Stereoselective synthesis of 2,3-diamino-2,3-dideoxy-β-d- mannopyranosyl uronates

Article abstract of DOI:10.1021/jo201179p

With the aim to find an efficient synthetic procedure for the construction of 2,3-diamino-2,3-dideoxy-β-d-mannuronic acids, we evaluated three mannosyl donors: (S)-phenyl 4,6-di-O-acetyl-2,3-diazido mannopyranoside, (S)-phenyl 2,3-diazido-4,6-O-benzylidene mannopyranoside, and (S)-phenyl 2,3-diazido mannopyranosyl methyl uronate. The first two mannosylating agents are rather unselective or slightly α-selective in their condensation with three different acceptors. The mannuronic acid donor on the other hand reliably provides the desired β-mannosidic linkage. A mechanistic rationale is put forward to account for the different behavior of the three donor types. Suitably protected 2,3-diazido mannuronic acids were employed to construct the all-cis-linked tetrasaccharide repeating unit of the capsular polysaccharide of Bacillus stearothermophilus, featuring two 2,3-diacetamido-2,3-dideoxy-β-d- mannuronic acids.

Full text of DOI:10.1021/jo201179p

FEATURED ARTICLE
pubs.acs.org/joc
Stereoselective Synthesis of 2,3-Diamino-2,3-dideoxy-β-
D-mannopyranosyl Uronates
Marthe T. C. Walvoort, Gert-Jan Moggrꢀe, Gerrit Lodder, Herman S. Overkleeft, Jeroen D. C. Codꢀee,* and
Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
S Supporting Information
b
ABSTRACT: With the aim to find an efficient synthetic
procedure for the construction of 2,3-diamino-2,3-dideoxy-
β-D-mannuronic acids, we evaluated three mannosyl donors:
(S)-phenyl 4,6-di-O-acetyl-2,3-diazido mannopyranoside, (S)-phenyl
2,3-diazido-4,6-O-benzylidene mannopyranoside, and (S)-phenyl
2,3-diazido mannopyranosyl methyl uronate. The first two
mannosylating agents are rather unselective or slightly R-selective
in their condensation with three different acceptors. The mannuronic acid donor on the other hand reliably provides the desired
β-mannosidic linkage. A mechanistic rationale is put forward to account for the different behavior of the three donor types. Suitably
protected 2,3-diazido mannuronic acids were employed to construct the all-cis-linked tetrasaccharide repeating unit of the capsular
polysaccharide of Bacillus stearothermophilus, featuring two 2,3-diacetamido-2,3-dideoxy-β-D-mannuronic acids.
’ INTRODUCTION
Functional groups on a glycosyl donor play a decisive role on
the stereochemical course of its glycosylation reactions. In our
studies toward the synthesis of anionic (bacterial) oligosaccharides,
we have recently disclosed that glycosylations of mannuronic
acid ester donors, that is, mannopyranosides of which the C-6 is
oxidized to a carboxylic acid ester, such as 1 (Figure 1), proceed
with a very high degree of β-selectivity.1 Initially, we postulated
that the observed β-selectivity was the result of the SN2-like
reaction of an intermediate R-triflate (2), in line with the seminal
Figure 1. Mannopyranosyl uronic esters studied previously.
work of Crich and co-workers on 4,6-O-benzylidene directed
β-mannosylations.2 We reasoned that the C-5 carboxylic ester is
sufficiently electron-withdrawing to stabilize the anomeric triflate
explaining the observed β-selectivity. It was reasoned that the
with respect to the oxacarbeniumꢀtriflate ion pair to allow for a
C-5 carboxylate was at the basis of this unusual conformational
β-selective displacement reaction. However, we were at that time
behavior. It also became apparent in our studies of the C-2 azido
mannuronic acid series that the introduction of the C-2 azide
functionality in 3 did not significantly alter the β-selectivity of the
glycosylation reaction with respect to the glycosylations of its C-2
unable to spectroscopically detect a single anomeric triflate
species. Examination of the activation of a series of 2-azido-
2-deoxy mannuronic acid ester donors, including thiomannoside
3, revealed that an anomeric triflate was formed from these
benzyloxy counterpart 1.3b Notably, this contrasts with the 4,
6-O-benzylidene β-mannosylation system in which the selec-
tivity has been shown to be sensitive to the nature of the C-2
substituent.6 Work from our laboratory has revealed that con-
densations involving 2-azido-2-deoxy-4,6-O-benzylidene mannosyl
donors proceed somewhat less β-selective than couplings with its
C-2-O-benzyl counterpart.7 To further investigate the influence
of different substitution patterns on glycosylation with mannosyl
and mannuronic acid ester donors, we here report the results
donors and that it exists as a mixture of 4C1 and 1C4 conformers,
4a and 4b, respectively, in which the latter species, having an
equatorially positioned triflate, surprisingly prevailed.3 Although
these studies showed the intermediacy of an anomeric triflate
species, the fact that this triflate species prefers to adopt an
“inverted” chair conformation lends support to an alternative
mechanistic rationale for the β-selectivity which invokes the 3H4
mannuronic acid ester oxacarbenium ion 5 as the product
forming intermediate (Figure 1).4 In line with the detailed
studies of Woerpel and co-workers on the stereochemical
alkylation of oxacarbenium ions,5 this intermediate is preferen-
tially attacked by an incoming nucleophile from the β-face,
Received: June 7, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
of our study of 2,3-diazido-2,3-dideoxy mannopyranosyl8 and
mannopyranosyl uronate donors. 2,3-Diacetamido-dideoxy
mannopyranosyl uronates are found in various bacterial capsular
polysaccharides,9 in which they are usually linked in a 1,2-cis
fashion to the next sugar residue. An efficient route of synthesis
toward these rare bacterial carbohydrates can help to elucide
their role in biology and immunology. We also report the
stereoselective assembly of the tetrasaccharide repeating unit
of the capsular polysaccharide of Bacillus stearothermophilus,
containing two 2,3-diacetamido-2,3-dideoxy-β-mannopyra-
nosyl uronates (47, Scheme 2).10
was obtained following an adaptation of the procedure described
by Guthrie and Murphy.13 Starting from 4,6-O-benzylidene-protected
methyl glucoside 9,14 double methanesulfonylation toward com-
pound 10 and subsequent epoxidation using potassium hydro-
xide in THF/MeOH resulted in crystalline compound 11 in 62%
over two steps. Selective trans-diaxial opening of the epoxide with
sodium azide in DMF at reflux temperature gave 2-azido-2-deoxy-
altropyranoside 12 in 93%.
Subsequent triflation of C-3-OH and SN2 substitution with
NaN3 in DMF at 80 °C resulted in diazido-containing manno-
pyranoside 13 via inversion of configuration at C-3.15 In one step,
the benzylidene and anomeric methyl function were hydrolyzed
with concomitant acetylation of the liberated alcohols to afford
compound 14 as an anomeric mixture (R/β = 5:1). Treatment of
’ RESULTS AND DISCUSSION
We investigated three types of 2,3-diazido mannosyl donors,
the 4,6-di-O-acetyl mannosides 6r and 6β, the 4,6-O-benzylidene
mannoside 7, and the mannuronic acid esters 8rand 8β(Scheme1).
The first two donors were selected because we previously re-
ported that the installment of electron-withdrawing groups such
as an O-acetate on C-4 and C-6 of a 2-azido mannosyl donor also
provides β-selective condensation reactions, depending on the
nature of the acceptor used.11 More recently, Kim and co-workers
reported on the stereodirecting effect of electron-withdrawing
groups at C-3, C-4, and C-6 in mannosylations.12 Donors 6, 7, and 8
were synthesized as depicted in Scheme 1. Key intermediate 13
compound 14 with PhSH and BF3 Et2O in DCE at 50 °C
3
resulted in R-thio donor 6r (24%) and β-thio donor 6β (58%),
which were readily separated. Subsequent deacetylation under
Zemplꢀen conditions gave diols 15r/β. Crystalline benzylidene
donor 7 was obtained from diol 15β using benzaldehyde di-
methylacetal and a catalytic amount of p-TsOH in 69% yield. To
obtain the mannuronic acid donors 8r/β, diols 15r/β were
subjected to regio- and chemoselective oxidation at C-6 using the
TEMPO/BAIB reagent combination.16,17 From diol 15r, com-
pound 16r was obtained in 76% yield after oxidation and
ensuing methylation. Under similar conditions, diol 15β was
Scheme 1. Synthesis of Donors 6ꢀ8a
a Reagents and conditions: (a) MsCl, pyridine; (b) KOH, THF/MeOH (11, 62% over two steps); (c) NaN3, NH4Cl, DMSO, 80 °C (12, 93%); (d) (i)
Tf2O, pyridine; (ii) NaN3, NH4Cl, DMF, 80 °C (13, 75%); (e) H2SO4, Ac2O (14, 98%); (f) PhSH, BF3 Et2O, DCE, 50 °C (6r, 24%; 6β, 58%);
3
(g) NaOMe, MeOH (15r, 100%; 15β, 98%); (h) PhCH(OMe)2, p-TsOH, MeCN (7, 69%); (i) (i) TEMPO, BAIB, DCM/H2O; (ii) MeI, K2CO3,
DMF (16r, 76%); (j) Ac2O, pyridine (8r, 91%; 8β, 100%); (k) (i) TEMPO, BAIB, EtOAc/H2O; (ii) MeI, K2CO3, DMF (16β, 91%).
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Figure 2. Overview of mannopyranosyl triflates.
transformed into 16β in a somewhat lower yield (50%). Changing
the organic solvent of the biphasic oxidation mixture from di-
chloromethane to ethyl acetate, in which the crystalline 15β
proved to be more soluble, led to an increased yield (91%) of
compound 16β. Methyl mannuronates 16r and 16β were
acetylated using Ac2O in pyridine to give donors 8r and 8β.
With the five donors, 6r/β, 7, and 8r/β, in hand, we first
investigated their activation in low-temperature NMR experi-
ments. Upon treatment of diacyl donor 6β with Ph2SO and
Tf2O18,19 in DCM-d2 at ꢀ80 °C, R-triflate 17 was rapidly formed
(see Figure 2). This species proved to be stable to +10 °C.
R-Configured donor 6r provided the same triflate but required a
higher temperature for complete activation (ꢀ40 °C). Using the
same activator system,20 benzylidene donor 7 was rapidly trans-
formed at ꢀ80 °C into R-triflate 18, which was stable up to 0 °C.
Similarly, β-diazido mannuronic acid donor 8β was completely
transformed into the corresponding anomeric triflate 19 at ꢀ80 °C.
In analogy to the monoazido mannuronic acid triflate 4, this species
exists as a mixture of 4C1 and 1C4 conformers (4C1/1C4 ∼ 4.5:1).
Decomposition of this triflate started around ꢀ10 °C, making
this species the least stable of the three diazido mannosidic
triflates, in contrast to what could be expected based on the
electron-withdrawing capacity of the different functional groups.
The result is in line, however, with the relatively low decomposi-
tion temperatures for mannuronic acid triflates 2 and 4, as
depicted in Figure 2.3 From the decomposition temperatures
of the three different mannuronates, 2, 4, and 19, it is clear that
the extra C-3 azide group in 19 has a stabilizing effect, as expected
on the basis of its electron-withdrawing capacity (F value
∼0.48).21 The last donor in the series, R-mannuronic acid 8r,
required a significantly higher temperature (ꢀ10 °C) for com-
plete activation than its β-configured counterpart. As in the case
of the monoazido mannuronic acid 3, the temperature required
for complete activation of the R-isomer 8r matched the decom-
position temperature of the anomeric triflate.
entries 1ꢀ3, the condensations with diacetyl diazido mannoside
6β proceeded with very little selectivity. Entries 4ꢀ6 show that
the benzylidene donor 7 is moderately R-selective. Clearly, these
results oppose the results obtained with 2,3-di-O-benzyl benzy-
lidene mannose.2 As described above, we have previously studied
2-azido-3-O-benzyl-4,6-O-benzylidene mannosyl donors and
found them to be moderately β-selective. More recently, Crich
and co-workers have reported on the condensations of an R-(S)-
phenyl 3-azido-2-O-benzyl-4,6-O-alkylidene mannopyranosyl
donor,22 which also proceed with moderate β-selectivity. The
substitution of a single O-benzyl group for an azide functionality
thus already causes a drop in selectivity. The introduction of two
azides leads to further erosion of β-selectivity, providing moder-
ate R-selectivity in two of the three cases studied here. Crich
and co-workers have rationalized the erosion of β-selectivity,
observed with small substituents at the C-2 or C-3 position, through
the observation that formation of the benzylidene mannosyl 4H3
oxacarbenium ion from the corresponding R-triflate proceeds
with concomitant compression of the R2ꢀC-2ꢀC-3ꢀR3 torsion
angle, which is easier if the substituents R2 and R3 are smaller.6a,23
The diazido case studied here supports this mechanistic rationale: the
presence ofthetwosmallazides(Avalue ∼0.45ꢀ0.62 kcal molꢀ1 24
)
allows the mannosyl triflate to readily collapse into the R-
4
selective H3 oxacarbenium ion. It should be noted that the
electron-withdrawing effect of the azide does not counterbalance
this steric effect, which has also been found for C-3-O-benzyl-C-
2-fluoro- and C-2-O-benzyl-C-3-fluorobenzylidene mannosides.6a
A similar rationale can account for the poor selectivity obtained
with donor 6β. Furthermore, Kim and co-workers have argued
that participation of a remote C-6-O-acetate can also account for
the formation of R-linked products from otherwise benzylated
mannosides.12 In the present case, we cannot exclude such a
mechanism to contribute to the formation of the R-mannosides.
Entries 7ꢀ9 show that the three diazido mannuronate dis-
accharides 29, 30, and 31 were all formed in a β-selective fashion.
Secondary alcohol 21 gave the poorest selectivity and yield in the
series, which parallels the results of condensations of this acceptor
with other mannuronate donors.3a Introduction of two azides on
the mannuronic acid core thus has little influence on the selectivity
of the mannuronic acid type donors, in contrast to the other two
types of donors studied here. A possible explanation for this
Next, β-thio donors 6β, 7, and 8β were surveyed in a set of
glycosylation reactions with primary acceptor 20 and secondary
acceptors 21 and 22. To this end, the donors were preactivated
(Ph2SOꢀTf2O) for 20 min at ꢀ80 °C before the addition of the
acceptor alcohols and warming to 0 °C. The results of the
condensations are summarized in Table 1. As can be seen from
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Table 1. Glycosylation Study of Donors 6β, 7, and 8βa
a Conditions: donor 6β or 7, Tf2O (1.3 equiv), Ph2SO (1.3 equiv), TTBP (2.5 equiv), DCM (0.05) at ꢀ80 °C, then add acceptor (1.5 equiv). Donor 8β,
Tf2O (1.3 equiv), Ph2SO (1.3 equiv), TTBP (2.5 equiv), DCM (0.05) at ꢀ80 f ꢀ60 °C, then add acceptor (1.5 equiv).
Having established that the diazido mannuronic acid donor 8β
is the donor of choice for the introduction of the 2,3-diamino-2,
3-dideoxy β-mannosidic bond, we sought to explore its utility in
the construction of a complex oligosaccharide. To this end, we selected
the repeating unit of the secondary cell wall polysaccharide of
Bacillus stearothermophilus, [f4)-β-D-ManpA2,3(NAc)2-(1f6)-R-
D-Glcp-(1f4)-β-D-ManpA2,3(NAc)2-(1f3)-R-D-GlcpNAc-(1f],9
Figure 3. 2,3-Diazido mannuronate oxacarbenium ions.
as a synthetic target (Scheme 2). This all-cis-linked oligosaccharide
features two β-linked diacetamino mannuronic acids in addition
to an R-glucose and an R-glucosamine moiety. We decided to
construct tetrasaccharide 47, having an aminopentanol spacer at its
reducing end, from three building blocks: reducing end glucosa-
mine 39, glucose mannuronic acid disaccharide 41, and terminal
mannuronic acid 44. We based our synthesis on the use of the
central disaccharide 41 because this type of disaccharide performed
well in the construction of Micrococcus luteus oliogomers, composed
of repeating [f6)-R-D-Glcp-(1f4)-β-D-ManpA2(NAc)-(1f]
units.3b The synthesis of these building blocks and the full
assembly of the tetrasaccharide is depicted in Scheme 2. The
synthesis of acceptor 39 started from hemiacetal 35,26a,b which
was transformed into N-phenyltrifluoroacetimidate 3626c in 96%
yield. The stereoselective condensation of this donor with
N-(benzyl)benzyloxycarbonyl-5-aminopentanol required some
optimization. When a mixture of 36 and the acceptor in DCM
was treated with a catalytic amount of TfOH at 0 °C, compound
37 was formed as an R/β mixture, with a slight preference for the
R-anomer. The addition of thiophene to the reaction mixture as
prescribed by Boons et al.27 to enhance the R-selectivity did not
result in a better selectivity. By using diethyl ether as the solvent
and lowering the reaction temperature to ꢀ40 °C, the stereo-
selectivity of the reaction was enhanced to provide product 37 in
77% yield and a 7:1 R/β ratio. Separation of the two anomers was
troublesome at this stage, and therefore, 37 was transformed into
alcohol 39 by subsequent deacetylation and silylidene formation.
After this sequence of reactions, pure R-configured acceptor 39
observation can be found in the preferred conformation of the
mannuronate oxacarbenium ions, in which the C-5 carboxylic
acid ester prefers to occupy a pseudoaxial position (as in 5, Figure 1),
making the 3H4 oxacarbenium ion energetically favored over its
3
4H3 counterpart. Nucleophilic attack at the H4 oxacarbenium
ion leads to the preferential formation of the β-product. Woerpel
and co-workers have established that an azido group follows the
preference of an O-alkyl substituent to occupy an axial orienta-
tion in an oxacarbenium ion intermediate.5a The relative stabi-
lities of the diazido mannuronic acid 3H4 and 4H3 oxacarbenium
ions 32 and 33 thus mirror those of the 2,3-di-O-benzyl
mannuronic acid, making the former favored over the latter and
providing a positive contribution to the formation of the β-linked
product (Figure 3). The same line of reasoning can be applied to
a product forming exploded transition state (34) in which the
triflate dissociates from the diazido mannuronic acid core leading
to partial oxacarbenium ion character at C-1, which is best accommo-
dated in a 3H4-like conformation. SN2-like reaction of this species
provides the β-linked product. Although it could be reasoned that
installment of two azides and the C-5 carboxylic acid ester would
provide a highly disarmed donor, which would be difficult to
activate, the yields obtained in the condensations of donor 8β with
alcohols 20 and 22 clearly show this not to be the case: the donors
can be activated at temperatures as low as ꢀ80 °C to provide
reactive glycosylating species. The conformational behavior of the
mannuronates could be at the basis of this unexpected reactivity.25
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Scheme 2. Construction of Tetrasaccharide 47a
a Reagents and conditions: (a) C(NPh)CF3ꢀCl, K2CO3, acetone/H2O (96%, R/β = 1.4:1); (b) N-(benzyl)benzyloxycarbonyl-5-aminopentanol,
TfOH (cat.), Et2O, ꢀ40 f ꢀ10 °C (77%, R/β = 7:1); (c) NaOMe, MeOH (quant.); (d) (tBu)2Si(OTf)2, DMF (76%); (e) 40, 16β, TfOH (cat.),
Et2O, ꢀ40 f ꢀ10 °C (96%); (f) 41, Ph2SO, Tf2O, DCM, ꢀ80 f ꢀ60 °C, then 39, ꢀ80 f ꢀ10 °C (99%); (g) Et3N, pyridine (94%); (h) TBSOTf,
Et3N, DCM, (88%); (i) 44, Ph2SO, Tf2O, TTBP, DCM, ꢀ80 °C, then 43, ꢀ30 °C overnight, (74%); (j) (i) TBAF, HOAc (96%); (ii) TBAF, HOAc
(75%); (k) KOH, H2O2, THF, H2O; (l) (i) Zn, AcOH, THF; (ii) Ac2O, NaHCO3, THF, H2O; (m) H2, Pd/C, H2O, THF, HCl (20%).
could be isolated in 76% yield. The disaccharide 41 was con-
structed using 6-O-Fmoc-protected glucose imidate donor 40
and (S)-phenyl diazido mannuronic acid 16β using conditions
we previously established for the R-selective condensation of 40
and the monoazido mannuronic acid counterpart of 16β.3b,28
The key disaccharide 41 was obtained in excellent yield as a single
anomer. Next, dimer 41 and glucosamine 39 were fused using
our standard Ph2SOꢀTf2O preactivation protocol in the absence
of any base to prevent undesired Fmoc cleavage. All-cis-linked
trisaccharide 42 was obtained in near quantitative yield as a single
diastereomer, highlighting the apt glycosylating capacity of the
diazido mannuronic acid donor. Liberation of the 600-OH under
mild basic conditions then set the stage for the final coupling, in
which the trisaccharide acceptor 43 was condensed with C-4-
O-TBS-protected diazido mannuronic acid 44, obtained from 16β
by treatment with TBSOTf and Et3N in 88% yield. The stereo-
chemical outcome of this reaction did not pose any problems, but
to obtain a profitable yield, some experimentation was required.
After trying different reaction temperatures and times, the best
conditions (reaction at ꢀ30 °C overnight) provided the fully
protected tetrasaccharide 45 in 74% yield. It is of interest to note
that the replacement of the electron-withdrawing C-4-O-acetyl in
8β by the less electron poor TBS ether in 44 does not adversely
affect the β-selectivity of the diazido mannuronic acid donor.
Deprotection of the tetrasaccharide started with the removal
of the silyl groups. It was found that the silylidene group could be
removed without affecting the C-4000-O-TBS ether.29 In fact, removal
of this latter silyl ether was extremely sluggish and deprotection
of the C-4000-OH required 72 h for completion. Next, the carbo-
xylic acid esters were saponified using KOOH in H2O/THF to
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provide the diacid. Initially, we tried to simultaneously reduce
the five azide groups and benzyl ethers and benzylcarbonate
functionality under Birch conditions.3b Unfortunately, this led to
partial fragmentation of the oligosaccharide through cleavage of
the β-mannuronic acid bonds, a side reaction we have also
observed in our synthesis of M. luteus [f6)-R-D-Glcp-(1f4)-
β-D-ManpA2(NAc)-(1f]n oligomers. We therefore resorted to
a stepwise reduction procedure, in which first the four azides
were reduced using zinc in acetic acid,30 followed by aqueous
acetylation of the liberated amines. Removal of the benzyl ethers
and benzyloxycarbonyl groups by treatment with H2 over Pd/C
in the presence of aqueous HCl completed the synthesis of the
target tetrasaccharide. The fully deprotected tetramer 47 was
purified by HPLC and isolated in 20% overall yield.
allowed to warm to 0 °C, after which Et3N or pyridine was added to
quench the reaction. Aqueous workup, passage of the residue through a
column of Sephadex LH-20 (eluted with DCM/MeOH, 1/1, v/v), and
purification using flash column chromatography (silica gel) gave the
coupled product.
Phenyl 4,6-Di-O-acetyl-2,3-diazido-2,3-dideoxy-1-thio-R/
β-D-mannopyranoside (6r/6β). Compound 14 (0.39 g, 1.08 mmol)
and PhSH (0.13 mL, 1.25 mmol) were dissolved in DCE (5.65 mL),
followed by the addition of BF3 Et2O (0.28 mL, 2.26 mmol), and the
3
solution was heated to 50 °C (5 h). Saturated aqueous NaHCO3 was
added, and the mixture was diluted with EtOAc. The organic layer was
washed with H2O (2ꢁ). Purification using column chromatography
(silica gel, 20% EtOAc in PE for the R-anomer, 25% EtOAc in PE for the
β-anomer) yielded the pure anomers 6r and 6β as off-white amorphous
solids (0.36 g, 0.89 mmol, 82%, R/β = 1:2.4). TLC Rf R-anomer 0.50,
β-anomer 0.34 (PE/EtOAc, 2/1, v/v). spectroscopic data for the
R-anomer: [R]20 +110.0 (c 1, DCM); IR (neat, cmꢀ1) 1034, 1227,
’ CONCLUSIONS
D
1728, 2106; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.45ꢀ7.51 (m, 2H, CHarom), 7.32ꢀ7.36 (m, 3H, CHarom), 5.54 (d, 1H,
J = 1.0 Hz, H-1), 5.31 (t, 1H, J = 9.9 Hz, H-4), 4.44 (ddd, 1H, J = 2.4, 5.6,
9.8 Hz, H-5), 4.23 (dd, 1H, J = 5.6, 12.3 Hz, H-6), 4.16 (dd, 1H, J = 1.3,
3.5 Hz, H-2), 4.09 (dd, 1H, J = 2.4, 12.3 Hz, H-6), 4.00 (dd, 1H, J = 3.5,
10.0 Hz, H-3), 2.16 (s, 3H, CH3 Ac), 2.05 (s, 3H, CH3 Ac); 13C-APT
NMR (CDCl3, 100 MHz, HSQC) δ 170.3, 169.2 (CdO Ac), 131.9
(Cq SPh), 131.9, 129.1, 128.2 (CHarom), 85.5 (C-1), 69.4 (C-5), 67.2 (C-4),
63.3 (C-2), 62.0 (C-6), 60.7 (C-3), 20.4, 20.4 (CH3 Ac); 13C-GATED
(CDCl3, 100 MHz) δ 85.5 (JC1,H1 = 169 Hz, C-1); HRMS [M + NH4]+
calcd for C16H22N7O5S 424.13976, found 424.13994. Spectroscopic
data for the β-anomer: [R]20D +14.4 (c 1, DCM); IR (neat, cmꢀ1) 1034,
1211, 1736, 2106; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.50ꢀ7.55 (m, 2H, CHarom), 7.30ꢀ7.34 (m, 3H, CHarom), 5.27 (t, 1H,
J = 10.0 Hz, H-4), 4.83 (d, 1H, J = 1.4 Hz, H-1), 4.21 (dd, 1H, J = 6.1,
12.2 Hz, H-6), 4.13ꢀ4.17 (m, 2H, H-2, H-6), 3.80 (dd, 1H, J = 3.7, 10.0
Hz, H-3), 3.60 (ddd, 1H, J = 2.8, 6.0, 9.6 Hz, H-5), 2.13 (s, 3H, CH3 Ac),
2.08 (s, 3H, CH3 Ac); 13C-APT NMR (CDCl3, 100 MHz, HSQC)
δ 170.0, 169.2 (CdO Ac), 132.9 (Cq SPh), 131.1, 128.8, 127.7 (CHarom),
86.1 (C-1), 76.3 (C-5), 66.8 (C-4), 64.0 (C-2), 63.8 (C-3), 62.2 (C-6),
Three different 2,3-diazido-2,3-dideoxy mannosylating agents
were evaluated for their potential to provide β-mannosidic bonds:
the 4,6-di-O-acetyl- and 4,6-O-benzylidene-2,3-diazido-2,3-dideoxy
mannopyranosyl donors proved to be rather unselective or slightly
R-selective. In contrast, 2,3-diazido-2,3-dideoxy mannuronic acid
esters provided the desired β-linked product with good selectivity.
The observed differences in stereochemical outcome suggest that
different mechanistic pathways take place: the 4,6-di-O-acetyl-
and 4,6-O-benzylidene systems react through an R-selective 4H3-
oxacarbenium ion-type intermediate (or corresponding transition
state), while the reactions of the mannuronate donors involve a
3
transition state with H4 oxacarbenium ion-like character. The
profitable β-mannosylating properties of the diazido mannuro-
nates were exploited in the stereoselective synthesis of an all-cis-
linked Bacillus stearothermophilus tetrasaccharide, featuring two
β-mannuronic acid linkages. It is expected that the methodology
described here can be readily applied in the synthesis of diamino
mannuronic acid containing polysaccharides of different bacteria,31
such as Bordetella pertussis, Pseudomonas aeruginosa, and Neisseria
meningitides. Current research is aimed at further unravelling the
reaction mechanism(s) underlying the β-selectivity and reactiv-
ity of mannuronic acids.
20.2, 20.2 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 86.1 (JC1,H1
=
155 Hz, C-1); HRMS [M + NH4]+ calcd for C16H22N7O5S 424.13976,
found 424.13984.
Phenyl 2,3-diazido-4,6-O-benzylidene-2,3-dideoxy-1-thio-
β-D-mannopyranoside (7). To a solution of compound 15β (0.38 g,
1.18 mmol) in dry acetonitrile (9 mL) were added PhCH(OMe)2
(0.33 mL, 2.2 mmol) and p-TsOH (cat). The resulting solution was
stirred overnight at rt, followed by the addition of Et3N until pH was
almost neutral. EtOAc was added, and the solution was washed with
saturated aqueous NaCl (2ꢁ), dried over Na2SO4, and concentrated
in vacuo. The title compound was obtained by crystallization from
EtOAc/PE as white fluffy crystals (0.33 g, 0.81 mmol, 69%): TLC Rf
0.52 (PE/EtOAc, 4/1, v/v); [R]20D +34.4 (c 1, DCM); melting point =
178ꢀ180 °C; IR (neat, cmꢀ1) 696, 978, 1078, 1096, 1263, 2099, 2151;
1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.44ꢀ7.53 (m,
4H, CHarom), 7.31ꢀ7.42 (m, 6H, CHarom), 5.66 (s, 1H, CH Ph), 4.90
(s, 1H, H-1), 4.35 (dd, 1H, J = 4.9, 10.6 Hz, H-6), 4.09ꢀ4.20 (m, 2H,
H-2, H-4), 3.87ꢀ3.96 (m, 2H, H-3, H-6), 3.47 (dt, 1H, J = 4.9, 9.5, 9.7 Hz,
H-5); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 136.6 (Cq Ph),
133.2 (Cq SPh), 132.0, 129.3, 129.1, 128.3, 125.8 (CHarom), 101.6 (CH Ph),
87.5 (C-1), 76.9 (C-4), 72.0 (C-5), 68.3 (C-6), 64.9 (C-2), 63.1 (C-3);
13C-GATED (CDCl3, 100 MHz) δ 87.5 (JC1,H1 = 157 Hz, C-1); HRMS
[M + H]+ calcd for C19H19N6O3S 411.12339, found 411.12343.
Methyl (Phenyl 4-O-acetyl-2,3-diazido-2,3-dideoxy-1-thio-
R-D-mannopyranosyl uronate) (8r). Compound 16r (0.24 g,
0.69 mmol) was treated with Ac2O/pyridine (6 mL, 1/3, v/v) until TLC
analysis indicated complete consumption of the starting material.
’ EXPERIMENTAL SECTION
General Procedure for the Low-Temperature NMR Experi-
ments. A mixture of the donor (30 μmol) and Ph2SO (39 μmol)20 was
coevaporated with toluene (2ꢁ). The residue was dissolved in DCM-d2
(0.6 mL) and transferred to an NMR tube under an argon atmosphere.
The tube was stoppered and sealed. The NMR magnet was cooled to
ꢀ80 °C, locked, and shimmed. In an acetone bath (ꢀ80 °C), the sample
was treated with Tf2O (39 μmol), shaken three times, and placed back in
1
the NMR magnet. The first H spectrum was immediately recorded.
Further temperature changes were executed depending on the spectra
recorded but always with multiples of 10 °C.
General Procedure for the Ph2SO/Tf2O-Mediated Glyco-
sylations. A mixture of the donor (1 equiv), Ph2SO (1.3 equiv), and
TTBP (2.5 equiv) was coevaporated twice with toluene. While the mixture
was under an argon atmosphere, freshly distilled DCM (0.05 M) was
added, followed by the addition of activated molecular sieves (3 Å). The
resulting mixture was stirred for 30 min at room temperature and cooled
to the activation temperature. Tf2O (1.3 equiv) was added in one portion,
and the activation progress was monitored by TLC analysis. In the case
of uronic acid donor 8β, the temperature was raised to ꢀ60 °C in 20 min
and cooled back to ꢀ80 °C. Then a solution of the acceptor (0.3ꢀ0.5 M
in DCM) was slowly added via the wall of the flask. The mixture was
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FEATURED ARTICLE
The mixture was diluted with EtOAc, washed with H2O and saturated
aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. Purifica-
tion using flash column chromatography (silica gel, 25% EtOAc in PE)
yielded the title compound as yellowish oil (0.25 g, 0.62 mmol, 91%):
were in accord with those previously reported:33 TLC Rf 0.56 (PE/
EtOAc, 2/3, v/v); 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.47ꢀ7.52 (m, 2H, CHarom), 7.35ꢀ7.40 (m, 3H, CHarom), 5.57 (s, 1H,
CH Ph), 4.89 (d, 1H, J = 2.8 Hz, H-1), 4.24 (dd, 1H, J = 5.0, 10.2 Hz,
H-6), 4.05ꢀ4.12 (m, 1H, H-5), 3.95 (dd, 1H, J = 1.0, 9.1 Hz, H-4), 3.68
(t, 1H, J = 10.3 Hz, H-6), 3.52 (d, 1H, J = 4.3 Hz, H-3), 3.49 (dd, 1H, J =
2.8, 4.3 Hz, H-2), 3.47 (s, 3H, OMe); 13C-APT NMR (CDCl3, 100 MHz,
HSQC) δ 137.1 (Cq Ph), 129.2, 128.3, 126.3 (CHarom), 102.7 (CH Ph),
95.3 (C-1), 77.9(C-4),68.9(C-6), 60.0(C-5), 55.8(OMe), 53.1(C-2), 50.7
(C-3); HRMS [M + H]+ calcd for C14H17O5 265.10705, found 265.10718.
Methyl 2-Azido-4,6-O-benzylidene-2-deoxy-R-D-altropyr-
anoside (12). Compound 11 (13.6 g, 52 mmol) was dissolved in
DMSO (260 mL), followed by the addition of NaN3 (10.1 g, 155 mmol)
and NH4Cl (24.9 g, 466 mmol). The mixture was heated overnight at
80 °C and subsequently diluted with EtOAc, washed with saturated
aqueous NaCl (3ꢁ), dried over Na2SO4, and concentrated in vacuo.
Purification using flash column chromatography (silica gel, 50% EtOAc
in PE) yielded the title compound as a colorless oil (14.8 g, 48.4 mmol,
93%): TLC Rf 0.51 (PE/EtOAc, 2/3, v/v); [R]20D +68.9 (c 1, DCM); IR
TLC Rf 0.43 (PE/EtOAc, 3/1, v/v); [R]20 +70.6 (c 1, DCM); IR
D
(neat, cmꢀ1) 748, 1049, 1211, 1751, 2106; 1H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 7.53ꢀ7.58 (m, 2H, CHarom), 7.30ꢀ7.36
(m, 3H, CHarom), 5.55 (d, 1H, J = 5.1 Hz, H-1), 5.42 (t, 1H, J = 6.8 Hz,
H-4), 4.65 (d, 1H, J = 6.5 Hz, H-5), 4.06 (dd, 1H, J = 3.4, 7.4 Hz, H-3),
4.00 (dd, 1H, J = 3.6, 4.9 Hz, H-2), 3.76 (s, 3H, CH3 CO2Me), 2.12 (s,
3H, CH3 Ac); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 169.1,
167.3 (CdO Ac, CO2Me), 131.9 (CHarom), 131.5 (Cq SPh) 129.0, 128.1
(CHarom), 83.8 (C-1), 71.3 (C-5), 68.4 (C-4), 60.7 (C-2), 60.1 (C-3),
52.6 (CH3 CO2Me), 20.4 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz)
δ 83.8 (JC1,H1 = 168 Hz, C-1); HRMS [M + Na]+ calcd for C15H16N6O5SNa
415.07951, found 415.07942.
Methyl (Phenyl 4-O-acetyl-2,3-diazido-2,3-dideoxy-1-thio-
β-D-mannopyranosyl uronate) (8β). Compound 16β (0.26 g,
0.74 mmol) was treated with Ac2O/pyridine (6 mL, 1/3, v/v) until TLC
analysis indicated complete consumption of the starting material. The
mixture was diluted with EtOAc, washed with H2O and saturated
aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. Purifica-
tion using flash column chromatography (silica gel, 50% EtOAc in PE)
yielded the title compound as a yellowish solid (0.29 g, 0.74 mmol,
quant.): TLC Rf 0.31 (PE/EtOAc, 3/1, v/v); [R]20D +19.8 (c 1, DCM);
IR (neat, cmꢀ1) 1049, 1219, 1751, 2106; 1H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 7.44ꢀ7.48 (m, 2H, CHarom), 7.26ꢀ7.32
(m, 3H, CHarom), 5.33 (t, 1H, J = 10.0 Hz, H-4), 5.00 (d, 1H, J = 1.3 Hz,
H-1), 4.26 (dd, 1H, J = 1.1, 3.6 Hz, H-2), 4.05 (dd, 1H, J = 3.4, 10.3 Hz,
H-3), 4.03 (d, 1H, J = 9.9 Hz, H-5), 3.69 (s, 3H, CH3 CO2Me), 2.06
(s, 3H, CH3 Ac); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 169.2,
166.7 (CdO Ac, CO2Me), 132.8 (Cq SPh), 131.4, 129.0, 128.0 (CHarom),
86.6 (C-1), 76.3 (C-5), 67.6 (C-4), 64.0 (C-2), 63.4 (C-3), 52.6 (CH3
CO2Me), 20.2 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 86.6
(JC1,H1 = 156 Hz, C-1); HRMS [M + NH4]+ calcd for C15H20N7O5S
410.12411, found 410.12400.
Methyl 4,6-O-Benzylidene-2,3-di-O-methanesulfonyl-
R-D-glucopyranoside (10). Compound 914 (17.4 g, 61.7 mmol) was
dissolved in pyridine (123 mL), and methanesulfonyl chloride (14.4 mL,
186 mmol) was dropwise added. The mixture was stirred overnight and
subsequently diluted with EtOAc and H2O. The layers were separated,
and the organic fraction was washed with saturated aqueous NaCl (2ꢁ),
dried over Na2SO4, and concentrated in vacuo. Crude compound 10 was
used in the next reaction step without further purification. A fraction was
crystallized for analytical purposes. Spectroscopic data were in accord
with those previously reported:32 TLC Rf 0.74 (DCM/acetone, 10/1, v/v);
1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.41ꢀ7.48 (m,
2H, CHarom), 7.35ꢀ7.40 (m, 3H, CHarom), 5.56 (s, 1H, CH Ph), 5.09
(t, 1H, J = 9.6 Hz, H-3), 5.03 (d, 1H, J = 3.7 Hz, H-1), 4.63 (dd, 1H, J =
3.7, 9.6 Hz, H-2), 4.34 (dd, 1H, J = 4.8, 10.4 Hz, H-6), 3.94 (td, 1H, J = 4.8,
9.8, 9.9 Hz, H-5), 3.79 (t, 1H, J = 10.4 Hz, H-6), 3.74 (t, 1H, J = 9.5 Hz,
H-4), 3.49 (s, 3H, OMe), 3.17 (s, 3H, CH3 Ms), 2.97 (s, 3H, CH3 Ms);
13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 136.2 (Cq Ph), 129.5, 128.4,
126.0 (CHarom), 101.9 (CH Ph), 98.78 (C-1), 78.9 (C-4), 77.1 (C-3), 75.8
(C-2), 68.6 (C-6), 62.2 (C-5), 56.0 (OMe), 38.9, 38.7 (CH3 Ms); HRMS
[M + Na]+ calcd for C16H22O10S2Na 461.05466, found 461.05430.
Methyl 2,3-Anhydro-4,6-O-benzylidene-R-D-allopyranoside
(11). Crude compound 10 (∼62 mmol) was dissolved in THF/MeOH
(500 mL, 2/3, v/v) followed by the addition of KOH (10.5 g, 187 mmol).
The mixture was refluxed at 70 °C overnight. Then H2O was added, the
mixture diluted with EtOAc, and the organic fraction was separated and
washed with H2O (3ꢁ), dried over Na2SO4, and concentrated in vacuo.
Crystallization (EtOAc/PE) yielded the title compound as a white fluffy
solid (10.2 g, 39.5 mmol, 62% over two steps). Spectroscopic data
1
(neat, cmꢀ1) 1042, 1242, 1736, 2106; H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 7.45ꢀ7.51 (m, 2H, CHarom), 7.29ꢀ7.38 (m,
3H, CHarom), 5.57 (s, 1H, CH Ph), 4.63 (s, 1H, H-1), 4.28 (dd, 1H, J = 5.2,
10.2 Hz, H-6), 4.16 (td, 1H, J = 5.2, 10.0, 10.0 Hz, H-5), 4.03 (s, 1H,
H-3), 3.76ꢀ3.81 (m, 2H, H-2, H-4), 3.75 (t, 1H, J = 10.3 Hz, H-6), 3.37
(s, 3H, OMe), 3.14 (bs, 1H, 3-OH); 13C-APT NMR (CDCl3, 100 MHz,
HSQC) δ 136.9 (Cq Ph), 128.9, 128.0, 126.0 (CHarom), 101.9 (CH Ph),
99.1 (C-1), 75.7 (C-4), 68.7 (C-6), 67.1 (C-3), 61.6 (C-2), 57.8 (C-5), 55.5
(OMe); 13C-GATED (CDCl3, 100 MHz) δ 99.1 (JC1,H1 = 171 Hz, C-1);
HRMS [M + H]+ calcd for C14H18N3O5 308.12410, found 308.12414.
Methyl 2,3-Diazido-4,6-O-benzylidene-2,3-dideoxy-R-
D-mannopyranoside (13). A solution of compound 12 (14.85 g,
48.4 mmol) in DCE (340 mL) was treated with pyridine (91 mL, 1.13 mol)
and Tf2O (18.9 mL, 112.5 mmol). The reaction was stirred for 30 min,
followed by the addition of H2O to quench. The mixture was diluted with
DCM, washed with H2O (3ꢁ), dried over Na2SO4, and concen-
trated in the presence of toluene (2ꢁ). The crude triflate (∼48 mmol)
was dissolved in DMF (110 mL). NaN3 (18.7 g, 288 mmol) and NH4Cl
(9.0 g, 168 mmol) were added, and the mixture was heated overnight at
80 °C. EtOAc and H2O were added, and the layers were separated. The
organic phase was washed with H2O (2ꢁ), dried over Na2SO4, and
concentrated in vacuo. Purification using column chromatography (silica
gel, 50% EtOAc in PE) furnished the title compound as a white amorphous
solid (12.1 g, 36.3 mmol, 75%): TLC Rf 0.75 (PE/EtOAc, 4/1, v/v);
[R]20D +94.0 (c 1, DCM); IR (neat, cmꢀ1) 1041, 1735, 2106, 2931; 1H
NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.47ꢀ7.52 (m, 2H,
CHarom), 7.35ꢀ7.41 (m, 3H, CHarom), 5.65 (s, 1H, CH Ph), 4.71 (d, 1H, J
= 1.4 Hz, H-1), 4.29 (dd, 1H, J = 10.6, 16.2 Hz, H-6), 4.14 (dd, 1H, J = 3.6,
10.2 Hz, H-3), 4.05 (dt, 1H, J = 1.6, 10.2 Hz, H-4), 3.90 (dd, 1H, J = 1.4, 3.6
Hz, H-2), 3.82ꢀ3.85 (m, 2H, H-5, H-6), 3.40 (s, 3H, OMe); 13C-APT
NMR (CDCl3, 100 MHz, HSQC) δ 136.8 (Cq), 129.0, 128.3, 125.8
(CHarom), 101.6 (CH Ph), 99.3 (C-1), 77.5 (C-4), 68.7 (C-6), 63.8 (C-5),
62.7 (C-2), 59.2 (C-3), 55.2 (OMe); HRMS [M + H]+ calcd for
C14H17N6O4 333.13058, found 333.13036.
Acetyl 4,6-Di-O-acetyl-2,3-diazido-2,3-dideoxy-R/β-
D-mannopyranoside (14). Compound 13 (20.7 mmol) was dis-
solved in Ac2O (35 mL) and treated with H2SO4 (0.3 mL) at 0 °C for 2
h. The mixture was diluted with EtOAc and quenched with saturated
aqueous NaHCO3. The organic fraction was washed with H2O and
saturated aqueous NaCl (2ꢁ). Purification using flash column chroma-
tography (silica gel, 50% EtOAc in PE) furnished the title compound as a
brownish oil (7.3 g, 20.5 mmol, 98%, R/β= 5:1): TLC Rf 0.45 (PE/EtOAc,
1/1, v/v); IR (neat, cmꢀ1) 1211, 1735, 2106; 1H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 6.12 (d, 1H, J = 1.6 Hz, H-1R), 5.85 (d, 0.2H, J=
0.9 Hz, H-1β), 5.33 (t, 1H, J = 10.1 Hz, H-4R), 5.21 (t, 0.2H, J = 9.9 Hz,
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H-4β), 4.22ꢀ4.27 (m, 0.2H, H-6β), 4.20 (dd, 1H, J = 4.6, 12.5 Hz,
H-6R), 4.11 (d, 0.2H, J = 2.3 Hz, H-2β), 4.07ꢀ4.14 (m, 1.2H, H-6R,
H-6β), 4.05ꢀ4.07 (m, 1H, H-3R), 3.95ꢀ4.00 (m, 2H, H-2R, H-5R),
3.73ꢀ3.80 (m, 0.4H, H-3β, H-5β), 2.20 (s, 0.6H, CH3 Ac-β), 2.17
(s, 3H, CH3 Ac-R), 2.15 (s, 3H, CH3 Ac-R), 2.13 (s, 0.6H, CH3 Ac-β),
2.09 (s, 3H, CH3 Ac-R); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ
170.3, 169.1, 169.1, 168.1, 167.9 (CdO Ac), 91.5 (C-1β), 90.6 (C-1R),
73.5 (C-5β), 70.4 (C-5R), 66.2 (C-4R), 65.7 (C-4β), 61.7 (C-2β), 61.5
(C-6R, C-6β), 61.3 (C-3β), 60.9 (C-2R), 59.8 (C-3R), 20.5, 20.4, 20.3,
(d, 1H, J=1.3Hz, H-1), 4.71(d, 1H, J=9.1Hz, H-5), 4.26(t, 1H,J=9.0Hz,
H-4), 4.09 (s, 1H, H-2), 3.91 (dd, 1H, J = 3.4, 9.4 Hz, H-3), 3.81 (s, 3H,
CH3 CO2Me), 3.68 (d, 1H, J = 1.9 Hz, 4-OH); 13C-APT NMR (CDCl3,
100 MHz, HSQC) δ 170.0 (CdO CO2Me), 132.1 (Cq SPh), 132.0,
129.2, 128.3 (CHarom), 86.2 (C-1), 71.6 (C-5), 68.2 (C-4), 62.7 (C-2),
61.7 (C-3), 52.9 (CH3 CO2Me); 13C-GATED (CDCl3, 100 MHz) δ 86.2
(JC1,H1 = 169 Hz, C-1); HRMS [M + NH4]+ calcd for C13H18N7O4S
368.11355, found 368.11356.
Methyl (Phenyl 2,3-diazido-2,3-dideoxy-1-thio-β-D-
mannopyranosyl uronate) (16β). Diol 15β (0.51 g, 1.58 mmol)
was dissolved in EtOAc (6 mL), and H2O (3 mL) was added. The mixture
was cooled to 0 °C, followed by the addition of TEMPO (50 mg, 0.32 mmol)
and BAIB (1.27 g, 3.95 mmol). The resulting emulsion was stirred at rt
for 1 h. The reaction was quenched by the addition of saturated aqueous
Na2S2O3, and the organic layer was washed with saturated aqueous
NaCl (2ꢁ), dried over MgSO4, and concentrated in vacuo. The crude
product was dissolved in dry DMF (9 mL) and treated with MeI
(0.3 mL, 4.74 mmol) and K2CO3 (0.66 g, 4.74 mmol) at rt overnight.
The mixture was diluted with EtOAc and H2O, and the organic layer was
washed with saturated aqueous NaCl (2ꢁ), dried over MgSO4, and
concentrated in vacuo. Purification using flash column chromatography
(silica gel, 33% EtOAc in PE) gave the title compound as an off-white
solid (0.50 g, 1.43 mmol, 91%): TLC Rf 0.29 (PE/EtOAc, 2/1, v/v);
20.3, 20.3 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 91.5 (JC1,H1
=
162 Hz, C-1β), 90.6 (JC1,H1 = 175 Hz, C-1R); HRMS [M + Na]+ calcd
for C12H16N6O7Na 379.09727, found 379.09719.
Phenyl 2,3-Diazido-2,3-dideoxy-1-thio-r-D-mannopyranoside
(15r). Compound 6r (0.78 g, 2.0 mmol) was suspended in MeOH
(10 mL) and treated with NaOMe (39 mg, 0.72 mmol) for 2 h. The
mixture was neutralized by the addition of Amberlite-H+, filtered, and
reduced in volume. The residue was taken up in EtOAc, washed with
saturated aqueous NaCl (2ꢁ), dried over Na2SO4, and concentrated in
vacuo. The product was obtained as a yellow oil (0.65 g, 2.0 mmol,
quant.): TLC Rf 0.16 (PE/EtOAc, 2/1, v/v); [R]20D +72.1 (c 1, DCM);
1
IR (neat, cmꢀ1) 727, 905, 1065, 2102, 3337; H NMR (CDCl3, 400
MHz, HHꢀCOSY, HSQC) δ 7.42ꢀ7.46 (m, 2H, CHarom), 7.29ꢀ7.35
(m, 3H, CHarom), 5.46 (s, 1H, H-1), 4.36 (bs, 1H, 4-OH), 4.05ꢀ4.15
(m, 3H, H-2, H-4, H-5), 3.86ꢀ3.92 (m, 2H, H-3, H-6), 3.79 (dd, 1H, J =
1.3, 12.3 Hz, H-6), 3.04 (bs, 1H, 6-OH); 13C-APTNMR(CDCl3, 100MHz,
HSQC) δ 132.4 (Cq SPh), 132.1, 129.2, 128.2 (CHarom), 86.1 (C-1),
73.3 (C-4), 66.4 (C-5), 63.8 (C-2), 62.9 (C-3), 61.3 (C-6); 13C-GATED
(CDCl3, 100 MHz) δ 86.1 (JC1,H1 = 168 Hz, C-1); HRMS [M + NH4]+
calcd for C12H18N7O3S 340.11863, found 340.11869.
[R]20 ꢀ13.8 (c 1, DCM); IR (neat, cmꢀ1) 1034, 1265, 1288, 1736,
D
2106, 3741; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.49ꢀ7.55 (m, 2H, CHarom), 7.28ꢀ7.36 (m, 3H, CHarom), 4.84 (s, 1H,
H-1), 4.22 (t, 1H, J = 9.6 Hz, H-4), 4.08 (d, 1H, J = 2.9 Hz, H-2),
3.81ꢀ3.86 (m, 4H, H-5, CH3 CO2Me), 3.72 (dd, 1H, J = 3.5, 9.7 Hz,
H-3), 3.60 (bs, 1H, 4-OH); 13C-APT NMR (CDCl3, 100 MHz, HSQC)
δ 169.2 (CdO CO2Me), 133.1 (Cq SPh), 131.8, 129.1, 128.2 (CHarom),
87.2 (C-1), 77.8 (C-5), 67.7 (C-4), 65.2 (C-3), 63.8 (C-2), 53.0 (CH3
CO2Me); 13C-GATED (CDCl3, 100 MHz) δ 87.2 (JC1,H1 = 155 Hz,
C-1); HRMS [M + Na]+ calcd for C13H14N6O4SNa 373.06894, found
373.06854.
Phenyl 2,3-Diazido-2,3-dideoxy-1-thio-β-D-mannopyranoside
(15β). Compound 6β (3.22 g, 7.93 mmol) was suspended in MeOH
(40 mL) and treated with NaOMe (43 mg, 0.79 mmol) for 1.5 h, after
which time the mixture was neutralized by the addition of Amberlite-H+,
filtered, and concentrated in vacuo. The title compound was obtained
as an off-white fluffy solid (2.50 g, 7.76 mmol, 98%): TLC Rf 0.39
Methyl 6-O-(4,6-Di-O-acetyl-2,3-diazido-2,3-dideoxy-R/
β-D-mannopyranosyl)-2,3,4-tri-O-benzyl-R-D-glucopyra-
noside (23). Donor 6β and acceptor 20 were condensed using the general
protocol for Ph2SO/Tf2O-mediated glycosylations to yield disaccharide 23
(75%, R/β = 1:1). TLC Rf R 0.44, β 0.15 (toluene/EtOAc, 2/3, v/v);
IR (neat, cmꢀ1) 1042, 1227, 1744, 2098, 2924. Spectroscopic data for
(PE/EtOAc, 1/1, v/v); [R]20 +22.7 (c 1, MeOH); IR (neat, cmꢀ1
)
D
1
1074, 2104, 3211, 3366; H NMR (CDCl3, 400 MHz, HHꢀCOSY,
HSQC) δ 7.45ꢀ7.50 (m, 2H, CHarom), 7.30ꢀ7.37 (m, 3H, CHarom),
4.87 (s, 1H, H-1), 4.10 (d, 1H, J = 3.3 Hz, H-2), 4.06 (t, 1H, J = 9.7 Hz,
H-4), 3.90 (dd, 1H, J = 3.2, 12.3 Hz, H-6), 3.84 (dd, 1H, J = 4.0, 12.2 Hz,
H-6), 3.69 (dd, 1H, J = 3.5, 9.9 Hz, H-3), 3.30ꢀ3.36 (m, 1H, H-5), 1.39
(bs, 2H, 4-OH, 6-OH); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ
133.4 (Cq SPh), 131.2, 129.1, 127.9 (CHarom), 86.4 (C-1), 80.9 (C-5),
66.2 (C-3), 65.6 (C-4), 64.7 (C-2), 61.3 (C-6); 13C-GATED (CDCl3,
100 MHz) δ 86.4 (JC1,H1 = 155 Hz, C-1); HRMS [M + Na]+ calcd for
C12H14N6O3SNa 345.07403, found 345.07380.
1
the R-anomer: H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.24ꢀ7.40 (m, 15H, CHarom), 5.22 (t, 1H, J = 10.0 Hz, H-40), 5.02
(d, 1H, J = 10.8 Hz, CHH Bn), 4.98 (d, 1H, J = 11.6 Hz, CHH Bn), 4.89 (d,
1H, J = 1.0 Hz, H-10), 4.80 (d, 1H, J = 10.6 Hz, CHH Bn), 4.80 (d, 1H,
J = 12.5 Hz, CHH Bn), 4.69 (d, 1H, J = 12.1 Hz, CHH Bn), 4.60 (d, 1H,
J = 3.0 Hz, H-1), 4.59 (d, 1H, J = 12.0 Hz, CHH Bn), 3.98ꢀ4.06 (m, 2H,
H-3, H-60), 3.96 (dd, 1H, J = 2.4, 12.4 Hz, H-60), 3.82ꢀ3.90 (m, 3H,
H-20, H-30, H-6), 3.73ꢀ3.78 (m, 2H, H-5, H-50), 3.65 (dd, 1H, J = 1.6,
11.2 Hz, H-6), 3.52 (dd, 1H, J = 3.6, 9.6 Hz, H-2), 3.46 (t, 1H, J = 9.2 Hz,
H-4), 3.38 (s, 3H, OMe), 2.09 (s, 3H, CH3 Ac), 2.02 (s, 3H, CH3 Ac);
13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 170.6, 169.3 (CdO Ac),
138.4, 138.0, 137.9 (Cq Bn), 128.5, 128.4, 128.0, 127.4 (CHarom), 97.9
(C-1), 97.7 (C-10), 82.0 (C-3), 79.9 (C-2), 77.2 (C-4), 75.8, 74.7, 73.3
(CH2 Bn), 69.5, 68.7 (C-5, C-50), 66.8 (C-40), 66.5 (C-6), 62.1 (C-20), 61.9
(C-60), 60.3 (C-30), 55.3 (OMe), 20.6, 20.6 (CH3 Ac); 13C-GATED
(CDCl3, 100 MHz) δ 97.9 (JC1,H1 = 163 Hz, C-1), 97.7 (JC1,H1 = 173 Hz,
C-10). Spectroscopic data for the β-anomer: 1H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 7.25ꢀ7.39 (m, 15H, CHarom), 5.12 (t, 1H, J = 9.9
Hz, H-40), 5.00 (d, 1H, J = 10.9 Hz, CHH Bn), 4.88 (d, 1H, J = 11.6 Hz,
CHH Bn), 4.81 (d, 1H, J = 10.8 Hz, CHH Bn), 4.79 (d, 1H, J = 12.0 Hz,
CHH Bn), 4.64 (d, 1H, J = 12.0 Hz, CHH Bn), 4.59 (d, 1H, J = 11.7 Hz,
CHHBn), 4.56 (d, 1H, J= 3.5 Hz, H-1), 4.33 (s, 1H, H-10),4.20(dd, 1H, J=
5.2, 12.3 Hz, H-60), 4.06ꢀ4.14 (m, 2H, H-6, H-60), 4.02 (t, 1H, J =
9.2 Hz, H-3), 3.83 (ddd, 1H, J= 1.4, 5.7, 9.7 Hz, H-5), 3.71 (d, 1H, J=3.3Hz,
Methyl (Phenyl 2,3-diazido-2,3-deoxy-1-thio-r-D-manno-
pyranosyl uronate) (16r). Diol 15r (0.37 g, 1.15 mmol) was
dissolved in DCM (4 mL), and H2O (2 mL) was added. The mixture was
cooled to 0 °C, followed by the addition of TEMPO (36 mg, 0.23 mmol)
and BAIB (0.93 g, 2.88 mmol). The resulting emulsion was stirred at rt
for 1.5 h. The reaction was quenched by the addition of saturated
aqueous Na2S2O3, and the organic layer was washed with saturated
aqueous NaCl (2ꢁ), dried over MgSO4, and concentrated in vacuo. The
crude product was dissolved in dry DMF (10 mL) and treated with MeI
(0.2 mL, 3.45 mmol) and K2CO3 (0.48 g, 3.45 mmol) at rt overnight.
The mixture was diluted with EtOAc and H2O, and the organic layer was
washed with saturated aqueous NaCl (2ꢁ), dried over MgSO4, and
concentrated in vacuo. Purification using flash column chromatography
(silica gel, 25% EtOAc in PE) gave the title compound as a yellowish
oil (0.29 g, 0.82 mmol, 71%): TLC Rf 0.70 (PE/EtOAc, 1/1, v/v);
[R]20D +86.4 (c 1, DCM); IR (neat, cmꢀ1) 727, 1078, 1250, 1439, 1734,
2102, 3487; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.47ꢀ7.52 (m, 2H, CHarom), 7.28ꢀ7.36 (m, 3H, CHarom), 5.50
7308
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FEATURED ARTICLE
H-20), 3.53 (dd, 1H, J = 5.9, 10.4 Hz, H-6), 3.49 (dd, 1H, J = 3.5, 9.7 Hz,
H-2), 3.43ꢀ3.47 (m, 1H, H-50), 3.35ꢀ3.41 (m, 5H, H-30, H-4, OMe),
2.10 (s, 3H, CH3 Ac), 2.03 (s, 3H, CH3 Ac); 13C-APT NMR (CDCl3,
100 MHz, HSQC) δ 170.7, 169.2 (CdO Ac), 138.6, 138.4, 138.0 (Cq Bn),
128.4, 128.1, 128.0, 127.9, 127.8, 127.6 (CHarom), 100.3 (C-10), 97.9 (C-1),
82.0 (C-3), 79.9 (C-2), 77.3 (C-4), 75.7, 74.5, 73.4 (CH2 Bn), 73.0 (C-50),
69.5 (C-5), 68.8 (C-6), 66.7 (C-40), 62.5 (C-20), 62.3 (C-60), 61.4 (C-30),
55.2 (OMe), 20.7, 20.6 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz)
δ 100.3 (JC1,H1 = 156 Hz, C-10), 97.9 (JC1,H1 = 162 Hz, C-1); HRMS
[M + Na]+ calcd for C38H44N6O11Na 783.29603, found 783.29585.
Methyl 4-O-(4,6-Di-O-acetyl-2,3-diazido-2,3-dideoxy-R/
β-D-mannopyranosyl)-2,3,6-tri-O-benzyl-R-D-glucopyrano-
side (24). Donor 6β and acceptor 21 were condensed using the general
protocol for Ph2SO/Tf2O-mediated glycosylations to yield disaccharide
24 (45%, R/β = 2:1). TLC Rf 0.24, 0.38 (PE/EtOAc, 2/1, v/v); IR
(neat, cmꢀ1) 1042, 1234, 1744, 2106, 2924. Spectroscopic data for the
R-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.25ꢀ7.41 (m, 15H, CHarom), 5.19 (t, 1H, J = 10.0 Hz, H-40), 5.15
(d, 1H, J = 1.7 Hz, H-10), 5.11 (d, 1H, J = 11.5 Hz, CHH Bn), 4.74 (d,
1H, J = 12.0 Hz, CHH Bn), 4.58ꢀ4.65 (m, 4H, CH2 Bn, H-1), 4.51
(d, 1H, J = 12.0 Hz, CHH Bn), 4.03 (dd, 1H, J = 4.6, 12.3 Hz, H-60), 3.92
(t, 1H, J = 9.1 Hz, H-3), 3.77ꢀ3.87 (m, 3H, H-30, H-50, H-60), 3.73ꢀ3.77
(m, 1H, H-5), 3.71 (t, 1H, J = 8.7 Hz, H-4), 3.65ꢀ3.68 (m, 2H, H-6),
3.55 (dd, 1H, J = 3.5, 9.6 Hz, H-2), 3.50 (dd, 1H, J = 1.9, 3.3 Hz, H-20),
3.41 (s, 3H, OMe), 2.10 (s, 3H, CH3 Ac), 2.03 (s, 3H, CH3 Ac); 13C-APT
NMR (CDCl3, 100 MHz, HSQC) δ 170.6, 169.3 (CdO Ac), 138.0,
137.8, 137.6 (Cq Bn), 128.7, 128.5, 128.4, 128.1, 128.0, 127.7, 127.5
(CHarom), 99.5 (C-10), 97.7 (C-1), 80.9 (C-3), 80.3 (C-2), 77.8 (C-4),
75.5, 73.5, 73.2 (CH2 Bn), 69.5, 69.4 (C-5, C-50), 69.0 (C-6), 67.0
(C-40), 62.1 (C-60), 62.0 (C-20), 60.3 (C-30), 55.4 (OMe), 20.7, 20.6
(CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 99.5 (JC1,H1 = 171 Hz,
C-10), 97.7 (JC1,H1 = 163 Hz, C-1). Spectroscopic data for the β-anomer:
1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.26ꢀ7.42 (m,
15H, CHarom), 5.06 (t, 1H, J = 10.0 Hz, H-40), 4.99 (d, 1H, J = 11.3 Hz,
CHH Bn), 4.86 (d, 1H, J = 11.3 Hz, CHH Bn), 4.77 (d, 1H, J = 12.3 Hz,
CHH Bn), 4.74 (d, 1H, J = 13.2 Hz, CHH Bn), 4.58ꢀ4.63 (m, 2H, CHH
Bn, H-1), 4.54 (d, 1H, J = 1.1 Hz, H-10), 4.39 (d, 1H, J = 12.1 Hz, CHH
Bn), 4.02 (dd, 1H, J = 4.3, 12.4 Hz, H-60), 3.91 (t, 1H, J = 8.8 Hz, H-3),
3.89 (t, 1H, J = 8.8 Hz, H-4), 3.80 (dd, 1H, J = 2.6, 12.4 Hz, H-60),
3.72ꢀ3.77 (m, 2H, H-5, H-6), 3.61ꢀ3.65 (m, 1H, H-6), 3.51 (dd, 1H, J =
3.6, 9.1 Hz, H-2), 3.38 (s, 3H, OMe), 3.37 (dd, 1H, J = 0.7, 3.4 Hz, H-20),
3.16 (ddd, 1H, J = 2.6, 4.2, 9.7 Hz, H-50), 2.94 (dd, 1H, J = 3.5, 10.2 Hz,
H-30), 2.08 (s, 3H, CH3 Ac), 1.97 (s, 3H, CH3 Ac); 13C-APT NMR
(CDCl3, 100 MHz, HSQC) δ 170.6, 169.1 (CdO Ac), 139.2, 128.0,
137.5 (Cq Bn), 128.7, 128.6, 128.4, 128.2, 128.1, 127.9, 127.3 (CHarom),
100.1 (C-10), 98.2 (C-1), 80.0 (C-3), 79.2 (C-2), 77.7 (C-4), 74.9, 73.7,
73.4 (CH2 Bn), 72.9 (C-50), 69.3 (C-5), 68.1 (C-6), 66.2 (C-40), 62.6
(C-20), 61.8 (C-60), 61.5 (C-30), 55.4 (OMe), 20.7, 20.6 (CH3 Ac);
13C-GATED (CDCl3, 100 MHz) δ 100.1 (JC1,H1 = 155 Hz, C-10), 98.2
(JC1,H1 = 164 Hz, C-1); HRMS [M + Na]+ calcd for C38H44N6O11Na
783.29603, found 783.29586.
4.30 (d, 1H, J = 3.5 Hz, H-4), 4.02ꢀ4.11 (m, 3H, H-2, H-50, H-6), 3.94
(dd, 1H, J = 2.4, 12.6 Hz, H-60), 3.82ꢀ3.92 (m, 4H, H-20, H-3, H-30,
H-60), 3.77 (s, 3H, OMe), 3.47 (s, 1H, H-5), 2.06 (s, 3H, CH3 Ac), 2.03
(s, 3H, CH3 Ac); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 170.6,
169.3 (CdO Ac), 155.5, 151.3, 138.0, 137.4 (Cq Ph, Bn), 129.2, 128.4,
128.2, 128.1, 127.9, 126.3, 118.8, 114.5 (CHarom), 103.4 (C-1), 101.1
(CH Ph), 93.2 (C-10), 76.2 (C-2), 75.1 (CH2 Bn), 74.0 (C-3), 71.1 (C-4),
69.1 (C-6), 68.6 (C-50), 66.6 (C-40), 66.2 (C-5), 62.0 (C-20), 61.5 (C-60),
60.5 (C-30), 55.6 (OMe), 20.7, 20.6 (CH3 Ac); 13C-GATED (CDCl3,
100 MHz) δ 103.4 (JC1,H1 = 159 Hz, C-1), 93.2 (JC1,H1 = 171 Hz, C-10);
HRMS [M + Na]+ calcd for C37H40N6O12Na 783.25964, found 783.25923.
Methyl 6-O-(2,3-Diazido-4,6-O-benzylidene-2,3-dideoxy-
R/β-D-mannopyranosyl)-2,3,4-tri-O-benzyl-R-D-glucopyra-
noside (26). Donor 7 and acceptor 20 were condensed using the
general protocol for Ph2SO/Tf2O-mediated glycosylations to yield dis-
accharide 26 (79%, R/β = 3:1). TLC Rf 0.65 (PE/EtOAc, 2/1, v/v);
IR (neat, cmꢀ1) 698, 743, 1030, 1067, 1072, 2106. Spectroscopic data
for the R-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.43ꢀ7.49 (m, 2H, CHarom), 7.25ꢀ7.40 (m, 18H, CHarom), 5.62 (s, 1H,
CH Ph), 5.01 (d, 1H, J = 10.8 Hz, CHH Bn), 4.95 (d, 1H, J = 11.1 Hz,
CHH Bn), 4.77ꢀ4.84 (m, 3H, CH2 Bn, H-10), 4.68 (d, 1H, J = 12.1 Hz,
CHH Bn), 4.60 (d, 1H, J = 11.1 Hz, CHH Bn), 4.59 (d, 1H, J = 3.5 Hz,
H-1), 4.17 (dd, 1H, J = 3.2, 8.8 Hz, H-60), 3.98ꢀ4.05 (m, 3H, H-3, H-30,
H-40), 3.85 (d, 1H, J = 2.8 Hz, H-20), 3.71ꢀ3.83 (m, 4H, H-5, H-50, H-6,
H-60), 3.63 (dd, 1H, J = 1.5, 11.3 Hz, H-6), 3.52 (dd, 1H, J = 3.5, 9.6 Hz,
H-2), 3.46 (t, 1H, J = 9.4 Hz, H-4), 3.37 (s, 3H, OMe); 13C-APT NMR
(CDCl3, 100 MHz, HSQC) δ 138.5, 137.9, 137.8, 136.8 (Cq), 129.0,
128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 125.8 (CHarom), 101.6
(CH Ph), 98.6 (C-10), 97.9 (C-1), 82.0 (C-3), 79.9 (C-2), 77.5 (C-40),
77.1 (C-4), 75.7, 74.9, 73.3 (CH2 Bn), 69.6 (C-5), 68.5 (C-60), 66.5 (C-6),
64.1 (C-50), 62.6 (C-20), 59.1 (C-30), 55.3 (OMe); 13C-GATED
(CDCl3, 100 MHz) δ 98.6 (JC1,H1 = 174 Hz, C-10), 97.9 (JC1,H1
=
171 Hz, C-1); HRMS [M + NH4]+ calcd for C41H48N7O9 782.35080,
found 782.35125.
Methyl 4-O-(2,3-Diazido-4,6-O-benzylidene-2,3-dideoxy-
R/β-D-mannopyranosyl)-2,3,6-tri-O-benzyl-R-D-glucopyra-
noside (27). Donor 7 and acceptor 21 were condensed using the
general protocol for Ph2SO/Tf2O-mediated glycosylations to yield dis-
accharide 27 (66%, R/β = 5:1). TLC Rf 0.40 (PE/EtOAc, 3/1, v/v);
IR (neat, cmꢀ1) 698, 737, 1028, 1047, 1096, 2106, 2928. Spectroscopic
data for the R-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.44ꢀ7.49 (m, 2H, CHarom), 7.23ꢀ7.41 (m, 18H, CHarom), 5.59 (s, 1H,
CH Ph), 5.16 (s, 1H, H-10), 5.11 (d, 1H, J = 11.4 Hz, CHH Bn), 4.74
(d, 1H, J = 12.1 Hz, CHH Bn), 4.60ꢀ4.68 (m, 3H, CHH Bn, CHH Bn,
H-1), 4.57 (d, 1H, J = 12.0 Hz, CHH Bn), 4.52 (d, 1H, J = 11.9 Hz, CHH
Bn), 4.05 (dd, 1H, J = 4.7, 10.3 Hz, H-60), 3.98ꢀ4.01 (m, 2H, H-30,
H-40), 3.94 (t, 1H, J = 9.1 Hz, H-3), 3.80ꢀ3.86 (m, 1H, H-50), 3.79
(t, 1H, J = 9.2 Hz, H-4), 3.63ꢀ3.74 (m, 4H, H-5, H-6, H-6, H-60),
3.53ꢀ3.58 (m, 2H, H-2, H-20), 3.39 (s, 3H, OMe); 13C-APT NMR
(CDCl3, 100 MHz, HSQC) δ138.1, 137.7, 136.9 (Cq), 129.0, 128.9, 128.8,
128.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.6, 127.0, 125.8 (CHarom),
101.6 (CH Ph), 100.0 (C-10), 97.7 (C-1), 81.2 (C-3), 80.3 (C-2), 77.3
(C-40), 76.7 (C-4), 75.5, 73.6, 73.2 (CH2 Bn), 69.4 (C-5), 68.8, 68.5 (C-6,
C-60), 64.8 (C-50), 62.6 (C-20), 59.2 (C-30), 55.4 (OMe); 13C-GATED
(CDCl3, 100MHz) δ100.0 (JC1,H1 =176Hz,C-10), 97.7(JC1,H1 =167Hz);
HRMS [M + NH4]+ calcd for C41H48N7O9 782.35080, found 782.35123.
p-Methoxyphenyl 3-O-(2,3-Diazido-4,6-O-benzylidene-
2,3-dideoxy-R/β-D-mannopyranosyl)-2-O-benzyl-4,6-O-
benzylidene-β-D-galactopyranoside (28). Donor 7 and ac-
ceptor 22 were condensed using the general protocol for Ph2SO/Tf2O-
mediated glycosylations to yield disaccharide 28 (81%, R/β = 1:1):
TLC Rf 0.44 (PE/EtOAc, 2/1, v/v); IR (neat, cmꢀ1) 696, 729,
1057, 1078, 1219, 1506, 2104; 1H NMR (CDCl3, 400 MHz,
HHꢀCOSY, HSQC) δ 7.51ꢀ7.60 (m, 4H, CHarom), 7.32ꢀ7.48
p-Methoxyphenyl 3-O-(4,6-di-O-acetyl-2,3-diazido-2,
3-dideoxy-R/β-D-mannopyranosyl)-2-O-benzyl-4,6-O-benzyli-
dene-β-D-galactopyranoside (25). Donor 6β and acceptor 22
were condensed using the general protocol for Ph2SO/Tf2O-mediated
glycosylations to yield disaccharide 25 (66%, R/β = 2.5:1). TLC Rf
R 0.75, β 0.50 (toluene/EtOAc, 1/1, v/v); IR (neat, cmꢀ1) 1049, 1219,
1504 1744, 2106, 2924, 3742. Spectroscopic data for the R-anomer: 1H
NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.52ꢀ7.56 (m, 2H,
CHarom), 7.39ꢀ7.43 (m, 3H, CHarom), 7.30ꢀ7.36 (m, 5H, CHarom),
7.06 (d, 2H, J = 9.1 Hz, CHarom), 6.83 (d, 1H, J = 9.1 Hz, CHarom), 5.57
(s, 1H, CH Ph), 5.24 (t, 1H, J = 10.1 Hz, H-40), 5.08 (d, 1H, J = 11.0 Hz,
CHH Bn), 5.02 (d, 1H, J = 1.1 Hz, H-10), 4.90 (d, 1H, J = 7.7 Hz, H-1),
4.73 (d, 1H, J = 11.1 Hz, CHH Bn), 4.37 (dd, 1H, J = 1.2, 12.4 Hz, H-6),
7309
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The Journal of Organic Chemistry
FEATURED ARTICLE
(m, 26H, CHarom), 7.06 (d, 4H, J = 9.0 Hz, CHarom), 6.80ꢀ6.85
(m, 4H, CHarom), 5.61 (s, 1H, CH Ph-R), 5.59 (s, 1H, CH Ph-β),
5.56 (s, 1H, CH Ph-R), 5.55 (s, 1H, CH Ph-β), 5.10 (d, 1H, J = 11.5
Hz, CHH Bn-β), 4.98 (s, 1H, H-10R), 4.98 (d, 1H, J = 10.8 Hz, CHH
Bn-R), 4.93(s, 1H, H-10β), 4.90 (d, 1H, J=7.8 Hz, H-1), 4.90 (d, 1H, J =
7.7 Hz, H-1), 4.79 (d, 1H, J = 10.9 Hz, CHH Bn-R), 4.67 (d, 1H, J =
11.6 Hz, CHH Bn-β), 4.36 (dd, 2H, J = 3.4, 12.2 Hz, H-6R, H-6β),
4.26ꢀ4.32 (m, 3H, H-4R, H-4β, H-60β), 4.00ꢀ4.22 (m, 8H, H-2R, H-2β,
H-30R, H-40R, H-50R, H-6R, H-6β, H-60β), 3.81ꢀ3.90 (m, 5H, H-20R,
H-3R, H-3β, H-40β, H-60R), 3.73ꢀ3.78 (m, 7H, H-60R, CH3 OMe-R, CH3
OMe-β), 3.51 (s, 1H, H-5), 3.46 (s, 1H, H-5), 3.30 (d, 1H, J = 3.5 Hz,
H-20β), 3.23ꢀ3.27 (m, 1H, H-50β), 3.21 (dd, 1H, J = 3.6, 10.1 Hz, H-30β);
13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 155.4, 155.4, 151.3, 138.5,
137.8, 137.6, 137.4, 137.0, 136.5 (Cq), 129.2, 129.1, 129.0, 128.9, 128.8,
128.7, 128.6, 128.3, 128.1, 127.9, 126.3, 126.2, 126.0, 125.8, 125.3, 118.9,
118.7, 114.5, 114.4 (CHarom), 103.4, 103.2 (C-1R, C-1β), 101.6, 101.5,
101.4 (C-10β, CH Ph, CH Ph), 101.1, 100.5 (CH Ph), 93.8 (C-10R), 79.1
(C-2), 77.5 (C-40R), 77.2, 76.7 (C-3), 76.2 (C-2), 75.6 (C-4), 75.5, 75.5
(CH2 Bn), 73.8 (C-40β), 70.9 (C-4), 69.1, 68.8 (C-6), 68.4, 68.3 (C-60R,
C-60β), 68.0 (C-50β), 66.6, 66.1 (C-5R, C-5β), 63.9 (C-50R), 62.5, 62.4 (C-
20R, C-20β), 60.3 (C-30β), 59.1 (C-30R), 55.6 (OMe); 13C-HMBC
(CDCl3, 100 MHz) δ 103.4 (JC1,H1 = 161 Hz, C-1), 103.2 (JC1,H1 = 159
Hz, C-1), 101.4 (JC1,H1 = 164 Hz, C-10β), 93.8 (JC1,H1 = 171 Hz, C-10R);
HRMS [M + NH4]+ calcd for C40H44N7O10 782.31442, found 782.31459.
Methyl 6-O-(Methyl 4-O-acetyl-2,3-diazido-2,3-dideoxy-
R/β-D-mannopyranosyl uronate)-2,3,4-tri-O-benzyl-R-D-gluco-
pyranoside (29). Donor 8β and acceptor 20 were condensed using
the general protocol for Ph2SO/Tf2O-mediated glycosylations to yield
disaccharide 29 (94%, R/β = 1:5.5). TLC Rf R 0.55, β 0.45 (toluene/
EtOAc, 3/1, v/v); IR (neat, cmꢀ1) 1065, 1751,2106, 2916. Spectroscopic
data for the β-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY,
HSQC) δ 7.26ꢀ7.38 (m, 15H, CHarom), 5.24 (t, 1H, J = 9.8 Hz, H-40),
5.00 (d, 1H, J = 10.9 Hz, CHH Bn), 4.87 (d, 1H, J = 11.7 Hz, CHH Bn),
4.81 (d, 1H, J = 10.9 Hz, CHH Bn), 4.78 (d, 1H, J = 12.0 Hz, CHH Bn),
4.64 (d, 1H, J = 12.1 Hz, CHH Bn), 4.58 (d, 1H, J = 11.7 Hz, CHH Bn),
4.55 (d, 1H, J = 3.5 Hz, H-1), 4.34 (s, 1H, H-10), 4.08ꢀ4.13 (m, 1H,
H-6), 4.01 (t, 1H, J = 9.2 Hz, H-3), 3.77ꢀ3.84 (m, 1H, H-5), 3.79 (d, 1H,
J = 9.6 Hz, H-50), 3.73 (s, 3H, CH3 CO2Me), 3.71 (d, 1H, J = 3.5 Hz,
H-20), 3.46ꢀ3.53 (m, 2H, H-30, H-6), 3.45 (dd, 1H, J = 3.6, 10.2 Hz,
H-2), 3.36 (t, 1H, J = 9.2 Hz, H-4), 3.35 (s, 3H, OMe), 2.08 (s, 3H, CH3
Ac); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 169.1, 166.8 (CdO
Ac, CO2Me), 138.6, 138.3, 138.0 (Cq Bn), 128.4, 128.3, 128.1, 128.0, 127.9,
127.7, 127.6 (CHarom), 100.2 (C-10), 97.8 (C-1), 81.9 (C-3), 79.9 (C-2),
77.2 (C-4), 75.7, 74.5 (CH2 Bn), 73.7 (C-5 or C-50), 73.4 (CH2 Bn),
69.4 (C-5 or C-50), 68.9 (C-6), 67.4 (C-40), 62.2 (C-20), 60.9 (C-30),
55.1 (OMe), 52.8 (CH3 CO2Me), 20.5 (CH3 Ac); 13C-GATED (CDCl3,
100 MHz) δ 100.2 (JC1,H1 = 159 Hz, C-10), 97.8 (JC1,H1 = 172 Hz, C-1);
HRMS [M + Na]+ calcd for C37H42N6O11Na 769.28038, found 769.28029.
Methyl 4-O-(Methyl 4-O-acetyl-2,3-diazido-2,3-dideoxy-
R/β-D-mannopyranosyl uronate)-2,3,6-tri-O-benzyl-R-D-gluco-
pyranoside (30). Donor 8β and acceptor 21 were condensed using
the general protocol for Ph2SO/Tf2O-mediated glycosylations to yield
disaccharide 30 (49%, R/β = 1:3.5). TLC Rf 0.27, 0.38 (PE/EtOAc,
2/1, v/v); IR (neat, cmꢀ1) 1041, 1751, 2106, 2924. Spectroscopic data
for the β-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC)
δ 7.22ꢀ7.45 (m, 15H, CHarom), 5.10 (t, 1H, J = 10.0 Hz, H-40), 5.02
(d, 1H, J = 11.4 Hz, CHH Bn), 4.84 (d, 1H, J = 11.4 Hz, CHH Bn), 4.78
(d, 1H, J = 12.1 Hz, CHH Bn), 4.72 (d, 1H, J = 12.1 Hz, CHH Bn), 4.60
(d, 1H, J = 3.7 Hz, H-1), 4.57 (d, 1H, J = 12.2 Hz, CHH Bn), 4.53 (d, 1H,
J = 0.9 Hz, H-10), 4.36 (d, 1H, J = 12.1 Hz, CHH Bn), 3.93 (t, 1H, J = 9.0
Hz, H-3), 3.87 (t, 1H, J = 9.2 Hz, H-4), 3.72ꢀ3.77 (m, 2H, H-5, H-6),
3.62 (dd, 1H, J = 2.2, 10.8 Hz, H-6), 3.49ꢀ3.53 (m, 5H, H-2, H-50, CH3
CO2Me), 3.38 (s, 3H, OMe), 3.27 (dd, 1H, J = 0.4, 3.3 Hz, H-20), 2.98
(dd, 1H, J = 3.4, 10.2 Hz, H-30), 2.07 (s, 3H, CH3 Ac); 13C-APT NMR
(CDCl3, 100 MHz, HSQC) δ 169.2, 166.6 (CdO Ac, CO2Me), 139.3,
138.0, 137.6 (Cq Bn), 128.8, 128.7, 128.4, 128.1, 127.8, 127.3, 127.1
(CHarom), 100.2 (C-10), 98.2 (C-1), 80.0 (C-4), 79.3 (C-2), 78.4 (C-3),
75.0 (CH2 Bn), 73.8 (C-50), 73.7, 73.4 (CH2 Bn), 68.9 (C-5), 68.0 (C-6),
67.4 (C-40), 62.5 (C-20), 60.9 (C-30), 55.4 (OMe), 52.6 (CH3 CO2Me),
20.5 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 100.2 (JC1,H1 = 159 Hz,
C-10), 98.2 (JC1,H1 = 168 Hz, C-1); Spectroscopic data for the R-anomer:
1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.28ꢀ7.40
(m, 15H, CHarom), 5.40 (d, 1H, J = 3.3 Hz, H-10), 5.29 (t, 1H, J = 8.2
Hz, H-40), 5.11 (d, 1H, J = 11.3 Hz, CHH Bn), 4.74 (d, 1H, J = 11.9 Hz,
CHH Bn), 4.69 (d, 1H, J = 11.2 Hz, CHH Bn), 4.61ꢀ4.65 (m, 2H, CHH
Bn, H-1), 4.55 (d, 1H, J = 11.8 Hz, CHH Bn), 4.48 (d, 1H, J = 11.8 Hz,
CHH Bn), 4.24 (d, 1H, J = 7.9 Hz, H-50), 3.97 (t, 1H, J = 9.1 Hz, H-3),
3.93 (dd, 1H, J = 3.5, 8.6 Hz, H-30), 3.87 (t, 1H, J = 9.3 Hz, H-4),
3.65ꢀ3.77 (m, 3H, H-5, H-6), 3.59 (s, 3H, CH3 CO2Me), 3.55ꢀ3.57
(m, 1H, H-2), 3.52 (t, 1H, J = 3.4 Hz, H-20), 3.39 (s, 3H, OMe), 2.09
(s, 3H, CH3 Ac); HRMS [M + Na]+ calcd for C37H42N6O11Na 769.28038,
found 769.28022.
p-Methoxyphenyl 3-O-(Methyl 4-O-acetyl-2,3-diazido-2,
3-dideoxy-R/β-D-mannopyranosyl uronate)-2-O-benzyl-4,
6-O-benzylidene-β-D-galactopyranoside (31). Donor 8β and
acceptor 22 were condensed using the general protocol for Ph2SO/
Tf2O-mediated glycosylations to yield disaccharide 31 (89%,
R/β = 1:7.5). TLC Rf R 0.55, β 0.45 (toluene/EtOAc, 2/1, v/v); IR
(neat, cmꢀ1) 1057, 1219, 1504, 1751, 2106. Spectroscopic data for the
β-anomer: 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.52ꢀ7.56 (m, 2H, CHarom), 7.28ꢀ7.44 (m, 8H, CHarom), 7.06 (d,
2H, J = 9.1 Hz,CHarom), 6.83 (d, 1H, J = 9.1 Hz, CHarom), 5.59 (s, 1H,
CH Ph), 5.13 (t, 1H, J = 10.0 Hz, H-40), 5.09 (d, 1H, J = 11.6 Hz, CHH
Bn), 4.87ꢀ4.89 (m, 2H, H-1, H-10), 4.66 (d, 1H, J = 11.6 Hz, CHH Bn),
4.32ꢀ4.38 (m, 2H, H-4, H-6), 4.18 (dd, 1H, J = 7.8, 9.9 Hz, H-2), 4.07
(dd, 1H, J = 1.4, 12.4 Hz, H-6), 3.88 (dd, 1H, J = 3.5, 9.9 Hz, H-3), 3.78
(s, 3H, OMe), 3.72 (s, 3H, CH3 CO2Me), 3.69 (d, 1H, J = 9.7 Hz, H-50),
3.50 (s, 1H, H-5), 3.32 (d, 1H, J = 3.3 Hz, H-20) 3.02 (dd, 1H, J = 3.5,
10.2 Hz, H-30), 2.07 (s, 3H, CH3 Ac); 13C-APT NMR (CDCl3, 100
MHz, HSQC) δ 169.2, 166.9 (CdO Ac, CO2Me), 155.3, 151.3, 138.6,
137.6 (Cq Ph, Bn), 128.7, 128.6, 128.3, 128.2, 127.8, 126.3, 126.2, 118.5,
114.4 (CHarom), 103.0 (C-1), 100.6 (C-10), 100.4 (CH Ph), 79.2 (C-2),
77.0(C-3),75.4(CH2 Bn),75.4(C-4), 73.5(C-50), 68.7 (C-6), 67.4 (C-40),
66.5 (C-5), 61.6 (C-20), 61.0 (C-30), 55.5 (OMe), 52.8 (CH3 CO2Me),
22.4 (CH3 Ac); 13C-GATED (CDCl3, 100 MHz) δ 103.0 (JC1,H1 = 158 Hz,
C-1), 100.6 (JC1,H1 = 161 Hz, C-10); HRMS [M + Na]+ calcd for
C36H38N6O12Na 769.24399, found 769.24405.
3,4,6-Tri-O-acetyl-2-azido-2-deoxy-1-O-(N-[phenyl]trifluoro-
acetimidoyl)-R/β-D-glucopyranoside (36). Compound 3526a,b
(0.95 g, 2.87 mmol) was dissolved in acetone (25 mL), followed by
the addition of N-(phenyl)trifluoroacetimidoyl chloride34 (0.87 mL,
5.73 mmol), K2CO3 (0.48 g, 3.44 mmol), and H2O (1 mL). After
stirring for 1.5 h at rt, the mixture was diluted with EtOAc and the
organic layer was washed with saturated aqueous NaCl (2ꢁ), dried over
Na2SO4, and concentrated in vacuo. Purification using flash column
chromatography (silica gel, 33% EtOAc in PE) yielded the title product
as a yellowish oil (1.38 g, 2.76 mmol, 96%, R/β = 1.4:1); TLC Rf
0.65 (PE/EtOAc, 2/1, v/v); IR (neat, cmꢀ1) 727, 907, 1209, 1747, 2114;
1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC, T = 328 K) δ
7.27ꢀ7.33 (m, 4.8H, CHarom), 7.09ꢀ7.15 (m, 2.4H, CHarom),
6.82ꢀ6.87 (m, 4.8H, CHarom), 6.43 (d, 1.4H, J = 2.6 Hz, H-1R), 5.59
(d, 1H, J = 8.2 Hz, H-1β), 5.48 (t, 1.4H, J = 9.9 Hz, H-3R), 5.11 (t, 1.4H,
J = 9.7 Hz, H-4R), 5.00ꢀ5.08 (m, 2H, H-3β, H-4β), 4.21ꢀ4.30 (m,
2.4H, H-6R, H-6β), 4.07ꢀ4.14 (m, 3.8H, H-5R, H-6R, H-6β),
3.69ꢀ3.76 (m, 2.4H, H-2R, H-2β), 3.63ꢀ3.69 (m, 1H, H-5β), 2.09
(s, 4.2H, CH3 Ac-R), 2.08 (s, 3H, CH3 Ac-β), 2.06 (s, 4.2H, CH3 Ac-R),
2.04 (s, 7.2H, CH3 Ac-R, CH3 Ac-β), 1.99 (s, 3H, CH3 Ac-β); 13C-APT
NMR (CDCl3, 100 MHz, HSQC) δ 170.0, 169.9, 169.4, 169.4, 169.2,
7310
dx.doi.org/10.1021/jo201179p |J. Org. Chem. 2011, 76, 7301–7315

The Journal of Organic Chemistry
FEATURED ARTICLE
169.1 (CdO Ac), 142.6 (Cq Ph), 128.6, 124.4, 118.9, 118.8 (CHarom),
115.6 (q, J = 284 Hz, CF3), 155.5 (q, J = 283 Hz, CF3), 94.9 (C-1β), 92.8
(C-1R), 72.3, 72.1 (C-4), 70.2, 69.8 (C-3, C-5), 67.5, 67.5 (C-3, C-5),
62.4 (C-2), 61.1 (C-6, C-6), 60.1 (C-2), 20.1, 20.1, 20.5, 20.0 (CH3 Ac);
HRMS [M(hemiacetal)+Na]+ calcd for C12H17N3O8Na 354.09079,
found 354.09059.
Compound 38 (0.52 mmol) was coevaporated with toluene (2ꢁ) and
dissolved in dry DMF (5 mL) under an argon atmosphere. The solution
was cooled to ꢀ40 °C, and di-tert-butylsilylbistriflate (0.19 mL, 0.6 mmol)
was dropwise added. The reaction was stirred for 1.5 h, followed by the
addition of pyridine (0.2 mL). The mixture was diluted with EtOAc,
washed with saturated aqueous NaCl (2ꢁ), dried over Na2SO4, filtered,
and concentrated in vacuo. Purification using flash column chromatog-
raphy (silica gel, 14% EtOAc in PE) gave the title compound as a
colorless oil (0.26 g, 0.39 mmol, 76%): TLC Rf 0.64 (PE/EtOAc, 3/1,
v/v); [R]20D +52.2 (c 1, DCM); IR (neat, cmꢀ1) 827, 1088, 1688, 2108,
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl O-3,4,6-Tri-
O-acetyl-2-azido-2-deoxy-R/β-D-glucopyranoside (37). Donor
36(0.52 g, 1.04 mmol) and N-(benzyl)benzyloxycarbonyl-5-aminopentanol
(0.51 g, 1.56 mmol) were together coevaporated with toluene (2ꢁ),
dissolved in dry Et2O (21 mL), and stirred on activated MS for 30 min
at rt. The solution was cooled to ꢀ40 °C, and TfOH (18 μL, 0.21 mmol)
was added. The mixture was allowed to warm to ꢀ10 °C in 1 h followed
by the addition of Et3N (0.1 mL). EtOAc was added, and the organic
phase was washed with saturatedaqueous NaCl (2ꢁ), dried over Na2SO4,
and concentrated in vacuo. The residue was dissolved in pyridine (6 mL)
and treated with Ac2O (2 mL) for 2 h, followed by the addition of EtOAc.
The solution was washed with saturated aqueous NaCl (2ꢁ), dried over
Na2SO4, and concentrated in vacuo. Purification using flash column
chromatography (silica gel, 50% EtOAc in PE) gave the title compound
as a yellowish oil (0.64 g, 0.99 mmol, 95%, R/β = 7.4:1). TLC Rf
0.41 (PE/EtOAc, 3/2, v/v); IR (neat, cmꢀ1) 698, 1030, 1219, 1694, 1746,
2108, 2922. Spectroscopic data for the R-anomer: 1H NMR (CDCl3, 400
MHz, HHꢀCOSY, HSQC) δ 7.13ꢀ7.40 (m, 10H, CHarom), 5.47 (t, 1H,
J = 9.9 Hz, H-3), 5.18 (d, 2H, J = 13.1 Hz, CH2 Z), 5.04 (t, 1H, J = 9.8 Hz,
H-4), 4.93 (d, 1H, J = 12.0 H, H-1), 4.50 (bs, 2H, CH2 Bn), 4.28 (dd, 1H,
J = 3.5, 12.2 Hz, H-6), 4.06 (d, 1H, J = 12.5 Hz, H-6), 3.94ꢀ4.02 (m, 1H,
H-5), 3.60ꢀ3.75 (m, 1H, CH2), 3.35ꢀ3.50 (m, 1H, CH2), 3.26 (dd, 1H,
J = 3.5, 10.6 Hz, H-2), 3.18ꢀ3.30 (m, 2H, CH2), 2.08 (s, 3H, CH3 Ac),
2.07 (s, 3H, CH3 Ac), 2.03 (s, 3H, CH3 Ac), 1.45ꢀ1.70 (m, 4H, CH2),
1.24ꢀ1.42 (m, 2H, CH2); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ
170.2, 169.7, 169.3 (CdO Ac), 156.1 (d, J =50Hz, CdO Z), 137.7 (Cq Z),
136.6 (d, J = 10 Hz, Cq Bn), 128.3, 127.6, 127.0 (CHarom), 97.5 (C-1),
70.0 (C-3), 68.3 (C-4), 68.3 (CH2), 67.3 (C-5), 66.8 (CH2 Z), 61.6 (C-6),
60.5 (C-2), 50.1 (d, J = 32 Hz, CH2 Bn), 46.3 (d, J = 91 Hz, CH2), 28.7
(CH2), 27.3 (d, J = 48 Hz, CH2), 23.0 (CH2), 20.4, 20.3 (CH3 Ac);
13C-GATED (CDCl3, 100 MHz) δ 97.5 (JC1,H1 = 171 Hz, C-1).
Diagnostic peak for the β-anomer: 13C-APT NMR (CDCl3, 100 MHz,
HSQC) δ 101.7 (C-1); HRMS [M + Na]+ calcd for C32H40N4O10Na
663.26366, found 663.26356.
1
2858, 2934, 3429; H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC,
T = 328 K) δ 7.16ꢀ7.34 (m, 10H, CHarom), 5.17 (s, 2H, CH2 Z), 4.75
(d, 1H, J = 3.4 Hz, H-1), 4.48 (s, 2H, CH2 Bn), 4.07 (dd, 1H, J = 4.6, 9.6
Hz, H-6), 3.97 (dd, 1H, J = 8.6, 10.1 Hz, H-3), 4.83 (t, 1H, J = 10.0 Hz,
H-6), 3.75 (ddd, 1H, J = 4.5, 9.4, 9.4 Hz, H-5), 3.65 (t, 1H, J = 8.8 Hz,
H-4), 3.57ꢀ3.63 (m, 1H, CH2), 3.36ꢀ3.44 (m, 1H, CH2), 3.18ꢀ3.27
(m, 2H, CH2), 3.14 (dd, 1H, J = 3.6, 10.2 Hz, H-2), 2.85 (bs, 1H, 3-OH),
1.48ꢀ1.62 (m, 4H, CH2), 1.25ꢀ1.38 (m, 2H, CH2), 1.06 (s, 9H,
CH3tBu), 0.99 (s, 9H, CH3tBu); 13C-APT NMR (CDCl3, 100 MHz,
HSQC) δ 156.3 (d, J = 48 Hz, CdO Z), 137.7, 136.7 (Cq Bn), 128.4,
128.3, 127.8, 127.7, 127.1 (CHarom), 98.0 (C-1), 77.9 (C-4), 71.3 (C-3),
68.1 (CH2), 67.0 (CH2 Z), 66.3 (C-6), 66.0 (C-5), 62.1 (C-2), 50.3 (d, J =
30 Hz, CH2 Bn), 46.5 (d, J = 95 Hz, CH2), 28.9, 27.7 (CH2), 27.3, 26.8
(CH3tBu), 23.3 (CH2), 22.5, 19.8 (CqtBu); HRMS [M + Na]+ calcd for
C34H50N4O7SiNa 677.33410, found 677.33397.
Methyl (Phenyl 4-O-[2,3,4-tri-O-benzyl-6-O-{9-fluorenyl-
methoxycarbonyl}-R-D-glucopyranosyl]-2,3-diazido-2,3-di-
deoxy-1-thio-β-D-mannopyranosyl Uronate) (41). Imidate 403b
(0.55 g, 0.65 mmol) and acceptor 16β (0.18 g, 0.5 mmol) were together
coevaporated with dry toluene (2ꢁ). Et2O(13 mL, driedover 4 ÅMSprior
to use) was added, and the mixture was cooled to ꢀ40 °C. TfOH (9 μL,
0.1 mmol) was added, and the mixture was allowed to warm to ꢀ10 °C.
Then pyridine (0.1 mL) was added, and the mixture was diluted with
EtOAc and washed with saturated aqueous NaCl (2ꢁ). The organic layer
was dried over Na2SO4, concentrated in vacuo, and purified using column
chromatography (silica gel, 20% EtOAc in PE) to yield the title compound
as a colorless oil (0.48 g, 0.48 mmol, 96%): TLC Rf 0.54 (PE/EtOAc, 3/1, v/v);
[R]20D +36.6 (c 1, DCM); IR (neat, cmꢀ1) 696, 737, 1070, 1252, 1744,
2106; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ 7.75 (d, 2H,
J=7.6 Hz, CHarom), 7.59 (dd, 2H, J= 7.6, 11.1 Hz, CHarom), 7.20ꢀ7.45 (m,
24H, CHarom), 5.00 (d, 1H, J = 3.9 Hz, H-10), 4.99 (d, 1H, J = 11.4 Hz,
CHH Bn), 4.89 (d, 1H, J = 4.89 Hz, CHH Bn), 4.67ꢀ4.81 (m, 4H, CHH
Bn, CH2 Bn, H-1), 4.57 (d, 1H, J = 10.8 Hz, CHH Bn), 4.33ꢀ4.44 (m, 3H,
CH2 Fmoc, H-60),4.30(dd, 1H,J= 2.5, 11.9 Hz, H-60), 4.22 (t, 1H, J=7.3Hz,
CH Fmoc), 4.12ꢀ4.17 (m, 2H, H-2, H-4), 3.94 (t, 1H, J = 9.4 Hz, H-30),
3.80 (d, 1H, J = 9.4 Hz, H-5), 3.72ꢀ3.77 (m, 4H, H-50, CH3 CO2Me), 3.70
(dd, 1H, J = 3.5, 9.8 Hz, H-3), 3.60 (t, 1H, J = 9.5 Hz, H-40), 3.52 (dd, 1H,
J = 3.3, 9.8 Hz, H-20); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 166.7
(CdO CO2Me), 154.8 (CdO Fmoc), 143.3, 143.1, 141.1 (Cq Fmoc),
138.5, 137.9, 137.8 (Cq Bn), 133.2 (Cq SPh), 131.3, 129.2, 128.3, 127.9,
127.8, 127.6, 127.1, 125.0, 125.0, 119.9 (CHarom), 99.6 (C-10), 87.3 (C-1),
81.0 (C-30), 79.9, 79.9 (C-20, C-5),76.5, 76.3 (C-4, C-40), 75.5, 75.1, 73.5
(CH2 Bn), 70.1 (C-50), 69.7 (CH2 Fmoc), 65.8 (C-3), 65.7 (C-60), 64.4
(C-2), 52.9 (CH3 CO2Me), 46.6 (CH Fmoc); 13C-GATED (CDCl3,
100 MHz) δ 99.6 (JC1,H1 = 172 Hz, C-10), 87.3 (JC1,H1 = 155 Hz, C-1);
HRMS [M + Na]+ calcd for C55H52N6O11SNa 1027.33070, found
1027.33138.
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl O-2-Azido-2-
deoxy-R-D-glucopyranoside(38).Compound 37 (0.64 g, 0.99 mmol)
was dissolved in MeOH (10 mL) and treated with NaOMe (cat.) for 4 h until
full consumption of the starting material was indicated by TLC analysis. The
mixture was neutralized by the addition of Amberlite-H+, filtered, and concen-
trated in vacuo. The title compound wasusedinthenextreactionstepwithout
further purification. TLC Rf 0.18 (PE/EtOAc, 1/3, v/v); IR (neat, cmꢀ1
)
1
1028, 1682, 2106, 2930, 3552. Spectroscopic data for the R-anomer: H
NMR (MeOH-d4, 400 MHz, HHꢀCOSY, HSQC) δ 7.64ꢀ7.71 (m, 2H,
CHarom), 7.08ꢀ7.33 (m, 8H, CHarom), 5.10 (d, 1H, J = 17.1 Hz, CH2 Z),
4.80 (bs, 1H, H-1), 4.43 (bs, 2H, CH2 Bn), 3.85 (t, 1H, J= 9.5 Hz, H-3), 3.77
(d, 1H,J= 11.9 Hz, H-6), 3.69 (dd, 1H, J=5.0,11.9Hz, H-6),3.49ꢀ3.64 (m,
2H, H-5, CH2), 3.36 (t, 1H, J = 9.3 Hz, H-4), 3.25ꢀ3.32 (m, 1H, CH2),
3.12ꢀ3.24 (m, 2H, CH2), 3.02 (dd, 1H, J = 2.9, 10.4 Hz, H-2), 1.39ꢀ1.60
(m, 4H, CH2), 1.20ꢀ1.38 (m, 2H, CH2); 13C-APT NMR (MeOH-d4,
100 MHz, HSQC) δ157.8 (d, J=53Hz, CdO Z), 138.7 (d, J=9Hz, Cq Z),
137.5 (d, J = 11 Hz, Cq Bn), 129.3, 128.6, 128.4, 128.1, 128.0 (CHarom), 99.0
(C-1), 73.3 (C-5), 72.1 (C-3), 71.7 (C-4), 68.5, 68.2 (CH2, CH2 Z), 64.0
(C-2), 62.1 (C-6), 51.2 (d, J = 19 Hz, CH2 Bn), 47.6 (d, J = 88 Hz, CH2),
29.8 (CH2), 28.4 (d, J = 46 Hz, CH2), 24.1 (CH2). Diagnostic peak for the
β-anomer: 13C-APT NMR (MeOH-d4, 100 MHz, HSQC) δ 102.9 (C-1);
HRMS [M + Na]+ calcd for C26H34N4O7Na 537.23197, found 537.23153.
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl O-2-Azido-4,
6-O-di-tert-butylsilylidene-2-deoxy-R-D-glucopyranoside (39).
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl O-(Methyl
4-O-[2,3,4-tri-O-benzyl-6-O-{9-fluorenylmethoxycarbonyl}-
R-D-glucopyranosyl]-2,3-diazido-2,3-dideoxy-β-D-manno-
pyranosyl Uronate)-2-azido-4,6-O-di-tert-butylsilylidene-2-
deoxy-R-D-glucopyranoside (42). Compound 41 (0.29g, 0.29mmol)
and Ph2SO (70 mg, 0.35 mmol) were together coevaporated with toluene
(2ꢁ). Freshly distilled DCM (5.8 mL) and activated molecular sieves (3 Å)
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FEATURED ARTICLE
were added under an argon atmosphere, and the resulting mixture was stirred
at rt for 20 min, followed by cooling to ꢀ80 °C. Tf2O (59 μL, 0.35 mmol)
was added, and the mixture was allowed to warm to ꢀ60 °C in 15 min. After
cooling back to ꢀ80 °C, a solution of compound 39 (0.26 g, 0.39 mmol) in
DCM (2 mL) was added. The reaction was warmed to ꢀ10 °C in 4 h, after
which time pyridine (0.2 mL) was added. The mixture was diluted with
EtOAc, washed with saturated aqueous NaCl (2ꢁ), dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by size-exclusion chroma-
tography (Sephadex LH-20, eluted with DCM/MeOH, 1/1, v/v) gave the
title compound as a colorless oil (0.45 g, 0.29 mmol, >98%): TLC Rf
0.97 (s, 9H, CH3tBu); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 167.1
(CdO CO2Me), 156.2 (d, J = 53 Hz, CdO Z), 138.5, 137.9, 137.7 (Cq
Bn), 136.6 (d, J = 17 Hz, Cq Bn), 128.4, 128.3, 128.2, 127.8, 127.6, 127.4,
127.1, 127.0 (CHarom), 100.9 (C-10), 98.7 (C-100), 97.3 (C-1), 80.8 (C-300),
79.7 (C-200), 79.4 (C-3), 77.2 (C-400), 76.8 (C-50), 75.9 (C-500), 75.4
(CH2 Bn), 74.9 (C-40), 74.9, 73.3 (CH2 Bn), 72.6 (C-4), 68.0 (CH2), 67.0
(CH2 Z), 66.5 (C-5), 66.3 (C-6), 63.1 (C-30), 62.5 (C-20), 62.4 (C-2), 61.4
(C-600), 52.5 (CH3 CO2Me), 50.2 (d, J = 25 Hz, CH2 Bn), 46.4 (d, J =
108 Hz, CH2), 28.8 (CH2), 27.4 (d, J = 34 Hz, CH2), 27.1, 26.8 (CH3tBu),
23.2 (d, J = 11 Hz, CH2), 22.4, 19.6 (CqtBu); 13C-GATED (CDCl3, 100
MHz) δ 100.9 (JC1,H1 = 160 Hz, C-10), 98.7 (JC1,H1 = 169 Hz, C-100), 97.3
(JC1,H1 = 170 Hz, C-1); HRMS [M + Na]+ calcd forC68H86N10O16SiNa
1349.58847, found 1349.58962.
0.36 (PE/EtOAc, 3/1, v/v); [R]20D +30.8 (c 1, DCM); IR (neat, cmꢀ1
)
1
698, 739, 1043, 1072, 1094, 1256, 1697, 1749, 2108, 2934; H NMR
(CDCl3, 400 MHz, HHꢀCOSY, HSQC, T = 328 K) δ 7.71 (d, 2H, J = 7.6
Hz, CHarom), 7.57 (t, 2H, J = 7.6 Hz, CHarom), 7.18ꢀ7.40 (m, 29H,
CHarom), 5.17 (s, 2H, CH2 Z), 5.09 (d, 1H, J = 3.1 Hz, H-100), 4.97 (d, 1H,
J = 11.1 Hz, CHH Bn), 4.92 (s, 1H, H-10), 4.87 (d, 1H, J = 10.9 Hz, CHH
Bn), 4.78 (d, 2H, J = 11.4 Hz, H-1, CHH Bn), 4.70ꢀ4.75 (m, 2H, CH2 Bn),
4.58 (d, 1H, J = 10.9 Hz, CHH Bn), 4.49 (s, 2H, CH2 Bn), 4.35ꢀ4.42 (m,
3H, H-600, CH2 Fmoc), 4.31 (dd, 1H, J = 2.1, 11.8 Hz, H-600), 4.21 (t, 1H, J =
7.5 Hz, CH Fmoc), 4.16 (t, 1H, J = 9.4 Hz, H-40), 4.01ꢀ4.08 (m, 2H, H-20,
H-6), 3.89ꢀ3.96 (m, 2H, H-3, H-300), 3.78ꢀ3.89 (m, 3H, H-4, H-50, H-6),
3.69ꢀ3.78 (m, 2H, H-5, H-500), 3.67 (s, 3H, CH3 CO2Me), 3.55ꢀ3.62 (m,
2H, H-400, CHH CH2), 3.48ꢀ3.54 (m, 2H, H-200, H-30), 3.36ꢀ3.45 (m, 1H,
CHH CH2), 3.27 (dd, 1H, J = 3.4, 10.1 Hz, H-2), 3.20ꢀ3.26 (m, 2H, CH2),
1.48ꢀ1.64 (m, 4H, CH2), 1.26ꢀ1.38 (m, 2H, CH2), 1.04 (s, 9H, CH3tBu),
0.97 (s, 9H, CH3tBu); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 166.9
(CdOCO2Me), 156.3 (d, J=50 Hz, CdOZ), 154.8(CdO Fmoc), 143.3,
143.1, 141.1, 141.1 (Cq Fmoc), 138.5, 137.8, 137.8, 137.7 (Cq Bn), 136.7 (d,
J = 17 Hz, Cq Bn), 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.5, 127.2,
127.0 (CHarom), 125.0, 124.9, 119.9 (CHarom Fmoc), 101.0 (C-10), 99.1 (C-
100), 97.4 (C-1), 80.9 (C-300), 79.7 (C-200), 79.4 (C-3), 76.7 (C-50), 76.4 (C-
400), 76.0 (C-4), 75.5 (C-40), 75.4, 75.0, 73.3 (CH2 Bn), 69.9 (C-500), 69.7
(CH2 Fmoc), 68.1 (CH2), 67.0 (CH2 Z), 66.6 (C-5), 66.3 (C-6), 65.6 (C-
600), 63.4 (C-30), 62.6 (C-20), 62.5 (C-2), 52.6 (CH3 CO2Me), 50.3 (d, J =
24 Hz, CH2 Bn), 46.6 (CH Fmoc), 46.4 (d, J = 109 Hz, CH2), 28.8 (CH2),
27.5 (d, J = 33 Hz, CH2), 27.2, 26.8 (CH3tBu), 23.3 (CH2), 22.5, 19.7
(CqtBu); 13C-GATED (CDCl3, 100 MHz) δ101.0 (JC1,H1 = 158 Hz, C-10),
99.1 (JC1,H1 = 170 Hz, C-100), 97.4 (JC1,H1 = 170 Hz, C-1); HRMS [M +
NH4]+ calcd for C83H100N11O18Si 1566.70116, found 1566.70311.
Methyl (Phenyl 2,3-diazido-4-O-tert-butyldimethylsilyl-
2,3-dideoxy-1-thio-β-D-mannopyranosyl Uronate) (44).
Compound 16β (0.35 g, 1.0 mmol) was dissolved in dry DCM (20 mL)
and cooled to 0 °C, followed by the addition of Et3N (0.84 mL, 6 mmol)
and TBSꢀOTf (0.45 mL, 2 mmol). The resulting solution was stirred
overnight at rt. Saturated aqueous NaHCO3 was added, and the mixture
was diluted with EtOAc. The organic fraction was separated, washed
with saturated aqueous NaCl (2ꢁ), dried over Na2SO4, and concen-
trated in vacuo. Purification using flash column chromatography (silica
gel, 10% EtOAc in PE) yielded the title compound as amorphous white
solids (0.41 g, 0.88 mmol, 88%): TLC Rf 0.67 (PE/EtOAc, 4/1, v/v);
[R]20 ꢀ10.6 (c 1, DCM); IR (neat, cmꢀ1) 827, 1057, 1441, 1742,
D
2106, 2927; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC) δ
7.38ꢀ7.43 (m, 2H, CHarom), 7.24ꢀ7.30 (m, 3H, CHarom), 4.87 (s, 1H,
H-1), 4.20 (d, 1H, J = 3.2 Hz, H-2), 4.04 (t, 1H, J = 9.3 Hz, H-4), 3.78 (d,
1H, J = 9.2 Hz, H-5), 3.73 (s, 3H, CH3 CO2Me), 3.56 (dd, 1H, J = 3.5,
9.5 Hz, H-3), 0.83 (s, 9H, CH3tBu), 0.18 (s, 3H, CH3 Me), 0.01 (s, 3H,
CH3 Me); 13C-APT NMR (CDCl3, 100 MHz, HSQC) δ 167.3 (CdO
CO2Me), 133.4 (Cq SPh), 131.2, 129.1, 127.9 (CHarom), 87.2 (C-1),
80.8 (C-5), 68.1 (C-3), 67.6 (C-2), 64.8 (C-4), 52.4 (CH3 CO2Me),
25.5 (CH3tBu), 17.8 (CqtBu), ꢀ4.8, ꢀ5.3 (CH3 Me); 13C-GATED
(CDCl3, 100 MHz) δ 87.2 (JC1,H1 = 155 Hz, C-1); HRMS [M + NH4]+
calcd for C19H32N7O4SSi 482.20003, found 482.20002.
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl 3-O-(Methyl
4-O-[6-O-{methyl 2,3-diazido-4-O-tert-butyldimethylsilyl-
2,3-dideoxy-β-D-mannopyranosyl Uronate}-2,3,4-tri-O-benzyl-
R-D-glucopyranosyl]-2,3-diazido-2,3-dideoxy-β-D-manno-
pyranosyl Uronate)-2-azido-4,6-O-di-tert-butylsilylidene-
2-deoxy-R-D-glucopyranoside (45). Compound 44 (30 mg, 65
μmol), Ph2SO (13 mg, 65 μmol), and TTBP (32 mg, 130 μmol) were
together coevaporated with toluene (2ꢁ). Freshly distilled DCM
(1.5 mL) and activated molecular sieves (3 Å) were added under an
argon atmosphere, and the resulting mixture was stirred at rt for 20 min,
followed by cooling to ꢀ80 °C. Tf2O (11 μL, 65 μmol) was added, and
the mixture was stirred at ꢀ80 °C for 20 min. Then a solution of com-
pound 43 (95 mg, 71 μmol) in DCM (1 mL) was added. The reaction
was stirred overnight at ꢀ30 °C and subsequently warmed to ꢀ10 °C,
followed by the addition of triethylamine (0.1 mL). The mixture was
diluted with EtOAc, washed with saturated aqueous NaCl (2ꢁ), dried
over Na2SO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography (silica gel, 20% EtOAc in PE) and subsequent
size-exclusion chromatography (Sephadex LH-20, eluted with DCM/
MeOH, 1/1, v/v) to remove hydrolyzed donor gave the title compound
as a colorless oil (81 mg, 48 μmol, 74%): TLC Rf 0.33 (PE/EtOAc,
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl O-(Methyl
4-O-[2,3,4-tri-O-benzyl-R-D-glucopyranosyl]-2,3-diazido-
2,3-dideoxy-β-D-mannopyranosyl Uronate)-2-azido-4,6-O-
di-tert-butylsilylidene-2-deoxy-R-D-glucopyranoside (43).
Compound 42 (0.39 g, 0.25 mmol) was dissolved in pyridine (5 mL)
and treated with triethylamine (0.53 mL, 3.79 mmol) for 3 h, followed by
addition of EtOAc. The organic phase was washed with H2O (1ꢁ) and
saturated aqueous NaCl (2ꢁ), dried over Na2SO4, filtered, and con-
centrated in vacuo. Purification using flash column chromatography
(silica gel, 33% EtOAc in PE) furnished the title compound as a colorless
oil (0.32 g, 0.24 mmol, 94%): TLC Rf 0.36 (PE/EtOAc, 2/1, v/v);
[R]20 +18.8 (c 1, DCM); IR (neat, cmꢀ1) 1028, 1072, 1686, 1751,
D
2108, 2858, 2934; 1H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC,
T = 328 K) δ 7.18ꢀ7.40 (m, 25H, CHarom), 5.17 (s, 2H, CH2 Z), 5.00
(d, 1H, J = 3.4 Hz, H-100), 4.93 (d, 1H, J = 11.2 Hz, CHH Bn), 4.91
(d, 1H, J = 0.8 Hz, H-10), 4.84 (d, 1H, J = 11.1 Hz, CHH Bn), 4.81
(d, 1H, J = 3.3 Hz, H-1), 4.77 (d, 1H, J = 11.2 Hz, CHH Bn), 4.71 (s, 2H,
CH2 Bn), 4.60 (d, 1H, J = 11.2 Hz, CHH Bn), 4.50 (bs, 2H, CH2 Bn),
4.14 (t, 1H, J = 9.4 Hz, H-40), 4.05 (dd, 1H, J = 4.6, 9.8 Hz, H-6), 4.02
(d, 1H, J = 3.1 Hz, H-20), 3.78ꢀ3.93 (m, 5H, H-3, H-300, H-50, H-500,
H-6), 3.70ꢀ3.78 (m, 2H, H-5, H-600), 3.66 (s, 3H, CH3 CO2Me),
3.55ꢀ3.64 (m, 3H, H-4, H-600, CHH CH2), 3.53 (dd, 1H, J = 3.3, 9.7 Hz,
H-30), 3.35ꢀ3.47 (m, 3H, H-200, H-400, CHH CH2), 3.28 (dd, 1H, J = 3.5,
10.0 Hz, H-2), 3.20ꢀ3.27 (m, 2H, CH2), 2.02 (bs, 1H, 600ꢀOH),
1.48ꢀ1.63 (m, 4H, CH2), 1.25ꢀ1.38 (m, 2H, CH2), 1.04 (s, 9H, CH3tBu),
4/1, v/v); [R]20 +10.9 (c 1, DCM); IR (neat, cmꢀ1) 696, 727, 907,
D
1
1692, 1751, 2106, 2931; H NMR (CDCl3, 400 MHz, HHꢀCOSY,
HSQC, T = 328 K, tentatively assigned based on 1H NMR of compound
42) δ 7.13ꢀ7.36 (m, 25H, CHarom), 5.15 (s, 2H, CH2 Z), 5.02 (d, 1H,
J = 3.4 Hz, H-100), 4.92 (d, 1H, J = 11.2 Hz, CHH Bn), 4.87 (s, 1H, H-10),
4.76ꢀ4.83 (m, 2H, H-1,CHH Bn), 4.72 (d, 1H, J = 11.2 Hz, CHH Bn),
4.63ꢀ4.69 (m, 2H, CH2 Bn),4.58 (d, 1H, J = 11.8 Hz, CHH Bn), 4.47
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FEATURED ARTICLE
(s, 2H, CH2 Bn), 4.32 (s, 1H, H-1000), 4.07 (t, 1H, J = 9.5 Hz, H-40),
3.96ꢀ4.03 (m, 2H, H-20, H-6), 3.89ꢀ3.96 (m, 2H, H-4000, H-600),
3.75ꢀ3.89 (m, 5H, H-3, H-300, H-50, H-500, H-6), 3.65ꢀ3.75 (m, 5H,
H-2000, H-5, CH3 CO2Me), 3.54ꢀ3.64 (m, 7H, H-4, H-5000, H-600, CH2,
CH3 CO2Me), 3.43ꢀ3.48 (m, 2H, H-30, H-400), 3.35ꢀ3.42 (m, 2H,
H-200, CH2), 3.26 (dd, 1H, J = 3.6, 9.9 Hz, H-2), 3.17ꢀ3.24 (m, 2H,
CH2), 3.12 (dd, 1H, J = 3.5, 9.5 Hz, H-3000), 1.46ꢀ1.63 (m, 4H, CH2),
1.25ꢀ1.37 (m, 2H, CH2), 1.01 (s, 9H, CH3tBu), 0.94 (s, 9H, CH3tBu),
0.83 (s, 9H, CH3tBu), 0.14 (s, 3H, CH3 Me), ꢀ0.03 (s, 3H, CH3 Me);
13C-APT NMR (CDCl3, 100 MHz, HSQC, tentatively assigned based
on 13C-APT NMR of compound 42) δ 167.7, 167.0 (CdO CO2Me),
156.3 (d, J = 53 Hz, CdO Z), 138.6, 138.5, 137.9, 137.8 (Cq Bn), 136.7
(d, J = 18 Hz, Cq Bn), 128.3, 127.9, 127.8, 127.7, 127.5, 127.1 (CHarom),
101.0 (C-10), 100.0 (C-1000), 98.8 (C-100), 97.4 (C-1), 81.1 (C-300), 79.6
(C-200, C-3), 77.5 (C-5000), 76.9 (C-500), 76.0, 75.9 (C-400, C-50), 75.3
(CH2 Bn), 74.7 (C-40), 74.4, 73.4 (CH2 Bn), 70.9 (C-4), 68.2 (CH2),
67.7 (C-4000), 67.2, 67.1 (C-600, CH2 Z), 66.6 (C-5), 66.4 (C-6), 64.9 (C-
3000), 63.3 (C-30), 62.7 (C-20), 62.5, 62.4 (C-2, C-2000), 52.7, 52.3 (CH3
CO2Me), 50.3 (d, J = 26 Hz, CH2 Bn), 46.5 (d, J = 107 Hz, CH2), 28.9
(d, J = 7 Hz, CH2), 27.5 (d, J = 35 Hz, CH2), 27.2, 26.9, 25.5 (CH3tBu),
23.3 (d, J = 10 Hz, CH2), 22.5, 19.7, 17.9 (CqtBu), ꢀ4.7, ꢀ5.3 (CH3
Me); 13C-GATED (CDCl3, 100 MHz) δ 101.0 (JC1,H1 = 157 Hz, C-10),
100.0 (JC1,H1 = 160 Hz, C-1000), 98.8 (JC1,H1 = 168 Hz, C-100), 97.4
(JC1,H1 = 169 Hz, C-1); HRMS [M + NH4]+ calcd for C81H112N17O20Si2
1698.78026, found 1698.78165.
N-(Benzyl)benzyloxycarbonyl-5-aminopentyl 3-O-(Methyl -
4-O-[6-O-{methyl 2,3-diazido-2,3-dideoxy-β-D-mannopyra-
nosyl Uronate}-2,3,4-tri-O-benzyl-R-D-glucopyranosyl]-2,
3-diazido-2,3-dideoxy-β-D-mannopyranosyl Uronate)-2-azido-
2-deoxy-R-D-glucopyranoside (46). A solution of compound 45
(69 mg, 41 μmol) in THF (1 mL) was cooled to 0 °C and treated with
acetic acid (9 μL, 0.16 mmol) and tetrabutylammonium fluoride (1 M in
THF, 82 μL, 82 μmol). The resulting solution was stirred for 3 h,
followed by the addition of H2O and EtOAc. The organic phase was
washed with saturated aqueous NaCl (2ꢁ), dried over Na2SO4, con-
centrated in vacuo, and purified using flash column chromatography
(silica gel, 50% EtOAc in PE) to yield the 4000-OTBS-protected inter-
mediate as a colorless oil (60 mg, 39 μmol, 96%). Spectroscopic data
are reported for the 4000-OTBS-protected intermediate: TLC Rf 0.44
(PE/EtOAc, 1/1, v/v); 1H NMR (CDCl3, 400 MHz, HHꢀCOSY,
HSQC, T = 328 K) δ 7.19ꢀ7.41 (m, 25H, CHarom), 5.20 (s, 2H, CH2
Z), 5.06 (d, 1H, J = 3.3 Hz, H-100), 4.97 (d, 1H, J = 11.1 Hz, CHH Bn),
4.83ꢀ4.93 (m, 3H, CHH Bn, H-1, H-10), 4.78 (d, 1H, J = 11.3 Hz,CHH
Bn), 4.75 (d, 1H, J = 11.9 Hz, CHH Bn), 4.69 (d, 1H, J = 11.7 Hz, CHH
Bn), 4.63 (d, 1H, J = 11.8 Hz, CHH Bn), 4.52 (s, 2H, CH2 Bn), 4.33
(s, 1H, H-1000), 4.16 (t, 1H, J = 8.7 Hz, H-40), 4.10 (d, 1H, J = 1.2 Hz, H-20),
4.05 (d, 1H, J = 8.4 Hz, H-50), 3.85ꢀ4.02 (m, 4H, H-3, H-300, H-6,
H-600), 3.77ꢀ3.82 (m, 1H, H-6), 3.74 (s, 6H, CH3 CO2Me), 3.54ꢀ3.72
(m, 9H, H-2000, H-30, H-4, H-4000, H-5, H-500, H-5000, H-600, CH2),
3.40ꢀ3.50 (m, 3H, H-200, H-400, CH2), 3.37 (dd, 1H, J = 3.4, 10.2 Hz,
H-2), 3.28 (bt, 2H, J = 5.6 Hz, CH2), 3.17 (dd, 1H, J = 3.5, 9.5 Hz,
H-3000), 1.52ꢀ1.68 (m, 4H, CH2), 1.32ꢀ1.40 (m, 2H, CH2), 0.88
(s, 9H, CH3tBu), 0.20 (s, 3H, CH3 Me), 0.02 (s, 3H, CH3 Me); 13C-
APT NMR (CDCl3, 100 MHz, HSQC) δ 167.7, 167.2 (CdO CO2Me),
156.4 (d, J = 50 Hz, CdO Z), 138.5, 138.4, 137.9, 137.8 (Cq), 136.7 (d,
J = 23 Hz, Cq Bn), 128.5, 128.5, 128.3, 128.2, 128.0, 127.9, 127.8, 127.6,
127.2 (CHarom), 100.6 (C-10), 100.2 (C-1000), 98.2 (C-100), 97.0 (C-1),
83.8 (C-3), 81.1 (C-300), 79.7 (C-200), 77.5 (C-5000), 76.2 (C-50), 75.8
(C-400), 75.4, 74.5 (CH2 Bn), 74.1 (C-40), 73.5 (CH2 Bn), 71.3, 71.0
(C-4, C-500), 69.6 (C-5), 67.9 (CH2), 67.7 (C-4000), 67.4 (C-600), 67.1
(CH2 Z), 64.9 (C-3000), 62.7 (C-30), 62.4 (C-2000), 62.4 (C-6), 62.1, 62.0
(C-2, C-20), 53.2, 52.4 (CH3 CO2Me), 50.3 (d, J = 20 Hz, CH2 Bn), 46.4
(d, J = 111 Hz, CH2), 28.8 (CH2), 28.0 (d, J = 51 Hz, CH2), 25.5
(CH3tBu), 23.2 (CH2), 17.9 (CqtBu), ꢀ4.7, ꢀ5.2 (CH3Me); 13C-GATED
(CDCl3, 100 MHz) δ 100.6 (JC1,H1 = 162 Hz, C-10), 100.2 (JC1,H1
=
160 Hz, C-1000), 98.2 (JC1,H1 = 171 Hz, C-100), 97.0 (JC1,H1 = 169 Hz, C-1).
The 4000-OTBS-protected intermediate (84 mg, 55 μmol) was dissolved
in THF (0.5 mL) and treated with acetic acid (13 μL, 0.22 mmol) and
tetrabutylammonium fluoride (1 M solution in THF, 0.17 mL, 0.17 mmol)
at 0 °C. The resulting mixture was stirred at rt for 2 days, after which time
H2O and EtOAc were added. The organic phase was washed with
saturated aqueous NaCl (2ꢁ), dried over Na2SO4, and concentrated in
vacuo. Purification using flash column chromatography (silica gel, 75%
EtOAc in PE) yielded the title compound as a colorless foam (60 mg,
42 μmol, 75%): TLC Rf 0.31 (PE/EtOAc, 1/2, v/v); [R]20D +28.1 (c 1,
DCM); IR (neat, cmꢀ1) 698, 731, 1028, 1070, 1683, 1749, 2102, 2927,
1
3495; H NMR (CDCl3, 400 MHz, HHꢀCOSY, HSQC, T = 328 K)
δ 7.14ꢀ7.39 (m, 25H, CHarom), 5.17 (s, 2H, CH2 Z), 5.07 (d, 1H, J =
3.4 Hz, H-100), 4.95 (d, 1H, J = 11.1 Hz, CHH Bn), 4.89 (d, 1H, J =
0.9 Hz, H-10), 4.83ꢀ4.87 (m, 2H, CHH Bn, H-1), 4.76 (d, 1H, J = 11.2 Hz,
CHH Bn), 4.73 (d, 1H, J = 11.9 Hz, CHH Bn), 4.67 (d, 1H, J = 11.8 Hz,
CHH Bn), 4.60 (d, 1H, J = 11.8 Hz, CHH Bn), 4.50 (s, 2H, CH2 Bn),
4.31 (s, 1H, H-1000), 4.16 (t, 1H, J = 8.6 Hz, H-40), 4.06ꢀ4.10 (m, 2H,
H-20, H-50), 4.02 (t, 1H, J = 9.5 Hz, H-4000), 3.96ꢀ4.01 (m, 1H, H-600),
3.83ꢀ3.95 (m, 3H, H-3, H-300, H-6), 3.77ꢀ3.80 (m, 4H, H-6, CH3
CO2Me), 3.75 (s, 3H, CH3 CO2Me), 3.63ꢀ3.72 (m, 5H, H-2000, H-5,
H-500, H-5000, H-600), 3.53ꢀ3.62 (m, 3H, H-30, H-4, CH2), 3.38ꢀ3.47
(m, 3H, H-200, H-400, CH2), 3.35 (dd, 1H, J = 3.4, 7.1 Hz, H-2), 3.33 (dd,
1H, J = 3.3, 6.7 Hz, H-3000), 3.26 (bt, 2H, J = 5.7 Hz, CH2), 1.52ꢀ1.65
(m, 4H, CH2), 1.30ꢀ1.40 (m, 2H, CH2); 13C-APT NMR (CDCl3, 100
MHz, HSQC, tentatively assigned based on 13C-APT NMR of com-
pound 45) δ 169.4, 167.5 (CdO CO2Me), 156.5 (d, J = 50 Hz, CdO
Z), 138.5, 138.4, 137.9, 137.8 (Cq Bn), 136.7 (d, J = 31 Hz, Cq Bn),
128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.6 (CHarom), 100.6 (C-10),
100.1 (C-1000), 98.2 (C-100), 97.0 (C-1), 83.7 (C-3), 81.2 (C-300), 79.6
(C-200), 76.1 (C-400, C-50), 75.5 (CH2 Bn), 74.8 (C-5000), 74.5 (CH2 Bn),
73.9 (C-40), 73.6 (CH2 Bn), 71.0 (C-5, C-500), 69.7 (C-4), 68.0 (C-600),
67.8 (d, J = 9 Hz, CH2), 67.4 (C-4000), 67.2 (CH2 Z), 62.7 (C-30), 62.5
(C-6), 62.4 (C-3000), 62.2 (C-2, C-30), 61.9 (C-20, C-2000), 53.2, 52.8
(CH3 CO2Me), 50.3 (d, J = 18 Hz, CH2 Bn), 46.5 (d, J = 114 Hz, CH2),
28.9 (CH2), 27.5 (d, J = 50 Hz, CH2), 23.2 (CH2); 13C-GATED
(CDCl3, 100 MHz) δ 100.6 (JC1,H1 = 162 Hz, C-10), 100.1 (JC1,H1
=
159 Hz, H-1000), 98.2 (JC1,H1 = 166 Hz, C-100), 97.0 (JC1,H1 = 169 Hz,
C-1); HRMS [M + NH4]+ calcd for C67H82N17O20 1444.59165, found
1444.59310.
5-Aminopentyl 3-O-(4-O-[6-O-{2,3-Di-N-acetamido-2,
3-dideoxy-β-D-mannopyranosyl Uronate}-R-D-glucopyranosyl]-
2,3-di-N-acetamido-2,3-dideoxy-β-D-mannopyranosyl Uronate)-
2-N-acetamido-2-deoxy-R-D-glucopyranoside (47). Compound
46 (85mg,60μmol) was dissolved in THF (1 mL) and treated with a freshly
prepared solution of aqueous KOOH (0.36 mL, 0.5 M, KOH/H2O2 = 1:2)
at 0 °C. The resulting solution was stirred at +4 °C overnight, after which
time the mixture was neutralized by the addition of 1 M aqueous HCl (pH ∼7).
EtOAc was added, and the organic phase was washed with saturated
aqueous NaCl (2ꢁ). The combined aqueous layers were extracted with
EtOAc (1ꢁ), and the organic fractions were together dried over Na2SO4
and concentrated in vacuo to give the crude diacid as a colorless oil (83 mg,
59 μmol): TLC Rf 0.09 (EtOAc/MeOH, 9/1, v/v + 1% AcOH); [R]20
D
+42.0 (c 0.2, DCM); IR (neat, cmꢀ1) 698, 735, 1028, 1072, 1605, 1694,
2106, 2924, 3437. The presence of two uronic acid moieties resulted in such
broadening of the NMR signals that accurate assignment was im-
possible; however, the disappearance of the CO2Me-signals was confirmed:
HRMS [M + H]+ calcd for C65H75N16O20 1399.53380, found 1399.53576.
The crude diacid (∼83 mg) was dissolved in THF/acetic acid (6 mL, 4/1, v/v)
and treated with zinc dust (0.29 g, 4.43 mmol) overnight. Full conversion to
the free amine-containing product was verified using LC-MS (Rt =6.91min,
10% f 90% B in C). The mixture was subsequently filtrated over a
Whatmann filter-containing glass-filter funnel using DCM/MeOH, and the
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The Journal of Organic Chemistry
FEATURED ARTICLE
filtrate was concentrated in vacuo. The residue was dissolved in THF/H2O
(4 mL, 1/1), and the mixture was basicified by the addition of solid
NaHCO3 (pH > 8). Acetic anhydride (0.11 mL, 1.18 mmol) was added,
and the reaction was allowed to stir at rt until LC-MS analysis indicated
complete conversion to the penta-N-acetamido intermediate (Rt = 9.00 min,
10% f 90% B in C). The mixture was diluted with DCM, washed with
saturated aqueous NaCl (1ꢁ), dried over Na2SO4, and concentrated in
vacuo. The residue was dissolved in THF/H2O (4 mL, 1/1) and treated
with 0.45 M aqueous KOH (0.13 mL) to remove any O-acetyls. The
mixture was then acidified by the addition of 1 M aqueous HCl (pH < 5)
and purged with argon. Palladium on activated charcoal (10 wt %, ∼20 mg)
was added, and the resulting suspension was consecutively purged with
argon and H2(g). The mixture was allowed to stir at rt under a blanket of H2.
When analysis by LC-MS indicated no further conversion to the product,
extra palladium black was added and H2 was again applied. Subsequently,
the mixture was filtered through a Whatmann filter-containing glass-filter
funnel, neutralized by the addition of saturated aqueous NaHCO3, and
concentrated in vacuo. Purification using HPLC and lyophilization resulted
in the title compound as a white fluffy solid (12 mg, 12 μmol, 20% over
five steps): 1H NMR (D2O, 600 MHz, HHꢀCOSY, HSQC, T = 313 K) δ
5.25 (d, 1H, J = 3.5 Hz, H-100), 5.09 (s, 1H, H-1Man), 5.04 (s, 1H, H-1Man),
4.97 (d, 1H, J = 3.0 Hz, H-1), 4.63 (d, 1H, J = 2.3 Hz, H-2Man), 4.42ꢀ
4.47 (m, 2H, H-2Man, H-3Man), 4.22 (dd, 1H, J = 3.5, 10.6 Hz, H-3Man),
van den Bos, L. J.; de Jong, A.-R.; Dinkelaar, J.; Lodder, G.; Overkleeft, H. S.;
van der Marel, G. A. J. Org. Chem. 2009, 74, 38–47. (c) Dinkelaar, J.; de Jong,
A.-R.; van Meer, R.; Somers, M.; Lodder, G.; Overkleeft, H. S.; Codꢀee,
J. D. C.; van der Marel, G. A. J. Org. Chem. 2009, 74, 4982–4991.
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4.12ꢀ4.18 (m, 2H, H-2, H-600), 4.04ꢀ4.08 (m, 3H, H-4Man, H-5Man
,
H-600), 3.97ꢀ4.04 (m, 3H, H-3, H-5Man, H-6), 3.88ꢀ3.95 (m, 2H, H-500,
H-6), 3.79ꢀ3.87 (m, 3H, H-4Man, H-5, CHH OꢀCH2), 3.74 (t, 1H, J =
10.7 Hz, H-300), 3.70 (t, 1H, J = 9.5 Hz, H-4), 3.63ꢀ3.67 (m, 1H, CHH
OꢀCH2), 3.59 (t, 1H, J = 9.6 Hz, H-400), 3.53 (dd, 1H, J = 3.6, 9.8 Hz,
H-200), 3.17 (t, 2H, J = 7.4 Hz, CH2-NH2), 2.21 (s, 3H, CH3 Ac), 2.21 (s,
3H, CH3 Ac), 2.19 (s, 3H, CH3 Ac), 2.11 (s, 3H, CH3 Ac), 2.09 (s, 3H, CH3
Ac), 1.74ꢀ1.88 (m, 4H, CH2), 1.56ꢀ1.67 (m, 2H, CH2); 13C-APT NMR
(D2O, 150 MHz, HSQC) δ 176.7, 176.1, 175.7, 175.7, 175.4, 175.2, 175.1
(CdO Ac, COOH), 100.8 (C-1Man), 100.5 (C-1Man), 99.5 (C-100), 97.9
(C-1), 82.2 (C-3), 79.5 (C-5Man, C-5Man), 73.5 (C-300), 72.7 (C-5), 72.4
(C-4Man), 72.2 (C-200), 71.8 (C-500), 69.6 (C-4), 69.5 (C-400), 68.7 (C-600),
68.6 (OꢀCH2) 67.5 (C-4Man), 61.5 (C-6), 54.5 (C-3Man), 54.4 (C-3Man),
53.3 (C-2), 52.6 (C-2Man), 51.9 (C-2Man), 40.4 (CH2ꢀNH2), 29.1, 27.5,
23.5 (CH2), 22.9, 22.8, 22.7 (CH3 Ac); 13C-HMBC (D2O, 150 MHz)
δ 100.8 (JC1,H1 = 162 Hz, C-1Man), 100.5 (JC1,H1 = 164 Hz, C-1Man), 99.5
(JC1,H1 = 171 Hz, C-100), 97.9 (JC1,H1 = 172 Hz, C-1); HRMS [M + H]+
calcd for C39H65N6O23 985.40956, found 985.41023.
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’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra of low-temperature
b
experiments and all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: marel_g@chem.leidenuniv.nl; jcodee@chem.leidenuniv.nl.
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’ ACKNOWLEDGMENT
We thank C. Erkelens and F. Lefeber for their assistance with
executing the NMR experiments. This research was supported by
Top Institute Pharma and The Netherlands Organization of
Scientific Research (NWO, Vidi grant). We thank Joris van Dam
for the journal cover art.
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