Stereodivergent Syntheses of altro and manno Stereoisomers of 2-Acetamido-1,2-dideoxynojirimycin

Article abstract of DOI:10.1002/ejoc.201701282

A stereoselective synthesis of 2-acetamido-1,2-dideoxyaltronojirimycin (8) and its manno epimer 9 is described. The synthetic approach is based on key bicyclic carbamate 7, which is easily accessible with high enantiomeric purity on a multigram scale by S

Full text of DOI:10.1002/ejoc.201701282

DOI: 10.1002/ejoc.201701282
Full Paper
Iminosugars
Stereodivergent Syntheses of altro and manno Stereoisomers of
-Acetamido-1,2-dideoxynojirimycin
2
[a]
[a,b]
and Antoni Riera*[a,b]
Alex de la Fuente, Xavier Verdaguer,
Abstract: A stereoselective synthesis of 2-acetamido-1,2-di- an efficient stereodivergent approach to five isomers of 2-acet-
deoxyaltronojirimycin (8) and its manno epimer 9 is described. amido-1,2-dideoxyiminosugars in high overall yields starting
The synthetic approach is based on key bicyclic carbamate 7, from the same key intermediate 7. The approach described in
which is easily accessible with high enantiomeric purity on a this paper is based on control of the stereoselectivity of the
multigram scale by Sharpless asymmetric epoxidation of 1,4- sulfite ring-opening reaction to give retention of configuration
pentadien-3-ol or 2,4-pentadien-1-ol. This procedure completes through anchimeric assistance from the endocyclic amine.
Introduction
and their galacto (5)[15] and allo (6)[16] isomers, have received
special attention (Figure 1). Most procedures for the synthesis
Carbohydrates are involved in a variety of metabolic processes.
Inhibitors of enzymes related to carbohydrate metabolism, such
as glycosidases or glycosyltransferases, have potential applica-
tions in the treatment of several diseases, including diabetes,
viral and bacterial infections, and cancer. Iminosugars — sac-
charides in which the ring oxygen has been substituted by a
nitrogen — are potent glycosidase inhibitors, acting as mimics
of iminosugars that have been described to date are based on
[17]
the chiral pool, starting from sugars or amino acids.
Con-
versely, our approach to iminosugar synthesis is based on the
key precursor 7, which is easily accessible in high enantiomeric
purity on a multigram scale by Sharpless asymmetric epoxid-
[18]
[19a]
ation of 2,4-pentadien-1-ol
or 1,4-pentadien-3-ol.
Carb-
amate 7 is a versatile intermediate that has been widely used
[
1,2]
of the corresponding glycosidic substrates.
Derivatization of
[19]
for the synthesis of several carbohydrate-related compounds.
iminosugars by modification of the nitrogen and the pseudo-
Following this approach we have reported efficient stereo-
[
3]
anomeric carbon has been widely reported. However, the in-
troduction of other substituents, such as halogens or amines,
to replace some of the hydroxyl groups of the skeleton, is rela-
selective procedures to obtain (2S)-2-acetamido iminosugars 4,
[14f,16]
5, and 6.
In our previous work, the (S) configuration of the
acetamide substituent at the 2-position was secured by substi-
tution reactions that took place with complete inversion of con-
figuration.
[
4]
tively uncommon and synthetically challenging. Iminosugars
in which an acetamido moiety replaces a hydroxyl group have
received considerable attention in recent years, due to their
high selectivity for hexosaminidases. This makes them poten-
[
5]
tially useful for the treatment of lysosomal storage disorders,
[
6]
[7]
Alzheimer's disease, some cancers, and other O-GlcNAcase-
related diseases. The acetamido moiety is crucial for the high
affinity of these compounds. Natural products of this family,
[
8]
[
9]
[
10]
[11]
such as siastatin B (1),
nagstatin (2),
and pochonicine
have been reported to show inhibitory activities that
[
12]
(
3),
range from low micromolar to nanomolar. Among the synthetic
compounds that have been reported,[ N-acetylglucosamine
13]
[
14]
analogues such as 2-acetamido-1,2-dideoxynojirimycin (4),
[
[
a] Institute for Research in Biomedicine (IRB Barcelona), The Barcelona
Institute of Science and Technology,
Baldiri Reixac 10, 08028 Barcelona, Spain
E-mail: antoni.riera@irbbarcelona.org
http://www.irbbarcelona.org
http://www.ursa.cat
b] Departament de Química Inorgànica i Orgànica, Secció Química Orgànica.
Universitat de Barcelona,
Figure 1. Natural and synthetic examples of acetamido iminosugars.
In this paper, we describe a new approach to the previously
unknown 2-acetamido-1,2-dideoxyaltronojirimycin (8) and its
manno epimer 9, both with the (R) configuration at the 2-posi-
tion (Figure 2). To achieve this, we took advantage of the anchi-
Martí i Franqués 1, 08028 Barcelona, Spain
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701282.
Eur. J. Org. Chem. 2017, 7179–7185
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meric effect of the ring nitrogen to carry out substitution reac-
tions with retention of configuration. These syntheses, which
are short, and gave high overall yields, give access to scaffolds
that can be easily modified to give inhibitors with more drug-
like properties.
Scheme 1. Retrosynthetic analysis for (2S) and (2R)-acetamido iminosugars.
PG = protecting group.
Figure 2. Stereodivergent approach to 2-acetamido-1,2-dideoxyiminosugars.
Results and Discussion
In our search to develop new methods to obtain (2R)-acetamido
iminosugars, we envisaged exploiting the basic character of the
ring nitrogen to generate a cyclic aziridinium cation; this could
be opened by nitrogen nucleophiles, resulting in a process with
overall retention of configuration. Thus, instead of having a
carbamate protecting group during the ring-opening of the
sulfate with azide (Scheme 1, left), we considered that with an
alkyl protecting group, the nucleophilic attack would take place
via the aziridinium ion with overall retention of configuration
Scheme 2. a) BnBr, NaH, DMF, room temp.; b) NaOH (6
M aq.), reflux; c) BnBr,
NaH, DMF, room temp.; d) (DHQD) Phal (hydroquinidine 1,4-phthalazinediyl
2
2 4 2 3 6 2 3 3 2 2 2
diether), K OsO ·2H O, K [Fe(CN) ], K CO , CH SO NH , MeCN/H O (1:1), room
(
Scheme 1, right). Anchimeric assistance by heteroatoms in cy-
[
20]
temp.
clic systems has been studied previously.
Although this ap-
proach has been applied to ring-expansion reactions in imino-
[
21]
sugar synthesis by Cossy et al., to the best of our knowledge, product was used directly in the next step. Attempts to obtain
it has not been used to open an epoxide, a sulfite, or a sulfate the corresponding sulfate by oxidation of the sulfite or treat-
[
22]
with retention of configuration.
ment of diol 12 with SO Cl /Et N
were unsuccessful. There-
2
2
3
We started our syntheses by preparing multigram amounts fore, ring-opening reactions of 13 with NaN were widely ex-
3
of carbamate 7 using the reported procedure. Optically pure 7 plored (Scheme 3, Table 1). Due to difficulties in handling the
was first protected as benzyl derivative 10 by treatment with intermediates, the three reactions were carried out consecu-
BnBr/NaH. Hydrolysis of the 2-oxazolidinone ring and protec- tively. The ratio of azido alcohols obtained was the same as
tion of the corresponding amino alcohol with BnBr/NaH gave when the reaction was carried out on pure 13; this shows that
fully benzyl-protected derivative 11 in 87 % yield. Dihydrox- the impurities formed in the first reactions have no effect on
[
14f]
ylation of this olefin under Sharpless conditions
2 in 48 % yield. The low yield was due to partial decomposi- conditions, a 78:22 mixture of isomers was obtained in 47 %
tion during chromatography (Scheme 2).
yield over three steps. Separation of the two products by chro-
Sulfite 13 was obtained as a mixture of diastereoisomers in matography was achieved in a straightforward manner.
moderate yield by treatment of 12 with SOCl /Et N. Its isolation The stereochemistry of 14 and 15 could not be determined
was complex due to its tendency to decompose, so the crude by either NMR spectroscopy or by X-ray diffraction studies.
gave diol the ring-opening reaction. After optimization of the reaction
1
2
3
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NMR spectroscopic analysis of the minor product allowed us
to identify it as the known 2-acetamido-1,2-dideoxymannojiri-
mycin (DMJNAc; 9), as its spectroscopic data were consistent
[
14c,23]
with the previously reported data.
The stereochemistry of
8
at C-2 and C-3 (iminosugar numbering) was determined using
NMR spectroscopic techniques. Coupling constant analysis of 3-
H showed an eq,eq coupling (J = 2.0 Hz) and an ax,eq coupling
(J = 4.5 Hz), consistent with an altro configuration. Further
NOESY analysis of this compound corroborated this configura-
tion through the absence of an nOe between 3-H and 5-H. This
allowed us to identify 2-acetamido-1,2-dideoxyaltronojirimycin
[
14e]
as the major isomer (Figure 3).
Scheme 3. a) (DHQD)
2
Phal, K
2
OsO
/Et
4
·2H
2
O, K
3
[Fe(CN)
6
], K
2
CO
O.
3
, CH
3
SO
2
NH
2
,
MeCN, H O, room temp.; b) SOCl
2
2
3
N; c) NaN
3
, acetone, H
2
Table 1. Conditions, overall yields, and dr for the conversion of 11 into 14/15
three steps).
(
Entry
NaN
3
[equiv.]
T [°C]
Yield [%]
14/15 ratio
1[a]
2
3
3
3
2
1.2
50
50
r.t.
35
71
19
34
47
54:47
60:40
80:20
78:22
4
[
a] Starting from pure 13.
Figure 3. Determination of the stereochemistry of 8.
Therefore, the same chemical transformations were applied to
both isomers to form the final (2R)-acetamido iminosugars. The
following reaction sequence was used: protection of the free
hydroxy group using BnBr/NaH; hydrogenation of the azide
catalysed by Pd/C; in-situ formation of the acetamide with
In summary, we have synthesized both the manno and altro
isomers of 2-acetamido-1,2-dideoxynojirimycin. Our procedure
is based on the ring-opening of a sulfite with an azide that
takes place with retention of configuration. We found that
when the piperidine nitrogen is protected with an alkyl group
such as benzyl, the nucleophilic ring-opening reaction takes
place with overall retention. Therefore, these results show the
ability of the endocyclic amine to generate a putative aziridin-
ium cation that can be attacked by the nucleophile. The subse-
quent hydrolysis of the sulfite was not stereospecific, and inver-
sion of configuration of the secondary hydroxy group took
Ac O/pyridine; and cleavage of the benzyl groups by hydrogen-
2
olysis. In both cases, the final iminosugars were formed in excel-
lent yields (Scheme 4).
Scheme 4. a) BnBr, NaH, DMF, room temp.; b) i) H
2
(3 bar), Pd/C, EtOAc;
ii) Ac O, pyr; c) H (5 bar), Pd/C, HCl (1.25 aq.), MeOH, room temp.
2
2
M
Scheme 5. Mechanism of formation of stereoisomers 14 and 15.
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place to a significant extent to give 14. It is known that a sulfite then was quenched with HCl (1
M
aq.) until pH 8, and the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic ex-
tracts were washed with brine (1 × 10 mL), and dried with MgSO4.
The solvent was removed under low pressure to give a white solid.
residue can be hydrolysed at either the S–O or the C–O bond
[
24]
to give two diastereomeric azido alcohols.
Although in gen-
eral, only the first product is observed, in this particular case,
the product formed through C–O cleavage, with an inverted
alcohol, turned out to be the major isomer (Scheme 5).
This material was dissolved in DMF (4 mL), and the resulting solu-
tion was added by cannula to a suspension of NaH (68 mg,
2.69 mmol) in DMF (2 mL) at 0 °C. After 10 min, benzyl bromide
(0.21 mL, 6.73 mmol) was added, and the reaction mixture was
stirred at room temp. for 16 h. H O (10 mL) was then added, and
2
the mixture was extracted with EtOAc (3 × 5 mL). The combined
Conclusions
organic extracts were dried with MgSO , and the mixture was puri-
4
Stereoselective syntheses of 2-acetamido-1,2-dideoxyaltronojiri- fied on silica·Et N (2.5 % v/v) using hexane/EtOAc to give 11
3
mycin (8) and its manno epimer 9 have been described, using (0.23 mg, 87 %) as a yellow oil. [α]2
0
= +12.7 (c = 0.2, CHCl
). H
1
D
3
NMR (400 MHz, CDCl ): δ = 7.42–7.20 (m, 15 H), 5.86 (m, 2 H), 4.53
s, 2 H), 4.46 (s, 2 H), 3.97 (m, 2 H), 3.77 (d, J = 14.5 Hz), 3.75 (dd,
Sharpless epoxidation as the source of chirality. This procedure
completes an efficient stereodivergent approach to five isomers
of 2-acetamido-1,2-dideoxyiminosugars with high overall yields,
starting from the same key intermediate 7. The approach de-
scribed in this paper is based on control of the stereoselectivity
of the sulfite ring-opening reaction to obtain retention of con-
figuration through anchimeric assistance from the endocyclic
amine.
3
(
J = 10.0, 5.0 Hz, 1 H), 3.50 (dd, J = 10.0, 6.0 Hz, 1 H), 3.17 (dd, J =
1
1
1
1
5
0.0, 5.0 Hz, 1 H), 3.08 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl ): δ =
3
39.2 (C), 138.8 (C), 138.3 (C), 129.4 (CH), 128.9 (CH), 128.3 (CH),
28.2 (CH), 128.2 (CH), 127.9 (CH), 127.6 (CH), 127.4 (CH), 126.9 (CH),
24.1 (CH), 73.2 (CH ), 72.3 (CH), 70.5 (CH ), 66.5 (CH ), 59.3 (CH),
8.2 (CH ), 48.8 (CH ) ppm. IR (film): ν = 3028, 2857, 1494, 1452,
1098, 1069, 735, 696 cm . HRMS (ESI): calcd. for C27H30NO2
00.22711; found 400.22695.
2
2
2
2
2
˜
–
1
4
4
(
,6-Di-O-benzyl-5-N-Benzyl-1-deoxymannojirimycin (12):
DHQD) Phal (21 mg, 0.03 mmol), K OsO (6 mg, 0.01 mmol), K CO
3
Experimental Section
2
2
4
2
General Remarks: All reactions were carried out in flame-dried
(135 mg, 0.97 mmol), and K [Fe(CN) ] (322 mg, 0.97 mmol) were
3 6
glassware under nitrogen. Anhydrous solvents were obtained using dissolved in MeCN/H O (1:1; 4 mL). The reaction mixture was cooled
2
a solvent purification system (PureSolv MD-3; Innovative Technol-
to 0 °C, and CH SO NH (32 mg, 0.32 mmol) was added. After
3 2 2
ogy, Inc.). All reagents were used as received. Optical rotations were
10 min, a solution of 11 (0.13 g, 0.32 mmol) in MeCN/H O (1:1;
2
measured at room temperature (23 °C), and concentrations are re- 2 mL) was added, and the mixture was allowed to warm to room
1
ported in g/100 mL. H NMR spectra were obtained at 400 MHz with
temp. The mixture was stirred until no starting material was ob-
served by TLC. Na SO (200 mg) was then added, and the mixture
1
3
tetramethylsilane as an internal standard. C NMR spectra were
obtained at 100.6 MHz, and were referenced to the solvent signal.
Chemical shifts are given in ppm. Chromatographic separations
2
3
was stirred for 1 h. It was then extracted with EtOAc (3 × 10 mL).
The combined organic extracts were washed with brine (10 mL),
and dried with MgSO . The mixture was purified on silica·Et N
were carried out with SiO (70–230 mesh).
2
4
3
(
2.5 % v/v) using hexane/EtOAc to give 12 (72 mg, 48 %) as a yellow
(
3
(
1
8S,8aR)-8-(Benzyloxy)-8,8a-dihydro-1H-oxazolo[3,4-a]pyridin-
-one (10): A solution of compound 7 (0.75 g, 4.82 mmol) in DMF
7 mL) was added by cannula to a stirred suspension of NaH (0.26 g,
0.83 mmol) in DMF (10 mL) at 0 °C. After 10 min, benzyl bromide
0.61 mL, 5.06 mmol) was added by syringe, and the mixture was
2
0
1
oil, as a single diastereomer. [α] = –7.2 (c = 0.15, CHCl ). H NMR
D
3
(400 MHz, CDCl ): δ = 7.34–7.24 (m, 15 H), 4.90 (d, J = 11.0 Hz, 1
3
H), 4.56 (d, J = 11.0 Hz, 1 H), 4.46 (s, 2 H), 4.17 (d, J = 13.0 Hz, 1 H),
.83 (dd, J = 10.5, 2.5 Hz, 1 H), 3.76 (dd, J = 10.5, 3.0 Hz, 2 H), 3.64
t, J = 8.5 Hz, 1 H), 3.57 (dd, J = 8.5, 3.0 Hz, 1 H), 3.27 (d, J = 12.5 Hz,
3
(
(
allowed to warm to room temperature. The mixture was stirred
vigorously for 4 h, then water (10 mL) was added, and the mixture
was extracted with EtOAc (3 × 20 mL). The combined organic ex-
tracts were dried with MgSO , and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
1
2
1
1
7
H), 2.91 (dd, J = 12.5, 4.5 Hz, 1 H), 2.38 (dt, J = 8.5, 2.5 Hz, 1 H),
.22 (dd, J = 12.5, 1.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl ): δ =
3
38.6 (C), 138.5 (C), 137.8 (C), 128.9 (CH), 128.4 (CH), 128.4 (CH),
28.0 (CH), 128.0 (CH), 127.8 (CH), 127.7 (CH), 127.2 (CH), 78.4 (CH),
5.9 (CH), 74.7 (CH ), 73.3 (CH ), 68.1 (CH), 66.8 (CH ), 64.8 (CH), 56.6
4
2
2
2
(
(
hexane/ethyl acetate, increasing the polarity ratio) to give 10
(
CH ), 54.7 (CH ) ppm. IR (film): ν˜ = 3406, 2911, 2859, 1452, 1097,
1.21 g, 89 %) as a slightly grey solid. [α] 2D 0 = +64.8 (c = 1.8, CHCl3).
2
2
–1
1
1066, 734, 697 cm . HRMS (ESI): calcd. for C27
found 434.23314.
H32NO 434.23259;
4
H NMR (400 MHz, CDCl ): δ = 7.41–7.29 (m, 5 H), 5.97 (dd, J = 10.5,
3
1
.5 Hz, 1 H), 5.82 (dd, J = 10.5, 2.5 Hz, 1 H), 4.73 (d, J = 11.5 Hz, 1
H), 4.52 (d, J = 11.5 Hz, 1 H), 4.46 (dd, J = 9.0, 8.0 Hz, 1 H), 4.15–
.06 (m, 2 H), 3.94 (m, 1 H), 3.70–3.58 (m, 2 H) ppm. 13C NMR
100 MHz, CDCl ): δ = 157.1 (CO), 137.3 (C), 128.6 (CH), 128.2 (CH),
2
-Azido-4,6-di-O-benzyl-5-N-benzyl-1,2-dideoxyaltronojirimy-
4
(
cin (14) and 2-Azido-4,6-di-O-benzyl-5-N-benzyl-1,2-dideoxy-
mannojirimycin (15): (DHQD) Phal (0.12 g, 0.15 mmol), K OsO
(
3
2
2
4
1
5
1
2
27.9 (CH), 126.4 (CH), 124.8 (CH), 74.0 (CH), 71.1 (CH ), 67.4 (CH ),
2 2
27 mg, 0.07 mmol), K CO (882 mg, 6.38 mmol), and K [Fe(CN) ]
2 3 3 6
4.5 (CH), 40.9 (CH ) ppm. IR (film): ν˜ = 3033, 2911, 1761, 1478,
2
(
2.1 g, 6.38 mmol) were dissolved in MeCN/H O (1:1; 15 mL). The
–
1
2
454, 1420, 1389, 1204, 1082, 1030 cm . MS (CI-NH ): m/z (%) =
3
reaction mixture was cooled to 0 °C, and CH SO NH (208 mg,
2
2
was allowed to warm to room temp. The mixture was stirred until
no starting material was observed by TLC. Na SO (3 g) was then
3
2
2
46 [M + 1] (64), 263 [M + 18] (100). C H NO (245.28): calcd.
1
4
15
3
.11 mmol) was added. After 10 min, a solution of 11 (0.84 g,
C 68.56, H 6.16, N 5.71; found C 68.85, H 6.01, N 5.64.
2R,3S)-N-Benzyl-3-benzyloxy-2-benzyloxymethyl-1,2,3,6-tetra-
hydropyridine (11): NaOH (6 aq.; 1.1 mL, 6.73 mmol) was added
.11 mmol) in MeCN/H O (1:1; 6 mL) was added, and the mixture
2
(
M
2
3
to a solution of 10 (0.17 g, 0.67 mmol) in MeOH/H O (9:1; 7 mL),
and the reaction mixture was stirred at reflux for 16 h. The reaction
added, and the mixture was stirred for 1 h. The mixture was ex-
tracted with EtOAc (3 × 30 mL). The organic phase was washed
2
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with brine (1 × 10 mL), and dried with MgSO , and concentrated in
vacuo.
71.1 (CH ), 68.9 (CH), 65.9 (CH), 59.9 (CH ), 50.4 (CH ) ppm. IR (film):
4
2
2
2
–
1
ν˜ = 2923, 2861, 2099, 1453, 1093, 1059 cm . HRMS (ESI): calcd. for
C H N O 549.28602; found 549.28552.
34 37 4 3
The resulting oil was dissolved in CH Cl (35 mL), and the solution
2
2
was cooled to 0 °C. Triethylamine (1.23 mL, 8.84 mmol) was added, 2-Acetamido-3,4,6-tri-O-benzyl-5-N-benzyl-1,2-dideoxyaltrono-
followed by the dropwise addition of SOCl2 (490 μL, 7.58 mmol).
jirimycin (17): Pd/C (13 mg, 0.01 mmol) was added to a solution
of 16 (133 mg, 0.24 mmol) in EtOAc (5 mL), and the mixture was
The reaction mixture was stirred at 0 °C for 1 h. H O (30 mL) was
2
then added, and the mixture was extracted with CH Cl (3 × 20 mL),
put under H (5 bar). The mixture was stirred at room temp. for
2
2
2
and concentrated in vacuo.
20 h. After this time, the palladium was removed by filtration
through Celite, which was then washed with MeOH. The solvents
were removed under low pressure.
The resulting orange oil was dissolved in acetone/water (2:1; 66 mL),
and NaN (164 mg, 2.52 mmol) was added. The mixture was stirred
3
The resulting colourless oil was dissolved in pyridine (2 mL), and
at 35 °C overnight. After this time, the acetone was removed under
low pressure, and the resulting aqueous phase was extracted with
EtOAc (3 × 30 mL). The organic phase was dried with MgSO , and
the crude material was purified on silica·Et N (2.5 % v/v) using
hexane/EtOAc to give 14 (0.34 g, 35 %) as a colourless oil, and 15
Ac O (48 μL, 0.39 mmol) was added. The reaction mixture was
2
stirred at 40 °C for 16 h. Then, H O (5 mL) was added and the
2
4
mixture was extracted with EtOAc (3 × 5 mL). The organic phase
3
was dried with MgSO , and the crude material was purified by chro-
4
matography on silica gel using hexane/EtOAc to give 17 (110 mg,
(110 mg, 11 %) as a colourless oil.
2
0
1
8
0 %) as a slightly yellow oil. [α] = +24.8 (c = 1.21, CHCl ). H NMR
D
3
Data for 14: [α]2 = +35.0 (c = 0.80, CHCl3). 1H NMR (400 MHz,
0
D
(400 MHz, CDCl ): δ = 7.38–7.20 (m, 20 H), 5.81 (t, J = 5.0 Hz, 1 H),
3
CDCl ): δ = 7.37–7.21 (m, 15 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.50 (d,
3
4.58 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 4.48 (d, J =
J = 12.0 Hz, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 12.0 Hz, 1
H), 4.10 (dd, J = 11.0, 4.0 Hz, 1 H), 3.97 (d, J = 14.0 Hz, 1 H), 3.89 (d,
J = 11.5 Hz, 1 H), 3.81 (s, 1 H), 3.71 (d, J = 14.0 Hz, 1 H), 3.60 (dd,
J = 11.5, 8.5 Hz, 1 H), 3.32 (dd, J = 10.5, 3.0 Hz, 1 H), 3.27–3.16 (m,
1
4
2.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.32 (d, J = 12.0 Hz, 1 H),
.29 (d, J = 12.0 Hz, 2 H), 3.98 (t, J = 3.5 Hz, 1 H), 3.89 (m, 2 H), 3.72
(d, J = 13.5 Hz, 1 H), 3.42 (ddd, J = 13.5, 5.5, 3.5 Hz, 1 H), 3.35 (dd,
J = 9.5, 7.5 Hz, 1 H), 3.28 (m, 1 H), 3.19 (m, 2 H), 3.09 (m, 1 H), 1.62
1
3
2
H), 3.08–3.01 (m, 2 H) ppm. C NMR (100 MHz, CDCl ): δ = 139.6
13
3
(s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 169.7 (CO), 138.9 (C),
3
(C), 137.9 (C), 137.2 (C), 128.5 (CH), 128.5 (CH), 128.4 (CH), 128.3
1
1
38.3 (C), 138.2 (C), 137.8 (C), 129.2 (CH), 128.6 (CH), 128.3 (CH),
28.3 (CH), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.7 (CH), 127.7 (CH),
(CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 127.2 (CH), 86.0
(
CH), 73.7 (CH ), 73.6 (CH), 71.32 (CH ), 71.0 (CH), 70.8 (CH ), 67.1
2 2 2
127.6 (CH), 127.6 (CH), 127.2 (CH), 83.1 (CH), 81.7 (CH), 73.0 (CH2),
71.7 (CH ), 71.3 (CH ), 70.7 (CH ), 67.9 (CH), 63.4 (CH), 58.5 (CH ),
(
CH), 58.6 (CH ), 50.2 (CH ) ppm. IR (film): ν = 3410, 2930, 2859,
2 2
˜
2
2
2
2
–
1
2
4
099, 1453, 1090, 1021 cm . HRMS (ESI): calcd. for C 7H N O
2 31 4 3
59.23907; found 459.23863.
38.0 (CH ), 23.0 (CH ) ppm. IR (film): ν = 3295, 2861, 1652, 1453,
˜
2 3
–1
1
098, 1066, 735, 697 cm . HRMS (ESI): calcd. for C36H41N O
2 4
Data for 15: [α] D2 0 = –19.3 (c = 0.75, CHCl3). 1H NMR (400 MHz,
565.30608; found 565.30538.
2-Acetamido-1,2-dideoxyaltronojirimycin (8): To a solution of 17
in MeOH; 3 mL) was added Pd/
C (12 mg, 0.01 mmol) and the reaction mixture was charged with
H2 (5 barg) and stirred at room temp. for 20 h. Palladium was fil-
tered through Celite washing with MeOH and solvents were re-
CDCl ): δ = 7.37–7.22 (m, 15 H), 4.68 (d, J = 11.5 Hz, 1 H), 4.57 (d,
3
J = 11.5 Hz, 1 H), 4.50 (s, 2 H), 4.10 (d, J = 13.5 Hz, 1 H), 3.80 (m, 3 (74 mg, 0.13 mmol) in HCl (1.25
H), 3.71 (m, 2 H), 3.86–3.66 (m, 5 H), 3.46 (d, J = 13.5 Hz, 1 H), 3.03
M
(
dd, J = 12.5, 5.5 Hz, 1 H), 2.78 (br., 1 H), 2.61 (m, 1 H), 2.37 (dd, J =
1
3
1
1
1
7
2.5, 2.5 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 138.6 (C),
3
38.1 (C), 137.7 (C), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), moved under low pressure. The crude was purified by chromatogra-
27.9 (CH), 127.8 (CH), 127.8 (CH), 127.7 (CH), 127.0 (CH), 78.3 (CH),
3.9 (CH ), 73.3 (CH ), 73.2 (CH), 67.7 (CH ), 62.8 (CH), 59.0 (CH), 57.6
phy on silica gel using CH Cl /MeOH/NH , 90:8:2 to give 8 (23 mg,
2 2 3
2
0
1
2
2
2
85 %) as a colourless oil. [α] = +11.7 (c = 0.55, H O). H NMR
2
D
(
1
CH ), 50.6 (CH ) ppm. IR (film): ν˜ = 3423, 2917, 2099, 1452, 1270, (400 MHz, D O): δ = 4.04 (dd, J = 4.5, 2.5 Hz, 1 H), 3.89 (dd, J = 5.0,
2
2
2
–
1
097, 1027 cm . HRMS (ESI): calcd. for C
H
N O 459.23907; 2.5 Hz, 1 H), 3.73 (dd, J = 12.0, 6.0 Hz, 1 H), 3.66 (dd, J = 12.0, 6.0 Hz,
2
7
31
4
3
found 459.23833.
1 H), 3.45 (m, 1 H), 3.32–3.24 (m, 2 H), 3.01 (m, 1 H), 2.02 (s, 3 H)
ppm. 13C NMR (100 MHz, D O, CF COOH internal reference): δ =
2
3
2
-Azido-3,4,6-tri-O-benzyl-5-N-benzyl-1,2-dideoxyaltronojiri-
1
74.4 (CO), 79.1 (CH), 77.3 (CH), 65.2 (CH), 642.0 (CH ), 59.3 (CH),
2
mycin (16): A solution of 14 (161 mg, 0.35 mmol) in DMF (4 mL)
was added by cannula to a suspension of NaH (27 mg, 1.05 mmol)
in DMF (1 mL) at 0 °C. After 10 min, benzyl bromide (64 μL,
3
8.6 (CH ), 21.8 (CH ) ppm. IR (film): ν = 3212, 3051, 2894, 1661,
2
3
–
˜
1
1437, 1200, 1130 cm . HRMS (ESI): calcd. for C H N O 205.11828;
8 17 2 4
found 205.11812.
0
.52 mmol) was added dropwise, and the reaction mixture was
stirred at room temp. until no starting material was observed by
2-Azido-3,4,6-tri-O-benzyl-5-N-benzyl-1,2-dideoxymannojiri-
mycin (18): A solution of 15 (102 mg, 0.22 mmol) in DMF (4 mL)
was added by cannula to a suspension of NaH (17 mg, 0.67 mmol)
TLC. Then, H O (5 mL) was added and the mixture was extracted
2
with CH Cl (3 × 5 mL). The combined organic phase was dried with
2
2
MgSO . The crude material was purified by chromatography on sil- in DMF (1 mL) at 0 °C. After 10 min, benzyl bromide (41 μL,
4
ica gel using hexane/EtOAc to give 16 (172 mg, 89 %) as a colour-
0.34 mmol) was added dropwise, and the reaction mixture was
less oil. [α]D = +10.5 (c = 1.55, CHCl ). H NMR (400 MHz, CDCl ): stirred at room temp. until no starting material was observed by
2
0
1
3
3
δ = 7.35–7.15 (m, 20 H), 4.57 (d, J = 12.0 Hz, 1 H), 4.52 (d, J =
TLC. Then, H O (5 mL) was added, and the mixture was extracted
2
1
4
2.0 Hz, 1 H), 4.45 (d, J = 11.5 Hz, 1 H), 4.40 (d, J = 11.5 Hz, 1 H),
.37 (d, J = 12.0 Hz, 1 H), 4.28 (d, J = 12.0 Hz, 1 H), 4.00–3.96 (m, 2
with CH Cl (3 × 5 mL). The organic phase was dried with MgSO ,
and the crude material was purified by chromatography on sil-
2
2
4
H), 3.89 (d, J = 13.5 Hz, 1 H), 3.83 (d, J = 13.5 Hz, 1 H), 3.44 (dd, J =
1.5, 8.5 Hz, 1 H), 3.37 (m, 1 H), 3.25 (m, 1 H), 3.20–3.12 (m, 3 H)
ica·Et N (2.5 % v/v) using hexane/EtOAc to give 18 (90 mg, 74 %)
3
2
0
1
1
as a slightly yellow oil. [α] = –30.1 (c = 0.59, CHCl3). H NMR
D
13
ppm. C NMR (100 MHz, CDCl ): δ = 139.3 (C), 138.4 (C), 138.2 (C),
(400 MHz, CDCl ): δ = 7.38–7.17 (m, 20 H), 4.77 (d, J = 11.0 Hz, 1
3
3
1
1
1
37.8 (C), 129.00 (CH), 128.3 (CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), H), 4.67 (d, J = 11.5 Hz, 1 H), 4.61 (d, J = 11.5 Hz, 1 H), 4.52 (d, J =
27.9 (CH), 127.7 (CH), 127.6 (CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 11.0 Hz, 1 H), 4.43 (s, 2 H), 4.12 (d, J = 13.5 Hz, 1 H), 3.86 (t, J =
27.2 (CH), 82.5 (CH), 82.0 (CH), 72.9 (CH ), 71.9 (CH ), 71.8 (CH ), 7.5 Hz, 1 H), 3.77 (m, 2 H), 3.74 (dt, J = 5.5, 3.0 Hz, 1 H), 3.64 (dd,
2
2
2
Eur. J. Org. Chem. 2017, 7179–7185
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7183
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
J = 7.5, 3.5 Hz, 1 H), 3.49 (d, J = 13.5 Hz, 1 H), 2.96 (dd, J = 12.5,
.5 Hz, 1 H), 2.65 (m, 1 H), 2.27 (dd, J = 12.5, 3.0 Hz, 1 H) ppm. 13
Keywords: Total synthesis · Carbohydrates · Iminosugars ·
Asymmetric synthesis · Neighboring-group effects
5
C
NMR (100 MHz, CDCl ): δ = 138.7 (C), 138.3 (C), 138.2 (C), 137.8 (C),
3
1
1
1
6
28.7 (CH), 128.7 (CH), 128.4 (CH), 128.3 (CH), 128.3 (CH), 128.2 (CH),
28.2 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH),
26.9 (CH), 81.6 (CH), 75.4 (CH), 74.2 (CH ), 73.0 (CH ), 72.3 (CH ),
[1] P. Compain, O. R. Martin (Eds.), Iminosugars: From Synthesis to Therapeutic
Applications, John Wiley & Sons, Chichester, England, 2007.
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2
2
2
7.6 (CH ), 63.4 (CH), 57.7 (CH ), 56.7 (CH), 50.6 (CH ) ppm. IR (film):
2
2
2
–
1
ν˜ = 2853, 2096, 1452, 1102, 1066 cm . HRMS (ESI): calcd. for
C H N O 549.2860; found 549.2855.
34 37 4 3
2
-Acetamido-3,4,6-tri-O-benzyl-5-N-benzyl-1,2-dideoxymanno-
6
2, 10277–10302.
jirimycin (19): Pd/C (17 mg, 0.01 mmol) was added to a a solution
of 18 (90 mg, 0.16 mmol) in EtOAc (4 mL), and the reaction mixture
was put under H (5 bar). The mixture was stirred at room temp.
for 20 h. After this time, the palladium was removed by filtration
through Celite, which was then washed with MeOH. The solvents
were removed under low pressure.
[
3] a) Y. Yu, T. Mena-Barragán, K. Higaki, J. L. Johnson, J. E. Drury, R. L. Lieber-
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2014, 9, 1460–1469; b) M. Aguilar-Moncayo, T. Takai, K. Higaki, T. Mena-
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The resulting colourless oil was dissolved in pyridine (2 mL), and
Ac O (24 μL, 0.23 mmol) was added. The reaction mixture was
stirred at room temp. for 16 h. Then, H O (5 mL) was added, and
the mixture was extracted with EtOAc (3 × 5 mL). The organic phase
2
2
3
713; d) E. M. Sánchez-Fernández, R. Rísquez-Cuadro, M. Chasseraud, A.
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was dried with MgSO , and the crude material was purified on sil-
4
ica·Et N (2.5 % v/v) using hexane/EtOAc to give 19 (74 mg, 80 %)
3
as a slightly yellow oil. [α]D = –8.1 (c = 0.79, CHCl3). 1H NMR
2
0
(400 MHz, CDCl ): δ = 7.37–7.20 (m, 20 H), 6.19 (d, J = 9.5 Hz, 1 H),
3
7
543; g) A. Siriwardena, D. P. Sonawane, O. P. Bande, P. R. Markad, S.
4
4
1
8
2
.90 (d, J = 11.0 Hz, 1 H), 4.78 (d, J = 11.0 Hz, 1 H), 4.53 (m, 1 H),
.47 (d, J = 11.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.42 (d, J =
2.0 Hz, 1 H), 4.14 (d, J = 13.5 Hz, 1 H), 3.81 (m, 2 H), 3.71 (t, J =
.5 Hz, 1 H), 3.55 (dd, J = 8.5, 4.5 Hz, 1 H), 3.29 (d, J = 13.5 Hz, 1 H),
.72 (dd, J = 12.0, 4.5 Hz, 1 H), 2.47 (dt, J = 8.5, 3.0 Hz, 1 H), 2.22
Yonekawa, M. B. Tropak, S. Ghosh, B. A. Chopade, D. J. Mahuran, D. D.
Dhavale, J. Org. Chem. 2014, 79, 4398–4404; h) M. Mondon, N. Fontelle,
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70–873; i) T. Wennekes, R. J. B. H. N. van den Berg, T. J. Boltje, W. E.
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1283.
1
3
(dd, J = 12.0, 2.0 Hz, 1 H), 1.93 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 169.8 (CO), 138.7 (C), 138.5 (C), 138.1 (C), 137.9 (C), 128.9
3
(
(
(
CH), 128.4 (CH), 128.4 (CH), 128.3 (CH), 128.3 (CH), 128.3 (CH), 127.9
CH), 127.9 (CH), 127.8 (CH), 127.6 (CH), 127.5 (CH), 127.1 (CH), 81.7
CH), 77.0 (CH), 74.8 (CH ), 73.3 (CH ), 71.1 (CH ), 66.5 (CH ), 64.5
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2
2
2
2
(
2
CH), 56.7 (CH ), 52.8 (CH ), 44.3 (CH), 23.5 (CH ) ppm. IR (film): ν˜ =
2
2
3
–
1
860, 1674, 1496, 1452, 1011 cm . HRMS (ESI): calcd. for
C H N O 565.3061; found 565.3050.
36 40 2 4
2
-Acetamido-1,2-dideoxymannojirimycin (9): Pd/C (spatula tip)
was added to a solution of 19 (20 mg, 0.04 mmol) in HCl (1.25 in
MeOH; 3 mL), and the mixture was put under H (5 bar). The mix-
ture was stirred at room temp. for 20 h. After this time, the palla-
dium was removed by filtration through Celite, which was then
washed with MeOH. The solvents were removed under low pres-
sure. The residue was purified by chromatography on silica gel
M
2
2000, 56, 1005–1012; h) V. M. Kasture, N. B. Kalamkar, R. J. Nair, R. S.
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[
(CH Cl /MeOH/NH , 90:8:2) to give 9 (7 mg, 95 %) as a white solid.
2 2 3
3
, 1513–1521; d) G. H. B. Maegawa, M. Tropak, J. Buttner, T. Stockley, F.
The spectroscopic data were consistent with previously reported
data.[
23] 1
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H NMR (400 MHz, CD OD): δ = 4.50 (s, 1 H), 3.82 (dd, J =
3
1
4
2
2
2
1.0, 3.0 Hz, 1 H), 3.72 (dd, J = 11.0, 5.5 Hz, 1 H), 3.60 (dd, J = 9.5,
.5 Hz, 1 H), 3.45 (t, J = 9.5 Hz, 1 H), 3.00 (dd, J = 13.0, 3.0 Hz, 1 H),
.79 (dd, J = 13.0, 2.5 Hz, 1 H), 2.47 (ddd, J = 9.5, 5.5, 3.0 Hz, 1 H),
[
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Sci. USA 2004, 101, 10804–10809.
.04 (s, 3 H) ppm. HRMS (ESI): calcd. for C H N O 205.11828; found
8
17
2
4
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1
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support. IRB Barcelona is the recipient of a Severo Ochoa Award
of Excellence from MINECO (Government of Spain). A. F. thanks
the Ministerio de Ciencia e Innovación for a doctoral fellowship.
[
Eur. J. Org. Chem. 2017, 7179–7185
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: September 12, 2017
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