A flexible route towards five-membered ring imino sugars and their novel 2-deoxy-2-fluoro analogues

Article abstract of DOI:10.1002/ejoc.200300163

A flexible route towards five-membered ring imino sugars starting from a chiral α,β-epoxy aldehyde has been developed. The approach relies on the use of the versatile epoxyamine intermediate 4, from which regiocontrolled epoxide opening affords diastereos

Full text of DOI:10.1002/ejoc.200300163

FULL PAPER
A Flexible Route Towards Five-Membered Ring Imino Sugars and Their Novel
2-Deoxy-2-fluoro Analogues
[a]
[a]
[b]
[a]
´
Tahar Ayad, Yves Genisson,* Sylvain Broussy, Michel Baltas, and
Liliane Gorrichon[a]
Keywords: Sugars / Aldehydes / Epoxide opening / Glycosyltransferase
A flexible route towards five-membered ring imino sugars
starting from a chiral α,β-epoxy aldehyde has been de-
veloped. The approach relies on the use of the versatile
epoxyamine intermediate 4, from which regiocontrolled ep-
oxide opening affords diastereoselective access to trisubsti-
logically relevant imino sugars 1,4-dideoxy-1,4-imino-
D-ara-
binitol (2) and 1,4-dideoxy-1,4-imino- -galactitol (3) as well
L
as their novel 2-deoxy-2-fluoro analogues, after oxidative
manipulation of the vinyl moiety.
tuted pyrrolidines. Described here is the nucleophilic attack ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
at C-2 of the pivotal epoxypyrrolidine 10, leading to the bio-
Germany, 2003)
Introduction
bacterial cell wall, and it is not normally involved in the hu-
man host metabolism. The disruption of cell wall bio-
synthesis resulting from the inhibition of arabinosyl-
transferase has been recognised as the mode of action of
important antibiotics, such as the antituberculosis agent
ethambutol.[9] Interestingly however, only few examples of
imino sugar-derived arabinosyltransferase inhibitors have
been reported.[10Ϫ12] In order to gain access to key building
blocks for the design of novel arabinosyltransferase inhibi-
tors, we decided to develop an asymmetric route to 1,4-
dideoxy-1,4-imino--arabinitol (2)[13Ϫ16] a naturally-occur-
ring broad-spectrum glycosidase inhibitor.[17] We also tar-
geted its homologue 1,4-dideoxy-1,4-imino--galactitol (3),
the  enantiomer of which is an inhibitor of the mycobact-
erial cell wall acting upon the incorporation of -galactofu-
ranose.[18,19] Finally we paid particular attention to the pos-
sibility of preparing deoxyfluoro analogues of these imino
sugars, as an increased lipophilicity could be beneficial
towards this membrane-located enzyme.
Imino sugars constitute a class of carbohydrate mimetics
that has already received considerable attention as major
glycosidase inhibitors.[1] Considered to some extent as tran-
sition-state analogues, these alkaloids could also, in prin-
ciple, interfere with the creation of glycosidic bonds. But
their development as glycosyltransferase inhibitors has been
limited by their intrinsic low inhibitory activity towards this
class of enzymes. Over the last 10 years however, polyhyd-
roxylated pyrrolidines and piperidines have inspired the de-
sign of novel potential glycosyltransferase inhibitors.[2] In
particular, enhanced potency, as well as selectivity towards
targeted enzymes, have been explored by simple N-substi-
tution of these alkaloids and incorporation of key structural
elements of either the natural glycosyl donor[3] or ac-
ceptor.[4] The field of therapeutic application of such com-
pounds seems promisingly broad since they could, for ex-
ample, be involved in treatment of fungal infections (chitine
synthase inhibition),[5] inflammatory processes or tumor
growth (α-1,3-fucosyltransferase inhibition),[6] glycosphingo-
lipid storage disorders (ceramide glucosyltranferase inhi-
bition),[7] and xenotransplant rejection (α-1,3-glucosyl-
transferase inhibition).[8]
In this context, we focused our attention on the inhi-
bition of arabinosyltransferase activity in mycobacteria.
-Arabinose (1) presents indeed two advantageous
characteristics: it is essential to the synthesis of the myco-
[a]
´
LSPCMIB, UMR 5068, Universite Paul Sabatier/CNRS,
118, route de Narbonne, 31062 Toulouse Cedex 04, France
Fax: (internat.) ϩ33-(0)5-61558245
Results and Discussion
E-mail: genisson@chimie.ups-tlse.fr
Following our continuous effort to develop an efficient
synthetic access to imino sugars from α,β-epoxy alde-
[b]
LCC/CNRS, 205,
Route de Narbonne, 31077 Toulouse Cedex 04, France
Eur. J. Org. Chem. 2003, 2903Ϫ2910
DOI: 10.1002/ejoc.200300163
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´
T. Ayad, Y. Genisson, S. Broussy, M. Baltas, L. Gorrichon
FULL PAPER
hydes,[20,21] we envisioned that the chiral epoxyamine inter-
mediate 4 (Scheme 1) could serve as an ideal precursor for
the targeted polyhydroxylated pyrrolidines. Indeed, we have
already shown that regiocontrolled C-3 epoxide hydrolysis
provides a route to pyrrolidine possessing the (2S,3S,4R)-
imino--xylitol configuration 6 (for matter of clarity, imino-
alditol carbon numbering have been used thoughout this
article). This route led to an efficient asymmetric synthesis
of the C6 imino sugar 1,4-dideoxy-1,4-imino--glucitol (7).
On the other hand, C-2 substitution of the same versatile
epoxyamine 4 would give rise to the desired (2R,3R,4R)-
imino--arabinitol stereochemical pattern 5.
Scheme 2. a: TBAF supported on silica gel, THF, room temp., 87%;
b: 3  H2SO4/p-dioxane, reflux, 70% of 9 from 8, 85% of a 94:6
mixture of 11 and its diastereomer from 10; c: Ph3P, CCl4, Et3N,
DMF, room temp., 71% of 10 from 8, 67% of 11 from 9; d: NaH,
BnBr, Bu4NI, THF, 80%
stereomer of the aminotriol previously obtained through C-
3 epoxide opening. Structure 9 was thus proposed for this
compound and its concise transformation into the indolizi-
dine (Ϫ)-lentiginosine unambiguously confirmed this stere-
ochemical attribution.[21] It appeared, however, that in the
context of this work, ring opening was more efficient once
the pyrrolidine heterocycle had already been prepared. In
Appel conditions (Ph3P, CCl4, Et3N, DMF, room temp.),[24]
primary alcohol was smoothly cyclised in 71% yield to ep-
oxypyrrolidine 10. Treatment of this derivative with aque-
ous H2SO4 in p-dioxane resulted in clean and highly regi-
ocontrolled oxirane hydrolysis, affording a 94:6 mixture (es-
timated by 1H NMR) of dihydroxypyrrolidines in 85%
Scheme 1. Stereocontrolled access to five-membered ring imino
sugars from the versatile epoxyamine 4
We thus started studying regioselective C-2 epoxide open- yield. The major diastereomer was separated by chromatog-
ing. Bearing in mind that the C-1 hydroxyl could direct this raphy after standard perbenzylation (NaH, BnBr, Bu4NI,
process, we first chose primary alcohol 8 as a substrate THF, 85% yield). It was shown to be identical to a sample
(Scheme 2). The latter was readily prepared by clean desilyl- prepared by cyclisation of aminotriol 9 produced under the
ation of our key intermediate 4 using TBAF supported on same aqueous acidic hydrolysis conditions. Therefore, it was
silica gel (THF, room temp., 87% yield). We first tried to considered to possess the desired (2R,3R,4R)--arabinitol
convert the 2,3-epoxy alcohol moiety into the desired triol configuration 12, which was ultimately proven by the total
via a base-catalysed Payne rearrangement with subsequent syntheses of the two known imino sugars 2 and 3 (vide in-
in situ nucleophilic trapping of the migrated epoxide.[22] fra).
Unfortunately, treatment of 8 under basic conditions (aque-
At this stage, we were interested in exploiting the greater
ous KOH, EtOH, 80 °C) resulted in complete decompo- reactivity of the C-2 position towards other nucleophiles,
sition. Another attractive option was to form a 1,2-cyclic such as fluoride anion for example. Deoxyfluoro analogues
carbonate by Lewis acid-catalysed intramolecular epoxide of imino sugars are indeed important compounds,[25] but
opening involving a phenylurethane intermediate.[23] We there are, to the best of our knowledge, no reported ex-
were however unable to prepare the latter precursor. In- amples of polyhydroxylated pyrrolidine derivatives where
stead, treatment of the primary alcohol 8 with phenyl isocy- an on-the-ring secondary hydroxyl group has been replaced
anate (Et3N, CH2Cl2, room temp., ca. 60% yield) afforded by fluorine.[26] Opening of the oxirane ring in 10 with fluor-
the cyclic ureas resulting from the N-acylation followed by ide anion would offer convenient access to such analogues.
spontaneous intramolecular C-3 nitrogen attack (isolated as
A rapid survey of the fluoride anion sources available
a ca. 1:1 mixture of C-1 carbamate and free primary al- indicated that neither TBAF nor iPr2NH·3HF gave useful
cohol). Although irrelevant to the present study, this reac- transformation when applied to 10, even under forced con-
tion was interestingly reminiscent of the carbonate anion ditions. More encouraging results were obtained with
oxirane opening we previously evidenced in these series.
We then turned our attention to aqueous acidic con- fourfold excess of reagent allowed formation of the ex-
KHF2. Heating at 140 °C for 5 h in ethylene glycol with a
ditions. Refluxing 8 in p-dioxane in the presence of 3  pected fluorhydrines. Although isolated in a modest
1
H2SO4 afforded a 70% yield of a single compound, a dia- 35Ϫ40% yield, H NMR of this compound revealed a re-
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Eur. J. Org. Chem. 2003, 2903Ϫ2910

A Flexible Route Towards Five-Membered Ring Imino Sugars
FULL PAPER
warding selectivity of ca. 95:5. Moreover, detailed NMR only slightly favored (60:40 ratio) during osmylation of the
studies (COSY and HSQC 2D experiments as well as analy- related epoxypyrrolidine 10]. The 2-deoxy-2-fluoro ana-
sis of the JH,F and JC,F coupling constants) indicated that logue 14 was dihydroxylated under the same conditions to
the fluorine atom had been, as desired, introduced on C-2 produce the expected diols 17 and 18 in comparable ef-
to afford 13 (Scheme 3). The preparation of this fluorhyd- ficiency and diastereofacial selectivity (isolated in 80% com-
rine was optimised running the reaction in commercially bined yield and in a 79:21 ratio). The R configuration was
available HF·pyridine complex at 60 °C for 24 h.[27] This assigned to the newly formed stereocenter in the major dia-
provided in 86% yield a 92:8 mixture favoring the same re- stereomer 17 by analogy with the studies mentioned above.
gioisomer 13 that could be easily separated by chromatog-
Preparation of C5 imino sugars required oxidative cleav-
raphy once benzylated under standard conditions (NaH, age of the vinyl moiety. This was more conveniently
BnBr, Bu4NI, THF, 83% yield) to give 14. Stereogenicity at achieved from diols 15 and 17 by treatment with NaIO4
C-2 was assumed to be resulting of a single inversion based followed by in situ NaBH4 reduction (EtOH/H2O, room
1
on the comparison of H NMR spectra of benzylated C-2 temp., 70% yield) which led to primary alcohols 19 and 20
fluro and hydroxy compounds 14 and 11. These results thus (Scheme 5), respectively.
opened a stereoselective access to a key intermediate in the
preparation of 2-deoxy-2-fluoro analogues of polyhydroxyl-
ated pyrrolidines of the -arabinitol configuration. It could
also be potentially generalised to other nucleophiles in or-
der to prepare diversely C-2 substituted five-membered ring
imino sugars.
Scheme 3. a: HF·pyridine, 60 °C, 85% of a 92:8 mixture of 13 and
its regioisomer; b: NaH, BnBr, Bu4NI, THF, 83%
Scheme 5. a: NaIO4 then NaBH4, EtOH/H2O, room temp., 70% of
With the vinylpyrrolidine intermediates 12 and 14 in
19 from 15, 70% of 20 from 17; b: Pd/C, 10 bar H2, cat. 12  HCl,
hands, we were in a position to study functionalisation of
the olefin. We originally planed to prepare an epoxide inter-
mediate, which would in turn allow derivatisation through
attack at the terminal position. Unfortunately, epoxidation
of olefin in 12 proved to be complicated by the presence of
the neighboring basic nitrogen atom.[28] We therefore pre-
pared diols 15 and 16 directly (69% combined yield) by
standard osmylation of the double bond (OsO4, NMO, p-
dioxane/H2O, 70 °C) (Scheme 4).[29] As already observed in
closely related studies, the stereochemical outcome of this
reaction moderately favored the R isomer 15 (80:20 ratio as
separated compounds).[30] Interestingly, this Si face selec-
tivity strongly diverge from the complete Re face stereocon-
tol displayed by the -xylitol diastereomer, suggesting a
major influence of the C-3 benzyloxy group on the steric
bias of these vinylpyrrolidines [the same Si face attack was
MeOH, 94Ϫ98%
Finally, the targeted imino sugars 2 and 3, as well as their
2-deoxy-2-fluoro analogues 21 and 22 were smoothly ob-
tained after a debenzylation step (Pd/C, 10 bar H2, cat. 12
 HCl, MeOH, 94Ϫ98% yield) (Scheme 5). Derivatives 2
and 3 displayed spectral and physical data in agreement
with that reported in the literature.
Conclusion
In conclusion, this work illustrates the flexibility of our
route to five-membered ring imino sugars from chiral α,β-
epoxy aldehydes. Central to this approach is the regiocon-
trolled C-2 oxirane ring opening of a pivotal epoxypyrroli-
dine. The 2,3-dihydroxy and 2-fluoro-3-hydroxy intermedi-
ates thus prepared were used in a short synthesis of imino
sugars 2 and 3, as well as their novel 2-deoxy-2-fluoro ana-
logues 21 and 22, via oxidative functionalisation of the ole-
fin. These compounds all represent valuable building blocks
for the elaboration of imino sugar-derived arabinosyl-
transferase inhibitors. We already demonstrated that tar-
geting of potential inhibitors of these mycobacterial en-
zymes can be achieved by attaching them to an acceptor-
like oligoarabinofuranoside.[31]
Scheme 4. a: OsO4, NMO, p-dioxane/H2O, 70 °C, 69% of a 80:20
mixture of 15 and 16 from 12, 80% of a 79:21 mixture of 17 and
18 from 14
Eur. J. Org. Chem. 2003, 2903Ϫ2910
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T. Ayad, Y. Genisson, S. Broussy, M. Baltas, L. Gorrichon
FULL PAPER
3
4
1.8 Hz and J6-H,5-H ϭ 18.4 Hz, 1 H, 6-H) 5.22 (ddd, J6Ј-H,4-H
1.2, J6Ј-H,6-H ϭ 1.8 Hz and J6Ј-H,5-H ϭ 10.3 Hz, 1 H, 6Ј-H), 3.80
(ABq, Jgem ϭ 13.7 Hz, ∆δaϪδb ϭ 23.8 Hz, 2 H, NCH2Ph),
3.69Ϫ3.65 (m, 2 H, 2-H and 4-H), 3.55 (d, J3-H,4-H ϭ 2.9 Hz, 1
ϭ
Experimental Section
2
3
2
General Remarks: The following solvents and reagents were dried
prior to use: carbon tetrachloride, dimethylformamide (from cal-
cium hydride, stored over 4-A molecular sieves), triethylamine
3
H, 3-H), 3.00 (s, 2 H, 2 ϫ 1-H) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 140.03 (Cquat. arom.), 135.11 (C-5), 128.60, 128.39, 127.09 (CH
arom.), 117.64 (C-6), 66.33 (C-4), 60.57 (C-3), 60.11 (C-1), 57.31
(C-2), 53.26 (NCH2Ph) ppm. MS (DCI, NH3): m/z ϭ 202 [M ϩ
H]ϩ (100). HRMS (DCI, NH3) calcd. for C13H16NO [M ϩ H]ϩ
202.1232, found 202.1239.
˚
(from calcium hydride, stored over potassium hydroxide pellets),
THF (freshly distilled from sodium/benzophenone). Thin layer
chromatography (TLC) reaction monitoring was carried out with
MachereyϪNagel ALUGRAM SIL G/UV254 (0.2 mm) plates
visualised with 10% phosphomolybdic acid in ethanol or Dragen-
dorff reagent as dipping solutions. Standard column chromatogra-
phy was performed with SDS 70Ϫ200 µm silica gel. Flash column
chromatography was carried out with SDS 35Ϫ70 µm silica gel.
Medium-pressure liquid chromatography was performed with a
JobinϪYvon apparatus using Merck 15Ϫ40 µm silica gel. NMR
spectroscopic data were obtained with Bruker AC200, AC250, and
AC400 instruments operating with 1H spectra at 200, 250, and
400 MHz, respectively, 13C spectra at 50, 63, and 100 MHz, respec-
tively, and 19F at 188 MHz (AC200). Chemical shifts are quoted
in parts per million (ppm) downfield from tetramethylsilane and
coupling constants are in Hertz. Infrared (IR) spectra were re-
corded on a PerkinϪElmer FT-IR 1725X spectrometer. Mass spec-
trometry (MS) data were obtained on a NERMAG R10-10 spec-
trometer. High resolution mass spectra (HRMS) were performed
on a ThermoFinnigan MAT 95 XL spectrometer (DCI). Optical
rotations were measured on a PerkinϪElmer model 141 polar-
imeter.
Diol 11: 3  aqueous H2SO4 (6.50 mL, 19.50 mmol) was added to
a solution of epoxypyrrolidine 10 (390 mg, 1.94 mmol) in p-dioxane
(8 mL). This mixture was refluxed for 5 h and allowed to cool be-
fore neutralisation with 3  aqueous NaOH (21.00 mL) followed by
solid NaHCO3. p-Dioxane was then evaporated off under reduced
pressure and the resulting aqueous phase extracted with CH2Cl2 (3
ϫ 100 mL) and with EtOAc (2 ϫ 50 mL). The combined organic
phases were successively washed with water and brine, dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel treated with 2.5% v/v Et3N (petroleum ether/EtOAc, gradient
from 70:30 to 40:60) to give 94:6 mixture of diastereomeric di-
hydroxypyrrolidines 11 and 6 (362 mg, 1.65 mmol, 85% yield). A
sample of major diastereomer 11 prepared by Appel cyclisation of
aminotriol 9 was used for characterisation. Rf ϭ 0.28 (petroleum
ether/EtOAc, 90:10). IR (neat): ν˜max ϭ 3418 (OϪH), 1609 (Cϭ
C), 1035 (CϪO) cmϪ1
.
1H NMR (250 MHz, CDCl3/D2O): δ ϭ
7.16Ϫ7.08 (m, 5 H, Ph), 5.74Ϫ5.61 (m, 1 H, 5-H), 5.25Ϫ5.14 (m,
Primary Alcohol 8: TBAF on silica gel (5.70 g at ca. 1.10 mmol of
fluoride/g, ca. 6.27 mmol) was added to a solution of silyl ether
4 (1.15 g, 2.51 mmol) in THF (25 mL). The reaction mixture was
vigorously stirred overnight and then filtered. The silica gel was
rinsed several times with ethyl acetate and the combined filtrates
concentrated in vacuo. The resulting crude product was purified by
flash column chromatography on silica gel (CH2Cl2/MeOH, gradi-
ent from 100:0 to 95:5) to give alcohol 8 (478 mg, 2.18 mmol, 87%
yield): Rf ϭ 0.25 (CH2Cl2/MeOH, 95:5). [α]2D5 ϭ ϩ9.0 (c ϭ 1.6,
CHCl3). IR (neat): ν˜max ϭ 3287 (OϪH), 1641 (CϭC), 1032 (C-O)
3
2 H, 2 ϫ 6-H), 3.83Ϫ3.78 (m, 1 H, 3-H), 3.63 (dd, J2-H,3-H
ϭ
ϭ
ϭ
3
2
3.3 Hz and J2-H,1Ј-H ϭ 7.1 Hz, 1 H, 2-H), 3.40 (ABq, Jgem
2
11.9 Hz, ∆δaϪδb ϭ 205.4 Hz, 2 H, NCH2Ph), 2.64 (d, J1-H,1Ј-H
10.8 Hz, 1 H, 1-H), 2.61Ϫ2.55 (m, 1 H, 4-H), 2.44 (dd, 3J1Ј-H,2-H ϭ
2
7.0 Hz and J1Ј-H,1-H ϭ 10.8 Hz, 1 H, 1Ј-H) ppm. 13C NMR
(63 MHz, CDCl3/D2O): δ ϭ 137.47 (C-5), 137.38 (Cquat. arom.),
129.06, 128.09, 127.03 (CH arom.), 119.30 (C-6), 83.28 (C-3), 76.27
(C-2), 74.49 (C-4), 58.78 (NCH2Ph), 57.53 (C-1) ppm. MS (DCI,
NH3): m/z ϭ 220 [M ϩ H]ϩ (100). HRMS (DCI, NH3) calcd. for
C13H18NO2 [M ϩ H]ϩ 220.1337, found 220.1335.
1
cmϪ1. H NMR (250 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 5 H, Ph),
5.93Ϫ5.75 (m, 1 H, 5-H), 5.40Ϫ5.28 (m, 2 H, 2 ϫ 6-H), 3.78 (AB
3
3
Dibenzyl Ether 12: NaH (80 mg of a 60% suspension in oil,
2.05 mmol) was added to a stirred solution of dihydroxypyrroli-
dines 11 and 6 (300 mg, 1.37 mmol) in anhydrous THF at 0 °C
under inert atmosphere. After gas evolution had ceased, the reac-
tion mixture was allowed to warm up to room temp. and tetrabu-
tylammonium iodide (25 mg, 0.07 mmol) was added, followed after
5 min by benzyl bromide (240 µL, 2.05 mmol). The mixture was
stirred at room temp. until TLC analysis showed that no starting
material remained (ca. 3 h 30) and the reaction was quenched by
addition of water (15 mL). The aqueous phase was extracted with
CH2Cl2 (3 ϫ 50 mL) and the combined organic phases were suc-
cessively washed with water and brine, dried with Na2SO4, filtered,
and concentrated under reduced pressure. The crude product was
part of an ABX, J1-H,2-H
ϭ 5.1, J1Ј-H,2-H ϭ 6.6 Hz and
2J1-H,1Ј-H ϭ 12.3 Hz, ∆δaϪδb ϭ 102.30 Hz, 2 H, 2 ϫ 1-H), 3.73
2
(ABq, Jgem ϭ 12.5 Hz, ∆δaϪδb ϭ 42.2 Hz, 2 H, NCH2Ph),
3.26Ϫ3.16 (m, 2 H, 3-H and 2-H), 3.00 (dd, 3J4-H,3-H ϭ 4.2 Hz and
3J4-H,5-H ϭ 7.2 Hz, 1 H, 4-H), 2.76 (m, 2 H, O-H and N-H) ppm.
13C NMR (63 MHz, CDCl3): δ ϭ 138.57 (Cquat. arom.), 136.53 (C-
5), 128.66, 128.51, 127.52 (CH arom.), 119.40 (C-6), 60.60 (C-1),
59.18 (C-4), 58.55 (C-3), 56.22 (C-2), 50.47 (NCH2Ph) ppm. MS
(DCI, NH3): m/z ϭ 220 [M ϩ Hϩ]. HRMS (DCI, NH3) calcd. for
C13H18N1O2 [M ϩ H]ϩ 220.1337, found 220.1334.
Epoxypyrrolidine 10: To a solution of amino alcohol 8 (220 mg,
1.00 mmol) in anhydrous DMF (4.50 mL) were successively added
Ph3P (526 mg, 2.00 mmol), CCl4 (194 mL, 2.00 mmol) and Et3N purified by medium pressure column chromatography on silica gel
(0.28 mL, 2.00 mmol). After stirring overnight at room temp. under (petroleum ether/CH2Cl2/Et2O, 69:25:6) to give 12 (437 mg,
inert atmosphere, MeOH (3 mL) was added. The reaction mixture
was then stirred for an additional 45 min before being concentrated
to dryness under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (petroleum ether/
EtOAc, 90:10) to give epoxypyrrolidine 10 (143 mg, 0.71 mmol,
71% yield). Rf ϭ 0.28 (petroleum ether/EtOAc, 90:10). [α]2D5 ϭ ϩ3.1
1.09 mmol, 80% yield) and the dibenzylated minor diastereomer
(28 mg, 0.07 mmol, 5% yield). Major diastereomer 12: Rf ϭ 0.25
(petroleum ether/EtOAc, 90:10). [α]2D5 ϭ Ϫ94.7 (c ϭ 0.95, CHCl3).
IR (neat): ν˜max ϭ 1624 (CϭC), 1097 (CϪO) cmϪ1 1H NMR
.
(250 MHz, CDCl3): δ ϭ 7.43Ϫ7.22 (m, 15 H, Ph), 6.04Ϫ5.89 (m,
2
3
1 H, 5-H), 5.44 (dd, J6-H,6Ј-H ϭ 1.7 Hz and J6-H,5-H ϭ 17.2 Hz, 1
2
3
(c ϭ 1.7, CHCl3). IR (neat): ν˜max ϭ 1601 (CϭC), 1264 (CϪO) H, 6-H), 5.33 (dd, J6Ј-H,6-H ϭ 1.7 Hz and J6Ј-H,5-H ϭ 10.2 Hz, 1
1
2
cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 7.31Ϫ7.26 (m, 5 H, Ph), H, 6Ј-H), 4.60 (ABq, Jgem ϭ 11.8 Hz, ∆δaϪδb ϭ 17.2 Hz, 2 H,
4
2
2
5.81Ϫ5.72 (m, 1 H, 5-H), 5.35 (ddd, J6-H,4-H ϭ 1.3, J6-H,6Ј-H
ϭ
OCH2Ph), 4.47 (ABq, Jgem ϭ 12.1 Hz, ∆δaϪδb ϭ 26.3 Hz, 2 H,
2906
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Eur. J. Org. Chem. 2003, 2903Ϫ2910

A Flexible Route Towards Five-Membered Ring Imino Sugars
FULL PAPER
1.2, CHCl3). IR (neat): ν˜max ϭ 1638 (CϭC), 1422 (CϪF), 1109
(CϪO) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.34Ϫ7.27 (m, 10
2
OCH2Ph), 3.98Ϫ3.91 (m, 2 H, 2-H and 3-H), 3.60 (ABq, Jgem
ϭ
13.3 Hz, ∆δaϪδb ϭ 224.2 Hz, 2 H, NCH2Ph), 3.05 (d, 2J1-H,1Ј-H ϭ
10.7 Hz, 1 H, 1-H), 2.94 (pseudo-t, J4-H,5-H ϭ J4-H,3-H ϭ 7.6 Hz, H, Ph), 5.98Ϫ5.86 (m, 1 H, 5-H), 5.54 (dd, 2J6-H,6Ј-H ϭ 1.2 Hz and
3
3
3
2
2
1 H, 4-H), 2.47 (dd, J1Ј-H,2-H ϭ 6.2 Hz, and J1Ј-H,1-H ϭ 10.7 Hz,
3J6-H,5-H ϭ 17.2 Hz, 1 H, 6-H), 5.35 (d, J6Ј-H,6-H ϭ 1.2 Hz and
1 H, 1Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 139.06 (C-5), 3J6Ј-H,5-H ϭ 10.1 Hz, 1 H, 6Ј-H), 4.98 (ddd, J2-H,1Ј-H ϭ 1.0,
3
138.63, 138.43 (Cquat. arom.), 129.16, 128.61, 128.48, 128.09, 3J2-H,1-H ϭ 5.5 Hz, and J2-H,F ϭ 53.5 Hz, 1 H, 2-H), 4.66 (ABq,
2
128.03, 127.91, 127.89, 127.20 (CH arom.), 119.46 (C-6), 89.57 (C-
2Jgem ϭ 11.8 Hz, ∆δaϪδb ϭ 26.2 Hz, 2 H, OCH2Ph), 4.05 (d,
3), 82.25 (C-2), 73.37 (C-4), 72.34 (OCH2Ph), 71.36 (OCH2Ph), 2Jgem ϭ 13.5 Hz, 1 H, NCH2Ph), 3.98 (dd, J3-H,2-H ϭ 6.9 Hz and
3
57.60 (NCH2Ph), 56.95 (C-1) ppm. MS (DCI, NH3): m/z ϭ 400 3J3-H,F ϭ 25.2 Hz, 1 H, 3-H), 3.18Ϫ3.09 (m, 2 H, 1-H and
[M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for C27H30NO2 [M ϩ NCH2Ph), 2.93 (pseudo-t, J4-H,3-H
ϭ
3J4-H,5-H ϭ 7.5 Hz, 1 H, 4-
3
H]ϩ 400.2276, found 400.2274.
H), 2.52 (ddd, J1Ј-H,2-H ϭ 5.5, 2J1Ј-H,1-H ϭ 11.9 Hz, and J1Ј-H,F
ϭ
3
3
34.3 Hz, 1 H, 1Ј-H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 138.39
(Cquat. arom.), 138.32 (C-5), 138.01 (Cquat. arom.), 129.04, 128.71,
128.62, 128.10, 128.05, 127.39 (CH arom.), 119.82 (C-6), 97.13 (d,
Fluorohydrine 13: A solution of epoxypyrrolidine 10 (250 mg,
1.24 mmol) in commercially available HF·pyridine was heated to
60 °C with vigorous stirring for 24 h. The reaction mixture was
then neutralised with solid NaHCO3 and concentrated to dryness
under reduced pressure. The resulting residue was extracted with
CH2Cl2 (3 ϫ 60 mL) and the combined organic phases were suc-
cessively washed with water and brine, dried with Na2SO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 92:8) to give fluorohydrine 13 and its regioisomer
(234 mg, 1.06 mmol, 85% yield) as a 92:8 mixture. A ca. 95:5 mix-
ture obtained by treatment with KHF2 was used for characteris-
1JC-2,F ϭ 181.2 Hz, C-2), 89.12 (d, JC-3,F ϭ 25.7 Hz, C-3), 73.38
2
3
3
(d, JC-4,F ϭ 4.1 Hz C-4), 72.47 (OCH2Ph), 58.00 (d, JC-1,F
ϭ
23.0 Hz, C-1), 57.38 (NCH2Ph) ppm. 19F NMR (188 MHz, CDCl3/
D2O): δ ϭ Ϫ64.09 to Ϫ 63.37 (m) ppm. MS (DCI, NH3): m/z ϭ
312 [M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for C20H23FNO
[M ϩ H]ϩ 312.1764, found 312.1763.
Diol 15: To a solution of vinyl pyrrolidine 12 (250 mg, 0.62 mmol)
in p-dioxane/H2O (80:20) (10 mL) were successively added NMO
(90 mg, 0.80 mmol) and OsO4 (240 µL of a 0.08  solution in
ation of the major compound 13. Rf ϭ 0.27 (petroleum ether/ tBuOH, 0.020 mmol). The mixture was then heated to 70 °C until
EtOAc, 92:8). IR (neat): ν˜max ϭ 3413 (OϪH), 1638 (CϭC), 1422 TLC analysis showed that no starting material remained (ca. 6 h)
(CϪF), 1076 (CϪO) cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ before being allowed to cool down to room temp. Solid NaHSO3
.
7.34Ϫ7.27 (m, 5 H, Ph), 5.92Ϫ5.86 (m, 1 H, 5-H), 5.43 (ddd, (100 mg, 0.96 mmol) was then added and stirring was maintained
2
3
4J6-H,4-H ϭ 0.7, J6-H,6Ј-H ϭ 1.6, J6-H,5-H ϭ 17.2 Hz, 1 H, 6-H), for a further 45 min at room temp. The resulting suspension was
4
2
3
5.37 (ddd, J6Ј-H,4-H ϭ 0.4, J6Ј-H,6-H ϭ 1.6 Hz, and J6Ј-H,5-H
ϭ
then filtered through celite and concentrated to dryness under re-
duced pressure. The crude product was first filtred over silica gel
3
3
10.1 Hz, 1 H, 6Ј-H), 4.89 (dddd, J2-H,1-H ϭ 1.2, J2-H,3-H ϭ 2.3,
3J2-H,1Ј-H ϭ 6.2 Hz, and J2-H,F ϭ 53.8 Hz, 1 H, 2-H), 4.16 (dddd, at atmospheric pressure (petroleum ether/EtOAc, gradient from
2
3
3
3
4J3-H,1-H ϭ 0.9, J3-H,2-H ϭ 2.2, J3-H,4-H ϭ 7.2 Hz, and J3-H,F
ϭ
70:30 to 40:60) and purified by medium pressure column chroma-
tography on silica gel (petroleum ether/CH2Cl2/Et2O/tBuOH,
2
26.3 Hz, 1 H, 3-H), 3.59 (ABq, Jgem ϭ 13.4 Hz, ∆δaϪδb ϭ
2
333.8 Hz, 2 H, NCH2Ph), 3.11 (dd, J1-H,1Ј-H ϭ 11.9 Hz and gradient from 38:50:10:2 to 35:50:10:5) to give diols 15 (148 mg,
3J1-H,F ϭ 23.4 Hz, 1 H, 1-H), 2.79 (pseudo-t, 3J4-H,3-H ϭ 3J4-H,5-H ϭ
0.34 mmol, 55% yield) and 16 (37 mg, 0.085 mmol, 14% yield).
7.8 Hz, 1 H, 4-H), 2.57 (ddd, J1Ј-H,2-H ϭ 6.1, J1Ј-H,1-H ϭ 12.0 Hz Rf ϭ 0.22 (major product), 0.20 (minor product) (petroleum ether/
3
2
and J1Ј-H,F ϭ 31.9 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CH2Cl2/Et2O/tBuOH, 38:50:10:2). Major diastereomer 15. [α]2D5
ϭ
3
CDCl3): δ ϭ 137.84 (Cquat. arom.), 137.58 (C-5), 129.28, 129.06, Ϫ41.4 (c ϭ 0.6, CHCl3). IR (neat): ν˜max ϭ 3423 (OϪH), 1093
1
128.52, 127.37 (CH arom.), 120.37 (C-6), 97.64 (d, JC-2,F
ϭ
(CϪO) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.39Ϫ7.30 (m, 15
2
2
180.7 Hz, C-2), 82.00 (d, JC-3,F ϭ 25.9 Hz, C-3), 74.85 (d, H, Ph), 4.52 (ABq, Jgem ϭ 11.5 Hz, ∆δaϪδb ϭ 14.3 Hz, 2 H,
3JC-4,F ϭ 4.7 Hz, C-4), 57.40 (d, JC-1,F ϭ 24.2 Hz, C-1), 57.34 OCH2Ph), 4.50 (ABq, Jgem ϭ 12.0 Hz, ∆δaϪδb ϭ 22.5 Hz, 2 H,
2
2
(NCH2Ph) ppm. 19F NMR (188 MHz, CDCl3/D2O) δ ϭ Ϫ62.93
OCH2Ph), 4.18 (d, J3-H,4-H ϭ 4.3 Hz, 1 H, 3-H), 4.05Ϫ4.00 (m, 1
3
to Ϫ62.22 (m) ppm. MS (DCI, NH3): m/z ϭ 222 [M ϩ Hϩ] (100). H, 5-H), 3.95 (d, J2-H,1Ј-H ϭ 5.0 Hz, 1 H, 2-H), 3.74 (AB of an
3
HRMS (DCI, NH3) calcd. for C13H17FNO [M ϩ H]ϩ 222.1294, ABX, 3J6-H,5-H ϭ 5.1, 3J6Ј-H,5-H ϭ 6.4 Hz, and 2J6-H,6Ј-H ϭ 11.5 Hz,
2
found 222.1294.
∆δaϪδb ϭ 30.6 Hz, 2 H, 2 ϫ 6-H), 3.79 (ABq, Jgem ϭ 13.2 Hz,
2
∆δaϪδb ϭ 291.0 Hz, 2 H, NCH2Ph), 3.14 (d, J1-H,1Ј-H ϭ 10.8 Hz,
3
3
Benzyl Ether 14: NaH (127 mg of a 60% suspension in oil,
3.16 mmol) was added portionwise to a stirred solution of fluoro-
hydrine 13 and its regioisomer (500 mg, 2.26 mmol) in anhydrous
THF at 0 °C under inert atmosphere. After the gas evolution had
ceased, the reaction mixture was allowed to warm up to room temp.
and tetrabutylammonium iodide (29 mg, 0.08 mmol) was added,
followed after 5 min by benzyl bromide (527 µL, 4.52 mmol). The
mixture was stirred at room temp. until TLC analysis showed that
no starting material remained (ca. 6 h) and the reaction was
quenched by addition of a saturated NH4Cl aqueous solution
(10 mL). The aqueous phase was extracted with CH2Cl2 (3 ϫ
1 H, 1-H), 2.83 (dd, J4-H,5-H ϭ 2.8 Hz and J4-H,3-H ϭ 4.2 Hz, 1
3
2
H, 4-H), 2.63 (dd, J1Ј-H,2-H ϭ 5.0 Hz and J1Ј-H,1-H ϭ 10.8 Hz, 2
H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 138.21, 137.90,
137.74 (Cquat. arom.), 128.99, 128.77, 128.72, 128.25, 128.20,
128.06, 127.55 (CH arom.), 83.50 (C-3), 80.45 (C-2), 72.02
(OCH2Ph), 71.64 (C-4), 71.14 (OCH2Ph), 69.08 (C-5), 64.65 (C-6),
58.60 (NCH2Ph), 56.92 (C-1) ppm. MS (DCI, NH3): m/z ϭ 434
[M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for C27H32NO4 [M ϩ
H]ϩ 434.2331, found 434.2330.
Diol 17: To a solution of vinyl pyrrolidine 14 (420 mg, 1.35 mmol)
60 mL) and the combined organic phases were successively washed in p-dioxane/H2O (75:25) (20 mL) were successively added NMO
with water and brine, dried with Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by medium
pressure column chromatography on silica gel (petroleum ether/
Et2O, 93:7) to give major compound 14 (584 mg, 1.88 mmol, 83%
yield). Rf ϭ 0.23 (petroleum ether/Et2O, 93:7). [α]2D5 ϭ Ϫ60.9 (c ϭ
(240 mg, 2.04 mmol) and OsO4 (1.38 mL of a 0.05  solution in
tBuOH, 0.07 mmol). The mixture was then heated to 60 °C until
TLC analysis showed that no starting material remained (ca. 5 h)
before being allowed to cool to room temp. Solid NaHSO3
(200 mg, 1.92 mmol) was then added and stirring was maintained
Eur. J. Org. Chem. 2003, 2903Ϫ2910
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2907

´
T. Ayad, Y. Genisson, S. Broussy, M. Baltas, L. Gorrichon
FULL PAPER
for a further 30 min at room temp. The resulting suspension was
then filtered through celite and concentrated to dryness under re-
duced pressure. The crude product was first filtered through silica
gel at atmospheric pressure (petroleum ether/EtOAc, 85:15) and
purified by medium pressure column chromatography on silica gel
Primary Alcohol 20: NaIO4 (50 mg, 1.30 mmol) was added to a
solution of diol 17 (300 mg, 0.87 mmol) in EtOH/H2O (80:20)
(15 mL). The mixture was stirred at room temp. until TLC analysis
showed that no starting material remained (ca. 1 h 20 min) and
then cooled to 0 °C before addition of NaBH4 (98 mg, 2.61 mmol).
(petroleum ether/CH2Cl2/Et2O/tBuOH, gradient from 38:50:10:2 to Stirring was maintained at this temperature for 30 min and the mix-
35:50:10:5) to give diols 17 (296 mg, 0.86 mmol, 63% yield) and 18
(78 mg, 0.23 mmol, 17% yield). Rf ϭ 0.21 (major product), 0.20
ture was allowed to react at room temp. for 4 h. Reaction was then
quenched by addition of a saturated aqueous solution of NH4Cl
(minor
product)
(petroleum
ether/CH2Cl2/Et2O/tBuOH, (3 mL), the aqueous phase was extracted with CH2Cl2 (3 ϫ 60 mL)
38:50:10:2). Major diastereomer 17. [α]2D5 ϭ Ϫ22.5 (c ϭ 1.05,
and the combined organic phases were successively washed with
water and brine, dried with Na2SO4, filtered, and concentrated un-
CHCl3). IR (neat): ν˜max ϭ 3431 (OϪH), 1637 (CϭC), 1450 (CϪF),
1095 (CϪO) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 7.43Ϫ7.27 der reduced pressure. The crude product was purified by medium
1
(m, 10 H, Ph), 4.98 (dd, 3J2-H,1Ј-H
ϭ
2
4.8 Hz and
pressure column chromatography on silica gel (petroleum ether/
2J2-H,F ϭ 52.4 Hz, 1 H, 2-H), 4.62 (ABq, Jgem ϭ 11.6 Hz, EtOAc, 85:15) to give alcohol 20 (192 mg, 0.48 mmol, 70% yield).
3
∆δaϪδb ϭ 39.6 Hz, 2 H, OCH2Ph), 4.26 (ddpseudo-t, J3-H,2-H
ϭ
Rf ϭ 0.23 (petroleum ether/EtOAc, 85:15). [α]2D5 ϭ Ϫ7.4 (c ϭ 1.0,
4J3-H,1-Hϭ 1.2, J3-H,4-H ϭ 5.2 Hz, and J3-H,F ϭ 21.2 Hz, 1 H, 3-
MeOH). IR (neat): ν˜max ϭ .
3412 (OϪH) cmϪ1 1H NMR
3
3
3
3
3
H), 4.06 (ddd, J5-H,4-H ϭ 2.8, J5-H,6Ј-H ϭ 5.2 Hz, and J5-H,6-H
ϭ
(400 MHz, CDCl3/D2O): δ ϭ 7.44Ϫ7.28 (m, 10 H, Ph), 4.99
2
3
3
6.6 Hz, 1 H, 5-H), 3.74 (ABq, Jgem ϭ 13.6 Hz, ∆ δaϪδb ϭ
(ddpseudo-t, J2-H,3-H ϭ3J2-H,1-H ϭ 1.0, J2-H,1Ј-H ϭ 4.8 Hz, and
311.0 Hz, 2 H, NCH2Ph), 3.70 (AB of an ABX, J6Ј-H,5-H ϭ 5.2, 2J2-H,F ϭ 52.4 Hz, 1 H, 2-H), 4.67 (ABq, Jgem ϭ 11.6 Hz,
3
2
3J6-H,5-H ϭ 6.6 Hz, and J6-H,6Ј-H ϭ 11.6 Hz, ∆δaϪδb ϭ 30.4 Hz,
∆δaϪδb
ϭ
36.0 Hz,
2
H, OCH2Ph), 4.25 (ddpseudo-t,
2
2
3
3
3
2 H, 2 ϫ 6-H), 3.21 (brdd, J1-H,1Ј-H ϭ 11.6 Hz and J1-H,F
ϭ
3J3-H,2-H
ϭ
4J3-H,1-H ϭ 1.4, J3-H,4-H ϭ 5.4 Hz, and J3-H,F
ϭ
3
3
3
20.8 Hz, 1 H, 1-H), 2.76 (dd, J4-H,5-H ϭ 2.8 Hz and J4-H,3-H
ϭ
21.6 Hz, 1 H, 3-H), 3.76 (AB of ABX, J5Ј-H,4-H ϭ 2.0, 3J5-H,4-H
3.4 Hz, and J5-H,5Ј-H ϭ 11.6 Hz, ∆δaϪδb ϭ 55.6 Hz, 2 H, 2 ϫ 5-
H), 3.72 (ABq. Jgem ϭ 13.2 Hz, ∆δaϪδb ϭ 268.5 Hz, 2 H,
ϭ
5.2 Hz, 1 H, 4-H), 2.68 (ddd, J1Ј-H,2-H ϭ 4.8, 2J1Ј-H,1-H ϭ 12.0 Hz,
3
2
3
2
and J1Ј-H,F ϭ 36.0 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz,
2
3
CDCl3): δ ϭ 137.61, 137.25 (Cquat. arom.), 129.11, 129.04, 129.00, NCH2Ph), 3.24 (brdd, J1Ј-H,1-H ϭ 11.8 Hz and J1-H,F ϭ 20.8 Hz,
1
3
128.68, 127.96 (CH arom.), 94.42 (d, JC-2,F ϭ 182.0 Hz, C-2),
1 H, 1-H), 2.76Ϫ2.73 (m, 1 H, 4-H), 2.72 (ddd, J1Ј-H,2-H ϭ 4.8,
83.46 (d, JC-3,F ϭ 27.2 Hz, C-3), 72.72 (OCH2Ph), 71.45 (d, 2J1Ј-H,1-H ϭ 12.0 Hz, and J1Ј-H,F ϭ 35.6 Hz, 1 H, 1Ј-H) ppm. 13C
2
3
3JC-4,F ϭ 2.4 Hz, C-4), 68.31(C-5), 64.31(C-6), 58.42 (d, JC-1,F
ϭ
NMR (100 MHz, CDCl3/D2O): δ ϭ 138.08, 137.91 (Cquat. arom.),
2
22.7 Hz, C-1), 58.13 (NCH2Ph) ppm. 19F NMR (188 MHz, CDCl3/ 129.10, 128.98, 128.97, 128.59, 128.45, 128.28, 127.87 (CH arom.),
1
2
D2O): δ ϭ Ϫ60.62 to Ϫ 59.92 (m) ppm. MS (DCI, NH3): m/z ϭ 94.88 (d, JC-2,F ϭ 180.3 Hz, C-2), 85.62 (d, JC-3,F ϭ 27.0 Hz, C-
346 [M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for C20H24FNO3 3), 72.78 (OCH2Ph), 70.72 (d, JC-4,F ϭ 2.7 Hz, C-4), 59.45(C-5),
3
[M ϩ H]ϩ 346.1818, found 346.1818.
58.57 (d, 2JC-1F ϭ 22.7 Hz, C-1), 57.97 (NCH2Ph) ppm. MS (DCI,
NH3): m/z ϭ 316 [M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for
C19H23FNO2 [M ϩ H]ϩ 316.1713, found 316.1712.
Primary Alcohol 19: NaIO4 (40 mg, 1.05 mmol) was added to a
solution of diol 15 (150 mg, 0.69 mmol) in EtOH/H2O (80:20)
(8 mL). The mixture was stirred at room temp. until TLC analysis
showed that no starting material remained (ca. 1 h 30 min) and
then cooled to 0 °C before addition of NaBH4 (77 mg, 2.05 mmol).
Stirring was maintained at this temperature for 30 min and the mix-
ture allowed to react at room temp. for 4 h. The reaction was then
quenched by addition of a saturated aqueous solution of NH4Cl,
the aqueous phase was extracted with CH2Cl2 (3 ϫ 50 mL) and the
combined organic phases were successively washed with water and
brine, dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column chroma-
tography on silica gel (petroleum ether/EtOAc, 80:20) to give al-
1,4-Dideoxy-1,4-imino-D-arabinitol (2): A solution of 19 (200 mg,
0.49 mmol) in MeOH (4 mL) containing 12  HCl (3 drops) and
10% Pd/C (60 mg) was allowed to react under an H2 atmosphere
(10 bar) with stirring. After 72 h, the reaction mixture was filtered
through celite and concentrated to dryness under reduced pressure.
The crude product was dissolved in H2O/MeOH (67:33) (10 mL),
acidic resin (Dowex 50 WX8, 100Ϫ200 mesh, 5 g) was added, and
the suspension was stirred slowly for 1 h before being filtered. The
resin was successively rinsed with water (200 mL) and methanol
(50 mL), taken up in 2.5  aqueous NH4OH (20 mL) and the mix-
ture stirred slowly for 1 h. The suspension was then filtered and the
cohol 19 (97 mg, 0.24 mmol, 70% yield). Rf ϭ 0.20 (petroleum resin rinsed with 2.5  aqueous NH4OH (200 mL). The resulting
ether/EtOAc, 80:20). [α]2D5 ϭ Ϫ23.4 (c ϭ 0.5, CHCl3). IR (neat):
ν˜max ϭ 3441 (OϪH), 1103 (CϪO) cmϪ1 1H NMR (400 MHz,
CDCl3): δ ϭ 7.38Ϫ7.30 (m, 15 H, Ph), 4.57 (ABq, 2Jgem ϭ 11.7 Hz,
solution was lyophilized and the residue obtained was purified by
flash column chromatography on silica gel treated with 2.5% v/v
Et3N, (CH2Cl2/MeOH/EtOH/NH4OH, gradient from 50:20:20:10
.
∆δaϪδb ϭ 16.5 Hz, 2 H, OCH2Ph), 4.49 (s, 2 H, OCH2Ph), 4.14 to 65:5:20:10) to give 2 (62 mg, 0.47 mmol, 94% yield). Rf ϭ 0.27
3
(d, J3-H,4-H ϭ 4.5 Hz, 1 H, 3-H), 3.94 (d, 3J2-H,1Ј-H ϭ 5.2 Hz, 1 H,
(CH2Cl2/MeOH/EtOH/NH4OH, 25:10:10:5). [α]2D5 ϭ ϩ7.8 (c ϭ 1.0,
2-H), 3.74 (AB of ABX, J5-H,4-H ϭ 1.9, J5Ј-H,4-H ϭ 3.1 Hz and H2O), ref.[14] [α]2D5 ϭ ϩ8.2 (c ϭ 0.25, H2O). IR (neat): ν˜max ϭ 3395
3
3
2J5-H,5Ј-H ϭ 11.2 Hz, ∆δaϪδb ϭ 42.7, 2 H, 2 ϫ 5-H), 3.73 (ABq,
(OϪH and NϪH) cmϪ1. H NMR (400 MHz, CD3OD/D2O): δ ϭ
1
2Jgem ϭ 13.2 Hz, ∆δaϪδb ϭ 242.0 Hz, 2 H, NCH2Ph), 3.14 (d, 4.23Ϫ4.20 (m, 1 H, 2-H), 4.00Ϫ3.99 (m, 1 H, 3-H), 3.86 (AB of
2J1-H,1Ј-H ϭ 10.7 Hz, 1 H, 1-H), 2.81 (m, 1 H, 4-H), 2.67 (dd, ABX, J5-H,4-Hϭ 4.8, 3J5Ј-H,4-H ϭ 9.2 Hz, and J5-H,5Ј-H ϭ 11.6 Hz,
3
2
3J1Ј-H,2-H ϭ 5.2 Hz and J1Ј-H,1-H ϭ 10.7 Hz, 1 H, 1Ј-H) ppm. 13C ∆δaϪδb ϭ 38.5 Hz, 2 H, 2 ϫ 5-H), 3.54 (ddd, J4-H,3-H ϭ 2.8,
2
3
NMR (100 MHz, CDCl3/D2O): δ ϭ 138.41, 138.15, 138.11 (Cquat. 3J4-H,5-H ϭ 4.8 Hz, and J4-H,5Ј-H ϭ 9.2 Hz, 1 H, 4-H), 3.49 (dd,
2
arom.), 128.95, 128.71, 128.66, 128.07, 128.02, 127.97, 127.93, 3J1-H,2-H ϭ 4.0 Hz and J1-H,1Ј-H ϭ 11.6 Hz, 1 H, 1-H), 3.30
2
3
2
127.48 (CH arom.), 85.57 (C-3), 80.75 (C-2), 72.19 (OCH2Ph),
(dpseudo-t, J1Ј-H,2-H ϭ ϭ
4J1Ј-H,3-H ϭ 0.8 Hz, and J1Ј-H,1-H
71.12 (OCH2Ph), 70.64 (C-4), 59.88 (C-5), 58.20 (NCH2Ph), 57.37 11.6 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CD3OD/D2O): δ ϭ
(C-1) ppm. MS (DCI, NH3): m/z ϭ 404 [M ϩ Hϩ] (100). HRMS 76.48 (C-3), 75.17 (C-2), 68.84 (C-4), 59.87 (C-5), 50.92 (C-1) ppm.
(DCI, NH3) calcd. for C26H30NO3 [M ϩ H]ϩ 404.2225, found MS (DCI, NH3): m/z ϭ 134 [M ϩ Hϩ] (100). HRMS (DCI, NH3)
404.2227.
calcd. for C5H12NO3 [M ϩ H]ϩ 134.0817, found 134.0816.
2908
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2003, 2903Ϫ2910

A Flexible Route Towards Five-Membered Ring Imino Sugars
1,4-Dideoxy-1,4-imino- -galactitol (3): A solution of 15 (125 mg, (35 mg) was allowed to react under a H2 atmosphere (10 bar) with
FULL PAPER
L
0.29 mmol) in MeOH (4 mL) containing 12  HCl (3 drops) and
10% Pd/C (35 mg) was allowed to react under a H2 atmosphere
(10 bar) with stirring. After 48 h, the reaction mixture was filtered
through celite and concentrated to dryness under reduced pressure.
The crude product was dissolved in H2O/MeOH (67:33) (10 mL),
acidic resin (Dowex 50 WX8, 100Ϫ200 mesh, 5 g) was added, and
the suspension was stirred slowly for 1 h before being filtered. The
resin was successively rinsed with water (200 mL) and methanol
(50 mL), taken up in 2.5  aqueous NH4OH (20 mL) and the mix-
ture stirred slowly for 1 h. The suspension was then filtered and the
resin rinsed with 2.5  aqueous NH4OH (200 mL). The resulting
solution was lyophilized and the residue purified by flash column
stirring. After 48 h, the reaction mixture was filtered through celite
and concentrated to dryness under reduced pressure. The crude
product was dissolved in H2O/MeOH (67:33) (10 mL), acidic resin
(Dowex 50 WX8, 100Ϫ200 mesh, 5 g) was added, and the suspen-
sion was stirred slowly for 1 h before being filtered. The resin was
successively rinsed with water (200 mL) and methanol (50 mL),
taken up in 2.5  aqueous NH4OH (20 mL) and the mixture stirred
slowly for 1 h. The suspension was then filtered and the resin rinsed
with 2.5  aqueous NH4OH (200 mL). The resulting solution was
lyophilized and the residue purified by flash column chromatogra-
phy on silica gel treated with 2.5% v/v Et3N, (CH2Cl2/MeOH/
EtOH/NH4OH, gradient from 70:12:12:6 to 79:3:12:6) to give 22
chromatography on silica gel treated with 2.5% v/v Et3N (CH2Cl2/ (68.0 mg, 0.41 mmol, 96% yield). Rf ϭ 0.28 (CH2Cl2/MeOH/EtOH/
MeOH/EtOH/NH4OH, gradient from 70:12:12:6 to 79:3:12:6) to
NH4OH, 70:12:12:6). [α]2D5 ϭ ϩ1.6 (c ϭ 0.95, MeOH). IR (neat):
give 3 (45 mg, 0.28 mmol, 95% yield). Rf ϭ 0.30 (CH2Cl2/MeOH/
ν˜max ϭ 3395 (OϪH and NϪH) cmϪ1
.
1H NMR (400 MHz,
EtOH/NH4OH, 70:12:12:6). [α]2D5 ϭ Ϫ2.40 (c ϭ 3.8, H2O), ref.[13] CD3OD/D2O): δ ϭ 4.92 (ddpseudo-t, J2-H,3-H ϭ J2-H,1Ј-H ϭ 1.2,
3
3
[α]2D5 ϭ ϩ3.0 (c ϭ 2.4, H2O) for the  enantiomer. IR (neat): ν˜max ϭ
3395 (OϪH and NϪH) cmϪ1. 1H NMR (400 MHz, CD3OD/D2O):
3J2-H,1-H ϭ 3.8 Hz, and J2-H,F ϭ 52.4 Hz, 1 H, 2-H), 4.33
2
3
3
(ddpseudo-t, J3-H,2-H
ϭ
4J3-H,1-H ϭ 1.2, J3-H,4-H ϭ 4.8 Hz, and
3
3
δ ϭ 4.10 (ddd, 4J3-H,1Ј-H ϭ 0.8, J3-H,4-H ϭ 4.5 Hz, and J3-H,2-H
ϭ
3J3-H,F ϭ 21.4 Hz, 1 H, 3-H), 3.78Ϫ3.74 (m, 1 H, 5-H), 3.65 (AB of
4.5 Hz, 1 H, 3-H), 4.08Ϫ4.05 (m, 1 H, 2-H), 3.80Ϫ3.76 (m, 1 H, ABX, 3J6-H,5-H ϭ 4.2, 3J6Ј-H,5-H ϭ 6.4 Hz, and 2J6-H,6Ј-H ϭ 11.4 Hz,
3
3
5-H), 3.44 (AB of ABX, J6-H,5-H ϭ 4.4, J6Ј-H,5-H ϭ 6.4 Hz, and
∆δaϪδb ϭ 32.4 Hz, 2 H, 2 ϫ 6-H), 3.21 (br.dd, 2J1-H,1Ј-H ϭ 13.3 Hz
2J6-H,6Ј-H ϭ 11.2 Hz, ∆δaϪδb ϭ 22.8 Hz, 2 H, 2 ϫ 6-H), 3.04 (AB and J1-H,F ϭ 20.6 Hz, 1 H, 1-H), 3.12 (ddd, J1-H,2-H ϭ 3.8,
3
3
3
3
2
3
of ABX, J1-H,2-H ϭ 2.4, J1Ј-H,2-H ϭ 4.4 Hz, and J1-H,1Ј-H
ϭ
2J1Ј-H,1-H ϭ 13.3 Hz, and J1Ј-H,F ϭ 35.5 Hz, 1 H, 1-H), 2.97
3
12.0 Hz, ∆δaϪδb ϭ 72.0 Hz, 2 H, 2 ϫ 1-H), 3.02 (t, J4-H,5-H
ϭ
(pseudo-t, 3J4-H,5-H ϭ 3J4-H,3-H ϭ 5.0 Hz, 1 H, 4-H) ppm. 13C NMR
3J4-H,3-H ϭ 4.8 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CD3OD/
(100 MHz, CD3OD/D2O): δ ϭ 99.69 (d, JC-2,F ϭ 177.0 Hz, C-2),
1
2
D2O): δ ϭ 78.18 (C-3), 77.97 (C-2), 71.57 (C-5), 67.84 (C-4), 64.48 76.53 (d, JC-3,F ϭ 27.0 Hz, C-3), 71.09 (C-5), 68.09 (C-4), 64.47
(C-6), 52.01 (C-1) ppm. MS (DCI, NH3): m/z ϭ 164 [M ϩ Hϩ]
(C-6), 50.84 (d, 2JC-1,F ϭ 24.3 Hz, C-1) ppm. 19F NMR (188 MHz,
(100). HRMS (DCI, NH3) calcd. for C6H14NO4 [M ϩ H]ϩ CD3OD/D2O): δ ϭ Ϫ58.03 to Ϫ57.36 (m) ppm. MS (DCI, NH3):
164.0923, found 164.0923.
m/z ϭ 166 [M ϩ Hϩ] (100). HRMS (DCI, NH3) calcd. for
C6H13FNO3 [M ϩ H]ϩ 166.0879, found 166.0878.
Deoxyfluoro Imino Sugar 21: A solution of 20 (166 mg, 0.52 mmol)
in MeOH (4 mL) containing 12  HCl (3 drops) and 10% Pd/C
(40 mg) was allowed to react under a H2 atmosphere (10 bar) with
stirring. After 48 h, the reaction mixture was filtered through celite
and concentrated to dryness under reduced pressure. The crude
product was dissolved in H2O/MeOH (67:33) (10 mL), acidic resin
(Dowex 50 WX8, 100Ϫ200 mesh, 5 g) was added, and the suspen-
sion was stirred slowly for 1 h before being filtered. The resin was
successively rinsed with water (200 mL) and methanol (50 mL),
taken up in 2.5  aqueous NH4OH (20 mL) and the mixture al-
lowed to stir slowly for 1 h. The suspension was then filtered and
the resin rinsed with 2.5  aqueous NH4OH (200 mL). The re-
sulting solution was lyophilized and the residue purified by flash
column chromatography on silica gel treated with 2.5% v/v Et3N,
(CH2Cl2/MeOH/EtOH/NH4OH, gradient from 70:12:12:6 to
79:3:12:6) to give 21 (68 mg, 0.50 mmol, 97% yield). Rf ϭ 0.30
(CH2Cl2/MeOH/EtOH/NH4OH, 70:12:12:6). [α]2D5 ϭ ϩ18.7 (c ϭ
Acknowledgments
`
T. A. acknowledges the ‘‘Ministere de l’Education Nationale de la
´ ´
Recherche et des Technologies’’ and the ‘‘Societe de Secours des
´
Amis des Sciences’’ for a grant. We thank N. Iche for her helpful
contribution.
[1]
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Med. Chem. 2001, 9, 3077Ϫ3092.
For a selected example directed towards β-1,4-galactosyl-
[3]
transferase see: R. Wang, D. H. Steensma, Y. Takaoka, J. W.
Yun, T. Kajimoto, C.-H. Wong, Bioorg. Med. Chem. 1997, 5,
661Ϫ672.
[4]
For a selected example directed towards β-1,4-galactosyl-
1
1.0, MeOH). IR (neat): ν˜max ϭ 3395 (OϪH and NϪH) cmϪ1. H
transferase see: C. Saotome, Y. Kanie, O. Kanie, C.-H. Wong,
NMR (400 MHz, CD3OD/D2O): δ ϭ 4.92 (ddpseudo-t, 3J2-H,3-H ϭ
Bioorg. Med. Chem. 2000, 8, 2249Ϫ2261.
I. Gautier-Lefebvre, J.-B. Behr, G. Guillerm, N. S. Ryder, Bio-
[5]
3
2
3J2-H,1Ј-H ϭ 1.4, J2-H,1-H ϭ 3.8 Hz, and J2-H,F ϭ 52.6 Hz, 1 H, 2-
H), 4.11 (ddpseudo-t, 3J3-H,2-H ϭ 4J3-H,1-H ϭ 1.2, 3J3-H,4-H ϭ 4.8 Hz
and J3-H,F ϭ 21.0 Hz, 1 H, 3-H), 3.70 (AB of ABX, J5-H,4-H
org. Med. Chem. Lett. 2000, 10, 1483Ϫ1486.
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R. Wischnat, R. Martin, C.-H. Wong, J. Org. Chem. 1998,
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3
ϭ
63, 8361Ϫ8365.
T. D. Butters, L. A. G. M. van den Broek, G. W. J. Fleet, T. M.
3
2
5.2, J5Ј-H,4-H ϭ 6.0 Hz, and J5-H,5Ј-H ϭ 11.2 Hz, ∆δaϪδb ϭ
25.2 Hz, 2 H, 2 ϫ 5-H), 3.25Ϫ3.08 (m, 2 H, 2 ϫ 1-H), 2.98 (pseudo-
[7]
Krulle, M. R. Wormald, R. A. Dwek, F. M. Platt, Tetrahedron:
Asymmetry 2000, 11, 113Ϫ124.
q, J4-H,5Ј-H ϭ J4-H,5-Hϭ J4-H,3-H ϭ 5.2 Hz, 1 H, 4-H) ppm. 13C
3
3
3
1
[8]
NMR (100 MHz, CD3OD/D2O): δ ϭ 99.60 (d, JC-2,F ϭ 177.0 Hz,
Y. J. Kim, M. Ichikawa, Y. Ichikawa, J. Am. Chem. Soc. 1999,
2
3
C-2), 77.38 (d, JC-3,F ϭ 26.0 Hz, C-3), 67.53 (d, JC-4,F ϭ 1.6 Hz,
C-4), 61.41 (C-5), 50.72 (d, 2JC-1,F ϭ 24.2 Hz, C-1) ppm. 19F NMR
(188 MHz, CD3OD/D2O): δ ϭ Ϫ58.08 to Ϫ57.46 (m) ppm. MS
(DCI, NH3): m/z ϭ 136 [M ϩ Hϩ] (100). HRMS (DCI, NH3)
calcd. for C5H11FNO2 [M ϩ H]ϩ 136.0774, found 136.0774.
121, 5829Ϫ5830.
R. E. Lee, K. Mikusova, P. J. Brennan, G. S. Besra, J. Am.
[9]
˘ ´
Chem. Soc. 1995, 117, 11829Ϫ11832 and references cited ther-
ein.
[10]
[11]
For ethambutol-imino sugar hybrids see: R. C. Reynolds, N.
Bansal, J. Rose, J. Freidrich, W. J. Suling, J. A. Maddry, Car-
bohydr. Res. 1999, 317, 164Ϫ179.
Deoxyfluoro Imino Sugar 22: A solution of 17 (150 mg, 0.43 mmol)
in MeOH (4 mL) containing 12  HCl (3 drops) and 10% Pd/C
For homologated aza analogs of arabinose see: J. A. Maddry,
Eur. J. Org. Chem. 2003, 2903Ϫ2910
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2909

´
T. Ayad, Y. Genisson, S. Broussy, M. Baltas, L. Gorrichon
FULL PAPER
N. Bansal, L. E. Bermudez, R. N. Comber, I. M. Orme, W. J.
Suling, L. N. Wilson, R. C. Reynolds, Bioorg. Med. Chem. Lett.
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For the synthesis of a donor-mimicking phosphonoimino sugar
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For recent asymmetric syntheses of 1,4-dideoxy-1,4-imino--
arabinitol see this ref. and the following three: M. Lombardo,
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fluoro analogue of the pyrrolidinic α-mannosidase inhibitor
1,4-didexoy-1,4-imino--mannitol see: B. Winchester, S. Al
Daher, N. C. Carpenter, I. Cenci di Bello, S. S. Choi, A. J.
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Action of m-CPBA resulted in the formation of an oxazocine
(CH2Cl2, room temp., ca. 60% yield) through a sigmatropic
[2,3]-Meisenheimer rearrangement, even after treatment with
one equivalent of acetic acid (for similar rearrangement of vi-
nylazetidines to oxazepines see: T. Kurihara, M. Doi, K.
Hamaura, H. Ohishi, S. Harusawa, R. Yoneda, Chem. Pharm.
Bull. 1991, 39, 811Ϫ813). Use of the chlorhydrate of 12 yielded
complex reaction mixture under same reaction conditions.
Other reagents such as in situ generated performic acid (H2O2
in formic acid, for related examples see: L. I. Ukhova, G. P.
Kukso, Chem. Heterocycl. Compd. (Eng. Transl.) 1982, 18,
66Ϫ70) resulted in either no reaction or complete decompo-
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[12]
[27]
[28]
[13]
[14]
[15]
[16]
[17]
[18]
[29]
[30]
Any attempts to further activate these diols as cyclic sulfates
failed due to the reluctance of the corresponding sulfites to
oxidation with standard RuCl3/NaIO4 reagent. Alternative
conditions such as KMnO4 in the presence of H2SO4 (M. S.
Berridge, M. P. Franceschini, E. Rosenfeld, T. J. Tewson, J.
Org. Chem. 1990, 55, 1211Ϫ1217) led to rapid decompostion.
It has been shown on a related N-Cbz derivative that the use
of either AD mix α or AD mix β did not allow any improve-
ment of the stereoselectivity (see ref.[13]). The R configuration
of the newly formed stereocenter in the major diastereomer was
attributed by analogy with pioneering work in these series (see:
R. C. Bernotas, Tetrahedron Lett. 1990, 31, 469Ϫ472). It was
unambiguously confirmed by chemical correlation with the tar-
geted 1,4-dideoxy-1,4-imino--galactitol.
[19]
ˇ
BeMiller, L. Petrus, Tetrahedron Lett. 2002, 43, 383Ϫ385.
[20]
[21]
[22]
[23]
[24]
[25]
´
T. Ayad, Y. Genisson, M. Baltas, L. Gorrichon, Synlett 2001,
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´
T. Ayad, Y. Genisson, M. Baltas, L. Gorrichon, Chem. Com-
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[31]
´
K. Marotte, T. Ayad, Y. Genisson, G. S. Besra, M. Baltas, J.
Prandi, Eur. J. Org. Chem. 2003, in press. In this paper we
describe the coupling of synthesised imino sugars with arabino-
furanoside moieties possessing a lipophilic chain, and the ac-
tivity of all compounds. Very promising inhibitory results are
presented for certain of these hybrid molecules.
[26]
For comparative biological studies involving the 6-deoxy-6-
Received March 11, 2003
2910
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2903Ϫ2910