First total synthesis of (+)-adenophorine, a naturally occurring inhibitor of glycosidases

Article abstract of DOI:10.1002/ejoc.200700459

The first total synthesis of a naturally occurring iminosugar, (+)-adenophorine, in 14 steps from the (+)-enantiomer of Garner's aldehyde, is reported. The strategy is based on the preparation and functionalization of enantiomerically pure trans-6-ethyl-2

Full text of DOI:10.1002/ejoc.200700459

FULL PAPER
DOI: 10.1002/ejoc.200700459
First Total Synthesis of (+)-Adenophorine, a Naturally Occurring Inhibitor of
Glycosidases
Morwenna S. M. Pearson,[a] Michel Evain,[b] Monique Mathé-Allainmat,[a] and
Jacques Lebreton*[a]
Dedicated to Dr. André Guingant on the occasion of his 60th birthday
Keywords: Iminosugars / Adenophorine / RCM / Allylation / Imine / Epoxidation
The first total synthesis of a naturally occurring iminosugar,
(+)-adenophorine, in 14 steps from the (+)-enantiomer of
Garner’s aldehyde, is reported. The strategy is based on
the preparation and functionalization of enantiomerically
pure trans-6-ethyl-2-hydroxymethyl-1,2,5,6-tetrahydro-
pyridine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
structural determination was accomplished by classical
NMR (1H and 13C NMR) and mass spectroscopy studies
(HRFABMS). Their inhibitory activities toward various
glycosidases showed IC50 values of around 30 µ with β-
galactosidase (bovine liver) for the α-1-C-alkylated 1,2-di-
deoxy-iminosugar 4 (Figure 1) and poor or no activity on
α-glucosidase (rice),[9] whereas 1-deoxy-iminosugars such as
α-1-deoxy-1-C-methylhomonojirimycin (named adenophor-
ine, 5, Figure 1) was active on α-glucosidase (IC50: 34 µ)
but not on β-galactosidase.[8] These results demonstrated
that α-1-C-alkylation of natural deoxy-iminosugars is not a
negative factor for glycosidase inhibition and that the pres-
ence and relative positions of the hydroxy substituents on
the iminosugar seem to be determinant for selectivity. How-
ever, the rules of selectivity are not yet clearly understood.
Introduction
Since the discovery of nojirimycin (1, Figure 1) in 1966,[1]
many iminosugars have been isolated from plants and mi-
croorganisms[2] and many syntheses of these compounds
have been reported.[3] These natural or unnatural analogues
of carbohydrates, in which the endocyclic oxygen atom is
replaced by a nitrogen atom, are believed to modulate and
to block the catalytic processes of glycosidases by mimick-
ing the sugar moieties of natural substrates of the en-
zymes.[4] Because of the involvement of glycosidases in vari-
ous important biological processes, such as intestinal diges-
tion, post-translational processing of glycoproteins, or lyso-
somal catabolism of glycoconjugates, potential glycosidase
inhibitors such as N- or C-alkylated iminosugars have been
designed as therapeutic solutions for several diseases
(type II diabetes, viral and bacterial infections, lysosomal
storage disorders, tumor metastasis).[5] Currently, two imi-
nosugars have been approved as therapeutic agents: miglitol
(2, Glyset®)[6] as a second-generation α-glucosidase inhibi-
tor for treatment of type II diabetes and N-butyl-deoxynoji-
rimycin (NB-DNJ, 3, Zavesca®)[7] as a glucosylceramide in-
hibitor in Gaucher disease. In 2000, Asano and co-workers
isolated a series of α-1-C-alkylated analogues of 1,2-dide-
oxynojirimycin (fagomine) and 1-deoxy-homonojirimycin
from Lobelia sessilifolia and Adenophora spp.[8,9] Their
[a] Université de Nantes, CNRS, Laboratoire de Synthèse Or-
ganique UMR 6513, Faculté des Sciences et des Techniques,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
Figure 1. Nojirimycin and homonojirimycin analogues.
Fax: +33-2-51124502
E-mail: jacques.lebreton@univ-nantes.fr
As part of our ongoing program involving the synthesis
of alkaloids, we have developed an efficient route to chiral
trans-6-alkyl-2-hydroxymethyl-1,2,5,6-tetrahydropyridines.[10]
[b] Université de Nantes, CNRS, Institut des Matériaux Jean
Rouxel UMR 6502, Faculté des Sciences et des Techniques
2 rue de la Houssinière, B. P. 92208, 44322 Nantes, France
4888
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4888–4894

First Total Synthesis of the Glycosidase Inhibitor (+)-Adenophorine
Scheme 1. Retrosynthetic analysis.
Recently, we reported the use of these intermediates for the
synthesis of enantiomerically pure 5-deoxyadenophorine
(6, Figure 1),[11] a naturally occurring α-1-C-ethyl-1-deoxy-
iminosugar, and of some α-1-C-alkyl analogues as racemic
mixtures, in the idose and galactose series.[12] We wish to
describe here the asymmetric total synthesis of (+)-adeno-
phorine (5), another rare example of a naturally occurring
iminosugar bearing a lipophilic substituent at the anomeric
position. The absolute configuration of this (+)-iminosugar,
isolated from Adenophora spp. by Ikeda and co-workers in
2000,[8] was determined three years later by optical rotation
measurements performed on the (–) enantiomer synthesized
by Davis et al.[13]
Iminosugars are frequently synthesized from carbo-
hydrates as chiral pool starting materials with use of an
amination–intermolecular cyclization sequence or an intra-
molecular reductive amination cyclization as the key step.[3c]
We intended, however, to access these types of polyhy-
droxylated piperidines from amino acids by our previously
described methodology.[10,11] In our strategy, the configura-
tion of each stereogenic center has to be controlled during
the building steps. We planned to construct the piperidine
moiety and to introduce the three hydroxy groups dia-
stereoselectively by applying key reactions as depicted in
the retrosynthetic Scheme 1: diastereoselective allylation of
imine 9, ring-closing metathesis reaction to build the trans-
2,6-disubstituted 1,2,5,6-tetrahydropyridine skeleton 11,
and an olefination step following the oxidation of the sele-
nide 13. The 1,2,5,6-tetrahydropyridine moiety 11 could
thus be prepared in an enantiomerically pure form from
(R)-(+)-Garner’s aldehyde enantiomer 7 as already de-
scribed.[11]
Results and Discussion
Preparation of trans-6-Ethyl-2-hydroxymethyl-1,2,5,6-
tetrahydropyridine Derivative 11
(+)-Garner’s aldehyde enantiomer 7 was prepared from
commercially available -methyl serinate hydrochloride in
72% overall yield by the three-step sequence reported by
McKillop and co-workers (Scheme 2).[14] This aldehyde was
then converted into amino alcohol 8 by means of a Horner–
Wadworth–Emmons olefination reaction [100% (E) iso-
mer], followed by acidic hydrolysis of the protecting
groups.[10,15] Condensation of propionaldehyde with 8 fur-
nished imine 9, to which excess allylmagnesium bromide
was added to give diethylenic amino alcohol 10 as an in-
separable 87:13 mixture of trans and cis diastereoisomers.
We have previously confirmed the relative configuration of
the major adduct trans-10 with the aid of a chelation model
and the X-ray structure of an elaborated piperidine inter-
mediate.[11]
From 10, the formation of a tetrahydropyridine ring
through a ring-closing metathesis reaction[16] was optimized
after the protection of the diethylenic amino alcohols trans-
10 and cis-10[17] as the corresponding trans and cis oxazol-
idinones, which were not separable on silica gel (Scheme 2).
Treatment of the diastereoisomeric mixture with second-
generation Grubbs’ catalyst and separation of the diastereo-
isomers by flash chromatography provided the pure tetra-
hydropyridine trans-11 in 74% yield over two steps.
Stereoselective Addition of the Secondary Hydroxy Groups
Of the reported methods concerning the transformation
of olefins into allylic alcohols,[18] we decided to apply a
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FULL PAPER
Scheme 2. Reagents and conditions: a) diethyl benzylphosphonate, n-BuLi, THF, –78 °C to room temp., 14 h, 75%; b) concentrated HCl,
MeOH, reflux, 4 h, 98%; c) EtCHO, MgSO4, THF, room temp., 12 h; d) excess allylmagnesium bromide, THF, Et2O, –78 °C to –10 °C,
6 h, 87%; e) carbonyldiimidazole, Et3N, CH2Cl2, 18 h, 88%; f) second-generation Grubbs’ cat. (5 mol-%), CH2Cl2, reflux, 1 h, 84% trans-
11, 10% cis-11.
three-step process designed to introduce the alcohol func-
tion in a regioselective and stereoselective manner. Epoxid-
ation of tetrahydropyridine trans-11 with a freshly distilled
solution of dimethyldioxirane (DMDO) in acetone[19,20] af-
forded a crude 81:19 mixture of endo/exo epoxides. The
known epoxide endo-12[11] was isolated in a consistent 60%
yield after separation by flash chromatography (Scheme 3).
When mCPBA was used as described previously,[11] the
yield of pure endo-12 could vary from 40 to 86%. Regiose-
lective opening of the epoxide ring with a “selenium-boron
complex” generated in situ from diphenyldiselenide and so-
dium borohydride provided compound 13 as a single prod-
uct, obtained in 72% yield after purification. When this
compound was oxidized with an aqueous solution of hydro-
gen peroxide, phenylselenic acid elimination occurred spon-
taneously to give allylic alcohol 14 (63% yield after purifi-
cation).
Our next goal was to obtain epoxide exo-15 stereoselec-
tively from allylic alcohol 14. We decided to avoid the use
of mCPBA as epoxidation agent because of its known abil-
ity to assist allylic alcohol epoxidation;[21] in a single assay,
we obtained a 1:1 mixture of epoxides endo- and exo-15
after subsequent benzylation. We therefore set out to carry
out the epoxidation reaction with DMDO, which could not
form any intermolecular hydrogen bond with the hydroxy
group. Under these conditions we obtained a crude 5:95
mixture of diastereoisomers 15, which were separable by
flash chromatography only after benzylation of the hydroxy
group (Scheme 3, steps d and e). The major product exo-15
was isolated in 41% yield over two steps from allylic alcohol
14 and its absolute configuration was unambiguously deter-
mined by an X-ray crystal structure (Figure 2).
Scheme 3. Reagents and conditions: a) DMDO, acetone, room
temp., 4 h, 60% endo-12 (exo-12 not isolated); b) Ph2Se2, NaBH4,
EtOH, room temp., 12 h, 72%; c) 50% aq. H2O2, THF, room
temp., 2 h, 63%; d) DMDO, acetone, room temp., 4 h; e) BnBr,
NaH, THF, room temp., 12 h, 41% for exo-15 (2 steps); f) mCPBA,
CH2Cl2, room temp., 72 h, 60% for exo-15 (2 steps); g) 1  H2SO4
(3 equiv.), 1:1 mixture of H2O/dioxane, 80 °C, 12 h; h) BnBr, NaH,
DMF, room temp., 2 h, 60% (2 steps); i) 8  NaOH, MeOH, 95 °C,
48 h, 76%; j) H2, HCl, Pd(OH)2, EtOH, room temp., 24 h, quant.
However, the yield could be optimized to 60% over two
steps when allylic alcohol 14 was protected beforehand by was unsuccessful. More strongly acidic conditions were nec-
treatment with benzyl bromide and the resulting benzylated essary to provide the desired product. In a first assay, con-
derivative (82% yield) was subjected to epoxidation with ducted in acetic acid in the presence of trifluoroacetic
mCPBA (Scheme 3, steps e and f). This process led to a acid,[24] a mixture of acylated derivatives of 16 was ob-
2:98 mixture of diastereoisomers, and purification by flash served. After methanolysis and benzylation of the two free
chromatography provided epoxide exo-15 in 73% yield. hydroxy groups under classical conditions, the expected
Opening of this epoxide by use of acetic acid as solvent or compound 17 could be purified in 32% yield over the three
with sodium acetate in acetic acid[22] or alkoxide in DMF[23] steps. In a secondary assay, treatment of epoxide 15 with
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Eur. J. Org. Chem. 2007, 4888–4894

First Total Synthesis of the Glycosidase Inhibitor (+)-Adenophorine
14 offer the possibility of performing modulations on the
adenophorine structure and we are currently investigating
the synthesis of adenophorine isomers.
Experimental Section
General Methods: All reactions were performed under N2 in flame-
dried flasks using anhydrous solvents and monitored by TLC (Kie-
selgel 60F254 MERCK aluminium sheet) with detection by UV light
and/or with ethanolic phosphomolybdic acid solution. Flash col-
umn chromatography was performed on silica gel (60 ACC 40–
63 µm, CARLO–ERBA REACTIFS - SDS). Optical rotation val-
ues were measured in a 100 mm cell on a Perkin–Elmer 341 polari-
meter with Na lamp radiation. Melting points were determined on
an RCH (C. REICHERT) microscope equipped with a Koffer heat-
ing system. IR spectra were recorded with a BRUKER Vector 22
spectrometer. NMR spectra were recorded on a BRUKER Av-
ance 300 at 300 MHz (1H) and 75 MHz (13C) or on a BRUKER
ARX 400 at 400 MHz (1H) and 100 MHz (13C), in an appropriate
solvent (Me4Si as an internal standard for CDCl3), and chemical
shifts were assigned with the aid of DEPT experiments and by 2D
correlation techniques (COSY and HMQC). Mass spectra were ac-
complished with an HP 5889A quadripolar spectrometer by elec-
tronic impact EI (70 eV) or chemical ionization CI (500 eV) with
NH3 gas. HRMS spectra were recorded at the “Centre Régional de
Mesures Physiques de l’Ouest” (CRMPO, Université de Rennes 1).
Dimethyldioxirane solution in acetone was prepared by the pro-
cedure of Adam et al. and the concentration was determined by
the iodometric titration method.[19]
Figure 2. Molecular diagram of exo-15. Atoms of the asymmetric
unit are depicted as ellipsoids at the 50% probability level.
sulfuric acid (3 equiv.) in a 1:1 water/dioxane mixture[25] af-
forded the single diol 16, which was benzylated for the puri-
fication step. In this way, compound 17 was prepared from
exo-15 in 60% yield for the two steps.
To achieve our total synthesis of adenophorine, cleavage
of the protecting groups was performed. In the first step,
hydrolysis of the oxazolidinone group was carried out under
basic conditions with aqueous NaOH in methanol at reflux.
Then, in the second step, hydrogenolysis of the resulting
dibenzylated derivative in an acidic medium[26] with
Pd(OH)2 as the catalyst afforded the expected adenophor-
1
ine as its hydrochloride. H and 13C NMR spectra mea-
sured in D2O/NaOD were compared to those in D2O pub-
lished by Asano and co-workers for natural (+)-adenophor-
ine.[8] No difference was observed for the chemical displace-
ments and coupling constants of the protons, while carbon
displacements were systematically shifted from 1.5 to
2 ppm. We concluded that we had successfully synthesized
the natural (+)-adenophorine, which was supported by the
optical rotation measurement of +44 (c = 0.16, H2O,
NaOD) in comparison with the literature value of +59.7 (c
= 1, H2O).[8]
Compounds 7 to 11 are described in a preceding paper published
by our group.[11]
(1aR,3R,7aR,7bS)-3-Ethylperhydro[1,3]oxazolo[3,4-a]oxireno[2,3-c]-
pyridin-5-one (endo-12): A freshly distilled solution of dimethyldi-
oxirane (47 mL, c = 0.05 , 2.36 mmol) was added to a solution of
tetrahydropyridine 11 (198 mg, 1.18 mmol) in acetone (5 mL), co-
oled to 0 °C. After stirring at 0 °C for 15 min and at room tempera-
ture for an additional 4 h, the solution was concentrated in vacuo
to give a crude 81:19 mixture of epoxides endo-12 and exo-12. Puri-
fication by flash chromatography (100% petroleum ether, then
EtOAc/petroleum ether 60%) afforded endo-12 (130 mg, 60%) as a
colorless oil (exo-12 was not isolated in a pure form). Rf = 0.35
(EtOAc/petroleum ether 80%). [α]2D0 = –10.8 (c = 0.926, CHCl3)
[ref.[11] [α]2D0 = –13.9 (c = 0.720, CHCl3)]. 1H NMR (300 MHz,
CDCl3): δ = 4.50 (t, J = 8.6 Hz, 1 H, 7-H), 4.32 (dd, J = 5.5, J =
8.6 Hz, 1 H, 7-H), 4.15 (dd, J = 5.5, J = 8.6 Hz, 1 H, 7a-H), 3.71
(m, 1 H, 3-H), 3.33 (t, J = 4.6 Hz, 1 H, 1a-H), 3.12 (d, J = 3.9 Hz,
1 H, 7b-H), 2.27 (dd, J = 7.8, J = 15.7 Hz, 1 H, 2-H), 1.76 (dd, J
= 5.3, J = 15.7 Hz, 1 H, 2-H), 1.63–1.46 (m, 2 H, CH3–CH2), 0.94
(t, J = 7.4 Hz, 3 H, CH3–CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.0 (C-5), 65.1 (7-C), 50.1, 49.9 (C-1a, C-7b), 48.8 (C-7a),
47.0 (C-3), 26.0, 25.3 (C-2, CH3–CH2), 10.5 (CH3–CH2) ppm. IR
Conclusions
Four years after the publication of the (–)-adenophorine
synthesis by Maughan and co-workers,[13] we have per-
formed the first total synthesis of naturally occurring (+)-
adenophorine in 14 steps from the Garner’s aldehyde en-
antiomer and in 3.5% overall yield. We have once again
exploited the synthetic potential of the trans-2,6-disubsti-
tuted 1,2,5,6-tetrahydropyridine key intermediate for the
preparation of enantiomerically pure α-1-C-alkyl-imi-
nosugars. Starting from (2S,6R)-6-ethyl-2-hydroxymethyl-
1,2,5,6-tetrahydropyridine, we have controlled the stereose-
lectivity of the introduction of the three secondary hydroxy
groups of adenophorine. Successive epoxidations of
enantiopure substituted tetrahydropyridines trans-11 and 14
and regioselective opening of these epoxides with selenium-
boron complex and water, respectively, could be achieved
with good stereoselectivity, undoubtedly controlled by the
conformation of the starting materials and the steric effects
induced by the substituents on the piperidine moiety. These
(CCl ): ν = 2923, 2853, 1742 cm–1. MS (EI): m/z (%) = 183 (6)
˜
4
[M]+, 154 (100), 92 (24), 55 (35).
(5R,7S,8S,8aR)-5-Ethyl-8-hydroxy-7-(phenylselenyl)perhydro[1,3]-
oxazolo[3,4-a]pyridin-3-one (13): Diphenyl diselenide (157 mg,
0.50 mmol) was suspended in dry ethanol (2 mL). At 0 °C, NaBH4
(38 mg, 1.01 mmol) was slowly added and the suspension was
stirred until complete dissolution. At room temperature, a solution
of the epoxide endo-12 (154 mg, 0.84 mmol) in ethanol (3 mL) was
added, and the reaction mixture was stirred overnight at room tem-
substituted tetrahydropyridine intermediates trans-11 and perature. At 0 °C, the yellow solution was quenched with a satu-
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M. S. M. Pearson, M. Evain, M. Mathé-Allainmat, J. Lebreton
FULL PAPER
rated aqueous solution of NH4Cl and concentrated under reduced
pressure. The residue was partitioned between EtOAc (20 mL) and
water (20 mL) and the aqueous phase was extracted with EtOAc
(twice). The combined organic fractions were washed with brine,
dried with anhydrous MgSO4, filtered, and concentrated under re-
duced pressure. Purification by flash chromatography (EtOAc/pe-
troleum ether, 40%) yielded 13 (205 mg, 72%) as a white solid. Rf
= 0.30 (EtOAc/petroleum ether 50%). M.p. 110 °C (CH2Cl2). [α]2D0
= –26.4 (c = 1.040, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.54–7.50 (m, 2 H, Ph), 7.32–7.62 (m, 3 H, Ph), 4.45 (m, 1 H, 8a-
H), 4.40–4.34 (m, 2 H, 1-H), 3.84 (m, 1 H, 5-H), 3.70 (br. s, 1 H,
8-H), 3.61 (m, 1 H, 7-H), 3.21 (d, J = 6.6 Hz, 1 H, OH), 2.70 (dt,
J = 6.3, J = 15.2 Hz, 1 H, 6-H), 1.95–1.75 (m, 2 H, 6-H, CH3–
CH2), 1.64 (m, 1 H, CH3–CH2), 0.96 (t, J = 7.4 Hz, 3 H, CH3–
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.9 (Ph), 158.0 (C-
3), 133.7, 129.5, 128.0 (Ph), 68.3 (C-8), 63.9 (C-1), 50.6, 50.2 (C-5,
C-8a), 41.9 (7-C), 26.8, 26.5 (C-6, CH3–CH2), 11.2 (CH3–
CH ) ppm. IR (CCl ): ν = ν = 3500–3100, 2925, 1722, 1434 cm–1.
8.0 Hz, 1 H, 1-H), 4.24 (m, 1 H, 5-H), 3.88 (m, 1 H, 8a-H), 3.76
(m, 1 H, 8-H), 1.84–1.54 (m, 2 H, CH3–CH2), 1.0 (t, J = 7.4 Hz, 3
H, CH3–CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.8 (C-3),
137.9 (Ph), 133.8, 123.2 (C-6, C-7), 128.3, 127.6, 127.3 (Ph), 69.8
(Ph-CH2-O), 67.1 (C-8), 63.9 (C-1), 53.0 (C-8a), 52.0 (C-5), 26.9
(CH –CH ), 10.0 (CH –CH ) ppm. IR (CCl ): ν = ν = 2926, 1734,
˜
˜
3
2
3
2
4
1423 cm–1. MS (CI): m/z = 291 [M + NH4]+, 274 [M + H]+. HRMS
(EI) calcd. for C16H19NO3 [M]+: 273.1365; found 273.1363.
This protected allylic alcohol (47 mg, 0.17 mmol) was dissolved in
CH2Cl2 (5 mL) and cooled to 0 °C. After addition of mCPBA
(170 mg, 70% in water, 0.69 mmol), the solution was stirred at 0 °C
for 1 h and at room temperature for an additional 72 h. An aque-
ous solution of Na2S2O3 (10%, 3 mL) was added and the mixture
was stirred at room temperature for 15 min before addition of a
saturated aqueous NaHCO3 solution (5 mL).The resulting solution
was stirred for a further 5 min and the aqueous phase was extracted
with CH2Cl2 (4ϫ). After drying over anhydrous MgSO4 and fil-
tration, the organic fraction was concentrated in vacuo to give a
crude 2:98 mixture of epoxides. Purification by flash chromatog-
raphy (EtOAc/petroleum ether 30%) afforded exo-15 (36 mg, 73%)
as white crystalline plates. The epoxide endo-15 was not isolated.
Rf = 0.35 (EtOAc/petroleum ether 40 %). M.p. 121 °C (from
˜
˜
2
4
MS (EI): m/z (%) = 341 (12) [M]+ (80Se), 339 (7) [M]+ (78Se), 312
(12) (80Se), 310 (6) (78Se), 184 (55), 99(42), 57 (100). HRMS (EI)
calcd. for C15H19NO380Se [M]+: 341.0530; found 341.0542.
(5R,8R,8aR)-5-Ethyl-8-hydroxy-1,5,8,8a-tetrahydro[1,3]oxazolo-
[3,4-a]pyridin-3-one (14): A solution of hydrogen peroxide (560 µL,
50% in water, 8.2 mmol) was added to a solution of the alcohol 13
(280 mg, 0.82 mmol) in THF (6 mL), cooled to 0 °C. The solution
was stirred at room temperature for 2 h. EtOAc (15 mL) and water
(15 mL) were added and the organic layer was washed with a satu-
rated aqueous solution of NaHCO3 and then with brine. After dry-
ing over anhydrous MgSO4, filtration, and removal of the solvent
under reduced pressure, the residue was purified by flash
chromatography (EtOAc/petroleum ether 10%, then EtOAc/petro-
leum ether 60%) to give 14 (95 mg, 63%) as white crystals. Rf =
CH2Cl2). [α]2D0 = –130.8 (c = 0.424, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 7.30–7.40 (m, 5 H, Ph), 4.77 (d, J = 12.1 Hz, 1 H, Ph-
CH2-O), 4.68 (d, J = 12.1 Hz, 1 H, Ph-CH2-O), 4.24–4.18 (m, 2 H,
6-H), 4.06 (td, J = 3.1, J = 7.2 Hz, 1 H, 2-H), 3.93–3.86 (m, 1 H,
6a-H), 3.81 (m, 1 H, 7-H), 3.39 (dd, J = 3.9, J = 6.8 Hz, 1 H, 7a-
H), 3.35 (m, 1 H, 1a-H), 1.78–1.67 (m, 2 H, CH3–CH2), 1.03 (t, J
= 7.4 Hz, 3 H, CH3–CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
158.0 (C-4), 137.2, 128.7, 128.3, 127.9 (Ph), 73.2 (Ph-CH2-O), 71.8
(C-7), 63.1 (C-6), 52.7, 52.0 (C-1a, C-7a), 51.0 (C-6a), 49.7 (C-2),
24.8 (CH –CH ), 10.0 (CH –CH ) ppm. IR (CCl ): ν = 3050, 2969,
˜
3
2
3
2
4
0.29 (90% EtOAc/petroleum ether). M.p. 134 °C (Et2O). [α]2D0
=
2927, 1742, 1464, 1421, 1226, 1040 cm–1. MS (CI): m/z = 307 [M
1
+ NH4]+, 290 [M + H]+.
–327.5 (c = 0.224, CHCl3). H NMR (300 MHz, CDCl3): δ = 6.10
(ddd, J = 2.2, J = 5.6, J = 10.2 Hz, 1 H, 7-H), 5.98 (dd, J = 3.3, J
= 10.2 Hz, 1 H, 6-H), 4.65 (dd, J = 4.2, J = 8.6 Hz, 1 H, 1-H), 4.40
(t, J = 8.6 Hz, 1 H, 1-H), 4.17 (m, 1 H, 5-H), 3.93–3.83 (m, 2 H,
8-H, 8a-H), 2.33 (d, J = 9.6 Hz, 1 H, OH), 1.78–1.48 (m, 2 H,
CH3–CH2), 0.98 (t, J = 7.5 Hz, 3 H, CH3–CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 157.9 (C-3), 132.4 (C-6), 125.5 (C-7), 63.9
(C-1), 62.1, 53.6 (C-8, C-8a), 52.0 (C-5), 26.7 (CH3–CH2), 10.2
(5R,6R,7S,8S,8aR)-8-Benzyloxy-5-ethyl-6,7-dihydroxyperhydro-
[1,3]oxazolo[3,4-a]pyridin-3-one (16): The epoxide exo-15 (175 mg,
0.605 mmol) was dissolved in a mixture of dioxane and water (1:1,
30 mL). An aqueous H2SO4 solution (1 , 1.8 mL, 1.81 mmol) was
added, and the mixture was stirred at 80 °C for 12 h. A saturated
aqueous NaHCO3 solution (20 mL) was added, and the mixture
was stirred at room temperature for 10 min. The aqueous phase
was extracted with EtOAc (3ϫ), and the combined organic extracts
were washed with brine. After drying over anhydrous MgSO4 and
filtration, the organic fraction was concentrated in vacuo to give
16 as a white oil. The residue was used without further purification.
Rf = 0.30 (EtOAc/petroleum ether 90 %). 1H NMR (300 MHz,
CDCl3): δ = 7.41–7.31 (m, 5 H, Ph), 4.80 (d, J = 11.6 Hz, 1 H, Ph-
CH2-O), 4.56 (d, J = 11.6 Hz, 1 H, Ph-CH2-O), 4.35–4.25 (m, 2 H,
6-H, 1-H), 4.24–4.16 (m, 2 H, 8a-H, 1-H), 3.93 (dd, J = 5.8, J =
10.1 Hz, 1 H, 5-H), 3.72 (br. s, 1 H, 7-H), 3.52 (br. s, 1 H, 8-H),
1.86 (m, 1 H, CH3–CH2), 1.66 (m, 1 H, CH3–CH2), 0.96 (t, J =
7.4 Hz, 3 H, CH3–CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.0 (C-3), 138.0, 128.8, 128.7, 128.3 (Ph), 75.4 (C-8), 73.1 (Ph-
CH2-O), 71.0 (C-7), 66.6 (C-6), 63.1 (C-1), 58.7 (C-5), 48.9 (C-8a),
(CH –CH ) ppm. IR (CCl ): ν = 3584, 3500–3100, 1724, 1429 cm–1.
˜
3
2
4
MS (EI): m/z (%) = 183 (3) [M]+, 154 (51), 98 (100), 83 (42). HRMS
(EI) calcd. for C9H13NO3 [M]+: 183.0895; found 183.0898.
(1aS,2R,6aR,7S,7aS)-7-Benzyloxy-2-ethylperhydro[1,3]oxazolo[3,4-
a]oxireno[2,3-d]pyridin-4-one (15): NaH (16 mg, 60% mineral oil
dispersion, 0.40 mmol) was slowly added to a solution of the allylic
alcohol 14 (61 mg, 0.33 mmol) in dry THF (3 mL), cooled to 0 °C.
The suspension was stirred at 0 °C until the evolution of H2 had
ceased (15 min) and at room temperature for an additional 15 min.
Benzyl bromide (59 µL, 0.50 mmol) was added and the mixture was
stirred at room temperature for 12 h. At 0 °C, a saturated aqueous
NH4Cl solution (5 mL) was added and the resulting aqueous phase
was extracted with EtOAc (3ϫ). The combined organic fractions
were washed with brine, dried with anhydrous MgSO4, and filtered.
After removal of the solvent under reduced pressure, the residue
was purified by flash chromatography (EtOAc/petroleum ether
30%) to give the expected benzylated derivative (74 mg, 82%) as
white crystalline plates. Rf = 0.34 (EtOAc/petroleum ether 30%).
23.4 (CH –CH ), 11.1 (CH –CH ) ppm. IR (CCl ): ν = 3418, 3032,
˜
3
2
3
2
4
2964, 2927, 2876, 1726, 1433, 1261 cm–1. MS (CI) or MS (EI):
m/z = no results, unstable compound.
(5R,6R,7S,8S,8aR)-6,7,8-Tribenzyloxy-5-ethylperhydro[1,3]oxazolo-
[3,4-a]pyridin-3-one (17): NaH (154 mg, 60% mineral oil dispersion,
3.63 mmol) was slowly added to a solution of the crude diol 16
1
M.p. 44 °C (from CH2Cl2). [α]2D0 = –271.1 (c = 0.820, CHCl3). H
NMR (300 MHz, CDCl3): δ = 7.40–7.30 (m, 5 H, Ph), 6.16–6.02
(m, 2 H, 6-H, 7-H), 4.68 (d, J = 12.0 Hz, 1 H, Ph-CH2-O), 4.59 (0.605 mmol) in dry DMF (30 mL), cooled to 0 °C. The suspension
(m, 1 H, 1-H), 4.49 (d, J = 12.0 Hz, 1 H, Ph-CH2-O), 4.37 (t, J = was stirred at 0 °C until the evolution of H2 had ceased (10 min)
4892
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4888–4894

First Total Synthesis of the Glycosidase Inhibitor (+)-Adenophorine
and at room temperature for an additional 10 min. Benzyl bromide
(289 µL, 2.42 mmol) was added, and the mixture was stirred at
room temperature for 2 h. At 0 °C, saturated aqueous NH4Cl solu-
tion (30 mL) was slowly added and the resulting aqueous phase
was extracted with Et2O (4ϫ). The combined organic fractions
were washed with brine (3ϫ), dried with anhydrous MgSO4, and
filtered. After removal of the solvent under reduced pressure, the
residue was purified by flash chromatography (EtOAc/petroleum
ether 30%) to give 17 (177 mg, 60% for the 2 steps from 15) as a
colorless oil. Rf = 0.38 (EtOAc/petroleum ether 30%). [α]2D0 = –47.2
H, 2-H or 6-H), 2.02 (m, 1 H, CH3–CH2), 1.65 (m, 1 H, CH3–
CH2), 0.97 (t, J = 7.5 Hz, 3 H, CH3–CH2) ppm. 1H NMR
(400 MHz, D2O, NaOD): δ = 3.90–3.75 (m, 2 H, 1-H), 3.71 (dd, J
= 6.0, J = 9.6 Hz, 1 H, 3-H), 3.45 (t, J = 9.6 Hz, 1 H, 4-H), 3.21
(m, 1 H, 2-H), 3.09 (t, J = 9.6 Hz, 1 H, 5-H), 2.62 (m, 1 H, 6-H),
1.83 (m, 1 H, CH3–CH2), 1.32 (m, 1 H, CH3–CH2), 0.93 (t, J =
7.6 Hz, 3 H, CH3–CH2) ppm. 13C NMR (75 MHz, CD3OD): δ =
73.2, 71.2, 69.7 (C-3, C-4, C-5), 57.7 (1-H), 59.0, 56.6 (C-2, C-6),
22.8 (CH3–CH2), 10.1 (CH3–CH2) ppm. 13C NMR (100 MHz,
D2O, NaOD): δ = 75.7 (C-4, C-5), 72.9 (C-3), 57.9 (C-2), 57.5 (C-
(c = 0.392, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.18 1), 54.4 (C-6), 24.8 (CH3–CH2), 9.7 (CH3–CH2) ppm. HRMS (ESI)
(m, 15 H, Ph), 4.71 (d, J = 11.0 Hz, 2 H, Ph-CH2-O), 4.52–4.32
(m, 5 H, 1-H, Ph-CH2-O), 4.26 (t, J = 8.7 Hz, 1 H, 1-H), 4.11 (ddd,
J = 2.6, J = 4.6, J = 8.7 Hz, 1 H, 8a-H), 4.04 (br. t, J = 7.9 Hz, 1
H, 5-H), 3.90 (t, J = 2.6 Hz, 1 H, 7-H), 3.57 (br. s, 1 H, 6-H), 3.37
(t, J = 2.6 Hz, 1 H, 8-H), 1.82 (m, 1 H, CH3–CH2), 1.65 (m, 1 H,
CH3–CH2), 0.93 (t, J = 7.4 Hz, 3 H, CH3–CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.1 (C-3), 138.0, 137.5, 137.3, 128.6,
128.4, 128.1, 127.9, 127.7 (Ph), 73.7, 73.1, 72.5, 72.4, 71.4, 71.1 (C-
6, C-7, C-8, Ph-CH2-O), 63.2 (C-1), 53.7 (C-5), 49.8 (C-8a), 23.4
calcd. for C8H18NO4 [M – Cl]+: 192.1236; found 192.1231.
X-ray Crystallographic Study: Data were collected on a Bruker–
Nonius KappaCCD diffractometer at 150 K using graphite-mono-
chromated Mo-Kα radiation (λ = 0.71073 Å) up to a resolution of
(sin θ/λ)max = 0.7 Å–1 at a temperature of 150 K. The structure was
solved by direct methods[27]and refined with the JANA2006 pro-
gram.[28] Non-hydrogen atoms were defined anisotropically. The
hydrogen atoms, all visible from the difference Fourier map, were
placed in geometrically optimized positions and refined with a “ri-
ding” model.
(CH –CH ), 10.7 (CH –CH ) ppm. IR (CCl ): ν = 3031, 2930,
˜
3
2
3
2
4
1748, 1496, 1456, 1426 cm–1. MS (CI): m/z = 505 [M + NH4]+, 488
[M + H]+. HRMS (ESI) calcd. for C30H34NO5 [M + H]+: 488.2437;
found 488.2443.
Crystal Data for exo-15: C16H19NO4, Mw
=
289.3,
0.42ϫ0.35ϫ0.12 mm3, orthorhombic, space group P212121 (no.
19), a = 4.8413(3), b = 12.5775(14), c = 23.537(3) Å, V =
(+)-Adenophorine Hydrochloride (5·HCl): The oxazolidinone 17
(131 mg, 0.27 mmol) was dissolved in MeOH (13 mL) and an aque-
ous solution of NaOH (8 , 3.4 mL, 2.70 mmol) was added. The
mixture was stirred at 95 °C for 72 h and the solvent was removed
under reduced pressure. The resulting white solid was dissolved in
CH2Cl2 (20 mL) and water was added (20 mL). The basic aqueous
phase was extracted with CH2Cl2 (6ϫ) and the combined organic
fractions were dried with anhydrous MgSO4 and filtered. After
concentration in vacuo, the white solid was purified by flash
chromatography (MeOH/CH2Cl2 10%) to give the expected amino
alcohol (94 mg, 76%) as a white solid. Rf = 0.50 (MeOH/CH2Cl2
10%). [α]2D0 = +17.6 (c = 0.424, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.34–7.25 (m, 15 H, Ph), 4.92 (d, J = 9.3 Hz, 2 H, Ph-
CH2-O), 4.80 (d, J = 10.8 Hz, 1 H, Ph-CH2-O), 4.69 (s, 2 H, Ph-
CH2-O), 4.62 (d, J = 10.8 Hz, 1 H, Ph-CH2-O), 3.84 (dd, J = 5.5,
J = 10.9 Hz, 1 H, HO–CH2), 3.78–3.68 (m, 3 H, 3-H, 4-H, HO–
CH2), 3.36 (m, 1 H, 2-H), 3.07 (t, J = 8.8 Hz, 1 H, 5-H), 2.64 (td,
J = 2.9, J = 8.8 Hz, 1 H, 6-H), 1.96 (m, 1 H, CH3–CH2), 1.25 (m,
1 H, CH3–CH2), 0.97 (t, J = 7.4 Hz, 3 H, CH3–CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.7, 138.3, 138.1, 128.4, 127.9,
127.8, 127.7, 127.6 (Ph), 83.8, 83.2, 81.5 (C-3, C-4, C-5), 75.5, 75.2,
72.9 (Ph-CH2-O), 58.1 (HO–CH2), 54.6, 54.1 (C-2, C-6), 24.8
1433.2(3) Å3,
Z = 4, Dcalcd. = =
1.341 gcm–3, µ(Mo-Kα)
0.096 mm–1. Of 18552 reflections measured, 4109 were unique (Rint
= 0.116). R1/wR2 [IՆ2σ(I)] = 0.0584/0.1039. R1/wR2 [all reflec-
tions] = 0.0988/0.1122, S = 1.28. Residual electron density is be-
tween –0.22 and 0.28 e– Å–3
CCDC-643149 contains the supplementary crystallographic data
for exo-15. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Acknowledgments
This program is supported by the Conseil Général de la Loire-
Atlantique, the Centre National de la Recherche Scientifique, the
Université de Nantes and the Ministère de l’Education Nationale,
de la Recherche et de la Technologie with a doctoral fellowship
for M. S. M. Pearson. We warmly thank Dr N. Asano (Hokuriku
University, Japan) and Dr. B. G. Davis (University of Oxford, UK)
for providing NMR spectra of adenophorine.
(CH –CH ), 10.3 (CH –CH ) ppm. IR (CCl ): ν = 3335, 3031,
˜
3
2
3
2
4
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This amino alcohol (54 mg, 0.12 mmol) was dissolved in ethanol
(10 mL) and a solution of HCl in propan-2-ol (5 , 50 µL,
0.24 mmol) was added. The solution was stirred at room tempera-
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The reaction mixture was filtered through celite and washed with
MeOH. Concentration in vacuo afforded (+)-adenophorine hydro-
chloride (5·HCl, 27 mg, quant.) as a colorless oil. [α]2D0 = +44 (c =
0.16, H2O, NaOD) [ref.[8] [α]2D0 = +59.7 (c = 1, H2O)]. 1H NMR
(300 MHz, CD3OD): δ = 3.83 (dd, J = 4.8, J = 12.0 Hz, 1 H, 1-
H), 3.78 (m, 1 H, 3-H or 4-H or 5-H), 3.62–3.47 (m, 3 H, 1-H, 3-
H and/or 4-H and/or 5-H), 3.43 (m, 1 H, 2-H or 6-H), 3.19 (m, 1
Eur. J. Org. Chem. 2007, 4888–4894
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4893

M. S. M. Pearson, M. Evain, M. Mathé-Allainmat, J. Lebreton
FULL PAPER
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Received: May 22, 2007
Published Online: July 30, 2007
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4894
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Eur. J. Org. Chem. 2007, 4888–4894