Stereoselective synthesis and biological evaluation of d-fagomine, d-3-epi-fagomine and d-3,4-epi-fagomine analogs from d-glyceraldehyde acetonide as a common building block

Article abstract of DOI:10.1039/c2ob26732b

The stereoselective synthesis of d-fagomine, d-3-epi-fagomine, and d-3-epi-fagomine analogs starting from readily available d-glyceraldehyde acetonide has been achieved. The synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation. The lack of a strong activity as glycosidase inhibitors of these compounds could be advantageous for their therapeutic use as chaperones.

Full text of DOI:10.1039/c2ob26732b

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PAPER
Stereoselective synthesis and biological evaluation of D-fagomine,
D-3-epi-fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde
acetonide as a common building block†
J. Alberto Díez,a José A. Gálvez,*a María D. Díaz-de-Villegas,*a Ramón Badorrey,a Barbara Bartholomewb
and Robert J. Nashb
Received 3rd September 2012, Accepted 10th October 2012
DOI: 10.1039/c2ob26732b
The stereoselective synthesis of D-fagomine, D-3-epi-fagomine, and D-3-epi-fagomine analogs starting
from readily available D-glyceraldehyde acetonide has been achieved. The synthesis involves
diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective
epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation. The lack of a
strong activity as glycosidase inhibitors of these compounds could be advantageous for their therapeutic
use as chaperones.
Introduction
The structural analogy of polyhydroxylated piperidines to sugars
confers to these compounds – known as iminosugars – remark-
able biological activity derived from their ability to inhibit a
number of enzymes of medicinal interest such as glycosidases1
among others. This diverse inhibitory activity of iminosugars has
Fig. 1 Structure of D-fagomine and D-3-epi-fagomine.
been exploited for the development of a new generation of
potential agents for the treatment of several diseases2 including
diabetes, lysosomal storage disorders, viral infections or cancer
metastasis.
fagomine led to analogues with a different biological activity, for
example 3-epi-fagomine (Fig. 1) was found to be a more potent
(2R,3R,4R)-2-Hydroxymethylpiperidine-3,4-diol, D-fagomine
inhibitor of isomaltase and β-galactosidases than fagomine
(Fig. 1), which was first isolated from the seeds of Japanese
whereas it does not inhibit α-galactosidase.7
buckwheat Fagopyrum esculentum Moench3 and later found in
In recent years fagomine8 and other analogs with stereogenic9
other plant sources,4 has a potent antihyperglycemic effect in
and substituent10 diversity have been the subject of several
streptozocin-induced diabetic mice and potentiates markedly
syntheses with later structural modification less exploited. In this
paper we report on the synthesis of new D-fagomine, D-3,4-epi-
fagomine, and D-3-epi-fagomine analogs (1, 2 and 3, Fig. 2)
immunoreactive insulin release.5 D-Fagomine also lowers post-
prandial blood glucose concentration and modulates bacterial
adhesion.6 This behavior confers to this compound a potential
bearing a 1,2-dihydroxyethyl substituent on C2.
practical use as a dietary supplement and functional food ingre-
dient with the ability to reduce the health risks associated with
an excessive intake of fast-digestible carbohydrates or an excess
Results and discussion
of potentially pathogenic bacteria.6 Variations in the structure of
Ring-closing metathesis (RCM) followed by asymmetric dihy-
droxylation (ADH) has provided efficient synthetic protocols to
gain access to a lot of polyhydroxylated piperidines and pyrroli-
dines.11 This synthetic strategy can be applied to the synthesis of
target compounds using dialkenyl amine B as a synthetic inter-
mediate. Ring closing metathesis has been used for the construc-
tion of the piperidine ring with the desired substituent at C2 and
diastereoselective dihydroxylation was used to introduce the
vicinal diol functionality in the required position. Diastereoselec-
tive anti-addition of vinyl organometallic reagents to imines
aDepartamento de Catálisis y Procesos Catalíticos, Instituto de Síntesis
Química y Catálisis Homogénea (ISQCH), CSIC – Universidad de
Zaragoza, Pedro Cerbuna 12, E-50009 Zaragoza, Spain.
E-mail: loladiaz@unizar.es, jagl@unizar.es; Fax: +34976761202;
Tel: +34976762274
bPhytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion,
SY23 3EB, UK
†Electronic supplementary information (ESI) available: Characterisation
spectra for compounds 4–14 and data of glycosidase inhibition assays
for compounds 1, 2 and 3. See DOI: 10.1039/c2ob26732b
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3
Fig. 3 JHa–Hb values for syn and anti aminodiols obtained in the
addition of organometallic reagents to imines derived from D-glyceralde-
hyde acetonide.
coupling constants between protons Ha and Hb for anti amino-
diols obtained by the addition of organometallic reagents to
imines derived from D-glyceraldehyde acetonide ranged from 3.9
to 5.0 Hz while for the corresponding syn aminodiols extended
over the range 7.4 to 8.4 Hz (Fig. 3). So the stereochemistry of
compound 5 has been assigned to be anti on the basis of the
JHa–Hb coupling constant value (4.5 Hz)15 and mechanistic
considerations.
Fig. 2 Retrosynthetic approach to D-fagomine, D-epi-3,4-fagomine,
and D-epi-3-fagomine analogs.
Before RCM dialkenyl amine 5 was converted into the corre-
sponding N-benzyloxycarbonyl derivative 6 to avoid problems
derived from the presence of the free secondary amine.16 The
reaction of 5 with benzylchloroformate in diethyl ether at room
temperature and in the presence of diisopropylethylamine led to
the desired N-benzyloxycarbonyl derivative 6 which was isolated
in 73% yield. Subsequent RCM in dichloromethane at room
temperature using Grubbs first-generation catalyst afforded tetra-
hydropyridine 7 in 89% isolated yield (Scheme 1).
With diastereomerically pure 7 in hand we focused our atten-
tion on the trans dihydroxylation of the double bond by oxi-
dation followed by attack with HO−. To this end
diastereoselective epoxidation with mCPBA was first tested.
Epoxidation of 7 with mCPBA in dichloromethane at room
temperature gave preferentially syn epoxide 8 (dr = 64/36). With
the use of THF as a solvent syn diastereoselectivity was slightly
increased (dr = 76/24) but the reaction rate diminished and it
was necessary to increase reaction time and mCPBA concen-
tration to obtain the epoxide with a good yield. The same reac-
tion using more reactive peroxy-trifluoroacetic acid as an
oxidizing agent in dichloromethane at 0 °C led to the preferential
formation of syn epoxide 8 with the same yield and diastereo-
selectivity in only 0.5 h. Syn diastereoselectivity slightly
increased with decreasing temperature. Working at −20 °C syn
epoxide 8 with an 82/18 diastereomeric ratio was obtained in
82% yield after 0.75 h. An additional decrease of temperature
did not improve diastereoselectivity and resulted in lower yield
(Table 1).
Scheme 1 Synthesis of tetrahydropyridine 7.
derived from D-glyceraldehyde C gave access to the dialkenyl
amine with the desired configuration (Fig. 2).
Starting N-homoallylimine 4 was obtained from D-glyceralde-
hyde acetonide, which is readily available on a gram scale from
the inexpensive precursor D-mannitol according to previously
described procedures.12 Addition of vinylmagnesium bromide to
the imine 4 pre-complexed with BF3·OEt2 in diethyl ether at
−20 °C proceeded with total diastereoselectivity13 to afford di-
alkenyl amine 5 with anti configuration in 51% isolated yield
(Scheme 1).
It has been previously described that addition of organometal-
lic reagents to BF3·OEt2 precomplexed imines derived from
D-glyceraldehyde acetonide leads to the preferential formation of
the corresponding anti diastereoisomer.14 A Felkin–Anh-type
model has been proposed to explain this selectivity.14a In
addition it has been observed as a general trend that the vicinal
Then we turned our attention to epoxidation of 7 with diox-
iranes as oxidizing agents. With the use of dimethyldioxirane,
generated in situ by oxidation of acetone with oxone®, epoxida-
tion of compound 7 in acetonitrile–water at 0 °C was not
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Table 1 Epoxidation of compound 7
Epoxidation
Entry reagent
T
T
Yielda
(°C) (h) (%)
Solvent
8/9b
1
2
3
4
5
6
7
8
9
mCPBAc
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN/H2O
rt 24
rt 48
rt 48
80
55
90
86
64/36
76/24
76/24
76/24
82/18
80/20
50/50
30/70
30/70
mCPBAc
Scheme 2 Synthesis of syn epoxide 11.
mCPBAd
CF3COOOH
CF3COOOH
CF3COOOH
Oxone®/acetone
Oxone®/CF3COCF3 CH3CN/H2O
Oxone®/CF3COCF3 CH3CN/H2O −20 24
0 0.5
−20 0.75 82
−40
2
24
3
71
35
100
60
0
0
1
a Determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
as an internal standard. b Determined by HPLC using a Waters
Spherisorb column. c [mCPBA] = 0.03 mM. d [mCPBA] = 0.06 mM.
diastereoselective and an equimolecular mixture of syn and anti
epoxides was obtained in 35% yield after 24 h. Nevertheless
epoxidation of compound 7 under the same reaction conditions
using (trifluoromethyl)methyldioxirane, generated in situ by oxi-
dation of trifluoroacetone with oxone®, led to the preferential
formation of anti epoxide 9, and a 70/30 mixture of anti and syn
epoxides was obtained in nearly quantitative yield after 3 h. The
reaction at −20 °C gave essentially the same diastereomeric ratio
but the reaction yield was seriously deteriorated (60% after
24 h).
Scheme 3 Basic hydrolysis of syn epoxide 8.
It is known that in addition to 1,3-allylic strain coordination of
the peracid to a nearby group can direct the direction of epoxida-
tion of double bonds by mCPBA.17 In this case interaction of the
peroxyacid with the dioxolane ring directed preferential syn
epoxidation of compound 7. On the other hand epoxidation of 7
with (trifluoromethyl)methyldioxirane in CH3CN–H2O preferen-
tially occurred from the less hindered face and compound 9,
with the epoxide ring opposite to the C2 substituent, was
obtained in excess. To potentiate the peroxyacid–substrate inter-
action and maximize the formation of syn epoxide the dioxolane
ring was hydrolyzed. Epoxidation of the obtained diol 10 with
peroxy-trifluoroacetic acid in dichloromethane at 0 °C proceeded
exclusively syn to the 1,2-ethanediol substituent at C2 to give syn
epoxide 11 in 90% yield18 after 0.5 h (Scheme 2). With the use
of mCPBA in dichloromethane at room temperature diastereo-
selectivity was also total but an extended reaction time (24 h)
was necessary to obtain epoxide 11 with a high yield (81%).18
Epoxide ring opening was next studied. Treatment of 8 with
KOH in dioxane–water at 90 °C led to the non-regioselective
opening of the epoxide with concomitant hydrolysis of the
N-benzyloxycarbonyl group and an equimolecular mixture of
trans diols 12 and 13 was obtained (Scheme 3).
Scheme 4 Synthesis of D-fagomine analog 1.
dioxolane moiety led to the desired D-fagomine analog 1 in 77%
combined yield (Scheme 4).
The relative stereochemistry of compound 1 was determined
1
from 1D gradient selective ROESY experiments and H NMR
coupling constant data. Selective irradiation at the resonance fre-
quency of H4 produced significant intensification of the H2
signal and selective irradiation at the resonance frequency of H5a
produced significant intensification of the H3 signal. This behav-
ior was indicative of a 1,3-diaxial type arrangement between H4
and H2 and between H5a and H3. In addition the coupling con-
stants JH3–H4 (9.4 Hz) and JH2–H3 (9.4 Hz) were in agreement
with a trans-diaxial disposition of H2, H3 and H4 (Fig. 4).
In contrast under the same reaction conditions regioselectivity
of the oxirane ring opening in compound 9 was total and diol 13
was exclusively obtained. Subsequent hydrolysis of the
When epoxide 11 was treated with KOH in dioxane–water at
65 °C D-3,4-epi-fagomine analog 2 was obtained with a high
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Fig. 5 Selected 1H NMR coupling constant for relative stereochemistry
determination of compound 3.
Fig. 4 Selected 1H NMR data for relative stereochemistry determi-
nation of compound 1.
the cis proton at C3 should be in an axial disposition with a Jae
between H3–H4 of 3.0 Hz. The other coupling constant for this
proton (10.5 Hz) fully agreed with a trans-diaxial disposition of
H2 and H3 (Fig. 5).
The inhibitory activity of compounds 1, 2 and 3 towards com-
mercially available glycosidases20 was assayed. The analysis of
the preliminary enzyme assays by % inhibition showed that none
of the compounds reached 50% inhibition of any glycosidase
that was tested at a concentration of 143 μg mL−1 at the
enzymes’ optimal pH values. D-Fagomine analog 1 gave weak
inhibition of Bacillus stearothermophilus α-glucosidase and
D-3,4-epi-fagomine, and D-3-epi-fagomine analogs 2 and 3
weakly inhibited β-galactosidase. This lack of glycosidase inhi-
bition could be advantageous for therapeutic use of such com-
pounds as chaperones.2b
Scheme 5 Synthesis of D-3,4-epi-fagomine analog 2.
Summary
In summary, we have reported the synthesis of new D-fagomine,
D-3,4-epi-fagomine, and D-3-epi-fagomine analogs (1, 2 and 3,
Fig. 2) bearing a 1,2-dihydroxyethyl substituent on C2 from
D-glyceraldehyde acetonide as a common precursor. Intermediate
dialkenylamine 5 with the desired configuration was obtained by
stereoselective anti-vinylation of BF3·OEt2 precomplexed homo-
allylimine 4. N-Carbobenzoxylation and subsequent ring-closing
metathesis gave access to tetrahydropyridine 7 from which the
D-fagomine analog was obtained using diastereoselective anti-
epoxidation with (trifluoromethyl)methyldioxirane followed by
regioselective ring-opening as key steps. In turn the D-3,4-epi-
fagomine analog was obtained from tetrahydropyridine 10,
obtained by hydrolysis of 7, using as key steps diastereoselective
syn-epoxidation with peroxy-trifluoroacetic acid followed by
regioselective ring-opening. The key step in the synthesis of the
D-3-epi-fagomine analog was diastereoselective dihydroxylation
of tetrahydropyridine 7 opposite to the C2 substituent. The bio-
logical evaluation of these compounds as glycosidase inhibitors
showed no significant inhibitory activity which could be advan-
tageous for therapeutic use of such compounds as chaperones.
Scheme 6 Synthesis of D-3-epi-fagomine analog 3.
regioselectivity (Scheme 5, 2/1 = 95/5) and isolated in 78%
yield as its trifluoroacetate by column chromatography adding
trifluoroacetic acid (1% v/v) to the eluent.
Using compound 7 as a substrate we then proceeded to syn-
thesize D-3-epi-fagomine analog 3 (Scheme 6). Stereoselective
cis-dihydroxylation of tetrahydropyridine 7 under Upjohn con-
ditions19 with a catalytic amount of OsO4 (5 mol%) and an
excess of NMO as a cooxidant in acetone–water at room temp-
erature afforded diol 14 as a single diastereoisomer in 85% iso-
lated yield. This remarkably high diastereoselectivity of the
dihydroxylation would arise from the steric congestion at the top
face of 7 which would cause the preferred approach of OsO4
from the bottom face of the molecule. Hydrolysis of the dioxo-
lane moiety with trifluoroacetic acid led to tetrol 15 from which
compound 3 was obtained in 93% combined yield by N-deben-
zylation using Pd/C in methanol–water under a hydrogen
atmosphere.
Experimental section
All reagents for reactions were of analytical grade and were used
as obtained from commercial sources. Reactions were carried out
using anhydrous solvents. Whenever possible the reactions were
monitored by TLC. TLC was performed on precoated silica
gel polyester plates and products were visualized using UV
light (254 nm), anisaldehyde, ninhydrin or ethanolic phospho-
molybdic acid solution followed by heating. Column
The relative stereochemistry of compound 3 was confirmed
from H NMR coupling constant data. The H4 signal showed
three small coupling constants (3.9, 3.1 and 3.0 Hz) indicating
an equatorial disposition of the proton at C4. As a consequence
1
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chromatography was performed using silica gel (Kieselgel 60,
230–400 mesh).
inhibitor. Final absorbances were read at 405 nm using a Versa-
max microplate reader (Molecular Devices).
Melting points were determined in open capillaries using a
Gallenkamp capillary melting point apparatus and are not cor-
rected. FTIR spectra of oils were recorded as thin films on NaCl
plates and FTIR spectra of solids were recorded as nujol disper-
sions on NaCl plates using a Thermo Nicolet Avatar 360 FT-IR
spectrometer, νmax values expressed in cm−1 are given for the
main absorption bands. Optical rotations were measured on a
Jasco 1020 polarimeter at λ 589 nm and 25 °C in a cell with
10 cm path length, [α]D values are given in 10−1 deg cm g−1 and
(S,E)-N-((2,2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-en-
1-amine (4). Anhydrous MgSO4 (6.26 g, 52.0 mmol) and 90%
purity 3-buten-1-amine (2.17 g, 27.5 mmol) were added succes-
sively to a stirred solution of 2,3-O-isopropylidene-D-glyceralde-
hyde (3.39 g, 26.0 mmol) in dry Et2O (20 mL) at room
temperature. After stirring at room temperature for 2 h the reac-
tion mixture was filtered and evaporated. The resultant oil was
dissolved in dry Et2O and used in the next step without further
1
1
concentrations are given in g per 100 mL. H NMR and 13C
purification. Purity of the imine was determined as 70% by H
NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
NMR spectra were acquired on a Bruker AV-500 spectrometer, a
Bruker AV-400 spectrometer or a Bruker AV-300 spectrometer
1
standard. H NMR (400 MHz, CDCl3) δ 1.35 (s, 3H), 1.41 (s,
1
3H), 2.27–2.37 (m, 2H), 3.36–3.53 (m, 2H), 3.86 (dd, J = 8.4,
J = 6.4, 1H), 4.15 (dd, J = 8.4, J = 6.8, 1H), 4.52 (ddd, J = 6.8,
J = 6.4, J = 5.0, 1H), 5.01 (bd, J = 10.2, 1H), 5.03 (dddd, J =
17.1, J = 1.5, J = 1.5, J = 1.5, 1H), 5.72 (dddd, J = 17.1, J =
10.2, J = 6.8, J = 6.8, 1H), 7.58 (ddd, J = 5.0, J = 1.1, J = 1.1,
1H); 13C NMR (100 MHz, CDCl3) δ 25.3 (CH3), 26.4 (CH3),
34.6 (CH2), 60.2 (CH2), 67.4 (CH2), 76.9 (CH), 110.1 (C),
116.3 (CH2), 135.7 (CH), 163.4 (CH).
operating at 500, 400 or 300 MHz for H NMR and 125, 100 or
75 MHz for 13C NMR at room temperature unless otherwise
stated using a 5 mm probe. The chemical shifts (δ) are reported
in parts per million from tetramethylsilane with the solvent reso-
nance as the internal standard.21 Coupling constants (J) are
quoted in hertzs. The following abbreviations are used: s,
singlet; d, doublet; m, multiplet; bs, broad singlet; bd, broad
doublet, dd, doublet of doublets; ddd, doublet of doublets of
doublets; bdd, broad doublet of doublets; dddd, doublet of
doublet of doublets of doublets. Selective ge-1D ROESY exper-
iments were performed with gradient pulses in the mixing time.
Spectra were acquired at 300 K with optimized mixing times and
128 transients per spectrum using the Bruker standard selrogp
pulse program. Special precautions such as degassing of the
sample were not taken. High resolution mass spectra were
recorded using a Bruker Daltonics MicroToF-Q instrument from
methanolic solutions using the positive electrospray ionization
mode (ESI+). Microanalyses were performed using a Perkin-
Elmer 2400 CHNS elemental analyser. Gas chromatography ana-
lyses were performed using an HP 5890 instrument equipped
with a flame ionization detector using a Supelco SPB®-5 30 m
× 0.25 mm × 0.25 μm capillary column. HPLC chromatography
analyses were performed using a Waters 600 HPLC system
equipped with a 2996 photodiode array detector using a Waters
Spherisorb® 4.6 × 250 mm silica column (5 μm packing).
N-{(S)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]allyl}-3-buten-
1-amine (5). BF3·OEt2 (2.03 g, 1.8 mL, 14.3 mmol) was added
dropwise to a solution of 70% purity crude imine 4 (3.74 g,
14.3 mmol) in dry Et2O (20 mL) at −20 °C under argon. After
stirring for 10 min at the same temperature a 1.0 M solution of
vinylmagnesium bromide in THF (36 mL, 36.0 mmol) was
added. The reaction mixture was stirred overnight at −20 °C and
then quenched with water (6 mL). The mixture was vacuum
filtered through a pad of Celite®, the organic layer dried over
anhydrous MgSO4, filtered and concentrated in vacuo to afford
compound 5 as a single diastereoisomer as determined by GC.
GC conditions: Supelco SPB®-5; T1 = 100 °C, t1 = 1 min, v1 =
5 °C min−1, T2 = 150 °C, t2 = 1 min, v2 = 15 °C min−1, T3 =
200 °C; tR (5) = 8.43.23 Purification of the crude product by
silica gel column chromatography (eluent: Et2O–hexanes, 7 : 3)
yielded compound 5 (1.53 g, 51%) as an oil. [α]D25 = +14.8 (c
1
1.00, CHCl3); IR absorptions (pure) νmax 3325, 1641; H NMR
(400 MHz, CDCl3) δ 1.34 (s, 3H), 1.41 (s, 3H), 2.20–2.28 (m,
2H), 2.30–2.50 (bs, 1H), 2.53 (ddd, J = 11.5, J = 6.8, J = 6.8,
1H), 2.74 (ddd, J = 11.5, J = 7.0, J = 7.0, 1H), 3.18 (dd, J = 8.2,
J = 4.5, 1H), 3.88 (dd, J = 8.2, J = 6.9, 1H), 3.98 (dd, J = 8.2,
J = 6.6, 1H), 4.14 (ddd, J = 6.9, J = 6.6, J = 4.5, 1H), 5.03
(dddd, J = 10.2, J = 2.1, J = 1.1, J = 1.1, 1H), 5.09 (dddd, J =
17.1, J = 2.1, J = 1.5, J = 1.5, 1H), 5.22 (ddd, J = 17.1, J = 1.8,
J = 0.9, 1H), 5.25 (ddd, J = 10.4, J = 1.8, J = 0.6, 1H), 5.63
(ddd, J = 17.1, J = 10.4, J = 8.2, 1H), 5.77 (dddd, J = 17.1, J =
10.2, J = 6.8, J = 6.8, 1H); 13C NMR (100 MHz, CDCl3) δ 25.0
(CH3), 26.2 (CH3), 34.0 (CH2), 46.2 (CH2), 62.9 (CH), 65.8
(CH2), 77.9 (CH), 109.1 (C), 116.4 (CH2), 118.6 (CH2), 136.1
(CH), 136.2 (CH); HRMS (FAB+) calcd for C12H22NO2 (MH+)
212.1645; found 212.1642.
Glycosidase inhibition assays
Glycosidase assays were conducted as described by Watson
et al.22 using p-nitrophenyl substrates. All enzymes and para-
nitrophenyl substrates were purchased from Sigma, with the
exception of β-mannosidase which came from Megazyme.
Assays were carried out in triplicate, and the values given are
means of the three replicates per assay. Enzymes were assayed at
27 °C in 0.1 M citric acid–0.2 M disodium hydrogen phosphate
buffers (McIlvaine) at the optimum pH for the enzyme. The
incubation mixture consisted of a 10 μL enzyme solution, 10 μL
of a 1 mg mL−1 aqueous solution of the sample and 50 μl of the
appropriate 5 mM para-nitrophenyl substrate made up in buffer
at the optimum pH for the enzyme. The reactions were stopped
by addition of 70 μL 0.4 M glycine (pH 10.4) during the expo-
nential phase of the reaction, which had been determined at the
beginning using uninhibited assays in which water replaced the
N-Benzyloxycarbonyl-N-{(S)-1-[(S)-2,2-dimethyl-1,3-dioxolan-
4-yl]allyl}-3-buten-1-amine (6). DIPEA (2.58 g, 20.0 mmol) and
95% benzylchloroformate (1.79 g, 10.0 mmol) were added to a
solution of compound 5 (1.41 g, 6.7 mmol) in CH2Cl2 (130 mL)
at room temperature and stirring was continued for 2 h at the
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same temperature. The reaction mixture was washed with water
and the organic extract was dried over anhydrous MgSO4,
filtered and concentrated in vacuo. Purification of the crude
product by silica gel column chromatography (eluent Et2O–
hexanes, 1 : 4) yielded compound 6 (1.69 g, 73%) as an oil.
[α]D25 = −20.2 (c 1.00, CHCl3); IR absorptions (pure) νmax 1701,
hexanes, 1 : 1) gave diastereomerically pure compound
8
(124 mg, 59%) as an oil. Oil [α]D25 = −93.6 (c 1.01, CHCl3); IR
absorptions (pure) νmax 1703; 1H NMR (400 MHz, CDCl3,
333 K) δ 1.38 (s, 3H), 1.45 (s, 3H), 1.80–1.93 (m, 1H),
1.93–2.02 (m, 1H), 2.86 (bdd, J = 11.9, J = 11.9, 1H),
3.29–3.38 (m, 1H), 3.42 (dd, J = 4.2, J = 4.2, 1H), 3.72–3.90
(m, 1H), 3.90–4.04 (m, 2H), 4.30 (ddd, J = 9.2, J = 5.7, J = 5.7,
1H), 4.38–4.61 (m, 1H), 5.11 (d, J = 12.4, 1H), 5.15 (d, J =
12.4, 1H), 7.23–7.44 (m, 5H); 13C NMR (100 MHz, CDCl3,
333 K) δ 25.0 (CH2), 25.6 (CH3), 26.9 (CH3), 35.1 (CH2), 51.4
(CH), 51.9 (CH), 52.3 (CH), 67.0 (CH2), 67.6 (CH2), 74.2 (CH),
109.5 (C), 127.9 (CH), 128.1 (CH), 128.5 (CH), 136.5 (C),
155.4 (C); HRMS (FAB+) calcd for C18H23NO5Na (MNa+)
356.1468; found 356.1465.
1
1641; H NMR (400 MHz, CDCl3, 333 K) δ 1.31 (s, 3H), 1.39
(s, 3H), 2.21–2.40 (m, 2H), 3.15–3.39 (m, 2H), 3.71 (dd, J =
8.4, J = 6.3, 1H), 3.97 (dd, J = 8.4, J = 6.4, 1H), 4.23–4.44 (m,
2H), 5.00–5.08 (m, 2H), 5.11 (d, J = 13.1, 1H), 5.14 (d, J =
13.1, 1H), 5.22–5.28 (m, 2H), 5.71 (dddd, J = 17.1. J = 10.3.
J = 6.9. J = 6.9, 1H), 5.99 (ddd, J = 17.1. J = 10.6. J = 6.4, 1H),
7.24–7.39 (m, 5H); 13C NMR (100 MHz, CDCl3, 333 K) δ 25.4
(CH3), 26.6 (CH3), 34.0 (CH2), 45.9 (CH2), 61.7 (CH), 67.2
(CH2), 67.3 (CH2), 76.8 (CH), 109.8 (C), 116.4 (CH2), 118.6
(CH2), 127.8 (CH), 128.0 (CH), 128.4 (CH), 133.5 (CH), 135.3
(CH), 136.7 (C), 156.0 (C); HRMS (FAB+) calcd for
C20H27NO4Na (MNa+) 368.1832; found 368.1819.
(1R,2R,6S)-3-Benzyloxycarbonyl-2-[(S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-7-oxa-3-azabicyclo[4.1.0]heptane (9). A 0.1 M solution
of aqueous Na2EDTA (0.25 mL 0.025 mmol) and 1,1,1-trifluor-
oacetone (1.5 g, 13.4 mmol) were added successively to a sol-
ution of 7 (400 mg, 1.26 mmol) in CH3CN (15 mL) at 0 °C.
Then a mixture of NaHCO3 (730 mg, 8.80 mmol) and oxone®
(3.5 g, 5.7 mmol) as a solid was added slowly over a period of
1 h at 0 °C. After being stirred for 3 h at 0 °C, the solid material
was removed by filtration and the filtrate was quenched with
water (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated in vacuo to afford a 30/70 mixture of
diastereomeric epoxides 8 and 9 as determined by HPLC. HPLC
conditions: Waters Spherisorb® silica column; mobile phase =
n-hexane–i-propanol, 97 : 3; flow rate 1 mL min−1, UV detection
at 215 nm; tR (8) = 10.7 min; tR (9) = 13.5 min. Purification of
the diastereomeric mixture by silica gel column chromatography
(eluent: Et2O–hexanes, 1 : 1) gave diastereomerically pure com-
pound 9 (261 mg, 63%) as an oil. [α]D25 = −79.5 (c 1.03,
(S)-1-Benzyloxycarbonyl-6-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-1,2,3,6-tetrahydropyridine (7). A solution of 6 (1.49 g,
4.3 mmol) in CH2Cl2 (80 mL) was slowly added to a solution of
Grubbs first generation catalyst (350 mg, 0.43 mmol) in CH2Cl2
(60 mL) at room temperature. The resulting solution was vigor-
ously stirred for 2 h at the same temperature and then evaporated
in vacuo. Purification of the residue by silica gel column chrom-
atography (eluent: Et2O–hexanes, 3 : 7) yielded compound 7
(1.21 g, 89%) as an oil. [α]D25 = −220.9 (c 1.00, CHCl3); IR
1
absorptions (pure) νmax 1701, 1656; H NMR (300 MHz, C6D6,
333 K) δ 1.28 (s, 3H), 1.40 (s, 3H), 1.50–1.62 (m, 1H),
1.89–2.11 (m, 1H), 2.80–2.95 (m, 1H), 3.75–3.88 (m, 1H),
3.88–4.04 (m, 1H), 4.04–4.20 (m, 2H), 4.52–4.77 (m, 1H), 5.09
(d, J = 12.4, 1H), 5.17 (d, J = 12.4, 1H), 5.63–5.76 (m, 1H),
5.83 (bd, J = 10.2, 1H), 7.02–7.31 (m, 5H); 13C NMR (75 MHz,
C6D6, 333 K) δ 24.9 (CH3), 25.8 (CH2), 27.0 (CH2), 38.8
(CH3), 54.9 (CH2), 67.4 (CH), 67.5 (CH), 78.6 (CH2), 109.7
(C), 125.9 (CH), 126.8 (CH), 128.1 (CH), 128.3 (CH), 128.7
(CH), 137.5 (C), 155.5 (C); HRMS (FAB+) calcd for
C18H23NO4Na (MNa+) 340.1519; found 340.1536.
1
CHCl3); IR absorptions (pure) νmax 1701; H NMR (300 MHz,
CDCl3, 333 K) δ 1.36 (s, 3H), 1.46 (s, 3H), 1.82–1.93 (m, 1H),
1.97–2.12 (m, 1H), 2.86–3.06 (m, 1H), 3.25–3.35 (m, 2H),
3.75–3.86 (m, 1H), 3.91 (dd, J = 8.6, J = 6.2, 1H), 4.07 (dd, J =
8.6, J = 6.6, 1H), 4.26–4.38 (ddd, J = 7.0, J = 6.6, J = 6.2, 1H),
4.52 (d, J = 7.0, 1H), 5.12 (d, J = 12.5, 1H), 5.17 (d, J = 12.5,
1H), 7.23–7.44 (m, 5H); 13C NMR (125 MHz, C6D6, 348 K) δ
22.1 (CH2), 25.1 (CH3), 26.3 (CH3), 36.4 (CH2), 49.7 (CH),
49.9 (CH), 54.1 (CH), 67.2 (CH2), 67.5 (CH2), 75.6 (CH), 109.9
(C), 128.3 (CH), 137.2 (C), 156.0 (C); HRMS (FAB+) calcd for
C18H23NO5Na (MNa+) 356.147468; found 356.1485.
(1S,2R,6R)-3-Benzyloxycarbonyl-2-[(S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-7-oxa-3-azabicyclo[4.1.0]heptane
(8). Trifluoroacetic
anhydride (609 mg, 2.90 mmol) was added dropwise to a stirred
suspension of urea–hydrogen peroxide (893 mg, 9.50 mmol)
and Na2CO3 (667 mg, 6.30 mmol) in CH2Cl2 (40 mL) at 0 °C.
The suspension was vigorously stirred for 10 min at 0 °C and
cooled down to −20 °C prior to the addition of a solution of 7
(200 mg, 0.63 mmol) in CH2Cl2 (10 mL). After stirring for
45 min at −20 °C the reaction was quenched by careful addition
of sat. aq. NaHCO3 (50 mL) and 40% aqueous NaHSO3
(20 mL) and vigorously stirred for a further 15 min. The aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic extracts were dried over anhydrous MgSO4, filtered and
concentrated in vacuo to afford an 82/18 mixture of diastereo-
meric epoxides 8 and 9 as determined by HPLC. HPLC con-
ditions: Waters Spherisorb® silica column; n-hexane–i-propanol,
97 : 3; flow rate 1 mL min−1, UV detection at 215 nm; tR (8) =
10.7 min; tR (9) = 13.5 min. Purification of the diastereomeric
mixture by silica gel column chromatography (eluent: Et2O–
(S)-1-[(S)-1-Benzyloxycarbonyl-1,2,5,6-tetrahydropyridin-2-
yl]-1,2-ethanediol
(10). Trifluoroacetic acid (457 mg,
4.00 mmol) was added to a solution of 7 (300 mg, 0.94 mmol)
in MeOH–H2O 4 : 1 (8 mL) at room temperature. After being
stirred overnight at room temperature the solvent was removed
in vacuo. Purification of the obtained residue purified by silica
gel column chromatography (eluent: Et2O–EtOAc, 6 : 4) gave
compound 10 (245 mg, 94%) as an oil. [α]D25 = −137.9 (c 0.87,
1
CHCl3); IR absorptions (pure) νmax 3396, 1676, 1652; H NMR
(400 MHz, CDCl3, 333 K) δ 1.99 (ddd, J = 17.5, J = 3.4, J =
3.4, 1H), 2.17–2.30 (m, 1H), 2.73 (bs, 2H), 2.94 (ddd, J = 13.3,
J = 12.0, J = 3.4, 1H), 3.56–3.67 (m, 3H), 4.17 (dd, J = 13.2,
J = 5.4, 1H), 4.41 (bd, J = 7.2, 1H), 5.16 (d, J = 12.4, 1H), 5.20
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9278–9286 | 9283

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(d, J = 12.4, 1H), 5.92–6.04 (m, 2H), 7.29–7.40 (m, 5H); 13C
NMR (100 MHz, CDCl3, 333 K) δ 24.7 (CH2), 38.8 (CH2), 53.7
(CH), 63.0 (CH2), 67.7 (CH2), 73.9 (CH), 125.9 (CH), 126.4
(CH), 127.9 (CH), 128.3 (CH), 128.7 (CH), 136.4 (C); HRMS
(FAB+) calcd for C15H19NO4Na (MNa+) 300.1206; found
300.1223.
HRMS (FAB+) calcd for C10H20NO4 (MH+) 218.1387; found
218.1387. Compound 13: M.p. = 120–122 °C; [α]D25 = +17.3 (c
1
0.50, CHCl3); IR absorptions (pure) νmax 3490, 1206; H NMR
(400 MHz, CDCl3) δ 1.37 (s, 3H), 1.45 (s, 3H), 1.46 (dddd, J =
12.6, J = 12.6, J = 12.6, J = 4.5, 1H), 1.96 (dddd, J = 12.6, J =
4.8, J = 2.5, J = 2.5, 1H), 2.42 (bs, 3H), 2.56 (dd, J = 9.0 J =
6.4, 1H), 2.63 (ddd, J = 12.6, J = 12.6, J = 2.5, 1H), 3.03 (ddd,
J = 12.6, J = 4.5, J = 2.5, 1H), 3.23 (dd, J = 9.0, J = 9.0, 1H),
3.44–3.57 (m, 1H), 3.98 (dd, J = 8.2, J = 6.4, 1H), 4.10 (dd, J =
8.2, J = 6.4, 1H), 4.18 (ddd, J = 6.4, J = 6.4, J = 6.4, 1H); 13C
NMR (100 MHz, D2O) δ 23.8 (CH3), 25.1 (CH3), 31.9 (CH2),
42.8 (CH2), 59.8 (CH), 63.7 (CH2), 73.4 (CH), 73.9 (CH), 75.2
(CH), 109.4 (C); HRMS (FAB+) calcd for C10H19NO4Na
(MNa+) 240.1206; found 240.1218.
(S)-1-[(1S,2R,6R)-3-Benzyloxycarbonyl-7-oxa-3-azabicyclo[4.1.0]-
heptan-2-yl]-1,2-ethanediol
(11). Trifluoroacetic
anhydride
(714 mg, 3.40 mmol) was added dropwise to a stirred suspen-
sion of urea–hydrogen peroxide (1.35 g, 11.00 mmol) and
Na2CO3 (614 mg, 7.40 mmol) in CH2Cl2 (50 mL) at 0 °C. The
suspension was vigorously stirred for 10 min at 0 °C and a solu-
tion of 10 (200 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added.
After stirring for 30 min at 0 °C the reaction was quenched by
careful addition of sat. aq. NaHCO3 (50 mL) and 40% aqueous
NaHSO3 (20 mL) and vigorously stirred for a further 15 min.
The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated in vacuo to afford crude epoxide 11 as
a single diastereoisomer as determined by HPLC. HPLC con-
ditions: Waters Spherisorb® silica column; mobile phase =
n-hexane–EtOH, 9 : 1; flow rate 1 mL min−1, UV detection at
215 nm; tR (11) = 12.6 min. Purification of the crude product by
silica gel column chromatography (eluent Et2O–EtOAc, 3 : 7)
yielded compound 11 (169 mg, 80%) as an oil. [α]D25 = −86.2
(c 0.40, CHCl3); IR absorptions (pure) νmax 3343, 1692; 1H NMR
(400 MHz, CDCl3, 333 K) δ 1.91 (ddd, J = 14.6, J = 12.8, J =
4.8, 1H), 1.99 (dddd, J = 14.6, J = 3.7, J = 2.0, J = 2.0, 1H),
2.63 (bd, J = 7.5, 1H), 2.87 (ddd, J = 13.8, J = 12.3, J = 3.6,
1H), 3.30 (bs, 1H), 3.36–3.44 (m, 1H), 3.47–3.70 (m, 3H),
3.74–3.99 (m, 2H), 4.37 (ddd, J = 9.3, J = 4.5, J = 1.2, 1H),
5.08–5.18 (m, 2H), 7.27–7.44 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 25.1 (CH2), 35.2 (CH2), 50.9 (CH), 51.7 (CH), 52.1
(CH), 62.3 (CH2), 68.0 (CH2), 70.0 (CH), 127.9 (CH), 128.4
(CH), 128.6 (CH), 136.0 (C), 156.3 (C); HRMS (FAB+) calcd
for C15H19NO5Na (MNa+) 316.1155; found 316.1176.
(2R,3R,4R)-2-[(S)-1,2-Dihydroxyethyl]piperidine-3,4-diol (1).
A solution of 9 (200 mg, 0.60 mmol) in dioxane (10 mL) and
0.3 M aqueous KOH (65 mL) was heated at 90 °C for 48 h. The
solvent was removed in vacuo and the residue was dissolved in
water (5 mL) and neutralized by addition of 2 M HCl. After the
addition of an additional amount of 2 M HCl (3 mL) the reaction
mixture was stirred overnight at room temperature. The solvent
was removed in vacuo, the residue dissolved in water (15 mL)
and the aqueous solution washed with CH2Cl2 (3 × 15 mL).
Removal of the solvent left the hydrochloride salt of compound
1 which was chromatographed using Dowex 50WX8-200 resin
to give the free amine 1 (82 mg, 77% yield) as an oil. [α]2D5
=
1
+16.9 (c 0.68, H2O); IR absorptions (pure) νmax 3384; H NMR
(400 MHz, D2O) δ 1.46 (dddd, J = 12.9, J = 12.9, J = 12.9, J =
4.5, 1H), 2.00 (dddd, J = 12.9, J = 4.9, J = 2.5, J = 2.5, 1H),
2.64 (ddd, J = 12.9, J = 12.9, J = 2.5, 1H), 2.73 (dd, J = 10.0
J = 3.5, 1H), 3.05 (ddd, J = 12.9, J = 4.5, J = 2.5, 1H), 3.32 (dd,
J = 10.0, J = 10.0, 1H), 3.53 (ddd, J = 12.9, J = 10.0, J = 4.5,
1H), 3.69 (dd, J = 11.9, J = 7.2, 1H), 3.75 (dd, J = 11.9, J = 3.2,
1H), 4.01 (ddd, J = 7.2, J = 3.5, J = 3.2, 1H); 13C NMR
(100 MHz, D2O) δ 32.0 (CH2), 43.0 (CH2), 62.1 (CH), 62.4
(CH2), 72.2 (CH), 73.1 (CH), 73.3 (CH); HRMS (FAB+) calcd
for C7H15NO4Na (MNa+) 200.0893; found 200.0889.
(2S,3S,4S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]piperidine-
3,4-diol (12) and (2S,3S,4S)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]piperidine-3,4-diol (13). A solution of 8 (110 mg, 0.33 mmol)
in dioxane (6 mL) and 0.3 M aqueous KOH (35 mL) was heated
at 90 °C for 72 h. The solvent was removed in vacuo, the residue
dissolved in CH2Cl2 (2 mL) and the solvent was removed
in vacuo again to give an equimolecular mixture of diastereo-
meric 12 and 13. Purification of the diastereomeric mixture by
silica gel column chromatography (eluent: EtOAc–MeOH, 1 : 1)
yielded 10 mg (14%) of diastereomerically pure compound 12 as
a white solid and 32 mg (44%) of diastereomerically pure com-
(2R,3S,4R)-2-[(S)-1,2-Dihydroxyethyl]piperidine-3,4-diol trifl-
uoroacetate salt (2·TFA). A solution of 11 (130 mg, 0.44 mmol)
in dioxane (10 mL) and 0.3 M aqueous KOH (40 mL) was
heated at 65 °C for 20 h. The solvent was removed in vacuo and
the residue was dissolved in water (5 mL). The aqueous solution
was washed with CH2Cl2 (3 × 10 mL) and chromatographed
using Dowex 50WX8-200 resin to give a 95/5 mixture of diaster-
eomeric compounds 2 and 1. Purification of the diastereomeric
mixture by silica gel column chromatography (eluent: EtOAc–
MeOH, 1 : 1 with 1% v/v TFA) yielded diastereomerically pure
trifluoroacetate 2·TFA (100 mg, 78%) as an oil. [α]D25 = −9.4 (c
0.95, CH3OH); IR absorptions (pure) νmax 3365, 1675; 1H NMR
(300 MHz, D2O) δ 1.82 (dddd, J = 14.6, J = 3.2, J = 3.2, J =
3.2, 1H), 2.14–2.33 (m, 1H), 3.24–3.36 (m, 2H), 3.58 (dd, J =
6.1, J = 1.1, 1H), 3.75–3.80 (m, 2H), 3.96–4.05 (m, 2H),
4.12–4.16 (m, 1H); 13C NMR (75 MHz, D2O) δ 23.1 (CH2),
39.4 (CH2), 55.0 (CH), 62.2 (CH2), 64.7 (CH), 65.4 (CH), 68.9
(CH); HRMS (FAB+) calcd for C7H16NO4 (MH+ − CF3CO2H)
178.1074; found 178.1074.
1
pound 13 as a white solid. Compound 12: H NMR (400 MHz,
CDCl3) δ 1.36 (s, 3H), 1.42 (s, 3H), 1.53 (dddd, J = 14.2, J =
3.3 J = 3.3 J = 3.3, 1H), 1.59 (bs, 3H), 1.94–2.01 (m, 1H), 2.83
(ddd, J = 12.5 J = 5.0, J = 3.3, 1H), 2.96 (ddd, J = 12.5, J =
12.5, J = 3.3, 1H), 3.13 (dd, J = 6.0 J = 2.0, 1H), 3.68 (dd, J =
3.8, J = 2.0, 1H), 3.88 (dd, J = 8.2, J = 7.2, 1H), 4.00 (ddd, J =
3.8, J = 3.3, J = 3.3, 1H), 4.10 (dd, J = 8.2, J = 6.2, 1H), 4.17
(ddd, J = 7.2, J = 6.2, J = 6.0, 1H); 13C NMR (100 MHz,
CDCl3) δ 25.5 (CH3), 26.8 (CH3), 29.4 (CH2), 40.8 (CH2), 56.1
(CH), 67.1 (CH2), 68.6 (CH), 69.5 (CH), 77.0 (CH), 100.1 (C);
9284 | Org. Biomol. Chem., 2012, 10, 9278–9286
This journal is © The Royal Society of Chemistry 2012

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yield) as an oil. [α]D25 = +24.6 (c 0.92, H2O); IR absorptions
(pure) νmax 3385; 1H NMR (400 MHz, D2O) δ 1.67–1.80
(m, 1H), 1.85 (dddd, J = 14.7, J = 3.9, J = 3.1, J = 3.0, 1H),
2.80–2.92 (m, 2H), 3.08 (dd, J = 10.1, J = 4.1, 1H), 3.67
(dd, J = 10.1, J = 3.0, 1H), 3.70 (dd, J = 12.0, J = 6.8, 1H), 3.75
(dd, J = 12.0, J = 3.3, 1H), 3.96 (ddd, J = 6.8, J = 4.1, J = 3.3,
1H), 4.07 (ddd, J = 3.9, J = 3.1, J = 3.0, 1H); 13C
NMR (100 MHz, D2O) δ 29.6 (CH2), 38.8 (CH2), 56.9
(CH), 62.5 (CH2), 67.4 (CH), 68.9 (CH), 71.36 (CH);
HRMS (FAB+) calcd for C7H16NO4 (MH+) 178.1074; found
178.1076.
(2S,3R,4S)-1-Benzyloxycarbonyl-2-[(S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]piperidine-3,4-diol (14). NMO (222 mg, 1.90 mmol)
and a solution of 2.5 wt% OsO4–H2O (0.36 mL, 0.03 mmol)
were added successively to a solution of 7 (300 mg, 0.94 mmol)
in acetone–H2O 3 : 2 (10 mL) and the reaction mixture was
stirred for 22 h at room temperature. Then an excess of Na2SO3
was added and stirring was continued for an additional 30 min.
The solid material was removed by filtration and acetone was
evaporated in vacuo. The obtained residue was diluted by the
addition of water (50 mL) and the aqueous solution washed with
Et2O (3 × 15 mL). The combined organic extracts were dried
over anhydrous MgSO4, filtered and concentrated in vacuo to
1
afford crude 14 as a single diastereoisomer as determined by H
Acknowledgements
NMR. Purification of the residue by silica gel column chromato-
graphy (eluent: EtOAc–hexanes, 8 : 2) yielded diastereomerically
pure compound 14 (280 mg, 85% yield) as a white solid. M.p. =
113–116 °C; [α]D25 = −29.5 (c 1.10, CHCl3); IR absorptions
Financial support from the Government of Aragón (GA E-102)
is acknowledged. JAD thanks the CSIC-JAE program for a pre-
doctoral fellowship.
1
(pure) νmax 3343, 1692; H NMR (400 MHz, CDCl3, 333K) δ
1.31 (s, 3H), 1.41 (s, 3H), 1.59–1.70 (m, 1H), 1.82 (dddd, J =
12.6, J = 12.5, J = 12.5, J = 4.8, 1H), 2.38 (bs, 2H), 2.91 (bdd,
J = 13.2, J = 12.6, 1H), 3.76 (dd, J = 8.0, J = 6.8, 1H), 3.96 (dd,
J = 8.0, J = 6.5, 1H), 3.96–4.05 (m, 1H), 4.05–4.17 (m, 1H),
4.13–4.26 (m, 2H), 4.38 (bd, J = 8.1, 1H), 5.12 (d, J = 13.2,
1H), 5.15 (d, J = 13.2, 1H), 7.22–7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3, 333 K) δ 25.4 (CH3), 26.7 (CH3), 27.9
(CH2), 39.7 (CH2), 60.0 (CH), 67.1 (CH), 67.6 (CH2), 67.8
(CH2), 67.9 (CH), 74.0 (CH), 110.2 (C), 127.8 (CH), 128.0
(CH), 128.5 (CH), 136.6 (C), 156.3 (C); HRMS (FAB+) calcd
for C18H25NO6Na (MNa+) 374.1574; found 374.1576. Anal
calcd for C18H25NO6 C 61.52%, H 7.17%, N 3.99%; found
C 61.40%, H 7.32%, N 3.39%.
Notes and references
1 Some reviews on the subject are: (a) A. E. Stütz, Iminosugars as Glycosi-
dase Inhibitors: Nojirimycin and Beyond, Wiley-VCH, Weinheim,
Germany, 1999; (b) N. Asano, R. J. Nash, R. J. Molyneux and
G. W. J. Fleet, Tetrahedron: Asymmetry, 2000, 11, 1645; (c) N. Asano,
Glycobiology, 2003, 13, 93R.
2 For recent reviews on this subject see: (a) P. Compain and O. R. Martin,
Iminosugars: From Synthesis to Therapeutic Applications, John Wiley,
Chichester, 2007; (b) R. J. Nash, A. Kato, C. Y. Yu and G. W. J. Fleet,
Future Med. Chem., 2011, 3, 1513; (c) G. Horne and F. X. Wilson, Prog.
Med. Chem., 2011, 50, 135; (d) D. S. Alonzi and T. D. Butters, Chimia,
2011, 65, 35; (e) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams and
R. Storer, Drug Discovery Today, 2011, 16, 107.
3 M. Koyama and S. Sakamura, Agric. Biol. Chem., 1974, 38, 1111.
4 See: S. Amézqueta, E. Galán, E. Fuguet, M. Carrascal, J. Abián and
J. L. Torres, Anal. Bioanal. Chem., 2012, 402, 1953 and references
herein.
5 (a) H. Nojima, I. Kimura, F. J. Chen, Y. Sugihara and M. Haruno, J. Nat.
Prod., 1998, 61, 397; (b) S. Taniguchi, N. Asano, F. Tomino and I. Miwa,
Horm. Metab. Res., 1998, 30, 679.
(2R,3R,4S)-1-Benzyloxycarbonyl-2-[(S)-1,2-dihydroxyethyl]-
piperidine-3,4-diol (15). Trifluoroacetic acid (292 mg,
1.60 mmol) was added to a solution of 14 (250 mg, 0.71 mmol)
in MeOH–H2O 3 : 1 (10 mL) at room temperature. After being
stirred overnight at room temperature the solvent was removed in
vacuo. The obtained residue was dissolved in water (25 mL) and
the aqueous solution washed with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated in vacuo to afford 214 mg of crude 15
6 L. Gómez, E. Molinar-Toribio, M. A. Calvo-Torras, C. Adelantado,
M. E. Juan, J. M. Planas, X. Cañas, C. Lozano, S. Pumarola, P. Clapés
and J. L. Torres, Br. J. Nutr., 2012, 107, 1739.
7 A. Kato, N. Asano, H. Kizu and K. Matsui, J. Nat. Prod., 1997, 60, 312.
8 Some recent syntheses of fagomine are: (a) J. Désiré, P. J. Dransfield,
P. M. Gore and M. Shipman, Synlett, 2001, 1329; (b) J. A. Castillo,
J. Calveras, J. Casas, M. Mitjans, M. P. Vinardell, T. Parella, T. Inoue,
G. A. Sprenger, J. Joglar and P. Clapés, Org. Lett., 2006, 8, 6067;
(c) H. Yokoyama, H. Ejiri, M. Miyazawa, S. Yamaguchi and Y. Hirai,
Tetrahedron: Asymmetry, 2007, 18, 852; (d) L. Bartalia, D. Scarpia,
A. Guarnaa, C. Prandib and E. G. Occhiato, Synlett, 2009, 913; Erratum:
Synlet, 2010, 239; (e) L. Babich, L. J. C. van Hemert, A. Bury,
A. F. Hartog, P. Falcicchio, J. van der Oost, T. van Herk, R. Wever and
F. P. J. T. Rutjes, Green Chem., 2011, 13, 2895; (f) J. Y. Kim, Y. Mua,
X. Jin, S. H. Park, V. T. Pham, D. K. Song, K. Y. Lee and W. H. Ham,
Tetrahedron, 2011, 67, 9426.
9 For synthesis of fagomine diastereoisomers see: (a) Y. Banba, C. Abe,
H. Nemoto, A. Kato, I. Adachi and H. Takahata, Tetrahedron: Asymmetry,
2001, 12, 817; (b) H. Takahata, Y. Banba, H. Ouchi, H. Nemoto, A. Kato
and I. Adachi, J. Org. Chem., 2003, 68, 3603; (c) E. Ciliberti,
R. Galvani, F. Gramazio, S. Haddas, F. Leonelli, P. Passacantilli and
G. Piancatelli, Eur. J. Org. Chem., 2007, 1463; (d) N. Kumari,
B. G. Reddy and Y. D. Vankar, Eur. J. Org. Chem., 2009, 160;
(e) L. Bartali, A. Casini, A. Guarna, E. G. Occhiato and D. Scarpi,
Eur. J. Org. Chem., 2010, 5831; (f) R. W. Bates and P. S. Ng, Tetra-
hedron Lett., 2011, 52, 2969; (g) P. K. Kundu and S. K. Ghosh, Tetra-
hedron: Asymmetry, 2011, 22, 1090.
1
which was used in the next step without further purification. H
NMR (300 MHz, D2O, 333 K) δ 1.97–2.18 (m, 1H), 2.19 (dddd,
J = 12.6, J = 12.2, J = 12.2, J = 5.0, 1H), 3.32 (ddd, J = 14.1,
J = 12.6, J = 3.4, 1H), 3.80 (dd, J = 11.9, J = 6.9, 1H), 3.94 (dd,
J = 11.9, J = 3.0, 1H), 4.31 (ddd, J = 10.0, J = 6.9, J = 3.0, 1H),
4.37–4.58 (m, 2H), 4.58–4.71 (m, 2H), 5.40–5.68 (m, 2H),
7.73–7.91 (m, 5H); 13C NMR (75 MHz, D2O, 333 K) δ 26.8
(CH2), 39.6 (CH2), 59.9 (CH), 63.8 (CH2), 66.6 (CH), 67.5
(CH), 68.5 (CH2), 69.1 (CH), 128.2 (CH), 128.8 (CH), 129.2
(CH), 136.8 (C), 157.8 (C).
(2R,3R,4S)-2-[(S)-1,2-Dihydroxyethyl]piperidine-3,4-diol (3).
A solution of crude 15 (214 mg) obtained as described above in
MeOH–H2O 3 : 1 (20 mL) was hydrogenated with molecular
hydrogen for 7 h at atmospheric pressure and room temperature
and in the presence of 10% Pd/C (30 mg) as a catalyst. The cata-
lyst was removed by filtration through a Celite® path and the
solvent evaporated in vacuo to afford 3 (117 mg, 93% combined
10 For synthesis of other fagomine analogues see: (a) F. Degiorgis,
M. Lombardo and C. Trombini, Org. Prep. Proced. Int., 1997, 29, 485;
(b) M. Sugiyama, Z. Hong, P. H. Liang, S. M. Dean, L. J. Whalen,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9278–9286 | 9285

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W. A. Greenberg and C. H. Wong, J. Am. Chem. Soc., 2007, 124, 14811;
(c) R. Fu, Y. Dua, Z. Y. Li, W. X. Xu and P. Q. Huang, Tetrahedron,
2009, 65, 9765.
diastereoisomers. Major compound JHa–Hb = 4.5 Hz, minor compound
JHa–Hb = 8.3 Hz.
16 For a helpful review discussing RCM reactions with amine containing
compounds see: P. Compain, Adv. Synth. Catal., 2007, 349, 1829.
17 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
11 For recent reviews see: (a) S. [Bas] A. M. W. van den Broek,
S. A. Meeuwissen, F. L. Delft and F. P. J. T. Rutjes, Natural Products
Containing Medium-Sized Nitrogen Heterocycles Synthesized by Ring-
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H. C. M. Vosloo, L. Delaude and A. Demonceau, Beilstein J. Org.
Chem., 2011, 7, 699; (d) I. Dragutan, V. Dragutana and A. Demonceau,
RSC Adv., 2012, 2, 719.
18 Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as
an internal standard.
19 V. VanRheenen, R. C. Kelly and D. Y. Cha, Tetrahedron Lett., 1976, 17,
1973.
20 α-D-Glucosidase from yeast (Saccharomyces cerevisiae), α-D-glucosidase
from Bacillus stearothermophilus, α-D-glucosidase from rice (Oryza
sativa), β-D-glucosidase from almond, α-D-galactosidase from green
coffee bean (Coffea sp.), β-D-galactosidase from bovine liver, α-D-manno-
sidase from jackbean (Canavalia ensiformis), β-D-mannosidase from
Cellullomonas fimi, β-D-glucuronidase from bovine liver, N-acetyl-β-D-
glucosaminidase from bovine kidney, and N-acetyl-β-D-glucosaminidase
from jack bean.
12 C. R. Schmid and J. D. Bryant, Org. Synth. Coll., 1998, 9, 450, 1995,
72.
13 Diastereoselectivity of the addition was determined by GC using a
Supelco-SPB®-5 capillary GC column.
14 (a) R. Díez, R. Badorrey, M. D. Díaz-de-Villegas and J. A. Gálvez,
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15 Addition of vinylmagnesium bromide to the imine 4 in the absence
of BF3·OEt2 in diethyl ether at −20 °C afforded a ca. 90/10 mixture of
21 Residual solvent signals set according to G. R. Fulmer, A. J. M. Miller,
N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M. Stolz, J. E. Bercaw
and K. I. Goldberg, Organometallics, 2010, 29, 2176.
22 A. A. Watson, R. J. Nash, M. R. Wormald, D. J. Harvey, S. Dealler,
E. Lees, N. Asano, H. Kizu, A. Kato, R. C. Griffiths, A. J. Cairns and
G. W. J. Fleet, Phytochemistry, 1997, 46, 255.
23 Under these conditions tR (syn) = 8.16 min, tR (anti) = 8.43 min.
9286 | Org. Biomol. Chem., 2012, 10, 9278–9286
This journal is © The Royal Society of Chemistry 2012