Studies directed toward the stereochemical structure determination of the naturally occurring glucosidase inhibitor, kotalanol: Synthesis and inhibitory activities against human maltase glucoamylase of seven-carbon, chain-extended homologues of salacinol

Article abstract of DOI:10.1021/jo800855n

(Chemical Equation Presented) The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio-D-arabinitol, analogues of the naturally occurring glycosidase inhibitor salacinol, are described. These compounds were designed on the b

Full text of DOI:10.1021/jo800855n

Studies Directed toward the Stereochemical Structure Determination
of the Naturally Occurring Glucosidase Inhibitor, Kotalanol:
Synthesis and Inhibitory Activities against Human Maltase
Glucoamylase of Seven-Carbon, Chain-Extended Homologues of
Salacinol
Ravindranath Nasi,† Brian O. Patrick,‡ Lyann Sim,§ David R. Rose,§ and B. Mario Pinto*,†
Department of Chemistry, Simon Fraser UniVersity, Burnaby, British Columbia, Canada V5A 1S6,
Department of Chemistry, UniVersity of British Columbia, VancouVer, Burnaby, British Columbia, Canada
V6T 1Z1, and Department of Medical Biophysics, UniVersity of Toronto and DiVision of Molecular and
Structural Biology, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9
bpinto@sfu.ca
ReceiVed April 18, 2008
The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio-D-arabinitol,
analogues of the naturally occurring glycosidase inhibitor salacinol, are described. These compounds
were designed on the basis of the structure activity data of chain-extended analogues of salacinol, with
the intention of determining the hitherto unknown stereochemical structure of kotalanol, the naturally
occurring seven-carbon chain-extended analogue of salacinol. The target zwitterionic compounds were
synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-thio-D-arabinitols at
the least hindered carbon atom of two 1,3-cyclic sulfates differing in stereochemistry at only one stereogenic
center. The desired cyclic sulfates were synthesized starting from D-glucose via Wittig olefination and
Sharpless asymmetric dihydroxylation. Deprotection of the coupled products by using a two-step sequence
afforded two sulfonium sulfates. Optical rotation data for one of our compounds indicated a correspondence
with that reported for kotalanol. However, comparison of 1H and 13C NMR spectral data of the synthetic
compounds with those of kotalanol indicated discrepancies. The collective data from this and published
work were used to propose a tentative structure for the naturally occurring compound, kotalanol.
Comparison of physical data of previously synthesized analogues with those for the recently isolated
six-carbon chain analogue, ponkoranol or reticulanol, also led to elucidation of this structure. Interestingly,
both our compounds inhibited recombinant human maltase glucoamylase (MGA), as expected from our
previous structure activity studies of lower homologues, with Ki values of 0.13 ( 0.02 and 0.10 ( 0.02
µM.
Introduction
recognition processes.1 Inhibition of these glycosidases can have
profound effects on quality control, maturation, transport, and
secretion of glycoproteins, and can alter cell-cell or cell-virus
recognition processes. This principle is the basis for the potential
use of glycosidase inhibitors for the treatment of various
Glycosidases are responsible for the processing of complex
carbohydrates which are essential in numerous biological
* Author to whom correspondence should be addressed. Fax: (604) 291- 4860.
† Simon Fraser University.
‡ University of British Columbia.
§ University of Toronto and Division of Molecular and Structural Biology,
Ontario Cancer Institute.
(1) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2351. Moremen,
K. W.; Trimble, R. B.; Herscovics, A. Glycobiology 1994, 4, 113.
6172 J. Org. Chem. 2008, 73, 6172–6181
10.1021/jo800855n CCC: $40.75 2008 American Chemical Society
Published on Web 07/24/2008

Structure Determination of Kotalanol
CHART 1
CHART 2
fraction prepared from the dried roots of S. reticulata yielded a
new class of glycosidase inhibitor, namely salacinol (1).11 The
structure of salacinol is unique, a ring sulfonium ion (1,4-
dideoxy-1,4-thio-D-arabinitol cation) stabilized by an internal
sulfate counterion (1-deoxy-L-erythrosyl-3-sulfate anion). Sa-
lacinol has been shown to be a potent inhibitor of intestinal
glucosidase enzymes,11–13 and thus capable of attenuating the
spike in blood glucose levels experienced by diabetics after
consuming a meal rich in carbohydrates.14 It is noteworthy that
a double-blind study of the effects of the extract from S.
reticulata on human patients with type-2 diabetes mellitus has
indeed shown that the extract is an effective treatment, with
side effects comparable to those of the placebo control group.15
The R-glucosidase inhibitory activities of salacinol were shown
to be as strong as those of voglibose and acarbose.16
Another bioassay-guided separation by the same group
resulted in the isolation of a second component, kotalanol (2),
which was reported to exhibit stronger inhibitory activities
against certain glycosidase enzymes. For example, kotalanol
showed more potent inhibitory activity against isomaltase than
either salacinol or acarbose.17 On the basis of NMR spectro-
scopic data, Yoshikawa et al. proposed a partial structure of
kotalanol (2),17 very similar to that of salacinol but with an
alditol side chain being extended by three carbons (Chart 2).
However, to date, the absolute configurations of the stereogenic
centers in the heptitol chain have not been determined. The
1-deoxy-4-thiopentofuranosyl portion of kotalanol was assigned
the identical D-arabinitol configuration as salacinol, based on
chemical degradation studies.17
disorders and diseases such as diabetes, cancer, and other viral
diseases;2,3 for example, acarbose, a pseudotetrasaccharide, and
voglibose, an aminocyclitol, are inhibitors of R-glucosidases and
have been approved for the clinical treatment of diabetes (Chart
1).4,5 Glycosidase inhibitors have also proved useful in the
investigation of disorders such as Gaucher’s disease.6 An
attractive approach to potent glucosidase inhibitors is to create
compounds that mimic the oxacarbenium ion-like transition state
of the enzyme-catalyzed reaction.7,8
Many of the natural and synthetic azasugars are believed to
mimic the transition state in either charge or shape, thus making
them good glycosidase inhibitors.9 They are presumed to be
partially protonated in the active site at physiological pH, thus
providing the stabilizing electrostatic interactions between the
inhibitor and the carboxylate residues in the enzyme active site.
An alternative approach to carbohydrate mimics is to replace
the ring oxygen atom of carbohydrates with other heteroatoms
such as sulfur and selenium. Indeed, sulfonium salts are known
to be quite stable, and have been proposed as mimics of the
oxacarbenium ion-like transition state.10
It is noteworthy that sulfonium ions with glucosidase inhibi-
tory properties occur naturally. Thus, in the course of studies
on antidiabetic principles of natural medicines, Yoshikawa et
al.11 discovered that a water-soluble fraction (25-100 mg/kg)
prepared from the roots and stems of Salacia reticulata strongly
inhibited elevations in rats’ serum glucose levels after the
administration of sucrose or maltose, but not glucose. To confirm
this activity, they conducted an additional study, a bioassay-
guided chromatography separation, in which a water-soluble
As part of our ongoing program aimed at the synthesis of
zwitterionic glycosidase inhibitors,10 we have focused recently
on the synthesis of chain-extended analogues of salacinol (1),
as well as the corresponding nitrogen and selenium analogues.18–22
Since the exact stereochemistry of kotalanol was not known, it
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De Paepe, A. M.; Chan, N. W. C.; Dacremont, G. A.; Van Costerm, R. N. Am. J.
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Clin. Cancer Res. 1997, 3, 1077–1086. Fiaux, H.; Popowycz, F.; Favre, S.;
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2005, 48, 4237–4246. Stutz., A. E., Ed. Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH: Weinheim, Germany, 1999.
(4) Holman, R. R.; Cull, C. A.; Turner, R. C. Diabetes Care 1999, 22, 960–
964.
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Bioorg. Med. Chem. 2002, 10, 1547–1554.
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74, 1301–1308.
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Akazawa, S.; Tominaga, Y. Diabetes Care 1998, 21, 256–260.
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M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.; Gow, I.; Elstein, D.; Zimran,
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Bull. 1998, 46, 1339–1340.
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A.; Szczepina, M. D.; Kumar, N. S.; Strerchi, E. E.; Nichols, B. L.; Pinto, B. M.;
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Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750–770. Zechel, D. L.; Withers,
S. G Acc. Chem. Res. 2000, 33, 11–18.
(20) (a) Liu, H.; Pinto, B. M. Can. J. Chem. 2006, 84, 1351–1362. (b) Liu,
H.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org. Chem. 2006, 71, 3007–3013.
(21) Nasi, R.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org. Chem. 2007, 72,
180–186.
(10) Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551–1580.
(11) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara,
J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367–8370.
(22) Liu, H.; Nasi, R.; Jayakanthan, K.; Heipel, H.; Sim, L.; Rose, D. R.;
Pinto, B. M. J. Org. Chem. 2007, 72, 6562–6572.
J. Org. Chem. Vol. 73, No. 16, 2008 6173

Nasi et al.
TABLE 1. Experimentally Determined Ki Valuesa
CHART 3
a Analysis of MGA inhibition was performed with maltose as the
substrate, and measuring the release of glucose. Absorbance
measurements were averaged to give a final result. b NA: not active.
CHART 4
was deemed necessary to study the structure-activity relation-
ships systematically by attaching side chains of different chain
length and different stereochemistry at the stereogenic centers
to the heteroanhydroalditols. In this regard, we have synthesized
several 5-carbon- and 6-carbon-chain analogues (Chart 3), and
some of these compounds have shown inhibitory activities in
the low micromolar range against recombinant human maltase
glucoamylase (MGA), a critical intestinal glucosidase involved
in the breakdown of glucose oligomers into glucose itself.18–22
The stereochemistries at the different stereogenic centers on the
side chain play significant roles, and structure-activity studies
revealed an interesting variation in the inhibitory power of these
compounds (Table 1).
The data presented above suggest that the most logical
structure for kotalanol (2) is 13a or 13b (Chart 4), in which the
configuration at C-6′ cannot yet be specified. We have chosen
the S-configuration at C-3′ to reflect a presumed common
biosynthetic pathway for salacinol and kotalanol. We therefore
describe herein the synthesis of these two candidates, together
with a comparison of their physical data with those of the natural
product in order to elucidate the structure of kotalanol. The
inhibitory activities of both compounds against human maltase
glucoamylase are also described.
In summary, the structure-activity relationships predict that
the common motif for inhibitory activity of the chain-extended
analogues of salacinol contains the S-configuration at C-2′, the
R-configuration at C-4′, and the S-configuration at C-5′, the
configuration of the stereogenic center C-3′ bearing the sulfate
group being unimportant. The choice of S-configuration at C-5′
is based on the lower Ki value for 7 vs 11.
SCHEME 1. Retrosynthetic Analysis
The inhibitory activities of the selenium compounds 6, 8, and
10 also corroborate the hypothesis. It is noteworthy that a recent
report from Yoshikawa et al. describes the isolation from Salacia
prinoides of a six-carbon chain analogue of salacinol, ponko-
ranol, that shows IC50 values against maltase, sucrase, and
isomaltase in the low micromolar range.23 Comparison of
physical data to those of our synthetic derivatives18,20,21 confirms
that ponkoranol is indeed compound 7. A U.S. patent also
describes a six-carbon-chain analogue isolated from Salacia
reticulata named reticulanol.24 Comparison of the physical data
indicate once again that this compound is also compound 7
above.
(23) Yoshikawa, M.; Xu, F.; Nakamura, S.; Wang, T.; Matsuda, H.; Tanabe,
G.; Muraoka, O. Heterocycles 2008, 75, 1397–1405.
(24) Asada, M.; Kawahara, Y.; Kitamura, S. U.S. Patent application
20070037870, February 15, 2007.
6174 J. Org. Chem. Vol. 73, No. 16, 2008

Structure Determination of Kotalanol
SCHEME 2. Synthesis of Compound 19
SCHEME 3. Dihydroxylation Reactions of Compound 19
TABLE 2
entry
compd
conditions
product
yield (%)
dra
1
2
3
19
19
19
OSO4, NMO
AD-mix ꢀ
AD-mix R
20
20:21
20
93
90
91
20:1
7:3
20:1
a
1
Determined by 500 MHz H NMR.
tereoisomer 20 was obtained as a major isomer. (Scheme 3,
Table 2). The stereochemical outcome of this dihydroxylation
follows Kishi’s empirical rule, which predicts that in the syn-
hydroxylation of acyclic allylic alcohols the relative stereo-
chemistry between the preexisting hydroxyl group and the
adjacent newly introduced hydroxyl group in the major product
is erythro.26 The syn-hydroxylation from the same side of the
allylalkoxy group, which is sterically more hindered, affords
the minor product.27Kishi’s rule has previously been shown to
apply in the dihydroxylation of a variety of carbohydrate allylic
systems.27
Compound 20 was benzylated under standard conditions to
give 22, which was then subjected to mild methanolysis by using
catalytic PTSA in methanol to effect selective removal of the
benzylidene group (Scheme 4) and give the corresponding diol
23 in 73% yield. The cyclic sulfate 14a was then obtained by
treatment of 23 with thionyl chloride and triethylamine followed
by oxidation with sodium periodate and ruthenium(III) chloride
as a catalyst (Scheme 4).
We next examined the asymmetric dihydroxylation reaction
using commercially available AD-mix ꢀ under the reported
standard conditions (AD-mix ꢀ in a 1:1 mixture of tert-
BuOH-H2O). However, a separable 7:3 diastereomeric mixture
(20 and 21) was obtained in which compound 20 was still the
predominant isomer (Table 2). The corresponding asymmetric
dihydroxylation of 19, using AD-mix-R with the intention of
obtaining the diastereoisomer of compound 20, was examined
next. Surprisingly, the AD-mix-R afforded compound 20
exclusively (Scheme 3). The unsatisfactory selectivity in the
dihydroxylation reaction can probably be attributed to unfavor-
able steric interactions between the bulky dihydroxylating
reagent and the BDA protecting group, situated next to the
olefinic reactive site. The stereochemistry at the C-6 position
in compound 20 was therefore inverted by the Mitsunobu
protocol to obtain the desired diol 21.
Accordingly, selective protection of the primary hydroxyl
group by using tert-butyldimethylsilyl chloride gave 24 in 91%
yield, which when treated under standard Mitsunobu conditions
afforded the ester 25 (Scheme 4). Removal of the p- nitrobenzoyl
and tert-butyldimethylsilyl groups with sodium methoxide and
tetrabutylammonium fluoride, respectively, gave the diol 21.
Compound 21 was obtained as a colorless crystalline solid,
Results and Discussion
The proposed strategy to synthesize compounds 13a and
13b involves alkylation of the anhydrothioalditol 1510 at the
heteroatom by a cyclic sulfate derivative, specifically, the
tri-O-benzyl-butane-2,3-diacetal-heptyl-1,3-cyclic sulfates
14a and 14b (Scheme 1). Our previous experience suggests
that selective attack of the heteroatom at the least hindered
primary center will occur. The butane-2,3-diacetal (BDA)
unit as a protecting group has been used extensively in the
total synthesis of natural products,25 and we have used it in
the synthesis of lower homologues.22 Relatively strong acidic
conditions are required for its removal, thus permitting the
selective removal of the benzylidene group in B prior to
installation of the 1,3-cyclic sulfate in A. Intermediate B
could be obtained from C via asymmetric dihydroxylation,
which could, in turn, be obtained from the D-glucose
derivative D by a Wittig reaction (Scheme 1).
The preparation of 16 was achieved from D-glucose via a
three-step sequence (Scheme 2). Thus, allyl D-glucopyranoside
was treated with 2,3-butanedione and trimethylorthoformate in
the presence of camphorsulfonic acid (CSA) in boiling methanol
to give an inseparable mixture of 2,3- and 3,4-BDA-protected
intermediates. This mixture was reacted directly with benzal-
dehyde dimethylacetal in the presence of a catalytic amount of
PTSA to yield the fully protected, and separable derivative 16
in 31% overall yield. Isomerization of the allyl glucoside 16
was effected with t-BuOK in DMF, and subsequent cleavage
of the resulting enol ether with I2 in THF:H2O gave the 2,3-
BDA-4, 6-O-benzylidene-D-glucopyranose (17). Treatment of
this hemiacetal with methyltriphenylphosphonium bromide
provided the olefinic product 18 (83%), which was benzylated
to afford compound 19.
With compound 19 in hand, our next goal was to introduce
the two hydroxyl groups. The OsO4-catalyzed dihydroxylation
of 19 proceeded smoothly in an acetone-water mixture with
N-methylmorpholine N-oxide (NMO) as reoxidant. The dias-
(25) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53–80. Hense, A.;
Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson, J.-F.; Warriner, S. L.;
Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997, 2023–2031.
(26) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247. Cha,
J. K.; Kim, N.-S. Chem. ReV. 1995, 95, 1761–1795.
(27) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. 1999, 64, 2982-
2983.
J. Org. Chem. Vol. 73, No. 16, 2008 6175

Nasi et al.
SCHEME 4. Synthesis of the Cyclic Sulfates 14a and 14b
SCHEME 5
TABLE 3. Comparison of 13C NMR Dataa and Discrepanciesb of
the Chemical Shifts of Compounds 13a and 13b Relative to Those
Reported for Kotalanol 2
position
13a
kotalanol
13b
1′
2′
3′
4′
5′
6′
7′
1
2
3
4
5
53.4 (-0.3)
68.0 (-1.4)
81.8 (+3.9)
68.1 (-2.4)
72.8 (+1.5)
75.5 (+3.0)
65.6 (+0.2)
50.3 (+0.1)
78.4 (+0.3)
79.3 (-0.1)
72.5 (+0.3)
60.0 (0)
53.7
67.4
77.9
70.5
71.3
72.5
65.3
50.2
78.1
79.4
72.2
60.0
53.3 (-0.4)
68.3 (+0.9)
80.5 (+2.5)
70.4 (-0.1)
73.5 (+1.8)
73.9 (+1.4)
64.6 (-0.7)
50.5 (+0.3)
78.4 (+ 0.3)
79.3 (-0.1)
72.5 (+0.3)
60.2 (+0.2)
suitable for single-crystal X-ray analysis (see the Supporting
Information), that established conclusively the absolute con-
figurations at the newly generated stereogenic center. With the
diol in hand, the cyclic sulfate 14b was synthesized following
the same reaction sequence as discussed above for the synthesis
of 14a. The structure of the cyclic sulfate 14b was also
confirmed by single-crystal X-ray analysis (Figure 1, Supporting
Information). The cyclic sulfates 14a and 14b were thus assigned
the structures 1,2,6-tri-O-benzyl-3,4-O-(2′,3′-dimethoxybutane-
2′,3′-diyl)-D-glycero-D-gulitol-5,7-cyclic sulfate and 2,6,7-tri-
O-benzyl-4,5-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-glycero-L-
gulitol-1,3-cyclic sulfate, respectively.28
The coupling reactions of the cyclic sulfate 14a with the
protected thioarabinitol were investigated next. 2,3,5-Tri-O-p-
methoxybenzyl-1,4-anhydro-4-thio-D-arabinitol (15)29 was pre-
pared by a method analogous to that developed for the synthesis
of the corresponding selenium derivative.30 The reaction of the
thioarabinitol 15 with the cyclic sulfate 14a was found to
proceed very slowly at 72 °C. We also observed that longer
reaction time led to decomposition of the coupling product. The
coupling reaction was therefore terminated before complete
consumption of the starting materials. The protected sulfonium
sulfate 29 was obtained as the sole product in 55% yield with
use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent. The
observed slow reactivity of the cyclic sulfate may be attributed
to the lack of release of torsional strain, in contrast to our earlier
studies with cyclic sulfates with fused six-membered rings.10
Alternatively, the opening of the cyclic sulfate might be impeded
by the steric hindrance provided by the protecting groups.
Deprotection of the coupled product 29 was performed with
two successive reactions. The sulfonium salt 29 was first treated
with Pd/C/H2 in aqueous acetic acid to effect hydrogenolytic
a In pyridine-d5. b Values in bold.
cleavage, followed by treatment with trifluoroacetic acid to yield
the desired zwitterionic compound 13a. Compound 13a was
then fully characterized by spectroscopic methods. The proton
1
and carbon signals in the H and 13C NMR spectra of 13a in
D2O were assigned unambiguously with the aid of 1H-1H
COSY, HMQC, and HMBC experiments. The stereochemistry
at the stereogenic sulfonium ion center was assigned by means
of a NOESY experiment, which showed an H-4 to H-1′
correlation, implying that isomer 13a has an anti relationship
between C-5 and C-1′. MALDI-TOF mass spectrometry in the
positive mode showed base peaks for masses attributable to M
+ Na and lower intensity peaks corresponding to M + H and
M + H - SO3H. The compounds were also characterized by
high-resolution mass spectrometry and compound 13a exhibited
a dimer cluster ion peak at lower intensity.
Analogously, the cyclic sulfate 14b was reacted with the
thioether 15 at 72 °C for 48 h in HFIP to give 30 in 61% yield.
Compound 30 was then deprotected, as above, to afford the
desired zwitterionic compound 13b (Scheme 5).
NMR analysis of 13a and 13b was carried out in both D2O
and pyridine-d5 solution (Figure 2, Supporting Information).
These studies revealed that the 1H NMR spectra in pyridine-d5
gave downfield shifts compared to those in D2O, together with
differential spectral patterns (Table 3). A careful comparison
indicated the most downfield resonances were those of H-2, H-3,
and H-2′ in D2O. In contrast, the NMR studies in pyridine-d5
showed the most downfield resonances (δ 5.34 for 13a and δ
6176 J. Org. Chem. Vol. 73, No. 16, 2008

Structure Determination of Kotalanol
a
TABLE 4. Comparison of H NMR Data and Discrepanciesb of
the Chemical Shifts of Compounds 13a and 13b Relative to Those
Reported for Kotalanol 2
1
CHART 5
position
13a
kotalanol (2)
13b
1′
2′
3′
4′
5′
6′
7′
1
2
3
4
5
4.84 (dd), 4.66 (dd) 4.93 (dd), 4.65 (dd) 4.91 (dd), 4.67 (dd)
5.09 (m)
5.34 (d)
5.31 (br s)
4.65 (m)
4.57 (m)
5.24 (m)
5.64 (dd)
5.12 (br s)
5.86 (dd-like)
4.88 (ddd-like)
5.16 (ddd)
5.47 (m)
5.05 (dd)
4.94 (dd)
4.76 (ddd)
4.49 (dd), 4.31 (dd) 4.50 (dd), 4.25 (dd) 4.41 (dd), 4.39 (dd)
4.30 (d)
5.09 (m)
5.16 (br s)
4.65 (m)
4.54 (d)
4.31 (br s)
5.08 (dd-like)
5.16 (br s)
4.64 (t-like)
4.54 (dd-like)
4.36 (dd), 4.32 (dd)
5.09 (m)
5.16 (br s)
4.65 (m)
13a and 13b, inhibited MGA with Ki values of 0.13 ( 0.02
and 0.10 ( 0.02 µM, respectively. The observed inhibition data
are consistent with the structure activity relationships established
previously for the lower homologues (Table 1). We note that
13a and 13b constitute the most active chain-extended analogues
of salacinol to date. However, we note also that extension of
the polyhydroxylated side chain does not confer any particular
advantage over salacinol, presumably because no additional
favorable contacts are formed with the enzyme-active site.
4.55 (d)
a In pyridine-d5. b Values in bold.
5.47 for 13b) for H-3′. The integrity of the compounds in this
solvent was confirmed by TLC and by TOCSY and HMBC
experiments.
Next, we turned to the comparison of the physical data of
compounds 13a and 13b with those reported for kotalanol 2
(Table 4).17 The specific rotation and melting point of 13b
Experimental Section
25
Enzyme Kinetics. Kinetic parameters of MGA with compounds
13a and 13b were determined by using the pNP-glucose assay to
follow the production of p-nitrophenol upon addition of enzyme
(500 nM). The assays were carried out in 96-well microtiter plates
containing 100 mM MES buffer pH 6.5 as inhibitor (at three
different concentrations), and p-nitrophenyl-D-glucopyranoside
(pNP-glucose, Sigma) as substrate (2.5, 3.5, 5, 7.5, 15, and 30 mM)
with a final volume of 50 uL. Reactions were incubated at 37 °C
for 35 min and terminated by addition of 50 uL of 0.5 M sodium
carbonate. The absorbance of the reaction product was measured
at 405 nm in a microtiter plate reader. All reactions were performed
in triplicate and absorbance measurements were averaged to give
a final result. Reactions were linear within this time frame. The
programGraFit4.0.14wasusedtofitthedatatotheMichaelis-Menten
equation and estimate the kinetic parameters, Km, Kmobs (Km in the
presence of inhibitor), and Vmax, of the enzyme. Ki values for each
inhibitor were determined by the equation Ki ) [I]/[(Kmobs/Km) +
1]. The Ki reported for each inhibitor was determined by averaging
the Ki values obtained from three different inhibitor concentrations.
Allyl 4,6-O-Benzylidene-2,3-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-
r,ꢀ-D-glucopyranoside (16). To a suspension of D-glucose (30 g,
0.16 mol) in allyl alcohol (100 mL) was added AcCl (1 mL) and
the reaction mixture was refluxed for 12 h. The reaction mixture
was cooled to room temperature and the reaction was quenched by
addition of excess triethylamine (5 mL). The solvent was removed
under reduced pressure and dried on high vacuum for 12 h. To the
residue in dry MeOH (200 mL) were added 2,3-butanedione (17.2
mL, 0.2 mol), trimethyl orthoformate (70 mL, 0.6 mol), and CSA
(500 mg) and the reaction mixture was refluxed for 24 h. When
TLC analysis of aliquots (hexanes:EtOAc, 1:1) showed total
consumption of the starting material, the reaction mixture was
cooled to room temperature and excess triethylamine (4 mL) was
added. The solvents were evaporated; the residue was dissolved in
EtOAc (200 mL), washed with brine, and dried over Na2SO4, then
concentrated to give brownish oil. The latter was dissolved in DMF
(100 mL) then benzaldehyde dimethylacetal (35 g, 0.16 mol) and
p-toluenesulfonic acid (300 mg) were added. The reaction mixture
was stirred at 60 °C on a rotary evaporator under vacuum for 2 h.
The reaction was then quenched by adding triethylamine, the solvent
was removed, and the residue was dissolved in EtOAc (150 mL),
washed with saturated aqueous NaCl (50 mL), dried over Na2SO4,
and concentrated to give brown syrup. Purification by column
chromatography on silica gel (hexanes:EtOAc, 1:1) yielded com-
([R]D + 12.0 (c 0.1, MeOH) and mp 169-171 °C, respec-
tively) were found to be in agreement with the reported values
([R]D27 +11.5 (MeOH); mp 175-177 °C) for kotalanol 2. The
25
optical rotation and melting point of 13a were found to be [R]D
+ 16.0 (c 0.1, MeOH) and mp 164-166 °C, respectively.
Comparison of the 1H and 13C NMR spectroscopic data of 13b
with those reported17 for kotalanol 2 revealed that the sets of
data in pyridine-d5 are not identical. A careful check of 1H NMR
data of kotalanol 2 and compound 13b indicated that there was
a difference in chemical shifts ((δ 0-0.17) (Table 4). However,
the most notable difference was the chemical shift of H-5′,
reported at δ 5.86 ppm in kotalanol 2. In contrast, no signal
below δ 5.47 ppm was observed in the spectrum of compound
13b. The H-5′ signals of 13a and 13b appeared at δ 4.65 and
δ 4.91, respectively. The 13C NMR data also revealed discrep-
ancies between those of 13b and those reported for kotalanol
2, especially for C-3′; specifically, C-3′ is shielded in kotalanol.
Comparison of accumulated data to date for related analogues
indicates that C-3′ exhibits an upfield shift when the sulfate
moiety at C-3′ and the hydroxyl group at C-5′ are anti to one
another. Thus, in kotalanol 2, C-3′ resonates at 77.9 ppm; the
corresponding shifts in 5, 9, and 11 are 78.9,18 77.6,20b and
78.3 ppm,21 respectively. This shielding can be attributed to
the γ-gauche effect of the axially oriented hydroxyl group (Chart
5) acting on C-3′. The proximity of the negatively charged
sulfate moiety to H-5′ would also account for the unusual
deshielding of this hydrogen. This leads us to speculate that
kotalanol 2 has the opposite configuration at C-5′ to 13a and
13b, with an anti relationship between the substituents at C-3′
and C-5′. This still leaves the configuration at C-6′ unspecified.
Finally, we comment on the inhibitory activities of the
compounds synthesized in this study against recombinant human
maltase glucoamylase (MGA), a critical intestinal glucosidase
involved in the processing of oligosaccharides of glucose into
glucose itself. The seven-carbon-chain analogues of salacinol,
(28) See: tentative rules for carbohydrate nomenclature: Biochemistry, 1971,
10, 3983-4004.
(29) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.; Snider,
B. B.; Pinto, B. M. Synlett 2003, 1259–1262.
1
(30) Liu, H.; Pinto, B. M. J. Org. Chem. 2005, 70, 753–755.
pound 16 as a white solid (22 g, 31%). Data for the ꢀ-isomer: H
J. Org. Chem. Vol. 73, No. 16, 2008 6177

Nasi et al.
NMR (CDCl3) δ 7.36-7.26 (Ar), 5.93 (1H, dddd, allyl), 5.53 (1H,
s, Ph-CH), 5.35 (1H, d, allyl), 5.19 (1H, d, allyl), 4.64 (1H, d, J1,2
) 7.8 Hz, H-1), 4.36 (1H, dd, allyl), 4.30 (1H, dd, J6a,6b ) 10.4
was stirred at room temperature for 2 h. The reaction was quenched
with ice water (50 mL) and the mixture was diluted with Et2O (100
mL). The organic layer was washed with H2O (50 mL) and brine
(50 mL). The organic phase was dried over anhydrous Na2SO4,
filtered, and concentrated. The crude product was purified by flash
chromatography [hexanes/EtOAc, 5:1] to give compound 19 as
colorless oil (7.31 g, 85%). [R]D23 -79.0 (c 1.0, CH2Cl2). 1H NMR
(CDCl3) δ 7.48-7.26 (10H, Ar), 5.87 (1H, ddd, J2,3 ) 8.0 Hz,
J2,1a ) 17.2 Hz, J2,1b ) 10.4 Hz, H-2), 5.43 (1H, dd, J1a,1b ) 1.8
Hz, H-1a), 5.38 (1H, s, Ph-CH), 5.30 (1H, dd, H-1b), 4.60 (2H,
dd, Ph-CH2), 4.53 (1H, dd, J3,4 ) 9.8 Hz, H-3), 4.47 (1H, dd, J7a,7b
) 10.7 Hz, J7a,6 ) 5.0 Hz, H-7a), 4.10 (1H, ddd, J6,7b ) 10.4 Hz,
J6,5 ) 9.3, Hz, H-6), 4.08 (1H, dd, J4,5 ) 1.9 Hz, H-4), 3.77 (1H,
dd, H-5), 3.61 (1H, dd, H-7b), 3.24, 3.19 (6H, 2 × -OMe), 1.34,
1.31 (6H, 2 × -Me). 13C NMR δ 138.1-126.3 (12C, Ar), 134.1
(C-2), 119.9 (C-1), 101.2 (Ph-CH), 99.5, 98.8, 78.9 (C-5), 71.7
(Ph-CH2), 70.3 (C-3), 69.9 (C-7), 67.9 (C-4), 67.5 (C-6), 48.2, 48.0
(2 × -OMe), 18.1, 18.0 (2 × -Me). Anal. Calcd for C27H34O7:
C, 68.92; H, 7.28. Found: C, 69.13; H, 7.57.
Hz, J6a,5 ) 4.8 Hz, H-6a), 4.16 (1H, dd, allyl), 3.99 (1H, dd, J3,2
)
9.6 Hz, H-3), 3.82 (1H, dd, J6b,5 ) 10.2 Hz, H-6b), 3.72 (1H, dd,
J4,5 ) 9.0 Hz, H-4), 3.69 (1H, dd, H-2), 3.45 (1H, ddd, H-5), 3.30,
3.28 (2 × -OMe), 1.33, 1.33 (2 × -Me). 13C NMR δ 137.4-117.2
(Ar, allyl), 101.4 (Ph-CH), 100.6 (C-1), 99.9, 99.6 (BDA), 78.0
(C-4), 70.5 (C-2, allyl), 69.7 (C-3), 68.9 (C-6), 67.6 (C-5), 48.2,
48.1 (2 × -OMe), 17.8, 17.8 (2 × -Me). Anal. Calcd for
C22H30O8: C, 62.55; H, 7.16. Found: C, 62.78; H, 6.89.
4,6-O-Benzylidene-2,3-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-r,ꢀ-
D-glucopyranose (17). t-BuOK (0.07 mol, 7.8 g) was added to a
solution of allyl-5,7-O-benzylidene-3,4-O-(2′,3′-dimethoxybutane-
2′,3′-diyl)-R,ꢀ-D-glucopyranoside (16) (16.2 g, 0.038 mol) in DMF
(200 mL), and the mixture was stirred for 2 h at 80 °C. The reaction
mixture was cooled to room temperature and extracted with EtOAc
(3 × 150 mL). The organic layer was washed with 1 M aqueous
HCl and dried over Na2SO4. The solvent was removed under
reduced pressure to give the enol ether as a brown syrup. The
residue was redissolved in a mixture of THF and water (4:1, 150
mL) and treated with iodine (0.07 mol) for 1.5 h. The reaction was
then quenched by addition of a saturated solution of Na2S2O3. The
organic layer was separated and the aqueous layer was extracted
with EtOAc (2 × 50 mL). The combined organic layers were
washed with brine solution, dried over Na2SO4, and concentrated.
The residue was purified by column chromatography to give 17 as
a white amorphous solid (12.2 g, 84%). Data for the ꢀ-isomer: 1H
NMR (CDCl3) δ 7.53-7.35 (5H, Ar), 5.54 (1H, Ph-CH), 5.29 (1H,
dd, J1,2 ) 3.5 Hz, J1,-OH ) 3.0 Hz, H-1), 4.70 (1H, dd, J3,2 ) 10.8
Hz, J3,4 ) 9.6 Hz, H-3), 4.22 (1H, dd, J6a,6b ) 10.2 Hz, J6a,5 ) 4.8
Hz, H-6a), 4.17 (1H, dd, H-2), 4.06 (1H, ddd, J5,4 ) 9.4 Hz, J5,6b
) 10.4, H-5), 3.76 (1H, dd, H-6b), 3.54 (1H, dd, H-4), 3.42, 3.39
(2 × -OMe), 3.01 (1H, br s, -OH), 1.39 (2 × -Me). 13C NMR
δ 137.4-126.7 (Ar), 102.2 (Ph-CH), 101.8, 101.7 (BDA), 92.4 (C-
1), 81.1 (C-4), 72.0 (C-2), 69.1 (C-3), 68.9 (C-6), 63.4 (C-5), 48.5,
48.4 (2 × -OMe), 19.1, 19.1 (2 × -Me). Anal. Calcd for
C19H26O8: C, 59.68; H, 6.85. Found: C, 59.82; H, 6.49.
6-O-Benzyl-5,7-O-benzylidene-3,4-O-(2′,3′-dimethoxybutane-
2′,3′-diyl)-D-glycero-D-gulo-heptitol (20). To a solution of 19 (3.2
g, 6.80 mmol) in acetone:water (9:1, 50 mL) at 0 °C were added
NMO (820 mg, 5.10 mmol) and OsO4 (340 mg, 0.034 mmol, 2.5
wt % solution in 2-methyl-2-propanol). The reaction mixture was
stirred at room temperature for 4 h before it was quenched with a
saturated solution of NaHSO3. After being stirred for an additional
15 min the reaction mixture was extracted with ethyl acetate and
the organic layer was washed with water and brine, dried, and
concentrated. Chromatographic purification of the residue (hexanes/
23
EtOAc, 2:1) afforded 20 (3.02 g, 88%) as a colorless oil. [R]D
-116.0 (c 0.1, CH2Cl2). 1H NMR (CDCl3) δ 7.40-7.23 (10H, Ar),
5.44 (1H, s, Ph-CH), 4.63 (2H, dd, Ph-CH2), 4.43 (1H, dd, J7a,7b
)
10.5 Hz, J7a,6 ) 5.1 Hz, H-7a), 4.25 (1H, dd, J3,4 ) 10.0 Hz, J3,2
) 5.1 Hz, H-3), 4.16 (1H, dd, J4,5 ) 2.5 Hz, H-4), 4.11 (1H, ddd,
J6,5 ) 9.2 Hz, J6,7b ) 10.4, H-6), 3.97 (1H, dd, H-5), 3.87 (1H, m,
H-1a), 3.79 (2H, m, H-2, H-1b), 3.63 (1H, dd, H-7b), 3.25, 3.18
(6H, 2 × -OMe), 2.86 (1H, OH-2), 2.33 (1H, OH-1), 1.32, 1.28
(6H, 2 × -Me). 13C NMR δ 138.1-126.3 (12C, Ar), 101.4 (Ph-
CH), 99.3, 98.9, 79.3 (C-5), 71.8 (Ph-CH2), 70.6 (C-2), 70.1 (C-
3), 69.9 (C-7), 67.7 (C-6), 67.7 (C-4), 63.8 (C-1), 48.3, 48.2 (2 ×
-OMe), 17.8, 17.7 (2 × -Me). Anal. Calcd for C27H36O9: C, 64.27;
H, 7.19. Found: C, 64.01; H, 7.44.
5,7-O-Benzylidene-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-
gluco-hept-1-enitol (18). n-BuLi (n-hexane solution, 0.058 mol, 2.90
equiv) was added dropwise to a solution of methyltriphenylphos-
phonium bromide (21.4, 0.06 mmol, 3.0 equiv) in dry THF (80
mL) at -78 °C under N2. The mixture was stirred for 1 h at the
same temperature. A solution of 17 (7.8 g, 0.02 mol) in dry THF
(10 mL) was introduced into the solution at -78 °C, and the
resulting solution was stirred for an additional 30 min. The reaction
was allowed to warm to room temperature and stirred for another
3 h. The reaction mixture was quenched by adding acetone, and
extracted with ether. The organic layer was washed with brine and
dried over Na2SO4, then concentrated in vacuo. Purification by
column chromatography on silica gel, (hexanes/EtOAc, 4:1) gave
1,2,6-Tri-O-benzyl-5,7-O-benzylidene-3,4-O-(2′,3′-dimethoxybu-
tane-2′,3′-diyl)-D-glycero-D-gulo-heptitol (22). A mixture of com-
pound 20 (2.90 g, 5.74 mmol) and 60% NaH (2.5 equiv) in DMF
(100 mL) was stirred in an ice bath for 1 h. A solution of benzyl
bromide (1.53 mL, 12.6 mmol) in DMF (10 mL) was added, and
the mixture was stirred at room temperature for 3 h. The reaction
was quenched with ice water and the mixture was diluted with Et2O
(100 mL). The organic layer was washed with H2O and brine. The
organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy [hexanes/EtOAc, 5:1] to give compound 22 as a colorless
oil (3.48 g, 88%). [R]D23 -102.4 (c 1.2, CH2Cl2). 1H NMR (CDCl3)
δ 7.43-7.21 (20H, Ar), 5.20 (1H, s, Ph-CH), 4.66-4.54 (6H, 3 ×
Ph-CH2), 4.40 (2H, m, H-3, H-7a), 4.29 (1H, dd, J4,5 ) 2.4 Hz,
J4,3 ) 9.9 Hz, H-4), 4.08 (1H, ddd, J6,7a ) 5.0 Hz, J6,7b ) 10.2 Hz,
J6,5 ) 9.5 Hz, H-6), 3.96 (1H, dd, H-5), 3.84 (1H, dd, J1a,2 ) 3.3
23
18 as a colorless oil (7.12 g, 91% yield). [R]D -139.0 (c 1.0,
CH2Cl2). 1H NMR (CDCl3) δ 7.45-7.26 (5H, Ar), 5.90 (1H, ddd,
J2,3 ) 7.4 Hz, J2,1a ) 16.8 Hz, J2,1b ) 10.4 Hz, H-2), 5.47 (1H, dd,
J1a,1b ) 1.5 Hz, H-1a), 5.39 (1H, s, Ph-CH), 5.30 (1H, dd, H-1b),
4.50 (1H, dd, J3,4 ) 9.8 Hz, H-3), 4.34 (1H, dd, J7a,7b ) 10.4 Hz,
J7a,6 ) 5.3 Hz, H-7a), 4.19 (1H, dddd, J6,7b ) 10.3 Hz, J6,5 ) 9.4
Hz, J6,-OH ) 4.5 Hz, H-6), 4.03 (1H, dd, J4,5 ) 2.7 Hz, H-4), 3.68
(1H, dd, H-5), 3.58 (1H, dd, H-7b), 3.30, 3.26 (6H, 2 × -OMe),
2.13 (1H, d, OH-6), 1.33, 1.31 (6H, 2 × -Me). 13C NMR δ
137.7-126.4 (6C, Ar), 134.0 (C-2), 119.4 (C-1), 101.6 (Ph-CH),
99.4, 98.8, 80.4 (C-5), 71.6 (C-7), 70.1 (C-3), 69.4 (C-4), 61.4 (C-
6), 48.3, 48.1 (2 × -OMe), 17.9, 17.8 (2 × -Me). Anal. Calcd
for C20H28O7: C, 63.14; H, 7.42. Found: C, 63.39; H, 7.37.
6-O-Benzyl-5,7-O-benzylidene-3,4-O-(2′, 3′-dimethoxybutane-
2′,3′-diyl)-D-gluco-hept-1-enitol (19). A mixture of compound 18
(6.89 g, 0.018 mol) and 60% NaH (1.5 equiv) in DMF (100 mL)
was stirred in an ice bath for 20 min. A solution of benzyl bromide
(2.56 mL, 0.02 mol) in DMF (10 mL) was added, and the mixture
Hz, J1a,1b ) 8.9 Hz, H-1a), 3.81 (1H, ddd, J2,3 ) 5.6 Hz, J2,1b
)
5.9 Hz, H-2), 3.78 (1H, dd, H-1b), 3.53 (1H, dd, H-7b), 3.24, 3.16
(6H, 2 × -OMe), 1.30, 1.28 (6H, 2 × -Me). 13C NMR δ
138.7-126.4 (24C, Ar), 101.2 (Ph-CH), 99.3, 98.9, 79.1 (C-5), 78.5
(C-2), 73.6, 72.5, 71.5 (Ph-CH2), 70.3 (C-1), 69.9 (C-7), 67.8 (C-
6), 66.6 (C-4), 48.1, 47.9 (2 × -OMe), 17.9 (2 × -Me). Anal.
Calcd for C41H48O9: C, 71.91; H, 7.06. Found: C, 72.02; H, 7.24.
1,2,6-Tri-O-benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-
glycero-D-gulo-heptitol (23). To a solution of 1,2,6-tri-O-benzyl-
5,7-O-benzylidene-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-glycero-
D-gulo-heptitol (22) (3.12 g, 4.55 mmol) in MeOH (150 mL) was
6178 J. Org. Chem. Vol. 73, No. 16, 2008

Structure Determination of Kotalanol
added p-toluenesulfonic acid (200 mg) and the reaction mixture
was stirred for 4 h at rt. The reaction was then quenched by addition
of excess Et3N, and the solvents were removed under vacuum to
give a pale yellow syrup that was purified by flash column
× -OMe), 26.2 (TBDMS), 16.6 (TBDMS), 18.1, 18.0 (2 × -Me),
-5.0, -5.5 (TBDMS). Anal. Calcd for C33H50O9Si: C, 64.05; H,
8.14. Found: C, 64.17; H, 8.38.
2-O-Benzyl-1,3-O-benzylidene-7-O-(tert-butyldimethylsilyl)-4,5-
O-(2′,3′-dimethoxybutane-2′,3′-diyl)-6-O-(4-nitrobenzoyl)-D-glycero-
L-gulo-heptitol (25). A solution of 24 (3.72 g, 6.01 mmol) in THF
(60 mL) containing p-nitrobenzoic acid (3.0 g, 18.0 mmol) and
triphenylphosphine (4.7 g, 18.0 mmol) was cooled to 0 °C. A
solution of diisopropyl azodicarboxylate (3.64 mL, 18.0 mmol)
in THF (30 mL) was added to the mixture over 2 h. After being
stirred for 20 h at ambient temperature, the reaction mixture
was concentrated and then partitioned between Et2O (200 mL)
and H2O (100 mL). The organic phase was washed with saturated
aqueous NaHCO3 (3 × 50 mL), followed by brine (50 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
under vacuum. The residue was purified by flash chromatography
(hexanes/EtOAc, 3:1) to give 25 as a colorless oil (2.96 g, 64%).
23
chromatography to give 23 (2.18 g, 79%). [R]D -86.4 (c 1.0,
CH2Cl2). 1H NMR (CDCl3) δ 7.33-7.26 (15H, Ar), 4.74-4.46 (6H,
3 × Ph-CH2), 4.18 (1H, dd, J3,4 ) 10.0 Hz, J3,2 ) 5.6 Hz, H-3),
4.09 (1H, dd, J4,5 ) 1.0 Hz, H-4), 4.02 (1H, dd, J5,6 ) 8.0 Hz,
J5,5-OH ) 7.9 Hz, H-5), 3.84 (3H, m, H2-7, H-1a), 3.73 (3H, m,
H-6, H-2, H-1b), 3.23, 3.15 (2 × -OMe), 2.76 (1H, d, 5-OH),
2.29 (1H, dd, 7-OH), 1.29, 1.26 (2 × -Me). 13C NMR δ
138.5-127.4 (Ar), 98.9, 98.6, 79.0 (C-2), 78.0 (C-6), 73.6, 72.6,
71.4 (3 × Ph-CH2), 70.9 (C-5), 69.4 (C-4), 69.2 (C-1), 67.1 (C-3),
61.7 (C-7), 48.4, 48.2 (2 × -OMe), 17.8, 17.7 (2 × -Me). Anal.
Calcd for C34H44O9: C, 68.44; H, 7.43. Found: C, 68.39; H, 7.23.
1,2,6-Tri-O-benzyl-3,4-di-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-
glycero-D-gulo-heptitol-5,7-cyclic Sulfate (14a). A mixture of 23 (2.0
g, 3.35 mmol) and Et3N (1.5 mL, 15.0 mmol) in CH2Cl2 (100 mL)
was stirred in an ice bath. Thionyl chloride (0.36 mL, 5.0 mmol)
in CH2Cl2 (10 mL) was then added dropwise over 15 min, and the
mixture was stirred for an additional 30 min. The mixture was
poured into ice-cold water and extracted with CH2Cl2 (2 × 100
mL). The combined organic layers were washed with brine and
dried over Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by flash column chromatog-
raphy (8:1, 5:1, 3:1 hexanes:EtOAc) to gave the diastereomeric
mixture of cyclic sulfites. To a solution of the cyclic sulfites in a
mixture of CH3CN:CCl4 (100 mL) were added sodium periodate
(1.48 g, 6.95 mmol) and RuCl3 (100 mg), followed by H2O (20
mL). The mixture was then stirred for 2 h at rt. The reaction mixture
was filtered through a silica bed and washed repeatedly with EtOAc.
The volatile solvents were removed, and the aqueous solution was
extracted with EtOAc (2 × 100 mL). The combined organic layers
were washed with saturated NaCl, dried over Na2SO4, and
evaporated under diminished pressure. The residue was purified
by flash column chromatography to give 14a as a white amorphous
solid (1.41 g, 63%). [R]D23 -57.3 (c 0.7, CH2Cl2). 1H NMR (CDCl3)
δ 7.34-7.26 (15H, Ar), 5.11 (1H, m, H-5), 4.68-4.51 (6H, 3 ×
Ph-CH2), 4.39 (3H, m, H2-7, H-6), 4.35 (1H, dd, J4,5 ) 1.9 Hz, J4,3
) 9.8 Hz, H-4), 4.20 (1H, dd, J3,2 ) 3.6 Hz, H-3), 3.80 (1H, dd,
J1a,1b ) 9.7 Hz, J1a,2 ) 5.8 Hz, H-1a), 3.75 (1H, ddd, H-2), 3.67
(1H, dd, J1b,2 ) 5.0 Hz, H-1b), 3.22, 3.12 (6H, 2 × -OMe), 1.32,
1.26 (6H, 2 × -Me). 13C NMR δ 138.4-127.3 (18C, Ar), 99.6,
98.9, 84.0 (C-5), 77.5 (C-2), 73.6, 72.7, 72.5 (Ph-CH2), 72.0 (C-
6), 69.2 (C-1), 67.1 (C-7), 68.8 (C-3), 65.9 (C-4), 48.4, 48.2 (2 ×
-OMe), 17.8, 17.6 (2 × -Me). Anal. Calcd for C34H42O11S: C,
61.99; H, 6.43. Found: C, 61.76; H, 6.44.
23
1
[R]D -53.1 (c 1.5, CH2Cl2). H NMR (CDCl3) δ 8.18-6.99
(14H, Ar), 5.41 (1H, s, Ph-CH), 5.33 (1H, ddd, J6,5 ) 1.9 Hz,
J6,7a ) 6.8 Hz, J6,7b ) 6.6 Hz, H-6), 4.52 (1H, d, Ph-CH2), 4.49
(1H, dd, J5,4 ) 10.0 Hz, H-5), 4.44 (1H, J1a,1b ) 10.4 Hz, J1a,2
) 5.0 Hz, H-1a), 4.42 (1H, d, Ph-CH2), 4.26 (1H, dd, J4,3 ) 2.0
Hz, H-4), 4.05 (1H, ddd, J2,3 ) 9.2 Hz, J2,1b ) 10.4 Hz, H-2),
4.00 (1H, dd, J7a,7b ) 10.0 Hz, J7a,6 ) 6.8 Hz, H-7a), 3.91 (1H,
dd, J7b,6 ) 6.6 Hz, H-7b), 3.82 (1H, dd, H-3), 3.62 (1H, dd,
H-1b), 3.27, 3.09 (6H, 2 × -OMe), 1.33, 1.32 (6H, 2 × -Me).
0.79 (9H, s, TBDMS), 0.03, 0.00 (6H, s, TBDMS). 13C NMR δ
164.6 (CdO), 150.4-123.4 (18C, Ar), 101.1 (Ph-CH), 99.1,
98.8, 78.1 (C-3), 73.7 (C-6), 70.9 (Ph-CH2), 69.6 (C-1), 66.8
(C-2), 65.2 (C-5), 64.9 (C-4), 59.9 (C-7), 47.9 (2 × -OMe),
25.6 (TBDMS), 18.0 (TBDMS), 17.6 (2 × -Me), -5.4, -5.5
(TBDMS). Anal. Calcd for C39H53NO11Si: C, 63.31; H, 7.22.
Found: C, 63.26; H, 7.12.
2-O-Benzyl-1,3-O-benzylidine-7-O-(tert-butyldimethylsilyl)-4,5-
O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-glycero-L-gulo-heptitol (26).
Compound 25 (2.70 g, 3.51 mmol) was dissolved in MeOH (50
mL) and 1 N NaOMe/MeOH (1.0 mL) was added. The mixture
was stirred at rt for 1 h and then Rexyn 101 (H+) was added to
adjust the pH to 7. The solvent was removed and the residue
was partitioned between Et2O (150 mL) and H2O (100 mL). The
organic layer was washed with brine (50 mL), dried over
anhydrous Na2SO4, and concentrated. The residue was purified
23
to give 26 as a white foam (2.05 g, 94%). [R]D -66.4 (c 1.6,
1
CH2Cl2). H NMR (CDCl3) δ 7.46-31 (Ar), 5.43 (1H, s, Ph-
CH), 4.61 (2H, s, Ph-CH2), 4.46 (1H, dd, J4,3 ) 2.4 Hz, J4,5
)
10.0 Hz, H-4), 4.42 (1H, dd, J1b,1a ) 10.5 Hz, J1b,2 ) 5.0 Hz,
H-1b), 4.22 (1H, dd, J5,6 ) 1.3 Hz, H-5), 4.11 (1H, ddd, J2,1b
)
10.4 Hz, J2,3 ) 9.2 Hz, H-2), 3.96 (1H, dd, H-3), 3.77 (1H, m,
H-6), 3.71 (2H, m, H2-7), 3.66 (1H, dd, H-1a), 3.20, 3.15 (2 ×
-OMe), 2.35 (1H, d, J-OH,6 ) 7.0 Hz, OH-6), 1.31, 1.27 (2 ×
-Me), 0.80 (9H, TBDMS), 0.016, 0.00 (TBDMS). 13C NMR δ
138.9-126.9 (12C, Ar), 101.1 (Ph-CH), 99.9, 99.5, 79.2 (C-2),
72.2 (Ph-CH2), 70.8 (C-1), 70.5 (C-6), 68.2 (C-2), 67.1 (C-5),
66.0 (C-4), 64.1 (C-7), 48.7, 48.5 (2 × -OMe), 26.5 (TBDMS),
18.9 (TBDMS), 18.5, 18.4 (2 × -Me), -4.57, -4.65 (TBDMS).
Anal. Calc. for C33H50O9Si: C, 64.05; H, 8.14. Found: C, 64.02;
H, 8.31.
6-O-Benzyl-5,7-O-benzylidene-1-O-(tert-butyldimethylsilyl)-3,4-
O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-glycero-D-gulo-heptitol (24).
A mixture of 20 (3.6 g, 7.13 mmol), imidazole (1.42 g, 21.0 mmol),
and TBDMSCl (1.18 g, 7.85 mmol) in dry DMF (80 mL) was
stirred at 0 °C under N2 for 2 h. The reaction was quenched by the
addition of ice-cold water, and the reaction mixture was partitioned
between Et2O (200 mL) and H2O (100 mL). The separated organic
phase was washed with H2O (50 mL) and brine (50 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated.
The residue was purified by flash chromatography (hexanes/EtOAc,
23
3:1) to give 24 as a colorless oil (3.98 g, 90%). [R]D -73.0 (c
2-O-Benzyl-1,3-O-benzylidene-4,5-O-(2′,3′-dimethoxybutane-
2′,3′-diyl)-D-glycero-L-gulo-heptitol (21). TBAF (1.0 M solution
in THF, 3.90 mL, 3.9 mmol) was added dropwise to a stirred
solution of the TBDMS-protected alcohol 26 (1.96 g, 3.25 mmol)
in THF (30 mL) at rt. After 2 h at rt, the reaction mixture was
concentrated and the residue was purified by flash chromatog-
raphy (EtOAc:hexanes ) 3: 7) to yield 21 as a white crystalline
1.5, CH2Cl2). 1H NMR (CDCl3) δ 7.41-7.21 (10H, Ar), 5.39 (1H,
s, Ph-CH), 4.55 (2H, dd, Ph-CH2), 4.40 (1H, dd, J7a,7b ) 10.6 Hz,
J7a,6 ) 5.0 Hz, H-7a), 4.25 (1H, dd, J5,4 ) 2.3 Hz, J5,6 ) 9.4 Hz,
H-6), 4.15 (1H, dd, J4,3 ) 9.7 Hz, H-4), 4.09 (2H, m, H-3, H-6),
3.83 (1H, dd, J1a,1b ) 9.5, J1a,2 ) 4.4 Hz, H-1a), 3.70 (1H, dd, J1b,2
) 3.8 Hz, H-1b), 3.65 (1H, ddd, J2,-OH ) 7.5 Hz, H-2), 3.59 (1H,
dd, J7b,6 ) 10.3 Hz, H-7b), 3.17, 3.11 (6H, 2 × -OMe), 2.50 (1H,
d, OH-2), 1.26, 1.21 (6H, 2 × -Me). 0.80 (9H, s, TBDMS), 0.00
(6H, s, TBDMS). 13C NMR δ 143.6-131.5 (12C, Ar), 101.3 (Ph-
CH), 99.3, 98.8 (BDA), 79.6 (C-5), 71.9 (Ph-CH2), 71.7 (C-2), 70.2
(C-7), 68.6 (C-4), 68.1 (C-6), 67.5 (C-3), 63.3 (C-1), 48.5, 48.3 (2
23
solid (1.48 g, 92%). Mp 118-120 °C; [R]D -128.4 (c 1.3,
1
CH2Cl2). H NMR (CDCl3) δ 7.43-7.26 (10H, Ar), 5.43 (1H,
s, Ph-CH), 4.62 (2H, dd, Ph-CH2), 4.46 (1H, dd, J4,3 ) 2.7 Hz,
J4,5 ) 9.7 Hz, H-4), 4.44 (1H, dd, J1a,1b ) 10.4 Hz, J1a,2 ) 5.0
Hz, H-1a), 4.17 (1H, dd, J5,6 ) 1.8 Hz, H-5), 4.12 (1H, ddd, J2,3
J. Org. Chem. Vol. 73, No. 16, 2008 6179

Nasi et al.
) 9.2 Hz, J2,1b ) 10.4, H-2), 3.99 (1H, dd, H-3), 3.85 (1H, ddd,
J7a,7b ) 11.0 Hz, J7a,6 ) 5.6, J7a, -OH ) 2.0, H-7a), 3.80 (1H, m,
H-6), 3.68 (1H, ddd, J7b,6 ) 10.0 Hz, J7b,-OH ) 9.8 Hz, H-7b),
3.64 (1H, dd, H-1b), 3.21, 3.16 (6H, 2 × -OMe), 2.63 (1H, d,
OH-6), 2.37 (1H, dd, OH-7), 1.31, 1.29 (6H, 2 × -Me). 13C
NMR δ 138.2-126.3 (12C, Ar), 101.3 (Ph-CH), 99.4, 99.3, 78.7
(C-3), 71.7 (Ph-CH2), 70.2 (C-1), 69.9 (C-5), 69.3 (C-6), 67.6
(C-2), 65.5 (C-7), 65.3 (C-4), 48.2, 48.1 (2 × -OMe), 17.9 (2
× -Me). Anal. Calcd for C27H36O9: C, 64.27; H, 7.19. Found:
C, 64.63; H, 7.44.
the aqueous solution was extracted with EtOAc (2 × 100 mL).
The combined organic layer was washed with saturated NaCl,
dried over Na2SO4, and evaporated under diminished pressure.
The residue was purified by flash column chromatography to
give 14b as a white solid (620 mg, 55%). Mp 124-126 °C;
23
1
[R]D -128.0 (c 1.0, CH2Cl2). H NMR (CDCl3) δ 7.36-7.25
(15H, Ar), 4.80-4.52 (6H, 3 × Ph-CH2), 4.47 (1H, dd, J4,3
)
1.8 Hz, J4,5 ) 10.2 Hz, H-4), 4.45 (1H, dd, J3,2 ) 9.8, Hz, H-3),
4.41 (1H, dd, J1a,1b ) 10.4 Hz, J1a,2 ) 4.6 Hz, H-1a), 4.32 (1H,
ddd, J2,1b ) 9.7 Hz, H-2), 4.24 (1H, dd, H-1b), 4.07 (1H, dd,
J5,6 ) 2.6 Hz, H-5), 3.87 (1H, dd, J7a,7b ) 10.0 Hz, J7a,6 ) 6.0
Hz, H-7a), 3.80 (1H, dd, J7b,6 ) 4.7 Hz, H-7b), 3.76 (1H, m,
H-6), 3.15, 3.13 (2 × -OMe), 1.30, 1.28 (2 × -Me). 13C NMR
δ 138.3-127.4 (18C, Ar), 99.7, 99.3, 83.2 (C-3), 73.9 (C-6),
73.6, 72.7, 72.5 (Ph-CH2), 71.8 (C-1), 69.6 (C-7), 66.9 (C-2),
66.8 (C-5), 64.8 (C-4), 48.4, 48.2 (2 × --OMe), 17.8, 17.7 (2
× -Me). Anal. Calcd for C34H42O11S: C, 61.99; H, 6.43. Found:
C, 61.76; H, 6.44.
2,6,7-Tri-O-benzyl-1,3-O-benzylidene-4,5-O-(2′,3′-dimethoxy-
butane-2′,3′-diyl)-D-glycero-L-gulo-heptitol (27). A mixture of
compound 21 (1.40 g, 2.77 mmol) and 60% NaH (1.5 equiv) in
DMF (100 mL) was stirred at 0 °C for 1 h. A solution of benzyl
bromide (0.74 mL, 6.01 mmol) in DMF (5 mL) was added, and
the mixture was stirred at room temperature for 2 h. The reaction
was quenched by addition of ice-cold water (50 mL) and the
mixture was diluted with Et2O (150 mL). The organic layer was
washed with H2O (50 mL) and brine (50 mL). The organic phase
was dried over anhydrous Na2SO4, filtered, and concentrated.
The crude product was purified by flash chromatography
[hexanes/EtOAc, 5:1] to give compound 27 as a white crystalline
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[2S,3S,4R,5S,6S]-
2,6,7-tri-O-benzyl-4,5-di-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-3-(sul-
fooxy)heptyl]-(R)-epi-sulfoniumylidine]-D-arabinitol Inner Salt (29).
The thioarabinitol 15 (210 mg, 0.42 mmol) and the cyclic sulfate
14a (308 mg, 0.46 mmol) were added to 1,1,1,3,3,3-hexafluor-
oisopropanol (HFIP) (3 mL) containing anhydrous K2CO3 (40
mg). The mixture was stirred in a sealed tube at 72 °C for 48 h.
The solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography (3:1 hexanes/
EtOAc and then 20:1, 15:1 EtOAc/MeOH). The coupled product,
29, was obtained as a white amorphous solid (258 mg, 52%).
[R]D23 -82.0 (c 0.5, CH2Cl2). 1H NMR (acetone-d6) δ 7.44-6.84
(27H, Ar), 4.93 (1H, J3′,4′ ) 1.7 Hz, J3′,2′ ) 5.1 Hz, H-3′),
4.85-4.22 (12H, 3 × Ph-CH2, 3 × Ph-CH2), 4.68 (1H, m, H-2),
23
solid (1.76 g, 92%). Mp 104-106 °C; [R]D -90.6 (c 0.7,
1
CH2Cl2). H NMR (CDCl3) δ 7.38-7.23 (20H, Ar), 4.88 (1H,
s, Ph-CH), 4.84-4.55 (6H, 3 × Ph-CH2), 4.42 (1H, dd, J4,3
)
2.7 Hz, J4,5 ) 9.7 Hz, H-4), 4.37 (1H, dd, J1a,1b ) 10.5 Hz, J1a,2
) 5.0 Hz, H-1a), 4.23 (1H, dd, J5,6 ) 2.2 Hz, H-5), 3.98 (1H,
dd, J2,1b ) 10.4 Hz, H-2), 3.90 (2H, d, J7,6 ) 5.6 Hz, H2-7),
3.79 (1H, dt, H-6), 3.33 (1H, dd, H-1b), 3.13 (1H, m, H-3), 3.13
(6H, 2 × -OMe), 1.30, 1.28 (6H, 2 × -Me). 13C NMR δ
138.6-126.4 (24C, Ar), 100.9 (Ph-CH), 99.3, 99.3, 78.1 (C-3),
73.3, 71.3, 71.2 (Ph-CH2), 73.3 (C-6), 69.6 (C-1), 69.5 (C-7),
67.7 (C-5), 67.4 (C-2), 65.4 (C-4), 48.0, 47.9 (2 × -OMe), 18.0,
17.9 (2 × -Me). Anal. Calcd for C41H48O9: C, 71.91; H, 7.06.
Found: C, 71.99; H, 7.19.
4.57 (1H, m, H-5′), 4.45 (1H, m, H-3), 4.37 (1H, dd, J1a′,1b′
)
13.5 Hz, J1a′,2′ ) 3.9 Hz, H-1a′), 4.35 (1H, m, H-6′), 4.30 (1H,
dd, J4′5′ ) 10.0 Hz, H-4′), 4.23 (1H, m, H-2′), 4.20 (1H, dd,
J1a,1b ) 13.5 Hz, J1a,2 ) 2.6 Hz, H-1a), 4.15 (1H, dd, J1b′,2′
)
2,6,7-Tri-O-benzyl-4,5-di-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-
glycero-L-gulo-heptitol (28). To a solution of 27 (1.60 g, 9.6 mmol)
in MeOH (100 mL) was added p-toluenesulfonic acid (200 mg),
and the reaction mixture was stirred for 6 h at rt. The reaction
was then quenched by addition of excess Et3N, the solvents were
removed, and the yellow syrup was purified by flash column
chromatography to give 28 as a white amorphous solid (1.08 g,
4.4 Hz, H-1b′), 4.06 (1H, dd, H-4), 4.00 (1H, dd, J1b,2 ) 3.9
Hz, H-1b), 3.94 (1H, dd, J7a′,7b′ ) 9.9 Hz, J7a′,6′ ) 6.5 Hz, H-7a′),
3.80, 3.79 (3 × -OMe), 3.70 (1H, dd, J5a,5b ) 10.0 Hz, J5a,4
)
6.9 Hz, H-5a), 3.61 (1H, dd, J7b′,6′ ) 5.4 Hz, H-7b′), 3.54 (1H,
dd, J5b,4 ) 8.5, H-5b), 3.20, 3.09 (2 × -OMe), 1.19, 1.18 (2 ×
-Me). 13C NMR δ 159.9-113.8 (32C, Ar), 99.2, 98.4, 83.3 (C-
3), 82.2 (C-2), 76.2 (C-6′), 75.6 (C-2′), 73.4 (C-3′), 72.9, 72.6,
72.0, 71.7, 71.3, 71.3 (3 × Ph-CH2, 3 × Ph-CH2), 69.8 (C-7′),
68.9 (C-4′), 68.8 (C-5′), 66.8 (C-5), 65.7 (C-4), 54.9, 54.8 (3 ×
-OMe), 49.4 (C-1′), 49.2 (C-1), 47.9, 47.1 (2 × -OMe), 17.4,
17.3 (2 × -Me). Anal. Calcd for C63H76O17S2: C, 64.71; H,
6.55. Found: C, 64.38; H, 6.52.
23
77%). [R]D -91.6 (c 0.6, CH2Cl2). 1H NMR (CDCl3) δ
7.33-7.21 (15H, Ar), 4.70-4.48 (6H, 3 × Ph-CH2), 4.35 (1H,
d, J4,5 ) 10.2 Hz, H-4), 4.14 (1H, dd, J5,6 ) 2.0 Hz, H-5), 3.90
(2H, m, H2-1), 3.76 (3H, m, H-2, H-6, H-7a), 3.65 (2H, m, H-3,
H-7b), 3.19, 3.16 (2 × -OMe), 2.65 (1H, J ) 8.9 3-OH), 2.25
(1H, dd, J ) 5.1, 7.6 Hz, 1-OH), 1.30, 1.29 (2 × -Me). 13C
NMR δ 137.9-126.8 (Ar), 99.1, 99.0, 78.3 (C-6), 75.3 (C-6),
73.4, 72.5, 71.7 (3 × Ph-CH2), 69.9 (C-2), 69.8 (C-7), 67.8 (C-
5), 66.9 (C-4), 61.4 (C-1), 48.4, 48.1 (2 × -OMe), 17.8, 17.7
(2 × -Me). Anal. Calcd for C34H44O9: C, 68.44; H, 7.43. Found:
C, 68.59; H, 7.39.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[2S,3S,4R,5S,6R]-
2,6,7-tri-O-benzyl-4,5-di-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-3-(sul-
fooxy)heptyl]-(R)-epi-sulfoniumylidine]-D-arabinitol Inner Salt (30).
To HFIP (3 mL) were added the thioarabinitol 15 (238 mg, 0.46
mmol), the cyclic sulfate 14b (324 mg, 0.49 mmol), and
anhydrous K2CO3 (40 mg). The mixture was stirred in a sealed
tube at 72 °C for 48 h. The solvent was removed under reduced
pressure, and the residue was purified by flash column chroma-
2,6,7-Tri-O-benzyl-4,5-di-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-
glycero-L-gulo-heptitol-1,3-cyclic Sulfate (14b). A mixture of 22
(1.0 g, 1.68 mmol) and Et3N (0.90 mL, 8.9 mmol) in CH2Cl2
(50 mL) was stirred at 0 °C. Thionyl chloride (0.2 mL, 2.7 mmol)
in CH2Cl2 (5 mL) was then added dropwise over 20 min, and
the mixture was stirred for an additional 30 min. The mixture
was poured into ice-cold water and extracted with CH2Cl2 (2 ×
100 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated. Column chromatography
(hexanes:EtOAc, 8:1, 5:1, 3:1) gave the diastereomeric mixture
of cyclic sulfites. To a solution of the cyclic sulfites in a mixture
of CH3CN:CCl4 (1:1, 60 mL) were added sodium periodate (0.70
g, 3.35 mmol) and RuCl3 (60 mg), followed by H2O (10 mL).
The mixture was then stirred for 2 h at room temperature. The
reaction mixture was filtered through a silica bed and washed
repeatedly with EtOAc. The volatile solvents were removed, and
tography (3:1 hexanes:EtOAc and then 15:1 EtOAc:MeOH) to
23
give 30 as a white amorphous solids (265 mg, 49%). [R]D
-
1
54.0 (c 0.5, CH2Cl2). H NMR (acetone-d6) δ 7.42-6.84 (27H,
Ar), 4.96-4.12 (12H, 3 × Ph-CH2, 3 × Ph-CH2), 4.90 (1H,
J3′,4′ ) 1.7 Hz, J3′,2′ ) 6.4 Hz, H-3′), 4.74 (1H, m, H-6′), 4.69
(1H, m, H-2), 4.52 (1H, dd, J4′5′ ) 9.6 Hz, H-4′), 4.46 (1H, m,
H-3), 4.39 (3H, m, H2-1′, H-2′), 4.35 (1H, m, H-5′), 4.18 (1H,
m, H-1a), 4.01 (2H, m, H-4, H-1b), 3.95 (1H, dd, J7a′,6′ ) 7.7
Hz, J7a′,
) 10.6 Hz, H-7a′), 3.81 (1H, dd, J7b′,6′ ) 3.8 Hz,
7b′
H-7b′), 3.80, 3.78, 3.77 (3 × -OMe), 3.63 (1H, dd, J5a,5b
)
10.0 Hz, J5a,4 ) 4.7 Hz, H-5a), 3.50 (1H, dd, J5b,4 ) 8.0 Hz,
H-5b), 3.14, 3.06 (2 × -OMe), 1.82 (2 × -Me). 13C NMR δ
159.9-113.8 (32C, Ar), 99.1, 98.6, 83.4 (C-3), 82.1 (C-2), 75.9
6180 J. Org. Chem. Vol. 73, No. 16, 2008

Structure Determination of Kotalanol
(C-6′), 75.1 (C-2′), 73.3 (C-3′), 73.1, 72.6, 72.4, 71.7, 71.7, 71.4
(3 × Ph-CH2, 3 × Ph-CH2), 71.3 (C-7′), 69.1 (C-5′), 67.9 (C-
4′), 66.7 (C-5), 65.3 (C-4), 54.8, 54.8 (3 × -OMe), 49.2 (C-
1′), 48.9 (C-1), 47.9, 47.3 (2 × -OMe), 17.5, 17.4 (2 × -Me).
Anal. Calcd for C63H76O17S2: C, 64.71; H, 6.55. Found: C, 64.93;
H, 6.65.
(13b). The sulfonium salt 30 (240 mg, 0.212 mmol) was
deprotected following the same procedure that was used for
compound 29, to give compound 13b as a crystalline solid. Mp
23
1
169-171; [R]D +12.0 (c 0.5, MeOH). H NMR (D2O) δ 4.61
(1H, dd, J2,1 ) 3.4 Hz, J2,3 ) 3.2 Hz, H-2), 4.35 (2H, m, H-2′,
H-3′), 4.32 (1H, dd, J3,4 ) 3.0 Hz, H-3), 3.98 (1H, dd, J5a,5b
)
1,4-Dideoxy-1,4-[[2S,3S,4R,5S,6S]-2,4,5,6-pentahydroxy-3-(sul-
fooxy)heptyl]-(R)-epi-sulfoniumylidine]-D-arabinitol Inner Salt
(13a). Compound 29 (78 mg, 0.075 mmol) was dissolved in a
mixture of CH3COOH:H2O (20 mL, 4:1) and the solution was
stirred with 10% Pd/C (100 mg) under 100 psi of H2 for 48 h.
The catalyst was removed by filtration through a bed of silica,
then washed with water (25 mL). The solvents were removed
under reduced pressure and 80% aqueous TFA (10 mL) was
added. The mixture was stirred at room temperature for 2 h.
The solvents were then evaporated under diminished pressure
and the residue was purified by flash column chromatography
10.4 Hz, J5a,4 ) 4.9 Hz, H-5a), 3.95 (3H, m, H-4, H-4′, H-1a′),
3.85-3.76 (3H, m, H-5b, H-6′, H-1b′), 3.74 (2H, d, H2-1), 3.69
(1H, dd, J5′,6′ ) 7.8 Hz, J5′,4′ ) 2.2 Hz, H-5′), 3.52 (2H, d, J7′,6′
) 5.4, H-7′). 13C NMR δ 78.9 (C-3′), 77.8 (C-3), 76.8 (C-2),
70.8 (C-5′), 71.7 (C-6′), 70.1 (C-4), 69.2 (C-4′), 66.6 (C-2′),
63.6 (C-7′), 59.2 (C-5), 50.4 (C-1′), 47.9 (C-1). HRMS Calcd
for C12H24O12NaS2 (M + Na) 447.0601, found 447.0589.
Acknowledgment. We are grateful to the Canadian Insti-
tutes for Health Research for financial support. Crystal-
lographic data were collected through the SCrALS (Service
Crystallography at Advanced Light Source) program at the
Small-Crystal Crystallography Beamline 11.3.1 (developed
by the Experimental Systems Group) at the Advanced Light
Source (ALS). The ALS is supported by the U.S. Department
of Energy, Office of Energy Sciences Materials Sciences
Division, under contract DE-AC03-76SF00098 at Lawrence
Berkeley National Laboratory.
23
to give 13a as a white crystalline solid. Mp 164-166. [R]D
1
+18.3 (c 0.6, MeOH). H NMR (D2O) δ 4.60 (1H, dd, J2,1
)
3.4 Hz, J2,3 ) 3.2 Hz, H-2), 4.36 (1H, dd, J3′,2′ ) 7.1 Hz, J3′,4′
) 2.7 Hz, H-3′), 4.32 (1H, ddd, J2′,1a′ ) 3.2 Hz, J2′b′ ) 7.6 Hz,
H-2′), 4.30 (1H, dd, J3,4 ) 3.1 Hz, H-3), 4.02 (1H, t, J4′5′ ) 2.7
Hz, H-4′), 3.95 (1H, dd, J5a,5b ) 11.1, J5a,4 ) 4.9 Hz, H-5a),
3.93 (1H, ddd, H-4), 3.88 (1H, dd, J1a′,1b′ ) 13.5 Hz, H-1a′),
3.81 (1H, dd, J5b,4 ) 7.6 Hz, H-5b), 3.72 (1H, dd, H-1b′), 3.71
(2H, d, H2-1), 3.68 (1H, dd, J5′,6′ ) 7.4 Hz, H-5′), 3.65 (1H, dd,
J7a′,6′ ) 3.2 Hz, J7a′,7b′ ) 11.2 Hz, H-7a′), 3.61 (1H, ddd, H-6′),
3.50 (1H, dd, J7b′,6′ ) 5.6 Hz, H-7b′). 13C NMR δ 81.1 (C-3′),
77.8 (C-3), 76.8 (C-2), 71.4 (C-5′), 71.0 (C-6′), 70.0 (C-4), 67.7
(C-4′), 66.7 (C-2′), 62.6 (C-7′), 59.1 (C-5), 50.2 (C-1′), 47.8
(C-1). HRMS Calcd for C12H24O12NaS2 (M + Na) 447.0601,
found 447.0601.
Supporting Information Available: General experimental
details, copies of 1H and 13C NMR spectra for all new
compounds, and X-ray crystallographic (CIF) files for com-
pounds 14b, 21, and 27. This material is available free of charge
via the Internet at http://pubs.acs.org.
1,4-Dideoxy-1,4-[[2S,3S,4R,5S,6R]-2,4,5,6-pentahydroxy-3-(sul-
fooxy)heptyl]-(R)-epi-sulfoniumylidine]-D-arabinitol Inner Salt
JO800855N
J. Org. Chem. Vol. 73, No. 16, 2008 6181