Rapid and practical synthesis of (-)-1-deoxyaltronojirimycin

Article abstract of DOI:10.1039/c0ob00747a

Herein a practical and scalable route to 1-deoxyaltronojirimycin is presented. The target is achieved in 9 steps and 43% yield featuring only two chromatographic purifications.

Full text of DOI:10.1039/c0ob00747a

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PAPER
Rapid and practical synthesis of (-)-1-deoxyaltronojirimycin†
Oskari K. Karjalainen and Ari M. P. Koskinen*
Received 19th September 2010, Accepted 4th November 2010
DOI: 10.1039/c0ob00747a
Herein a practical and scalable route to 1-deoxyaltronojirimycin is presented. The target is achieved in 9
steps and 43% yield featuring only two chromatographic purifications.
including glycosyl transferases,7 glycogen phosphorylase,8 sugar
Introduction
R
nucleoside mutase9 and metalloproteinases.10 Zavescaꢀ has also
shown some promise as a male contraceptive.11 Iminosugar deriva-
tives have been reported to be active against the Flaviviridae viral
family,12 cytotoxic against several cancer cell lines13 and to inhibit
angiogenesis.14 Hence the need to be able to produce practical
amounts of nojirimycin analogues with varying stereochemical
configurations is apparent. Herein we wish to describe a practical
route to (-)-1-deoxyaltronojirimycin (5); a nojirimycin analogue
having altrose stereochemistry.15 The compound itself shows
modest activity towards glycosidases,16 however it serves as a
proof-of-concept towards derivatives having such stereochemistry.
The story of the nojirimycins begins with the isolation of nojir-
imycin (1, Fig. 1) in 1966 by Inuoye et al. from several strains of
Streptomyces.1 This highly polar “heterosugar” was first identified
as an antibiotic and later recognized as a glucosidase inhibitor.2 In
1976, Bayer chemists discovered that the stable, naturally occuring
1-deoxynojirimycin (2, originally synthesized in 1966 by Paulsen
et al.3) is a potent a-glucosidase inhibitor. Since these seminal
discoveries nojirimycins have attracted a great deal of attention
both from the academia4 as well as the pharma industry. Two
derivatives of 2 are currently in the market for the treatment
of two different human conditions. The inhibitory power of 2
R
is being realized in miglitol (Glysetꢀ, 3), a drug for treating type II
diabetes mellitus.5 The drug effectively lowers blood sugar levels by
inhibiting the break down of dietary sugars. On the other hand,
Results and discussion
Due to the high interest the synthetic community has had in these
so called azasugars, many imaginative synthetic routes have been
deviced. Nojirimycins and derivatives thereof have been accessed
for example from carbohydrates, amino acids and tartaric acid.17
Our laboratory has had a long term interest in diastereoselective
synthesis of enantiopure (vicinal) amino alcohols from amino
acids. Previously we described the diastereoselective synthesis of
(-)-1-deoxygalactonojirimycin (DGJ, 6) using the general strategy
outlined in Scheme 1.18 Disconnection along the C1–N bond
gives rise to an open-chain compound 8 with a leaving group
at C1. This can be thought to be derived from the differentially
protected bis-allylic alcohol 9. This is in turn accesible from
Garner’s aldehyde (10) and a protected propargyl alcohol 11
via formal reductive coupling. We have successfully accessed
R
N-butyl-DNJ (Zavescaꢀ, 4) is being used for the treatment of
Gaucher disease, a serious lysosomal storage disorder previously
R
only treatable through enzyme replacement therapy.6 Zavescaꢀ
inhibits the biosynthesis of glycosphingolipids, thereby decreasing
their accumulation in the body. Besides these two targets, inhibi-
tion of several other enzymes have been or are being investigated,
Fig. 1 Nojirimycin and several of its derivatives.
Department of Chemistry, School of Science and Technology, Aalto Uni-
versity, P.O. Boc 16100 (Kemistintie 1), FI-00076, Aalto, Finland. E-mail:
ari.koskinen@tkk.fi
† Electronic Supplementary Information (ESI) available: Copies of 1H and
13C spectra are included in the ESI. See DOI: 10.1039/c0ob00747a/
Scheme 1 General retrosynthetic strategy.
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allylic alcohols such as 9 through Horner–Wadsworth–Emmons
reaction between an amino acid derived b-keto phosphonate
and the corresponding aldehyde followed by diastereoselective
reduction.19 However, we noted that the diastereoselectivity of
the reduction is highly sensitive to the actual substrate, and more
importantly partial racemization of the phosphonate becomes
a problem in large scale synthesis. To overcome this problem,
we have used a zinc nucleophile generated by hydrozirconation–
transmetallation sequence to couple (-)-10 and 12 with exceptional
syn (>20 : 1) selectivity (Scheme 2).20 Now we wanted to be able to
access the anti relationship between the C4 and C5 substituents.
This would in turn call for reversal of diastereoselectivity in the
coupling step. Despite a promising literature precedent, we were
not able to reverse the diastereoselectivity.21 Instead, we turned
our attention to lithiated nucleophiles, as it is known that their
addition to 10 proceeds with anti preference.
Scheme 4 First generation approach to (-)-5.
is a good ligand for osmium as the black Os(VI) was still present
even after three chromatographic runs. Nevertheless, adequate
amounts of pure 19 could be produced through this route for
further experiments.
Scheme 2 Key reductive coupling.
Attempted mesylation of the primary alcohol only led to
decomposition upon isolation. On the other hand, the tosylate
20 was found to be relatively stable. Our first attempt (TsCl, NEt3,
CH2Cl2) delivered the tosylate in meager 35% yield. In an effort
to improve the yield, we tried numerous bases and conditions
(Table 1). Increasing the temperature significantly improved the
yield (entry 2). Added secondary base (DMAP) did not improve
the yield, on the contrary significant decomposition was evident
(entry 3). We also attempted to catalyze the reaction with dibutyl
tinoxide as reported.27 However, the substrate proved to be
reluctant to such catalysis (entries 4 and 5). We then proceeded
to test several other bases, of which N-methyl imidazole proved
to be the best, delivering the desired monotosylate 20 in 67–76%
yield. It should be noted, that under no conditions we detected
any bistosylated products.
The synthesis commenced with the addition of lithiated 12
to the (-)-Garner aldehyde (Scheme 3).22 We found out that if
performed in THF, the addition proceeded smoothly and in useful
diastereomeric ratio (>15 : 1). No difference in diasteremeric ratio
was detected in the presence of HMPA. We then envisioned that
reduction of the triple bond with Red-Al would deliver the anti
congener of 13. Instead a mixture of 15 and the allene 16 was
produced as evidenced by the high carbon shift at d = 207.9 ppm.23
Under no conditions could the undesired elimination of TBSO be
supressed.
With every functionality in place we were now ready for the
ring closure. Removal of the N,O-acetal and the BOC-group was
accomplished with hydrochloric acid in methanol in quantitative
Table 1 Monotosylation of 19a
T/◦C
Yield (%)b
Scheme 3 Alkynylation of 10 and attempted reduction.
Entry Base
Additive
1
2
3
4
5
6
7
8
9
1.3 eq NEt3
—
—
-10–RT 35
In order to avoid problems in the reduction step, we protected
the secondary alcohol of 14 as the benzyl ether24 (Scheme 4)
followed by desilylation of the primary alcohol. NH4F·HF proved
to be a far superior desilylation reagent compared to the standard
TBAF (tetrabutylammonium fluoride) both in terms of price and
practicality, as no hard to remove tetrabutyl ammonium residues
are formed in the reaction. In fact, simple silica gel filtration after
the desilylation was to provide 17 in more than adequate purity.
Treatment of 17 with 2 equivalents of Red-Al produced exclusively
the desired trans-allylic alcohol 18 in near quantitative yield, again
without any need to resort to chromatography. Osmium catalyzed
dihydroxylation under modified Upjohn conditions provided the
tetraol 19 in 81% yield (6 : 1 dr25).26 The diastereomeric mixture
proved to be extremely difficult to purify. One of the diasteremers
1.3 eq NEt3
1.3 eq NEt3
1.0 eq NEt3
1.1 eq NEt3
5.0 eq pyr.
2.0 eq DMAP
5.0 eq 2,4,6-collidine 0.2 eq DMAP
0–RT
58
0.1 eq DMAP
2% Bu2SnO
5% Bu2SnO
—
RT
0
0
n. i.c
n. i.c
40
0–RT
n. r.d
45
—
0
0
0
66
1.2 eq N-methyl
imidazole
—
67–76
a Reaction conditions: A flame-dried flask under argon was loaded with
19 (125 mg, 0.30 mmol, 100 mol%) and 3 mL of CH2Cl2. The flask
was cooled down to the appropriate temperature, after which base was
added followed by TsCl (63 mg, 0.33 mmol, 105 mol%). Stirred until
complete consumption of starting material or for 48 h. b Isolated yields
after chromatography. c Not isolated. d No reaction took place.
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yield. The cyclization was effected by treating the crude salt
with calcium carbonate in methanol, yielding the piperidine
21 in 68% yield after chromatography. If the cyclization was
effected using triethyl amine or diisopropylethyl amine the crude
reaction mixture was difficult to purify due to the oily amine
salts. Hydrogenolysis of the remaining protecting group under
acidic conditions delivered 5·HCl in quantitative yield, thereby
completing the synthesis in 32% overall yield over 9 steps.
However, we were not satisfied with the hard-to-purify dihy-
droxylation production 19, nor with the low yielding tosylation
step. To this end another leaving group was envisioned. Allylic
chlorination of 18 delivered the chloride 22 in good yield (88%)
with no need for chromatographic purification (Scheme 5). Sub-
sequent dihydroxylation delivered 23 in passable yield (81%) and
without erosion of the diastereomeric ratio (6 : 1). Moreover, the
diastereomers were now much easier to separate due to lack of the
primary hydroxyl group. The dihydroxylation was also attempted
using KMnO4. Without buffering (CH2Cl2, 1.5 equivalents of
KMnO4) no reaction took place, however when buffered with
NaHCO3 complete decomposition was observed. Deprotection
and cyclization worked with similar efficiency compared to the
tosylate (78%, 2 steps). After hydrogenolysis of the benzyl protec-
tion, (-)-altroDNJ hydrocloride (-)-5 was obtained in improved
43% overall yield. Furthermore one chromatographic purification
was omitted.
KMnO4, 20 g K2CO3, 5 mL 1 M NaOH, diluted to 300 mL
with water), vanillin (3 g vanillin, 2.5 mL conc. H2SO4, 1.5 mL
acetic acid, 125 mL EtOH) and UV-light (l = 254 nm). Flash
chromatography was performed on Merck Silica Gel 60 silica.
The celite used in filtrations was either Fluka Celite 501 or
Sigma–Aldrich Celite 535 Coarse. NMR spectra were recorded
on Bruker Avance 400 spectrometer. The spectra were calibrated
either to TMS (1H: d 0.00 ppm), MeOD (1H: d 3.34 ppm, 13C
d: 49.86 ppm), CDCl3 (13C: d 77.0 ppm), Cl2CDCDCl2 (1H: d
6.00 ppm, 13C d: 73.8), toluene-d8 (1H: d 2.09 ppm, 13C d: 20.4)
or to D2O (1H: d 4.70 ppm, 13C: d 49.5 ppm, MeOH as internal
standard) depending on the used solvent. Spectra were recorded
◦
at 25 C, unless otherwise stated. Heating of the NMR-samples
was performed using a probe heater. IR spectra were recorded
on Perkin–Elmer Spectrum One FTIR machine. Optical rotations
were measured with Perkin–Elmer 343 polarimeter using sodium
lamp and a 10 cm quartz cuvette. HRMS spectra were recorded on
Waters Micromass LCT Premier (ESI/TOF) mass spectrometer.
tert-Butyldimethyl(prop-2-ynyloxy)silane (12)
To a solution of propargyl alcohol (1.00 g, 17.8 mmol, 100 mol%)
in dry dichloromethane (7 mL) under argon was added tert-
butyldimethylsilylchloride (2.68 g, 17.8mmol, 100mol%) followed
by imidazole (2.43 g, 35.7 mmol, 200 mol%). The flask was
equipped with a condenser after which the solution was heated to
reflux. After 2 h the starting material was consumed by TLC and
the flask was allowed to cool to room temperature. The reaction
was quenched with 10 mL of ice-cold water. The resulting mixture
was filtered through a pad of celite. The filtrate was transferred to
a separating funnel and the phases were separated. The aqueous
phase was extracted 3 ¥ 10 mL CH2Cl2. Combined organic phases
were washed with brine (25 mL), dried over Na2SO4 and the
bulk of the solvent was evaporated. Distillation under reduced
pressure afforded 2.63 g (98%) of clear colorless liquid. Bp = 52 ◦C
1
(14 torr);28 Rf 0.68 (1 : 2 EtOAc/Hex, permanganate); H-NMR
(CDCl3) d ppm 4.31 (d, 2H, J = 2.4 Hz), 2.39 (t, 1H, J = 2.5 Hz),
0.91 (s, 9H), 0.13 (s, 6H)
Scheme 5 Improved endgame.
(S)-tert-butyl 4-((R)-1-(benzyloxy)-4-hydroxybut-2-yn-1-yl)-2,2-
dimethyloxazolidine-3-carboxylate (17)
Conclusions
A flame-dried flask under argon was charged with 12 (23.7 g,
138.0 mmol, 130 mol%) and 275 mL of dry THF. The solution was
cooled to -78 C and n-BuLi (57.5 mL, 135.0 mmol, 125 mol%,
Herein we have desribed a method for producing (-)-altroDNJ
hydrochloride in 9 steps with 43% overall yield. Only two
chromatographic purifications in the late stages are required,
making the route fast and efficient.
◦
2.35 M in hexanes) was added over 10 min. The resulting mixture
was stirred for an hour. Then 2 (22.7 g, 98.8 mmol, 100 mol%) was
added as a THF solution (115 mL + 20 mL for washing, pre-cooled
to -78 ◦C) via cannula over 1 h. The resulting solution was stirred
for 1 h and then quenched by adding 100 mL of sat. NH4Cl. The
cooling bath was removed and replaced by a warm water bath.
After reaching room temperature, the aqueous layer was extracted
with EtOAc (2 ¥ 50 mL). The combined organic phases were dried
over Na2SO4 and concentrated to yield 42.3 g of crude product
as slightly yellow oil. Analytical sample was prepared by flash
column chromatography (10% ethyl acetate/hexanes).
Experimental section
Dichloromethane and tetrahydrofuran were obtained from a
solvent drier (MB SPS-800, neutral alumina). Methanol was
distilled from Mg(OMe)2. Dimethyl formamide was distilled from
˚
molecular sieves (5 A) and ninhydrin. Other solvents used in
reactions and in chromatography were of p.a. quality. Reagents
were obtained from Sigma–Aldrich or from Acros Organics and
used as such, unless otherwise stated. TLC monitoring was
performed on Merck silica gel 60 F254 (230–400 mesh, aluminium)
plates. Stains used to visualize the plates were permanganate (3 g
Rf 0.56 (2 : 1 Hex/EtOAc); [a]2D0 = -35.0 (c 2.83, DCM) lit. -35.8
(c 1.1 CDCl3)17; HRMS Found 422.2337 Calculated for 422.2339
C20H37NNaO5Si [M + Na]; H-NMR (400 MHz, C6D6, 60 ◦C)
1
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4.64 (br. s, 1 H), 4.21 (d, J = 2.0, 2 H), 4.00 (m, 2 H), 3.72 (dd, J =
8.5, 7.2, 1 H), 1.69 (s, 3 H), 1.46 (s, 3 H), 1.39 (s, 9 H), 0.94 (s, 9
H), 0.09 (s, 6 H); 13C-NMR 154.1, 94.9, 84.5, 82.5, 81.3,72.5, 65.0,
64.1, 62.5, 28.3, 25.8, 25.2, 22.9, 18.5, 13.9, -5.2
(S)-tert-butyl 4-((R,E)-1-(benzyloxy)-4-hydroxybut-2-en-1-yl)-
2,2-dimethyloxazolidine-3-carboxylate (18)
A flame-dried flask under argon charged with compound 17
(3.40 g, 9.10 mmol, 100 mol%) and dry THF (45 mL) was placed
in an ice/water bath. Then Red-Al was added dropwise (5.55 mL,
18.2 mmol, 65 w-% in tol.). After 15 min of stirring, the reaction
was quenched by dropwise addition of MeOH (1 mL, until no
further gas evolution occurs). Then 5 g of Rochelle’s Salt was added
followed by 5 mL of sat. aq. rochelle’s salt. After 30 min of stirring
the mixture was filtered through a pad of celite (filter cake was
washed with 3 ¥ 30 mL of methylene chloride) and concentrated.
The crude residue was dissolved in methylene chloride and filtered
through a pad of silica gel (washed with 50% EtOAc/Hexanes).
After concentration 3.43 g (99%) of colorless oil was obtained.
Rf 0.35 (1 : 1 EtOAc/Hex) [a]2D0 = -48.2 (c 2.0 DCM); HRMS
Found 400.2118 Calculated for 400.2100 C21H31NNaO5 [M + Na];
1H-NMR (400 MHz, CDCl3) d = 7.38–7.19 (m, 5 H), 5.92–5.77
(m, 1 H), 5.76–5.60 (m, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.36 (d, J =
11.7 Hz, 1 H), 4.26–3.82 (m, 6 H),◦2.46–2.14 (m, 1 H), 1.62–1.33
(m, 15 H); 13C-NMR (CDCl3, 50 C) 152.6, 138.3, 133.1, 129.6,
128.3, 127.7, 127.5, 93.9, 80.0, 70.9, 64.7, 62.5, 60.4, 28.4, 27.1,
24.9, 23.4; IR nmax/cm-1 = 3460, 2979, 1698, 1391, 1366 (neat)
A flask under argon was charged with the crude product from
theprevious reaction(42.3g, assumedcirca 98.0mmol, 100 mol%),
and dry DMF (100 mL). The solution was cooled to 0 ◦C and
benzyl bromide (15.4 mL, 130 mmol, 130 mol%) was added
together with KI (830 mg, 5 mmol, 5 mol%). Finally sodium
hydride (4.8 g, 120 mmol, 120 mol%, 60% dispersion in mineral
oil) was added as a single portion. After the gas evolution had
stopped the slurry was diluted with 100 mL of dry THF. After
1 h of stirring, the reaction was quenched by adding 60 mL of
sat. NaHCO3 (dropwise at first, until gas no longer forms) and
then diluted with 150 mL of water. The mixture was extracted
with EtOAc (3 ¥ 100 mL). The combined organic phases were
washed with water (200 mL) and brine, dried over Na2SO4 and
concentrated. The residue was filtered through a pad of silica gel
(eluted with 5% EtOAc/Hexanes) to yield 52.4 g of light yellow oil.
Analytical sample was prepared by flash column chromatography
(5% Ethyl acetate/hexanes).
Rf 0.66 (30% EtOAc/Hex); [a]2D0 = -76.5 (c 2.0 DCM); HRMS
Found 512.2825 Calculated for 512.2832 (C27H43NNaO5Si) [M +
Na]; 1H-NMR (400 MHz, CDCl3) 7.21–7.39 (m, 5 H), 4.83 (app.
t, J = 11.3 Hz, 1 H), 4.69–4.74 (m, 0.5 H, rotameric species), 4.51
(dd, J = 12.1, 7.2 Hz, 1 H), 4.45–4.48 (m, 0.5 H, rotameric species),
4.37 (d, J = 13.4 Hz, 2 H), 4.23–4.29 (m, 1 H), 4.09–4.15 (m, 0.5 H
rotameric species), 4.01 (app. t, J = 8.2 Hz, 1H), 3.95–3.99 (m, 0.5
H, rotameric species); 13C-NMR: 152.7, 152.0, 138.3, 137.9, 128.9,
128.7, 128.5, 128.3, 128.0, 95.4, 94.8, 81.8, 80.7, 80.3, 71.4, 71.2
68.3, 67.7, 65.1, 64.7, 61.1, 60.8, 52.2, 28.8, 26.6, 26.3, 26.2, 26.0,
(S)-tert-butyl 4-((1S,2R,3S)-1-(benzyloxy)-2,3,4-
trihydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate (19)
To a solution of 18 (2.28 g, 6.06 mmol, 100 mol%) and citric acid
(1.40 g, 7.27 mmol, 120 mol%) in acetone/H2O (8 : 1, 27 ml) was
added OsO4 (770 mL [4% in H2O], 0.12 mmol, 2 mol%). To the
resulting yellow solution was added N-methylmorpholine N-oxide
(0.98 g, 7.27 mmol, 120 mol%) as a single portion. The light green
solution was stirred for 6 h, until complete by TLC (color also
changes gradually back to yellow). Acetone was evaporated with
rotary evaporator, the aqueous residue was acidified with 1 M HCl
(c. 3 mL) and diluted (20 mL H2O). Extraction (3 ¥ 20 mL EtOAc),
brine wash and drying yielded 2.54 g of dark foamy matter.
Separation of the diastereomeric mixture (c. 6 : 1) is extremely
difficult. Repeated chromatographic runs (3–4) on MeOH–DCM
or EtOAc–DCM gives the product as white foamy matter.
25.6, 24.1, 18.7, -4.6 (c. 2 : 1 mixture of rotamers): IR: nmax/cm-1
=
3351, 1705, 1390, 1366, 1089, 837 (neat)
The product from the previous reaction (52.8 g, assumed circa
98 mmol, 100 mol%) was dissolved in MeOH (80 mL) under
ambient conditions. NH4HF·HF (11.5 g, 200 mmol, 200 mol%)
was added and the resulting mixture was stirred for 18 h. To quench
the reaction, 30 g of silica gel was added to the reaction mixture.
After 30 min of stirring, the solution was diluted with 350 mL of
CH2Cl2, passed through a pad of silica (washed with 10% MeOH–
CH2Cl2) and concentrated. The crude product was dissolved in
20% EtOAc/Hexanes and filtered through a pad of silica. After
concentration 34.0 g (91% over 3 steps) of pale yellow oil was
obtained. Analytical sample was obtained by chromatographic
purification (20% → 30% → 50% EtOAc/Hexanes).
Rf 0.22 (65% EtOAc/Hex + 1% MeOH); [a]2D0 = -32.6 (c =
2.0, DCM); HRMS Found 434.2161 Calculated for 434.2155
◦
1
C21H33NNaO7 [M + Na]; H-NMR (400 MHz, TCE, 90 C) d =
7.43–7.31 (m, 5 H), 4.80 (d, J = 11.3 Hz, 1 H), 4.72 (d, J = 11.2 Hz,
1H), 4.30–4.21 (m, 2 H), 4.10–3.99 (m, 2 H), 3.92 (ddd, J = 9.7,
5.0, 2.6 Hz, 1 H), (app. t, J = 5.0 Hz, 2H), 3.66 (td, J = 8.6, 3.0 Hz,
1 H), 3.12 (br. s, 1H), 2.80 (app. d, J = 4.9 Hz, 1H), 2.16 (app. t, J =
5.21, 1H), 1.63 (s, 3H), 1.58–1.55 (m, 12H); 13C-NMR (100 MHz,
TCE, 90 ◦C) 137.9, 128.3, 127.8, 127.7, 94.0, 80.7, 80.0, 74.7, 72.7,
70.2, 64.8, 63.6, 58.2, 28.4, 26.7; IR nmax/cm-1 = 3420, 1695, 1667,
1395, 1366 (neat)
Rf 0.47 (1 : 1 EtOAc/Hex); [a]2D0 = -54.9 (c 1.0 DCM); HRMS
Found 398.1953 Calculated for 398.1943 C21H29NNaO5 [M + Na];
1H-NMR (400 MHz, CDCl3, 50 ◦C) 7.21–7.40 (m, 5 H), 4.80 (d,
J = 12.1 Hz 1 H), 4.52 (d, J = 12.1 Hz 1 H), 4.12–4.36 (m, 4 H),
3.93–4.06 (m, 1H), 1.27–1.70 (m, 15 H); 13C-NMR (CDCl3) 152.5,
151.5, 137.6, 137.3, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6, 94.9,
94.2, 85.7, 85.4, 82.5, 80.4, 79.9, 70.9, 67.9, 97.8, 64.6, 64.4, 60.4,
60.1, 50.7, 28.3, 26.5, 25.5, 24.8, 23.5 (rotamerism);1H NMR =
(400 MHz, TOLUENE-d8, 100 ◦C) d = 7.28–7.20 (m, 2 H), 7.16–
7.08 (m, 2 H), 7.08–7.00 (m, 1 H), 4.71 (d, J = 11.7 Hz, 1 H), 4.69
(app. d, J = 12.1 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 4.27–4.18
(m, 1 H), 4.09 (d, J = 2.6 Hz, 1 H), 3.98–3.90 (m, 2 H), 3.87–3.79
(m, 1 H), 1.71–1.57 (m, 3 H), 1.51–1.44 (m, 3 H), 1.40–1.31 (m, 9
H) IR: nmax/cm-1 = 3436, 2978, 1683, 1392, 1366 (neat)
(S)-tert-butyl 4-((1S,2R,3S)-1-(benzyloxy)-2,3-dihydroxy-4-
(tosyloxy)butyl)-2,2-dimethyloxazolidine-3-carboxylate (20)
To a stirred solution of 19 (540 mg, 1.33 mmol, 100 mol%)
and p-toluenesulfonylchloride (280 mg, 1.46 mmol, 110 mol%)
in dry CH2Cl2 (6 mL) under argon was added N-methyl imidazole
(250 mL, 2.13 mmol, 150 mol%) at 0 ◦C. After 4 h of stirring
the reaction was quenched with water (10 mL). Aqueous phase
1234 | Org. Biomol. Chem., 2011, 9, 1231–1236
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was extracted 3 ¥ 5 mL CH2Cl2. Combined organic phases
were washed with brine, dried over Na2SO4 and concentrated.
Chromatographic purification (EtOAc–CH2Cl2, 0%->30%) gave
510 mg of colorless oil. Decomposes if heated!
Rf 0.84 (65% EtOAc/Hex + 1% MeOH) [a]2D0 = -20.4 (c =
1.0, DCM) HRMS Found 588.2244 Calculated for 588.2243
C28H39NNaO9S [M + Na]; 1H-NMR (400 MHz, CDCl3) d = 7.67–
7.74 (m, 2 H), 7.20–7.31 (m, 7 H), 4.41–4.82 (m, 2 H), 3.84–4.21
(m, 7 H), 3.34 (br. s, 1 H), 2.36 (s, 3 H), 1.33–1.57 (m, 15 H)
13C-NMR: We were unable to obtain a clear spectrum due to the
extensive rotamerism and heat sensitivity IR nmax/cm-1 = 3392,
1661, 1396, 1366, 1176 (neat)
dropwise at 0 ◦C. The mixture was diluted with water 120 mL and
extracted 3 ¥ 80 mL of Et2O. Combined organic phases were
dried over Na2SO4 and concentrated. The yellow residue was
dissolved in 20% EtOAc/hexanes and filtered through a pad of
silica gel. After concentration 2.82 g (88%) of slightly yellow oil
was obtained.
Rf 0.74 (60% Et2O/Hex); [a]2D0 = -47.5 (c. 1.93, DCM); HRMS
Found 418.1755 Calculated for 418.1761 C21H30NNaO4Cl [M +
Na]; H-NMR (400 MHz, Tol, 90 ◦C) d = 7.24–6.94 (m, 5 H),
1
5.71–5.57 (m, 2 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.26 (d, J = 12.1 Hz,
1 H), 4.08 (t, J = 6.0 Hz, 1 H), 3.97 (dd, J = 2.6, 8.8 Hz, 1 H),
3.87 (t, J = 6.0 Hz, 1 H), 3.71–3.68 (m, 2 H), 3.65 (dd, J = 6.0,
8.6 Hz, 1 H), 1.56 (s, 3 H), 1.46 (s, 2 H), 1.37 (s, 7 H); 13C-NMR
(100 MHz, Tol, 90 ◦C) 152.7, 139.4, 133.8, 130.4, 128.9, 128.4,
(3S,4R,5S,6S)-5-(benzyloxy)-6-(hydroxymethyl)piperidine-3,4-
diol (21)
94.8, 80.4, 80.0, 72.0, 65.3, 61.5, 44.2, 28.9, 27.6 IR nmax/cm-1
=
3436, 1698, 1387 (neat)
Compound 20 (500 mg, 0.88 mmol, 100-mol%) was dissolved in
MeOH (4 mL) and the flask was then cooled to 0 ◦C. Freshly
prepared, saturated HCl(g)/MeOH was added (c. 4 mL) and the
cooling bath was removed. After 1 h of stirring, starting material
was completely consumed. Solvent was evaporated to give 430 mg
of crude as white foam.
(S)-tert-butyl 4-((1S,2R,3R)-1-(benzyloxy)-4-chloro-2,3-
dihydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate (23)
To a stirred solution of 2 (2.79 g, 7.39 mmol, 100 mol%)
in acetone/H2O (8 : 1, 40 mL) was added citric acid (2.49 g,
12.93 mmol, 175 mol%) followed by OsO4 (0.94 mL, 0.15 mmol,
2 mol%, 4 w-% in H2O). After the addition of osmium, the solution
changed to yellow/green in color. Finally N-methyl morpholine
N-oxide (1.1 g, 8.13 mmol, 110 mol%) was added and the flask was
sealed with a cap. After 18 h of stirring the color had changed to
bright yellow. To quench the reaction 470 mg of sodium thiosulfate
was added. In 5 min black precipitate had formed. Acetone was
evaporated under reduced pressure and the residue was dissolved
in 35 mL of water. The aqueous mixture was extracted with EtOAc
(3 ¥ 25 mL). Combined organic phases were dried over Na2SO4
and concentrated to give 2.84 g of foamy glass-like product.
Chromatographic purification (30% → 50% → 60% EtOAc/Hex)
yielded 2.08 g (65%) of pure 23 and 390 mg of mixed 23 and
2,3-epi-23. Combined yield 2.47 g (81%), 6 : 1 dr (by NMR).
Rf 0.56 (60% EtOAc/Hex); [a]2D0 = -35.1 (c. 1.93, DCM); HRMS
Found 452.1812 Calculated for 452.1816 C21H32NNaO6Cl [M +
Na]; 1H-NMR (400 MHz, tetrachloroethane-d2, 60 ◦C) d = 7.43–
7.31 (m, 5 H), 4.79 (d, J = 11.3 Hz, 1 H), 4.65 (d, J = 11.3 Hz,
1 H), 4.28–4.21 (m, 2 H), 4.09–3.95 (m, 3 H), 3.69–3.57 (m, 3
H), 1.62 (s, 3 H), 1.57–1.51 (m, 12 H); 13C-NMR: (100 MHz,
TETRACHLOROETHANE-d2, 60 ◦C) 137.7, 128.4, 128.8, 127.9,
94.0, 80.8, 78.9, 74.6, 71.7, 70.4, 63.3, 58.2, 46.5, 28.3, 28.2, 26.5;
IR nmax/cm-1 = 3369, 1659, 1399 (neat)
HRMS Found 426.1651 Calculated for 426.1586 C20H29NO7S
1
[M + H]; H NMR (400 MHz, MeOD) d = 7.84–7.79 (m, 2 H),
7.46–7.42 (m, 2 H), 7.42–7.31 (m, 5 H), 4.73 (d, J = 11.0 Hz, 1 H),
4.68 (d, J = 11.0 Hz, 1 H), 4.15 (dd, J = 5.8, 9.8 Hz, 1 H), 4.09
(dd, J = 7.0, 9.8 Hz, 1 H), 4.00–3.88 (m, 3 H), 3.82 (dd, J = 7.7,
11.6 Hz, 1 H), 3.70 (dd, J = 1.5, 8.1 Hz, 1 H), 3.60 (td, J = 4.3,
8.0 Hz, 1 H); 13C-NMR (100 MHz, MeOD): 147.5, 139.8, 135.1,
132.0, 130.4, 129.9, 129.9, 78.7, 76.0, 73.0, 72.4, 70.0, 60.4, 57.1,
22.4
To an ice-cold solution of the crude from previous reaction
(420 mg, 0.85 mmol, 100 mol%) in MeOH (8 mL) was added
calcium carbonate (295 mg, 2.13 mmol, 250 mol%) and the
resulting mixture was stirred for 3 h at 0 ◦C. The ice-cold solution
was then filtered through a pad of celite (filter cake was washed
2 ¥ 1 mL ice-cold MeOH) and concentrated to yield 550 mg of
slightly yellow sticky solid. Chromatographic purification (20%
MeOH–CHCl3 + 1% aq. ammonia (25%)) yielded 204 mg (69%,
over 2 steps) of the title compound.
Rf 0.24 (20% MeOH–CHCl3 + 1% aq. ammonia (25%)); [a]D20
=
–43.5 (c 2.02 MeOH); HRMS Found 254.1397 Calculated for
254.1406 C13H20NO4; 1H NMR (400 MHz, MeOD) d = 7.43–7.22
(m, 5 H), 4.69 (d, J = 11.3 Hz, 1 H), 4.51 (d, J = 11.3 Hz, 1 H), 4.12
(t, J = 3.5 Hz, 1 H), 3.82–3.71 (m, 3 H), 3.67 (dd, J = 2.9, 11.0 Hz,
1 H), 3.05 (dd, J = 1.8, 13.9 Hz, 1 H), 2.86 (td, J = 3.4, 10.0 Hz,
1 H), 2.71 (ddd, J = 0.7, 2.2, 13.9 Hz, 1 H); 13C-NMR (100 MHz,
METHANOL-d4) 140.8, 130.2, 129.9, 129.5, 76.1, 72.8, 71.8, 69.7,
62.9, 57.2, 47.5; IR nmax/cm-1 = 3307, 2925, 2884, 1454, 1074 (neat)
(3S,4R,5S,6S)-5-(benzyloxy)-6-(hydroxymethyl)piperidine-3,4-
diol (21) from 23
To a flask charged with 23 (560 mg, 1.3 mmol, 100 mol%)
was added ice-cold, freshly prepared HCl(g)/MeOH (10 mL).
The solution was stirred at room temperature for 40 min and
then heated gently to 50 ◦C. After further 40 min of stirring
the starting material was consumed by TLC, and the previously
colorless solution had turned yellow. Solvent was evaporated to
yield 430 mg of yellow glass-like gel. The residue was then dissolved
in methanol (12 mL) and the ion exchange resin was added (Merck
ionenaustaucher II, 500 mg). The mixture was heated to 50 ◦C and
stirred for 16 h. The reaction was not complete by TLC, so 200 mg
(S)-tert-butyl 4-((R,E)-1-(benzyloxy)-4-chlorobut-2-en-1-yl)-2,2-
dimethyloxazolidine-3-carboxylate (22)
A flame-dried flask was charged with 18 (3.05 g, 8.08 mmol,
100 mol%), dry DMF (60 mL) and then cooled to 0 ◦C. POCl3
(1.63 mL, 17.8 mmol, 220 mol%) was added as a single portion.
The cooling bath was removed and the solution was stirred for
3 h. The previously colorless solution had taken a bright yellow
color. The reaction was quenched by adding sat. NaHCO3 (25 mL)
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more of the resin was added and stirred for further 5 h at reflux.
The mixture was filtered through a fritted funnel and concentrated.
The crude product was purified by flash chromatography (20%
MeOH–CHCl3 + 1% NH4OH [25%]) to yield 258 mg of slightly
yellow oil (78%) which solidifies into a gummy solid on standing.
Spectroscopically identical to one prepared from 20.
11 C. M. Walden, T. D. Butters, R. A. Dwek, Frances M. Platt and A. C.
Van Der Spoel, Hum. Reprod., 2006, 21, 1309–1315.
12 J. Chang, L. Wang, D. Ma, X. Qu, H. Guo, X. Xu, P. M. Mason, N.
Bourne, R. Moriarty, B. Gu, J-T. Guo and T. M. Block, Antimicrob.
Agents Chemother., 2009, 53, 1501–1508; A. J. Stevens, M. E. Gahan,
S. Mahalingam and P. A. Keller, J. Med. Chem., 2009, 52, 7911–7926.
13 M. Padro´, J. A. Castillo, L. Go´mez, J. Joglar, P. Clape´s and C. de Bolo´s,
Glycoconjugate J., 2010, 27, 277–285.
14 Y. Zhou, Y. Zhao, K. M. O’Boyle and P. V. Murphy, Bioorg. Med.
Chem. Lett., 2008, 18, 954–958.
(-)-1-Deoxyaltronojirimycin hydrochloride ((-)-5 HCl)
15 For recent publications concerning altroDNJ see: A. M. C. H. van
den Nieuwendijk, M. Ruben, S. E. Engelsma, M. D. P. Risseeuw,
R. J. B. H. N. van den Berg, R. G. Boot, J. M. Aerts, J. Brussee, G. A.
van der Marel and H. S. Overkleeft, Org. Lett., 2010, 12, 3957–3959;
S. K. Bagal, S. G. Davies, J. A. Lee, P. M. Roberts, A. J. Russell, P. M.
Scott and J. E. Thomson, Org. Lett., 2010, 12, 136–139; R. Rengasamy,
M. J. Curtis-Long, H. W. Ryu, K. Y. Oh and K. H. Park, Bull. Korean
Chem. Soc., 2009, 30, 1531–1534; P. D. Dhavale, S. D. Markad, N. S.
Karanjule and J. PrakashaReddy, J. Org. Chem., 2004, 69, 4760–4766.
16 A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L. Yu, T. Okamoto,
Y. Banba, H. Ouchi, H. Takahata and N. Asano, J. Med. Chem., 2005,
48, 2036–2044.
To a stirred solution of 21 (125 mg, 0.494 mmol, 100 mol%) in
MeOH (5 mL) and conc. HCl (100 mL, 1.00 mmol, 200 mol%)
was added Pd/C (100 mg, 0.05 mmol, 10 mol%, 5% in Pd). H2
atmosphere was then introduced and the solution was vigorously
stirred for 1 h. The mixture was filtered through a pad of celite
and concentrated to yield 106 mg (100%) of the title compound as
white foam.
Rf 0.00 (20% MeOH–DCM + 1% NH4OH [25%]); [a]2D0 = -36.7
(c. 1.00, MeOH; lit. -33.2 (c. 0.5, MeOH),29 31.0 (c. 2.0, MeOH)30);
HRMS Found 164.0923 Calculated for 164.0923 C6H15NO4 [M +
H]; 1H-NMR (400 MHz, D2O) d = 4.12–4.07 (m, 1 H), 4.00–3.87
(m, 3 H), 3.77 (dd, J = 6.8, 12.8 Hz, 1 H), 3.36–3.27 (m, 2 H), 3.17
(dd, J = 2.7, 13.5 Hz, 1 H); 13C-NMR (100 MHz, D2O (MeOH
iSTD) 69.4, 67.1, 64.6, 59.1, 56.8, 49.9, 44.9
17 For synthetic methods see: M. S. Pearson, M. Mathe-Allainmat, V.
Fargeas and J. Lebreton, Eur. J. Org. Chem., 2005, 11, 2159–2191; K.
Afarinkia and A. Bahar, Tetrahedron: Asymmetry, 2005, 16, 1239–1287;
and ref. 4.
18 O. K. Karjalainen, M. Passiniemi and A. M. P. Koskinen, Org. Lett.,
2010, 12, 1145–1147.
19 A. M. P. Koskinen and P. M. Koskinen, Tetrahedron Lett., 1993, 34,
6765–6768; P. M. Koskinen and A. M. P. Koskinen, Methods Enzymol.,
1999, 311, 458–479.
Notes and references
20 P. Wipf and W. Xu, Tetrahedron Lett., 1994, 35, 5197–5200.
21 T. Murakami and K. Furusawa, Tetrahedron, 2002, 58, 9257–9263.
22 H. Gruza, K. Kiciak, A. Krasin´ski and J. Jurczak, Tetrahedron:
Asymmetry, 1997, 8, 2627–2631.
1 S. Inouye, T. Tsuruoka and T. Niida, J. Antibiotics, 1966, 19, 288–292.
2 T. Niwa, S. Inouye, T. Tsuruoka and T. Niida, Agrig. Biol. Chem., 1970,
34, 966–967.
3 H. Paulsen, Angew. Chem., Int. Ed. Engl., 1966, 5, 495–511.
4 For an excellent introduction to the subject see: A. Stutz, Iminosugars
as glycosidase inhibitiors: Nojirimycin and beyond, Wiley-VCH, New
York, 1999; P. Compain and O. R. Martin, Iminosugars: From synthesis
to therapeutic applications, Wiley-VCH, New York, 2007.
5 E. Fattorusso and O. T. Scafati, Modern Alkaloids, Wiley-VCH, New
York, 2008, 111-133.
6 T. Cox, R. Lachmann, C. Hollak, J. Aerts, S. van Weely, M. Hribicek,
F. Platt, T. Butters, R. Dwek, C. Moyses, I. Gow, D. Elstein and A.
Zimran, Lancet, 2000, 355, 1481–1485.
7 P. Compain and O. R. Martin, Curr. Top. Med. Chem., 2003, 3, 541–560.
8 M. Bols, R. Hazelle and I. B. Thomsen, Chem.–Eur. J., 1997, 3, 940–
947; L. Somsak, V. Nagy, Z. Hadady, T. Docsa and P. Gergely, Curr.
Pharm. Des., 2003, 9, 1177–1189.
9 R. E. Lee, M. D. Smith, R. J. Nash, R. C. Griffiths, M. McNeil, R. K.
Grewal, W. Yau, G. S. Besra, P. J. Brennan and G. W. Fleet, Tetrahedron
Lett., 1997, 38, 6733–6736.
10 H. Moriyama, T. Tsukida, Y. Inoue, K. Yokota, K. Yoshino, H. Kondo,
N. Miura and S.-I. Nishimura, J. Med. Chem., 2004, 47, 1930–1938;
R-J. Wang, C-H. Yang and M-L. Hu, J. Agrig. Food Chem, 2010, 58,
8988–8993.
23 The allene 16 has the following spectorscopic properties: 1H-NMR
(400 MHz, CDCl3) d = 5.21 (dd, J = 13.0 Hz, 6.6 Hz, 1 H), 4.85 (app.
d, J = 5.7 Hz, 2 H), 3.80–4.44 (m, 5 H), 1.58 (bs, 3 H), 1.50 (s, 9H); 13C-
NMR (100 MHz, CDCl3) 207.9, 153.8, 151.7, 94.3, 92.1, 90.9, 80.9,
80.0, 71.0, 70.3, 64.6, 62.0, 61.2, 28.2, 26.2, 25.7, 24.5, 22.9; HRMS
Found 292.1535 Calculated for 292.1525 (C14H23NO4 + Na).
24 S. Czernecki, C. Georgoulis and C. Provelenghiou, Tetrahedron Lett.,
1976, 17, 3535–3536.
25 The diastereoselectivity is in full agreement with published data; K. J.
Cha, W. G. Christ and Y. Kishi, Tetrahedron Lett., 1983, 37, 3943–1946.
26 V. VanRheenen, R. C. Kelly and D. Y. Cha, Tetrahedron Lett., 1976, 17,
1973–1976; P. Dupau, R. Epple, A. A. Thomas, V. V. Fokin and K. B.
Sharpless, Adv. Synth. Catal., 2002, 344, 421–433.
27 M. J Martinelli, R. Vaidyanathan, J. M. Pawlak, N. K. Nayyar, U. P.
Dhokte, C. W. Doecke, L. M. H. Zollars, E. D. Moher, V. V. Khau and
B. Kosˇmrlj, J. Am. Chem. Soc., 2002, 124, 3578–3585.
28 A. De Mico, R. Margarita, L. Parlantini, A. Vescovi and G. Piancatelli,
J. Org. Chem., 1997, 62, 6974–6977.
29 O. V. Singh and H. Han, Tetrahedron Lett., 2003, 44, 2387–2392.
30 P. D. Dhavale, S. D. Markad, N. S. Karanjule and J. PrakashaReddy,
J. Org. Chem., 2004, 69, 4760–4766.
1236 | Org. Biomol. Chem., 2011, 9, 1231–1236
This journal is
The Royal Society of Chemistry 2011
©