Stereoselective access to the β-D-N-acetylhexosaminyl-(1→4)-1-deoxy-D-nojirimycin disaccharide series avoiding the glycosylation reaction

Article abstract of DOI:10.1002/ejoc.201402555

The synthesis of β-D-GlcNAc-, β-D-GalNAc-, β-D-ManNAc-, and β-D-TalNAc-(1→4)-DNJ iminosugar disaccharides has been achieved, avoiding the glycosylation reaction, using a mixed tetracetonide of lactose [2,3:5,6:3′,4′-tri-O-isopropylidene-(6′-O-2-methoxy-2-methylethyl)-lactose dimethyl acetal] as starting material. The synthetic process is based on the transformation of the reducing unit of suitably protected β-D-hexosaminyl-(1→4)-aldehydo-D-glucose dimethyl acetal disaccharides into a deoxynojirimycin derivative. Key steps of the synthesis are: (a) the selective oxidation of the 5-position of the D-glucose unit, (b) release of the aldehydo function, (c) double reductive aminocyclisation of the 1,5-dicarbonyl disaccharide intermediate, and (d) complete deprotection. The title disaccharides of four stereoseries were prepared through an approach that does not require a glycosylation step. Starting from known compounds, all obtained from lactose, the DNJ unit was constructed through C-5 oxidation of the reducing D-glucopyranosyl unit followed by a stereoselective double-reductive aminocyclisation of the 1,5-dicarbonyl disaccharide intermediates.

Full text of DOI:10.1002/ejoc.201402555

FULL PAPER
DOI: 10.1002/ejoc.201402555
Stereoselective Access to the β-
D
-N-Acetylhexosaminyl-(1Ǟ4)-1-deoxy- -
D
nojirimycin Disaccharide Series Avoiding the Glycosylation Reaction[‡]
Lorenzo Guazzelli,[a][‡‡] Giorgio Catelani,[a] Felicia D’Andrea,*[a] Tiziana Gragnani,[a] and
Alessio Griselli[a]
Keywords: Carbohydrates / Iminosugars / Oxidation / Cyclization / Amination / Diastereoselectivity
The synthesis of β-
and β- -TalNAc-(1Ǟ4)-DNJ iminosugar disaccharides has
been achieved, avoiding the glycosylation reaction, using a
D
-GlcNAc-, β-
D
-GalNAc-, β-
D
-ManNAc-,
β-D-hexosaminyl-(1Ǟ4)-aldehydo-D-glucose dimethyl acetal
disaccharides into a deoxynojirimycin derivative. Key steps
of the synthesis are: (a) the selective oxidation of the 5-posi-
D
mixed tetracetonide of lactose [2,3:5,6:3Ј,4Ј-tri-O-isoprop- tion of the
D-glucose unit, (b) release of the aldehydo func-
ylidene-(6Ј-O-2-methoxy-2-methylethyl)-lactose
acetal] as starting material. The synthetic process is based on
the transformation of the reducing unit of suitably protected
dimethyl
tion, (c) double reductive aminocyclisation of the 1,5-dicar-
bonyl disaccharide intermediate, and (d) complete deprotec-
tion.
Introduction
Iminosugars are sugars wherein the endocyclic oxygen is
replaced by a basic nitrogen atom; such compounds consti-
tute one of the most attractive classes of carbohydrate mim-
ics. Polyhydroxylated piperidines and pyrrolidines as well as
their derivatives are found in nature[1] and they have been
studied for their biological activity.[2] The most valuable
property of iminosugars is their ability to act as glycosidase
inhibitors. The nitrogen atom is protonated at physiological
pH and the charged structure resembles the glycosyl cation
involved in the enzyme-catalysed glycosylation process and
matches both the electronic and steric requirements re-
quired to bind the enzyme active site. In addition, poly-
hydroxylated saturated nitrogen heterocycles also inhibit
glycosyltransferases.[3]
Over the last 40 years, iminosugars have attracted a great
deal of interest as possible therapeutic agents[4] against can-
cer, cystic fibrosis, diabetes and as antiviral agents, and the
scope of their biological activity has constantly expanded.
Two of the first generation iminosugar drugs, Glyset[5] and
Zavesca,[6] which are closely related to the naturally occur-
ring 1-deoxy-d-nojirimycin (DNJ), are currently on the
market (Figure 1).
Figure 1. First generation of azasugars: the parent compound DNJ
and the marketed drugs Glyset and Zavesca.
Glyset has been licensed for use in the treatment of
type II diabetes[5a,5b] and Zavesca for treatment of type I
Gaucher’s disease[6a,6b] and Niemann–Pick type C.[6c,6d]
DNJ and N-butyldeoxynojirimycin are also being
studied for the treatment of lysosomal storage disor-
ders.[7b,7d] These disorders are caused by deficiency of lyso-
somal enzymes (β-glucocerebrosidase, α-galactosidase, β-
galactosidase, and β-hexosaminidase) and are commonly
known as Pompe disease.[7a,7c,7e] In spite of these undeni-
ably relevant biological results, most of the first generation
monosaccharide iminosugars suffered from a lack of selec-
tivity, resulting in side-effects in the clinic. To overcome this
drawback, new compounds with potential for lead optimis-
ation are desired.
The transition state for the reaction catalysed by a typical
glycosidase involves di- or oligosaccharides. One possible
modification of the original iminosugar skeleton is to attach
a glycosyl residue to one of the hydroxyl functions. This
new binding pattern with the enzyme could give higher en-
zymatic selectivity. Synthetic efforts have been directed
[‡] Chemical Valorisation of Milk-Derived Carbohydrates, 31. Part
30: Ref.[19c]
[a] Dipartimento di Farmacia, Università di Pisa,
Via Bonanno 33, 56126 Pisa, Italy
E-mail: felicia.dandrea@farm.unipi.it
www.farm.unipi.
[‡‡] Present address: Centre for Synthesis and Chemical Biology,
University College Dublin,
Belfield, Dublin 4, Ireland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402555.
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Figure 2. Retrosynthetic approach to the β-d-N-acetylhexosaminyl-(1Ǟ4)-1-deoxy-d-nojirimycin disaccharides.
towards the synthesis of di- and oligosaccharide imino- ductive amination strategy developed in our previous
sugars,[8] and in some cases the larger structures proved work.[11]
to be better inhibitors than the parent monosaccharide
Protected derivatives of different hexosaminyl disacchar-
compounds.[9] Although several synthetic approaches have ides, ManNAc-, TalNAc-, GalNAc, and GlcNAc-β-(1Ǟ4)-
been developed during the past decades to prepare mono- d-glucose, which were prepared recently starting from lact-
saccharide iminosugars,[2a,10] including condensation reac- ose,[19] were used as starting materials to access the corre-
tions, amination reactions, organometallic catalysis, pericy- sponding iminosugar disaccharide mimics 1–4 (Figure 2) by
clic reactions, and addition reactions, the typical ap- following the above approach, which was first studied for
proach[8] that is used to prepare di- and oligosaccharide the ManNAc- and TalNAc series.[20] The planned approach
iminosugars is to perform a glycosylation reaction between utilises two transformations: the regioselective oxidation of
a suitably protected glycosyl donor and a selectively depro- the 5-position and stereoselective double reductive amin-
tected iminosugar acceptor.
ation, as outlined in Figure 2.
Some years ago, we presented a complementary way to
synthesise the β-d-galactose-(1Ǟ4)-1-deoxynojirimycin
starting from lactose and avoiding the glycosylation step.[11]
The synthetic pathway involved the stereoselective double
reductive amination of a 1,5-dicarbonyl disaccharide.
Results and Discussion
Compounds 6–9 were chosen as precursors for the syn-
Similar approaches have also been used by Stutz et al. to thesis of the title compounds and they were obtained in the
prepare new iminosugar disaccharides starting from cello- previous preparations of hexosaminyl containing disaccha-
biose,[12] maltose[12] and maltulose.[13] Sporadic examples of rides[19] from the same tetra-acetonide disaccharide 5 (Fig-
hexosaminyl-containing iminosugar disaccharides have ure 3).[21] Several manipulations of the nonreducing end al-
been reported, and these compounds have been investigated lowed for amination with either retention or inversion of
as potential heparanase inhibitors,[14] aza-analogues of the configuration of the 2Ј-position and also for inversion of
repeating unit in peptidoglycan,[15] potential endoglycosid- configuration of the 4Ј-position.
ase inhibitors,[16] azapseudodisaccharides related to allos-
The synthetic approach presented here involves selective
amidin,[17] and transition-state analogues for lysozyme.[18] transformations of the reducing end to the different stereo-
Owing to the interest in this rather unexplored class of aza- series. To oxidise the hydroxyl group in the 5-position, the
disaccharides, we turned our attention to the synthesis of 5,6-O-isopropylidene group should be selectively removed.
four representatives 1–4 (Figure 2), applying the double re- Previously, good results (ca. 70% yield) were obtained on
Figure 3. β-d-Hexosaminyl-(1Ǟ4)-d-glucose derivatives from the common acetonide 5.
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1-Deoxy-d-nojirimycin Disaccharide Synthesis
oxygenated disaccharide analogues of galacto[22] and stannylidene acetal intermediates. The presence of the axial
talo[23] series by using 80% aq. acetic acid at 40 °C. Com- acetamido group in 10 suppresses the formation of the
parable results were obtained by treating 7 and 9 under the 3Ј,4Ј-stannylidene acetal ring by steric hindrance, favouring
same conditions. Corresponding diols 11 and 13 were iso- regioselective oxidation of the 5,6 diol.
lated in 80 and 74% yields, respectively. For 6 and 8, the
A slightly longer sequence was required to overcome the
acetal ring in 3Ј,4Ј was also removed, thereby showing sim- side oxidation reaction and obtain better results for the
ilar reactivity between the fused cycle and the one involving GalNAc series (Scheme 2). Selective benzyl ether protection
the primary position, and tetraol disaccharides 10[19a] and of the 3Ј,4Ј-diol function of 12 was achieved through a
12 were again obtained with satisfactory yield (79 and 69%, short sequence involving (a) regioselective 5,6-di-O-iso-
respectively).
propylidenation with 2-methoxypropene (2-MP) and pyrid-
Oxidation of the 5-position can be regioselectively inium tosylate[25] as acid catalyst; (b) routine 3Ј,4Ј-di-O-
achieved by application of the well-known procedure[24] benzylation; (c) selective removal of the 5,6-isopropylidene
based on treatment of stannylidene acetal intermediates protection (80% aq. acetic acid). In this way, 19 was ob-
with N-bromosuccinimide (NBS). In this way, the two 5,6- tained in 53% overall yield from 12. Finally, regioselective
OH free disaccharides 11 and 13 were efficiently trans- stannylidene-mediated C-5 oxidation led to 5-uloside 20
formed into the 5-ulose derivatives 15 and 17, respectively, (Bu2SnO in toluene at reflux, then NBS in chloroform, 89%
in reasonable yields (Scheme 1). The stannylidene acetal yield).
mediated oxidation of tetraols 10 and 12 proved to be
The aldehydo group of 14, 15, 17 and 20 was deprotected
strongly influenced by the stereochemistry of the 2Ј-posi- by treatment with 90% aq. CF3COOH, which also caused
tion. Whereas in the case of the TalNAc disaccharide 10, the removal of the 2,3-O-isopropylidene acetal protection.
with an axially oriented 2Ј-substituent, the 5-keto disaccha- The 1,5-dicarbonyl disaccharide intermediates, comprising
ride 14 was isolated in high yield (68%), in the case of the a complex mixture of tautomeric forms (shown by NMR
galacto analogue 12, displaying an equatorial C-2Ј group, analysis), were submitted without further purification to a
the desired 5-uloside 16 was isolated in poor yield (28%) double-reductive aminocyclisation by treatment with
and a mixture of other oxidised side compounds was evi- NaBH3CN (2.2 equiv.) and BnNH2·HCl (1 equiv.) in
dent. This was not completely unexpected considering the MeOH at 60 °C for 12 h (Scheme 3).
result reported for the analogous tetraol derivative of lact-
For the TalNAc- and ManNAc- derivatives 21 and 22,
ose, in which the corresponding 4Ј-keto derivative was iso- respectively, an acetylation reaction (Ac2O–Py, 1:2; 24 h) of
lated as a by-product.[11] For 12, the situation appears to be the crude reaction mixtures was required to simplify purifi-
more complex because the di-oxidised product is probably cation. Iminosugar disaccharides 21–24 were isolated with
also formed. The mixture of compounds obtained arises acceptable yields (42–69%) and their structure and stereo-
1
from competitive oxidation of the two 5,6- and 3Ј,4Ј- chemistry were confirmed unambiguously by H, 13C and
Scheme 1. Preparation of 5-uloside derivatives 14–17. Reagents and conditions: (i) 80% aq. AcOH, 40 °C, 2–4 h (for 10 see Attolino et
al.[19]); (ii) a. Bu2SnO, toluene, reflux, 12 h; b. NBS, CHCl3, room temp, 0.5–2 h.
Scheme 2. Preparation of 5-uloside derivative 20. Reagents and conditions: (i) a. 2-MP, PyOHTs, CH2Cl2, room temp, 45 min; b. BnBr,
NaH, DMF, room temp, 15 h; (ii) 80% aq. AcOH, 40 °C, 2 h; (iii) a. Bu2SnO, toluene, reflux, 12 h; b. NBS, CHCl3, room temp, 0.5 h.
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Scheme 3. Preparation of β-d-N-acetylhexosaminyl-(1Ǟ4)-DNJ derivatives 21–24. Reagents and conditions: (i) 90% aq. TFA, room temp,
2–5 h; (ii) a. BnNH3+Cl–, NaBH3CN, MeOH, 60 °C, 12–24 h (for 23 and 24); b. pyridine–Ac2O (2:1), room temp, 24 h (only for 21 and
22).
2D NMR experiments. Coupling constants for the DNJ tuted analogues from a common dicarbonyl intermediate
unit are summarised in Table 1. In particular, the high value
of the J4,5 coupling constant excludes the alternative ido
configuration.
by simply changing the primary amine employed. It is note-
worthy that, as in this case, the aminocyclisation of xylo
configured aldohexos-5-uloses[11,26–28] takes place with
complete stereoselectivity, leading to the isolation of the
sole iminosugar with a gluco configuration. The stereoselec-
tivity of the aminocyclisation reaction relies on the direc-
tion of the hydride attack on the cyclic iminium ion inter-
mediate. This is formed through the first amination of the
more reactive aldehyde group followed by the second intra-
molecular amination of the C-5 ketone function. The high
diastereodifferentiation observed in the aminocyclisation of
xylo-1,5-dicarbonyl hexoses can be explained by taking into
account both stereoelectronic factors (preference of axial
hydride attack on cyclic iminium ions) and conformational
effects (all equatorial orientation on the more stable half-
chair conformer).
Table 1. Coupling constants [Hz] of the azapyranose unit.
J1ax,1eq J1ax,2 J1eq,2 J2,3 J3,4 J4,5 J5,6a J5,6b J6a,6b
21[a] 11.8
22[a] 11.3
23[a] 11.2
24[a] 11.2
10.5 5.2
10.7 5.1
10.1 4.5
10.2 4.7
9.4
9.4
8.8
8.9
9.4
9.4
8.8
8.9
9.6
9.4
9.7
9.2
3.1
2.7
2.1
1.8
2.3
2.7
2.1
2.2
12.7
12.8
12.3
12.4
[a] Spectra taken in CD3CN.
Since the first paper by Baxter and Reitz,[26] the double-
reductive aminocyclisation of aldohexos-5-uloses has usu-
ally been used to prepare iminosugars and their derivatives,
and this approach represents an easy way to access substi-
Scheme 4. Preparation of β-d-N-acetylhexosaminyl-(1Ǟ4)-DNJ 1–4. Reagents and conditions: (i) NaOMe–MeOH (0.33 m), MeOH, 0 °C,
5 h; (ii) a. NiCl2·6H2O, NaBH4, MeOH, room temp; 0.5–1 h; b. Ac2O, MeOH, room temp, 0.5–1 h; c. NaOMe–MeOH (0.33 m), THF–
MeOH (1:5), 0 °C, 2–3 h; iii. H2, 10% Pd-C, HCl–MeOH (1%), MeOH, room temp, 5–12 h.
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1-Deoxy-d-nojirimycin Disaccharide Synthesis
Avance II operating at 250.12 MHz or with a Varian INOVA600
spectrometer. 13C NMR spectra were recorded with the same spec-
trometers operating at 62.9 or 150 MHz. The assignments were
made, when possible, with the aid of DEPT, HETCOR, COSY, and
HSQC experiments. The first-order proton chemical shifts δ are
referenced to either residual CD3CN (δH 1.94 ppm, δC 1.28 ppm)
or residual CD3OD (δH 3.31 ppm, δC 49.0 ppm) and J-values are
given in Hz. All reactions were followed by TLC on Kieselgel 60
F254 with detection by UV light and/or with ethanolic 10% phos-
phomolybdic or sulfuric acid, and heating. Kieselgel 60 (E. Merck,
Compounds 21 and 22 were routinely deprotected
through an initial de-O-acetylation (MeONa/MeOH),
which afforded 25 and 26, respectively, in good yield (83–
94%), followed by catalytic hydrogenolysis (H2, Pd/C 10%
in 1.3 m methanolic HCl), which led to the target disaccha-
ride mimics β-d-TalNAc- and β-d-ManNAc-(1Ǟ4)-DNJ as
hydrochlorides (1 and 2, Scheme 4) in quantitative yield.
In case of derivatives 23 and 24, an additional reduction
of the azido function was required. This was efficiently
accomplished with the NiCl2·6H2O/NaBH4 system,[29] and 70–230 and 230–400 mesh, respectively) was used for column and
flash chromatography. Solvents were dried and purified by distil-
lation according to standard procedures,[30] and stored over 4 Å
molecular sieves activated for at least 24 h at 200 °C. MgSO4 was
used as the drying agent for solutions. Compound 4-O-(2-acet-
amido-6-O-benzyl-3,4-O-isopropylidene-2-deoxy-β-d-talopyranos-
yl)-2,3:5,6-di-O-isopro-pylidene-aldehydo-d-glucose dimethyl acetal
(6),[19a] 4-O-(2-acetamido-2,6-di-O-benzyl-2-deoxy-β-d-mannopyr-
anosyl)-2,3:5,6-di-O-isopropylidene-aldehydo-d-glucose dimethyl
acetal (7),[19a] 4-O-(2-azido-6-O-benzyl-3,4-O-isopropylidene-2-
deoxy-β-d-galactopyranosyl)-2,3:5,6-di-O-isopropylidene-alde-
the crude reaction mixtures were directly N-acetylated with
Ac2O in MeOH. During this reaction, the expected
iminosugars 27 and 28, respectively, were formed, as were
their 6-O-acetyl analogues 27a and 28a (not shown).
Good overall yields of 27 and 28 (85 and 91%, respec-
tively, from 23 and 24) were obtained when the crude mate-
rial obtained from the N-acetylation reaction were submit-
ted to classical de-O-acetylation under Zemplen condition.
Evidently, the formation of 27a and 28a is caused by the
close proximity of the primary 6-OH group to the endo- hydo-d-glucose dimethyl acetal (8),[19b] 4-O-(2-azido-3,4,6-tri-O-
benzyl-2-deoxy-β-d-glucopyranosyl)-2,3:5,6-di-O-isopropylidene-
aldehydo-d-glucose dimethyl acetal (9)[19c] and 4-O-(2-acetamido-
6-O-benzyl-2-deoxy-β-d-talopyranosyl)-2,3-O-isopropylidene-alde-
hydo-d-glucose dimethyl acetal (10)[19a] were prepared according to
the reported procedures.
cyclic acylamonium, thus competing with the solvent
(MeOH) to consume the excess of acetic anhydride. The
remaining target disaccharide mimics β-d-GalNAc- and β-
d-GlcNAc-(1Ǟ4)-DNJ (3 and 4, Scheme 4) were obtained
again as hydrochlorides after catalytic hydrogenolysis (H2,
Pd/C 10% in 1.3 m methanolic HCl).
4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-galactopyranosyl)-
2,3:5,6-di-O-isopropylidene-aldehydo- -glucose Dimethyl Acetal
D
(18): Pyridyl tosylate (PyHOTs, 18 mg, 0.071 mmol) and freshly
distilled 2-methoxypropene (142 μL, 1.5 mmol) were added to a
suspension of 12 (388 mg, 0.71 mmol) in anhydrous CH2Cl2
(8 mL). After 45 min, TLC analysis (EtOAc) revealed the complete
disappearance of the starting material and the formation of a major
product (Rf = 0.49). The reaction mixture was diluted with CH2Cl2
and washed with satd aq. NaHCO3 (5 mL). The aq. phase was
extracted with CH2Cl2 (3ϫ 20 mL) and the combined organic ex-
tracts were dried, filtered and concentrated under diminished pres-
sure. The crude residue (525 mg) was dissolved in anhydrous DMF
(6 mL) and the solution was added dropwise to a suspension of pre-
washed (hexane, 3ϫ 30 mL) NaH (60% in mineral oil, 114.2 mg,
2.85 mmol) in anhydrous DMF (6 mL) cooled to 0 °C. The mixture
was stirred for 30 min at 0 °C, then BnBr (0.21 mL, 1.71 mmol)
was added and the reaction mixture was further stirred at room
temperature until the starting material was completely reacted
(15 h, TLC, hexane/EtOAc, 4:6). Excess NaH was destroyed by
adding MeOH (1 mL) whilst stirring at 0 °C, and then the solvents
were evaporated under diminished pressure. The residue was parti-
tioned between H2O (30 mL) and Et2O (20 mL). The organic phase
was separated and the aqueous layer was extracted with Et2O (3ϫ
20 mL). The combined organic phases were dried, filtered and con-
centrated under diminished pressure. Flash chromatographic puri-
fication over silica gel of the crude product (hexane/EtOAc, 75:25)
gave pure 18 (398 mg, 73% from 12) as a clear syrup. Rf = 0.68
(hexane/EtOAc, 1:1); [α]D = –40.3 (c = 1.13, CHCl3). 1H NMR
(250.13 MHz, CD3CN): δ = 7.46–7.27 (m, 15 H, Ar-H), 4.84 (d,
Jgem = 11.1 Hz, 1 H, PhCH2), 4.76 (d, Jgem = 11.6 Hz, 1 H, PhCH2),
4.63 (d, Jgem = 11.6 Hz, 1 H, PhCH2), 4.60 (d, J1Ј,2Ј = 7.9 Hz, 1 H,
Conclusions
We have reported convenient access to a potential new
class of glycosydase inhibitors: β-d-2-NAc-hexosaminyl-
(1Ǟ4)-DNJ. Representatives of four stereoseries (talo,
manno, galacto, and gluco) were prepared avoiding the glyc-
osylation step that is usually required to construct disac-
charide iminosugars. This work further confirms the stereo-
selectivity of the double reductive amination for xylo con-
figured aldohexos-5-uloses. A library of analogous imino-
sugars could easily be prepared by using differently substi-
tuted primary amines in the aminocyclisation reaction.
Furthermore, the collection of compounds available
through the synthetic scheme presented here will allow for
a systematic study of the effect of the acetamido group on
the inhibitory properties of this new class of potential
glycosidase inhibitors as well as enable an exploration of
the effect of the different stereochemistry at the C-2Ј and
C-4Ј positions. This is expected to provide unique insight
into the function–structure relationships of β-d-2-NAc-
hexosaminyl-(1Ǟ4)-1-deoxynojirimycin. Further studies in
this direction are underway and will be presented in the
near future.
Experimental Section
1Ј-H), 4.55 (d, Jgem = 11.1 Hz, 1 H, PhCH2), 4.52 (d, Jgem
=
General Methods: Melting points were determined with a Kofler
hot-stage apparatus and are uncorrected. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter at 20Ϯ2 °C. 1H
NMR spectra were recorded in appropriate solvents with a Bruker
11.8 Hz, 1 H, PhCH2), 4.44 (d, Jgem = 11.8 Hz, 1 H, PhCH2), 4.35–
4.30 (m, 2 H, 1-H, 2-H), 4.25 (dt, J4,5 = 5.0, J5,6a = J5,6b = 6.4 Hz,
1 H, 5-H), 4.10 (dd, J6a,6b = 8.3 Hz, 1 H, 6-Hb), 4.07 (dd, J2,3
=
5.2, J3,4 = 1.4 Hz, 1 H, 3-H), 4.02 (dd, 1 H, 6-Ha), 3.97 (br. d, J3Ј,4Ј
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= 2.9 Hz, 1 H, 4Ј-H), 3.92 (dd, 1 H, 4-H), 3.61 (dd, J2Ј,3Ј = 10.4 Hz, 4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D
-glucopyranosyl)-2,3-
1 H, 2Ј-H), 3.60–3.51 (m, 3 H, 5Ј-H, 6Ј-Ha, 6Ј-Hb), 3.47 (dd, 1 H,
3Ј-H), 3.30, 3.27 (2s, each 3 H, 2ϫOCH3), 1.41, 1.32, 1.31, 1.30
O-isopropylidene-aldehydo-
D-glucose Dimethyl Acetal (13): Selective
hydrolysis of 9 (494 mg, 0.64 mmol) was performed according to
[4s, each 3 H, 2ϫC(CH3)2] ppm. 13C NMR (62.9 MHz, CD3CN): δ the general procedure. The reaction was stopped after 3.5 h and
= 139.7, 139.2, 139.1 (3ϫAr-C), 129.3–128.5 (Ar-CH), 110.9, 108.9
[2ϫC(CH3)2], 106.0 (C-1), 102.3 (C-1Ј), 81.3 (C-3Ј), 78.6 (C-3), 77.8
the crude product was purified by flash chromatography (hexane/
EtOAc, 2:3) to give pure 13 (344 mg, 74%) as a white solid; m.p.
(C-5), 76.1 (C-2), 76.0 (C-4), 75.6, 73.9, 72.9 (3ϫPhCH2), 74.0 (C- 93–95 °C; Rf = 0.49 (hexane/EtOAc, 1:4); [α]D = –53.5 (c = 1.14,
5Ј), 73.8 (C-4Ј), 69.1 (C-6Ј), 66.1 (C-6), 65.1 (C-2Ј), 56.0, 53.7
CHCl3). 1H NMR (250.13 MHz, CD3CN): δ = 7.59–7.19 (m, 15
(2ϫOCH3), 27.7, 27.1, 26.8, 25.3 [2ϫC(CH3)2] ppm. C41H53N3O11 H, Ar-H), 4.84 (d, Jgem = 11.3 Hz, 1 H, PhCH2), 4.79 (d, Jgem
=
(763.89): C 64.47, H 6.99, N 5.50; found C 64.50, H 7.02, N 5.53.
11.3 Hz, 1 H, PhCH2), 4.75 (d, Jgem = 10.9 Hz, 1 H, PhCH2), 4.57
(d, Jgem = 10.9 Hz, 1 H, PhCH2), 4.56 (d, J1Ј,2Ј = 7.8 Hz, 1 H, 1Ј-
H), 4.54 (d, Jgem = 10.8 Hz, 1 H, PhCH2), 4.47 (d, Jgem = 10.8 Hz,
1 H, PhCH2), 4.45 (dd, J2,3 = 7.1, J1,2 = 6.1 Hz, 1 H, 2-H), 4.35
(d, 1 H, 1-H), 4.26 (br. d, 1 H, 3-H), 3.82–3.74 (m, 4 H, 4-H, 5-H,
6-Ha, 6-Hb), 3.73 (dd, J5Ј,6Јb = 3.6, J6Јa,6Јb = 10.8 Hz, 1 H, 6Ј-Hb),
General Procedure for Selective De-O-isopropylidenation of 7–9 and
18: A solution of appropriate protected sugar 7–9 or 18 (1 mmol) in
80% aq. AcOH (19 mL) was stirred at 40 °C until the TLC analysis
revealed the complete reaction of the starting material with forma-
tion of slower moving products. The solution was then cooled to
room temperature and co-evaporated with toluene (4ϫ 20 mL) un-
der diminished pressure. Purification of the crude residue by flash
chromatography on silica gel gave products 11–13 and 19.
3.66 (dd, J5Ј,6Јa = 2.0 Hz, 1 H, 6Ј-Ha), 3.63 (dd, J2Ј,3Ј = 9.3, J3Ј,4Ј
=
8.7 Hz, 1 H, 3Ј-H), 3.49 (dd, J4Ј,5Ј = 9.0 Hz, 1 H, 4Ј-H), 3.39 (dd,
1 H, 2Ј-H), 3.38 (m, 1 H, 5Ј-H), 3.37, 3.35 (2s, each 3 H, 2ϫOCH3),
3.21 (br. s, 1 H, 5-OH), 2.95 (br. t, J6a,OH = J6b,OH = 3.5 Hz, 1 H,
6-OH), 1.36, 1.35 [2s, each 3 H, C(CH3)2] ppm. 13C NMR
(62.9 MHz, CD3CN): δ = 139.5, 139.4, 139.3 (3ϫAr-C), 129.2–
128.6 (Ar-CH), 110.6 [C(CH3)2], 106.5 (C-1), 101.5 (C-1Ј), 83.7 (C-
4Ј), 78.7 (C-3Ј), 78.0 (C-3), 77.0 (C-4), 76.7 (C-2), 75.6 (C-5Ј), 75.7,
75.4, 74.1 (3ϫPhCH2), 73.0 (C-5), 69.6 (C-6Ј), 67.7 (C-2Ј), 63.2 (C-
6), 56.1, 54.4 (2ϫOCH3), 27.8, 27.3 [C(CH3)2] ppm. C38H49N3O11
(723.81): calcd. C 63.06, H 6.82, N 5.81; found C 63.12, H 6.87, N
5.83.
4-O-(2-Acetamido-3,6-di-O-benzyl-2-deoxy-β-
D-mannopyranosyl)-
2,3-O-isopropylidene-aldehydo- -glucose Dimethyl Acetal (11): Se-
D
lective hydrolysis of 7 (1.20 g, 1.73 mmol) was performed according
to the general procedure. The reaction was stopped after 4 h and
the crude product was purified by flash chromatography (CHCl3/
MeOH, 93:7) to give pure 11 (898 mg, 80%) as a clear syrup. Rf =
0.32 (CHCl3/MeOH, 9:1); [α]D = –52.0 (c = 1.0, CHCl3). 1H NMR
(250.13 MHz, CD3CN): δ = 7.61–7.25 (m, 10 H, Ar-H), 6.66 (d,
J2Ј,NH = 9.1 Hz, 1 H, NH), 4.79 (m, J1Ј,2Ј = 1.5 Hz, 1 H, 2Ј-H),
4.77 (d, 1 H, 1Ј-H), 4.74 (d, Jgem = 11.0 Hz, 1 H, PhCH2), 4.56 (s,
2 H, PhCH2), 4.47 (dd, J1,2 = 6.1, J2,3 = 7.1 Hz, 1 H, 2-H), 4.38
(d, Jgem = 11.0 Hz, 1 H, PhCH2), 4.33 (d, 1 H, 1-H), 4.18 (dd, J3,4
= 0.7 Hz, 1 H, 3-H), 3.78–3.52 (m, 8 H, 4-H, 5-H, 6-Ha, 6-Hb, 6Ј-
Ha, 6Ј-Hb, 2ϫOH), 3.44 (m, 2 H, 3Ј-H, 4Ј-H), 3.33, 3.32 (2s, each
3 H, 2ϫOCH3), 3.32 (m, 2 H, 5Ј-H, OH), 1.87 (s, 3 H, CH3CON),
1.37 [s, 6 H, C(CH3)2] ppm. 13C NMR (62.9 MHz, CD3CN): δ =
171.5 (CO), 139.6, 139.5 (2ϫAr-C), 129.2–128.4 (Ar-CH), 110.6
[C(CH3)2], 106.2 (C-1), 100.4 (C-1Ј), 81.1 (C-3Ј), 78.3 (C-3), 78.1
(C-4), 76.8 (C-5Ј), 76.6 (C-2), 73.9, 71.4 (2ϫPhCH2), 73.0 (C-5),
70.8 (C-6Ј), 67.6 (C-4Ј), 63.4 (C-6), 55.9, 54.3 (2ϫOCH3), 49.9 (C-
2Ј), 27.8, 27.0 [C(CH3)2], 23.3 (CH3CON) ppm. C33H47NO12
(649.73): calcd. C 61.00, H 7.29, N 2.16; found C 61.12, H 7.45, N
2.30.
4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-galactopyranosyl)-2,3-
O-isopropylidene-aldehydo- -glucose Dimethyl Acetal (19): Selective
D
hydrolysis of 18 (380 mg, 0.50 mmol) was performed according to
the general procedure. The reaction was stopped after 2 h and the
crude product was purified by flash chromatography (hexane/
EtOAc, 2:3) to give pure 19 (263 mg, 73%) as a white solid; m.p.
131–135 °C; Rf = 0.39 (hexane/EtOAc, 1:4); [α]D = –30.9 (c = 1.02,
CHCl3). 1H NMR (250.13 MHz, CD3CN): δ = 7.47–7.27 (m, 15
H, Ar-H), 4.84 (d, Jgem = 11.2 Hz, 1 H, PhCH2), 4.77 (d, Jgem
=
11.5 Hz, 1 H, PhCH2), 4.64 (d, Jgem = 11.5 Hz, 1 H, PhCH2), 4.55
(d, Jgem = 11.2 Hz, 1 H, PhCH2), 4.51 (d, Jgem = 11.9 Hz, 1 H,
PhCH2), 4.45 (d, Jgem = 11.9 Hz, 1 H, PhCH2), 4.47 (d, J1Ј,2Ј
=
3
7.8 Hz, 1 H, 1Ј-H), 4.38–4.31 (m, 2 H, 1-H, 2-H), 4.24 (br. d, J =
6.3 Hz, 1 H, 3-H), 3.99 (br. d, 1 H, 4Ј-H), 3.80–3.67 (m, 4 H, 4-H,
5-H, 6-Ha, 6-Hb), 3.63 (dd, J2Ј,3Ј = 10.4 Hz, 1 H, 2Ј-H), 3.61–3.54
(m, 3 H, 5Ј-H, 6Ј-Ha, 6Ј-Hb), 3.53 (dd, J3Ј,4Ј = 2.8 Hz, 1 H, 3Ј-H),
3.43, 3.17 (2br. s, each 1 H, 5-OH, 6-OH), 3.30, 3.27 (2s, each 3 H,
2ϫOCH3), 1.33 [2s, each 3 H, C(CH3)2] ppm. 13 C NMR
(62.9 MHz, CD3CN): δ = 139.7, 139.2, 139.0 (3ϫAr-C), 129.3–
128.5 (Ar-CH), 110.5 [C(CH3)2], 106.1 (C-1), 101.5 (C-1Ј), 81.4 (C-
3Ј), 78.0 (C-3), 76.2 (C-2), 76.0 (C-4), 75.6, 73.9, 72.8 (3ϫPhCH2),
74.0 (C-5Ј), 73.6 (C-4Ј), 72.9 (C-5), 69.1 (C-6Ј), 64.8 (C-2Ј), 63.2 (C-
6), 56.0, 53.7 (2ϫOCH3), 27.6, 27.2 [C(CH3)2] ppm. C38H49N3O11
(723.81): calcd. C 63.06, H 6.82, N 5.81; found C 63.01, H 6.80, N
5.78.
4-O-(2-Azido-6-O-benzyl-2-deoxy-β-
D-galactopyranosyl)-2,3-O-iso-
propylidene-aldehydo- -glucose Dimethyl Acetal (12): Selective hy-
D
drolysis of 8 (2.40 g, 3.79 mmol) was performed according to the
general procedure. The reaction was stopped after 4 h and the
crude product was purified by flash chromatography (CHCl3/
MeOH, 93:7) to give pure 12 (1.40 g, 68%) as a white solid; m.p.
130–133 °C; Rf = 0.38 (EtOAc); [α]D = –1.57 (c = 1.03, MeOH).
1H NMR (250.13 MHz, CD3CN/D2O): δ = 7.36–7.27 (m, 5 H, Ar-
H), 4.51 (d, Jgem = 11.9 Hz, 1 H, PhCH2), 4.45 (d, Jgem = 11.9 Hz,
1 H, PhCH2), 4.43 (d, J1Ј,2Ј = 7.9 Hz, 1 H, 1Ј-H), 4.41 (dd, J1,2
6.5, J2,3 = 6.2 Hz, 1 H, 2-H), 4.33 (d, 1 H, 1-H), 4.26 (dd, J3,4
=
=
General Procedure for the Regioselective C-5 Oxidation of 10–13
0.9 Hz, 1 H, 3-H), 3.78–3.60 (m, 5 H, 3Ј-H, 4Ј-H, 5Ј-H, 6-Ha, 6- and 19: A solution of appropriate sugar 10–13 or 19 (1 mmol) in
Hb), 3.58 (m, 3 H, 6Ј-Ha, 6Ј-Hb, 4-H), 3.42 (m, 2 H, 2Ј-H, 5-H), toluene (62 mL) was treated with Bu2SnO (1.1 equiv.), heated to
3.28, 3.27 (2s, each 3 H, 2ϫOCH3), 1.35, 1.33 [2s, each 3 H, reflux, and subjected to azeotropic removal of water with a Dean–
C(CH3)2] ppm. 13C NMR (62.9 MHz, CD3CN/D2O): δ = 139.0 Stark apparatus. The reaction mixture was heated to reflux over-
(Ar-C), 129.3–128.7 (Ar-CH), 111.3 [C(CH3)2], 105.8 (C-1), 101.6
night and concentrated under diminished pressure. The residue was
(C-1Ј), 78.1 (C-3),76.8 (C-4), 76.6 (C-2), 74.3 (C-3Ј), 73.9 (PhCH2), diluted with anhydrous CHCl3, covered with aluminium foil, co-
72.6 (C-5Ј, C-5), 69.9 (C-6Ј), 69.2 (C-4Ј), 65.5 (C-2Ј), 62.9 (C-6), oled to 0 °C, treated with freshly crystallised NBS (1 equiv.) and
56.0, 53.8 (2ϫOCH3), 27.9, 27.2 [C(CH3)2] ppm. C24H37N3O11
(543.58): calcd. C 53.03, H 6.86, N 7.73; found C 53.12, H 6.83, N
7.75.
further stirred at room temperature until the starting compound
was completely reacted (TLC). The mixture was concentrated to
a small volume under diminished pressure and purified by flash
6532
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6527–6537

1-Deoxy-d-nojirimycin Disaccharide Synthesis
chromatography on silica gel to afford pure 5-ulose derivatives 14–
17 and 20.
NMR (62.9 MHz, CD3CN/D2O): δ = 210.7 (C-5), 139.0 (Ar-C),
129.3–128.7 (Ar-CH), 111.9 [C(CH3)2], 105.6 (C-1), 101.1 (C-1Ј),
81.1 (C-4), 79.6 (C-3), 76.3 (C-2), 74.7 (C-3Ј), 72.7 (PhCH2), 72.6
(C-5Ј), 69.0 (C-4Ј), 69.9 (C-6Ј), 67.7 (C-6), 65.1 (C-2Ј), 56.2, 54.4
(2ϫOCH3), 27.5, 26.9 [C(CH3)2] ppm. C24H35N3O11 (541.56):
calcd. C 53.23, H 6.51, N 7.76; found C 53.20, H 6.53, N 7.70.
4-O-(2-Acetamido-6-O-benzyl-2-deoxy-β-
propylidene-
D-talopyranosyl)-2,3-O-iso-
D
-xylo-hexos-5-ulose Dimethyl Acetal (14): Regioselec-
tive oxidation of 10[19a] (453.6 mg, 0.81 mmol) was performed ac-
cording to the general procedure. The reaction was stopped after
1.5 h, purified with CHCl3 then CHCl3/MeOH (9:1) to give pure
4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-glucopyranosyl)-2,3-
14 (300 mg, 67%) as a clear syrup. Rf = 0.41 (CHCl3/MeOH, 8:2);
[α]D = –64.6 (c = 1.06, CHCl3). H NMR (250.13 MHz, CD3CN/ gioselective oxidation of 13 (337 mg, 0.47 mmol) was performed
O-isopropylidene- -xylo-hexos-5-ulose Dimethyl Acetal (17): Re-
D
1
D2O): δ = 7.63–7.26 (m, 5 H, Ar-H), 4.56 (d, J1Ј,2Ј = 1.7 Hz, 1 H,
1Ј-H), 4.51 (s, 2 H, PhCH2), 4.47 (m, 1 H, 2Ј-H), 4.43, 4.33 (2d,
according to the general procedure. The reaction was stopped after
1.5 h, purified eluting with hexane then hexane/EtOAc (65:35), af-
J6a,6b = 15.2 Hz, each 1 H, 6-Ha, 6-Hb), 4.39 (d, J3,4 = 1.7 Hz, 1 fording pure 17 (259 mg, 77%) as a clear syrup. Rf = 0.63 (hexane/
H, 4-H), 4.33 (d, J1,2 = 6.4 Hz, 1 H, 1-H), 4.32 (dd, J2,3 = 5.9 Hz, EtOAc, 3:7); [α]D = –77.0 (c = 1.25; CHCl3 ). 1 H NMR
1 H, 2-H), 4.24 (dd, 1 H, 3-H), 3.77 (m, 1 H, 4Ј-H), 3.71 (dd, J2Ј,3Ј (250.13 MHz, CD3CN): δ = 7.41–7.21 (m, 15 H, Ar-H), 4.82 (s, 2
= 2.8, J3Ј,4Ј = 4.7 Hz, 1 H, 3Ј-H), 3.63 (m, 3 H, 5Ј-H, 6Ј-Ha, 6Ј- H, PhCH2), 4.77 (d, Jgem = 10.9 Hz, 1 H, PhCH2), 4.65 (dd, J6a,6b
Hb), 3.30, 3.28 (2s, each 3 H, 2ϫOCH3), 1.90 (s, 3 H, CH3CON),
= 19.9, J6b,OH = 3.3 Hz, 1 H, 6-Hb), 4.59 (d, Jgem = 10.9 Hz, 1 H,
1.28 [s, 6 H, C(CH3)2] ppm. 13C NMR (62.9 MHz, CD3CN/D2O): PhCH2), 4.54 (d, Jgem = 11.8 Hz, 1 H, PhCH2), 4.50 (dd, J6a,OH
=
δ = 211.3 (C-5), 173.3 (CO), 139.1 (Ar-C), 129.3–128.6 (Ar-CH), 3.3 Hz, 1 H, 6-Ha), 4.47 (d, Jgem = 11.8 Hz, 1 H, PhCH2), 4.46 (d,
111.6 [C(CH3)2], 105.8 (C-1), 100.1 (C-1Ј), 81.4 (C-4), 79.4 (C-3), J1Ј,2Ј = 7.9 Hz, 1 H, 1Ј-H), 4.45 (d, J3,4 = 1.8 Hz, 1 H, 4-H), 4.39
76.1 (C-2), 75.1 (C-5Ј), 73.9 (PhCH2), 70.0 (C-6Ј), 68.9 (C-3Ј), 68.4 (d, J1,2 = 5.7 Hz, 1 H, 1-H), 4.33 (dd, J2,3 = 6.8 Hz, 1 H, 2-H), 4.28
(C-4Ј), 68.2 (C-6), 56.1, 54.5 (2ϫOCH3), 52.7 (C-2Ј), 27.4, 26.6 (dd, 1 H, 3-H), 3.74 (dd, J6Јa,6Јb = 11.2, J5Ј,6Јb = 9.3 Hz, 1 H, 6Ј-
[C(CH3)2], 23.0 (CH3CON) ppm. C26H39NO12 (557.59): calcd. C Hb), 3.66 (dd, J5Ј,6Јa = 9.3 Hz, 1 H, 6Ј-Ha), 3.61 (dd, J2Ј,3Ј = 9.3,
56.01, H 7.05, N 2.51; found C 56.11, H 7.15, N 2.62.
J3Ј,4Ј = 8.6 Hz, 1 H, 3Ј-H), 3.55 (dd, 1 H, 2Ј-H), 3.49 (dd, J4Ј,5Ј =
9.5 Hz, 1 H, 4Ј-H), 3.41 (ddd, 1 H, 5Ј-H), 2.95 (br. t, 1 H, 6-OH),
3.39, 3.36 (2s, each 3 H, 2ϫOCH3), 1.39, 1.34 [2s, each 3 H,
C(CH3)2] ppm. 13C NMR (62.9 MHz, CD3CN): δ = 211.2 (C-5),
140.0, 139.9, 139.8 (3 ϫ Ar-C), 129.9–129.2 (Ar-CH), 112.1
[C(CH3)2], 106.1 (C-1), 101.6 (C-1Ј), 84.3 (C-4Ј), 81.9 (C-4), 80.2
(C-3), 79.1 (C-3Ј), 77.0 (C-2), 76.5, 76.1, 74.8 (3ϫPhCH2), 76.4 (C-
5Ј), 70.1 (C-6Ј), 68.6 (C-6), 56.7, 55.3 (2ϫOCH3), 28.1, 27.7
[C(CH3)2] ppm. C38H47N3O11 (721.79): calcd. C 63.23, H 6.56, N
5.82; found C 63.25, H 6.59, N 5.85.
4-O-(2-Acetamido-3,6-di-O-benzyl-2-deoxy-β- -mannopyranosyl)-
D
2,3-O-isopropylidene- -xylo-hexos-5-ulose Dimethyl Acetal (15):
D
Regioselective oxidation of 11 (380.8 mg, 0.58 mmol) was per-
formed according to the general procedure. The reaction was
stopped after 30 min, and purified eluting with CHCl3 then CHCl3/
MeOH (95:5) to afford pure 15 (352.6 mg, 94%) as a clear syrup.
Rf = 0.27 (CHCl3/MeOH, 95:5); [α]D = –65.4 (c = 1.12, CHCl3).
1H NMR (250.13 MHz, CD3CN): δ = 7.60–7.25 (m, 10 H, Ar-H),
6.70 (d, J2Ј,NH = 9.4 Hz, 1 H, NH), 4.93 (m, J1Ј,2Ј = 1.6 Hz, 1 H,
2Ј-H), 4.67 (d, 1 H, 1Ј-H), 4.77 (d, Jgem = 10.9 Hz, 1 H, PhCH2), 4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D
-galactopyranosyl)-2,3-
-xylo-hexos-5-ulose Dimethyl Acetal (20): Re-
gioselective oxidation of 19 (1.05 g, 1.46 mmol) was performed ac-
4.54 (s, 2 H, PhCH2), 4.45–4.34 (m, 5 H, 1-H, 2-H, 4-H, 6-Ha, 6-
Hb), 4.40 (d, Jgem = 10.9 Hz, 1 H, PhCH2), 4.24 (dd, J2,3 = 6.8, J3,4
O-isopropylidene-D
= 1.7 Hz, 1 H, 3-H), 3.75 (dd, J5Ј,6Јb = 2.3, J6Јa,6Јb = 10.8 Hz, 1 H, cording to the general procedure. The reaction was stopped after
6Ј-Hb), 3.66 (dd, J5Ј,6Јa = 5.2 Hz, 1 H, 6Ј-Ha), 3.57 (br. t, 1 H, 6- 1.5 h, and purified with hexane then hexane/EtOAc (65:35) to af-
OH), 3.48–3.43 (m, 2 H, 3Ј-H, 4Ј-H), 3.41–3.34 (m, 2 H, 5Ј-H, 4- ford pure 20 (943 mg, 89%) as a white foam. Rf = 0.65 (hexane/
OH), 3.36, 3.32 (2s, each 3 H, 2ϫOCH3), 1.90 (s, 3 H, CH3CON),
EtOAc, 3:7); [α]D = –56.8 (c = 1.08, CHCl3 ). 1 H NMR
1.33, 1.30 [2s, each 3 H, C(CH3)2] ppm. 13C NMR (62.9 MHz, (250.13 MHz, CD3CN): δ = 7.48–7.27 (m, 15 H, Ar-H), 4.83 (d,
CD3CN): δ = 210.9 (C-5), 171.5 (CO), 139.6, 139.5 (2ϫAr-C),
129.3–128.5 (Ar-CH), 111.6 [C(CH3)2], 106.0 (C-1), 99.6 (C-1Ј),
Jgem = 11.0 Hz, 1 H, PhCH2), 4.79 (d, Jgem = 11.5 Hz, 1 H, PhCH2),
4.66 (d, Jgem = 11.5 Hz, 1 H, PhCH2), 4.61 (dd, J6a,6b = 10.2, J6b,OH
81.8 (C-4), 80.8 (C-3Ј), 79.8 (C-3), 76.9 (C-5Ј), 76.4 (C-2), 73.9, = 5.4 Hz, 1 H, 6-Hb), 4.54 (d, Jgem = 11.0 Hz, 1 H, PhCH2), 4.50
71.4 (2ϫPhCH2), 70.7 (C-6Ј), 68.4 (C-6), 67.6 (C-4Ј), 55.9, 54.7 (d, Jgem = 11.9 Hz, 1 H, PhCH2), 4.50 (dd, J6a,OH = 5.4 Hz, 1 H,
( 2 ϫ O C H 3 ) , 4 9 . 5 ( C - 2 Ј ) , 2 7 . 7 , 2 6 . 7 [ C ( C H 3 ) 2 ] , 2 3 . 2 6-Ha), 4.45 (d, Jgem = 11.9 Hz, 1 H, PhCH2), 4.37 (d, J1Ј,2Ј = 8.0 Hz,
(CH3CON) ppm. C33H45NO12 (647.71): calcd. C 61.19, H 7.00, N
2.16; found C 61.30, H 7.11, N 2.28.
1 H, 1Ј-H), 4.36 (m, 2 H, 1-H, 4-H), 4.22 (m, 2 H, 2-H, 3-H), 4.00
(dd, J4Ј,5Ј = 3.1, J3Ј,4Ј = 1.5 Hz, 1 H, 4Ј-H), 3.74 (dd, J2Ј,3Ј
=
10.2 Hz, 1 H, 2Ј-H), 3.62–3.53 (m, 3 H, 5Ј-H, 6Ј-Ha, 6Ј-Hb), 3.51
(dd, 1 H, 3Ј-H), 3.32–3.30 (2s, each 3 H, 2ϫOCH3), 3.11 (t, 1 H, 6-
OH), 1.36, 1.32 [2s, each 3 H, C(CH3)2] ppm. 13C NMR (63 MHz,
CD3CN): δ = 210.8 (C-5), 139.6, 139.4, 139.0 (3ϫAr-C), 129.3–
128.6 (Ar-CH), 111.4 [C(CH3)2], 105.8 (C-1), 101.0 (C-1Ј), 81.5 (C-
3Ј), 81.2 (C-4), 79.6 (C-3), 76.2 (C-2), 75.6, 73.9, 72.8 (3ϫPhCH2),
74.4 (C-5Ј), 73.5 (C-4Ј), 69.1 (C-6Ј), 68.2 (C-6), 64.2 (C-2Ј), 56.2–
54.2 (2ϫOCH3), 27.4, 27.0 [C(CH3)2] ppm. C38H47N3O11 (721.79):
calcd. C 63.23, H 6.56, N 5.82; found C 63.18, H 6.50, N 5.78.
4-O-(2-Acetamido-6-O-benzyl-2-deoxy-β-
D-galactopyranosyl)-2,3-
O-isopropylidene- -xylo-hexos-5-ulose Dimethyl Acetal (16): Re-
D
gioselective oxidation of 12 (179 mg, 0.33 mmol) was performed
according to the general procedure. The reaction was stopped after
1 h. Purification of the concentrated reaction mixture by flash
chromatography on silica gel (CHCl3 then CHCl3/MeOH, 97:3)
gave pure 16 (55 mg, 28%) as a clear syrup. Rf = 0.44 (CHCl3/
MeOH, 9:1). 1H NMR (250.13 MHz, CD3CN/D2O): δ = 7.40–7.25
(m, 5 H, Ar-H), 4.60, 4.58 (2d, J6a,6b = 19.8 Hz, each 1 H, 6-Hb,
6-Ha), 4.51 (d, Jgem = 11.8 Hz, 1 H, PhCH2), 4.45 (d, Jgem
11.8 Hz, 1 H, PhCH2), 4.39 (d, J1Ј,2Ј = 7.9 Hz, 1 H, 1Ј-H), 4.40 (dd,
J3,4 = 1.8, J2,3 = 6.5 Hz, 1 H, 3-H), 4.36 (d, J1,2 = 5.8 Hz, 1 H, 1-
=
General Procedure for the Synthesis of Azadisaccharide Derivatives
21–22: The appropriate 5-keto sugar 14 or 15 (1 mmol) was dis-
solved in 90% aq. CF3COOH (12 mL) and the solution was stirred
H), 4.29 (dd, 1 H, 2-H), 4.26 (d, 1 H, 4-H), 3.73–3.45 (m, 5 H, 2Ј- at room temperature. After 2–5 h, TLC analysis revealed the com-
H, 3Ј-H, 4Ј-H, 6Ј-Ha, 6Ј-Hb), 3.43 (m, 1 H, 5Ј-H), 3.31, 3.28 (2s, plete disappearance of the starting material and the formation of
each 3 H, 2ϫOCH3), 1.36, 1.30 [2s, each 3 H, C(CH3)2] ppm. 13C a more retained product. The solution was co-evaporated with tolu-
Eur. J. Org. Chem. 2014, 6527–6537
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6533

F. D’Andrea et al.
FULL PAPER
ene (4ϫ 30 mL) under diminished pressure. To a solution of the
139.2 (3ϫAr-C), 129.4–128.0 (Ar-CH), 99.8 (C-1Ј), 78.2 (C-3Ј),
obtained crude material in anhydrous MeOH (25 mL), 76.9 (C-4), 74.7 (C-5Ј), 74.6 (C-3), 73.7, 71.2 (2ϫPhCH2O), 70.3
BnNH2·HCl (1 equiv.) and NaBH3CN (2.2 equiv.) were added. The (C-6Ј), 69.8 (C-2), 68.9 (C-4Ј), 64.4 (C-5), 60.9 (C-6), 56.4
mixture was heated to 60 °C, stirred until the starting material was (PhCH2N), 53.2 (C-1), 49.9 (C-2Ј), 23.1 (CH3CON), 21.4–20.6
completely reacted (TLC, 12–24 h), cooled to room temperature
and concentrated under diminished pressure. The crude residue was
dissolved in a mixture of pyridine and Ac2O (2:1 v/v, 6 mL) and
stirred at room temperature for 24 h. The solution was co-evapo-
rated with toluene (4ϫ 20 mL) under diminished pressure and the
crude residue was purified by flash chromatography on silica gel to
afford pure 21–22.
(CH3COO) ppm. C43H52N2O13 (804.88): calcd. C 64.17, H 6.51, N
3.48; found C 64.28, H 6.63, N 3.60.
General Procedure for the Synthesis of Azadisaccharide Derivatives
23–24: The appropriate 5-keto sugar 17 or 20 (1 mmol) was dis-
solved in 90% aq. CF3COOH (12 mL) and stirred at room tem-
perature. After 2–5 h, TLC analysis revealed the complete disap-
pearance of the starting material and the formation of a more re-
tained product. The solution was co-evaporated with toluene (4ϫ
10 mL) under diminished pressure. The crude product obtained
was dissolved in anhydrous MeOH (25 mL), and BnNH2·HCl
(1 equiv.) and NaBH3CN (2.2 equiv.) were added. The mixture was
heated to 60 °C and stirred until the starting material was com-
pletely reacted (TLC, 12–24 h). The solution was cooled to room
temperature and concentrated under diminished pressure. Purifica-
tion of the crude residue by flash chromatography on silica gel gave
pure 23–24.
4-O-(2-Acetamido-3,4-di-O-acetyl-6-O-benzyl-2-deoxy-β-
D-talopyr-
anosyl)-N-benzyl-2,3,6-tri-O-acetyl-1,5-dideoxy-1,5-imino-
D-glucitol
(21): The sequence of reactions was applied to 14 (787 mg,
1.41 mmol) according to the general procedure. Purification of the
crude product required two flash chromatographic purifications
(first eluent: hexane/EtOAc (1:4) + 0.1% Et3N; second eluent:
CHCl3/iPrOH, 85:15) and pure 21 (448 mg, 42% from 14) was iso-
lated as a white foam. Rf = 0.40 (EtOAc); [α]D = –29.4 (c = 1.14,
CHCl3). 1H NMR (250.13 MHz, CD3CN): δ = 7.63–7.23 (m, 10
H, Ar-H), 6.06 (d, J2Ј,NH = 10.0 Hz, 1 H, NHAc), 5.28 (dd, J3Ј,4Ј
= J4Ј,5Ј = 3.6 Hz, 1 H, 4Ј-H), 5.03 (dd, J2,3 = J3,4 = 9.4 Hz, 1 H, 3-
H), 5.00 (dd, J2Ј,3Ј = 4.4 Hz, 1 H, 3Ј-H), 4.76 (ddd, J1ax,2 = 10.5,
J1eq,2 = 5.2 Hz, 1 H, 2-H), 4.75 (d, J1Ј,2Ј = 1.7 Hz, 1 H, 1Ј-H), 4.66
(dd, J5,6b = 2.3, J6a,6b = 12.7 Hz, 6-Hb), 4.57 (d, Jgem = 11.8 Hz, 1
H, PhCH2O), 4.54 (m, 1 H, 2Ј-H), 4.49 (d, Jgem = 11.8 Hz, 1 H,
4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-galactopyranosyl)-N-
benzyl-1,5-dideoxy-1,5-imino- -glucitol (23): The hydrolysis–amino-
D
cyclisation reaction of 20 (918 mg, 1.27 mmol) was set up as de-
scribed in the general procedure. Purification of crude product by
flash chromatography on silica gel (hexane/EtOAc (3:7) + 0.1%
Et3N) afforded pure 23 (528 mg, 58% from 20) as a white foam. Rf
= 0.37 (hexane/EtOAc, 1:4); [α]D = –10.8 (c = 1.06, CHCl3). 1H
NMR (250.13 MHz, CD3CN): δ = 7.48–7.24 (m, 20 H, Ar-H), 4.82
(d, Jgem = 11.0 Hz, 1 H, PhCH2O), 4.80 (d, Jgem = 11.4 Hz, 1 H,
PhCH2O), 4.16 (dd, J5,6a = 3.1 Hz, 1 H, 6-Ha), 4.07 (d, Jgem
=
13.6 Hz, 1 H, PhCH2N), 3.97 (dd, J4,5 = 9.6 Hz, 1 H, 4-H), 3.92
(m, J5Ј,6Јa = 6.4, J5Ј,6Јb = 6.3 Hz, 1 H, 5Ј-H), 3.63 (dd, J6Јa,6Јb
9.8 Hz, 1 H, 6Ј-Hb), 3.54 (dd, 1 H, 6Ј-Ha), 2.90 (dd, J1eq,1ax
=
=
PhCH2O), 4.65 (d, Jgem = 11.4 Hz, 1 H, PhCH2O), 4.53 (d, Jgem
=
11.8 Hz, 1 H, 1-Heq), 3.25 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 2.64
(dt, 1 H, 5-H), 2.16 (dd, 1 H, 1-Hax), 2.09, 2.04, 2.02, 1.91, 1.90
(5s, each 3 H, CH3COO), 1.96 (s, 3 H, CH3CON) ppm. 13C NMR
(62.9 MHz, CD3CN): δ = 171.4–170.4 (CO), 139.7, 139.2 (2ϫAr-
C), 129.4–128.0 (Ar-CH), 99.7 (C-1Ј), 79.2 (C-4), 76.8 (C-3), 75.7
(PhCH2O), 73.4 (C-5Ј), 69.8 (C-2), 69.3 (C-3Ј), 68.6 (C-6Ј), 67.5
(C-4Ј), 64.3 (C-5), 60.1 (C-6), 56.5 (PhCH2N), 53.1 (C-1), 49.7 (C-
2Ј), 23.3 (CH3CON), 21.5–20.8 (5ϫCH3COO) ppm. C38H48N2O14
(756.79): calcd. C 60.31, H 6.39, N 3.70; found C 60.39, H 6.47, N
3.77.
11.0 Hz, 1 H, PhCH2O), 4.50 (d, Jgem = 11.5 Hz, 1 H, PhCH2O),
4.45 (d, Jgem = 11.5 Hz, 1 H, PhCH2O), 4.36 (d, J1Ј,2Ј = 7.8 Hz, 1
H, 1Ј-H), 4.31 (br. s, 1 H, OH), 4.16 (d, Jgem = 13.6 Hz, 1 H,
PhCH2N), 4.04 (dd, J6a,6b = 12.3, J5,6b = 2.1 Hz, 1 H, 6-Hb), 3.98
(dd, J4Ј,5Ј = 0.8, J3Ј,4Ј = 2.6 Hz, 1 H, 4Ј-H), 3.93 (dd, J5,6a = 2.1 Hz,
1 H, 6-Ha), 3.76 (ddd, J5Ј,6Јa = 5.7, J5Ј,6Јb = 6.7 Hz, 1 H, 5Ј-H), 3.70
(dd, J2Ј,3Ј = 10.2 Hz, 1 H, 2Ј-H), 3.61 (dd, 1 H, 3Ј-H), 3.55 (dd, J4,5
= 9.7, J3,4 = 8.8 Hz, 1 H, 4-H), 3.55 (m, 2 H, 6Ј-Ha, 6Ј-Hb), 3.33
(ddd, J2,3 = 8.8, J1ax,2 = 10.1, J1eq,2 = 4.5 Hz, 1 H, 2-H), 3.22 (d,
Jgem = 13.6 Hz, 1 H, PhCH2N), 3.21 (dd, 1 H, 3-H), 2.75 (dd,
J1ax,1eq = 11.2 Hz, 1 H, 1-Heq), 2.65 (br. s, 1 H, OH), 2.27 (dt, 1 H,
5-H), 2.22 (br. s, 1 H, OH), 1.92 (dd, 1 H, 1-Hax) ppm. 13C NMR
(62.9 MHz, CD3CN): δ = 139.9, 139.4, 139.1, 138.9 (4ϫAr-C),
129.8–127.9 (Ar-CH), 102.7 (C-1Ј), 82.9 (C-4), 81.6 (C-3Ј), 78.1 (C-
3), 75.6, 73.8, 72.3 (3ϫPhCH2O), 74.4 (C-5Ј), 73.3 (C-4Ј), 70.5 (C-
2), 69.6 (C-6Ј), 67.0 (C-5), 64.5 (C-2Ј), 57.9 (C-6), 57.0 (PhCH2N),
56.3 (C-1) ppm. C40H46N4O8 (710.82): calcd. C 67.59, H 6.52, N
7.88; found C 67.55, H 6.50, N 7.79.
4-O-(2-Acetamido-4-O-acetyl-3,6-di-O-benzyl-2-deoxy-β-
D-manno-
pyranosyl)-N-benzyl-2,3,6-tri-O-acetyl-1,5-dideoxy-1,5-imino-
D
-
glucitol (22): The sequence of reactions was applied to 15 (744 mg,
1.15 mmol) according to general procedure. Purification of the
crude product required two flash chromatographic purifications
(first eluent: hexane/EtOAc (2:3) + 0.1% Et3N; second eluent:
EtOAc) and pure 22 (391 mg, 44% from 15) was obtained as a
white foam. Rf = 0.24 (hexane/EtOAc, 4:6); [α]D = –46.4 (c = 1.1,
CHCl3). 1H NMR (250.13 MHz, CD3CN): δ = 7.31–7.13 (m, 15
H, Ar-H), 6.18 (d, J2Ј,NH = 9.9 Hz, 1 H, NHAc), 4.92 (dd, J2,3
=
4-O-(2-Azido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-glucopyranosyl)-N-
J3,4 = 9.4 Hz, 1 H, 3-H), 4.86 (dd, J3Ј,4Ј = 8.2, J4Ј,5Ј = 9.6 Hz, 1 H,
benzyl-1,5-dideoxy-1,5-imino- -glucitol (24): The hydrolysis–
D
4Ј-H), 4.72 (ddd, J1Ј,2Ј = 1.5, J2Ј,3Ј = 4.1 Hz, 1 H, 2Ј-H), 4.66 (m, aminocyclisation reaction of 17 (252 mg, 0.64 mmol) was set up as
1 H, 2-H), 4.59 (m, 1 H, 6-Hb), 4.58 (d, Jgem = 11.6 Hz, 1 H, described in the general procedure. Purification of crude product
PhCH2O), 4.56 (d, Jgem = 11.4 Hz, 1 H, PhCH2O), 4.56 (d, 1 H, by flash chromatography on silica gel (hexane/EtOAc (3:7) + 0.1%
1Ј-H), 4.41 (d, Jgem = 11.6 Hz, 1 H, PhCH2O), 4.26 (d, Jgem
11.4 Hz, 1 H, PhCH2O), 4.13 (dd, J6a,6b = 12.8, J5,6a = 2.7 Hz, 1 = 0.48 (EtOAc); [α]D = –9.9 (c = 1.16, CHCl3). 1H NMR
H, 6-Ha), 3.98 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 3.81 (dd, J3,4 (250.13 MHz, CD3CN): δ = 7.40–7.18 (m, 20 H, Ar-H), 4.84 (s, 2
J4,5 = 9.4 Hz, 1 H, 4-H), 3.52–3.42 (m, 4 H, 3Ј-H, 5Ј-H, 6Ј-Ha, 6Ј- H, PhCH2O), 4.76 (d, Jgem = 11.0 Hz, 1 H, PhCH2O), 4.54 (d, Jgem
=
Et3N) afforded pure 24 (284 mg, 69% from 17) as a white foam. Rf
=
Hb), 3.15 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 2.79 (dd, J1ax,1eq
=
= 11.0 Hz, 1 H, PhCH2O), 4.53 (d, Jgem = 11.6 Hz, 1 H, PhCH2O),
4.47 (d, Jgem = 11.6 Hz, 1 H, PhCH2O), 4.46 (d, J1Ј,2Ј = 8.1 Hz, 1
H, 1Ј-H), 4.16 (d, Jgem = 13.5 Hz, 1 H, PhCH2N), 4.07 (dd, J6a,6b
= 12.4, J5,6b = 2.2 Hz, 1 H, 6-Hb), 3.90 (dd, J5,6a = 1.8 Hz, 1 H, 6-
Ha), 3.68–3.54 (m, 5 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-Ha, 6Ј-Hb), 3.66 (dd,
11.3, J1eq,2 = 5.1 Hz, 1 H, 1-Heq), 2.55 (dt, J5,6a = J5,6b = 2.7 Hz,
1 H, 5-H), 2.00 (dd, J1ax,2 = 10.7 Hz, 1 H, 1-Hax), 1.93, 1.88, 1.85,
1.83 (4s, each 3 H, CH3COO), 1.80 (s, 3 H, CH3CON) ppm. 13C
NMR (62.9 MHz, CD3CN): δ = 170.8–170.4 (CO), 139.8, 139.3,
6534
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6527–6537

1-Deoxy-d-nojirimycin Disaccharide Synthesis
J4,5 = 9.2, J3,4 = 8.9 Hz, 1 H, 4-H), 3.42 (dd, J2Ј,3Ј = 8.4 Hz, 1 H, C); 129.8–127.9 (Ar-CH), 101.3 (C-1Ј), 83.2 (C-4), 80.7 (C-3Ј), 78.3
2Ј-H), 3.42 (ddd, J1eq,2 = 4.7, J1ax,2 = 10.2 Hz, 1 H, 2-H), 3.27 (dd, (C-3), 76.4 (C-5Ј), 73.7, 71.4 (2ϫPhCH2O), 70.7 (C-6Ј), 70.4 (C-2),
J2,3 = J3,4 = 8.9 Hz, 1 H, 3-H), 3.24 (d, Jgem = 13.5 Hz, 1 H, 67.7 (C-4Ј), 67.3 (C-5), 59.2 (C-6), 57.2 (PhCH2N), 56.5 (C-1), 49.8
PhCH2N), 2.83 (dd, J1ax,1eq = 11.2 Hz, 1 H, 1-Heq), 2.33 (m, 1 H,
(C-2Ј), 23.1 (CH3CON) ppm. C35H44N2O9 (636.73): calcd. C 66.02,
5-H), 1.96 (dd, 1 H, 1-Hax) ppm. 13C NMR (62.9 MHz, CD3CN): H 6.97, N 4.40; found C 66.00, H 6.96, N 4.39.
δ = 139.8, 139.3, 139.2, 139.1 (4ϫAr-C), 130.1–128.3 (Ar-CH),
General Procedure for the Transformation of 23–24 into N-Acet-
102.8 (C-1Ј), 84.1 (C-4Ј), 82.8 (C-4), 79.0 (C-3Ј), 78.4 (C-3), 76.4,
765.9, 74.3 (3ϫPhCH2O), 75.6 (C-5Ј), 70.7 (C-2), 69.7 (C-6Ј), 67.8
(C-2Ј), 67.1 (C-5), 58.1 (C-6), 57.5 (PhCH2N), 56.7 (C-1) ppm.
amido Derivatives 27–28: Azide derivative 23 or 24 (1 mmol) was
dissolved in anhydrous MeOH (20 mL) and the solution was cooled
to 0 °C. NiCl2·6H2O (5 equiv.) and NaBH4 (8 equiv.) were added,
and the resulting mixture was stirred at room temperature until the
starting compound was completely reacted (TLC, 0.5–1 h). Solvent
was evaporated under diminished pressure and the residue was par-
titioned between EtOAc (40 mL) and brine (40 mL). The organic
C
40H46N4O8 (710.82): calcd. C 67.59, H 6.52, N 7.88; found C
67.56, H 6.54, N 7.85.
General Procedure for De-O-acetylation of 21 and 22: To a solution
of the appropriate azasugar 21 or 22 (1 mmol) in anhydrous MeOH
(10 mL), a methanolic solution of MeONa (0.33 m, 5 mL) was phase was separated and the aqueous layer was extracted with
added. The reaction mixture was stirred at 0 °C until TLC analysis
showed the complete disappearance of the starting material (4–5 h)
and the formation of a lower moving product. The solution was
neutralised with solid NaHCO3 and the suspension was filtered
and concentrated under diminished pressure. Purification of crude
product by flash chromatography on silica gel afforded pure 25 or
26.
EtOAc (3ϫ 40 mL). The collected organic extracts were dried, fil-
tered and concentrated under diminished pressure. The crude resi-
due was dissolved in a MeOH/Ac2O mixture (4:1, 15 mL) and
stirred at room temperature. When TLC (0.5–1 h) analysis showed
the disappearance of the starting material, the solution was co-
evaporated with toluene (4ϫ 20 mL) under diminished pressure.
To a solution of the obtained crude product in anhydrous THF/
MeOH (1:5, 16 mL) a methanolic solution of MeONa (0.33 m,
3 mL) was added. The reaction mixture was stirred at 0 °C until
TLC analysis showed the disappearance of the higher moving prod-
ucts 27a and 28a (2–3 h). The solution was neutralised with solid
NaHCO3 and the suspension was filtered and concentrated under
diminished pressure. Purification of crude product by flash
chromatography on silica gel afforded pure 27 or 28.
4-O-(2-Acetamido-6-O-benzyl-2-deoxy-β-
D-talopyranosyl)-N-
benzyl-1,5-dideoxy-1,5-imino- -glucitol (25): De-O-acetylation of
D
21 (300 mg, 0.40 mmol) gave 25 (165 mg, 94% yield) as a white
foam after flash chromatography on silica gel (CHCl3/iPrOH, 4:1).
1
Rf = 0.40 (CHCl3/MeOH, 4:1); [α]D = –42.5 (c = 1.01, CHCl3). H
NMR (250.13 MHz, CD3CN): δ = 7.41–7.22 (m, 10 H, Ar-H), 6.83
(d, J2Ј,NH = 9.6 Hz, 1 H, NH), 4.69 (br. s, 1 H, OH), 4.62 (d, J1Ј,2Ј
= 1.7 Hz, 1 H, 1Ј-H), 4.55 (br. s, 1 H, OH), 4.54 (s, 2 H, PhCH2O), 4-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-galactopyranos-
4.46 (m, 1 H, 2Ј-H), 4.15 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 4.08 yl)-N-benzyl-1,5-dideoxy-1,5-imino- -glucitol (27): The sequence of
D
(br. s, 1 H, OH), 3.94 (dd, J6a,6b = 12.1, J5,6b = 2.1 Hz, 1 H, 6-Hb), reactions was applied to azide 23 (200 mg, 0.28 mmol) according
3.88–3.60 (m, 7 H, 6-Ha, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-Ha, 6Ј-Hb, OH), 3.49 to the general procedure. Purification of crude product by flash
(dd, J3,4 = 9.0, J4,5 = 9.3 Hz, 1 H, 4-H), 3.33 (m, 2 H, 2-H, OH),
3.20 (dd, J2,3 = 8.5 Hz, 1 H, 3-H), 3.19 (d, Jgem = 13.6 Hz, 1 H, afforded pure 27 (174 mg, 85% from 23) as a white solid; m.p.
PhCH2N), 2.73 (dd, J1ax,1eq = 11.1, J1eq,2 = 4.5 Hz, 1 H, 1-Heq), 149–151 °C (hexane/EtOAc); Rf = 0.42 (CHCl3/MeOH, 9:1); [α]D
chromatography on silica gel (CHCl3/MeOH (95:5) + 0.1% Et3N)
1
2.15 (dt, J5,6a = 2.1 Hz, 1 H, 5-H), 1.93 (s, 3 H, CH3CON), 1.86 = +3.72 (c = 1.13, CHCl3). H NMR (250.13 MHz, CD3CN): δ =
(dd, J1ax,2 = 11.1 Hz, 1 H, 1-Hax) ppm. 13C NMR (62.9 MHz, 7.40–7.22 (m, 20 H, Ar-H), 6.64 (d, J2Ј,NH = 9.3 Hz, 1 H, NH),
CD3CN): δ = 172.4 (CO), 139.9, 139.2 (2ϫAr-C); 129.9–127.9 (Ar- 4.79 (d, Jgem = 11.2 Hz, 1 H, PhCH2O), 4.70 (d, Jgem = 11.6 Hz, 1
CH), 101.9 (C-1Ј), 83.9 (C-4), 78.2 (C-3), 75.1 (C-5Ј), 73.8
H, PhCH2O), 4.67 (d, J3,OH = 1.1 Hz, 1 H, 3-OH), 4.55 (d, Jgem =
(PhCH2O), 70.5 (C-6Ј), 70.1 (C-2), 69.1 (C-3Ј), 68.4 (C-4Ј), 67.6 12.2 Hz, 1 H, PhCH2O), 4.54 (d, J1Ј,2Ј = 8.5 Hz, 1 H, 1Ј-H), 4.52
(C-5), 59.9 (C-6), 57.3 (PhCH2N), 56.6 (C-1), 53.2 (C-2Ј), 23.7 (d, Jgem = 11.2 Hz, 1 H, PhCH2O), 4.51 (d, Jgem = 11.6 Hz, 1 H,
(CH3CON) ppm. C28H38N2O9 (546.61): calcd. C 61.52, H 7.01, N
PhCH2O), 4.45 (d, Jgem = 12.2 Hz, 1 H, PhCH2O), 4.13 (d, Jgem =
5.12; found C 61.49, H 6.99, N 5.09.
13.5 Hz, 1 H, PhCH2N), 4.06–3.94 (m, 2 H, 2Ј-H, 6-Hb), 3.91
(br. d, 1 H, 4Ј-H), 3.80–3.70 (m, 2 H, 6-Ha, 5Ј-H), 3.66 (dd, J2Ј,3Ј
4-O-(2-Acetamido-3,6-di-O-benzyl-2-deoxy-β-
D-mannopyrano-syl)-
= 10.8, J3Ј,4Ј = 2.7 Hz, 1 H, 3Ј-H), 3.60 (dd, J5Ј,6Јb = 7.0, J6Јa,6Јb
=
N-benzyl-1,5-dideoxy-1,5-imino- -glucitol (26): De-O-acetylation of
D
9.5 Hz, 1 H, 6Ј-Hb), 3.49 (dd, J5Ј,6Јa = 5.1 Hz, 1 H, 6Ј-Ha), 3.47
(dd, J3,4 = 8.8, J4,5 = 9.5 Hz, 1 H, 4-H), 3.31 (m, 1 H, 2-H), 3.18
(d, Jgem = 13.5 Hz, 1 H, PhCH2N), 3.17 (ddd, J2,3 = 9.1 Hz, 1 H,
22 (264 mg, 0.32 mmol) gave 26 (169 mg, 83%) as a clear syrup
after flash chromatography on silica gel (CHCl3/iPrOH, 93:7). Rf
= 0.20 (CHCl3/iPrOH, 97:3); [α]D = –59.3 (c = 1.02, CHCl3). 1H
NMR (250.13 MHz, CD3CN): δ = 7.42–7.26 (m, 15 H, Ar-H), 6.50
(d, J2Ј,NH = 10.2 Hz, 1 H, NH), 4.87 (m, 1 H, 2Ј-H), 4.72 (d, J1Ј,2Ј
= 1.3 Hz, 1 H, 1Ј-H), 4.71 (d, Jgem = 11.0 Hz, 1 H, PhCH2O), 4.58
(d, Jgem = 12.2 Hz, 1 H, PhCH2O), 4.53 (d, Jgem = 12.2 Hz, 1 H,
PhCH2O), 4.50 (br. s, 1 H, OH), 4.39 (d, Jgem = 11.0 Hz, 1 H,
3-H), 3.03 (br. d, J2,OH = 3.2 Hz, 1 H, 2-OH), 2.73 (dd, J1eq,2
=
4.7 Hz, 1 H, 1-Heq), 2.68 (br. t, 1 H, 6-OH), 2.20 (dt, J5,6a = J5,6b
= 2.1 Hz, 1 H, 5-H), 1.92 (dd, J1ax,2 = 11.3, J1ax,1eq = 11.1 Hz, 1
H, 1-Hax), 1.89 (s, 3 H, CH3CON) ppm. 13C NMR (62.9 MHz,
CD3CN): δ = 171.2 (CO), 140.0, 139.6, 139.4, 139.2 (4ϫAr-C),
129.7–127.9 (Ar-CH), 103.4 (C-1Ј), 83.2 (C-4), 80.5 (C-3Ј), 78.4 (C-
3), 75.4, 73.8, 72.9 (3ϫPhCH2O), 74.3 (C-5Ј), 73.6 (C-4Ј), 70.4 (C-
2), 69.9 (C-6Ј), 67.1 (C-5), 58.0 (C-6), 57.1 (PhCH2N), 56.3 (C-1),
53.0 (C-2Ј), 23.4 (CH3CON) ppm. C42H50N2O9 (726.85): calcd. C
69.40, H 6.93, N 3.85; found C 69.38, H 6.90, N 3.83.
PhCH2O), 4.15 (d, Jgem = 13.5 Hz, 1 H, PhCH2N), 4.21 (d, Jgem
=
13.5 Hz, 1 H, PhCH2N), 3.97 (dd, J6a,6b = 12.3, J5,6b = 2.0 Hz, 1
H, 6-Hb), 3.79 (m, 1 H, 6Ј-Hb), 3.72 (br. t, 1 H, OH), 3.64–3.46 (m,
5 H, 3Ј-H, 5Ј-H, 6Ј-Ha, 6-Ha, 4-H), 3.43–3.28 (m, 2 H, 2-H, 4Ј-H),
3.13 (br. s, 1 H, OH), 2.98 (br. s, 1 H, OH), 3.21 (dd, J2,3 = J3,4
=
8.4 Hz, 1 H, 3-H), 2.74 (dd, J1ax,1eq = 11.2, J1eq,2 = 4.5 Hz, 1 H, 1- 4-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-
D-glucopyranosyl)-
Heq), 2.17 (dt, J4,5 = 9.5, J5,6a = 2.0 Hz, 1 H, 5-H), 1.87 (dd, J1ax,2
= 11.2 Hz, 1 H, 1-Hax), 1.91 (s, 3 H, CH3CON) ppm. 13C NMR
(62.9 MHz, CD3CN): δ = 171.7 (CO), 140.0, 139.4, 139.3 (3ϫAr-
N-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (28): The sequence of re-
actions was applied to 24 (179 mg, 0.25 mmol), according to the
general procedure. Purification of crude product by flash
Eur. J. Org. Chem. 2014, 6527–6537
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6535

F. D’Andrea et al.
FULL PAPER
chromatography on silica gel (CHCl3/MeOH (95:5) + 0.1% Et3N)
(CH3CON) ppm. C14H27ClN2O9 (402.83): calcd. C 41.74, H 6.76,
afforded pure 28 (180 mg, 91% from 24) as a white foam. Rf = 0.36 N 6.95; found C 41.72, H 6.49, N 6.92.
(CHCl3/MeOH, 95:5). [α]D = +16.4 (c = 1.0, CHCl3). 1H NMR
(250.13 MHz, CD3CN): δ = 7.41–7.12 (m, 21 H, Ar-H, NH), 4.76
4-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-
yl)-N-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (3): Hydrogenolysis
D
-galactopyranos-
(d, Jgem = 11.3 Hz, 1 H, PhCH2O), 4.65 (d, Jgem = 11.3 Hz, 1 H,
PhCH2O), 4.64 (d, J1Ј,2Ј = 8.6 Hz, 1 H, 1Ј-H), 4.63 (d, Jgem
of 27 (140 mg, 0.193 mmol) gave pure 3 (58 mg, 75%) as a white
solid after crystallisation (MeOH/iPrOH); m.p. 145–147 °C
(MeOH/iPrOH); Rf = 0.05 (CHCl3/MeOH, 1:1); [α]D = +25.7 (c =
1.0, MeOH). 1H NMR (600 MHz, CD3OD/D2O): δ = 4.61 (d, J1Ј,2Ј
= 8.9 Hz, 1 H, 1Ј-H), 3.97 (dd, J2Ј,3Ј = 10.2 Hz, 1 H, 2Ј-H), 3.83
(m, 3 H, 6-Ha, 6-Hb, 4Ј-H), 3.80 (dd, J5Ј,6Јb = 7.4, J6Јa,6Јb = 11.4 Hz,
=
12.3 Hz, 1 H, PhCH2O), 4.52 (d, Jgem = 10.9 Hz, 1 H, PhCH2O),
4.46 (d, Jgem = 10.9 Hz, 1 H, PhCH2O), 4.35 (d, Jgem = 12.3 Hz, 1
H, PhCH2O), 4.18 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 4.05–3.78
(m, 2 H, 6-Ha, 6-Hb), 3.96 (m, 1 H, 2Ј-H), 3.75–3.42 (m, 6 H, 4-H,
3Ј-H, 4Ј-H, 5Ј-H, 6Ј-Ha, 6Ј-Hb), 3.41 (ddd, J1ax,2 = 11.1, J1eq,2
3.9, J2,3 = 8.8 Hz, 1 H, 2-H), 3.29 (dd, J3,4 = J2,3 = 8.8 Hz, 1 H, 3-
H), 3.17 (d, Jgem = 13.6 Hz, 1 H, PhCH2N), 2.75 (dd, J1ax,1eq
=
1 H, 6Ј-Hb), 3.79–3.70 (m, 3 H, 2-H, 4-H, 6Ј-Ha), 3.69 (dd, J3Ј,4Ј
3.1 Hz, 1 H, 3Ј-H), 3.62 (m, 1 H, 5Ј-H), 3.54 (dd, J2,3 = J3,4
=
=
=
9.0 Hz, 1 H, 3-H), 3.32 (dd, J1eq,2 = 5.1, J1ax,1eq = 11.5 Hz, 1 H, 1-
Heq), 3.22 (m, 1 H, 5-H), 2.89 (dd, J1ax,2 = 11.5 Hz, 1 H, 1-Hax),
2.02 (s, 3 H, CH3CON) ppm. 13C NMR (150 MHz, CD3OD/D2O):
δ = 174.2 (CO), 103.1 (C-1Ј), 78.8 (C-4), 77.2 (C-5Ј), 76.6 (C-3),
72.5 (C-3Ј), 69.5 (C-4Ј), 68.3 (C-2), 62.5 (C-6Ј), 60.3 (C-5), 58.3 (C-
6), 54.4 (C-2Ј), 46.1 (C-1), 23.2 (CH3CON) ppm. C14H27ClN2O9
(402.83): calcd. C 41.74, H 6.76, N 6.95; found C 41.73, H 6.74, N
6.94.
12.0 Hz, 1 H, 1-Heq), 2.26 (br. d, 1 H, 5-H), 1.92 (dd, 1 H, 1-Hax),
1.92 (s, 3 H, CH3CON) ppm. 13C NMR (62.9 MHz, CD3CN): δ =
171.7 (CO), 139.8, 139.5, 139.1, 139.0 (4ϫAr-C), 129.8–127.8 (Ar-
CH),103.0 (C-1Ј), 83.7 (C-3Ј), 83.5 (C-4), 79.4 (C-4Ј), 78.6 (C-3),
76.1, 75.5, 73.8 (3ϫPhCH2O), 75.1 (C-5Ј), 70.4 (C-2), 69.8 (C-6Ј),
67.2 (C-5), 58.1 (C-6), 57.1 (PhCH2N), 56.4 (C-1), 56.3 (C-2Ј), 23.5
(CH3CON) ppm. C42H50N2O9 (726.85): calcd. C 69.40, H 6.93, N
3.85; found C 69.37, H 6.89, N 3.81.
4-O-(2-Acetamido-2-deoxy-β-
D-glucopyranosyl)-1,5-dideoxy-1,5-
General Procedure for Hydrogenolysis of 25–28: To a solution of
the appropriate protected azasugar 25–28 (1 mmol) in anhydrous
MeOH (32 mL) and 1% methanolic HCl (10 mL, pH 3), 10% Pd
on charcoal (120 mg) was added and the mixture was stirred at
room temperature under H2 (atmospheric pressure) until the start-
ing compound was completely reacted (TLC, 5–12 h). The suspen-
sion was filtered through a small layer of Celite and co-evaporated
with toluene (4ϫ 30 mL) under diminished pressure. Crystallisa-
tion or lyophilisation afforded pure 1–4.
imino- -glucitol Hydrochloride (4): Hydrogenolysis of 28 (118 mg,
D
0.16 mmol) gave pure 4 (53 mg, 82%) as a white solid after crystal-
lisation (MeOH/iPrOH); m.p. 162–165 °C (MeOH/iPrOH); Rf =
0.11 (CHCl3/MeOH, 1:1); [α]D = +11.5 (c = 0.92, MeOH). 1H
NMR (600 MHz, CD3OD/D2O): δ = 4.62 (d, J1Ј,2Ј = 8.2 Hz, 1 H,
1Ј-H), 3.91 (br. d, J6Јa,6Јb = 11.1 Hz, 1 H, 6Ј-Hb), 3.81 (m, 2 H, 6-
Ha, 6-Hb), 3.72–3.60 (m, 4 H, 2-H, 4-H, 2Ј-H, 6Ј-Ha), 3.52 (m, 2
H, 3-H, 3Ј-H), 3.38 (m, 1 H, 5Ј-H), 3.30 (dd, J1eq,2 = 5.3, J1ax,1eq
= 11.9 Hz, 1 H, 1-Heq), 3.28 (m, 1 H, 4Ј-H), 3.21 (br. d, J4,5
=
9.6 Hz, 1 H, 5-H), 2.89 (dd, J1ax,2 = 11.1 Hz, 1 H, 1-Hax), 2.01 (s,
3 H, CH3CON) ppm. 13C NMR (62.9 MHz, CD3OD/D2O): δ =
173.9 (CO), 102.9 (C-1Ј), 79.0 (C-4), 78.2 (C-4Ј), 76.6 (C-3), 75.5
(C-3Ј), 72.0 (C-5Ј), 68.3 (C-2), 62.6 (C-6Ј), 60.3 (C-5), 58.3 (C-6),
57.5 (C-2Ј), 47.0 (C-1), 23.1 (CH3CON) ppm. C14H27ClN2O9
(402.83): calcd. C 41.74, H 6.76, N 6.95; found C 41.69, H 6.70, N
6.89.
4-O-(2-Acetamido-2-deoxy-β-
imino- -glucitol Hydrochloride (1): Hydrogenolysis of 25 (165 mg,
0.30 mmol) gave pure 1 (118 mg, 98%) as a hygroscopic solid after
lyophilisation from water. Rf = 0.08 (CHCl3/MeOH, 7:3); [α]D
–17.2 (c = 1.0, MeOH). H NMR (600 MHz, CD3OD/D2O): δ =
4.72 (s, 1 H, 1Ј-H), 4.40 (d, J2Ј,3Ј = 3.9 Hz, 1 H, 2Ј-H), 3.96 (dd,
J5,6a = 4.4, J6a,6b = 12.2 Hz, 1 H, 6-Hb), 3.85–3.80 (m, 3 H, 2-H,
D-talopyranosyl)-1,5-dideoxy-1,5-
D
=
1
6-Ha, 6Ј-Hb), 3.79–3.70 (m, 4 H, 4-H, 6Ј-Ha, 3Ј-H, 4Ј-H), 3.57 (m, Supporting Information (see footnote on the first page of this arti-
1
1 H, 5Ј-H), 3.54 (t, J2,3 = J3,4 = 8.5 Hz, 1 H, 3-H), 3.32 (dd, J1eq,2 cle): Copies of the H and 13C NMR spectra of compounds 11–15
1
= 4.9, J1ax,1eq = 11.7 Hz, 1 H, 1-Heq), 3.21 (m, 1 H, 5-H), 2.89 (dd,
J1ax,2 = 11.7 Hz, 1 H, 1-Hax), 1.98 (s, 3 H, CH3CON) ppm. 13C
NMR (62.9 MHz, CD3OD): δ = 174.4 (CO), 101.9 (C-1Ј), 79.0 (C-
4), 77.9 (C-5Ј), 76.1 (C-3), 69.4 (C-2), 68.9, 68.2 (C-3Ј, C-4Ј), 62.6
(C-6Ј), 60.2 (C-5), 58.3 (C-6), 53.8 (C-2Ј), 46.9 (C-1), 23.4
(CH3CON) ppm. C14H27ClN2O9 (402.83): calcd. C 41.74, H 6.76,
N 6.95; found C 41.69, H 6.70, N 6.89.
and 17–28; copies H,13C NMR COSY and HSQC spectra of 1–4.
Acknowledgments
This research was supported by the Ministero dell’Università e
della Ricerca (MIUR, Rome, Italy) within the frame of the COFIN
national project (2010–2011).
4-O-(2-Acetamido-2-deoxy-β-
imino- -glucitol Hydrochloride (2): Hydrogenolysis of 26 (168.5 mg,
0.26 mmol) gave pure 2 (109 mg, 97%) as a hygroscopic solid after
lyophilisation from water. Rf = 0.08 (CHCl3/MeOH, 7:3); [α]D
–21.8 (c = 1.04, MeOH). H NMR (600 MHz, CD3OD/D2O): δ =
4.82 (s, 1 H, 1Ј-H), 4.55 (d, J2Ј,3Ј = 4.1 Hz, 1 H, 2Ј-H), 3.89 (dd,
D-mannopyranosyl)-1,5-dideoxy-1,5-
D
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: May 8, 2014
Published Online: August 27, 2014
Eur. J. Org. Chem. 2014, 6527–6537
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6537