Skeletal rearrangement of seven-membered iminosugars: Synthesis of (-)-adenophorine, (-)-1-epi-adenophorine and derivatives and evaluation as glycosidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.03.035

The mirror image of natural product (+)-adenophorine along with its 1-epi-, 1-homo-analogs and other derivatives have been synthesized and evaluated as glycosidase inhibitors. The synthetic strategy is based on the skeletal rearrangement of tetrahydroxylated C-alkyl azepanes obtained via a Staudinger/azaWittig/alkylation sequence starting from a sugar-derived azidolactol. Several organometallic species have been investigated for the alkylation step including organomagnesium, organolithium, organozinc, organoaluminum and organocerium reagents. While diallylzinc proved to be the most efficient to introduce an allyl substituent, disappointing results were obtained with the other organometallic species leading either to lower yields or no reaction. Enzymatic assays indicate that (-)-adenophorine is a moderate α-l-fucosidase inhibitor.

Full text of DOI:10.1016/j.bmc.2013.03.035

Bioorganic & Medicinal Chemistry 21 (2013) 4803–4812
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Skeletal rearrangement of seven-membered iminosugars: Synthesis
of (ꢀ)-adenophorine, (ꢀ)-1-epi-adenophorine and derivatives
and evaluation as glycosidase inhibitors
Martine Mondon a, Frédéric Lecornué a, Jérôme Guillard a, Shinpei Nakagawa b, Atsushi Kato b,
Yves Blériot a,
⇑
a Université de Poitiers, Equipe ‘Synthèse Organique’, Groupe Glycochimie, UMR-CNRS 7285, IC2MP, 4 rue Michel Brunet, 86022 Poitiers, France
b Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 2 April 2013
The mirror image of natural product (+)-adenophorine along with its 1-epi-, 1-homo-analogs and other
derivatives have been synthesized and evaluated as glycosidase inhibitors. The synthetic strategy is based
on the skeletal rearrangement of tetrahydroxylated C-alkyl azepanes obtained via a Staudinger/azaWit-
tig/alkylation sequence starting from a sugar-derived azidolactol. Several organometallic species have
been investigated for the alkylation step including organomagnesium, organolithium, organozinc,
organoaluminum and organocerium reagents. While diallylzinc proved to be the most efficient to intro-
duce an allyl substituent, disappointing results were obtained with the other organometallic species lead-
ing either to lower yields or no reaction. Enzymatic assays indicate that (ꢀ)-adenophorine is a moderate
Keywords:
Adenophorine
Azepane
Glycosidase inhibition
Iminosugar
Natural product
a-L-fucosidase inhibitor.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Iminosugar C-glycosides have also been identified as natural
products.10 Among them, (+)-adenophorine was isolated by Asano
in 2000 along with its glucoside from Adenophorae radix, a tradi-
tional Chinese crude drug named ‘Sya-zin’.11 It is a rare example
Iminosugars, sugar analogs in which the endocyclic oxygen has
been replaced by nitrogen, constitute a major class of sugar mimet-
ics.1 Their promising therapeutic potential is illustrated by the ap-
proval of GlysetÒ2 and ZavescaÒ3 (Fig. 1) for the treatment of type II
diabetes and Gaucher disease, respectively. Many other patholo-
gies are currently under investigation4 including cystic fibrosis5
and Fabry disease.6 GlysetÒ and ZavescaÒ both exhibit an alkyl sub-
stituent on the nitrogen that improves the lipophilic balance of
these polyhydroxylated molecules. Moving the alkyl chain from
the endocyclic nitrogen to the pseudoanomeric carbon leads to an-
other class of important iminosugars, the iminosugar C-glycosides
that can be seen as glycoconjugates with a stable substituent at the
C-1 position. Iminosugar C-glycosides are usually more potent and
selective compared to the more synthetically accessible iminoald-
itols, an improved efficacy that can be attributed in part to a better
location of the alkyl chain in order to favourably interact with the
target glycoenzyme.7 As a consequence, a vast array of pharmaco-
phores has been introduced at this position yielding iminosugars
with improved selectivity and/or potency towards glycosidases,8
enabling the modulation of new therapeutically relevant
pathways.9
of an
the pseudoanomeric position. It inhibits a selection of glycosidases
in vitro including several -glucosidases and coffee bean -galac-
a-D-HNJ homolog with a hydrophobic alkyl substituent at
a
a
tosidase. Its total synthesis has been achieved in 2007 by Lebr-
eton12 and its structure firmly established in 2003 by Davis13
through the synthesis of its enantiomer (ꢀ)-adenophorine, a
L-imi-
nosugar C-glycoside (Fig. 1).
The absence of inhibition data for (ꢀ)-adenophorine combined
with the recent biological potential of unnatural
-iminosugars14
including their synergistic effect with
-iminosugars,15 prompted
L
D
us to explore an alternative chemical approach to (ꢀ)-adenopho-
rine and analogs and evaluate them as glycohydrolase inactivators.
Synthesis of iminosugar C-glycosides has been extensively
investigated.16 Most of the reported synthetic strategies are based
either on an intramolecular reductive amination or on the late
alkylation of the iminosugar pseudoanomeric carbon through the
use of an electrophilic iminosugar donor. This latter approach ap-
pears as the best strategy for late stage diversification but has been
much less explored due to the difficult generation of stable electro-
philic iminosugars. Piperidinose donors have been developed by
Johnson,17 Vasella18 and Schmidt19 and nucleophilic addition to
the endocyclic C@N bond of a six-membered iminosugar-derived
⇑
Corresponding author. Tel.: +33 5 49 45 39 66.
E-mail address: yves.bleriot@univ-poitiers.fr (Y. Blériot).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.03.035

4804
M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
OH
OH
OH
H
H
N
N
N
N
HO
HO
HO
HO
HO
OH
HO
OH
OH
OH
OH
Glyset®
OH
OH
OH
Zavesca®
(+)-adenophorine
(-)-adenophorine
H
N
H
N
H
N
HO
HO
HO
HO
HO
OH
OH
OH
OH
1-deoxyadenophorine
α-1-C-ethylfagomine
5-deoxyadenophorine
Figure 1. Structure of GlysetÒ, ZavescaÒ, (+)-adenophorine, (ꢀ)-adenophorine, 1-deoxy-adenophorine, 5-deoxy-adenophorine and
a-1-C-ethylfagomine.
cyclic imine or nitrone has been reported by Davis20 and Vasella,21
respectively. Our interest in the synthesis22 and skeletal rearrange-
ment23 of seven-membered iminosugars forced us to combine both
aspects to develop a new strategy based on the C-alkylation of a se-
ven-membered electrophilic iminosugar and its subsequent ring
previously gave the best conversion for this step. In our previous
work, only organomagnesium reagents were explored leading to
the expected C-alkyl azepanes 224 in moderate to good yield (38–
58% from azidolactol 1) and good stereoselectivity (>95/5) except
for the vinyl derivatives 2c and 2d (67:33 ratio). These results
forced us to examine other metals for the introduction of an allyl
or ethyl group including aluminum, lithium, cerium and zinc-
based reagents (Scheme 2; Table 1).
Addition of organomagnesium, organolithium, organoalumi-
num, organozinc and organocerium reagents to imine and related
N,O-acetals is well-documented.26 In the field of iminosugars,
RMgX and RLi have been widely used to introduce aryl and alkyl
chains.27 Allyl zinc bromide has been successfully employed to
generate diallyl trihydroxypiperidines.28
isomerisation. This route allowed the preparation of both L- and
D
-iminosugar C-glycosides from a common sugar-based azidolactol
precursor exploiting a Staudinger/azaWittig ring expansion.24 We
would like to disclose herein the use of this methodology to access
(ꢀ)-adenophorine and analogs in order to evaluate their potency
towards a panel of glycosidases.
2. Results and discussion
In a typical procedure, azidolactol 1 was converted into the
crude bicyclic N,O acetal 1’ which was directly reacted at 0 °C with
3 equiv of the organometallic species. After 2 h, the reaction was
quenched, worked up and purified by flash chromatography. We
observed that the allyl-derived organozinc and organoaluminum
reagents proved almost as efficient as AllMgBr (entry 1) to perform
C-allylation furnishing the C-7 S-configured allyl azepane 2a in 62%
and 51% yield, respectively (entries 3 and 4) while the organoceri-
um reagent provided only traces of 2a (5%, entry 2). Unfortunately,
switching to the required ethyl organometallic species failed to
give the corresponding azepanes (entries 5 and 6). Use of ethyl lith-
ium proved inefficient generating the C-7 R-configured ethyl aze-
pane 2b in only 17% yield (entry 7) compared to EtMgBr (49%,
entry 4). In all cases only one diastereomer was isolated except
for CH2@CHMgBr (entry 8). This lack of diastereomeric control
2.1. Synthesis
Azidolactol 125 is well suited for the preparation of (ꢀ)-aden-
ophorine that displays an
a-L-ido-like configuration and was pre-
pared as follows (Scheme 1). Methyl
a-D-glucopyranoside was
protected as its 4,6-O-benzylidene A followed by benzylation of
the free alcohols to furnish the fully protected compound B. Regio-
selective benzylidene opening produced the primary alcohol C that
was tosylated and further displaced with sodium azide to give
azide D. Acetolysis of D and subsequent deacetylation furnished
azidolactol 1 in seven steps and 39–46% overall yield.
Introduction of the ethyl group at the pseudoanomeric position
can be performed either through addition of a vinyl or ethyl-based
organometallic reagent. Both types of nucleophiles were investi-
gated and compared to the allyl-derived organometallics that
O
OCH3
OH
O
OCH3
OH
O
OCH3
OBn
HO
HO
O
O
a
b
Ph
O
Ph
O
OH
OH
OBn
A
B
c
O
OH
O
OCH3
OBn
O
OCH3
OBn
N3
BnO
N3
BnO
HO
f, g
d, e
OBn
BnO
OBn
OBn
OBn
1
D
C
Scheme 1. Synthesis of azidolactol 1. Reagents and conditions: (a) benzylidene dimethyl acetal, CH3CN, CSA, 85 °C, 6 h, 76% yield; (b) BnBr, NaH, DMF, rt, overnight, 83%
yield; (c) LiAlH4 (4.7 equiv) AlCl3 (4 equiv), CH2Cl2/Et2O, reflux, 2 h, 86% yield; (d) TsCl, pyridine, rt, overnight, 91% yield; (e) NaN3, DMF, 90 °C, 2 h; (f) Ac2O (7 equiv), conc.
H2SO4 (0.5 equiv), CH2Cl2, rt, 30 min.; (g) NaOMe, MeOH, rt, 30 min, 80–94% yield over 3 steps.

M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
4805
solid
sequence. Noteworthy flash chromatography purification of the
resulting polar C-alkyl hydroxyaminoazepanes 2a–d proved te-
dious leading to loss of material. This problem was solved by
applying a three steps sequence starting from azidolactol 1 includ-
ing the N-benzylation of the crude C-alkyl azepane. This sequence
allowed the introduction of an allyl, an ethyl or a vinyl group
affording the corresponding azepanes 3a, 3b, 3c and 3d in 53%,
38% and 29% (3c + 3d), respectively. With the N-protected alkyl
azepanes 3a–d in hands, the skeletal rearrangement under Mitsun-
obu conditions was performed and yielded the corresponding
piperidines 4a–d (34–67%) and the fully protected azepanes 5a–d
(10–30%) with overall retention of configuration. Formation of
the piperidines results from a nucleophilic attack at the aziridini-
um methylene carbon of the fused-piperidine-aziridinium inter-
mediate while the azepanes are obtained through a nucleophilic
attack at the aziridinium methine carbon (Scheme 4).
Ester hydrolysis in piperidines 4a–d under mild basic condi-
tions (K2CO3, MeOH) afforded the corresponding hydroxymethyl
piperidines 6a–d that were uneventfully hydrogenolyzed to fur-
nish the target tetrahydroxylated piperidines 7a–c including (ꢀ)-
adenophorine 7c which spectroscopic data were in good agree-
ment with the literature. We were also interested in the biological
evaluation of the corresponding alkyl azepanes 8a–c that were
quantitatively obtained as their hydrochloride salt by hydrogenol-
ysis of azepanes 3a–d under mild acidic conditions (Scheme 5).
Hydrophobic homonojirimycin analogs displaying fewer hydro-
xyl groups have also been isolated from Adenophora spp. including
NH
N3
H
N
supported
O
R
O
OH
PPh
3
RM
7
3
HO
BnO
OBn
BnO
OBn
THF, 40 °C
BnO
OBn
OBn
OBn
OBn
1
1'
2
Scheme 2. Synthesis of azepanes 2.
Table 1
Synthesis of C-allyl, C-ethyl and C-vinyl azepanes 2a–d from azidolactol 1 using
various organometallic reagents
Entry
R
Metal Azepane Yield (%)
C-7
configuration
d.r.
1
2
3
4
4
5
All
All
All
All
Et
Mg
Ce
Zn
Al
Mg
Ce
2a
2a
2a
2a
2b
2b
58
S
S
S
S
R
<5:95
<5:95
<5:95
<5:95
>95:5
5
62
51
49
No
reaction
No
reaction
17
Et
6
Et
Et
Zn
Li
2b
7
8
2b
2c/2d
R
R/S
>95:5
67:33
CH@CH2 Mg
38
was further exploited as it produces the minor vinyl azepane 2d
displaying the required C-7 S configuration that should be easily
amenable to the target (ꢀ)-adenophorine.
1-deoxy-adenophorine, 5-deoxy-adenophorine and
a-1-C-ethyl-
fagomine (Fig. 1) that demonstrated potent glycosidase inhibi-
tion.11 Hydrophobically modified analogues of adenophorine
have also been reported to improve their metabolic stability.30 In
this context, the Staudinger/azaWittig/alkylation approach allows
the functionalization of both C-2 and C-6 positions of the piperi-
dine ring and the introduction of hydrophobic chains at these
positions. The access to a new hydrophobic 2,6-diethyl-3,4,5-trihy-
droxypiperidine starting from the advanced precursor 6c was
explored. Oxidation of hydroxymethylpiperidine 6c under Swern
conditions followed by olefination with a Wittig reaction gener-
ated the bis vinyl derivative 9 (46% yield over two steps). The C-2
symmetry of 9 was confirmed by the simplification of its NMR
spectra. Final hydrogenolysis furnished the target trihydroxypiper-
idine 10 (Scheme 6).
The stereochemical outcome of this ring opening reaction can
be tentatively explained as follows (Scheme 3). Treatment of
hemiaminal 10 with the organomagnesium reagent leads to a se-
ven-membered imine 100 than can be attacked from both Re and
Si faces. With aromatic and conjugated species such as AllMgBr
(or PhMgBr24), a
p–stacking interaction could take place with the
sugar benzyl groups to favour the attack on the Si face of the imine
yielding the 3,7-trans C-allyl azepane 2a. A similar interaction has
been invoked in the case of related 6,8-diazabicyclo[3.2.1]oct-6-
ene scaffold.29 With alkyl species such as EtMgBr (or MeMgBr24),
an intramolecular delivery of the nucleophile guided by the 3-OH
could operate yielding to the attack on the Re face of the imine gen-
erating the 3,7-cis C-ethyl azepane 2b. Such hypothesis is sup-
ported by the formation of the 3,7-cis C-alkyl azepane using
homoallyl magnesium bromide (unpublished results) and the for-
mation of both 3,7-cis and 3,7-trans C-vinyl azepanes 2c and 2d
respectively using vinyl magnesium bromide that can be consid-
ered to behave both as an alkyl and conjugated nucleophile.
Overall, as no significant yield improvement was observed by
varying the nature of the organometallic reagent, organomagne-
sium reagents were used for the alkylation step in the synthetic
2.2. Biological activity
Inhibition by the tri- and tetrahydroxylated piperidines 7a–c,
10 and tetrahydroxylated azepanes 8a–c of the following glycosi-
dases was studied (Fig. 2): a-glucosidases (rice, yeast, rat intestinal
maltase, A. niger), b-glucosidases (almond, bovine liver, A. niger),
π stacking
interaction
H
N
O
R
N
7
RM
3
OM
HO
OBn
O
M
O
BnO
BnO
BnO
BnO
OBn
HN
N
N
RM
RM = AllMgBr, PhMgBr
O
O
OM
R'M = EtMgBr, MeMgBr, homoAllMgBr
OBn
OBn
OBn
H
OBn
OBn
OBn
BnO
R'
OBn
OBn
N
N
7
1'
1''
3
OM
HO
BnO
OBn
OBn
R'M
intramolecular
delivery
Scheme 3. Proposed mechanism to rationalize the stereochemical outcome of the bicycle 10 ring opening reaction.

4806
M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
OBn
Et
NBn
N
BnO
BnO
BnO
Et
OBn
Ph
BnO
PhCO
2
BnO
six-membered
BnO
PhCO
Bn Et
N
2
Bn Et
N
Mitsunobu
iminosugar
Ph3PO
HO
OBn OBn
OBn BnO
BnO
Bn Et
OBn
Et
Ph
PhCO
N
2
PhCO
2
N
BnO
BnO
OBn BnO
seven-membered
iminosugar
Scheme 4. Mechanism of the azepane skeletal rearrangement under Mitsunobu conditions.
BzO
Bn
N
*
Bn
N
*
Bn
N
*
R
R
R
a-c
d
+
1
HO
BnO
OBn
BzO
BnO
OBn
BnO
OBn
OBn
OBn
OBn
3a
3b
4a
4b
5a
5b
R = allyl, S (53%)
R = ethyl, R (38%)
R = allyl, S (67%)
R = ethyl, R (34%)
R = allyl, S (21%)
R = ethyl, R (30%)
3c R = vinyl, R (17%)
4c R = vinyl, R (63%)
5c R = vinyl, R (10%)
3d
4d
5d
R = vinyl, S (12%)
R = vinyl, S
inseparable
R = vinyl, S
e
f
OH
OH
H.HCl
Bn
H.HCl
N
R
N
R
f
N
R
*
*
*
HO
OH
BnO
OBn
HO
OH
HO
OH
OBn
OH
8a R = propyl, S (quant.)
6a R = allyl, S (76%)
7a R = propyl, S (quant.)
8b
R = ethyl, R (95%)
6b
7b
R = ethyl, R (77%)
6c R = vinyl, R (70%)
6d
R = ethyl, R (quant.)
8c R = ethyl, S (quant.)
7c R = ethyl, S (quant.)
R = vinyl, S (44%)
Scheme 5. Synthesis of C-alkyl piperidines 7a–c and C-alkyl azepanes 8a–c. Reagents and conditions: (a) PPh3 polymer bound, THF, 40 °C, overnight; (b) AllMgBr or EtMgBr
or CH2@CHMgBr, THF, 1 h, rt; (c) BnBr, K2CO3, DMF; (d) PPh3, DIAD, p-nitrobenzoic acid, THF; (e) K2CO3, MeOH, THF; (f) H2, 10% Pd/C, Pd black, MeOH, 1 M HCl. Bz = p-
nitrobenzoate.
a
a
-galactosidase (coffee beans), b-galactosidase (bovine liver),
-mannosidase (Jack beans), b-mannosidase (snail), -rhamnos-
-fucosidase (bovine kidney), b-glucuronidases
OH
H.HCl
N
Bn
N
a-L
Bn
N
c
a, b
idase (P. decumbens), a-L
(E. coli, bovine liver), trehalase (porcine kidney), and amylogluco-
sidases (A. niger, Rhizopus sp).
BnO
OBn
HO
OH
BnO
OBn
OBn
OH
OBn
This study (Table 2) revealed that (ꢀ)-adenophorine 7c is a mod-
6c
9
10
erate
a-L-fucosidase inhibitor (IC50 72 lM). The epimer at the
pseudoanomeric position 7b is also a
a-L-fucosidase inhibitor (IC50
Scheme 6. Synthesis of trihydroxypiperidine 10. Reagents and conditions: (a)
oxalyl chloride, DMSO, Et3N, CH2Cl2, ꢀ78 °C; (b) PPh3CH3+Brꢀ, BuLi, CH2Cl2, 46%
over two steps; (c) H2, 10% Pd/C, Pd black, MeOH, 1M HCl, quant.
208 M). The one carbon elongated analog 7a yields also a weak
l
fucosidase inactivator (IC50 713
lM) and a weak b-glucuronidase
H
N
H
N
H
H
N
N
HO
HO
HO
HO
HO
OH
OH
HO
OH
HO
OH
OH
OH
OH
OH
7a
7c
10
7b
H
N
H
N
H
N
HO
HO
OH
OH
8a
HO
OH
OH
HO
HO
OH
OH
HO
8b
8c
Figure 2. Structure of iminosugar C-glycosides assayed in this work.

Table 2
Concentration of iminosugars and its derivatives giving 50% inhibition of various glycosidases (in bold)
Enzyme
IC50 (lM)
H
N
H
N
H
N
H
N
H
N
H
N
H
N
HO
HO
HO
HO
HO
HO
OH
OH
HO
HO
OH
HO
OH
OH
OH
HO
OH
HO
OH
OH
OH
OH
HO
HO
OH
OH
OH
7a
7b
7c
10
8a
8b
8c
a
-Glucosidase
Rice
Yeast
NIa (0%)b
NI (40.0%)
NI (0%)
NI (1.4%)
NI (42.6%)
NI (13.2%)
NI (0%)
NI (10.4%)
NI (26.8%)
NI (5.1%)
NI (1.3%)
NI (13.0%)
713
NI (0%)
NI (0%)
NI (0%)
NI (0%)
NI (1.7%)
NI (2.0%)
NI (0%)
839
NI (1.0%)
NI (0%)
NI (0%)
NI (0%)
NI (5.1%)
NI (24.6%)
NI (0%)
NI (1.2%)
NI (12.1%)
NI (0%)
NI (0%)
NI (9.0%)
NI (3.3%)
NI (0%)
NI (16.9%)
NI (32.8%)
NI (0%)
NI (8.7%)
NI (20.3%)
NI (5.1%)
NI (0%)
NI (2.4%)
208
NI (11.0%)
NI (0%)
NI (0%)
NI (1.9%)
NI (0%)
NI (0%)
NI (0%)
NDc
NI (23.5%)
NI (13.7%)
NI (0.2%)
NI (48.7%)
487
NI (0%)
NI (7.5%)
526
NI (11.0%)
NI (0%)
231
NI (37.2%)
NI (18.1%)
NI (0.1%)
NI (0%)
Rat intestinal maltase
Aspergillus niger
Almond
Bovine liver
Aspergillus niger
Coffee beans
Bovine liver
Jack beans
NI (6.1%)
NI (33.5%)
NI (12.6%)
NI (0%)
NI (0.6%)
NI (6.5%)
NI (0%)
NI (0%)
NI (37.7%)
72
NI (0%)
b-Glucosidase
NI (21.4%)
NI (21.6%)
NI (0%)
NI (3.7%)
NI (9.7%)
NI (0.4%)
NI (0.3%)
NI (0%)
NI (0%)
NI (6.0%)
NI (9.1%)
NI (46.0%)
541
NI (1.6%)
NI (3.6%)
NI (14.8%)
NI (0%)
ND
a
-Galactosidase
b-Galactosidase
-Mannosidase
b-Mannosidase
a
Snail
NI (0%)
a
a
-
-
L
-Rhamnosidase
-Fucosidase
Penicillium decumbens
Bovine kidney
E.coli
Bovine liver
Porcine kidney
Aspergillus niger
Rhizopus sp
NI (5.3%)
NI (36.7%)
NI (3.1%)
NI (0.1%)
NI (3.9%)
NI (0.8%)
NI (0%)
L
NI (0%)
b-Glucuronidase
586
NI (0%)
NI (0%)
NI (0%)
NI (7.2%)
NI (0.8%)
NI (6.0%)
NI (0%)
NI (12.9%)
NI (0.5%)
NI (4.9%)
NI (4.1%)
NI (3.4%)
ND
a,
a
-Trehalase
NI (0%)
NI (0%)
ND
Amyloglucosidase
NI (0%)
NI 0%)
NI (0%)
NI (0%)
a
b
c
NI: no inhibition (less than 50% inhibition at 1000 lM).
(): inhibition% at 1000
lM.
ND: not determined.

4808
M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
inhibitor (IC50 586
l
M). The more hydrophobic 2,6-diethyl deriva-
organic layer was washed with water (15 mL), dried over MgSO4
and concentrated under reduced pressure after filtration. The resi-
due was purified by flash chromatography (EtOAc/MeOH 95/5).
tive 10 demonstrated no effect as glycosidase inhibitor. The azepane
derivatives display a very different glycosidase inhibition profile
compared to their piperidine counterparts. The ring homolog of
(ꢀ)-adenophorine 8c is a weak inhibitor of bovine liver b-glucosi-
4.3. General procedure for the synthesis of azepanes 3a–d
dase (IC50 487
-rhamnosidase (IC50 231
inhibit glycosidases significantly while the propyl derivative 8a is
a weak inhibitor of yeast -glucosidase (IC50 839 M) and bovine
lM), bovine liver b-galactosidase (IC50 526
l
M) and
a-
L
lM). Its epimer at C-2 8b does not
Starting from azidolactol 1 (4 g, 8.42 mmol), the crude azepane
2a was obtained in 2 steps as described before and engaged, with-
out purification, in the next benzylation step. To a cooled solution
(0 °C) of crude 2a and benzyl bromide (1.6 mL, 12.8 mmol) in DMF
(80 mL), was added K2CO3 (3.5 g, 25.2 mmol). The mixture was
stirred at room temperature for 14 h, quenched with saturated
aqueous NH4Cl, and extracted with EtOAc/toluene (2:1). The or-
ganic layer was washed with water, dried over MgSO4 and concen-
trated under reduced pressure, after filtration. The residue was
purified by flash chromatography (EtOAc/petroleum ether 10:90)
to afford azepane 3a as colorless syrup (2.53 g, 53%, 3 steps).
a
l
liver b-galactosidase (IC50 541 lM).
3. Conclusion
In summary, a new route to (ꢀ)-adenophorine 7c based on the
skeletal rearrangement of a C-alkyl azepane has been deviced.
Compound 7c is a moderate
a very distinctive inhibitory profile compared to (+)-adenophorine,
a potent and selective
-glucosidase inactivator.11 The structurally
a-L-fucosidase inhibitor and exhibits
a
related azepanes 8a–c proved to be weak glycosidase inhibitors.
This suggests that introduction of an ethyl or a propyl group at
C-1 on the azepane ring is detrimental to their glycosidase inhibi-
tory potential as the known 3R, 4R, 5R, 6S tetrahydroxyazepane31 is
4.3.1. (3R,4R,5R,6S,7S) 7-Allyl-1-benzyl-4,5,6-
tris(benzyloxy)azepan-3-ol (3a)
[
a]
D = ꢀ14 (c 0.94, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.37–
7.20 (m, 20H, ArH), 5.86–5.76 (m, 1H, –CH@), 5.05–4.98 (m, 2H,
H2C@), 4.71 (d, J = 11.7 Hz, 1H, OCHHPh), 4.63 (d, J = 11.7 Hz, 1H,
OCHHPh), 4.58 (s, 2H, OCH2Ph), 4.39 (qAB, 2H, OCH2Ph), 4.10 (dd,
J = 7 and 2.5 Hz, 1H, H-5), 4.02 (m, 1H, H-3), 3.86–3.76 (m, 3H,
H-4, NCH2), 3.54 (dd, J = 6.5 and 2.5 Hz, 1H, H-6), 3.49 (brd,
J = 10.8 Hz, OH), 3.20 (q, J = 7-6.5 Hz, 1H, H-7), 2.90–2.80 (m, 2H,
2H-2), 2.39 (m, 2H, CH2 allyl); 13C NMR (100 MHz, CDCl3): d
139.7, 138.6, 138.4, 137.9 (4 ArC), 136.7 (–CH@), 128.9, 128.5,
128.41, 128.39, 128.0, 127.98, 127.88, 127.82, 127.77, 127.6,
127.1 (ArCH), 116.7 (CH2@), 86.2 (C-4), 83.9 (C-5), 80.1 (C-6),
73.3, 72.7, 71.6 (3 CH2Ph), 69.2 (C-3), 62.6 (C-7), 58.6 (NCH2),
53.0 (C-2), 30.2 (CH2 allyl); HRMS (ESI) m/z: [M+Na]+ calcd for
a potent inhibitor of coffee bean
a-galactosidase (Ki 54
lM) and
bovine kidney -fucosidase (4.6
a
lM).
4. Experimental
4.1. Material and methods
All reagents were used as purchased from commercial suppliers
without further purification. THF was distilled under anhydrous
conditions. TLC plates (Macherey-Nagel, ALUGRAMÒ SIL G/UV254
,
0.2 mm silica gel 60 Å) were visualized under 254 nm UV light
and/or by dipping the TLC plate into a solution of 3 g of phospho-
molybdic acid in 100 mL of ethanol followed by heating with a heat
gun. Flash column chromatography was performed using Mache-
C37H41NO4Na: 586.2933; found: 586.2933.
4.3.2. (3R,4R,5R,6S,7R)-1-Benzyl-4,5,6-tris(benzyloxy)-7-
ethylazepan-3-ol (3b)
rey-Nagel silica gel 60 (15–40 lm). NMR experiments were re-
corded with a Bruker Avance 400 spectrometer at 400 MHz for
1H nuclei and at 100 MHz for 13C nuclei. The chemical shifts are ex-
pressed in part per million (ppm) relative to TMS (d = 0 ppm) and
the coupling constant J in Hertz (Hz). NMR multiplicities are re-
ported using the following abbreviations: br = broad, s = singulet,
d = doublet, t = triplet, q = quadruplet, m = multiplet. HRMS were
obtained from the Mass Spectrometry Service, ICOA, at Orleans,
France, using a MICROMASS ZABSPEC-TOF spectrometer and a
VARIAN MAT311 spectrometer.
Starting from azidolactol 1 (2 g, 4.21 mmol), azepane 3b was
obtained as described above as colorless syrup (870 mg, 38% over
3 steps).
[a]
D = 22 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.33–7.19
(m, 20H, ArH), 4.71–4.45 (m, 6H, 3CH2Ph), 3.97–3.83 (m, 5H, H-3,
H-4, H-5, NCH2), 3.73 (dd, J = 7.5, 2.4 Hz, 1H, H-6), 3.22 (dd,
J = 14.4, 8.5 Hz, 1H, 1H-2), 2.78 (m, 1H, H-7), 2.57 (dd, J = 14.4,
2.2 Hz, 1H, 1H-2), 1.84 (m, 1H, CHH ethyl), 1.64 (m, 1H, CHH ethyl),
0.92 (t, J = 14.4, 2.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): d
140.9, 138.5, 138.4, 138.1 (4 ArC), 128.5–126.9 (ArCH), 84.4 (C-5
or C-4), 82.6 (C-6), 82.2 (C-4 or C-5) 73.7, 73.4, 72.5 (3 CH2Ph),
68.7 (C-3), 63.0 (C7), 57.5 (NCH2), 50.2 (C-2), 19.9 (CH2 ethyl),
12.11 (CH3); HRMS (ESI) m/z: [M+H]+ calcd for C36H42NO4:
552.3113; found: 552.3107.
4.2. General procedure for the synthesis of azepanes 2a–d
Triphenylphosphine polymer bound (250 mg, 0.78 mmol,
3.2 mmol/g) was added to a solution of azidolactol 1 (250 mg,
0.53 mmol) in anhydrous THF (5 mL). The reaction mixture was
stirred at 40 °C for 17 h, then filtered through a Celite plug eluted
with THF, and the solvent removed under reduced pressure. The
crude product was taken in Et2O (5 mL), filtered again through a
Celite plug, and the filtrate concentrated to give the crude bicyclic
4.3.3. (3R,4R,5R,6S,7R)-1-Benzyl-4,5,6-tris(benzyloxy)-7-
vinylazepan-3-ol (3c) and (3R,4R,5R,6S,7S)-1-benzyl-4,5,6-
tris(benzyloxy)-7-vinylazepan-3-ol (3d)
Starting from azidolactol 1 (2 g, 4.21 mmol), azepanes 3c and 3d
were obtained as described above as colorless oils with the more
polar compound 3c (393 mg, 17%, over 3 steps) and the less polar
compound 3d (277 mg, 12%, over 3 steps).
N,O-acetal as
a pale yellow oil. The organometallic reagent
(3 equiv, allylmagnesium chloride 2 M solution in THF, ethylmag-
nesium bromide 3 M solution in Et2O, vinylmagnesium bromide
1 M solution in THF) was added to a solution of crude bicyclic
N,O-acetal in THF (5 mL) at 0 °C except for ethyl lithium for which
reaction was performed at ꢀ78 °C. The reaction was stirred at room
temperature for 2 h with Grignard and organozinc reagents,32 and
at 0 °C for 2 h with organocerium reagents.33 The reaction was
quenched with saturated aqueous NH4Cl (10 mL), diluted with
EtOAc (10 mL) at 0 °C and extracted with EtOAc (3 ꢁ 15 mL). The
Compound 3c: [a]
D = 29 (c 1.26, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.31–7.25 (m, 20H, ArH), 6.24 (ddd, J = 17.1, 10.2,
8.9 Hz, 1H, –CH@), 5.30 (dd, J = 10.2, 2.0 Hz, 1H, @CHH), 5.17 (dd,
J = 17.1, 1.5 Hz, 1H, @CHH), 4.71–4.42 (3 OCH2Ph), 3.97 (m, 1H,
H-3), 3.86 (dd, J = 7.6, 4.0 Hz, 1H, H-5), 3.80 (dd, J = 4.0, 2.5 Hz,
1H, H-4), 3.71 (d, J = 13.8 Hz, 1H, NCHHPh), 3.68 (dd, J = 7.6,
3.1 Hz, 1H, H-6), 3.59 (d, J = 13.8 Hz, 1H, NCHHPh), 3.42 (dd,

M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
4809
J = 8.9, 3.1 Hz, 1H, H-7), 3.06 (dd, J = 13.2, 8.2 Hz, 1H, H-2), 2.66-
2.61 (m, 2H, OH, H-2); NMR (100 MHz, CDCl3): d 139.3, 138.5,
138.2, 138.1 (4 ArC), 133.9 (–CH@), 128.6–127.0 (ArCH), 119.6
(@CH2), 84.16, 84.12 (C-4, C-6), 81.3 (C-5), 73.8, 73.1, 72.5 (3
CH2Ph), 69.2 (C-3), 64.7 (C-7), 59.6 (NCH2), 52.0 (C-2); HRMS
(ESI) m/z: [M+H]+ calcd for C36H40NO4: 550.2957; found: 550.2953.
2.34 (m, 1H, CHH allyl); 13C NMR (100 MHz, CDCl3): d 163.9 (CO),
150.5, 140.0, 138.3, 138.2, 139.0, 137.6 (6 ArC), 135.8 (–CH@),
130.9 (ArCH), 128.7, 128.6, 128.5, 128.4, 128.3, 128.08, 128.06,
128.0, 127.93, 127.86, 127.77, 126.9 (ArCH), 123.5 (ArCH), 115.8
(CH2@), 85.7 (C-6), 79.3, 79.0 (C-4, C-5), 72.9, 72.8, 72.6 (3
OCH2Ph), 70.5 (C-3), 64.3 (C-7), 50.6 (NCH2), 49.3 (C-2), 35.0 (CH2
allyl); HRMS (ESI) m/z: [M+H]+ calcd for C44H45N2O7: 713.3221;
found: 713.3220.
Compound 3d: [
a]
D = ꢀ22 (c 1.08, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.31–7.20 (m, 20H, ArH), 5.97 (ddd, J = 16.9, 10.2,
8.2 Hz, 1H, –CH@), 5.34 (dd, J = 10.2, 1.5 Hz, 1H, @CHH), 5.22 (dd,
J = 16.9, 1.5 Hz, 1H, @CHH), 4.73 (d, J = 11.6 Hz, 1H, OCHHPh),
4.66 (d, J = 11.6 Hz, 1H, OCHHPh), 4.66 (s, 2H, OCH2Ph), 4.47 (d,
J = 11.4 Hz, 1H, OCHHPh), 4.40 (d, J = 11.4 Hz, 1H, OCHHPh), 4.11
(dd, J = 7.2, 4.2 Hz, 1H, H-5), 3.97 (m, 1H, H-3), 3.75 (dd, J = 7.2,
2.2 Hz, 1H, H-4), 3.72 (d, J = 13.6 Hz, 1H, NCHHPh), 3.67 (d,
J = 13.6 Hz, 1H, NCHHPh), 3.54–3.49 (m, 2H, H-6, H-7), 2.90–2.81
(m, 2H, 2 H-2); NMR (100 MHz, CDCl3): d 139.2, 138.6, 138.5,
137.7 (4 ArC), 132.6 (–CH@), 128.9–126.9 (ArCH), 119.8 (@CH2),
86.1 (C-4), 83.8 (C-5), 80.8 (C-6), 73.6, 72.8, 72.4 (3 CH2Ph), 69.2
(C-3), 65.1 (C-7), 59.3 (NCH2), 53.0 (C-2); HRMS (ESI) m/z:
[M+H]+ calcd for C36H40NO4: 550.2957; found: 550.2956.
4.4.2. (2S,3R,4R,5S,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
ethylpiperidin-2-yl)methyl 4-nitrobenzoate (4b) and
(3R,4R,5R,6S,7R)-1-benzyl-4,5,6-tris(benzyloxy)-7-ethylazepan-
3-yl 4-nitrobenzoate (5b)
Piperidine 4b (132 mg, 34%) and azepane 5b (116 mg, 30%)
were obtained from azepane 3b (210 mg, 0.382 mmol) as de-
scribed above.
Compound 4b [a]
D = 13 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3): d 8.21 (d, J = 8.9 Hz, 2H, ArH), 8.01 (d, J = 8.9 Hz, 2H, ArH),
7.33–7.21 (m, 20H, ArH), 4.84 (m, 2H, CH2Ph), 4.74 (dd, J = 11.5,
5.4 Hz, 1H, CHHOBz), 1H, 4.70–4.51 (m, 5H, 2CH2Ph, CHHOBz),
3.98 (qAB, J = 14.5 Hz, 2H, CH2N), 3.84–3.77 (m, 2H, H-3, H-4),
3.70 (dd, J = 7.8, 5.7 Hz, 1H, H-5), 3.54 (q, J = 7.0–5.4 Hz, 1H, H-2),
2.98 (q, J = 7.3–6.0 Hz, 1H, H-6), 1.82 (m, 1H, CHH ethyl), 1.57 (m,
1H, CHH ethyl), 0.98 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3): d 164.5 (CO), 150.4, 140.2, 138.8, 138.5, 138.2, 135.6 (6
ArC), 130.7 (ArCH), 128.4–127.1 (ArCH), 123.4 (ArCH), 80.0 (C-5),
78.9 and 78.7 (C-3 and C-4), 75.1, 72.9, 72.8 (3 CH2Ph), 65.4 (CH2O-
CO), 61.6 (C-6), 59.1 (NCH2), 58.0 (C-2), 22.4 (CH2 ethyl), 16.0
(CH3); HRMS (ESI) m/z: [M+H]+ calcd for C43H45N2O7: 701.3221;
found: 701.3218.
4.4. General procedure for the synthesis of piperidines 4a–d
Diisopropyl azodicarboxylate (DIAD) (0.16 mL, 0.80 mmol,) was
added to a solution of azepane 3a (230 mg, 0.408 mmol), triphen-
ylphosphine (214 mg, 0.80 mmol) and p-nitrobenzoic acid
(103 mg, 0.60 mmol) in THF (4 mL) at 0 °C. The resulting solution
was stirred for 30 min at room temperature and concentrated in
vacuo. Separation by flash column chromatography (EtOAc/petro-
leum ether, 5:95) gave the piperidine 4a as a pale yellow oil
(195 mg, 67%) and a less polar azepane 5a as a pale yellow oil
(61 mg, 21%).
Compound 5b: [a]
D = 33.4 (c 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3): d 8.21 (d, J = 8.9 Hz, 2H, ArH), 8.05 (d, J = 8.5 Hz, 2H, ArH),
7.31–7.18 (m, 20H, ArH), 5.41 (brd, J = 8.8 Hz, 1H, H-3), 4.70 (d,
J = 12 Hz, 1H, CHHPh), 4.69 (d, J = 11.4 Hz, 1H, CHHPh), 4.65 (s,
2H, CH2Bn), 4.58 (d, J = 12 Hz, 1H, CHHPh), 4.53 (d, J = 11.4 Hz,
1H, CHHPh), 4.12 (d, J = 14.2 Hz, 1H, CHHN), 3.97 (brs, 1H, H-4),
3.88–3.83 (m, 3H, CHHN, H-5, H-6), 3.59 (dd, J = 14.5, 9.0 Hz, 1H,
H-2), 2.85 (dm, J = 7 Hz, 1H, H-7), 2.63 (d, J = 14.3 Hz, 1H, H-2),
1.96 (m, 1H, CHH ethyl), 1.70 (m, 1H, CHH ethyl), 0.96 (t,
J = 7.3 Hz, 3H, CH3 ethyl); 13C NMR (100 MHz, CDCl3): d 163.6
(CO), 150.5, 140.1, 138.6, 138.2, 138.0, 135.7 (6 Carom), 130.7-
123.4 (CHarom), 83.0 and 82.7 (C-5, C-6), 81.1 (C-4), 73.6, 73.5,
72.4 (3 CH2Ph), 71.7 (C-3), 63.8 (C-7), 57.5 (NCH2), 46.3 (C-2),
19.3 (CH2), 12.0 (CH3); HRMS (ESI) m/z: [M+H]+ calcd for
4.4.1. (2S,3R,4R,5S,6S)-6-Allyl-1-benzyl-3,4,5-
tris(benzyloxy)piperidin-2-yl)methyl 4-nitrobenzoate (4a) and
(3R,4R,5R,6S,7S)-7-allyl-1-benzyl-4,5,6-tris(benzyloxy)azepan-
3-yl 4-nitrobenzoate (5a)
Compound 4a: [a]
D = 22 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3):
d 8.25 (d, J = 8 Hz, 2H, ArH), 8.10 (d, J = 8 Hz, 2H, ArH), 7.39–7.07
(m, 20H, ArH), 5.89–5.79 (m, 1H, –CH@), 5.07–5.03 (m, 2H,
@CH2), 4.96 (d, J = 10.7 Hz, 1H, OCHHPh), 4.94 (d, J = 10.7 Hz, 1H,
OCHHPh), 4.82 (d, J = 10.7 Hz, 1H, OCHHPh), 4.80 (dd, J = 11.9,
8.6 Hz, 1H, CHHOCO), 4.66–4.55 (m, 3H, OCHH Ph), 4.52 (dd,
J = 11.9, 3.5 Hz, 1H, CHHOCO), 3.90 (dd, J = 9.9, 5.9 Hz, 1H, H-3),
3.84 (d, J = 13.4 Hz, 1H, CHHN), 3.78 (t, J = 9.9, 8.7 Hz, 1H, H-4),
3.64 (d, J = 13.4 Hz, 1H, CHHN), 3.50 (dd, J = 10.1, 8.7, Hz, 1H, H-
5), 3.32 (ddd, J = 8.6, 5.9, 3.5 Hz, 1H, H-2), 3.27 (ddd, J = 10.1, 8.5,
4.5 Hz, 1H, H-6), 2.78 (m, 1H, CHH allyl), 2.35 (m, 1H, CHH allyl);
13C NMR (100 MHz, CDCl3): d 164.4 (CO), 150.6, 139.2, 138.7,
138.4, 138.0, 135.7 (6 ArC), 135.3 (–CH@), 130.9 (ArCH), 128.63,
128.58, 128.54, 128.52, 128.3, 128.1, 127.97, 127.91, 127.7, 127.2
(ArCH), 123.5 (ArCH), 116.7 (CH2@), 84.5 (C-4), 80.5 (C-5), 77.4
(C-3), 75.7, 75.3, 72.8 (3 CH2Ph), 60.6 (CH2OCO), 57.3 (C-6), 55.1
(C-2), 50.1 (NCH2), 32.8 (CH2 allyl); HRMS (ESI) m/z: [M+H]+ calcd
for C44H45N2O7: 713.3221; found: 713.3221.
C43H45N2O7: 701.3221; found: 701.3222.
4.4.3. (2S,3R,4R,5S,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
vinylpiperidin-2-yl)methyl 4-nitrobenzoate (4c) and
(3R,4R,5R,6S,7R)-1-benzyl-4,5,6-tris(benzyloxy)-7-vinylazepan-
3-yl 4-nitrobenzoate (5c)
Piperidine 4c (168 mg, 63%) and less polar azepane 5c (26.7 mg,
10%) were obtained from azepane 3c (210 mg, 0.382 mmol) as de-
scribed above.
Compound 4c: [a]
D = 35 (c 1.36, CHCl3); 1H NMR (400 MHz,
Compound 5a: [
a
]
D = ꢀ34.7 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3): d 8.17 (d, J = 8.9 Hz, 2H, ArH), 8.01 (d, J = 8.9 Hz, 2H, ArH),
7.34–7.21 (m, 20H, ArH), 5.85 (dt, J = 16.9, 10.0 Hz, 1H, –CH@),
5.38 (dd, J = 10.0, 1.6 Hz, 1H, @CHH), 5.14 (dd, J = 16.9, 1.4 Hz,
1H, @CHH), 4.87 (qAB, J = 10.7 Hz, 2H, CH2Ph), 4.68 (qAB,
J = 11.7 Hz, 2H, CH2Ph), 4.60 (m, 2H, CH2OCO), 4.50 (qAB,
J = 11.5 Hz, 2H, CH2Ph), 3.93 (s, 2H, NCH2), 3.84 (m, 2H, H-3, H-4),
3.67 (m, 2H, H-2, H-5), 3.54 (dd, J = 10.0, 6.1 Hz, 1H, H-6); 13C
NMR (100 MHz, CDCl3): d 164.4 (CO), 150.4 (ArC), 138.8, 138.7,
138.2, 138.0 (4 ArC), 135.5 (ArC), 133.7 (–CH@), 130.6 (ArCH),
128.5-127.2 (ArCH), 123.4 (ArCH), 120.7 (CH2@), 80.2, 80.1, 79.1
(C-3, C-4, C-5), 75.6, 72.8, 71.9 (3 CH2Ph), 64.4 (CH2OCO), 61.0
CDCl3): d 8.20 (d, J = 8 Hz, 2H, ArH), 8.04 (d, J = 8 Hz, 2H, ArH),
7.39–7.19 (m, 20H, ArH), 6.04–5.94 (m, 1H, –CH@), 5.70 (ddd,
J = 10.8, 4.7, 1.5 Hz, 1H, H-3), 5.11–5.05 (m, 2H, @CH2), 4.72 (d,
J = 11.7 Hz, 1H, OCHHPh), 4.69 (d, J = 12.2 Hz, 1H, OCHHPh), 4.65
(d, J = 11.7 Hz, 1H, OCHHPh), 4.57 (d, J = 11.2 Hz, 1H, OCHHPh),
4.54 (d, J = 12.2 Hz, 1H, OCHHPh), 4.48 (d, J = 11.2 Hz, 1H,
OCHHPh), 4.17 (brd, J = 6.2 Hz, 1H, H-4), 4.10 (dd, J = 6.2, 2 Hz,
1H, H-5), 3.90 (m, 2H, NCH2), 3.60 (dd, J = 8.9, 2 Hz, 1H, H-6),
3.53 (td, J = 8.9, 4.3 Hz, 1H, H-7), 3.22 (dd, J = 13.7, 10.8 Hz, 1H,
H-2), 2.91 (dd, J = 13.7, 4.7 Hz, 1H, H-2), 2.60 (m, 1H, CHH allyl),

4810
M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
(C-6), 58.9 (C-2), 56.4 (NCH2); HRMS (ESI) m/z: [M+Na]+ calcd for
43H42N2O7Na: 721.2889; found: 721.2889.
Compound 5c: [
D = 48 (c 0.26, CHCl3); 1H NMR (400 MHz,
ethyl), 13.0 (CH3 ethyl); HRMS (ESI) m/z: [M+H]+ calcd for
C36H42NO4: 552.3113; found: 552.3111.
C
a]
4.5.3. (2S,3R,4R,5S,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
vinylpiperidin-2-yl)methanol (6c)
CDCl3): d 8.24 (d, J = 8 Hz, 2H, ArH), 8.05 (d, J = 8 Hz, 2H, ArH),
7.33–7.19 (m, 20H, ArH), 6.36 (ddd, J = 17.0, 10.2, 9.1 Hz, 1H, –
CH@), 5.45 (brd, J = 7.7 Hz, 1H, H-3), 5.32 (dd, J = 10.2, 1.9 Hz, 1H,
@CHH), 5.17 (dd, J = 17.0, 1.5 Hz, 1H, @CHH), 4.68-4.42 (m, 6H, 3
CH2Ph), 3.99 and 3.85 (2s, 1H and 2H, H-4, H-5, H-6), 3.72 (qAB,
J = 13.8, 2H, NCH2), 3.50 (hidden in part, 1H, 1H-2), 3.48 (dd,
J = 9.1, 2.9 Hz, 1H, H-7), 2.72 (dd, J = 13.0, 2.8 Hz, 1H, 1H-2); 13C
NMR (100 MHz, CDCl3): d 163.5 (CO), 150.5, 139.1, 138.3, 137.9,
135.6 (ArC), 132.8 (–CH@), 130.7 (ArCH), 128.5–127.1 (ArCH),
123.5 (ArCH), 120.4 (CH2@), 85.1, 81.7, 80.6 (C-4, C-5, C-6), 73.6
(C-3), 73.5, 72.9, 72.4 (3 CH2Ph), 64.0 (C-7), 59.4 (NCH2), 48.5 (C-
2); HRMS (ESI) m/z: [M+H]+ calcd for C43H43N2O7: 699.3070;
found: 699.3065.
Piperidine 6c was obtained as a colorless oil (69 mg, 70%) from
piperidine 4c (124 mg, 0.177 mmol) as described above.
[a]
D = 35 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.35–7.24
(m, 20H, ArH), 5.76 (ddd, J = 17.0, 10.2, 9.2 Hz, 1H, –CH@), 5.31 (d,
J = 10.2 Hz, 1H, @CHH), 5.06 (d, J = 17.0 Hz, 1H, @CHH), 4.93
(d, J = 10.8 Hz, 1H, CHHPh), 4.81 (d, J = 10.8 Hz, 1H, CHHPh), 4.80
(d, J = 11.3 Hz, 1H, CHHPh), 4.65 (d, J = 11.3 Hz, 1H, CHHPh), 4.46
(qAB, J = 11.5 Hz, 2H, CH2Ph), 3.91 (t, J = 9.2, 8.9 Hz, 1H, H-4),
3.84 (dd, J = 9.2, 5.96 Hz, 1H, H-3), 3.79 (m, 3H, CH2N, CHHO),
3.64 (dd, J = 8.9, 6.2 Hz, 1H, H-5), 3.65 (m, 1H, CHHO), 3.46 (dd,
J = 9.2, 6.2 Hz, 1H, H-6), 3.33 (ddd, J = 7.9, 5.96, 4.2 Hz, 1H, H-2),
2.82 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3): d 138.9, 138.8,
138.1, 137.9 (4 ArC), 134.4 (–CH@), 128.5–126.6 (ArCH), 120.2
(CH2@), 81.2 (C-3), 80.2 (C-5), 79.7 (C-4), 75.5, 74.2, 71.8 (3 CH2Ph),
61.9 (C-2), 60.8 (CH2OH), 60.6 (C-6), 56.4 (NCH2); HRMS (ESI) m/z:
[M+H]+ calcd for C36H40NO4: 550.2957; found: 550.2951.
4.4.4. (2S,3R,4R,5S,6S)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
vinylpiperidin-2-yl)methyl 4-nitrobenzoate (4d) and
(3R,4R,5R,6S,7S)-1-benzyl-4,5,6-tris(benzyloxy)-7-vinylazepan-
3-yl 4-nitrobenzoate (5d)
Piperidine 4d and azepane 5d were obtained as an inseparable
mixture (301 mg, 67%), from azepane 3d (353 mg, 0.643 mmol) as
described above.
4.5.4. (2S,3R,4R,5S,6S)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
vinylpiperidin-2-yl)methanol (6d)
Piperidine 6d (155 mg, 44% yield over 2 steps) and azepane 3d
(78 mg, 22% over 2 steps) were obtained from mixture of com-
pounds 4d and 5d (265 mg, 0.378 mmol) as described above after
separation by flash chromatography.
4.5. General procedure for the synthesis of piperidines 6a–d
Potassium carbonate (378 mg, 2.7 mmol) was added to a solu-
tion of piperidine 4a (190 mg, 0.266 mmol) in MeOH/THF (12 mL,
10:2). The mixture was stirred at room temperature for 4 h,
quenched with saturated aqueous NH4Cl, and extracted with
EtOAc. The organic layer was washed with brine, dried over MgSO4
and concentrated under reduced pressure after filtration. The resi-
due was purified by flash chromatography (EtOAc/petroleum ether
10:90) to afford piperidine 6a as colorless oil (114 mg, 76% yield).
[a]
D = 31.3 (c 1.44, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.29–
7.23 (m, 20H, ArH), 5.72 (ddd, J = 17.2, 10.2, 7.8 Hz, 1H, –CH@),
5.42 (dd, J = 17.2, 1.2 Hz, 1H, @CHH), 5.32 (dd, J = 10.2, 1.5 Hz,
1H, @CHH), 4.92 (d, J = 10.8 Hz, 1H, CHHPh), 4.85 (d, J = 10.8
Hz, 1H, CHHPh), 4.77 (d, J = 10.3 Hz, 1H, CHHPh), 4.65
(d, J = 11.4 Hz, 1H, CHHPh), 4.63 (d, J = 10.3 Hz, 1H, CHHPh), 4.56
(d, J = 11.4 Hz, 1H, CHHPh), 3.98–3.73 (m, 6H, H-3, H-4 ou H-5,
CH2N, CH2OH), 3.43 (t, J = 9.4, 7.8 Hz, 1H, H-4 ou H-5), 3.38 (t,
J = 9.4, 7.8 Hz, 1H, H-6), 3.11 (q, J = 6.8-5.6 Hz, 1H, H-2), 2.53 (dd,
J = 6.8, 5.6 Hz, 1H, OH); 13C NMR (100 MHz, CDCl3): d 139.7,
138.8, 138.3, 137.8 (4 ArC), 137.7 (–CH@), 128.5–127.1 (ArCH),
120.3 (CH2@), 83.4, 82.3, 80.2 (C-3, C-4, C-5), 75.7, 75.3, 73.5 (3
CH2Ph), 63.8 (C-6), 57.08, 57.00 (CH2OH, C-2), 52.8 (NCH2); HRMS
(ESI) m/z: [M+Na]+ calcd for C36H39NO4Na: 572.2776; found:
572.2777.
4.5.1. (2S,3R,4R,5S,6S)-6-Allyl-1-benzyl-3,4,5-
tris(benzyloxy)piperidin-2-yl)methanol (6a)
1H NMR (400 MHz, CDCl3): d 7.35–7.10 (m, 20H, ArH)), 5.86 (m,
1H, –CH@), 5.17–5.13 (m, 2H, @CH2), 4.93 (d, J = 10.7 Hz, 2H,
2CHHPh), 4.83 (d, J = 10.7 Hz, 1H, CHHPh), 4.62 (d, J = 10.7 Hz,
1H, CHHPh), 4.55 (qAB, 2H, CH2Ph), 4.02 (d, J = 12.7 Hz, 1H, CHHN),
3.98 (dd, J = 9.6, 6.2 Hz, 1H, H-3), 3.76 (like t, J = 9.6, 9.0 Hz, 1H, H-
4), 3.68–3.58 (m, 2H, CH2OH), 3.52 (dd, J = 10.6, 9.0 Hz, 1H, H-5),
3.40 (d, J = 12.7 Hz, 1H, CHHN), 3.11–3.01 (m, 2H, H-2, H-6), 2.86
(m, 1H, H-7), 2.67 (d, J = 8.2 Hz, 1H, OH), 2.31 (m, 1H, H-7); 13C
NMR (100 MHz, CDCl3): d 138.6, 138.4, 138.1, 137.8 (4 ArC),
135.4 (–CH@), 128.9–127.5 (ArCH), 117.6 (CH2@), 84.8 (C-4), 79.9
(C-5), 77.2 (C-3), 75.8, 75.5, 72.8 (3 CH2Ph), 56.3 (C-2), 56.2
(CH2OH), 55.5 (C-6), 49.7 (NCH2), 32.4 (CH2 allyl); HRMS (ESI) m/
z: [M+H]+ calcd for C37H42NO4: 564.3113; found: 564.3111.
4.6. General procedure for the synthesis of piperidines 7a–d and
azepanes 8a–c
To a solution of piperidine 6a (43 mg, 0.076 mmol) in CH3OH
(6 mL) was added 10% Pd/C (22 mg), Pd black (22 mg) and a 1 M
HCl aqueous solution (0.15 mL, 0.15 mmol). The solution was
purged with N2 followed by H2 then stirred under a H2 atmosphere.
After stirring overnight at room temperature, the reaction mixture
was purged with N2, filtered over a Celite pad eluted with CH3OH.
The filtrate was concentrated under reduced pressure to give
piperidine 7a (18 mg, quantitative yield) as its hydrochloride salt.
4.5.2. (2S,3R,4R,5S,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-
ethylpiperidin-2-yl)methanol (6b)
Piperidine 6b was obtained as a colorless oil (161 mg, 77%) from
piperidine 4b (265 mg, 0.378 mmol) as described above.
[
a]
D = 4.1 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.35–7.13
4.6.1. (2S,3R,4R,5S,6S)-2-(hydroxymethyl)-6-propylpiperidine-
(m, 20H, ArH), 4.87 (d, J = 10.8 Hz, 1H, CHHPh), 4.81 (d, J = 10.8 Hz,
1H, CHHPh), 4.74 (d, J = 11.4 Hz, 1H, CHHPh), 4.65 (d, J = 11.7
Hz, 1H, CHHPh), 4.61 (d, J = 11.7 Hz, 1H, CHHPh), 4.54 (d,
J = 11.4 Hz, 1H, CHHPh), 3.85 (m, 5H, H-3, H-4 and 3H CH2N or
CH2OH), 3.64 (m, 2H, H-5, CHHO or CHHN), 3.27 (m, 1H, H-2),
2.93 (br s, 1H, OH), 2.83 (m, 1H, H-6), 1.80 (m, 1H, CHH ethyl),
1.30 (m, 1H, CHH ethyl), 0.86 (t, J = 7.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d 139.7, 138.8, 138.4, 138.0 (4 ArC), 128.5–
127.4 (ArCH), 79.7, 79.4, 79.3 (C-3, C-4, C-5), 75.4, 73.8, 72.9
(3 CH2Ph), 61.2 (C-2, C-6), 60.9, 60.5 (NCH2, CH2OH), 21.8 (CH2
3,4,5-triol (7a)
[
a]
D = ꢀ34 (c 0.2, MeOH); 1H NMR (400 MHz, CD3OD): d 3.95
(dd, J = 11.9, 4.8 Hz, 1H, CHHOH), 3.90–3.84 (m, 2H, H-3, CHHOH),
3.73 (t, J = 6.8 Hz, 1H, H-4), 3.66–3.61 (m, 1H, H-2), 3.59 (t, J = 7.1,
6.8 Hz, 1H, H-5), 3.37–3.33 (m, 1H, H-6), 2.12 (m, 1H, CHH), 1.67
(m, 1H, CHH), 1.54 (m, 2H, CH2), 1.02 (t, J = 7.6 Hz, 3H, CH3); 13C
NMR (100 MHz, CD3OD): d = 73.2 (C-4), 71.6 (C-5), 69.8 (C-3),
57.9 (C-6), 57.7 (CH2OH), 56.6 (C-2), 31.9 (CH2 propyl), 19.8 (CH2
propyl), 14.1 (CH3 propyl); HRMS (ESI) m/z: [M+H]+ calcd for
C9H20NO4: 184.1687; found: 184.1685.

M. Mondon et al. / Bioorg. Med. Chem. 21 (2013) 4803–4812
4811
4.6.2. (2R,3S,4R,5R,6S)-2-Ethyl-6-(hydroxymethyl)piperidine-
3,4,5-triol (7b)
4.6.7. (2R,3R,4R,5S,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-2,6-
divinylpiperidine (9)
Piperidine 6b (11 mg, 0.020 mmol) was deprotected as de-
scribed for 7a to give piperidine 7b (4.5 mg, quantitative yield)
as its hydrochloride salt.
Oxalyl chloride (0.13 mL, 1.45 mmol) was added to a stirred
solution of DMSO (0.14 mL, 1.94 mmol) in dry CH2Cl2 (3.5 mL) at
ꢀ78 °C and the resulting mixture was stirred at this temperature
for 30 min. A solution of piperidine 6c (266 mg, 0.484 mmol) in
dry CH2Cl2 (1.5 mL) was added to the reaction mixture at ꢀ78 °C
and stirred for 1 h at this temperature. Then, Et3N (0.4 mL,
2.87 mmol) was added at ꢀ78 °C and stirred for an additional
30 min at rt. The reaction mixture was diluted with water and ex-
tracted with CH2Cl2. The organic layers were washed with brine,
dried over MgSO4 and concentrated to give the crude aldehyde that
was used for the next reaction without further purification. n-
Butyllithium (0.8 mL of a 2.5 M solution in hexanes, 2.0 mmol)
was added to a solution of methyltriphenylphosphonium bromide
(692 mg, 1.94 mmol) in THF (3.5 mL) at 0 °C. After 30 min, the solu-
tion was cooled to ꢀ50 °C and a solution of the crude aldehyde in
THF (3 mL) was added dropwise. The mixture was stirred between
ꢀ30 and ꢀ20 °C for 1 h, quenched with water and extracted with
EtOAc. Flash chromatography purification (EtOAc/petroleum ether
10:90) gave piperidine 9 (122 mg, 46% over 2 steps) as an oil.
[a]
D = 7.5 (c 0.08, H2O); 1H NMR (400 MHz, D2O): d 4.13 (t,
J = 3.4 Hz, 1H, H-4), 4.03 (m, 2H, H-3, H-5), 3.86 (m, 2H, CH2OH),
3.57 (m, 1H, H-6), 3.40 (ddd, J = 6.4, 4.8, 1.4 Hz, H-2), 1.85–1.75
(m, 2H, CH2 ethyl), 0.96 (t, J = 7.4 Hz, 3H, CH3); 13C NMR
(100 MHz, D2O): d 66.85, 66.80, 66.3 (C-3, C-4, C-5), 59.0 (CH2OH),
56.5 (C-2, C-6), 20.7 (CH2 ethyl), 8.4 (CH3 ethyl); HRMS (ESI) m/z:
[M+H]+ calcd for C8H18NO4: 192.1236; found: 192.1237.
4.6.3. (2S,3S,4R,5R,6S)-2-Ethyl-6-(hydroxymethyl)piperidine-
3,4,5-triol (7c)
Piperidine 6d (32 mg, 0.058 mmol) was deprotected as de-
scribed for 7a to give piperidine 7c (13.3 mg, quantitative yield)
as its hydrochloride salt.
[a]
D = ꢀ27 (c 0.28, CH3OH); 1H NMR (400 MHz, D2O): d 3.94 (dd,
J = 12.6, 4.6 Hz, 1H, CHHOH), 3.85–3.79 (m, 2H, H-5, CHHOH), 3.69
(m, 1H, H-6), 3.62 (t, J = 8.7 Hz, 1H, H-4), 3.44 (dd, J = 9.7, 8.7 Hz,
1H, 1H, H-3), 3.21 (ddd, J = 9.7, 6.5, 4.4 Hz, H-2), 1.95 (m, 1H,
CHH ethyl), 1.66 (m, 1H, CHH ethyl), 0.95 (t, J = 7.6 Hz, 3H, CH3);
13C NMR (100 MHz, D2O): d = 72.3 (C-4), 70.3 (C-3), 68.1 (C-5),
56.1 (C-6), 55.6 (C-2), 55.0 (CH2OH), 21.3 (CH2 ethyl), 8.2 (CH3
ethyl); HRMS (ESI) m/z: [M+H]+ calcd for C8H18NO4: 192.1236;
found: 192.1235.
4.6.8. Aldehyde
1H NMR (400 MHz, CDCl3): d 9.91 d, J = 4.2 Hz, 1H, CHO), 7.32–
7.21 (m, 20H, ArH), 5.74 (dt, J = 16.8, 9.5–10.1 Hz, 1H, –CH@), 5.35
(dd, J = 10.1, 1.5 Hz, 1H, @CHH), 5.12 (dd, J = 16.8, 1.2 Hz, 1H,
@CHH), 4.86 (d, J = 10.9 Hz, 1H, CHHPh), 4.78 (d, J = 10.9 Hz,
1H, CHHPh), 4.64 (d, J = 11.6 Hz, 1H, CHHPh), 4.58 (d, J = 11.6
Hz, 1H, CHHPh), 4.51 (2H, CH2Ph), 4.00 (t, J = 8.6 Hz, 1H, H-4),
3.84 (d, J = 14.3 Hz, 1H, CHHN), 3.80 (dd, J = 8.6, 6.4 Hz, 1H, H-3),
3.70 (d, J = 14.3 Hz, 1H, CHHN), 3.65 (dd, J = 8.6, 5.4 Hz, 1H, H-5),
3.54 (dd, J = 9.5, 5.4 Hz, 1H, H-6), 3.41 (dd, J = 6.4, 4.2 Hz, 1H, H-
2); 13C NMR (100 MHz, CDCl3): d 201.9 (CHO), 137.6 (ArC), 136.9
(ArC), 134.1 (ArC), 127.5–126.3 (12ArCH), 78.9 (C-5), 77.8 (C-4),
77.5 (C-3), 74.1, 72.1, 71.0 (3 CH2Ph), 65.3 (C-2), 60.5 (C-6),
57.08, 54.9 (NCH2).
4.6.4. (2S,3S,4R,5R,6R)-2-Propylazepan-3,4,5,6-tetraol (8a)
Azepane 3a (30 mg, 0.053 mmol) was deprotected as described
for 7a to give 8a as its hydrochloride salt (12.8 mg, quantitative
yield).
[a]
D = ꢀ15 (c 0.24, CH3OH); 1H NMR (400 MHz, CD3OD): d 4.20
(m, 1H, H-6), 3.82 (like t, 1H, J = 7.3, 7.0 Hz, H-4), 3.78 (dd, J = 7.3,
2.0 Hz, 1H, H-5), 3.62 (dd, J = 7.6, 7.0 Hz, 1H, H-3), 3.41 (m, 1H,
H-2), 3.31 (m, 2H, 2H-7), 1.90 (m, 1H, CHH), 1.75 (m, 1H, CHH),
1.58 (m, 1H, CHH), 1.46 (m, 1H, CHH), 1.0 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (100 MHz, CD3OD): d 76.6(C-5), 74.7 (C-4), 73.4 (C-3),
67.5 (C-6), 61.4 (C-2), 46.2 (C-7), 33.7 (CH2), 19.4 (CH2), 14.2
(CH3); [M+H]+ calcd for C9H20NO4: 206.1392; found: 206.1394.
Compound 9 [a]
D = 6.3 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.37–7.25 (m, 20H, ArH), 5.88 (dt, J = 16.8, 10.1, 2H, –
CH@), 5.30 (dd, J = 10.1, 1.8 Hz, 2H, @CHH), 5.04 (dd, J = 16.8,
1.6 Hz, 2H, @CHH), 4.86 (s, 2H, CH2Ph), 4.56 (d, J = 11.5 Hz, 2H,
2CHHPh), 4.50 (d, J = 11.5 Hz, 2H, 2CHHPh), 3.89 (t, J = 9.4 Hz, 1H,
H-4), 3.72 (dd, J = 9.4, 6.2 Hz, 2H, H-3, H-5), 3.66 (s, 2H, CH2N),
3.59 (dd, J = 10.1, 6.2 Hz, 2H, H-2, H-6); 13C NMR (100 MHz, CDCl3):
d 139.2, 139.1, 138.3 (3 ArC), 135.0 (–CH@), 123–126.9 (7ArCH),
119.6 (CH2@), 80.4 (C-3, C-5), 79.2 (C-4), 75.6 (CH2Ph), 71.9
(2CH2Ph), 62.8 (C-2, C-6), 55.5 (NCH2); HRMS (ESI) m/z: [M+H]+
calcd for C37H40NO3: 546.3008; found: 546.3011.
4.6.5. (2R,3S,4R,5R,6R)-2-Ethylazepan-3,4,5,6-tetraol (8b)
Azepane 3b (41 mg, 0.074 mmol) was deprotected as described
for 7a to give azepane 8b (16.2 mg, 95%) as its hydrochloride salt.
[a]
D = 4 (c 0.3, MeOH); 1H NMR (400 MHz, CD3OD): d 4.16 (dd,
J = 8.3, 3.4 Hz, 1H, H-6), 3.85-3.86 and 3.80–3.79 (m, 2H and m,
1H, H-3, H-4, H-5), 3.33 (dd, J = 13.0, 8.3 Hz, 1H, H-7), 3.27 ((t,
J = 6.7 Hz, 1H, H-2), 3.15 (dd, J = 13.0, 3.4 Hz, 1H, H-7), 1.71–1.63
(m, 2H, CH2 ethyl), 0.93 (t, J = 7.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CD3OD): d 79.1, 73.7, 72.6 (C-3, C-4, C-5), 67.5 (C-6),
58.7 (C-2), 47.8 (C-7), 25.7 (CH2 ethyl), 10.4 (CH3 ethyl); HRMS
(ESI) m/z: [M+Na]+ calcd for C8H17NO4: 214.1055; found: 214.1055.
4.6.8. (2S,3R,4R,5S,6R)-2,6-Diethylpiperidine-3,4,5-triol (10)
Piperidine 9 (41 mg, 0.074 mmol) was deprotected as described
for 7a to give piperidine 10 (16.2 mg, 95%) as its hydrochloride salt.
[a]
D = 3 (c 0.4, MeOH); 1H NMR (400 MHz, CD3OD): d 4.08 (t,
J = 3.6 Hz, 1H, H-4), 3.91 (m, 2H, H-3, H-5), 3.33 (m, 2H, H-2, H-
6), 1.91 (m, 2H, 2CHH), 1.75 (m, 2H, 2CHH), 1.02 (t, J = 7.5 Hz, 6H,
2ꢁCH3); 13C NMR (100 MHz, CD3OD): d = 68.39 (C-3, C-5), 68.25
(C-4), 58.37 (C-2, C-6), 22.37 (2CH2), 9.67 (2CH3); HRMS (ESI) m/
z: [M+H]+ calcd for C9H20NO3: 190.1443; found: 190.1440.
4.6.6. (2S,3S,4R,5R,6R)-2-Ethylazepan-3,4,5,6-tetraol (8c)
Azepane 3c (35 mg, 0.0637 mmol) was deprotected as de-
scribed for 7a to give 8c (15 mg, quantitative yield) as its hydro-
chloride salt.
[a]
D = ꢀ16 (c 0.3, MeOH); 1H NMR (400 MHz, CD3OD): d 4.23–
Acknowledgments
4.20 (m, 1H, H-6), 3.87–3.80 (m, 2H, H-4, H-5), 3.66 (dd, J = 7.8,
6.3 Hz, 1H, H-3), 3.42–3.36 (m, 1H, H-2), 3.34-3.25 (m, 2H, 2H-7),
2.04–1.94 (m, 1H, CHH ethyl), 1.94–1.81 (m, 1H, CHH ethyl), 1.10
(t, J = 7.4 Hz, 3H, CH3); 13C NMR (100 MHz, CD3OD): d 76.5, 75.0
(C-4, C-5), 73.1 (C-3), 67.6 (C-6), 62.5 (C-2), 46.4 (C-7), 24.4 (CH2
ethyl), 9.7 (CH3 ethyl); [M+Na]+ calcd for C8H17NO4: 214.1055;
found: 214.1055.
We thank Eric Bourdeaud for his contribution to this work.
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