Internally protected amino sugar equivalents from enantiopure 1,2-oxazines: Synthesis of variably configured carbohydrates with C-branched amino sugar units

Article abstract of DOI:10.1002/chem.201001060

A stereodivergent synthesis of differently configured C2-branched 4-amino sugar derivatives was accomplished. The Lewis acid mediated rearrangement of phenylthio-substituted 1,2-oxazines delivered glycosyl donor equivalents that can directly be employed in glycosidation reactions. Treatment with methanol provided internally protected amino sugar equivalents that have been transformed into the stereoisomeric methyl glycosides 28, ent-28, 29, ent-29 and 34 in two simple reductive steps. Reaction with natural carbohydrates or bicyclic amino sugar precursors allowed the synthesis of homo-oligomeric di- and trisaccharides 44, 46 and 47 or a hybrid trisaccharide 51 with natural carbohydrates. Access to a bivalent amino sugar derivative 54 was accomplished by reaction of rearrangement product 10 with 1,5-pentanediol. Alternatively, when a protected L-serine derivative was employed as glycosyl acceptor, the glycosylated amino acid 60 was efficiently prepared in few steps. In this report we describe the synthesis of unusual amino sugar building blocks from enantiopure 1,2-oxazines that can be attached to natural carbohydrates or natural product aglycons to produce new natural product analogues with potential applications in medicinal chemistry. Make it simple: A Lewis acid mediated rearrangement of 1,2-oxazines delivers internally protected amino sugar equivalents that can be incorporated into oligosaccharides. Deprotection of the amino sugar precursors by simple reductive steps provides new natural product analogues having C2-branched 4-amino sugar units with different absolute and relative configurations.

Full text of DOI:10.1002/chem.201001060

FULL PAPER
DOI: 10.1002/chem.201001060
Internally Protected Amino Sugar Equivalents from Enantiopure
1,2-Oxazines: Synthesis of Variably Configured Carbohydrates with
C-Branched Amino Sugar Units
Fabian Pfrengle and Hans-Ulrich Reissig*[a]
Dedicated to Professor Richard R. Schmidt on the occasion of his 75th birthday
Abstract: A stereodivergent synthesis
of differently configured C2-branched
4-amino sugar derivatives was accom-
plished. The Lewis acid mediated rear-
rangement of phenylthio-substituted
1,2-oxazines delivered glycosyl donor
equivalents that can directly be em-
ployed in glycosidation reactions.
Treatment with methanol provided in-
ternally protected amino sugar equiva-
lents that have been transformed into
the stereoisomeric methyl glycosides
28, ent-28, 29, ent-29 and 34 in two
simple reductive steps. Reaction with
natural carbohydrates or bicyclic amino
sugar precursors allowed the synthesis
of homo-oligomeric di- and trisacchar-
ides 44, 46 and 47 or a hybrid trisac-
charide 51 with natural carbohydrates.
Access to a bivalent amino sugar deriv-
ative 54 was accomplished by reaction
of rearrangement product 10 with 1,5-
pentanediol. Alternatively, when a pro-
tected l-serine derivative was em-
ployed as glycosyl acceptor, the glyco-
sylated amino acid 60 was efficiently
prepared in few steps. In this report we
describe the synthesis of unusual
amino sugar building blocks from
enantiopure 1,2-oxazines that can be
attached to natural carbohydrates or
natural product aglycons to produce
new natural product analogues with
potential applications in medicinal
chemistry.
Keywords: allenes · amino sugars ·
carbohydrates
rearrangement
·
glycosidation
·
Introduction
There are two major possibilities to synthesize new amino
sugar derivatives: one is the chemical or enzymatic modifi-
cation of existing carbohydrates, the second involves the de
novo strategy.[5] The construction of sugars from smaller
The occurrence of amino sugar moieties in the glycome of
animals and humans is mainly restricted to glucosamine, gal-
actosamine, and sialic acids.[1] However, an enormous diver-
sity of amino sugars, including several C-branched deriva-
tives, can be found in many natural products and in a variety
of antibiotics.[2] By replacing these carbohydrates by synthet-
ic analogues a large number of antibacterial compounds
such as aminoglycoside and glycopeptide mimetics with a
decreased resistance and toxicity profile has been discov-
ered.[3] This has led to remarkable success in the therapy of
bacterial infections and genetic disorders.[4]
À
fragments by C C-bond forming reactions allows to employ
cheap starting materials and to synthesize structurally relat-
ed carbohydrates from common precursors. Particularly ad-
vantageous is the preparation of carbohydrate building
blocks that can directly be used in the synthesis of oligosac-
charides or other glycoconjugates without further protecting
group transformations.[6]
In this context, we recently described de novo approaches
towards different classes of amino sugars and their mimetics
starting from enantiopure 1,2-oxazines,[7] which are surpris-
ingly versatile intermediates for the stereoselective synthesis
of a variety of carbohydrate related compounds such as
polyhydroxylated pyrrolidines, azetidines or polyols.[8]
Among these differently configured C2-branched 4-amino
sugars A have been generated from bicyclic compounds B
by a sequence of glycosidation reaction, stereoselective car-
[a] Dr. F. Pfrengle, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax : (+49)30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
À
bonyl reduction and reductive cleavage of the N O bond
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001060.
(Scheme 1).[9] A novel Lewis acid mediated rearrangement
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of 1,2-oxazines C delivered these key intermediates by an
À
aldol-type C C-bond forming reaction. As crucial precur-
sors for the transformation into phenylthio-substituted com-
pounds C, the required enantiomerically pure 1,2-oxazines
D can be obtained by a [3+3]-cyclization of lithiated
alkoxyACHTUNGTRENNUNG
allenes E and glyceraldehyde-derived nitrones F.[10]
Since protected glyceraldehyde is easily available in both
enantiomeric forms our concept allows the preparation of
all compounds and hence the desired final product A as d-
or as l-configured compound.
Scheme 2. Synthesis of phenylthio-substituted 1,2-oxazines syn-7, anti-7
and syn-8. a) THF, À788C, 2 h; b) 2 + Et2AlCl, Et2O, then to 1, À788C,
Scheme 1. Retrosynthetic analysis of C2-branched d- or l-amino sugars
A.
2 h; c) InCl3, H2O, MeCN, 2 h; d) HCACTHUNTRGNE(UNG OMe)3, CAN, CH2Cl2, 1 h; e)
PhSSiMe3, TMSOTf, CH2Cl2, 3 h. CAN=cerium ammonium nitrate;
TMSOTf=trimethylsilyl trifluoromethanesulfonate.
Herein, we disclose our detailed results on the Lewis acid
mediated rearrangement of phenylthio-substituted 1,2-oxa-
zines C, and on the application of the resulting glycosyl
donor equivalents B towards the stereocontrolled synthesis
of diversely configured amino sugars as components of oli-
gosaccharides and glycosylated amino acids.
fluoromethanesulfonate (TMSOTf) smoothly afforded bicy-
clic 1,2-oxazinone 9 in good yield (Scheme 3). The TBS-pro-
tected derivative 10 could be obtained by either protection
of 9 with tert-butyldimethylsilyl chloride or directly from
1,2-oxazine syn-7, when this compound was treated with
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf).
The closely related 1,2-oxazine syn-11 bearing a phenylsele-
no substituent at the C2 atom of the dioxolane moiety was
also exposed to TMSOTf as Lewis acid thus furnishing the
desired product 12 in moderate yield (not yet optimized).
This result reveals that the phenylseleno substituent also
provides suitable electronic properties for a successful rear-
rangement. Although we did not investigate the reactivity of
compounds such as 12 it is evident that the phenylseleno
group offers new synthetic options. It may be used for radi-
cal reactions or—after oxidation and elimination—may
allow the preparation of novel C2-branched glycals.
When 1,2-oxazine anti-7 was treated with TMSOTf quite
a number of different compounds has been detected in the
NMR spectra of the crude product mixture (Scheme 4).
These could be assigned to compounds 13–16. The products
are formed as unprotected and TMS-protected hydroxyke-
tones or as internal hemiketals (each as a mixture of two
diastereomers). For simplification of the mixture it was first
treated with tetra-n-butylammonium fluoride (TBAF) to
Results and Discussion
Starting points for our synthetic route were 1,2-oxazines
syn-3, anti-3 and syn-4, which are smoothly accessible in a
stereodivergent manner from lithiated alkoxyallenes 1 and
d-glyceraldehyde-derived nitrone 2 (Scheme 2).[7] In order
to exchange the dimethyl substituents in the dioxolane ring
by a phenylthio group a new method for the mild cleavage
of acetonides was developed providing diols syn-5, anti-5
and syn-6 in good yields.[11] Formation of the corresponding
orthoesters with trimethyl orthoformate[12] followed by
Lewis-acid-catalyzed substitution of the methoxy by a phe-
nylthio group[13] delivered the desired rearrangement precur-
sors syn-7, syn-8 and anti-7.
To achieve the desired rearrangement to the bicyclic com-
pound 9 1,2-oxazine derivative syn-7 was exposed to differ-
ent Lewis acids. Treatment with SnCl4, which was the re-
agent of choice in similar reactions,[9b] was not successful in
this case, but the use of two equivalents of trimethylsilyl tri-
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Internally Protected Amino Sugar Derivatives
FULL PAPER
Scheme 5. Rearrangement of methoxy-substituted 1,2-oxazine syn-8 into
tricyclic compound 18. a) TMSOTf (2 equiv), CH2Cl2, À308C to RT, 16 h.
tion of the Lewis acid to the distal oxygen of the dioxolane
ring of the precursor 1,2-oxazines leads to a ring opening
followed by an aldol-type cyclization of the resulting carbe-
nium ions syn-19 or anti-19 to give key intermediates 21 or
23. The excellent diastereoselectivity in the formation of 21
can be explained by a chair-like transition state 20 where
the phenylthio substituent adopts an equatorial position.
Depending on the nature of the group R two different suc-
ceeding sequences are possible. In the case of R=TMSE,
this group undergoes a very fast fragmentation into ethene
and a TMSX species leading to bicyclic ketone 9. On the
other hand, simple alkoxy groups such as methoxy in 21 do
not undergo a similarly fast fragmentation and therefore a
1,2-alkyl shift under retention of configuration generates the
more stable carbenium ion 22. This rearranged intermediate
finally produced tricyclic compound 18 by N,O-acetal forma-
tion of the remaining oxygen with the cationic centre. In
contrast to compounds 9 and 18, which were isolated as
single diastereomers, rearrangement product 13 derived in
the anti-series was obtained as a mixture of diastereomers.
Scheme 3. Rearrangement of 1,2-oxazine syn-7 into bicyclic ketones 9
and 10. Rearrangement of phenylseleno-substituted 1,2-oxazine syn-11
into 12. a) TMSOTf (2 equiv), CH2Cl2, À308C to RT, 16 h; b) TBSOTf,
À308C to RT, CH2Cl2, 16 h; c) TBSCl, imidazole, THF, 4 h; d) HC-
ACHTUNGTRENNUNG(OMe)3, CAN, CH2Cl2, 1 h; e) PhSeSiMe3, TMSOTf, CH2Cl2, 3 h; f)
TMSOTf (2 equiv), CH2Cl2, À308C to RT, 16 h.
Scheme 4. Conversion of 1,2-oxazine anti-7 into bicyclic ketone 17. a)
TMSOTf (2.5 equiv), CH2Cl2, À308C to RT, 21 h; b) TBAF, THF, 7 h; c)
TBSOTf, NEt3, CH2Cl2, 3 h. TBAF=tetra-n-butylammonium fluoride;
TBSOTf=tert-butyldimethylsilyl triflate.
give compound 13 being in equilibrium with its hemiketal
15. Subsequent protection with TBSOTf provided the final
rearrangement product 17 as a 3:1 mixture of diastereomers.
The 1,2-oxazine syn-8, which bears the 4-methoxy instead
of the (2-trimethylsilyl)ethoxy (TMSEO) substituent, rear-
ranged under Lewis acidic conditions into tricyclic com-
pound 18, which is in analogy to previously observed trans-
formations (Scheme 5).[14,15]
Plausible reaction pathways leading to rearrangement
products 9, 13 and 18 are depicted in Scheme 6. Coordina-
Scheme 6. Proposed reaction pathways leading to compounds 9, 13 and
18.
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H.-U. Reissig and F. Pfrengle
The cyclization of carbenium ion anti-19 leading to inter-
mediate 23 can not proceed via a chair-like transition state
(similar to 20), since the bulky hydroxymethyl group would
have to occupy an axial position. Therefore a twisted boat-
like transition state of this subunit probably leads to the
poor selectivity for the position of the phenylthio group as
observed for product 13.
Rearrangement products 9 and 17 can be regarded as in-
ternally protected amino sugar equivalents which can direct-
ly be used for the formation of glycosides. This feature was
first demonstrated by the stereodivergent synthesis of
simple C-branched amino sugars 28 and 29. Starting with bi-
cyclic 1,2-oxazine 9 as common precursor these two diaste-
reomeric methyl glycosides were efficiently prepared in
three steps (Scheme 7). Stereoselective reduction of the car-
bonyl group of 9 with sodium borohydride followed by
NBS-activated substitution of the phenylthio moiety using
methanol and subsequent hydrogenolytic cleavage of the
Plausible explanations for the observed stereoselectivities
of the reductions of 9 and 25 with the employed hydride re-
agents as well as for the stereoselective generation of 25 and
26 are presented in Figure 1. Apparently, the hydride re-
agent has to attack compound 9 from the side of the pyran
moiety, since the N-benzyl group of the 1,2-oxazine unit effi-
ciently shields this direction. On the other hand, when the
axially positioned methoxy group has been introduced first
to give 25, this substituent sufficiently blocks the pyran side,
hence leading to an attack of the hydride reagent from the
opposite direction. It should be mentioned here that the use
of sodium borohydride gave an 8:1 mixture of epimers, only
the very bulky L-selectride allowed stereoselective reduction
at low temperature.
À
N O bond with concurrent debenzylation furnished C2-
branched amino sugar derivative 28 featuring d-talose con-
figuration.
Figure 1. Crucial intermediates in the stereodivergent syntheses of amino
sugar derivatives 28 and 29.
The activation of 9 and 24 by N-bromosuccinimide very
likely generates oxocarbenium ions 30 and 31, respectively,
which should have a halfchair-like conformation of the
pyran moiety. The stereoelectronically favored axial attack
of the alcohol directly generates the pyran chairs of 25 and
26 which directly benefit by the anomeric effect.
Starting from l-glyceraldehyde-derived nitrone ent-2,[16]
the two enantiomeric amino sugars ent-28 (l-talose configu-
ration) and ent-29 (l-idose configuration) have analogously
been prepared, demonstrating that all described compounds
are easily accessible in either of the two enantiomeric series
via ent-syn-3 (Scheme 8).
Scheme 7. Stereodivergent synthesis of C2-branched amino sugar deriva-
tives 28 and 29. a) NaBH4, EtOH, À408C, 3 h; b) NBS, MeOH, 30 min;
c) H2, Pd/C, MeOH, 18 h; d) Li
bromosuccinimide.
N
Most remarkably, change of the order of the first two
steps afforded the epimeric amino sugar derivative 29 with
inverted configuration at C3. Now the reaction of 9 with
NBS in methanol followed by the stereoselective reduction
of the carbonyl group of 25 with l-selectride gave com-
pound 27, an epimer of 26. The final hydrogenolysis step af-
forded C2-branched methyl glycoside 29 with d-idose con-
figuration.
Scheme 8. Syntheses of enantiomeric amino carbohydrate derivatives ent-
28 and ent-29.
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Internally Protected Amino Sugar Derivatives
FULL PAPER
Aminopyrans 28 and ent-28 have already been evaluated
towards their potential as components of new multivalent
anti-inflammatory agents[17] and compared with the corre-
sponding dimethyl-substituted analogues which exhibited
most remarkable properties as ligands of gold nanoparticles
in their binding abilities to selectins.[18]
When rearrangement product 17 was treated with NBS in
methanol, the expected products 32a/b were formed only in
low yield (Scheme 9). However, when a standard glycosyla-
tion protocol[19] for thio donors was employed, the diastereo-
mers 32a/b were obtained which could be easily separated
by column chromatography.
which is in contrast to amino sugars 28 and 29 (Scheme 8)
where the two cis-hydroxymethyl groups force the ring into
a slightly twisted boat-like conformation. This was proven
by X-ray crystallographic analysis of compound 29.[9a]
Protected rearrangement products 10 and 17 can directly
be employed as glycosyl donor equivalents. This was demon-
strated by reacting them not just with methanol or other
simple alcohols but with suitably protected rhamnose deriv-
ative 39[21] or with amino sugar precursor 25 using the NIS/
TfOH activation protocol (Scheme 10). The resulting disac-
charide precursors 37 and 38 were obtained as single diaste-
reomers in very good yields; they were further elaborated to
disaccharides as described below.
Scheme 9. Synthesis of amino sugar derivative 34. a) NIS, cat. TfOH,
MeOH, MeCN, 4 ꢃ molecular sieves, 2.5 h; b) TBAF, THF, 18 h; c)
NaBH4, EtOH, 2 h; d) H2, Pd/C, MeOH, 18 h. NIS=N-iodosuccinimide;
TfOH=trifluoromethanesulfonic acid.
Scheme 10. Reactions of glycosyl donor equivalent 10. a) 25 or 39, NIS,
TfOH, CH2Cl2, 4 ꢃ molecular sieves, 2-4 h. PMP=4-methoxyphenyl.
We propose that after NIS/TfOH activation of the phenyl-
thio group the pyran ring in cationic intermediate 35 is gen-
erated in a halfchair-like conformation, with the siloxymeth-
yl substituent in a pseudoaxial position (Figure 2) which
allows the attack of the alcohol from both sides. Depending
on the solvent used diastereomeric ratios of 1.2:1 (CH2Cl2)
to 1.7:1 (MeCN) were obtained. After separation of the dia-
stereomers the major isomer 32a was treated with TBAF
giving the corresponding desilylated product that was subse-
quently reduced with sodium borohydride to furnish bicyclic
alcohol 33 as a single diastereomer in good yield. The hy-
dride reagent attacks intermediate 36 exclusively from the
side of the 1,2-oxazine moiety, since the opposite side appa-
rently is strongly shielded by the hydroxymethyl and the
methoxy group (Figure 2). A final hydrogenolysis provided
the desired C2-branched amino sugar derivative 34 having a
d-glucose configuration.[20] As in glucose itself all substitu-
ents adopt equatorial positions in a chair-like conformation,
Likewise, the reaction of the diastereomeric product 17
with glycosyl acceptors 25 or 42[9b] provided the coupled dis-
accharide precursors 40 and 41 in good yield but as mixtures
of the two possible anomers (Scheme 11). In the reaction of
17 with methanol (Scheme 9) the alcohol was used in large
excess and there the diastereomeric ratio could be improved
by switching from CH2Cl2 to MeCN as solvent. This was not
possible for the examples depicted in Scheme 11. No conver-
sion to the expected products was observed in MeCN which
probably traps the intermediate oxocarbenium ion.
Tricyclic rearrangement product 18 also reacted smoothly
with alcohols. For example, NIS-promoted reaction with
Figure 2. Crucial intermediates in the stereoselective synthesis of amino
sugar derivative 34.
Scheme 11. Reactions of glycosyl donor equivalent 17. a) alcohol 25 or
42, NIS, TfOH, CH2Cl2, 4 ꢃ molecular sieves, 4 h.
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H.-U. Reissig and F. Pfrengle
rhamnose derivative 39 furnished 43 as a 3:1 mixture of dia-
stereomers in moderate yield (Scheme 12). Compound 18
was considerably more reactive than glycosyl donor equiva-
lents 10 and 17 making further activation of NIS by TfOH
unnecessary. Since the two resulting isomers could not be
separated by column chromatography, further transforma-
tions of 43, which may lead to new unusual carbohydrate
mimetics, have not yet been examined. We assume that the
major isomer is formed by the attack of the rhamnose deriv-
ative 39 to the sterically more open exo-face of 18 (cis to
the three bridge-head hydrogens).
Scheme 12. Reaction of glycosyl donor equivalent 18 with l-rhamnose
derivative 39. a) NIS, CH2Cl2, 4 ꢃ molecular sieves, 1 h.
Scheme 14. Synthesis of trisaccharide 46. a) TBAF, THF, 18 h; b) 10, NIS,
TfOH, 4 ꢃ molecular sieves, CH2Cl2, 4 h; c) Li
RT, 3 h; d) 1 bar H2, Pd/C, MeOH, 42 h.
ACHTUNGRTEN(NNUG sBu)3BH, THF, 08C to
After glycosylation reactions of the rearrangement prod-
ucts the resulting dimeric compounds 38 and 41a have been
used for the synthesis of di- and trisaccharides containing
C2-branched 4-amino sugar units. First, disaccharide equiva-
lent 38 was stereoselectively transformed into 44 by reduc-
tion of the carbonyl groups with L-selectride and subsequent
hydrogenolysis which induces debenzylation and cleavage of
compound 41a was smoothly transformed by three simple
steps into fully deprotected disaccharide mimetic 47 in very
good overall yield (Scheme 15). As in all previous cases the
two carbonyl groups of 41a were reduced to give the corre-
sponding secondary alcohols with perfect levels of stereo-
control. All described oligosaccharides bearing amino sugar
units of different configurations may have potential as ami-
noglycoside mimetics.[23]
À
the N O bonds (Scheme 13). The overall yield for the three
steps leading to the novel disaccharide 44 is good.
Scheme 13. Synthesis of disaccharide 44. a) LiACTHNURTGNENG(U sBu)3BH, THF, 08C, 2 h;
b) 1 bar H2, Pd/C, MeOH, 19 h.
Scheme 15. Synthesis of disaccharide mimetic 47. a) NaBH4, EtOH, 08C,
1 h; b) TBAF, THF, 18 h; c) 1 bar H2, Pd/C, MeOH, 18 h.
When compound 38 was desilylated with TBAF it can
serve as a glycosyl acceptor. Glycosidation with glycosyl
donor equivalent 10 delivered the trimeric compound 45
which was stereoselectively converted into trisaccharide 46
by the reductive steps as already described for the prepara-
tion of dimer 44 (Scheme 14).[22] Considering the complexity
of trisaccharide 46 the overall yield of 55% for the three
steps is again remarkable. The reactions described in
Schemes 13 and 14 underscore the potential of our protocol
to generate oligosaccharides of type 44 and 46 in a repetitive
manner.
Syntheses of hybrid systems of the presented amino sugar
derivatives with natural carbohydrates are also easily possi-
ble. This was exemplarily demonstrated by using the desily-
lated intermediate derived from 37 as glycosyl acceptor in
the reaction with commercially available l-fucosyl donor 48
(Scheme 16). The resulting trisaccharide equivalent 49 was
stereoselectively reduced to furnish 50 and a final hydroge-
nolysis with palladium on charcoal provided partially pro-
tected trisaccharide 51.
The option to employ rearrangement products such as 10
as protected amino sugar equivalents has been followed to
prepare bivalent amino sugar derivatives such as 54
A disaccharide mimetic containing a d-glucose configured
C2-branched amino sugar unit is also accessible. Dimeric
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Internally Protected Amino Sugar Derivatives
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Scheme 18. Reaction of glycosyl donor equivalent ent-10 with l-serine de-
rivative 52. a) NIS, TfOH, CH2Cl2, 4 ꢃ molecular sieves, 4 h.
Scheme 16. Synthesis of hybrid trisaccharide 51. a) TBAF, THF, RT, 18 h;
b) NIS, 4 ꢃ molecular sieves, CH2Cl2, RT, 1 h; c) LiACHTUNTRGNE(UNG sBu)3BH, THF,
À308C, 3 h; d) Crystallization of a-Fuc anomer from Et2O (64%); e)
1 bar H2, Pd/C, MeOH/EtOAc, RT, 16 h (67%).
(Scheme 17). Compound 10 was combined with 1,5-pentane-
diol generating product 52 in good yield, which connects the
two internally protected amino sugar units by a polymethy-
lene linker. Stereoselective reduction of the carbonyl
groups, deprotection by removal of the TBS groups, and
subsequent hydrogenolysis furnished the desired bivalent
carbohydrate derivative 54 in reasonable overall yield.[24]
Finally, we examined the possibility to use the available
glycosyl donor for the synthesis of carbohydrate–peptide
conjugates. For this purpose N-Boc-protected l-serine deriv-
ative 55 was employed as glycosyl acceptor. Glycosidation
with rearrangement product ent-10 furnished the expected
coupling product 56 in good yield (Scheme 18).
Further transformations of 56 should allow the prepara-
tion of various glycosylated l-serine derivatives. This has al-
ready been demonstrated by the synthesis of glycosylated l-
serine derivative 60 bearing an amino sugar unit with d-
talose configuration (Scheme 19). Protection of 24 with
acetic acid anhydride or with TBSOTf provided excellent
precursors for the NIS/TfOH-promoted coupling with l-
serine derivative 55 to give the desired products 57 and 58
Scheme 19. Synthesis of glycosylated l-serine derivative 60. a) Ac2O,
DMAP, pyridine, 4 h; b) 55, NIS, TfOH, CH2Cl2, 4 ꢃ molecular sieves,
2 h; c) TBSOTf, 2,6-lutidine, CH2Cl2, 5 h; d) 55, NIS, TfOH, CH2Cl2, 4 ꢃ
molecular sieves, 1 h; e) 1 bar H2, Pd/C, EtOAc, 12 h; f) Ac2O, DMAP,
pyridine, 2 h; g) SmI2, THF, 1 h. DMAP=N,N-dimethylaminopyridine.
as single diastereomers in moderate to good yields. Since a
smooth removal of the TBS-protection group in 58 was not
possible, further studies were performed with acetylated in-
termediate 57. Hydrogenolysis of 57 by Pd/C catalysis did
À
not lead to cleavage of the N O bond, but only to debenzy-
À
lation of the starting material. Gratifyingly, the N O bond
of the resulting 1,2-oxazine 59 could smoothly be cleaved by
samarium diiodide in tetrahydrofuran after N-acetylation of
the obtained intermediate.[8a,25] The resulting glycosylated l-
serine derivative 60 should be a
good building block for the in-
corporation into peptides pro-
viding novel compounds being
of interest for chemical biol-
ogy.[26]
Conclusion
A fairly efficient approach to
variably
configured
C2-
branched 4-amino sugars is pre-
sented. The Lewis acid mediat-
ed rearrangement of enantio-
pure 1,2-oxazines directly deliv-
Scheme 17. Synthesis of bivalent amino sugar derivative 54. a) NIS, TfOH, CH2Cl2, 4 ꢃ molecular sieves, 5 h;
b) LiACHTUNGTRENNUNG(sBu)3BH, THF, 08C, 2 h; c) TBAF, THF, 12 h; d) 1 bar H2, Pd/C, MeOH, 24 h.
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H.-U. Reissig and F. Pfrengle
ers internally protected amino sugar building blocks as
common intermediates, which are suitable for the smooth
incorporation into oligosaccharides or glycosylated amino
acids. Rearrangement products such as 10 and 17 can direct-
ly be used as glycosyl donor equivalents in glycosidations
with simple alcohols, natural carbohydrate derivatives, car-
bohydrate mimetics, or with amino acid derivatives. Simple
subsequent reductive transformations deliver the free amino
sugar units under mild conditions. By this strategy methyl
glycosides with various configurations (28, 29, ent-28, ent-29
and 34), di- and trisaccharides (44, 46, 47 and 51), a bivalent
amino sugar derivative (54), and a glycosylated l-serine de-
rivative (60) have been synthesized with a minimum of pro-
tective group transformations. Of particular importance is
the fact that the amino sugar equivalents are easily available
in both enantiomeric series. In addition, due to the easy
availability of the starting 1,2-oxazines such as syn-3 many
compounds are smoothly accessible in fair scale (up to gram
quantities).
products are modified or replaced by synthetic analogues.
Unusual amino sugar building blocks such as presented in
this work can, for example, be incorporated into new amino-
glycoside mimetics in order to improve the understanding of
the molecular mechanism of aminoglycoside–RNA interac-
tions.[28]
Experimental Section
General Methods: See Supporting Information.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
12.8 mmol), cerium ammonium nitrate (577 mg, 1.05 mmol) and trimethyl
orthoformate (4.21 mL, 4.08 g, 38.4 mmol) were dissolved in CH2Cl2
(170 mL) and the mixture was stirred for 1 h. After addition of a saturat-
ed solution of Na2CO3, the layers were separated and the aqueous layer
was extracted twice with CH2Cl2. The combined organic layers were
dried with MgSO4, filtered and concentrated to dryness. The resulting
colorless oil was dissolved in CH2Cl2 (90 mL). Freshly distilled (phenyl-
thio)trimethylsilane (6.05 mL, 5.84 g, 32.0 mmol) and trimethylsilyl tri-
flate (139 mL, 171 mg, 0.768 mmol) were added and the mixture was
stirred for 3 h. The reaction mixture was quenched by addition of 10%
aqueous NaOH solution and after separation of the layers the aqueous
phase was extracted twice with CH2Cl2. The combined organic layers
were dried with MgSO4, filtered and concentrated. Fast flash column
chromatography (silica gel, EtOAc/hexane 1:20) afforded syn-7 (d.r. 1:1)
as colorless oil (5.40 g, 89%), which should be stored in the freezer due
The presented results complement our previous reports
about the synthesis of enantiopure aminopyrans and amino-
oxepanes such as 61–64 which are available via Lewis acid
mediated cyclizations of 1,2-oxazines[9b,c] or related 1,3-diox-
olanyl-substituted enol ethers[27] (Figure 3).
to its low stability. [a]D22
=
À55.8 (c=1.35, CHCl3); diastereomer a:
1H NMR (CDCl3, 500 MHz): d=0.06 (s, 9H, SiMe3), 0.96–1.15 (m, 2H,
CH2Si), 3.33 (dd, J=6.8, 1.0 Hz, 1H, 3-H), 3.71–3.89 (m, 2H, OCH2),
4.09–4.19 (m, 5H, NCH2, 5’-H, 6-H), 4.39–4.45 (m, 1H, 6-H), 4.74 (dd,
J=3.4, 1.8 Hz, 1H, 5-H), 4.94 (dd, J=13.6, 6.8 Hz, 1H, 4’-H), 6.63 (s,
1H, 2’-H), 7.21–7.37 (m, 6H, Ph), 7.38–7.42 (m, 1H, Ph), 7.43–7.46 (m,
1H, Ph), 7.50–7.55 (m, 1H, Ph), 7.56–7.61 ppm (m, 1H, Ph); 13C NMR
(CDCl3, 126 MHz): d=À1.3 (q, SiMe3), 17.6 (t, CH2Si), 58.4 (t, NCH2),
60.5 (t, C-6), 62.8 (d, C-3), 64.7 (t, OCH2), 66.7 (t, C-5’), 74.6 (d, C-4’),
93.5 (d, C-5), 112.2 (d, C-2’), 127.2–133.7 (several d, s, Ph), 150.0 ppm (s,
C-4); diastereomer b: 1H NMR (CDCl3, 500 MHz): d=0.08 (s, 9H,
SiMe3), 0.96–1.15 (m, 2H, CH2Si), 3.43 (dd, J=7.7, 1.1 Hz, 1H, 3-H),
3.71–3.89 (m, 2H, OCH2), 4.06 (dd, J=9.3, 6.0 Hz, 1H, 5’-H), 4.09–4.19
(m, 1H, 6-H), 4.23 (t, J=9.3 Hz, 1H, 5’-H), 4.39–4.45 (m, 3H, NCH2, 6-
H), 4.59 (ddd, J=9.3, 7.7, 6.0 Hz, 1H, 4’-H), 4.76 (dd, J=3.4, 1.8 Hz, 1H,
5-H), 6.65 (s, 1H, 2’-H), 7.21–7.37 (m, 6H, Ph), 7.38–7.42 (m, 1H, Ph),
7.43–7.46 (m, 1H, Ph), 7.50–7.55 (m, 1H, Ph), 7.56–7.61 ppm (m, 1H,
Ph); 13C NMR (CDCl3, 126 MHz): d=À1.3 (q, SiMe3), 17.6 (t, CH2Si),
58.4 (t, NCH2), 60.5 (t, C-6), 63.7 (d, C-3), 66.1 (t, C-5’), 64.7 (t, OCH2),
Figure 3. Enantiopure aminopyrans 61, 62 and 64, and aminooxepane 63.
These compounds have been termed as carbohydrate
mimetics since they represent C-glycosides of the C2-
branched amino sugars described here. The use of thiophen-
yl-substituted 1,2-oxazine derivatives now allows not only
the synthesis of mimetics but of “real” carbohydrates bear-
ing an anomeric center (Scheme 20). The pyranose skeleton
of the branched amino sugars, comprising atoms a–g, is de-
rived from their linear arrangement in the precursor 1,2-ox-
azines which rearrange in an aldol-type reaction.
76.4 (d, C-4’), 93.5 (d, C-5), 112.4 (d, C-2’), 127.2–133.7 (several d, s, Ph),
À1
À
À
150.0 ppm (s, C-4); IR (film): n˜ = 3090–2840 (=C H, C H), 1670 cm
(C=C); ESI-TOF: m/z: calcd for [C25H33NO4SSi+H]+: 472.1972; found:
472.1945.
(1S,5S,6S,8S)-2-Benzyl-8-hydroxymethyl-6-phenylthio-3,7-dioxa-2-aza-
ACHUTNGRENUbNG icycloAHCTUNGTRENN[GUN 3.3.1]nonan-9-one (9): 1,2-Oxazine syn-7 (4.50 g, 9.54 mmol) was
dissolved in CH2Cl2 (100 mL), cooled to À308C and treated with trime-
thylsilyl triflate (3.47 mL, 4.25 g, 19.1 mmol). The mixture was allowed to
reach RT over 16 h without removing the cooling bath. After quenching
the reaction mixture with H2O, the layers were separated and the aque-
ous phase was extracted twice with CH2Cl2. The combined organic layers
were dried with MgSO4, filtered and concentrated. Column chromatogra-
phy (silica gel, EtOAc/hexane 1:3) provided 9 as colorless oil (2.67 g,
75%). [a]2D2 =+57.5 (c=0.44, CHCl3); 1H NMR (CDCl3, 500 MHz): d=
2.29 (brs, 1H, OH), 2.98 (ddt, J=6.4, 3.2, 1.5 Hz, 1H, 5-H), 3.34 (t, J=
1.5 Hz, 1H, 1-H), 3.69 (dd, J=10.9, 5.5 Hz, 1H, 8-CH2), 3.73 (td, J=5.5,
1.5 Hz, 1H, 8-H), 3.94 (d, J=13.3 Hz, 1H, NCH2), 3.98 (dd, J=10.9,
5.5 Hz, 1H, 8-CH2), 4.19 (d, J=13.3 Hz, 1H, NCH2), 4.52 (ddd, J=12.0,
6.4, 0.9 Hz, 1H, 4-H), 4.76 (dd, J=12.0, 3.2 Hz, 1H, 4-H), 5.07 (s, 1H, 6-
Our methods should be very useful for chemical glycodi-
versifications where the original carbohydrates in natural
Scheme 20. Synthesis of amino sugar derivatives by Lewis acid promoted
rearrangement of 1,2-oxazines.
11922
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11915 – 11925

Internally Protected Amino Sugar Derivatives
FULL PAPER
H), 7.24–7.37 (m, 8H, Ph), 7.45–7.51 ppm (m, 2H, Ph); 13C NMR
(CDCl3, 125 MHz): d=54.4 (d, C-5), 61.2 (t, NCH2), 62.6 (t, 8-CH2), 68.5
(t, C-4), 71.5 (d, C-1), 81.1 (d, C-8), 88.4 (d, C-6), 128.0, 128.3, 128.7,
129.1, 129.4, 132.1, 132.9, 135.5 (6 d, 2 s, Ph), 204.1 ppm (s, C-9); IR
addition of CH2Cl2 the layers were separated and the aqueous phase was
extracted twice with CH2Cl2. The combined organic layers were dried
with MgSO4, filtered and concentrated. Column chromatography (silica
gel, EtOAc/hexane 1:2) provided 25 as colorless crystals (1.01 g, 85%).
(film): n˜ = 3450 (OH), 3090–2860 (=C H, C H), 1730 cmÀ1 (C=O); ESI-
TOF: m/z: calcd for [M+H]+: 372.1264; found: 372.1264; elemental anal-
ysis calcd (%) for C20H21NO4S (371.5): C 64.67, H 5.70, N 3.77, S 8.63,
found: C 64.85, H 5.42, N 3.79, S 8.41.
1
M.p. 968C; [a]2D2 =+172.2 (c=0.54, CHCl3); H NMR (CDCl3, 500 MHz):
À
À
d=2.69 (m, 1H, 5-H), 3.19 (t, J=2.0 Hz, 1H, 1-H), 3.37 (s, 3H, OMe),
3.88 (dd, J=11.8, 5.0 Hz, 1H, 8-CH2), 3.96 (d, J=12.9 Hz, 1H, NCH2),
4.01 (dd, J=11.8, 5.0 Hz, 1H, 8-CH2), 4.11 (td, J=5.0, 2.0 Hz, 1H, 8-H),
4.19 (d, J=12.9 Hz, 1H, NCH2), 4.42 (ddd, J=12.0, 2.5, 2.0 Hz, 1H, 4-
H), 4.68 (ddd, J=12.0, 4.1, 1.4 Hz, 1H, 4-H), 5.25 (s, 1H, 6-H), 7.26–
7.35 ppm (m, 5H, Ph); 13C NMR (CDCl3, 126 MHz): d=53.6 (d, C-5),
55.1 (q, OMe), 58.6 (t, NCH2), 63.4 (t, 8-CH2), 70.2 (d, C-1), 70.4 (t, C-4),
74.2 (d, C-8), 104.3 (d, C-6), 128.1, 128.8, 129.1, 135.1 (3d, s, Ph),
À
(1S,5S,6S,8S)-2-Benzyl-8-(tert-butyldimethylsiloxymethyl)-6-phenylthio-
3,7-dioxa-2-azabicycloACHTUNGTRENNUNG[3.3.1]nonan-9-one (10):
Method A: 1,2-Oxazine syn-7 (105 mg, 0.222 mmol) was dissolved in
CH2Cl2 (2 mL), cooled to À308C and treated with tert-butyldimethylsilyl
triflate (155 mL, 178 mg, 0.666 mmol). The mixture was allowed to reach
RT over 16 h without removing the cooling bath. After cooling to 08C,
NEt3 (47 mL, 34 mg, 0.333 mmol) was added followed by addition of a sa-
turated solution of NH4Cl. The layers were separated and the aqueous
phase was extracted twice with CH2Cl2. The combined organic layers
were dried with Na2SO4, filtered and concentrated. Column chromatogra-
phy (silica gel, EtOAc/hexane 1:10) provided 10 as colorless crystals
(68 mg, 63%).
204.0 ppm (s, C-9); IR (KBr): n˜
= 3490 (OH), 2990–2820 (C H),
1725 cmÀ1 (C=O); ESI-TOF: m/z: calcd for [M+H]+: 294.1336; found:
294.1344; elemental analysis calcd (%) for C15H19NO5 (293.3): C 61.42, H
6.53, N 4.78, found: C 61.09, H 6.41, N 4.97.
(1R,5S,6S,8S,9R)-2-Benzyl-8-hydroxymethyl-6-methoxy-3,7-dioxa-2-aza-
bicycloACHTUNTRGNEU[GN 3.3.1]nonan-9-ol (26): Compound 24 (250 mg, 0.670 mmol) was
dissolved in MeOH (10 mL). N-Bromosuccinimide (171 mg, 1.01 mmol)
was added and the mixture was stirred for 30 min at RT. The reaction
Method B: Compound 9 (570 mg, 1.53 mmol) was dissolved in THF
(6 mL). Imidazole (209 mg, 3.07 mmol) and TBSCl (345 mg, 2.30 mmol)
were added and the resulting reaction mixture was stirred for 4 h at RT.
The mixture was filtered and after addition of water the mixture was ex-
tracted three times with Et2O. The combined organic layers were dried
with Na2SO4, filtered and concentrated. Column chromatography (silica
gel, EtOAc/hexane 1:10) provided 10 as colorless crystals (580 mg, 78%).
M.p. 818C; [a]2D2 =+22.9 (c=0.48, CHCl3); 1H NMR (CDCl3, 500 MHz):
d=0.00, 0.03 (2 s, 6H, SiMe2), 0.84 (s, 9H, tBu), 3.02 (m, 1H, 5-H), 3.57
(t, J=1.6 Hz, 1H, 1-H), 3.71 (ddd, J=8.0, 5.5, 1.6 Hz, 1H, 8-H), 3.86 (dd,
J=9.8, 5.5 Hz, 1H, 8-CH2), 3.94 (dd, J=9.8, 8.0 Hz, 1H, 8-CH2), 3.98 (d,
J=14.2 Hz, 1H, NCH2), 4.15 (d, J=14.2 Hz, 1H, NCH2), 4.43 (ddd, J=
11.9, 7.2, 0.4 Hz, 1H, 4-H), 4.71 (dd, J=11.9, 3.3 Hz, 1H, 4-H), 5.04 (m,
1H, 6-H), 7.26–7.39 (m, 8H, Ph), 7.47–7.50 ppm (m, 2H, Ph); 13C NMR
(CDCl3, 126 MHz): d=À5.5 (q, SiMe2), 18.1, 25.8 (s, q, tBu), 54.7 (d, C-
5), 61.2 (t, 8-CH2), 61.7 (t, NCH2), 68.1 (t, C-4), 71.8 (d, C-1), 81.6 (d, C-
8), 88.5 (d, C-6), 127.5, 128.0, 128.4, 128.7, 129.2, 131.9, 133.2, 136.3 (6 d,
mixture was quenched by the addition of
a saturated solution of
NaHCO3. After addition of CH2Cl2 the layers were separated and the
aqueous phase was extracted twice with CH2Cl2. The combined organic
layers were dried with Na2SO4, filtered and concentrated. Column chro-
matography (silica gel, EtOAc/hexane 1:1) and recrystallisation from
EtOAc/hexane provided 26 as colorless crystals (190 mg, 96%). M.p.
1
1378C; [a]2D2 =+126.8 (c=0.62, CHCl3); H NMR (CDCl3, 500 MHz): d=
2.03 (m, 1H, 5-H), 2.79 (s, 1H, OH), 3.02 (m, 1H, 1-H), 3.37 (s, 3H,
OMe), 3.39 (s, 1H, OH), 3.80 (dt, J=12.1, 0.8 Hz, 1H, 4-H), 3.81–3.84
(m, 1H, 8-CH2), 3.97 (ddd, J=6.1, 4.4, 1.4 Hz, 1H, 8-H), 4.03 (dd, J=
11.0, 6.1 Hz, 1H, 8-CH2), 4.08 (d, J=13.9 Hz, 1H, NCH2), 4.27 (dt, J=
9.6, 3.3 Hz, 1H, 9-H), 4.31 (d, J=13.9 Hz, 1H, NCH2), 4.38 (dd, J=12.1,
4.5 Hz, 1H, 4-H), 5.05 (d, J=1.2 Hz, 1H, 6-H), 7.26–7.30, 7.31–7.36 ppm
(2 m, 5H, Ph); 13C NMR (CDCl3, 126 MHz): d=39.1 (d, C-5), 55.0 (q,
OMe), 61.1 (t, NCH2), 61.9 (d, C-1), 64.0 (t, 8-CH2), 64.3 (d, C-9), 66.1 (t,
C-4), 73.9 (d, C-8), 102.6 (d, C-6), 127.6, 128.6, 128.7, 137.4 ppm (3 d, s,
Ph); IR (KBr): n˜ =3330 (OH), 3000–2830 cmÀ1 (C H); ESI-TOF: m/z:
À
À
À
2 s, Ph), 204.5 ppm (s, C-9); IR (KBr): n˜ = 3070–2840 (=C H, C H),
1720 cmÀ1 (C=O); ESI-TOF: m/z: calcd for [M+H]+: 486.2129; found:
486.2130; elemental analysis calcd (%) for C26H35NO4SSi (485.7): C
64.29, H 7.26, N 2.88, S 6.60, found: C 64.28, H 7.36, N 2.85, S 6.74.
calcd for [M+H]+: 296.1492; found: 296.1506; elemental analysis calcd
(%) for C15H21NO5 (295.3): C 61.00, H 7.17, N 4.74; found: C 61.16, H
7.09, N 4.77.
(1R,5S,6S,8S,9S)-2-Benzyl-8-hydroxymethyl-6-methoxy-3,7-dioxa-2-aza-
ACHUTNGRENUbNG icycloHCATUNGTRENN[UGN 3.3.1]nonan-9-ol (27): Compound 25 (130 mg, 0.440 mmol) was
(1R,5S,6S,8S,9R)-2-Benzyl-8-hydroxymethyl-6-phenylthio-3,7-dioxa-2-
azabicycloACHTUNGTRENNUNG[3.3.1]nonan-9-ol (24): Ketone 9 (1.10 g, 2.96 mmol) was dis-
dissolved in THF (3 mL) and the solution was cooled to À308C. A solu-
tion of L-selectride (1.0m in THF, 1.45 mL, 1.45 mmol) was added care-
fully and the mixture was stirred at this temperature for 3 h. After
quenching the reaction mixture with a saturated solution of NH4Cl,
EtOAc and H2O were added. The layers were separated and the aqueous
phase was extracted twice with EtOAc. The combined organic layers
were dried with Na2SO4, filtered and concentrated. Column chromatogra-
phy (silica gel, EtOAc/hexane 2:1) and recrystallisation from EtOAc/
hexane provided 27 as colorless crystals (95 mg, 73%). M.p. 1128C;
[a]2D2 = +147.1 (c=0.22, CHCl3); 1H NMR (CDCl3, 500 MHz): d=2.17
(m, 1H, 5-H), 2.88 (m, 1H, 1-H), 3.43 (s, 3H, OMe), 3.68 (dd, J=9.3,
2.0 Hz, 1H, OH), 3.87 (ddd, J=11.9, 9.3, 3.9 Hz, 1H, 8-CH2), 3.92 (dd,
J=12.2, 1.5 Hz, 1H, 4-H), 3.97 (ddd, J=11.9, 3.9, 2.0 Hz, 1H, 8-CH2),
4.16 (d, J=13.1 Hz, 1H, NCH2), 4.20 (dt, J=5.9, 3.9 Hz, 1H, 8-H), 4.29
(d, J=13.1 Hz, 1H, NCH2), 4.34 (dd, J=12.2, 2.6 Hz, 1H, 4-H), 4.39 (dd,
J=8.6, 3.7 Hz, 1H, 9-H), 4.46 (d, J=8.6 Hz, 1H, OH), 5.05 (s, 1H, 6-H),
7.24–7.34 ppm (m, 5H, Ph); 13C NMR (CDCl3, 126 MHz): d=37.8 (d, C-
5), 55.1 (q, OMe), 56.8 (t, NCH2), 59.5 (d, C-1), 61.8 (d, C-9), 64.8 (t, 8-
CH2), 66.1 (t, C-4), 66.5 (d, C-8), 102.3 (d, C-6), 127.7, 128.5, 128.6,
solved in EtOH (22 mL) and the solution was cooled to À408C. Sodium
borohydride (198 mg, 5.21 mmol) was added and the mixture was stirred
at this temperature for 3 h. Then the solvent was removed in vacuo and
the residue was dissolved in CH2Cl2 and H2O. The layers were separated
and the aqueous phase was extracted twice with CH2Cl2. The combined
organic layers were dried with MgSO4, filtered and concentrated. Recrys-
tallisation from EtOAc/hexane provided 24 as colorless crystals (1.00 g,
90%). M.p. 1678C; [a]D22 =À48.7 (c=0.77, CHCl3); 1H NMR (CDCl3,
500 MHz): d=2.23 (dd, J=7.6, 3.4 Hz, 1H, OH), 2.27 (s, 1H, 5-H), 3.06
(s, 1H, 1-H), 3.67 (d, J=10.7 Hz, 1H, OH), 3.69–3.75 (m, 2H, 8-H, 8-
CH2), 3.84 (dt, J=10.7, 2.9 Hz, 1H, 9-H), 4.03 (d, J=14.0 Hz, 1H,
NCH2), 4.06 (m, 1H, 8-CH2), 4.23 (d, J=14.0 Hz, 1H, NCH2), 4.26–4.33
(m, 2H, 4-H), 5.03 (s, 1H, 6-H), 7.24–7.36 (m, 8H, Ph), 7.45–7.49 ppm
(m, 2H, Ph); 13C NMR (CDCl3, 126 MHz): d=40.4 (d, C-5), 61.2 (d, C-
1), 62.1 (t, NCH2), 63.4 (t, 8-CH2), 66.0 (t, C-4), 70.3 (d, C-9), 80.5 (d, C-
8), 86.9 (d, C-6), 127.6, 127.7, 128.6, 128.7, 129.2, 131.2, 134.2, 137.1 ppm
(6 d, 2 s, Ph); IR (KBr): n˜ = 3305 (OH), 2960–2855 cmÀ1 (C H); ESI-
À
TOF: m/z: calcd for [M+H]+: 374.1421; found: 374.1433; elemental anal-
ysis calcd (%) for C20H23NO4S (373.5): C 64.32, H 6.21, N 3.75, S 8.59;
found: C 64.31, H 6.02, N 3.76, S 8.99.
136.3 ppm (3 d, s, Ph); IR (KBr): n˜ = 3400, 3350 (OH), 3010–2830 cmÀ1
+
À
(C H); ESI-TOF: m/z: calcd for [M+H] : 296.1492; found: 296.1496; el-
(1S,5R,6S,8S)-2-Benzyl-8-hydroxymethyl-6-methoxy-3,7-dioxa-2-aza-
bicycloACHTUNGTRENNUNG[3.3.1]nonan-9-one (25): Ketone 9 (1.50 g, 4.03 mmol) was dis-
solved in MeOH (50 mL). N-Bromosuccinimide (899 mg, 5.26 mmol) was
added and the mixture was stirred for 30 min at RT. The reaction mixture
was quenched by the addition of a saturated solution of NaHCO3. After
emental analysis calcd (%) for C15H21NO5 (293.5): C 61.00, H 7.17, N
4.74; found: C 60.98, H 7.21, N 4.71.
Methyl 4-amino-2,4-dideoxy-2-hydroxymethyl-a-d-talopyranoside (28): A
suspension of palladium on charcoal (10% Pd, 100 mg) in MeOH (3 mL)
Chem. Eur. J. 2010, 16, 11915 – 11925
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11923

H.-U. Reissig and F. Pfrengle
was saturated with hydrogen for 1 h. After addition of bicyclic alcohol 26
(62 mg, 0.210 mmol) in MeOH (2 mL), hydrogen was bubbled through
the mixture for another 30 min and the reaction mixture was stirred
under an atmosphere of hydrogen for 18 h. Filtration through a short pad
of celite and concentration of the solution to dryness afforded methyl
glycoside 28 as pale yellowish oil (37 mg, 85%). Purity according to
NMR: >95%. [a]2D2 =+92.8 (c=1.06, H2O); 1H NMR (D2O, 500 MHz):
d=2.07 (td, J=5.9, 3.8 Hz, 1H, 2-H), 3.14 (dd, J=4.1, 2.3 Hz, 1H, 4-H),
3.37 (s, 3H, OMe), 3.70 (dd, J=11.8, 3.6 Hz, 1H, 6-H), 3.71 (dd, J=11.4,
5.9 Hz, 1H, 2-CH2), 3.75 (dd, J=11.4, 3.8 Hz, 1H, 2-CH2), 3.77 (dd, J=
11.8, 7.8 Hz, 1H, 6-H), 3.91 (ddd, J=7.8, 3.6, 2.3 Hz, 1H, 5-H), 4.22 (dd,
J=5.9, 4.1 Hz, 1H, 3-H), 4.88 ppm (s, 1H, 1-H); 13C NMR (D2O,
126 MHz): d=44.7 (d, C-2), 49.5 (d, C-4), 54.5 (q, OMe), 57.3 (t, 2-CH2),
61.5 (t, C-6), 66.0 (d, C-3), 70.1 (d, C-5), 100.4 ppm (d, C-1); IR (film): n˜
extracted twice with EtOAc. The combined organic layers were dried
with Na2SO4, filtered and concentrated. Column chromatography (silica
gel, EtOAc/hexane 2:1) provided the product as a colorless oil (55 mg,
73%). [a]2D2 =+119.6 (c=0.43, CHCl3); 1H NMR (CDCl3, 500 MHz): d=
0.06, 0.07 (2 s, 6H, SiMe2), 0.86 (s, 9H, tBu), 1.92 (mc, 1H, 5’-H), 2.17
(mc, 1H, 5-H), 2.79 (mc, 1H, 1-H), 3.00 (mc, 1H, 1’-H), 3.34 (s, 3H,
OMe), 3.56 (dd, J=9.8, 4.8 Hz, 1H, 8-H), 3.78, 3.85 (dd, J=11.8, 1.5 Hz,
1H, dd, J=12.2, 1.6 Hz, 1H, 4-H, 4’-H), 3.90 (dd, J=9.7, 6.0 Hz, 1H, 8’-
CH2), 4.02 (dd, J=9.7, 8.0 Hz, 1H, 8’-CH2), 4.10–4.20 (m, 1H, 4’-H), 4.12
(d, J=13.2 Hz, 1H, NCH2), 4.17 (d, J=13.2 Hz, 1H, NCH2), 4.24–4.31
(m, 3H, 4-H, NCH2, OH), 4.34 (dd, J=9.1, 4.7 Hz, 1H, 9’-H), 4.37 (dd,
J=8.0, 6.0 Hz, 1H, 8’-H), 4.39–4.45 (m, 2H, 8-CH2, 9-H), 4.49 (mc, 1H,
8-CH2), 4.62 (d, J=9.1 Hz, 1H, OH), 4.962, 4.964 (2 s, 1 H each, 6-H, 6’-
H), 7.21–7.39 ppm (m, 10H, Ph); 13C NMR (CDCl3, 126 MHz): d=À5.4,
À5.3 (2 q, SiMe2), 18.2, 25.9 (s, q, tBu), 38.01, 38.02 (2 d, C-5, C-5’), 55.2
(q, OMe), 57.4, 58.0 (2 t, NCH2), 57.8 (d, C-1), 58.5 (d, C-1’), 62.51, 62.52
(2 t, 8-CH2, 8’-CH2), 63.9 (d, C-9’), 66.4 (t, C-4), 66.6 (d, C-9), 66.7 (t, C’-
4), 67.7 (d, C-8’), 68.3 (d, C-8), 101.2, 102.3 (2 d, C-6, C-6’), 127.1, 127.48,
127.50, 128.2, 128.4, 128.6, 137.0, 138.0 ppm (6 d, 2 s, Ph); IR (film): n˜ =
= 3600–3000 (OH, NH), 2990–2730 cmÀ1 (C H); ESI-TOF: m/z: calcd
À
for [C8H17NO5+H]+: 208.1179; found: 208.1180.
Methyl 4-amino-2,4-dideoxy-2-hydroxymethyl-a-d-idopyranoside (29): A
suspension of palladium on charcoal (10% Pd, 80 mg) in MeOH (3 mL)
was saturated with hydrogen for 1 h. After addition of bicyclic alcohol 27
(60 mg, 0.203 mmol) in MeOH (2 mL) hydrogen was bubbled through
the mixture for another 30 min and the reaction mixture was stirred
under an atmosphere of hydrogen for 18 h. Filtration through a short pad
of celite and concentration of the solution to dryness afforded methyl
glycoside 29 as colorless crystals (37 mg, 88%). Purity according to
3470 (OH), 3090–2840 cmÀ1 (=C H, C H); ESI-TOF: m/z: calcd for
[M+H]+: 673.3515; found: 673.3475; elemental analysis calcd (%) for
C35H52N2O9Si (672.9): C 62.47, H 7.79, N 4.16; found: C 61.94, H 7.80, N
4.03.
À
À
a-d-Idopyranoside 44: A suspension of palladium on charcoal (10% Pd,
60 mg) in MeOH (4 mL) was saturated with hydrogen for 1 h. After addi-
tion of the above described product (67 mg, 0.10 mmol) in MeOH
(3 mL), hydrogen was bubbled through the mixture for another 30 min
and the reaction mixture was stirred under an atmosphere of hydrogen
for 18 h. Filtration through a short pad of celite and concentration of the
solution to dryness afforded 44 as colorless oil (35 mg, 73%). Purity ac-
cording to NMR: >95%. [a]2D2 =+64.2 (c=0.55, MeOH); 1H NMR
(CD3OD, 500 MHz): d=0.12 (s, 6H, SiMe2), 0.93 (s, 9H, tBu), 1.65, 1.71
(dt, J=11.6, 4.3 Hz, 1H, dt, J=11.9, 4.7 Hz, 1H, 2-H, 2’-H), 2.88–2.92
(m, 2H, 4-H, 4’-H), 3.40 (s, 3H, OMe), 3.62–3.79 (m, 7H, 3-H, 3’-H, 6-H,
2-CH2, 2’-CH2), 3.83 (dd, J=11.0, 5.2 Hz, 1H, 6’-H), 3.88 (dd, J=11.0,
5.2 Hz, 1H, 6’-H), 4.02 (dd, J=10.5, 5.6 Hz, 1H, 6-H), 4.12 (dd, J=10.1,
5.2 Hz, 1H, 5’-H), 4.21 (mc, 1H, 5-H), 4.76, 4.87–4.92 ppm (d, J=4.7 Hz,
1H, 1-H, m, 1H, hidden by solvent residue peak, 1-H, 1’-H); 13C NMR
(CD3OD, 126 MHz): d=À6.6 (q, SiMe2), 17.8, 25.1 (s, q, tBu), 47.0–49.0
(2 d, C-2, C-2’), 54.0, 54.2 (2 d, C-4, C-4’), 54.7 (q, OMe), 59.5, 59.6 (2 t,
2-CH2, 2’-CH2), 62.5 (t, C-6), 67.1 (t, C-6’), 68.3 (d, C-5), 70.2 (d, C-5’),
70.7, 70.8 (2 d, C-3, C-3’), 99.1, 100.1 ppm (2 d, C-1, C-1’); IR (film): n˜ =
1
NMR: >95%. M.p. 1428C; [a]2D2 =+74.7 (c=0.18, H2O); H NMR (D2O,
500 MHz): d=1.77 (m, 1H, 2-H), 2.96 (dd, J=6.5, 4.3 Hz, 1H, 4-H), 3.46
(s, 3H, OMe), 3.67 (t, J=6.5 Hz, 1H, 3-H), 3.74 (dd, J=7.9, 3.6 Hz, 1H,
2-CH2), 3.75–3.80 (m, 2H, 6-H), 3.81 (dd, J=8.7, 3.6 Hz, 1H, 2-CH2),
4.18 (ddd, J=8.1, 4.3, 4.2 Hz, 1H, 5-H), 5.77–5.85 ppm (m, 1H, 1-H,
hidden by the solvent residue peak); 13C NMR (D2O, 126 MHz): d=45.0
(d, C-2), 50.9 (d, C-4), 53.5 (q, OMe), 57.1, 58.0 (2 t, C-6, 2-CH2), 67.9 (d,
C-3), 68.5 (d, C-5), 97.4 ppm (d, C-1); IR (KBr): n˜ = 3360–3175 (OH,
+
NH), 2980–2820 cmÀ1 (C H); ESI-TOF: m/z: calcd for [C8H17NO5+H] :
208.1179; found: 208.1185.
À
Disaccharide precursor 38: To
a solution of ketone 10 (500 mg,
1.03 mmol) and alcohol 25 (400 mg, 1.34 mmol) in CH2Cl2 (20 mL) were
added 4 ꢃ molecular sieves (700 mg) and N-iodosuccinimide (463 mg,
2.06 mmol). After stirring the mixture for 30 min at RT it was cooled to
08C and trifluoromethanesulfonic acid (17 mL, 0.206 mmol) was added.
The mixture was stirred at RT for 4 h, then diluted with CH2Cl2 and fil-
tered through a short pad of celite. The solution was subsequently
washed with a saturated solution of NaHCO3 and a 1m solution of
Na2S2O3, dried with MgSO4, filtered and concentrated. Column chroma-
tography (silica gel, EtOAc/hexane 1:3) provided 38 as colorless crystals
(543 mg, 79%). M.p. 588C; [a]2D2 =+117.2 (c=0.15, CHCl3); 1H NMR
(CDCl3, 400 MHz): d=0.02, 0.04 (2 s, 6H, SiMe2), 0.83 (s, 9H, tBu), 2.03
(mc, 1H, 5’-H), 2.65 (mc, 1H, 5-H), 3.14 (m, 1H, 1-H), 3.29 (mc, 1H, 1’-
H), 3.34 (s, 3H, OMe), 3.84 (dd, J=8.9, 4.9 Hz, 1H, 8’-CH2), 3.89–3.93
(m, 3H, 8-CH2, NCH2), 3.98 (d, J=12.4 Hz, 1H, NCH2), 4.04 (t, J=
8.9 Hz, 1H, 8’-CH2), 4.07–4.20 (m, 4H, 4’-H, 8’-H, NCH2), 4.20 (dd, J=
6.5, 2.2 Hz, 1H, 8-H), 4.38 (dd, J=10.4, 1.6 Hz, 1H, 4’-H), 4.40 (dd, J=
11.8, 5.4 Hz, 1H, 4-H), 4.71 (dd, J=11.8, 3.8 Hz, 1H, 4-H), 4.97 (d, J=
1.5 Hz, 1H, 6’-H), 5.04 (d, J=1.4 Hz, 1H, 6-H), 7.21–7.36 ppm (m, 10H,
Ph); 13C NMR (CDCl3, 126 MHz): d=À5.5 (q, SiMe2), 18.1, 25.8 (s, q,
tBu), 53.2 (d, C-5’), 53.8 (d, C-5), 54.9 (q, OMe), 58.5, 59.4 (2 t, NCH2),
61.2 (t, 8’-CH2), 65.6 (t, 8-CH2), 67.6 (d, C-1), 69.9 (t, C-4’), 70.1 (d, C-1’),
70.9 (t, C-4), 72.8 (d, C-8), 75.3 (d, C-8’), 103.5 (d, C-6’), 104.2 (d, C-6),
127.5, 127.8, 128.4, 128.5, 128.8, 129.6, 135.4, 136.0 (6 d, 2 s, Ph), 204.1,
3375–3125 (OH, NH), 2970–2830 cmÀ1 (C H); ESI-TOF: m/z: calcd for
À
[C21H44N2O9Si+H]+: 497.2889; found: 497.2890.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie (PhD
fellowship to F.P.), the Deutsche Forschungsgemeinschaft (SFB 765) and
Bayer Schering Pharma AG. We thank L. Schefzig, M. Kandziora, and D.
Nikolic for experimental support and Dr. R. Zimmer for assistance
during the preparation of this manuscript.
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Walsh, Chem. Rev. 2005, 105, 425–448. Selected examples: c) B. R.
Griffith, C. Krepel, X. Fu, S. Blanchard, A. Ahmed, C. E. Edmiston,
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H 7.23, N 4.19; found: C 62.82, H 7.34, N 4.07.
Reduction of disaccharide precursor 38: Compound 38 (75 mg,
0.112 mmol) was dissolved in THF (2.5 mL) and the solution was cooled
to 08C. A solution of L-selectride (1.0m in THF, 336 mL, 0.336 mmol)
was added and the mixture was stirred at this temperature for 2 h. After
quenching the mixture with a saturated solution of NH4Cl, EtOAc and
H2O were added. The layers were separated and the aqueous phase was
11924
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Chem. Eur. J. 2010, 16, 11915 – 11925

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Published online: September 14, 2010
Chem. Eur. J. 2010, 16, 11915 – 11925
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www.chemeurj.org
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