = 8.2, 4.4 Hz, 1H, H-3), 3.99
(dd, J = 8.0, 6.4 Hz, 1H, H-6b), 4.01 (dd, J = 11.2, 3.7 Hz, 1H, H-1b),
4.08 (ddd, J = 8.2, 3.7, 3.4v, 1H, H-2), 4.12 (ddd, J = 7.8, 6.4,
4.1 Hz, 1H, H-5), 4.69 (d, J = 0.9 Hz, 1H, H-10), 5.37 (dd,
J = 3.2, 0.9 Hz, 1H, H-20). 13C NMR (200 MHz, CDCl3) d: ꢀ3.68/
ꢀ3.66 [Si(CH3)2], 14.4 [CO(CH2)6CH3], 19.3 [SiC(CH3)3], 23.7
[CO(CH2)5CH2CH3], 25.5 [COCH2CH2(CH2)5CH3], 26.0/26.9/27.3/
27.5 [C(CH3)2], 26.6 [3C, SiC(CH3)3], 30.20/30.25 [CO(CH2)2(CH2)2(-
CH2)2CH3], 32.9 [CO(CH2)4CH2CH2CH3], 35.2 [COCH2(CH2)5CH3],
62.9 (C-60), 66.8 (C-6), 69.0 (C-40), 69.7 (C-1), 72.8 (C-20), 73.2 (C-
4), 73.6 (C-30), 77.3 (C-2), 78.3 (C-5), 78.6 (C-50), 80.3 (C-3), 100.8
(C-10), 109.7/110.0 [C(CH3)2], 174.8 (OCOCH2). FABMS m/z (%):
687 ([M+Na]+, 80), 73 (100). FABHRMS calcd for C32H60O12SiNa
[M+Na]+: 687.3752; found: 687.3728.
Following the method described above, 24c (176 mg,
0.209 mmol), 24d (219 mg, 0.281 mmol), 24e (272 mg,
0.316 mmol), and 24f (278 mg, 0.330 mmol) were converted to
6-O-(tert-butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
titol-1-yl 2-O-octanoyl-b- -mannopyranoside (25c, 128 mg, 92%),
1,2:3,4-di-O-isopropylidene-5-O-methoxymethyl- -glucitol-6-yl
2-O-otanoyl-b- -mannopyranoside (25d, 150 mg, 90%), 4-O-(tert-
butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene- -glucitol-1-yl
2-O-octanoyl-b- -mannopyranoside (25e, 169 mg, 79%), and 4-O-
(tert-butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene- -glucitol-1-yl
D-galac-
D
D
D
D
D
L
2-O-octanoyl-b-D-mannopyranoside (25f, 142 mg, 65%), respectively.
Compound 25c: A colorless amorphous. ½a D25
ꢀ25.9 (c 1.01,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3395, 1744, 1254, 1215, 1072. 1H NMR
(400 MHz, CD3OD) d: 0.09 [s, 6H, Si(CH3)2], 0.90 [t, J = 7.2 Hz, 3H,
CO(CH2)6CH3], 0.91 [s, 9H, SiC(CH3)3], 1.28–1.35 [m, 8H, CO(CH2)2
(CH2)4CH3], 1.34/1.35/1.37/1.38 [eash s, 3H, C(CH3)2], 1.62 [tdd,
J = 7.2, 7.2, 7.2 Hz, 2H, COCH2CH2(CH2)4CH3], 2.35/2.39 [each dt,
J = 16.0, 7.2 Hz, 1H, COCH2(CH2)5CH3], 3.26 (ddd, J = 9.2, 6.0,
2.8 Hz, 1H, H-50), 3.50 (dd, J = 9.6, 9.2 Hz, 1H, H-40), 3.63 (dd,
J = 9.6, 3.2 Hz, 1H, H-30), 3.70 (dd, J = 12.0, 6.0 Hz, 1H, H-60a), 3.71
(dd, J = 11.2, 4.0 Hz, 1H, H-6a), 3.85 (dd, J = 10.8, 2.8 Hz, 1H, H-
1a), 3.87 (dd, J = 11.2, 2.8 Hz, 1H, H-6b), 3.897 (dd, J = 12.0,
2.8 Hz, 1H, H-60b), 3.898 (dd, J = 7.6, 7.6 Hz, 1H, H-3), 3.95 (dd,
J = 7.6, 7.6 Hz, 1H, H-4), 3.96 (dd, J = 10.8, 2.8 Hz, 1H, H-1b), 4.01
(ddd, J = 7.6, 4.0, 2.8 Hz, 1H, H-5), 4.05 (ddd, J = 7.6, 2.8, 2.8 Hz,
1H, H-2), 4.72 (d, J = 0.8 Hz, 1H, H-10), 5.38 (dd, J = 3.2, 0.8 Hz, 1H,
H-20). 13C NMR (100 MHz, CD3OD) d: ꢀ5.2/ꢀ5.1 [Si(CH3)2], 14.4
[CO(CH2)6CH3], 19.3 [SiC(CH3)3], 23.7 [CO(CH2)5CH2CH3], 26.0
[COCH2CH2(CH2)5CH3], 26.4 [3C, SiC(CH3)3], 27.4/27.5 (3C)
[C(CH3)2], 30.17/30.20 [CO(CH2)2(CH2)2(CH2)2CH3], 32.9 [CO(CH2)4-
CH2CH2CH3], 35.1 [COCH2(CH2)5CH3], 63.0 (C-60), 64.5 (C-6), 69.0
(C-40), 69.6 (C-1), 72.8 (C-20), 73.6 (C-30), 78.6 (C-3), 78.8/78.9 (C-
4 and C-50), 81.1 (C-2), 82.6 (C-5), 100.9 (C-10), 110.8/110.9
[C(CH3)2], 175.0 (OCOCH2). FABMS m/z (%): 687 ([M+Na]+, 100).
FABHRMS calcd for C32H60O12SiNa [M+Na]+: 687.3752; found:
687.3758.
Compound 25f: A colorless amorphous. ½a D24
ꢀ25.4 (c 1.04,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3402, 1744, 1254, 1215, 1161, 1072. 1H
NMR (400 MHz, CD3OD) d: 0.11/0.14 [each s, 3H, Si(CH3)2], 0.90
[t, J = 7.2 Hz, 3H, CO(CH2)6CH3], 0.92 [s, 9H, SiC(CH3)3], 1.27–1.38
[m, 8H, CO(CH2)2(CH2)4CH3], 1.31/1.32/1.35/1.40 [eash s, 3H,
C(CH3)2], 1.63 [tdd, J = 7.6, 7.6, 7.6 Hz, 2H, COCH2CH2(CH2)4CH3],
2.35/2.40 [each t, J = 16.0, 7.6 Hz, 1H, COCH2(CH2)5CH3], 3.26
(ddd, J = 9.6, 5.6, 2.4 Hz, 1H, H-50), 3.49 (dd, J = 9.6, 9.6 Hz, 1H, H-
40), 3.64 (dd, J = 9.6, 3.2 Hz, 1H, H-30), 3.701 (dd, J = 12.4, 5.6 Hz,
1H, H-60a), 3.704 (dd, J = 10.8, 5.2 Hz, 1H, H-1a), 3.89 (dd, J = 8.0,
3.6 Hz, 1H, H-3), 3.901 (dd, J = 8.0, 7.6 Hz, 1H, H-6a), 3.904 (dd,
J = 12.0, 2.4 Hz, 1H, H-60b), 3.94 (dd, J = 8.0, 6.4 Hz, 1H, H-6b),
3.95 (dd, J = 3.6, 3.6 Hz, 1H, H-4), 4.00 (dd, J = 10.8, 5.2 Hz, 1H, H-
1b), 4.14 (ddd, J = 8.0, 5.2, 5.2 Hz, 1H, H-2), 4.16 (ddd, J = 7.6, 6.4,
3.6v, 1H, H-5), 4.70 (s, 1H, H-10), 5.36 (d, J = 3.2 Hz, 1H, H-20). 13C
NMR (100 MHz, CD3OD) d: ꢀ3.7/ꢀ3.5 [Si(CH3)2], 14.4 [CO(CH2)6-
CH3], 19.2 [SiC(CH3)3], 23.7 [CO(CH2)5CH2CH3], 25.3 [COCH2CH2(-
CH2)5CH3], 26.0/26.9/27.36/27.40 [C(CH3)2], 26.6 [3C, SiC(CH3)3],
30.21/30.23 [CO(CH2)2(CH2)2(CH2)2CH3], 32.9 [CO(CH2)4CH2CH2-
CH3], 35.1 [COCH2(CH2)5CH3], 62.9 (C-60), 66.6 (C-6), 68.9 (C-40),
70.9 (C-1), 72.6 (C-4), 72.7 (C-20), 73.6 (C-30), 76.7 (C-2), 78.6/
78.7 (C-5 and C-50), 81.4 (C-3), 100.5 (C-10), 109.5/110.3
[C(CH3)2], 174.8 (OCOCH2). FABMS m/z (%): 687 ([M+Na]+, 100).
FABHRMS calcd for C32H60O12SiNa [M+Na]+: 687.3752; found:
687.3741.
Compound 25d: A colorless amorphous. ½a D24
ꢀ28.7 (c 0.70,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3418, 1744, 1373, 1250, 1215, 1157,
1072, 1034. 1H NMR (400 MHz, CD3OD) d: 0.90 [t, J = 6.8 Hz, 3H,
CO(CH2)6CH3], 1.28–1.35 [m, 8H, CO(CH2)2(CH2)4CH3], 1.35/1.37/
1.38/1.39 [eash s, 3H, C(CH3)2], 1.62 [tt, J = 7.2, 7.2 Hz, 2H, COCH2-
CH2(CH2)4CH3], 2.38 [t, J = 7.2 Hz, 2H, COCH2(CH2)5CH3], 3.26 (ddd,
J = 9.2, 6.4, 2.8 Hz, 1H, H-50), 3.36 (s, 3H, OCH3), 3.50 (dd, J = 9.2,
9.2 Hz, 1H, H-40), 3.61 (dd, J = 10.4, 6.0 Hz, 1H, H-6a), 3.64 (dd,
J = 9.2, 3.6 Hz, 1H, H-30), 3.70 (dd, J = 12.0, 6.4 Hz, 1H, H-60a), 3.81

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
957
3.1.20. Esterification of trisalcohols (25b–25f)
(dd, J = 3.2, 0.9 Hz, 1H, H-20). 13C NMR (100 MHz, CDCl3) d: ꢀ5.4/
ꢀ5.3 [Si(CH3)2], 13.8 (2C)/13.9/14.1 (acyl CH3), 18.4 [SiC(CH3)3],
22.2 (2C)/22.3/22.6 (acyl CH2), 24.3/24.45/24.48/25.0 (COCH2CH2),
25.9 [3C, SiC(CH3)3], 26.8/27.0/27.07/27.09 [C(CH3)2], 28.96/29.03
[CO(CH2)2(CH2)2(CH2)2CH3], 31.2 (2C)/31.3/31.7 (acyl CH2), 33.9/
34.0 (2C)/34.1 (COCH2), 62.5 (C-60), 63.1 (C-6), 65.8 (C-40), 68.2
(C-1), 68.4 (C-20), 71.0 (C-30), 72.5 (C-50), 77.3 (C-3), 77.6 (C-4),
79.9 (C-2), 81.5 (C-5), 99.1 (C-10), 109.7/109.8 [C(CH3)2], 172.3/
172.6/172.9/173.4 (OCOCH2). FABMS m/z (%): 981 ([M+Na]+, 1),
99 (100). FABHRMS calcd for C50H90O15SiNa [M+Na]+: 981.5947;
found: 981.5955.
To a solution of 25b (164 mg, 0.276 mmol) and N,N-dimethyl-
aminopyridine (DMAP, 101 mg, 0.828 mmol) in a mixture of CH2-
Cl2 (2.8 mL) and pyridine (0.09 mL, 1.10 mmol) was added
hexanoic anhydride (0.25 mL, 1.10 mmol) at room temperature,
and the mixture was stirred at room temperature for 30 min. After
the reaction was quenched with water, the resulting mixture was
extracted with CH2Cl2. The extract was successively washed with
aqueous sodium bicarbonate, water and brine, and condensed in
vacuo. The residue was purified by means of column chromatogra-
phy (n-hexane–EtOAc, 15/1) to give 2,3:4,5-di-O-isopropylidene-1-
methoxymethyl-D-galactitol-6-yl 3,4,6-tri-O-hexanoyl-2-O-octa-
Compound 26d: A colorless oil. ½a D24
ꢀ24.1 (c 0.84, CHCl3). IR
ꢁ
noyl-b-
D
-mannopyranoside (26b, 241 mg, 98%) as a colorless oil.
(neat) cmꢀ1: 1748, 1369, 1246, 1219, 1161, 1103, 1069, 1042. 1H
NMR (400 MHz, CDCl3) d: 0.86–0.92 (m, 12H, acyl CH3), 1.23–
1.32 (m, 20H, acyl CH2), 1.38/1.39/1.42/1.43 [eash s, 3H, C(CH3)2],
1.50–1.67 (m, 8H, acyl CH2), 2.18/2.22/2.23/2.29 (each dt, J = 15.2,
7.6, Hz, 1H, COCH2), 2.33 (t, J = 7.6 Hz, 2H, COCH2), 2.40/2.44 (each
dt, J = 16.0, 8.0 Hz, 1H, COCH2), 3.36 (s, 3H, OCH3), 3.62 (dd, J = 10.4,
6.8 Hz, 1H, H-6a), 3.66 (ddd, J = 9.6, 5.6, 2.4 Hz, 1H, H-50), 3.80 (ddd,
J = 6.8, 6.4, 2.8 Hz, 1H, H-5), 3.88 (dd, J = 8.0, 7.6 Hz, 1H, H-1a), 3.96
(dd, J = 6.8, 6.4 Hz, 1H, H-4), 4.01 (dd, J = 8.0, 6.4 Hz, 1H, H-1b), 4.01
(dd, J = 6.8, 4.8 Hz, 1H, H-3), 4.16 (ddd, J = 7.6, 6.4, 4.8 Hz, 1H, H-2),
4.17 (dd, J = 12.0, 2.4 Hz, 1H, H-60a), 4.18 (dd, J = 10.4, 2.8 Hz, 1H,
H-6b), 4.25 (dd, J = 12.0, 5.6 Hz, 1H, H-60b), 4.64/4.75 (each d,
J = 6.8 Hz, 1H, OCH2O), 4.68 (s, 1H, H-10), 5.06 (dd, J = 10.0, 2.8 Hz,
1H, H-30), 5.27 (dd, J = 10.0, 9.6 Hz, 1H, H-40), 5.51 (d, J = 2.8 Hz,
1H, H-20). 13C NMR (100 MHz, CDCl3) d: 13.8 (2C)/13.9/14.0 (acyl
CH3), 22.2 (2C)/22.3/22.6 (acyl CH2), 24.3/24.43/24.48/25.0
½
a 2D5
ꢁ
ꢀ29.5 (c 0.92, CHCl3). IR (neat) cmꢀ1: 1748, 1161, 1099,
1069. 1H NMR (400 MHz, CDCl3) d: 0.88 (t, J = 7.2 Hz, 9H, acyl
CH3), 0.90 (t, J = 7.2 Hz, 3H, acyl CH3), 1.20–1.37 (m, 20H, acyl
CH2), 1.357/1.359/1.37/1.41 [each s, 3H, C(CH3)2], 1.51–1.69 (m,
8H, acyl CH2), 2.18/2.22/2.23/2.28/2.41/2.45 (each dt, J = 15.6,
7.6 Hz, 1H, COCH2), 2.34 (t, J = 7.2 Hz, 2H, COCH2), 3.38 (s, 3H,
OCH3), 3.62 (dd, J = 10.8, 6.4 Hz, 1H, H-6a), 3.657 (dd, J = 8.0,
6.8 Hz, 1H, H-4), 3.661 (ddd, J = 10.0, 5.6, 2.4 Hz, 1H, H-50), 3.67
(dd, J = 11.2, 6.8 Hz, 1H, H-1a), 3.73 (dd, J = 8.0, 8.0 Hz, 1H, H-3),
3.80 (dd, J = 11.2, 2.4 Hz, 1H, H-1b), 4.09 (dd, J = 10.8, 2.4 Hz, 1H,
H-6b), 4.10–4.16 (m, 2H, H-2 and H-5), 4.18 (dd, J = 12.4, 2.4 Hz,
1H, H-60a), 4.25 (dd, J = 12.4, 5.6 Hz, 1H, H-60b), 4.68/4.70 (each d,
J = 6.4 Hz, 1H, OCH2O), 4.84 (d, J = 0.8 Hz, 1H, H-10), 5.07 (dd,
J = 10.0, 3.2 Hz, 1H, H-30), 5.28 (dd, J = 10.0, 10.0 Hz, 1H, H-40),
5.54 (dd, J = 3.2, 0.8 Hz, 1H, H-20). 13C NMR (100 MHz, CDCl3) d:
13.8 (2C)/13.9/14.1 (acyl CH3), 22.2 (2C)/22.3/22.6 (acyl CH2),
24.3/24.4/24.5/25.0 (COCH2CH2), 26.95/27.00 (3C) [C(CH3)2],
28.96/29.00 [CO(CH2)2(CH2)2(CH2)2CH3], 31.2 (2C)/31.3/31.7 (acyl
CH2), 33.9/34.0 (2C)/34.1 (COCH2), 55.3 (OCH3), 62.4 (C-60), 65.8
(C-40), 67.6 (C-1), 68.5 (C-20), 69.8 (C-6), 71.0 (C-30), 72.6 (C-50),
78.0/78.1 (C-3 and C-4), 79.9/80.2 (C-2 and C-5), 96.6 (OCH2O),
98.6 (C-10), 110.0/110.2 [C(CH3)2], 172.2/172.7/173.0/173.4
(OCOCH2). FABMS m/z (%): 911 ([M+Na]+, 6), 99 (100). FABHRMS
calcd for C46H80O16Na [M+Na]+: 911.5344; found: 911.5344.
Following the method described above, 25c (92.7 mg,
0.139 mmol), 25d (130 mg, 0.219 mmol), 25e (146 mg,
0.214 mmol), and 25f (122 mg, 0.183 mmol) were converted to
6-O-(tert-butyldimethylsilyl)-2,3:4,5-di-O-isopropylidene-
(COCH2CH2),
25.6/26.3/27.1/27.4
[C(CH3)2],
28.98/29.03
[CO(CH2)2(CH2)2(CH2)2CH3], 31.2 (2C)/31.3/31.7 (acyl CH2), 33.94/
33.97/34.0/34.1 (COCH2), 55.9 (OCH3), 62.4 (C-60), 65.78 (C-40),
65.84 (C-1), 68.4 (C-20), 70.5 (C-6), 70.9 (C-30), 72.6 (C-50), 76.1
(C-2), 76.6/76.7 (C-4 and C-5), 78.9 (C-4), 96.7 (OCH2O), 99.2 (C-
10), 109.6/110.2 [C(CH3)2], 172.3/172.7/172.9/173.4 (OCOCH2).
FABMS m/z (%): 911 ([M+Na]+, 19), 99 (100). FABHRMS calcd for
C
46H80O16Na [M+Na]+: 911.5344; found: 911.5341.
Compound 26e: A colorless oil. ½a D24
ꢀ25.7 (c 1.52, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1748, 1250, 1157, 1072. 1H NMR (400 MHz, CDCl3)
d: 0.07/0.11 [each s, 3H, Si(CH3)2], 0.86–0.91 (m, 12H, acyl CH3),
0.89 [s, 9H, SiC(CH3)3], 1.11–1.37 (m, 20H, acyl CH2), 1.32/1.35/
1.37/1.40 [eash s, 3H, C(CH3)2], 1.50–1.68 (m, 8H, acyl CH2), 2.17/
2.22/2.23/2.28/2.40/2.45 (each dt, J = 15.6, 7.2 Hz, 1H, COCH2),
2.34 (t, J = 7.2 Hz, 2H, COCH2), 3.66 (ddd, J = 10.0, 5.6, 2.4 Hz, 1H,
H-50), 3.80 (dd, J = 11.6, 3.2 Hz, 1H, H-1a), 3.83 (dd, J = 4.8, 4.4 Hz,
1H, H-4), 3.87 (dd, J = 8.0, 8.0 Hz, 1H, H-6a), 3.95 (dd, J = 8.4,
4.4 Hz, 1H, H-3), 3.98 (dd, J = 11.6, 2.8 Hz, 1H, H-1b), 3.99 (dd,
J = 8.0, 6.0 Hz, 1H, H-6b), 4.06 (ddd, J = 8.4, 3.2, 2.8 Hz, 1H, H-2),
4.08 (ddd, J = 8.0, 6.0, 4.8 Hz, 1H, H-5), 4.17 (dd, J = 12.0, 2.4 Hz,
1H, H-60a), 4.23 (dd, J = 12.0, 5.6 Hz, 1H, H-60b), 4.77 (s, 1H, H-10),
5.04 (dd, J = 10.0, 3.2 Hz, 1H, H-30), 5.27 (dd, J = 10.0, 10.0 Hz, 1H,
H-40), 5.52 (d, J = 3.2 Hz, 1H, H-20). 13C NMR (100 MHz, CDCl3) d:
ꢀ4.3/ꢀ4.0 [Si(CH3)2], 13.8 (2C)/13.9/14.0 (acyl CH3), 18.3
[SiC(CH3)3], 22.2 (2C)/22.3/22.6 (acyl CH2), 24.2/24.4/24.5/25.0
(COCH2CH2), 25.2/26.4/26.8/27.0 [C(CH3)2], 26.0 [3C, SiC(CH3)3],
28.96/29.03 [CO(CH2)2(CH2)2(CH2)2CH3], 31.2 (2C)/31.3/31.7 (acyl
CH2), 33.9/34.0 (2C)/34.1 (COCH2), 62.4 (C-60), 65.7 (C-40), 66.2
(C-6), 68.31 (C-1), 68.33 (C-20), 71.0 (C-30), 72.4 (C-4), 72.6 (C-50),
75.7 (C-2), 76.7 (C-5), 78.7 (C-3), 99.2 (C-10), 108.5/108.8
[C(CH3)2], 172.3/172.6/172.8/173.4 (OCOCH2). FABMS m/z (%):
981 ([M+Na]+, 2), 99 (100). FABHRMS calcd for C50H90O15SiNa
[M+Na]+: 981.5947; found: 981.5965.
D
-galactitol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl-b-
pyranoside (26c, 125 mg, 94%), 1,2:3,4-di-O-isopropylidene-5-O-
methoxymethyl- -glucitol-6-yl 3,4,6-tri-O-hexanoyl-2-O-octa-
noyl-b- -mannopyranoside (26d, 101 mg, 51%), 4-O-(tert-butyldi-
methylsilyl)-2,3:5,6-di-O-isopropylidene- -glucitol-1-yl 3,4,6-tri-
O-hexanoyl-2-O-octanoyl-b- -mannopyranoside (26e, 198 mg,
94%), and 4-O-(tert-butyldimethylsilyl)-2,3:5,6-di-O-isopropyli-
dene- -glucitol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl-b- -man-
D-manno-
D
D
D
D
L
D
nopyranoside (26f, 170 mg, 97%), respectively.
Compound 26c: A colorless oil. ½a D24
ꢀ26.7 (c 1.05, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1748,1246, 1161, 1099, 1069. 1H NMR (800 MHz,
CDCl3) d: 0.068/0.070 [each s, 3H, Si(CH3)2], 0.877/0.881/0.882/
0.898 (each t, J = 7.1 Hz, 3H, acyl CH3), 0.900 [s, 9H, SiC(CH3)3],
1.22–1.35 (m, 20H, acyl CH2), 1.34/1.35/1.38/1.39 [eash s, 3H,
C(CH3)2], 1.52–1.59 (m, 4H, acyl CH2), 1.61–1.66 (m, 4H, acyl
CH2), 2.18/2.21 (each ddd, J = 15.8, 8.5, 7.4 Hz, 1H, COCH2), 2.24/
2.28/2.32/2.34/2.39/2.43/ (each dt, J = 15.8, 7.6 Hz, 1H, COCH2),
3.66 (ddd, J = 9.9, 5.7, 2.5 Hz, 1H, H-50), 3.70 (dd, J = 11.2, 4.1 Hz,
1H, H-6a), 3.86 (dd, J = 11.2, 3.0 Hz, 1H, H-6b), 3.87 (dd, J = 6.8,
6.8 Hz, 1H, H-4), 3.88 (dd, J = 6.8, 6.8 Hz, 1H, H-3), 3.90 (dd,
J = 11.9, 2.5 Hz, 1H, H-1a), 3.99 (dd, J = 11.9, 3.2 Hz, 1H, H-1b),
4.03 (ddd, J = 6.8, 4.1, 3.0 Hz, 1H, H-5), 4.05 (ddd, J = 6.8, 3.2,
2.5 Hz, 1H, H-2), 4.16 (dd, J = 12.1, 2.5 Hz, 1H, H-6a0),4.25 (dd,
J = 12.1, 5.7 Hz, 1H, H-60b), 4.81 (d, J = 0.9 Hz, 1H, H-10), 5.05 (dd,
J = 10.1, 3.2 Hz, 1H, H-30), 5.27 (dd, J = 10.1, 9.9 Hz, 1H, H-40), 5.54
Compound 26f: A colorless oil. ½a D25
ꢀ23.5 (c 1.08, CHCl3). IR
ꢁ
(neat) cmꢀ1: 1748, 1250, 1219, 1161, 1099, 1072. 1H NMR
(400 MHz, CDCl3) d: 0.07/0.11 [each s, 3H, Si(CH3)2], 0.86–0.92
(m, 12H, acyl CH3), 0.89 [s, 9H, SiC(CH3)3], 1.24–1.35 (m, 20H, acyl
CH2), 1.31/1.35/1.38/1.40 [eash s, 3H, C(CH3)2], 1.51–1.68 (m, 8H,

958
N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
acyl CH2), 2.17/2.22/2.23/2.28/2.31/2.35/2.39/2.44 (each dt,
J = 16.0, 7.6 Hz, 1H, COCH2), 3.65 (ddd, J = 10.0, 5.6, 2.4 Hz, 1H, H-
50), 3.69 (dd, J = 10.8, 6.0 Hz, 1H, H-1a), 3.77 (dd, J = 8.0, 4.0 Hz,
1H, H-3), 3.83 (dd, J = 4.8, 4.0 Hz, 1H, H-4), 3.88 (dd, J = 8.0,
7.2 Hz, 1H, H-6a), 3.94 (dd, J = 10.8, 4.0 Hz, 1H, H-1b), 3.98 (dd,
J = 8.0, 6.4 Hz, 1H, H-6b), 4.08 (ddd, J = 7.2, 6.4, 4.8 Hz, 1H, H-5),
4.14 (ddd, J = 8.0, 6.0, 4.0 Hz, 1H, H-2), 4.17 (dd, J = 12.4, 2.4 Hz,
1H, H-60a), 4.24 (dd, J = 12.4, 5.6 Hz, 1H, H-60b), 4.79 (d,
J = 0.8 Hz, 1H, H-10), 5.07 (dd, J = 10.0, 3.2 Hz, 1H, H-30), 5.26 (dd,
J = 10.0, 10.0 Hz, 1H, H-40), 5.52 (dd, J = 3.2, 0.8 Hz, 1H, H-20). 13C
NMR (100 MHz, CDCl3) d: ꢀ4.2/ꢀ4.0 [Si(CH3)2], 13.8 (2C)/13.9/
14.1 (acyl CH3), 18.3 [SiC(CH3)3], 22.2 (2C)/22.3/22.6 (acyl CH2),
24.2/24.4/24.5/25.0 (COCH2CH2), 25.1/26.4/26.9/27.0 [C(CH3)2],
26.0 [3C, SiC(CH3)3], 28.98/29.04 [CO(CH2)2(CH2)2(CH2)2CH3], 31.2
(2C)/31.3/31.7 (acyl CH2), 33.9/34.0 (2C)/34.1 (COCH2), 62.4 (C-
60), 65.8 (C-40), 66.1 (C-6), 68.4 (C-20), 70.3 (C-1), 71.0 (C-30), 72.2
(C-4), 72.6 (C-50), 75.8 (C-2), 76.8 (C-5), 80.1 (C-3), 98.5 (C-10),
108.5/109.3 [C(CH3)2], 172.7/172.9 (2C)/173.4 (OCOCH2). FABMS
m/z (%): 981 ([M+Na]+, 3), 99 (100). FABHRMS calcd for C50H90O15
SiNa [M+Na]+: 981.5947; found: 981.5958.
CH2), 1.52–1.59 (m, 4H, acyl CH2), 1.62–1.69 (m, 4H, acyl CH2),
2.18/2.21 (each dt, J = 15.6, 7.2 Hz, 1H, COCH2), 2.27/2.31 (each
dt, J = 15.8, 7.4 Hz, 1H, COCHH), 2.34/2.37 (each dt, J = 15.6,
7.6 Hz, 1H, COCH2), 2.39/2.46 (each dt, J = 15.4, 7.2 Hz, 1H, COCH2),
3.62 (dd, J = 8.9, 1.4 Hz, 1H, H-3), 3.63 (d, J = 6.2 Hz, 2H, H-6), 3.66
(dd, J = 8.9, 1.6 Hz, 1H, H-4), 3.73 (dd, J = 10.1, 6.4 Hz, 1H, H-1a),
3.83 (ddd, J = 10.0, 4.2, 2.2 Hz, 1H, H-50), 3.897 (dd, J = 10.1,
6.4 Hz, 1H, H-1b), 3.899 (td, J = 6.2, 1.6 Hz, 1H, H-5), 4.04 (ddd,
J = 6.4, 6.4, 1.4 Hz, 1H, H-2), 4.16 (dd, J = 12.4, 2.2 Hz, 1H, H-60a),
4.28 (dd, J = 12.4, 4.2 Hz, 1H, H-60b), 4.90 (d, J = 0.8 Hz, 1H, H-10),
5.16 (dd, J = 10.2, 3.2 Hz, 1H, H-30), 5.30 (dd, J = 10.2, 10.0 Hz, 1H,
H-40), 5.47 (dd, J = 3.2, 0.8 Hz, 1H, H-20). 13C NMR (175 MHz, CD3-
OD) d: 14.2 (2C)/14.3/14.5 (acyl CH3), 23.36/23.38/23.41/23.8 (acyl
CH2), 25.5/25.59/25.62/26.3 (COCH2CH2), 30.2/30.3 [CO(CH2)2
(CH2)2(CH2)2CH3], 32.3/32.4/32.5/33.0 (acyl CH2), 34.8/34.9/35.0/
35.2 (COCH2), 63.0 (C-60), 65.0 (C-6), 66.8 (C-40), 69.6 (C-2), 70.5
(C-20), 71.2 (C-3), 71.3 (C-4), 71.9 (C-5), 72.68 (C-30), 72.70 (C-1),
73.5 (C-50), 100.0 (C-10), 173.7/173.8/174.7/175.0 (OCOCH2). FAB-
MS m/z (%): 787 ([M+Na]+, 100). FABHRMS calcd for C38H68O15Na
[M+Na]+: 787.4456; found: 787.4465.
Compound 1d: A colorless amorphous. ½a D25
ꢀ27.9 (c 0.21,
ꢁ
3.1.21. Preparation of acremomannolipin A analogs (1b–1f)
A solution of 26b (221 mg, 0.249 mmol) in 90% aqueous trifluo-
roacetic acid (TFA, 2.5 mL) was stirred at 0 °C for 30 min. After re-
moval of the solvent, the residue was co-evaporated five times
with MeOH in vacuo. The residue was purified by means of column
CHCl3). IR (neat) cmꢀ1: 3391, 1748, 1246, 1165, 1099, 1069. 1H
NMR (700 MHz, CD3OD) d: 0.90 (t, J = 7.2 Hz, 6H, acyl CH3), 0.91/
0.92 (each t, J = 7.2 Hz, 3H, acyl CH3), 1.24–1.42 (m, 20H, acyl
CH2), 1.52–1.59 (m, 4H, acyl CH2), 1.62–1.70 (m, 4H, acyl CH2),
2.19/2.21 (each dt, J = 15.6, 7.6 Hz, 1H, COCH2), 2.27/2.31 (each
dt, J = 15.8, 7.4 Hz, 1H, COCH2), 2.34/2.37 (each dt, J = 15.6,
8.1 Hz, 1H, COCHHCH2), 2.40/2.47 (each dt, J = 15.4, 7.2 Hz, 1H,
COCH2), 3.57 (dd, J = 8.2, 2.0 Hz, 1H, H-4), 3.58 (dd, J = 12.1,
6.0 Hz, 1H, H-1a), 3.66 (dd, J = 12.1, 4.6 Hz, 1H, H-1b), 3.68 (dd,
J = 10.6, 6.6 Hz, 1H, H-6a), 3.74 (ddd, J = 6.0, 4.8, 4.6 Hz, 1H, H-2),
3.80 (ddd, J = 8.2, 6.6, 2.6 Hz, 1H, H-5), 3.82 (ddd, J = 10.0, 4.2,
2.2 Hz, 1H, H-50), 3.83 (dd, J = 4.8, 2.0 Hz, 1H, H-3), 4.10 (dd,
J = 10.6, 2.6 Hz, 1H, H-6b), 4.14 (dd, J = 12.2, 2.2 Hz, 1H, H-60a),
4.28 (dd, J = 12.2, 4.2 Hz, 1H, H-60b), 4.91 (d, J = 0.8 Hz, 1H, H-10),
5.16 (dd, J = 10.0, 3.2 Hz, 1H, H-30), 5.29 (dd, J = 10.0, 10.0 Hz, 1H,
H-40), 5.50 (dd, J = 3.2, 0.8 Hz, 1H, H-20). 13C NMR (175 MHz,
CD3OD) d: 14.2 (2C)/14.3/14.5 (acyl CH3), 23.36/23.38/23.42/23.8
(acyl CH2), 25.5/25.60/25.62/26.4 (COCH2CH2), 30.2/30.3
[CO(CH2)2(CH2)2(CH2)2CH3], 32.3/32.4/32.5/33.0 (acyl CH2), 34.8/
34.9/35.0/35.2 (COCH2), 63.1 (C-60), 64.2 (C-1), 66.8 (C-40), 70.5
(C-20), 70.6 (C-3), 71.7 (C-5), 72.7 (C-30), 73.37 (C-4), 73.39 (C-6),
73.5 (C-50), 75.1 (C-2), 100.6 (C-10), 173.77/173.84/174.8/175.0
(COCH2). FABMS m/z (%): 787 ([M+Na]+, 4), 99 (100). FABHRMS
calcd for C38H68O15Na [M+Na]+: 787.4456; found: 787.4442.
chromatography (CHCl3–MeOH, 50/1) to give
D
-galactitol-6-yl
3,4,6-tri-O-hexanoyl-2-O-octanoyl-b-
D-mannopyranoside (1b,
ꢁ
165 mg, 88%) as a colorless amorphous. ½a D25
ꢀ26.1 (c 0.95, CHCl3).
IR (neat) cmꢀ1: 3383, 1748, 1246, 1165, 1099, 1065. 1H NMR
(800 MHz, CDCl3) d: 0.90 (t, J = 7.1 Hz, 6H, acyl CH3), 0.91/0.92
(each t, J = 7.1 Hz, 3H, acyl CH3), 1.24–1.42 (m, 20H, acyl CH2),
1.51–1.59 (m, 4H, acyl CH2), 1.63–1.70 (m, 4H, acyl CH2), 2.19/
2.21 (each dt, J = 15.6, 7.4 Hz, 1H, COCH2), 2.27/2.31 (each dt,
J = 15.9, 7.3 Hz, 1H, COCH2), 2.34/2.37 (each dt, J = 15.8, 7.6 Hz,
1H, COCH2), 2.39/2.46 (each dt, J = 15.4, 7.3 Hz, 1H, COCH2), 3.59
(dd, J = 9.2, 1.4 Hz, 1H, H-4), 3.63 (d, J = 6.2 Hz, 2H, H-1), 3.64 (dd,
J = 9.2, 1.4 Hz, 1H, H-3), 3.70 (dd, J = 10.3, 7.5 Hz, 1H, H-6a), 3.83
(ddd, J = 9.9, 4.3, 2.1 Hz, 1H, H-50), 3.89 (td, J = 6.2, 1.4 Hz, 1H, H-
2), 3.92 (dd, J = 10.3, 5.0 Hz, 1H, H-6b), 4.04 (ddd, J = 7.5, 5.0,
1.4 Hz, 1H, H-5), 4.14 (dd, J = 12.3, 2.1 Hz, 1H, H-60a), 4.28 (dd,
J = 12.3, 4.3 Hz, 1H, H-60b), 4.94 (d, J = 0.7 Hz, 1H, H-10), 5.16 (dd,
J = 10.1, 3.2 Hz, 1H, H-30), 5.30 (dd, J = 10.1, 9.9 Hz, 1H, H-40), 5.49
(dd, J = 3.2, 0.7 Hz, 1H, H-20). 13C NMR (200 MHz, CDCl3) d: 14.2
(2C)/14.3/14.5 (acyl CH3), 23.36/23.38/23.41/23.8 (acyl CH2),
25.5/25.58/25.62/26.3 (COCH2CH2), 30.2/30.3 [CO(CH2)2(CH2)2
(CH2)2CH3], 32.3/32.36/32.45/33.0 (acyl CH2), 34.8/34.9/35.0/35.2
(COCH2), 63.0 (C-60), 65.0 (C-1), 66.8 (C-40), 70.2 (C-5), 70.5 (C-20),
71.27 (C-3), 71.33 (C-4), 71.8 (C-2), 72.7 (C-30), 73.2 (C-6), 73.5
(C-50), 100.3 (C-10), 173.75/173.83/174.7/175.0 (OCOCH2). FABMS
m/z (%): 787 ([M+Na]+, 25), 99 (100). FABHRMS calcd for C38H68O15
Na [M+Na]+: 787.4456; found: 787.4478.
Compound 1e: A colorless amorphous. ½a D24
ꢀ29.6 (c 2.96,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3391, 1748, 1246, 1161, 1103, 1069. 1H
NMR (700 MHz, CD3OD) d: 0.90 (t, J = 7.3 Hz, 6H, acyl CH3), 0.91/
0.93 (each t, J = 7.2 Hz, 3H, acyl CH3), 1.24–1.45 (m, 20H, acyl
CH2), 1.52–1.59 (m, 4H, acyl CH2), 1.63–1.70 (m, 4H, acyl CH2),
2.19/2.21 (each dt, J = 15.4, 7.4 Hz, 1H, COCH2), 2.27/2.35 (each
dt, J = 15.8, 7.4 Hz, 1H, COCH2), 2.35/2.38 (each dt, J = 15.8,
7.6 Hz, COCH2), 2.40/2.48 (each dt, J = 15.5, 7.4 Hz, 1H, COCH2),
3.60 (dd, J = 11.2, 6.0 Hz, 1H, H-6a), 3.63 (dd, J = 7.8, 2.0 Hz, 1H,
H-4), 3.69 (ddd, J = 7.8, 6.0, 3.6 Hz, 1H, H-5), 3.76 (dd, J = 12.4,
7.3 Hz, 1H, H-1a), 3.77 (dd, J = 11.2, 3.6 Hz, 1H, H-6b), 3.83 (dd,
J = 4.2, 2.0 Hz, 1H, H-3), 3.84 (ddd, J = 10.0, 4.3, 2.2 Hz, 1H, H-50),
3.88 (ddd, J = 7.3, 5.6, 4.2 Hz, 1H, H-2), 3.89 (dd, J = 12.4, 5.6 Hz,
1H, H-1b), 4.15 (dd, J = 12.3, 2.2 Hz, 1H, H-60a), 4.28 (dd, J = 12.3,
4.3 Hz, 1H, H-60b), 4.91 (d, J = 1.0 Hz, 1H, H-10), 5.17 (dd, J = 10.0,
3.2 Hz, 1H, H-30), 5.29 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 5.48 (dd,
J = 3.2, 1.0 Hz, 1H, H-20). 13C NMR (175 MHz, CD3OD) d: 14.2 (2C)/
14.3/14.5 (acyl CH3), 23.35/23.37/23.40/23.8 (acyl CH2), 25.5/
25.58/25.61/26.3 (COCH2CH2), 30.2/30.3 [CO(CH2)2(CH2)2(CH2)2-
CH3], 32.33/32.35/32.4/33.0 (acyl CH2), 34.8/34.9/35.0/35.2
(COCH2), 63.0 (C-60), 64.9 (C-6), 66.8 (C-40), 70.4 (C-20), 70.8 (C-3),
Following the method described above, 26c (21.0 mg,
0.0219 mmol), 26d (83.0 mg, 0.0919 mmol), 26e (198 mg,
0.203 mmol), and 26f (112 mg, 0.117 mmol) were converted to
D
-galactitol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl-b-
ranoside (1c, (16.1 mg, 96%), -glucitol-6-yl 3,4,6-tri-O-hexanoyl-
2-O-octanoyl-b- -mannopyranoside (1d, 47.0 mg, 67%),
-glucitol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl-b- -mannopy-
ranoside (1e, 108 mg, 70%), and -glucitol-1-yl 3,4,6-tri-O-hexa-
-mannopyranoside (1f, 63.0 mg, 71%),
D-mannopy-
D
D
D
D
L
noyl-2-O-octanoyl-b-
D
respectively.
Compound 1c: A colorless amorphous. ½a D24
ꢀ28.1 (c 1.61,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3391, 1748, 1246, 1165, 1103, 1069. 1H
NMR (700 MHz, CD3OD) d: 0.90 (t, J = 7.2 Hz, 6H, acyl CH3), 0.91/
0.92 (each t, J = 7.2 Hz, 3H, acyl CH3), 1.23–1.41 (m, 20H, acyl

N. Tsutsui et al. / Bioorg. Med. Chem. 22 (2014) 945–959
959
72.1 (C-1), 72.6 (C-30), 73.0 (C-5), 73.2 (C-2), 73.5 (C-50), 73.7 (C-4),
100.0 (C-10), 173.7/173.8/174.7/175.0 (OCOCH2). FABMS m/z (%):
787 ([M+Na]+, 100). FABHRMS calcd for C38H68O15Na [M+Na]+:
787.4456; found: 787.4434.
were grown at 27 °C in the YPD (the complete medium yeast ex-
tract-peptone-dextrose) and harvested in the early logarithmic
growth phase. The cells were resuspended in fresh YPD, and the
optical density was adjusted to 0.5 at 660 nm. The cells were
spread onto the YPD agar medium containing 0.12 M MgCl2 and
then put a filter paper disk (3 mm in diameter) in each section.
Compound 1f: A colorless amorphous. ½a D25
ꢀ15.5 (c 0.55,
ꢁ
CHCl3). IR (neat) cmꢀ1: 3418, 1744, 1246, 1161, 1099, 1069. 1H
NMR (500 MHz, CD3OD) d: 0.90 (t, J = 7.2 Hz, 6H, acyl CH3), 0.91/
0.92 (each t, J = 6.9 Hz, 3H, acyl CH3), 1.22–1.40 (m, 20H, acyl
CH2), 1.51-1.60 (m, 4H, acyl CH2), 1.61–1.70 (m, 4H, acyl CH2),
2.18/2.21 (each dt, J = 15.4, 7.5 Hz, 1H, COCH2), 2.26/2.31 (each
dt, J = 15.8, 7.4 Hz, 1H, COCH2), 2.33/2.37 (dt, J = 15.5, 7.5 Hz, 1H,
COCH2), 2.39/2.47 (each dt, J = 15.5, 7.2 Hz, 1H, COCH2), 3.595
(dd, J = 7.8, 2.0 Hz, 1H, H-4), 3.599 (dd, J = 11.2, 6.0 Hz, 1H, H-6a),
3.65 (dd, J = 10.6, 6.9 Hz, 1H, H-1a), 3.67 (ddd, J = 7.8, 6.0, 3.7 Hz,
1H, H-5), 3.76 (dd, J = 11.2, 3.7 Hz, 1H, H-6b), 3.78 (dd, J = 4.6,
2.0 Hz, 1H, H-3), 3.82 (ddd, J = 10.0, 4.3, 2.0 Hz, 1H, H-50), 3.89
(ddd, J = 6.9, 4.6, 4.0 Hz, 1H, H-2), 3.97 (dd, J = 10.6, 4.0 Hz, 1H,
H-1b), 4.14 (dd, J = 12.3, 2.0 Hz, 1H, H-60a), 4.28 (dd, J = 12.3,
4.3 Hz, 1H, H-60b), 4.91 (d, J = 0.9 Hz, 1H, H-10), 5.16 (dd, J = 10.0,
3.2 Hz, 1H, H-30), 5.29 (dd, J = 10.0, 10.0 Hz, 1H, H-40), 5.49 (dd,
J = 3.2, 0.9 Hz, 1H, H-20). 13C NMR (125 MHz, CD3OD) d: 14.2 (2C)/
14.3/14.5 (acyl CH3), 23.37/23.39/23.43/23.8 (acyl CH2), 25.5/
25.58/25.62/26.4 (COCH2CH2), 30.2/30.3 [CO(CH2)2(CH2)2(CH2)2-
CH3], 32.3/32.4/32.5/33.0 (acyl CH2), 34.8/34.9/35.0/35.2 (COCH2),
63.0 (C-60), 64.8 (C-6), 66.8 (C-40), 70.5 (C-20), 71.0 (C-3), 72.66
(C-30), 72.68 (C-1), 73.0 (C-5), 73.4 (C-50), 73.57 (C-2), 73.65
(C-4), 100.3 (C-10), 173.7/173.8/174.7/175.0 (OCOCH2). FABMS m/
Next, 5
lL of DMSO or the compound which was dissolved in
DMSO at a concentration of 100
lM was spotted onto each paper
and the cells were incubated at 27 °C for 3 days.
Acknowledgments
This study was performed as a research program of the Project
for Development of Innovative Research on Cancer Therapeutics
(P-Direct), Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan.
References and notes
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439.
3. (a) Tsutsui, N.; Tanabe, G.; Kita, A.; Sugiura, R.; Muraoka, O. Tetrahedron Lett.
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W. D.; Hudson, C. S. J. Am. Chem. Soc. 1939, 61, 1270.
z
(%): 787 ([M+Na]+, 100). FABHRMS calcd for C38H68O15Na
[M+Na]+: 787.4456; found: 787.4432.
7. (a) Khan, A. T.; Khan, M. M. Carbohydr. Res. 2010, 345, 2139; (b) Roberts, J. C.;
Nagasawa, H. T.; Zera, R. T.; Fricke, R. F.; Goon, D. J. W. J. Med. Chem. 1987, 30,
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4. Bioassay of acremomannolipin A homologs
The Schizosaccharomyces pombe strains used in this study are
calcineurin deletion cells (h+ leu1 ura4-D18 ppb1::ura4+). The cells