Expanding the scope of aminosugars: Synthesis of 2-amino septanosyl glycoconjugates using septanosyl fluoride donors

Article abstract of DOI:10.1002/chem.201003721

A general strategy amenable to the strerocontrolled synthesis of complex, ring-expanded analogues of natural aminoglycosides has been developed. Central to the method is the utilization of septanosyl fluorides as glycosyl donors in facile and selective glycosylation reactions. The septanosyl fluorides proved to be the best choice for the glycosylations because of their accessibility and the scope of aglycones that they could glycosylate. Moreover, a high degree of stereoselectivity was observed in the glycosylations, exclusively giving 1,2-trans-glycosides. 2-Amino septanosyl fluorides were prepared from D-glucose, D-galactose, and D-mannose. Other routes to the septanosyl glyconjugates, especially with regard to alternate donor types, were systematically investigated. Since routes to the individual donor types were being explored, factors that exert a controlling influence on the acid-mediated cyclization of 1,6-hydroxy-aldehydes were determined. The newly prepared 2-amino septanosyl glycoconjugates illustrate the scope of the reaction and how it may be utilized for the preparation of other ring-expanded analogues of glycosylated natural products. Copyright

Full text of DOI:10.1002/chem.201003721

FULL PAPER
DOI: 10.1002/chem.201003721
Expanding the Scope of Aminosugars: Synthesis of 2-Amino Septanosyl
Glycoconjugates Using Septanosyl Fluoride Donors
Jaideep Saha and Mark W. Peczuh*[a]
Abstract: A general strategy amenable
to the strerocontrolled synthesis of
complex, ring-expanded analogues of
natural aminoglycosides has been de-
veloped. Central to the method is the
utilization of septanosyl fluorides as
glycosyl donors in facile and selective
glycosylation reactions. The septanosyl
fluorides proved to be the best choice
for the glycosylations because of their
accessibility and the scope of aglycones
that they could glycosylate. Moreover,
a high degree of stereoselectivity was
observed in the glycosylations, exclu-
sively giving 1,2-trans-glycosides. 2-
Amino septanosyl fluorides were pre-
pared from d-glucose, d-galactose, and
d-mannose. Other routes to the septa-
nosyl glyconjugates, especially with
regard to alternate donor types, were
routes to the individual donor types
were being explored, factors that exert
a controlling influence on the acid-
mediated cyclization of 1,6-hydroxy-al-
dehydes were determined. The newly
prepared 2-amino septanosyl glycocon-
jugates illustrate the scope of the reac-
tion and how it may be utilized for the
preparation of other ring-expanded an-
alogues of glycosylated natural prod-
ucts.
systematically
investigated.
Since
Keywords: amino sugars · carbohy-
drates · fluorides · glycosylation ·
natural products · septanose
Introduction
bound by Concanavalin A (ConA) in a way that mimics
pyranoses.[7] Motivated both by our experience with the
(ConA) model system and by the importance of aminosu-
gars underlying the fields of chemical biology and drug dis-
covery, we investigated the synthesis of ring-expanded ana-
logues of aminosugars. To date, reactions for the formation
of septanosyl glycosides have employed strategies used for
pyranosides.[8] For example, 1,2-anhydrosugars[9] or thiogly-
cosides[10] have been utilized as donor species, although al-
ternative routes have been reported.[11,12] Although these
strategies delivered a wide variety of septanose glycoconju-
gates, they all have some limitations. Anhydrosugars and
thioglycosides have been applied almost exclusively to sep-
tanosides that lack exocyclic hydroxymethyl groups at the
C6 position; our work with ConA suggests that this hydrox-
ymethyl group is important if septanosides are to mimic pyr-
anosides. In our experience, the anhydrosugar and thioglyco-
side routes have been problematic for donors that incorpo-
rate a C6 hydroxymethyl group. Other routes seem arduous
in their ability to be applied generally. That is, we aimed to
develop a donor that could be coupled to a variety of agly-
cones in a modular fashion by glycosylation rather than seri-
ally conducting a multi-step synthesis of individual targets.
We therefore sought a route that would provide practical
yields of septanosides containing aglycones of expanded
scope and complexity.
Glycosylated natural products exert their effects on biologi-
cal systems by binding to RNA, DNA, proteins, protein–nu-
cleic acid complexes, and even small molecules within a
lipid bilayer.[1,2] In many cases an aminosugar moiety is criti-
cally important to the activity of the molecule. As the appre-
ciation for the significance of these carbohydrate-mediated
interactions grows, a means to prepare analogues that can
modify the activity of the parent molecule becomes necessa-
ry.[3] Slight changes in activity that correlate with minor
structural modifications can reveal the important relation-
ships underlying the affected biological processes. Addition-
ally, highly active analogues can be utilized as potential ther-
apeutics. A number of compelling strategies for varying the
carbohydrate moiety on glycoslyated natural products have
been developed recently.[4] Examples in which an aminosu-
gar analogue on a natural product brought about new activi-
ties range from the antibiotic activity of vancomycin[5] to the
anti-proliferative activity of staurosporine.[6]
We are interested in the preparation and characterization
of carbohydrate analogues that contain seven membered
ring sugars (septanoses) in place of pyranose sugars. We
have demonstrated that septanose monosaccharides can be
[a] J. Saha, Prof. M. W. Peczuh
We recently described a method for converting protected
pyranoses to methyl 2-amino septanosides.[13] In that work,
we prepared methyl 2-amino septanosides (i.e., 1–3,
Scheme 1) from d-glucose, d-galactose, and d-mannose
starting materials 4–6. We thus embarked a broader investi-
gation on the scope of the synthetic sequence, especially in
Department of Chemistry, University of Connecticut
55 North Eagleville Road, U-3060, Storrs, CT 06269 (USA)
Fax : (+1)860-486-2981
E-mail: mark.peczuh@uconn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003721.
Chem. Eur. J. 2011, 17, 7357 – 7365
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7357

assigned by considering the Cram chelate model that sets
3
C2 stereochemistry[15] in conjunction with JH1,H2 coupling
constants, the magnitudes of which (5.6–8.0 Hz) were diag-
nostic of
a trans or anti configuration. Additionally,
13C NMR chemical shifts of the C1 carbons were consistent
with a and b assignments from other septanoses that have
been prepared.[13]
To further demonstrate that the C2 group was driving cyc-
lization and selective glycoside formation in the 2-amino
system, we prepared another methyl 2-amino septanoside
derived from d-xylose (Scheme 3). The synthesis of 16 from
Scheme 1. Methyl 2-amino septanosides 1–3 prepared from glycosyl
amines 4–6 in the preliminary report of this work. Bn=benzyl, Ac=
acetyl.
terms of the aglycone that can append to the septanose. It
soon became apparent that the tandem cyclization–glycosy-
lation method that was used to make simple septanosides
was insufficient for more complex aglycones. We therefore
explored the synthesis of new 2-amino septanosyl donors
from hydroxy aldehydes that were intermediates in the earli-
er method. Here we report on that investigation, which cul-
minated in the identification of septanosyl fluorides as val-
uable donors for the synthesis of a variety of 2-amino septa-
nosyl glycoconjugates.
Results and Discussion
Scope of the original cylization–glycosylation method: In
our preliminary report on the synthesis of 2-amino septano-
sides,[13] methyl septanosides 1, 2, and 3 were prepared by a
multi-step sequence starting from the N-benzyl glycosyla-
mines of d-glucose, d-galactose, and d-mannose, respectively
(4–6, Scheme 1). In addition to describing a new route to 2-
amino septanosides, two key observations resulted from the
investigation. First, cyclic acetal formation was preferred to
acyclic dimethyl acetal formation. This was noteworthy be-
cause, in a previous study that used 2-deoxy septanosides as
intermediates, mixtures of cyclic acetal and acyclic dimethyl
acetal were obtained under the same reaction conditions
(e.g., 7 converted to 8 and 9, Scheme 2).[14] Second, the 1,2-
trans glycosides were the exclusive products formed from
the cyclization reaction. We argued that the protecting
groups on the C2 amine were playing an important steric
role for the selective formation of the cyclic acetal of a spe-
cific anomeric configuration. Anomeric stereochemistry was
Scheme 3. Synthesis of methyl a-2-amino septanoside 16 from d-xylose
10. Reagents, conditions, and yields: a) BnNH2, pTsOH, 70%; b) CH2 =
CHMgBr, THF, 08C to RT, 71%; c) 9-fluorenylmethoxycarbonyl (Fmoc)-
Cl, N,N-diisopropylethylamine (DIPEA), 99%; d) O3, dimethyl sulfide
(DMS), CH2Cl2, 91%; e) pTsOH, MeOH, 70%; f) HNEt2, MeCN, 93%.
10 is also used to illustrate the previously reported method
for the conversion of protected pyranose lactols to methyl 2-
aminoseptanosides. In the event, tri-O-benzyl xylose 10 is
converted to the N-benzyl glycosyl amine 11 under known
conditions.[13,15] Addition of a vinyl Grignard to the glycosyl
amine (presumably in the hydroxy imine form) provided al-
lylic amine 12 (50% over two steps). Addition was highly
stereoselective; we isolated only one diastereomer of 12,
which was consistent with Grignard additions to glycosyl
amines 4–6. Earlier investigations using d-glucose showed
that the choice of subsequent protecting group on the allyla-
mine was critical to successfully isolating the cyclized prod-
ucts (see the Supporting Information). 9-Fluorenylmethoxy-
carbonyl (Fmoc) protection of amine 12 followed by ozono-
AHCTUNGTREGlNNNU ysis gave hydroxy aldehyde 14 in 91% yield over two steps.
Scheme 2. Cyclization of tert-butyl dimethylsilyl (TBS) protected hydroxy
aldehyde 7. Reagents, conditions, and yields: a) pTsOH, CH3OH, RT;
8=36% (3:2 a/b), 9=42%.
Compounds with bis-protection on the nitrogen atom (e.g.,
1
13–16) gave H and 13C NMR spectra that contained multi-
7358
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7357 – 7365

Expanding the Scope of Aminosugars
FULL PAPER
Table 1. Conversion of septanose 17 to septanosides 18a–23a under
ple signals for each resonance; we ascribed this to the hy-
droxy-aldehyde/hemiacetal equilibrium (14 and 15) and also
acidic conditions.[a]
Alcohol (R’OH)
Glycosylation
Yield [%]
Deprotection[b]
Yield [%]
À
to multiple rotamers about the carbamate C N bonds. With-
out regard to the specifics of the 14–15 equilibrium, intro-
duction of the product of ozonolysis to acidic methanol de-
livered methyl a-septanoside 16 in 70% yield. Once the
Fmoc group was removed, as in 16a (93% yield), the NMR
spectra once again could be readily interpreted. Shown in
allyl alcohol (18)
18a, 85
19a, 71
20a, 69
21a, 78
22a, 73
23a, 88
24a, 0
18b, 88
19b, 75
20b, 82
21b, 80
22b, 92
23b, 85
NA
allyloxy ethanol (19)
azido ethanol (20)
cyclohexyl methanol (21)
chloroethanol (22)
n-octanol (23)
1
Figure 1 are details of H NMR spectra for 16 and 16a that
(S)-phenyl b-2,3,4,-tri-O-benzyl
glucoside (24)
illustrate these observations; they are representative of the
differences between spectra of the Fmoc protected and de-
protected species for nearly all the new molecules described
here. The efficient and selective formation of 16 demonstrat-
[a] Conditions: pTsOH, CH2Cl2, and alcohol (ꢀ100 equiv for 18–23,
ꢀ10 equiv for 24). [b] Fmoc deprotection.
the alcohol was essentially used
as a co-solvent in these reac-
tions. Product septanosides ex-
clusively of the a-configuration
were obtained in good yields
(69–88%). Attempted reaction
with (S)-phenyl b-2,3,4-tri-O-
benzyl glucoside (24) under the
established conditions failed to
provide the desired disacchar-
ide, both at RT and when heat-
ing 1,2-dichloroethane (DCE)
to reflux.[16] Overall, this route
provided facile access to 2-
amino septanosyl derivatives
using simple alcohols as co-sol-
vents, but it suffered from two
major limitations. First, acid-
sensitive functional groups in
both the donor and acceptor
could not be utilized due to the
1
Figure 1. Detail of H NMR spectrum of 16 (left) and 16a (right).
acid used in the reaction.
ed that, at least in the 2-amino series and in contrast to the
2-deoxy series, the C2 functionality favored cyclization over
formation of the acyclic dimethyl acetal. Moreover, the 1,2-
trans glycoside was formed and was presumably directed by
the functionality at C2. The synthesis of 16 also expanded
the scope of pyranoses that are amenable to this strategy.
We next focused on preparing 2-amino glycosides with ad-
ditional aglycones through the cyclization–glycosylation
route. To be effective, the strategy needed to deliver 2-
amino septanosides with aglycones that were more elaborate
than the simple methyl glycosides that had already been
prepared. Scope in this regard was evaluated using hemiace-
tal 17 as the latent glycoside (Table 1) in the presence of an
alcohol to give septanosides 18a–23a. In each case a large
excess (ꢀ100 equiv) was required to affect the cyclization;
Second, the choice of acceptors was restricted to simple al-
cohols due to the excess equivalents required by the reac-
tion. To make use of a general strategy that would enable us
to incorporate the seven-membered amino sugar into com-
plex natural-product-like frameworks, a septanosyl donor
capable of providing product glycosides with good yields
and selectivity was necessary. The investigation then turned,
therefore, toward the preparation of such a donor.
Development of septanosyl fluorides as donors: Forays into
the development of new donors made use of septanose 17
(Scheme 4). The strategies for their syntheses were based on
precedents from the pyranose literature. Conversion of 17 to
different donor types occured in a way that is similar to
pyranoses. Characterization of the donors presented chal-
lenges due to the nature of the protecting group on the C2
nitrogen; this challenge would be common to the develop-
ment of a pyranose donor. As presented later, the preva-
lence of idiosyncratic intramolecular reactions when using
the septanosyl donors is, however, distinct from pyranoses.
Chem. Eur. J. 2011, 17, 7357 – 7365
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7359

M. W. Peczuh and J. Saha
1H and 13C chemical shifts. The conversion was apparent by
the disappearence of the typical allylic ddd signal at d=
5.89 ppm (of 18a) and subsequent formation of a methyl
signal (of 27) at d=1.21 ppm. To confirm the structure of
27, a sample was subjected to Fmoc deprotection to give
27a (88%), the NMR spectra of which clearly supported the
proposed structure. Hemiacetal 17 was also converted to
septanosyl fluoride 28 in 48% yield using diethylaminosul-
fur trifluoride (DAST) under neutral conditions.[20] Forma-
tion of the septanosyl fluoride was monitored by a distinct
downfield shift (dH 5.60 ppm) exhibited by the anomeric
proton (H1) for 28 and with a dd splitting pattern with large
coupling constant, JHÀF =53.5, 6.5 Hz.[21] Preliminary glyco-
sylations (see below) showed that the septanosyl fluoride
was a better donor based on ease of preparation and yield
of the glycosylation reaction. We therefore looked to opti-
mize the yield of the fluoride itself and also to expand the
scope of the donors. Results of this investigation are shown
in Table 2. Changing the solvent from THF to CH2Cl2 in-
Scheme 4. Conversion of hemiacetal 17 to septanosyl donors. Reagents,
conditions, and yields: a) Ac2O, py. 35%; b) HNEt2, MeCN, 25a=80,
26a=87, 27a=88, 28a=80%; c) EtSH, BF3·OEt2, 08C to RT, 64%;
d) See Table 1, 85%; e) RhCl
Table 2.
ACHTUNGRTEN(NUNG PPh3), toluene/EtOH, 758C, 80%; f) See
Table 2. Conversion of septanoses 17, 29, and 30 to septanosyl fluorides
28, 31, and 32.
Lactol
Conditions
Product
Yield
[%]
Lactol 17 was converted to the a-anomeric acetate 25 in
low yield (35%) under standard acetylation conditions. Re-
moval of the Fmoc group from 25 provided 25a (80%
yield). The C1 acetate group did not migrate to the amine
as a result of the deprotection; this was considered corrobo-
rative evidence for the trans-1,2 nature of 25. Selective for-
mation of the a anomer of 25 also suggested that this was
the preferred configuration septanose 17. In fact, the NMR
spectra of 17a, obtained through Fmoc deprotection of 17
itself,[13] indicated that only the cyclic hemiacetal was pres-
ent.[17] Attempts at preparation of the anomeric trichloro-
17
17
17
29
30
THF, À208C to RT
28
28
28
31
32
48
57
85
58
67
CH2Cl2, À208C to RT
CH2Cl2, À788C to À608C
CH2Cl2, À788C to À608C
CH2Cl2, À788C to À608C
creased the yield of conversion of 17 to 28 from 48 to 57%.
Lowering the temperature of the reaction led to an addi-
tional boost to the yield (to 85% for 28). 2-Amino septano-
ses 29 and 30, derived from d-galactose and d-mannose,
were converted to their corresponding septanosyl fluorides
31 and 32 (Scheme 5) in 58 and 67% yields, respectively,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
only starting material 17 or Fmoc-deprotected material 17a
were isolated from test reactions. Based on these results, we
ruled out other donors that might be accessed through base-
mediated reactions. Reaction of 17 with ethane thiol in the
presence of a Lewis acid gave dithioethyl acetal 26 (in 64%
yield) instead of the expected (S)-ethyl 2-amino-septano-
side; attempted formation of the (S)-ethyl glycoside through
cyclization of 26 resulted in an intractable product mixture
and was not further pursued. We next enlisted allyl septano-
side 18a, which was prepared in 85% yield from 17.[18] Allyl
pyranosides served as precursors of acid-labile vinyl glyco-
sides which have found application in glycosylation reac-
tions; we planned on using the same strategy with septano-
sides. Isomerization of the terminal alkene in 18a with Wil-
kinsonꢁs catalyst under reported conditions delivered isopro-
penyl septanoside 27 (80%, Scheme 4).[19] As had been ob-
served in the synthesis of 2-amino septanosides (e.g., 1a),
Scheme 5. d-Glucose, d-galactose, and d-mannose-derived septanoses 17,
29, and 30 along with their corresponding septanosyl fluorides 28, 31, and
32.
under the reaction conditions that had been established for
the conversion of 17 to 28.
Glycosylations and intramolecular reations of the septanosyl
fluorides: With access to septanosyl donors 27, 28, 31, and
32 secured, we next subjected them to a glycosylation of
model acceptor 1,2:3,4-di-O-isopropylidene-d-galactose (33)
(Scheme 6). Reactions using vinyl septanoside 27 as a donor
were attempted with either N-iodosuccinimide or TMS-tri-
flate (TMSOTf) as activators, but only the donor and ac-
ceptor were isolated from the reaction mixtures in these re-
actions. Alternatively, activation of septanosyl fluoride 28
1
the H and 13C NMR spectra of Fmoc protected donor 27
contained multiple signals for each resonance; we ascribed
this to the hydroxy-aldehyde–hemiacetal equilibrium and ro-
À
tamers about the carbamate C N bonds. Conversion of 18a
to 27 was determined based on TLC analysis and diagnostic
7360
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7357 – 7365

Expanding the Scope of Aminosugars
FULL PAPER
tramolecular reaction for septanosyl oxocarbeniums. We
therefore investigated the behavior of 28 (which differs in
configuration at C2 and C3 relative to 32) under the glyco-
sylation reaction conditions but in the absence of an accept-
or. A new product, 37 (Scheme 7), was isolated in 61%
yield. NMR analysis confirmed the presence of the Fmoc
group and only four benzyl signals, which raised the possibil-
ity of intramolecular attack at C1 of oxocarbenium 36 by
the C5 benzyloxy group as observed before by us in other
examples.[24,28] Reaction through the C5 benzyloxy group is
probably the dominant pathway. We propose that formation
of the oxazoladinone in 35 is unique and arises only because
the C5 pathway is shut down in this system. Specifically, the
disubstituted amine at C2 blocks attack by the C5 benzyloxy
group while simultaneously positioning the carbamate
oxygen nearby the oxocarbenium carbon. Characterization
of the per-acetyl-protected derivative 38 by NMR and MS
analysis (see the Supporting Information) confirmed the
structure of 37. The differential reactivity of 28 relative to
32 is consistent with work on related molecules and under-
scores the complex reactivity of septanosides, specifically
the occurrence of intramolecular reactions.
The intramolecular cyclizations that followed upon the ac-
tivation of 28 and 32 in the absence of acceptors provided
strong evidence that the oxocarbenium ion intermediates
were in fact cyclic. Formation of 37 from 36 was used as a
test for oxonium ion generation in other contexts. Specifical-
ly, when lactol 17 was subjected to acid (para-toluene sul-
fonic acid (pTsOH)) in CH2Cl2, no reaction occurred; we in-
itially anticipated formation of 37 under these conditions
too, from 36. The conditions were the same as those used in
the formation of 1a and 18a–23a from 17 save for the ab-
sence of alcoholic nucleophiles. The result suggested that,
under the acidic conditions of the reaction, cyclic oxocarbe-
nium ion 36 did not form. As a consequence, glycosides
such as 1a and 18a–23a probably formed via acyclic oxocar-
benium ions. Moreover, the C2 carbamate group likely facil-
itates coordination to the acid and directs glycoside bond
formation (see the Supporting Information).[29] Isolation of
Scheme 6. Glycosylation of model substrate 1,2:3,4-di-O-propylidine-d-
galactose 33 with donors 28 and 31. See text and Table 3 for reagents,
conditions, and yields.
using TMS-triflate (TMSOTf) in the presence of 33 provid-
ed pyranosyl septanoside 33a in 65% isolated yield
(Method A).[22] The yield of the glycosylation was increased
to 70% when a combination of AgClO4 and SnCl2 were
used to activate fluoride 28 in the presence of 33 (Method
B).[20,23] Encouraged by this result, donors 31 and 32 were
used to glycosylate 33 under the same conditions. Donor 31,
derived from d-galactose, delivered glycoside 33c in a simi-
lar yield (68%) as the glycosylation using d-glucose derived
donor 28. When the reaction was conducted using the d-
mannose derived donor 32, an unexpected product was ob-
tained.
To our surprise, the attempted glycosylation of 33 with 32
under conditions we had used for 28 and 31 (AgClO4, SnCl2,
Method B) did not give the corresponding disaccharide.
Rather, NMR analysis of the isolated product lacked signals
from the aglycon entirely. This was accompanied by the fact
that the spectrum was remarkably simple, in contrast to the
products of glycosylation prior to Fmoc deprotection which
are usually characterized by their complicated NMR spectra.
Formation of a fused oxazolidinone, 35, through a mecha-
nism depicted in Scheme 7, seemed likely. Oxocarbenium
ion formation (e.g., 34) for the mannose-configured systems
is known to be facile,[24,25] and examples of oxazolidinones
arising from similarly functionalized pyranose examples are
known.[26] Also, the structure of
the proposed product was con-
sistent with the NMR spectra
and MS data. When 32 was sub-
jected to the similar reaction
conditions (Method A or B),
but in the absence of a glycosyl
acceptor, the same product, 35,
was obtained in both cases in
69 and 76% yield (Scheme 7).
Akin to the way that groups
adjacent to the electrophilic
center in a pyranosyl oxocarbe-
nium ion influence the configu-
ration of the forming bond in a
glycosylation reaction,[8a,27] we
expected that they would exert
a similar influence during an in- Scheme 7. Intramolecular reactions of oxocarbenium ions 34 and 36.
Chem. Eur. J. 2011, 17, 7357 – 7365
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7361

M. W. Peczuh and J. Saha
Scheme 8. Acceptors and their corresponding glycosylation/deprotection products described in Table 3.
dithioacetal 26 (Scheme 4), formed under Lewis acidic con-
ditions is also consistent with this model.
reaction was relatively efficient (70%). Further investigation
into the donating ability of 27 was not pursued, however.
Septanosyl fluoride 28 was used to glycosylate monosacchar-
ide acceptors 24, 33, 39–41, n-alcohols 22–23, protected l-
serine 42, and cholesterol 43. The acceptors were chosen to
resemble those likely to be encountered in the synthesis of
natural oligosaccharides and glycoconjugates. The acceptors
are organized in Scheme 8 based on the nature of the alco-
hol that participates in the glycosylation reaction. That is, al-
cohols 22–24, 33, 39, 40, and 42 are primary, whereas 41 and
43 are secondary.
With the preparation and reactivity of the 2-amino septa-
nosyl donors more fully characterized, we sought to evaluate
the scope of acceptors that could be glycosylated by septa-
nosyl fluorides 28 and 31. Scheme 8 shows the collection of
acceptors and the glycosylation products derived from them.
Also, Table 3 reports on the glycosylation conditions used,
the yield of the glycosylation reaction itself, and the yield
for the removal of the Fmoc protecting group after glycosy-
lation. Also shown in Table 3 is the result of a reaction be-
tween ispropenyl septanoside 27 and n-octanol (23). In con-
trast to the result from the earlier glycosylation attempt be-
tween 27 and 33 in which activation was not observed, this
Glycosylations involving secondary alcohols resulted in
lower yields than those with primary alcohols, suggesting
that sterics have some effect on the efficiency of the reac-
tion. Donor 31, derived from d-galactose, was used to glyco-
sylate 33 and methyl 2,3-O-isopropylidene b-d-ribofurano-
side (39) with yields that were similar to glucose derived
donor 28. Notably, the products isolated from glycosylations
involving donors 28 and 31 were solely of the a-configura-
tion. Anomeric stereochemistry was assigned based on 13C
Table 3. Glycosylation and Fmoc deprotection reactions.
Donor
Acceptor
Method[a]
Glycosylation
Yield [%][b]
Deprotection
Yield [%][b]
27
28
28
28
28
28
28
28
28
28
28
28
28
31
31
23
22
23
24
33
33
39
40
41
41
42
43
44
33
39
A
A
A
A
A
B
B
A
A
B
B
A
A
B
B
23a, 70
22a, 58
23a, 60
24a, 54
33a, 65
33a, 70
39a, 60
40a, 53
41a, 29
41a, 40
42a, 63
43a, 44
44a, 60
33c, 68
39c, 55
23b, 83
22b, 92
23b, 85
24b, 84
33b, 75
3
chemical shifts and JH1,H2 coupling constants as we had pre-
viously done with the methyl 2-aminoseptanosides.[30] As in
the original syntheses of the methyl septanosides, we ascribe
the selectivity for a-septanosides to the stereochemistry of
C2 and the bulk of its amino-substituent.
39b, 82
40b, 80
41b, 76
A glycosylation where septanosyl fluoride 28 was the
donor and TMS-azide 44 was the acceptor gave 44a in 60%
yield in a 20:1 a/b ratio of anomers. The deterioration of se-
lectivity in this glycosylation relative to the other reactions
can be explained by considering the small size and linearity
of the azide nucleophile. These attributes may allow it to
partially evade steric interactions when attacking from the b
face. Importantly, access to the septanosyl azide opens the
possibility of further derivatization and functionalization of
the 2-amino septanoside motif through known reactions.[31]
ND
43b, 84
44b, 81
33d, 80
39d, 90
[a] Method A: 27 or 28 (0.1 mmol), alcohol (0.2–0.25 mmol), 4 ꢂ mol
sieves, TMSOTf (0.1–0.12 mmol), in dry CH2Cl2, at À308C to RT.
Method B: 28 or 31 (0.1 mmol), alcohol (0.2–0.25 mmol), AgClO4–SnCl2
(0.16 mmol each), 4 ꢂ Mol sieves in dry Et2O, at À308C to RT. [b] Yield
of isolated product.
7362
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7357 – 7365

Expanding the Scope of Aminosugars
FULL PAPER
Methyl a-2-(N-Benzyl, N’-Fmoc)-amino-3,4,5-tri-O-benzyl-d-idoside (16):
14/15 (0.04 g, 0.052 mmol) was taken in a mixture of MeOH/CH2Cl2 (2:1,
3 mL) and pTsOH (0.02 g, 0.104 mmol) was added. The reaction was
stirred for 8 h at RT and then neutralized with TEA (15 mL). The solvent
mixture was removed in vacuo and the residue was purified by column
chromatography using Hex/EtOAc (7:3) as eluent to give 16 (0.028 g,
70%) as an oil. Rf =0.65 (7:3 Hex/EtOAc); [a]D =21.8 (c=0.7, CH2Cl2);
1H NMR (500 MHz, CDCl3): d=7.82–7.00 ( m, 28H), 5.22–5.00 (overlap-
ping signals, 1H), 4.91–4.49 (overlapping signals, 7H), 4.42–4.30 (overlap-
ping signals, 2H), 4.26–4.15 (overlapping signals, 1H), 4.12–4.06 (m, 1H),
4.01–3.83 (overlapping signals, 1H), 3.78–3.53 (overlapping signals, 3H),
3.41–3.21 (overlapping signals, 2H), 3.17–3.02 (m, 1H), 2.88 (s, 0.3H),
2.83–2.71 ppm (overlapping signals, 1H); 13C NMR (125 MHz, CDCl3):
d=158.1, 157.6, 156.5, 156.1, 144.4, 144.2, 144.0, 143.9, 143.8, 141.8, 141.7,
141.5, 141.3, 141.2, 139.3, 139.2, 138.7 (2), 138.6, 138.5, 138.3(2), 138.2,
137.7, 137.4, 129.0, 128.4, 128.3(2), 128.2, 128.1(2), 128.0(2), 127.9, 127.8,
127.6, 127.5(2), 127.2, 127.1, 127.0 (2), 126.4, 125.9, 125. 4, 125.3, 125.0(2),
124.7, 124.4, 124.1, 120.7, 120.6, 120.1, 119.9, 100.9, 100.3, 99.9, 99.8, 89.8,
89.5, 89.3, 89.0, 79.9, 79.2, 76.5, 76.3, 76.2, 76.2, 75.8, 75.7, 75.4, 75.2, 75.1,
73.8, 73.7, 73.2, 68.3, 68.1, 67.2, 66.3, 66.2, 65.2, 65.0, 60.7, 60.6, 60.4, 58.8,
58.5, 58.3, 56.2, 55.8, 55.2, 55.0, 54.4, 50.4, 48.5, 47.3(2), 47.1, 31.6, 29.0,
25.3, 22.7 ppm; HRMS: m/z: calcd for C50H49NO7Na+: 798.3401
[M+Na]+; found: 798.3403.
Conclusion
The preparation of 2-amino septanosides has been accom-
plished in two different reaction courses. One of the routes
was cyclization of a 1,6-hydroxy aldehyde by using pTsOH
and alcohols at room temperature. The other one was
through a septanosyl fluoride as glycosyl donor following
standard activation of the donor in the presence of variety
of acceptors. Based on the unique reactivity observed for
the 2-amino septanoses, we postulated that the two reaction
conditions employed for the formation of the seven-mem-
bered amino sugar followed different mechanistic pathways.
Activation of septanosyl fluoride likely generated a cyclic
oxocarbenium ion intermediate, which then reacted with the
acceptor to produce the corresponding glycosides akin to re-
actions observed for pyranoses. In the case of hydroxy-alde-
hyde cyclization and glycosylation however, an acyclic oxo-
carbenium pathway seemed to dominate. Test reactions that
delivered bicyclic molecules 35 and 38 as well as formation
of dithioacetal 26 supported this pathway. The results of this
investigation lead us to conclude that septanosyl fluorides,
specifically 28 and 31, are effective glycosyl donors for the
preparation of a variety of 2-amino septanoside glycoconju-
gates. Preparation of the septanosyl fluorides using DAST as
fluorinating reagent makes use of the highly populated hem-
iacetal species such as 17, 29, and 30 in the hemiacetal–hy-
droxy-aldehyde equilibrium. Glycosylations involving the
septanosyl fluorides gave good reaction yields and high se-
lectivity for the formation of a-septanoside linkages.
The new donors, the synthesis and reactivity of which
have been demonstrated here, enable the glycosylation of a
variety of aglycones with yields and selectivities that make
them synthetically useful for the discovery of bioactive gly-
coconjugates. We show the direct and modular addition of a
septanose residue to an aglycone rather than a multi-step
approach. Additionally, this is the first report of amino-sep-
tanoses being used in glycosylation reactions; moreover, the
new septanosides contain the exocyclic hydroxymethyl
group that is important for protein–carbohydrate interac-
tions. The work provides a methodology which can serve as
a starting point to the application of investigation of new
septanose containing glycoconjugates.
Methyl a-2-(N-Benzyl)-amino-3,4,5-tri-O-benzyl-d-idoside (16a): A solu-
tion of 16 (0.015 g, 0.02 mmol) in dry CH3CN (1.5 mL) was treated with
diethylamine (21 mL, 0.2 mmol) and stirred for 3 h at RT. The reaction
mixture was then evaporated to dryness and the crude material was sub-
jected to column chromatography (7:3 Hex/EtOAc) to give 16a (0.01 g,
93%) as white solid. Rf =0.48 (7:3 Hex:EtOAc); [a]D =7.2 (c=0.6,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.35–7.24 (m, 20H), 4.97 (d,
J=2.2 Hz, 1H), 4.95 (d, J=2.4 Hz, 1H), 4.87 (d, J=10.7 Hz, 1H), 4.76
(d, J=11.5 Hz, 1H), 4.67 (d, J=11.4 Hz, 1H), 4.61 (d, J=10.6 Hz, 1H),
4.49 ( d, J=6.6 Hz, 1H), 3.95 ( d, J=12.9 Hz, 1H), 3.79 ( d, J=13.1 Hz,
1H), 3.74–3.71 ( m, 2H), 3.67–3.55 ( m, 3H), 3.40 ( s, 3H), 2.88 ppm (dd,
J=8.6, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 139.1, 138.5, 138.2,
128.7, 128.6, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.0, 124.9, 120.3,
106.6, 89.0, 80.5, 79.3, 76.7, 76.4, 74.0, 62.2, 59.0, 55.1, 53.5 ppm; HRMS:
m/z: calcd for C35H40NO5: 554.2901 [M+H]+; found: 554.2882.
General procedure for the formation of septanosyl fluorides: A solution
of 2-amino septanosyl lactol (0.10 g, 0.11 mmol) in dry CH2Cl2 (2 mL)
was cooled to À788C. Diethylaminosulfur trifluoride (DAST, 31 mL in
1 mL CH2Cl2) was added to the reaction and the mixture was stirred for
1.5 h under N2 over which time the reaction warmed to À608C. Upon
completion of the reaction, as monitored by TLC, the reaction mixture
was poured onto an ice cold solution of saturated NaHCO3 (10 mL). The
mixture was extracted with CH2Cl2 (3ꢃ5 mL) and dried over Na2SO4.
The solvent was removed under reduced pressure and the residue was
purified by flash column chromatography (4:1 Hex/EtOAc with 0.5%
TEA) to give the corresponding glycosyl fluoride. Because of the com-
plex nature of their spectra, the Fmoc protected septanosyl fluorides
were not exhaustively characterized, but rather the Fmoc-deprotected de-
rivatives.
General procedure for removal of N-Fmoc groups from septanosyl fluo-
rides 28, 31, and 32: Fmoc protected material (0.022 mmol) was dissolved
in dry CH3CN (1.2 mL). Diethylamine (23 mL, neat) was added to this so-
lution and the mixture was stirred at RT for 5 h. After, the solvent was
removed under reduced pressure and the residue was purified by column
chromatography (3:2 Hex/EtOAc) to give the corresponding Fmoc-de-
protected compounds.
Experimental Section
General Methods: Unless otherwise noted, all reactions were conducted
at room temperature under nitrogen atmosphere and all the solvents and
reagents were purchased commercially and used as received. Reactions
were monitored by TLC (silica gel, 60 ꢂ, F254, 250 nm). TLC was visual-
ized either under UV light or by charring with 2.5% p-anisaldehyde in
H2SO4, acetic acid, and ethanol solution or by ninhydrin solution for pri-
mary and secondary amine compounds. Flash column chromatography
was conducted on silica gel (60 ꢂ, 32–63 mm). Optical rotations were
measured at 22Æ28C. 1H NMR spectra were recorded at 300, 400, and
500 MHz with chemical shifts referenced to (CH3)4Si (dH 0.00 ppm), or
the residual signal in CDCl3 (dH 7.27 ppm) or CD3OD (dH 3.31 ppm). 13C
spectra were collected at 75, 100, and 125 MHz and referenced to the re-
sidual signal in CDCl3 (dC 77.2) or CD3OD (dC 49.0 ppm).
2-(N-Benzyl)-amino-3,4,5,7-tetra-O-benzyl-d-glycero-d-ido-septanosyl
fluoride (28a): 28a was isolated as a colorless oil (80%). Rf =0.68 (7:3
Hex:EtOAc); 1H NMR (400 MHz, CDCl3): d=7.41–7.13 (m, 25H), 5.60
(dd, J=53.5, 6.5 Hz, 1H), 5.03 (d, J=11.3 Hz, 1H), 4.94 (d, J=10.6 Hz,
1H), 4.89–4.85 (m, 2H), 4.72–4.68 (m, 2H), 4.63–4.59 (m, 2H), 4.07–4.00
(m, 2H), 3.93–3.84 (m, 2H), 3.81–3.70 (m, 3H), 3.63 (t, J=9.3 Hz, 1H),
3.13–3.04 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): d=140.3, 138.9,
138.4, 138.1, 137.8, 128.8, 128.7 (2), 128.6 (2), 128.4 (2), 128.2, 128.1,
128.0, 127.9, 127.7, 127.4, 127.1, 115.3, 113.0, 89.8, 79.3, 78.4, 76.7, 76.2,
Chem. Eur. J. 2011, 17, 7357 – 7365
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7363

M. W. Peczuh and J. Saha
75.4, 73.9, 71.9, 70.2, 61.5, 61.2, 53.1 (2) ppm; HRMS: m/z: calcd for
C42H45NO5F: 662.3282 [M]+; found: 662.3233.
J=11.9 Hz, 1H), 4.43 (d, J=11.9 Hz, 1H), 4.32 (dd, J=4.8, 2.2 Hz, 1H),
4.24 (d, J=7.8 Hz, 1H), 4.11–4.02 (m, 4H), 3.98–3.90 (m, 2H), 3.86–3.74
(m, 2H), 3.68–3.54 (m, 3H), 2.86 (t, J=5.12 Hz, 1H), 1.50 (s, 3H), 1.43
(s, 3H), 1.33 (s, 3H), 1.27 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
141.1, 139.2, 139.0, 138.9, 138.4, 128.6, 128.5, 128.4 (2), 128.3, 128.2, 128.0,
127.9, 127.8, 127.7, 127.6, 126.8, 109.5, 108.8, 102.6, 96.5, 87.3, 80.6, 77.1,
75.2, 74.4, 74.1, 73.4, 71.3, 70.9, 70.8, 69.6, 67.0, 66.8, 63.2, 52.1, 26.3, 26.2,
25.2, 24.6 ppm; HRMS: m/z: calcd for C54H64NO11: 902.4479 [M]+; found
902.4520.
2-(N-Benzyl)-amino-3,4,5,7-tetra-O-benzyl-d-glycero-l-gluco-septanosyl
fluoride (31a): 31a (76%, colorless oil). Rf =0.61 (7:3 Hex/EtOAc);
1H NMR (400 MHz, CDCl3): d=7.39–7.23 (m, 25H), 5.60 (dd, J=51.0,
5.7 Hz, 1H), 5.09–5.02 (m, 1H), 4.95–4.86 (m, 2H), 4.78–4.71 (m, 1H),
4.68–4.62 (m, 2H), 4.50 (d, J=11.9 Hz, 1H), 4.43 (d, J=11.7 Hz, 1H),
4.08–4.0 (m, 3H), 3.89–3.72 (m, 3H), 3.60–3.56 (m, 2H), 3.03–2.96 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=140.4, 138.7, 138.6, 138.3,
138.1, 133.3, 129.9, 128.6 (2), 128.5, 128.4 (2), 128.3, 128.1, 128.0, 127.9,
127.8 (2), 127.1, 112.9, 110.6, 87.4, 79.0, 76.0, 75.5, 75.1, 74.3, 73.6, 71.6,
69.0, 62.8, 62.5, 52.2 ppm; HRMS: m/z: calcd for C42H45NO5F: 662.3282
[M]+; found: 662.3291.
Oxazolidinone (35): Obtained in 76% as colorless oil. Rf =0.50 (7:3 Hex/
EtOAc); [a]D =13.9 (c=0.4, CH2Cl2); 1H NMR (500 MHz, CDCl3): d=
7.69–7.67 (m, 2H), 7.44–7.01 (m, 23H), 5.51 (brs, 1H), 4.61–4.50 (m,
4H), 4.47–4.36 (m, 5H), 4.32 (d, J=4.2 Hz, 1H), 4.23–4.15 (m, 3H), 4.02
(d, J=11.3 Hz, 1H), 3.70 (dd, J=9.1, 4.5 Hz, 1H), 3.43–3.37 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=157.5, 143.8, 141.5, 138.0, 137.7,
137.4, 128.6, 128.5, 128.4 (2), 128.2, 128.1, 128.0 (2), 127.9, 127.8, 127.2,
126.7, 124.7 (2), 120.0, 98.8, 78.2, 76.4, 73.7, 73.4, 72.4, 71.4, 70.2, 69.0,
67.8, 50.1, 47.3 ppm; HRMS: m/z: calcd for C43H44NO7: 686.3118 [M]+;
found 686.3071.
2-(N-Benzyl)-amino-3,4,5,7-tetra-O-benzyl-d-glycero-d-galacto-septano-
syl fluoride (32a): 32a (74%, colorless oil). Rf =0.48 (7:3 Hex:EtOAc);
1H NMR (400 MHz, CDCl3): d=7.37–7.14 (m, 25H), 5.19 (dd, J=49.0,
7.7 Hz, 1H), 4.66–4.37 (m, 8H), 3.96–3.76 (m, 5H), 3.71–3.62 (m, 3H),
3.40–3.33 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=140.5, 138.5,
138.4, 138.0, 137.9, 128.7, 128.6 (2), 128.5 (2), 128.2 (2), 128.1, 128.0,
127.9, 127.8, 127.1, 116.5, 114.3, 80.9, 78.4, 78.1, 77.7 (2), 73.6, 73.4, 73.2,
72.2, 70.8, 62.2, 61.9, 53.2 ppm; HRMS: m/z: calcd for C42H45NO5F:
662.3282 [M]+; found:662.3228.
2-(N-Acetyl)-amino-3,4,7-tri-O-acetyl-1,6-anhydro-d-glycero-d-ido-septa-
nose (38): 10% Pd/C (0.03 g) was added to a solution of 37 (0.03 g,
0.05 mmol) in MeOH/CHCl3 (2:1, 3 mL) and the mixture was stirred at
RT for 12 h under positive pressure of H2 gas. After, the reaction mixture
was filtered through celite and the filtrate was evaporated to dryness.
The residue was re-dissolved in absolute MeOH (2 mL) and to it was
added NH4HCO2 (0.010 g) and 10% Pd/C (0.010 g). The solution was
heated to reflux at 808C for 4 h. After, the mixture was filtered through
celite and the solvent was removed in vacuo. The residue was dissolved
in pyridine (2 mL) and Ac2O (0.1 mL) was added. The reaction was
stirred for 8 h at room temperature. Solvents were removed in vacuo and
the residue was purified by column chromatography (1:3 Et2O/CH2Cl2)
to give 38 (0.01 g, 54% in 3 steps). Rf =0.25 (1:3 Et2O/CH2Cl2); [a]D =
37.9 (c=0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=6.09 (brs, 1H),
5.10 (brs, 1H), 4.95 (dd, J=10.1, 3.8 Hz, 1H), 4.92 (dd, J=6.1, 3.0 Hz,
1H), 4.86 (dd, J=6.1, 3.8 Hz, 1H), 4.78 (dd, J=8.0, 3.8 Hz, 1H), 4.35 (dt,
J=10.0, 3.7 Hz, 1H), 4.18–4.17 (m, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.02
(s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3): d=171.0(2), 170.0,
169.3, 102.7, 79.7, 73.3, 70.9, 65.3, 63.0, 58.3, 23.2, 21.0, 20.8, 20.6 ppm.
HRMS: m/z: calcd for C15H22NO9: 360.1295 [M]+; found 360.1304.
Glycosylation Method A (TMSOTf as the activator): The designated
donor (i.e., 28, 0.025 mmol) and the acceptor (2–2.5 equiv) were dis-
solved in dry CH2Cl2 (2–3 mL) under N2 in presence of freshly activated
4 ꢂ molecular sieves. The mixture was stirred for 30 min at RT and then
cooled to À308C. TMSOTf (1.2 equiv, 5.5 mL neat, or 105 mL of a 290 mm
solution in CH2Cl2) was added to the reaction and the mixture was al-
lowed to warm to RT over a period of 2 h. Upon completion, as moni-
tored by TLC, the reaction was neutralized by adding TEA (2 equiv,
7 mL) and filtered through celite. The solvent was removed under re-
duced pressure and the crude material was purified by column chroma-
tography using 9:1 Hex/EtOAc as eluent to obtain the product glyco-
sides.
Method B (AgClO4–SnCl2 as activator): AgClO4 (1.6 equiv) and SnCl2
(1.6 equiv) was added to an oven dried round-bottom flask. Dry Et2O
(1 mL) was added, then freshly activated powdered 4 ꢂ molecular sieves
(0.4 g). The solution was cooled to À308C and kept under N2. To this so-
lution was added the acceptor (2–3 equiv) as a solution in Et2O (1–
2 mL), followed by the donor (1 equiv in 1 mL Et2O) and the reaction
was slowly allowed to warm to RT over a period of 4 h. Upon completion
of reaction, as monitored by TLC, the reaction mixture was diluted with
Et2O (2–3 mL) and filtered through celite. The filtrate was quenched by
saturated NaHCO3 (ꢀ5 mL) and extracted in Et2O (2ꢃ5 mL). The or-
ganic layer was then dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude residue was purified by column chro-
matography using 9:1 Hex/EtOAc as eluent to obtain the product glyco-
sides.
Methyl 2,3,4,5-tetra-O-benzyl-7-O-(2-(N-benzyl)-amino-3,4,5,7-tetra-O-
benzyl-a-d-glycero-d-idoseptanosyl)-b-d-glycero-d-guloseptanoside
(40b): Obtained in 80% as colorless oil. Rf =0.42 (7:3 Hex/EtOAc);
[a]D =38.0 (c=0.6, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.36–7.09
(m, 45H), 5.03 (d, J=11.2 Hz, 1H), 4.93 (d, J=10.6 Hz, 1H), 4.85–4.81
(m, 3H), 4.75 (d, J=6.8 Hz, 1H), 4.67–4.61 (m, 7H), 4.52–4.47 (m, 2H),
4.43–4.32 (m, 3H), 4.17 (t, J=7.76 Hz, 1H), 4.05 (d, J=12.9 Hz, 1H),
3.96–3.85 (m, 5H), 3.83–3.63 (m, 6H), 3.61–3.52 (m, 2H), 3.48 (s, 3H),
2.84 ppm (dd, J=7.3, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
140.8, 139.1, 139.0, 138.6 (2), 138.2 (2), 128.6, 128.5(2), 128.4, 128.3 (2),
128.2(2), 128.0, 127.9, 127.8(2), 127.7(2), 127.6, 127.5, 127.4, 126.8, 106.5,
106.3, 90.1, 81.6, 80.0, 79.5, 79.0, 78.3, 77.4, 76.5, 76.0, 75.6, 75.2, 73.7,
73.6, 72.7 (2), 70.4, 70.2, 69.0, 61.8, 56.5, 53.5 ppm; HRMS: m/z: calcd for
C78H84NO12:1226.5994 [M]+; found 1226.5918.
1,2:3,4-Di-O-isopropylidene-6-O-(2-(N-Benzyl)-amino-3,4,5,7-tetra-O-
benzyl-a-d-glycero-d-idoseptanosyl)-a-d-galactose (33b): Obtained in
75% yield as a yellow oil. Rf =0.32 (7:3 Hex/EtOAc); [a]D =0.94 (c=0.7,
CH2Cl2);1H NMR (400 MHz, CDCl3): d=7.38–7.10 (m, 25H), 5.55 (d,
J=4.8 Hz, 1H), 5.0 (d, J=11.0 Hz, 1H), 4.92 (d, J=10.6 Hz, 1H), 4.86–
4.79 (m, 2H), 4.73–4.54 (m, 6H), 4.33 (dd, J=5.0, 2.4 Hz, 1H), 4.29 (d,
J=7.8 Hz, 1H), 4.05–3.95 (m, 4H), 3.87–3.78 (m, 3H), 3.73–3.63 (m,
4H), 2.87 (dd, J=8.9, 7.0 Hz, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.34 (s,
3H), 1.26 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=141.2, 139.1,
138.7, 138.3, 138.2, 128.6 (2), 128.5 (2), 128.4 (2), 128.3, 128.0, 127.9,
127.8, 127.7, 127.5, 126.9, 109.5, 108.7, 105.2, 96.6, 90.2, 79.7, 79.6, 76.5,
76.1, 75.1, 73.8, 71.2, 70.9, 70.8, 70.5, 69.2, 66.6, 66.2, 62.2, 53.5, 26.3, 26.2,
25.1, 24.7 ppm; HRMS m/z C54H64NO11 calcd 902.4479 [M]+; found
902.4444.
Cholesteroyl a-2-(N-Benzyl)-amino-d-glycero-d-idoseptanoside (43b):
Obtained in 84% yield as white solid. Rf =0.72 (7:3 Hex/EtOAc); [a]D =
9.8 (c=0.5, CH2Cl2);1H NMR (400 MHz, CDCl3): d=7.38–7.13 (m,
25H), 5.25 (d, br,1H), 5.0 (d, J=11.2 Hz, 1H), 4.91 (d, J=10.4 Hz, 1H),
4.88–4.82 (m, 2H), 4.67 (d, J=10.8 Hz, 1H), 4.61–4.60 (m, 2H), 4.54–4.53
(m, 1H), 4.03 (d, J=12.8, 1H), 3.97 (d, J=10.2 Hz, 1H), 3.88–3.78 (m,
2H), 3.72–3.65 (m, 2H), 3.59 (dd, J=10.0, 1.9 Hz, 1H), 3.52 (t, d=
6.1 Hz, 1H), 3.48–3.44 (m, 2H), 2.83 (t, J=8.0 Hz, 1H), 2.37–2.25 (m,
2H), 2.07–1.69 (m, 9H), 1.58–1.28 (m, 10H), 1.20–1.12 (m, 4H), 1.04–
0.89 (m, 15H), 0.71 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=141.2
(2), 139.1, 138.8, 138.7, 138.2, 138.1, 128.6, 128.5, 128.4, 128.3, 128.0,
127.9, 127.8(2), 127.7, 127.5 (2), 126.9, 121.7, 102.5, 90.2, 85.0, 79.8, 79.5,
76.4, 75.9, 75.1, 73.7, 73.0, 70.8, 70.3, 69.0, 62.0, 57.0, 56.3, 53.7, 50.3, 42.5,
40.5, 40.0, 39.7, 37.3, 37.0, 36.4, 36.0, 32.1, 29.9, 28.4, 28.2, 28.0, 27.6, 27.4,
1,2:3,4-Di-O-isopropylidene-6-O-(2-(N-Benzyl)-amino-3,4,5,7-tetra-O-
benzyl-d-glycero-l-glucoseptanosyl)-a-d-galactose (33d): Obtained in
80% yield as colorless oil. Rf =0.24 (7:3 Hex:EtOAc); [a]D =3.8 (c=0.8,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.40–7.22 (m, 25H), 5.54 (d,
J=4.9 Hz, 1H), 5.03 (d, J=11.3 Hz, 1H), 4.88–4.82 (m, 3H), 4.73 (d, J=
11.6 Hz, 1H), 4.67–4.62 (m, 2H), 4.59 (dd, J=7.9, 2.2 Hz, 1H), 4.53 (d,
7364
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7357 – 7365

Expanding the Scope of Aminosugars
FULL PAPER
26.7 (2), 25.7 (2), 24.5, 24.0, 23.0, 22.7, 21.3, 19.6, 18.9, 12.0 ppm; HRMS:
Peczuh, N. L. Snyder, W. S. Fyvie, Carbohydr. Res. 2004, 339, 1163–
1171.
m/z calcd for C69H90NO6: 1028.6768 [M]+; found:1028.6739.
[10] a) M. A. Boone, F. E. McDonald, J. Lichter, S. Lutz, R. Cao, K. I.
Hardcastle, Org. Lett. 2009, 11, 851–854; b) S. Castro, W. S. Fyvie, S.
Hatcher, M. W. Peczuh, Org. Lett. 2005, 7, 4709–4712.
[11] a) N. V. Ganesh, S. Raghothama, R. Sonti, N. Jayaraman, J. Org.
Chem. 2010, 75, 215–218; b) N. V. Ganesh, N. Jayaraman, J. Org.
Chem. 2007, 72, 5500–5504.
[12] J. C. McAuliffe, O. Hindsgaul, Synlett 1998, 307–309.
[13] J. Saha, M. W. Peczuh, Org. Lett. 2009, 11, 4482–4484.
[14] S. Castro, M. W. Peczuh, J. Org. Chem. 2005, 70, 3312–3315.
[15] a) L. Cipolla, L. Lay, F. Nicotra, C. Pangrazio, L. Panza, Tetrahedron
1995, 51, 4679–4690; b) L. Cipolla, M. R. Fernandes, M. Gregori, C.
Airoldi, F. Nicotra, Carbohydr. Res. 2007, 342, 1813–1830.
[16] Methyl a-2,3,4-tri-O-benzyl glucoside also failed to provide a prod-
uct glycoside under these reaction conditions.
[17] Attempted preparation of N-septanosyl amine from 17a and benzyl-
amine gave a complex mixture of products and was not further pur-
sued.
[18] See, for example, a) (trifluoroacetimidate) Z. Zhang, B. Yu, J. Org.
Chem. 2003, 68, 6309–6313; b) (glycosyl sulfonylcarbamate) R. J.
Hinklin, L. L. Kiessling, J. Am. Chem. Soc. 2001, 123, 3379–3380;
c) (methyl 3,5-dinitrosalicylate) L. Petersen, J. B. Laursen, K.
Larsen, M. S. Motawia, K. J. Jensen, Org. Lett. 2003, 5, 1309–1312;
d) (glycosyl phthalate) K. S. Kim, D. B. Fulse, J. Y. Baek, B-Y. Lee,
H. B. Jeon, J. Am. Chem. Soc. 2008, 130, 8537–8547.
2-(N-Benzyl)-amino-3,4,5,7-tetra-O-benzyl-d-glycero-d-ido-septanosyl
azide (44b): A solution of 27 (0.022 g, 0.03 mmol) in dry CH2Cl2 (1.5 mL)
with 4 ꢂ mol. sieves was cooled to À258C. TMSN3 (9 mL , 0.067 mmol)
and TMSOTf (5 mL, 0.032 mmol) were added successively to the solution.
The reaction mixture was slowly warmed to RT over 4 h while a new yel-
lowish spot was observed during TLC. The mixture was neutralized with
TEA and evaporated to dryness. The crude material was purified with
column chromatography (4:1 Hex/EtOAc) to give 44a (0.014 g, 60%).
The isolated compound was subjected to Fmoc deprotection without fur-
ther characterization. The crude material was dissolved in dry CH3CN
(1 mL) and diethylamine was added (11 mL, 0.1 mmol) and stirred for 3 h
at room temperature. The solvent was removed in vacuo and purified by
column chromatography (9:1 Hex/EtOAc) to give 44b (0.009 g, 81%) as
a white solid. Rf =0.6 (7:3 Hex/EtOAc); [a]D =43.5 (c=0.6, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.40–7.18 (m, 25H), 5.13 (d, J=8.0,
1H), 5.03–4.96 (m, 2H), 4.87–4.82 (m, 2H), 4.68–4.59 (m, 4H), 3.97–3.92
(m, 2H), 3.86–3.77 (m, 3H), 3.73–3.64 (m, 3H), 2.71 ppm (t, J=8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=140.4, 138.8, 138.3, 138.0, 137.9,
128.7, 128.6, 128.4, 128.3, 128.1 (2), 128.0, 127.9, 127.7, 127.2, 95.1, 89.8,
79.6 (2), 76.6, 76.2, 75.3, 73.8, 71.6, 70.4, 61.8, 53.8 ppm; HRMS: m/z:
calcd for C42H44NO5Na+: 707.3204 [M+Na]+; found: 707.3113.
[19] Allyl glycoside donors: a) G. Boons, S. Isles, J. Org. Chem. 1996, 61,
4262–4271; b) P. Wang, P. Haldar, Y. Wang, J. Org. Chem. 2007, 72,
5870–5873. Propargyl glycoside donors: S. Hotha, S. Kashyap, J.
Am. Chem. Soc. 2006, 128, 9620–9621.
[20] K. Toshima, Carbohydr. Res. 2000, 327, 15–26, and references there-
in.
Acknowledgements
This work was supported by an NSF CAREER award to MWP (CHE-
054631).
[21] P. C. Lin, A. K. Adak, S. H. Ueng, L. D. Huang, K. T. Huang, J. A.
Ho, C. C. Lin, J. Org. Chem. 2009, 74, 4041–4048.
[22] S. Hashimoto, M. Hayashi, R. Noyori, Tetrahedron Lett. 1984, 25,
1379–1382.
[23] a) T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981, 431–432;
b) K. C. Nicolaou, A. Chucholowski, R. E. Dolle, J. L. Randall, J.
Chem. Soc. Chem. Commun. 1984, 1155–1156; c) H. Kunz, H. Wald-
mann, J. Chem. Soc. Chem. Commun. 1985, 638–640; d) H. P.
Wessel, Tetrahedron Lett. 1990, 31, 6863–6866; e) H. P. Wessel, N.
Ruiz, J. Carbohydr. Chem. 1991, 10, 901–910.
[1] a) J. S. Thorson, T. J. Hosted, J. Jiang, J. B. Biggins, J. Ahlert, Curr.
Org. Chem. 2001, 5, 139–167; b) A. C. Weymouth-Wilson, Nat.
Prod. Rep. 1997, 14, 99–110; c) J. S. Thorson, T. Vogt in Carbohy-
drate-Based Drug Discovery (Ed.: C.-H. Wong), Wiley-VCH, Wein-
heim, 2003, pp. 685–707.
[2] D. Kahne, C. Leimkuhler, W. Lu, C. Walsh, Chem. Rev. 2005, 105,
425–448.
[3] a) F. Pfrengle, H.-U. Reissig, Chem. Soc. Rev. 2010, 39, 549–557;
b) D. B. Werz, P. H. Seeberger, Chem. Eur. J. 2005, 11, 3194–3206;
c) T. K. Ritter, C.-H. Wong in Carbohydrate-Based Drug Discovery
[24] S. Markad, S. Xia, B. Surana, M. D. Morton, C. M. Hadad, M. W.
Peczuh, J. Org. Chem. 2008, 73, 6341–6354.
[25] S. Markad, S. M. Miller, M. D. Morton, M. W. Peczuh, Tetrahedron
Lett. 2010, 51, 1209–1212.
(Ed.: C.-H. Wong), Wiley-VCH, Weinheim, 2003, pp. 899–928.
ˇ
ˇ
[4] a) V. Kren, T. Rezanka, FEMS Microbiol. Rev. 2008, 32, 858–889;
b) J. M. Langenhan, B. R. Griffith, J. S. Thorson, J. Nat. Prod. 2005,
68, 1696–1711.
[26] a) K. Rꢅck-Braun, A. Stamm, S. Engel, H. Kunz, J. Org. Chem.
1997, 62, 967–975; b) A. Bouali, P. Boullanger, D. Lafont, Carbo-
hydr. Res. 1992, 228, 81–93.
[27] a) H. H. Jensen, C. M. Pedersen, M. Bols, Chem. Eur. J. 2007, 13,
7576–7582; b) D. Crich, Acc. Chem. Res. 2010, 43, 1144–1153.
[28] W. S. Fyvie, M. W. Peczuh, Carbohydr. Res. 2004, 339, 2363–2370.
[29] a) J. Mulzer, A. Meier, J. Org. Chem. 1996, 61, 566–572; b) Y. Nishi-
gaichi, K. Tamura, N. Ueda, H. Iwamoto, A. Takuwa, Tetrahedron
Lett. 2008, 49, 2124–2127; c) V. H. Rawal, C. Michoud, J. Org.
Chem. 1993, 58, 5583–5584.
[30] Additional details on the assignment of anomeric stereochemistry
are provided in the Supporting Information.
[31] a) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249–
1262; b) H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 8,
1128–1137; c) E. M. Sletten, C. R. Bertozzi, Angew. Chem. 2009,
121, 7108–7133; Angew. Chem. Int. Ed. 2009, 48, 6974–6998.
[5] a) M. Ge, Z. Chen, H. Russell Onishi, J. Kohler, L. L. Silver, R.
Kerns, S. Fukuzawa, C. Thompson, D. Kahne, Science 1999, 284,
507–511; b) R. Kerns, S. D. Dong, S. Fukuzawa, J. Carbeck, J.
Kohler, L. Silver, D. Kahne, J. Am. Chem. Soc. 2000, 122, 12608–
12609.
[6] a) L. J. Wilson, R. Malaviya, C. Yang, R. Argentieri, B. Wang, X.
Chen, W. V. Murray, D. Cavender, Bioorg. Med. Chem. Lett. 2009,
19, 3333–3338; b) S. Delarue-Cochin, I. McCort-Tranchepain, Org.
Biomol. Chem. 2009, 7, 706–716.
[7] a) S. Castro, M. Duff, N. L. Snyder, M. Morton, C. V. Kumar, M.W
Peczuh, Org. Biomol. Chem. 2005, 3, 3869–3872; b) M. R. Duff, Jr.,
W. S. Fyvie, S. D. Markad, A. E. Frankel, C. V. Kumar, J. A. Gascꢄn,
M. W. Peczuh, Org. Biomol. Chem. 2011, 9, 154–164.
[8] a) L. M. Mydock, A. V. Demchenko, Org. Biomol. Chem. 2010, 8,
497–510; b) K. C. Nicolaou, H. J. Mitchell, Angew. Chem. 2001, 113,
1624–1672; Angew. Chem. Int. Ed. 2001, 40, 1576–1624; c) B. G.
Davis, J. Chem. Soc. Perkin Trans. 1 2000, 2137–2160.
Received: December 23, 2010
Revised: March 21, 2011
Published online: May 12, 2011
[9] a) M. DeMatteo, N. L. Snyder, M. Morton, D. M. Baldisseri, C. M.
Hadad, M. W. Peczuh, J. Org. Chem. 2005, 70, 24–38; b) M. W.
Chem. Eur. J. 2011, 17, 7357 – 7365
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7365