A selective and rapid access to six- or seven-membered ring iminosugars via 6,8-diazabicyclo[3.2.1]oct-6-ene intermediates

Article abstract of DOI:10.1002/ejoc.200500754

A selective and rapid access to six- or seven-membered ring iminosugars is reported. The key step of the strategy involves the highly regio- and stereoselective reduction of 6,8-diazabicyclo[3.2.1]oct-6-ene intermediates, depending on the nature of imine

Full text of DOI:10.1002/ejoc.200500754

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500754
A Selective and Rapid Access to Six- or Seven-Membered Ring Iminosugars
via 6,8-Diazabicyclo[3.2.1]oct-6-ene Intermediates
Tony Tite,[a] Andriamihamina Tsimilaza,[a] Marie-Christine Lallemand,*[a]
François Tillequin,[a] Pascale Leproux,[b] Francine Libot,[b] and Henri-Phillipe Husson*[c]
Keywords: Iminosugars / Regioselectivity / Ring expansion / Diastereoselectivity
A selective and rapid access to six- or seven-membered ring
iminosugars is reported. The key step of the strategy involves
the highly regio- and stereoselective reduction of 6,8-diaza-
bicyclo[3.2.1]oct-6-ene intermediates, depending on the na-
ture of imine substituents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
been reported so far, despite data in the literature[9] indicat-
ing that many of these compounds have higher glycosidase-
Introduction
The iminosugars have been widely studied as inhibitors inhibition potencies than their five- or six-membered ring
of oligosaccharide-processing enzymes such as glycosidases counterparts.
and glycosyltransferases.[1,2] Several glycosidases inhibitors
This enhancement may be due to the flexibility of the
have already been tested or approved in the treatment of perhydroazepine ring system, which then allows the ring to
diabetes,[3] Gaucher’s disease,[4] HIV infection,[5] viral infec- adopt quasi-flattened conformations, which are much more
tions,[6] and cancer.[7] Much effort has been devoted toward favorable to binding within the active site of the enzyme.[10]
the syntheses of five- and six-membered ring iminocyclitol
With the aim of researching new carbohydrates mimetics,
families,[8] notably the 1-deoxy analogues. Relatively few we describe here a selective and rapid access to substituted
preparations of the seven-membered ring homologues have six- or seven-membered ring iminosugars via a 6,8-diaza-
Scheme 1. Syntheses of six- or seven-membered ring iminosugars.
bicyclo[3.2.1]oct-6-ene intermediate[11] from the trihydroxy-
[a] Laboratoire de Pharmacognosie, Faculté des Sciences Pharma-
ceutiques et Biologiques, UMR 8638 associée au CNRS et à
lated 5-cyano-8a-oxazolopiperidine 1 (Scheme 1).
l’Université René Descartes,
4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France
Fax: +33-1-40-46-96-58
E-mail: marie-christine.lallemand@univ-paris5.fr
[b] Laboratoire de Spectrométrie de Masse, Faculté des Sciences
Results and Discussion
Pharmaceutiques et Biologiques, UMR 8638 associée au CNRS
et à l’Université René Descartes,
After benzylation of the hydroxyl functions of compound
1, obtained in a facile, three-step synthesis from commer-
cially available starting materials,[12] the addition of a lith-
ium derivative on the cyano group of 2 led to the 6,8-diaza-
4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France
[c] Laboratoire de Chimie Thérapeutique, Faculté des Sciences
Pharmaceutiques et Biologiques, UMR 8638 associée au CNRS
et à l’Université René Descartes,
4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France
Eur. J. Org. Chem. 2006, 863–868
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
863

M.-C. Lallemand, H.-P. Husson et al.
SHORT COMMUNICATION
bicyclo[3.2.1]oct-6-ene imines 3. In the ESI mass spectrum (ESI/MS)[13] of the crude reaction mixture recorded at 30 V
of the diazabicyclo compound 3a, a peak for the protonated of the skimmer was effected, and the products ions, ob-
1
molecule was observed at m/z = 625, and in the H NMR tained from ERMS experiments (Energy resolved mass
spectrum, two doublets were observed at δ = 4.06 (J = spectrometry)[14] from collision of [MH]+ ions, show the
3.5 Hz) and 5.46 ppm (J = 2.5 Hz), which are attributed presence of 5a with a very low relative abundance (1–
1
to bridgehead 1-H and 5-H, respectively; a H,13C COSY 3%).[15]
analysis indicates an equatorial configuration.
In contrast, in the butyl series, the piperidine derivative
The next step involved the one-pot reduction and ring- 5b was formed from the aliphatic imine 3b under the same
enlargement process of the 6,8-diazabicyclo[3.2.1]oct-6-ene experimental conditions; however, a trace of the seven-
imines 3 – this occurs in a regio- and diastereoselective membered-ring compound 4b was observed only by mass
manner. This key step permitted the selective synthesis of spectrometry – the relative abundances were from 4 to
six- and seven-membered iminosugars, compounds 4a and 6%.[16] The relative configuration of the newly created ste-
5b, respectively, according to the nature of the substitution reogenic center (C-7) of 5b was determined directly from
pattern at the imine carbon atom (Scheme 1). In the phenyl the NMR spectroscopic data and by comparison with the
series, treatment of imine 3a with a large excess of LiAlH4 literature.[17] Indeed, the 2-H/7-H coupling constant of
(20 equiv.) afforded the polyhydroxyazepane compound 4a, 4.5 Hz indicates a R/R configuration for the C-2/C-7 ste-
which was characterized by 1D- and 2D NMR experiments. reocenters.
The coupling constant J2-H/3-H = 8.5 Hz indicates that 2-H
These regioselective imine reductions proved to be highly
and 3-H are trans to each other. In the crude mixture, no dependent on their substitution patterns. In the butyl series,
trace of the six-membered ring derivative 5a could be char- morpholine intermediates previously described[11] may be
acterized by NMR spectroscopy. To confirm this selective involved for the unique formation of compound 5b (Fig-
synthesis of compound 4a, an electrospray mass spectrum ure 1).
Figure 1. π-Stacking interaction favoring the piperidine system.
864
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 863–868

A Selective and Rapid Access to Six- or Seven-Membered Ring Iminosugars
SHORT COMMUNICATION
Indeed, these intermediates, which were obtained by a imental conditions (LiAlH4 20 equiv.) afforded the unprece-
preferential attack of the alcohol function on the si face of dented bicyclic aminal 7 as a single diastereomer 7S.
imine 3b and are favored by a π-stacking interaction be-
The structure of 7 was ascertained by typical NMR
tween an adjacent benzyl group and the phenyl group of chemical shifts; a signal at δ = 4.50 ppm and one at δ =
the oxazolidine ring, may be reduced to a piperidine system 55.0 ppm, observed in the 1H and 13C NMR spectra,
by LiAlH4 (Figure 1). In the phenyl series, a π-stacking in- respectively, were attributed to that arising from the C-7
teraction between the aromatic groups could avoid the for- reduced position. The erythro configuration is indicated by
mation of the transient morpholine and permit only the ac- the small coupling constant (J = 4.5 Hz) between 2-H and
cess of the seven-membered ring derivative 4a (Figure 2).
7-H. It is interesting to mention that the electrospray spec-
To confirm the π-stacking interaction during the forma- trum of the reduction mixture exhibits peaks for two pro-
tion of the azepan compound, we decided to extend this tonated molecules, one at m/z = 617 for compound 7 and
methodology by using an aromatic furan substituent the other at m/z = 619. The collision-induced dissociation
(Scheme 2). Treatment of the imine 6 under the same exper- (CID) of [MH]+ (m/z = 619) produced the characteristic
Figure 2. π-Stacking interaction favoring the azepane system.
Scheme 2. The use of furan as imine substituent.
Eur. J. Org. Chem. 2006, 863–868
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
865

M.-C. Lallemand, H.-P. Husson et al.
SHORT COMMUNICATION
Figure 3. CID of [MH]+ of compound 8.
was stirred continuously for one more hour. The reaction mixture
was then quenched by adding a saturated aqueous sodium hydro-
gen carbonate solution (30 mL). The mixture was extracted with
CH2Cl2 (120 mL×4), the combined organic layers were dried with
Na2SO4 and filtered, and the solvent was evaporated under reduced
pressure. Flash chromatography of the resulting yellow oil on silica
gel (cyclohexane/ether, 9:1) yielded 2 (1.5 g, 75%) as an oil. Rf =
daughter ions of the seven-membered ring compound 8
with peaks at m/z = 482, 374, and 282 (Figure 3), which are
analogues of the product ions observed for 4a (492 and 384)
and 4b (472 and 364).
The isolation of compound 7 supports the formation of
an intermediate of type A (Figure 2). Consequently, this
methodology, applied with a heterocyclic aromatic substitu-
ent, avoids the formation of the transient morpholine and
permits the quasi-exclusive access of the seven-membered
ring compounds 8.
In conclusion, we have demonstrated that trihydroxylated
2-cyano-6-oxazolopiperidine 1 is a useful building block for
ring-expansion reactions. The choice of the precursor in the
reduction reactions permitted a selective access for the con-
struction of chiral 2,3-disubstituted-4,5,6-trihydroxya-
zepane or for the construction of chiral diamines containing
a 2-substituted-4,5,6-trihydroxypiperidine skeleton. Con-
sidering the high potential of so-called “azasugars” for drug
discovery, we now envision extending this methodology to
the preparation of new carbohydrate mimics. This synthetic
work and the biological evaluations are in progress, and the
results will be reported in due course.
0.57 (cyclohexane/ether, 8:3). [α]D –73 (c = 1, CHCl ). IR (KBr): ν
˜
3
= 2229 cm–1. 1H NMR (CDCl3): δ = 3.67 (dd, J = 8, 9 Hz, 1 H, 8-
H), 3.7–3.8 (m, 2 H, 5-H and 6-H), 3.8–3.9 (m, 1 H, 7-H), 3.87 (t,
J = 8 Hz, 1 H, 2-H), 4.00 (t, J = 8 Hz, 1 H, 3-H), 4.41 (t, J = 8 Hz,
1 H, 2-H), 4.44 (d, J = 8 Hz, 1 H, 8a-H), 4.6–4.7 (2d AB, J =
11.5 Hz, 2 H, O–CH2-Ph), 4.8–5.0 (2d AB, J = 11.5 Hz, 2 H, O–
CH2-Ph), 4.9–5.0 (2d AB, J = 10.5 Hz, 2 H, O–CH2-Ph), 7.2–7.4
(m, 20 H, arom.) ppm. 13C NMR (CDCl3): δ = 48.8 (C-5), 62.9
(C-3), 73.8 (O–CH2-Ph), 74.0 (O–CH2-Ph), 74.8 (C-2), 76.6 (O–
CH2-Ph), 78.2 (C-6), 81.9 (C-8), 82.0 (C-7), 92.6 (C-8a), 113.1
(CN), 127–129 (CH arom.), 136.3–138.7 (Cq arom.) ppm. MS
(ESI): m/z = 547 [M + H]+. HRMS (C35H35N2O4): calcd. 547.2597;
found 547.2590.
General Procedure for Compounds 3a and 3b: A lithium derivative
(0.57 mmol) was added to a solution of compound 2 (250 mg,
0.45 mmol) in dry ether (1.7 mL), under argon at –78 °C. The reac-
tion mixture was stirred for 1 h at –78 °C and 3 h at 0°C. The reac-
tion mixture was then quenched by the addition of ice. The mixture
was extracted with CH2Cl2 (120 mL×4), the combined organic lay-
ers were dried with Na2SO4 and filtered, and the solvent was evapo-
rated under reduced pressure. Flash chromatography of the re-
sulting yellow oil on silica gel (CH2Cl2/MeOH, 18:1) yielded 3a
(200 mg, 70%) or 3b (207 mg, 75%) as oils.
Experimental Section
(3R,5R,6S,7R,8S,8aR)-6,7,8-Tribenzyloxy-3-phenylhexahydro-5H-
oxazolo[3,2-a]pyridine-5-carbonitrile (2): Sodium hydride (865 mg,
36.2 mmol) was added to a solution of compound 1 (1 g,
3.62 mmol) in dry DMF (40 mL), under argon. The reaction mix-
ture was stirred for 1 h at room temperature and cooled to 0 °C. A
solution of freshly distilled benzyl bromide (9.5 mL, 79.64 mmol)
was then added dropwise. Stirring was continued for 22 h at room
temperature. After the addition of methanol (l7 mL), the mixture
(2R)-2-Phenyl-2-[(1R,2S,3R,4R,5S)-2,3,4-trisbenzyloxy-7-phenyl-
6,8-diazabicyclo[3.2.1]oct-6-en-8-yl]ethanol (3a): Rf = 0.35 (CH2Cl2/
MeOH, 18:1). [α]D –29 (c = 1, CHCl ). IR (KBr): ν = 3297 cm–1.
˜
3
1H NMR (CDCl3): δ = 1.85 (s, 1 H, OH), 3.24 (t, J = 7.5 Hz, 1 H,
3-H), 3.45 (t, J = 5 Hz, 1 H, CH2–OH), 3.56 (dd, J = 3.5, 7.5 Hz,
866
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 863–868

A Selective and Rapid Access to Six- or Seven-Membered Ring Iminosugars
SHORT COMMUNICATION
1 H, 2-H), 3.6–3.7 (m, 2 H, CH2–OH and CH-Ph), 3.71 (dd, J = butyl), 2.2–2.5 (br. s, 3 H, 2 NH and OH), 2.60 (dd, J = 11, 14 Hz,
2.5, 7.5 Hz, 1 H, 4-H), 4.06 (d, J = 3.5 Hz, 1 H, 1-H), 4.46 (s, 2 H, 1 H, 6-H), 2.86 (dd, J = 5, 14 Hz, 1 H, 6-H), 3.1–3.2 (m, 1 H, 5-
O–CH2-Ph), 4.56 and 4.65 (2d AB, J = 11 Hz, 2 H, O–CH2-Ph),
4.76 and 4.82 (2d AB, J = 12 Hz, 2 H, O–CH2-Ph), 5.46 (d, J =
2.5 Hz, 1 H, 5-H), 7.0–7.7 (m, 25 H, arom.) ppm. 13C NMR
(CDCl3): δ = 65.0 (–CH2–OH), 65.3 (–CH-Ph), 65.9 (C-1), 72.6
H), 3.22 (dd, J = 4.5, 7 Hz, 1 H, 2-H), 3.3–3.4 (m, 1 H, 7-H), 3.68
(dd, J = 4, 10.5 Hz, 1 H, –CH2–OH), 3.79 (t, J = 7.5 Hz, 1 H, 4-
H), 3.8–3.9 (m, 2 H, –CH2–OH and 3-H), 3.91 (dd, J = 4, 7.5 Hz,
1 H, –CH-Ph), 4.29 (s, 2 H, O–CH2-Ph), 4.59 and 4.69 (2d AB, J
(O–CH2-Ph), 72.7 (O–CH2-Ph), 75.6 (O–CH2-Ph), 79.4 (C-2), 81.0 = 11.5 Hz, 2 H, O–CH2-Ph), 4.75 (s, 2 H, O–CH2-Ph), 7.0–7.6 (m,
(C-4), 83.9 (C-3), 85.4 (C-5), 127–129 (CH arom.), 131–139.5 (Cq
arom.), 174.3 (C-7) ppm. MS (ESI): m/z = 625 [M + H]+. HRMS
(C41H41N2O4): calcd. 625.3066; found 625.3078.
20 H, arom.) ppm. 13C NMR (CDCl3): δ = 14.1 (CH3 butyl), 22.8,
28.6, 34.5 (CH2 butyl), 44.3 (C-6), 51.0 (C-2), 61.2 (C-7), 63.7
(–CH2–OH), 66.3 (–CH-Ph), 72.2 (O–CH2-Ph), 72.9 (O–CH2-Ph),
74.3 (O–CH2-Ph), 77.5 (C-5), 79.5 (C-3), 81.8 (C-4), 127–129 (CH
arom.), 138.0, 138.4, 138.7, 140.2 (Cq arom.) ppm. MS (CI, NH3):
m/z = 609 [M + H]+. HMRS (C39H49N2O4): calcd. 609.3692; found
609.3587.
(2R)-2-Phenyl-2-[(1R,2S,3R,4R,5S)-2,3,4-trisbenzyloxy-7-butyl-6,8-
diazabicyclo[3.2.1]oct-6-en-8-yl]ethanol (3b): Rf = 0.35 (CH2Cl2/
MeOH, 18:1). [α]D –17.5 (c = 0.95, CHCl ). IR (KBr): ν = 3277,
˜
3
1945, 1878, 1809, 1631 cm–1. 1H NMR (CDCl3): δ = 0.87 (t, J =
7 Hz, 3 H, CH3 butyl), 1.2–1.4 (m, 4 H, CH2 butyl), 2.1–2.2 (m, 1
H, CH2 butyl), 2.4–2.5 (m, 1 H, CH2 butyl), 3.25 (t, J = 7 Hz, 1
H, 3-H), 3.45 (t, J = 5 Hz, 1 H, CH2–OH), 3.5–3.6 (m, 3 H, 1-H,
CH-Ph and 2-H), 3.6–3.7 (m, 2 H, 4-H and CH2–OH), 4.25 and
4.52 (2d AB, J = 12 Hz, 2 H, O–CH2-Ph), 4.72 and 4.74 (2d AB,
J = 11 Hz, 2 H, O–CH2-Ph), 4.80 and 4.84 (2d AB, J = 12 Hz, 2
H, O–CH2-Ph), 5.27 (d, J = 3 Hz, 1 H, 5-H), 7.1–7.4 (m, 20 H,
arom.) ppm. 13C NMR (CDCl3): δ = 13.7 (CH3), 22.5, 27.7, 32.2
(CH2 butyl), 64.9 (–CH2–OH), 65.1 (C-1), 66.6 (–CH-Ph), 72.5 (2×
O–CH2-Ph), 75.5 (O–CH2-Ph), 79.3 (C-2), 80.9 (C-4), 83.9 (C-3),
84.7 (C-5), 126–129 (CH arom.), 138.8–139.5 (Cq arom.), 179.7 (C-
7) ppm. MS (ESI): m/z = 605 [M + H]+. HMRS (C39H45N2O4):
calcd. 605.3379; found 605.3391.
(2R)-2-Phenyl-2-[(1R,2S,3R,4R,5S,7S)-2,3,4-trisbenzyloxy-7-(fu-
ran-2-yl)-6,8-diazabicyclo[3.2.1]oct-8-yl]ethanol (7): Oi1. Rf = 0.44
(CH2Cl2/MeOH, 20:1). [α]D –197 (c = 0.9, CHCl ). IR (KBr): ν =
˜
3
2922, 2868, 1602, 734 cm–1. 1H NMR (CDCl3): δ = 2.54 (br. s, 2
H, OH and NH), 3.48 (t, J = 4.5 Hz, 1 H, 1-H), 3.64 (m, 4 H, 2-
H, 4-H, and –CH2-OH), 3.84 (t, J = 5 Hz, 1 H, –CH-Ph), 4.22 (m,
1 H, 3-H), 4,18–4,31 [dd AB, J = 12 Hz, 2 H, O–CH2-Ph], 4.50 (d,
J = 4.5 Hz, 1 H, 7-H), 4.56 (d, J = 2.5 Hz, 1 H, 5-H), 4.70 and 4.6
(2d AB, J = 11.5 Hz, 2 H, O–CH2-Ph), 4.73 and 4.80 (2d AB, J =
12 Hz, 2 H, O–CH2-Ph), 6.27 (dd, J = 2, 3 Hz, 1 H, furan), 6.30
(d, J = 3 Hz, 1 H, furan), 6.90 (d, J = 2 Hz, 1 H, furan), 7.0–7.5
(m, 20 H, arom.) ppm. 13C NMR (CDCl3): δ = 55.0 (C-7), 61.2
(C-1), 65.4 (CH-Ph), 66.3 (CH2–OH), 71.2 (O–CH2-Ph), 72.6 (O–
CH2-Ph), 74.0 (C-5), 75.0 (O–CH2-Ph), 81.5 (C-3), 82.7 (C-2), 83.9
(C-4), 106.5 (CH furan), 110.2 (CH furan), 127.3–129.0 (CH
arom.), 138.4–139.9 (Cq arom.), 141.1(CH furan), 152.9(Cq furan)
ppm. MS (CI, NH3): m/z = 617 [M + H]+. HMRS (C39H41N2O5):
calcd.617.3015; found 617.3028.
General Procedure for Compounds 4a, 5b, and 7: The imine deriva-
tive (0.2 mmol) dissolved in ether was added dropwise to a suspen-
sion of LiAlH4 (145 mg, 3.9 mmol) in dry ether (2 mL) at –10 °C
under argon. The reaction mixture was stirred for 12 h at room
temperature. The mixture was then quenched by adding an aqueous
sodium hydroxide solution (1 , 0.3 mL) and washed with distilled
water (0.6 mL). The resulting precipitate was filtered through Ce-
lite® and extracted with THF. The combined organic layers were
evaporated under reduced pressure. Flash chromatography of the
resulting oil on silica gel yielded 4a (CH2Cl2/MeOH, 18:0.2; 94 mg;
75%), 5b (CH2Cl2/MeOH, 18:1; 97 mg; 80%), or 7 (cyclohexane/
ethyl acetate: 6:4; 86 mg; 70%).
(2R)-2-Phenyl-2-[(1R,2S,3R,4R,5S)-2,3,4-trisbenzyloxy-7-furan-6,8-
diazabicyclo[3.2.1]oct-6-en-8-yl]ethanol (6): A solution of nBuLi
(2.5  in hexane, 1.52 mL, 4.39 mmol) was added to a solution of
TMEDA (0.57 mL, 4.39 mmol) in dry THF (3 mL) at –20 °C under
argon. A solution of furan (0.363 mL, 4.94 mmol) was then added
dropwise, and the mixture was cooled to – 30 °C. Thereafter com-
pound 2 (412 mg, 0.76 mmol) was added, and the reaction mixture
was warmed to –20 °C. Stirring was continued for 2 h at –20 °C.
The reaction mixture was quenched by adding a saturated aqueous
ammonium chloride solution and extracted with CH2Cl2
(10 mL×5), the combined organic layers were dried with Na2SO4
and filtered, and the solvent was evaporated under reduced pres-
sure. Flash chromatography of the resulting crude on silica gel (cy-
clohexane/ethyl acetate, 6:4) yielded 6 (348 mg, 75%%) as an oil.
(2R)-2-Phenyl-2-[[(2R,3R,4S,5R,6R)-4,5,6-tribenzyloxy-2-phenyl-
hexahydro-1H-azepin-3-yl]amino]ethanol (4a): Oil. Rf = 0.15
(CH2Cl2/MeOH, 18:1). [α]D –23.5 (c = 1, CHCl ). IR (KBr): ν =
˜
3
3452, 2929, 1601, 1452 cm–1. H NMR (CDCl3): δ = 2.00 (br. s, 3
1
H, NH and OH), 2.88 (dd, J = 4.5, 8 Hz, 1 H, –CH-Ph), 2.94 (dd,
J = 3.5, 15 Hz, 1 H, 7-H), 2.98 (t, J = 8.5 Hz, 1 H, 3-H), 3.04 (dd,
J = 8, 10.5 Hz, 1 H, –CH2-OH), 320 (dd, J = 4.5, 10.5 Hz, 1 H,–
CH2-OH), 3.31 (dd, J = 3.5, 15 Hz, 1 H, 7-H), 3.55 (d, J = 8.5 Hz,
1 H, 2-H), 3.6–3.7 (m, 2 H, 4-H and 6-H), 3.93 (dd, J = 6.5, 8 Hz,
1 H, 5-H), 4.51 and 4.97 (2d AB, J = 11 Hz, 2 H, O–CH2-Ph), 4.61
and 4.75 (2d AB, J = 11 Hz, 2 H, O–CH2-Ph), 4.62 (s, 2 H, O–
CH2-Ph), 6.8–8.0 (m, 25 H, arom.) ppm. 13C NMR (CDCl3): δ =
48.8 (C-7), 62.1 (–CH-Ph), 63.1 (C-3), 66.8 (–CH2-OH), 71.1 (C-
2), 72.0 (O–CH2-Ph), 74.7 (O–CH2-Ph), 75.5 (O–CH2-Ph), 81.3 (C-
6 or C-4), 81.9 (C-4 or C-6), 84.9 (C-5), 127–129 (CH arom.), 138.1,
138.5, 140.7, 144.3 (Cq arom.) ppm. MS (ESI): m/z = 629 [M +
H]+. HRMS (C41H45N2O4): calcd. 629.3377; found 629.3379.
Rf = 0.37 (cyclohexane/ethyl acetate, 6:4). [α]D –153 (c = 1, CHCl3).
1
IR (NaCl): ν = 3279, 2922, 2360, 1618 cm–1. H NMR (CDCl ): δ
˜
3
= 3.35 (t, J = 7.5 Hz, 1 H, 4-H), 3.54 (t, J = 5 Hz, 1 H, –CH2–
OH), 3.62 (dd, J = 4, 7.5 Hz, 1 H, 3-H), 3.71 (m, 2 H, –CH2–OH
and CH-Ph), 3.81 (dd, J = 3, 7 Hz, 1 H, 5-H), 4.1 (d, J = 4 Hz, 1
H, 2-H), 4.48 and 4.62 (2d AB, J = 12 Hz, 2 H, O–CH2-Ph), 4.66
and 4.76 (2d AB, J = 11 Hz, 2 H, O–CH2-Ph), 4.80 (dd, J = 12 Hz,
2 H, O–CH2-Ph), 5.67 (d, J = 3 Hz, 1 H, 1-H), 6.44 (dd, J = 1.5,
3.5 Hz, 1 H, furan), 6.79 (d, J = 3.5 Hz, 1 H, furan), 7.10–7.40 (m,
20 H, arom.), 7.43 (d, J = 1.5 Hz, 1 H, furan) ppm. 13C NMR
(CDCl3): δ = 65.2 (CH2–OH), 65.5 (CH-Ph), 66.6 (C-2), 72.3 (O–
(2R)-2-[(2R,3S,4S,5R)-2-[(7R)-7-Aminopentyl]-3,4,5-trisbenzyloxy- CH2-Ph), 72.6 (O–CH2-Ph), 75.8 (O–CH2-Ph), 78.8 (C-3), 81.1 (C-
piperidin-1-yl]-2-phenylethanol (5b): Oil. Rf = 0.15 (CH2Cl2/MeOH,
5), 83.8 (C-4), 85.3 (C-6), 112.2, 115.8 (CH furan), 127.6–128.9
(arom.), 137.9–139.7 (Caq arom.), 145.5, 148.7, 164.2 ppm. MS (CI,
NH3): m/z = 615 [M + H]+. HMRS (C39H39N2O5): calcd. 615.2859;
found 615.2849.
18:1.5). [α]D –25 (c = 1, CHCl ). IR (KBr): ν = 3366, 3300, 3172,
˜
3
1875, 1452, 1067 cm–1. H NMR (CDCl3): δ = 0.96 (t, J = 7 Hz, 3
1
H, CH3 butyl), 1.2–1.5 (m, 5 H, CH2 butyl), 1.6–1.7 (m, 1 H, CH2
Eur. J. Org. Chem. 2006, 863–868
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
867

M.-C. Lallemand, H.-P. Husson et al.
SHORT COMMUNICATION
[9] H. Li, Y. Blériot, J. M. Mallet, E. Rodriguez-Garcia, P. Vogel,
Y. Zhang, P. Sinay, Tetrahedron: Asymmetry 2005, 16, 313–319
and references cited herein.
[10] X. Qian, F. Moris-Varas, M. C. Fitzgerald, C. H. Wong, Bi-
oorg. Med. Chem. 1996, 4, 2055–2063.
[11] S. Cutri, M. Bonin, L. Micouin, H.-P. Husson, J. Org. Chem.
2003, 68, 2645–2651.
Acknowledgments
The authors are grateful to Dr. N. Kunesch for her interest in this
research and Dr. L. Micouin for fruitful discussions.
[12] E. Poupon, B. X. Luong, A. Chiaroni, N. Kunesch, H.-P. Hus-
son, J. Org. Chem. 2000, 65, 7208–7210.
[1]
a) H. Li, Y. Blériot, C. Chantereau, J. M. Mallet, M. Sollog-
oub, Y. Zhang, E. Rodriguez-Garcia, P. Vogel, J. Jimenez-Bar-
bero, P. Sinay, Org. Biomol. Chem. 2004, 2, 1492–1499 and ref-
erences cited herein; b) M. S. M. Pearson, M. Mathé-Allain-
mat, V. Fargeas, J. Lebreton, Eur. J. Org. Chem. 2005, 2159–
2191.
B. Winchester, G. W. Fleet, Glycobiology 1992, 2, 199–210.
A. Mitrakou, N. Tountas, A. E. Raptis, R. J. Bauer, H. Schulz,
S. A. Raptis, Diabetes Med. 1998, 15, 657–660.
[13] Mass spectra were obtained on a quadruple/time-of-flight (Q-
Tof) instrument (Micromass, Manchester, UK). The samples
were infused into the Z-spray source by a syringe pump at
10 µL/min. Fragmentation was performed by using argon as
the collision gas. The acquisition mass range was from m/z = 90
to 700, and 20–50 scans were averaged to produce the spectra.
[14] S. A. Mc Luckey, G. L. Glish, R. G. Cooks, Int. J. Mass Spec-
trom. Ion Phys. 1981, 39, 2, 219–230.
[15] Product ions obtained from ERMS experiments for 4a: m/z =
521, 492, and 384. Product ions obtained from ERMS experi-
ments for 5a: m/z = 401.
[16] Product ions obtained from ERMS experiments for 4b: m/z =
501, 472, and 364. Product ions obtained from ERMS experi-
ments for 5b: m/z = 592, 484, and 416.
[2]
[3]
[4]
T. D. Butter, R. A. Dwek, F. M. Platt, Curr. Top. Med. Chem.
2003, 3, 561–574.
[5] P. Vogel, Current Drug Metabolism 2004, 5, 329–361.
[6] P. Greimel, J. Spreiz, A. E. Stûtz, T. M. Wronigg, Curr. Top.
Med. Chem. 2003, 3, 513–523.
[7] N. Zitzmann, A. S. Mehta, S. Carrouée, T. D. Butters, F. M.
Platt, J. McCauley, B. S. Blumberg, R. A. Dwek, T. M. Block,
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11878–11882.
[8] A. E. Stütz, Iminosugars as Glycosidase Inhibitors. Nojirimycin
and Beyond, Wiley-VCH, Weiheim, 1999.
[17] O. Froelich, P. Desos, M. Bonin, J.-C. Quirion, H.-P. Husson,
J. Zhu, J. Org. Chem. 1996, 61, 6700–6702.
Received: October 3, 2005
Published Online: January 3, 2006
868
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 863–868