Synthesis of an aza analogue of 2-deoxy-D-ribofuranose and its homologues

Article abstract of DOI:10.1016/S0008-6215(01)00132-X

Azasugars were obtained in one-pot reactions by catalytic reduction reactions of amino group precursors in aldosugars followed by intramolecular reductive amino alkylation reactions. (3R,4S)-4-[(1S)-1,2-Dihydroxyethyl]pyrrolidin-3-ol was obtained from D-xylose by two different strategies through 3-C-cyano-3-deoxy-D-ribo-pentofuranose or 3-C-azidomethyl-3-deoxy-D-ribo-pentofuranose in 6 and 16% overall yields, respectively. The oxidative cleavage of the diol group in the corresponding Fmoc-azasugar followed by deprotection afforded (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol. (3R,4S)-4-[(1S,2R)-1,2,3-Trihydroxypropyl]pyrrolidin-3-ol was synthesized from diacetone-D-glucose through 3-deoxy-3-C-nitromethyl-D-allose and the overall yield was 7%.

Full text of DOI:10.1016/S0008-6215(01)00132-X

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Carbohydrate Research 333 (2001) 115–122
Synthesis of an aza analogue of 2-deoxy-
and its homologues
D-ribofuranose
Vyacheslav V. Filichev, Malene Brandt, Erik B. Pedersen*
Department of Chemistry, Uni6ersity of Southern Denmark, Odense Uni6ersity, DK-5230 Odense M, Denmark
Received 20 January 2001; received in revised form 23 April 2001; accepted 11 May 2001
Abstract
Azasugars were obtained in one-pot reactions by catalytic reduction reactions of amino group precursors in
aldosugars followed by intramolecular reductive amino alkylation reactions. (3R,4S)-4-[(1S)-1,2-Dihydroxy-
ethyl]pyrrolidin-3-ol was obtained from
D
-xylose by two different strategies through 3-C-cyano-3-deoxy-
D-ribo-pen-
tofuranose or 3-C-azidomethyl-3-deoxy-D-ribo-pentofuranose in 6 and 16% overall yields, respectively. The oxidative
cleavage of the diol group in the corresponding Fmoc-azasugar followed by deprotection afforded (3R,4R)-4-(hy-
droxymethyl)pyrrolidin-3-ol. (3R,4S)-4-[(1S,2R)-1,2,3-Trihydroxypropyl]pyrrolidin-3-ol was synthesized from diace-
tone-
D-glucose through 3-deoxy-3-C-nitromethyl-D-allose and the overall yield was 7%. © 2001 Elsevier Science Ltd.
All rights reserved.
Keywords: Azasugar; Iminosugar; ‘Masked’ 3-C-aminomethyl sugars; Reductive amination; (3R,4R)-4-(Hydroxymethyl)pyrro-
lidin-3-ol
1. Introduction
lidin-3-ol which was used in the preparation of
1%-aza carbacyclic thymidine analogues5 and
aza-C-nucleosides.6 Bols et al. published7 a
The discovery of the glycosidase inhibitor
activity of the natural product nojirimycin
initiated the synthesis of various hydroxylated
piperidines and hydroxylated pyrrolidines
called azasugars or iminosugars.1 This group
of inhibitors are now finding application as
anti-HIV, anticancer and antidiabetic agents2
(Fig. 1).
multistep synthesis of 1 from
D
-mannose and
its inhibitory potency against purine nu-
cleoside phosphorylase. Goskesen and Lundt
prepared
lidin-3-ol (2) from
weak inhibitor of a-
(3S,4R)-4-(hydroxymethyl)pyrro-
-xylose and found it a
, b-
glucosidase.8
D
D
D
Previous results have shown that pyrro-
lidine analogues of 2-deoxy- -ribofuranose,
D
having a nitrogen instead of the anomeric
carbon, and a methylene group instead of the
ring oxygen are inhibitors of glycosidases.3
Jaeger and Biel4 reported
a
synthesis
of racemic 1-benzyl-4-(hydroxymethyl)pyrro-
* Corresponding author. Tel.: +45-65502555; fax: +45-
66158780.
E-mail address: ebp@chem.sdu.dk (E.B. Pedersen).
Fig. 1. Examples of azasugars.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00132-X

116
V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
Recently the synthesis of 2-deoxy-ribofura-
nose-type 1-azasugar was published by two
groups. Bols and Hansen9 synthesized
triflouroacetic salt of trans-3-hydroxy-4-(hy-
droxymethyl)pyrrolidine (3) from (Z)-1,4-
dichloro-2-butene in nine steps and attempted
enzymatic purification of the enantiomers.
Ichikawa and Makino10 synthesized 3 in a
multi-gram scale from fumaric acid monoethyl
ester. The key step in this strategy included
asymmetric epoxidation and epoxide-opening
using cyanide anion (Yamamoto’s aluminium
reagent), with separation of regioisomers after
tosylation of the ring-opened products.
Fig. 2. Synthetic plan for the synthesis of azasugars by an
intramolecular aminoalkylation reaction. Possible amino
group precursors are shown in the rectangular forms.
There have also been reports on the synthe-
sis of azasugars from aminosugars in reductive
amination reactions.11–13 In this work we also
use a reductive amination reaction for forma-
tion of the heterocyclic ring (Fig. 2). It is
believed that masking the aldehydo as a hemi-
acetal allows the use of an amino precursor,
which can be reduced to an amino group prior
to the reductive amination reaction in a one-
pot reaction. Tedious chromatographic sepa-
ration of anomers of pyranose and furanose
forms prior to the reduction reaction is not
needed, making this route more attractive.
Retro synthetic analysis suggested the intro-
duction of an amino group in the sugar from
easily reducible precursor groups such as CN,
N3 and NO2. As the key sugar synthones, we
choose different types of furanos-3-uloses to
obtain the corresponding azasugar homo-
logues which can be cleaved to give 3.
difficult to avoid decomposition during work-
up unless a larger amount of sodium carbon-
ate was used in the hydrolysis step. In this
way 1,2-O-isopropylidene-a-
D
-xylofuranose
-xylo-
(6) and 1,2:3,5-di-O-isopropylidene-a-
D
furanose (5) were obtained in 67 and 15%
yield, respectively (Scheme 1).
The reaction of 7 with KCN in 2:1 diethyl
ether–water took place stereoselectively to
give only the xylo cyanoisomer (previously
obtained in a two step synthesis by treatment
of 7 with NaCN–NaHCO3 affording the ribo
cyanohydrin and subsequent epimerization
under basic condition with DBU–acetoni-
trile).16 The cyano compound was treated with
phenyloxythiocarbonyl chloride and 4-(N,N-
dimethylamino)pyridine (DMAP) in aceto-
nitrile to give 8. From the reduction reaction
of 8 using tributyltin hydride in the presence
of a,a%-azobisisobutyronitrile (AIBN), Calvo-
Mateo et al.17 isolated 5-O-(tert-butyl-
dimethylsilyl)-3-C-cyano-3-deoxy-1,2-O-iso-
propylidene-a- -ribo-pentofuranose (9) con-
D
2. Results and discussion
taminated with pentofuranos-3-ulose (7)
which was described as an inseparable mix-
ture. However, by column chromatography
we isolated 9 and 5-O-(tert-butyldimethylsi-
lyl)-3-C-cyano-3-deoxy-1,2-O-isopropylidene-
The azasugar 12 was synthesized by two
different strategies, both starting from 5-O-
(tert-butyldimethylsilyl)-1,2-O-isopropylidene-
a-
starting material was synthesized as earlier
described14,15 from
-xylose (4) via its 1,2-O-
D
-erythro-pentofuranos-3-ulose (7). This
a- -xylo-pentofuranose (10). The assignment
D
of the epimers was confirmed by NOE experi-
ments. NOE (3–4%) was observed between
3-H and 4-H in 10 when each of them were
irradiated, whereas no NOE was found be-
tween the same protons in 9. The NOEs be-
tween 2-H and 3-H confirmed in a similar
manner the assignment showing the greater
NOE (3–5%) for 9 versus 2% for the same
D
isopropylidene derivative 6 which was sily-
lated and oxidized with a CrO3–Py–Ac2O
complex. When applying the procedure of
Moravcova et al.14 to the synthesis of 6 from
4, by an acid-catalyzed reaction with acetone,
followed by partial hydrolysis, we found it

V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
117
protons in 10. Using 50% aqueous acetic
acid18 for the hydrolysis of protecting groups
in 9, did not in our results give complete
hydrolysis of the isopropylidene group after 1
h. Instead, we found it preferable to use 70%
aqueous acetic acid which led to 3-C-cyano-3-
deoxy- -ribo-pentofuranose (11) in 65% yield.
D
The azasugar 12 was obtained by a reductive
amination reaction using hydrogen over 10%
Pd–C in water in an autoclave for 24 h.
An alternative way for the synthesis of 12
started from the 3-methylene analogue 13
which was obtained in 85% yield in a Wittig
Scheme 2. (a) CH3P(C6H5)3Br/n-BuLi/THF; (b) (1) BH3/
THF; (2) NaOH/H2O2; (3) MsCl/Py; (c) (CH3)2NH···HN3 or
NaN3/DMF; (d) 70% AcOH; (e) H2/200 psi/Pd–C/H2O; (f)
FmocCl/dioxane/10% aq NaHCO3; (g) (1) NaIO4; (2)
NaBH4; (h) NEt3/acetonitrile.
reaction from 7 with CH3PPh3Br using n-BuLi
in dry THF (Scheme 2). Sodium hydride in
DMSO as earlier described19 in this step was
not used here in order to avoid contamination
with sulfur compounds, which later on could
poison the catalyst during the reductive ami-
nation reaction. Compound 14 was obtained
in three steps from 1318 and for the prepara-
tion of 15 it was treated with ten equiv of
sodium azide or 1.1 equiv of the DMF soluble
dimethylammonium azide instead of lithium
azide18 which is no longer readily available.
Dimethylammonium azide20 was easily synthe-
sized as previously described by treatment of
an equal molar amount of sodium azide and
dimethylammonium hydrochloride in DMF at
70 °C for 4 h, and subsequent removal of
sodium chloride by filtration at 10 °C and
crystallization of the product at −70 °C. In
these two syntheses of azides, partial removal
of the tert-butyldimethylsilyl protecting group
was observed and compounds 15 and 16 were
isolated in the ratio 3:2 with both reagents.
Deblocking the mixture of 15 and 16 with
70% acetic acid afforded the azido sugar 17 in
82% yield. Reductive amination under the
Scheme 1. (a) (CH3)2CO/H+; (b) (1) TBDMSiCl/Py; (2)
CrO3/Py/Ac2O/CH2Cl2; (c) (1) KCN/Et2O/H2O; (2)
PhOC(S)Cl/DMAP/acetonitrile; (d) (n-Bu)3SnH/AIBN/tolu-
ene; (e) 70% AcOH; (f) H2/200 psi/Pd–C/H2O.

118
V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
yield by treatment of the azasugar 12 with
9-fluorenylmethyl chloroformate (FmocCl) in
1:1 dioxane and 10% aqueous NaHCO3 for 24
h.22 Sodium periodate oxidation of 18 yielded
an aldehydo sugar which was immediately
reduced with sodium borohydride to give the
expected Fmoc protected azasugar 19 in 99%
yield, which in turn was deprotected by NEt3
in acetonitrile for 15 h to yield the azasugar 3
in 95% yield.
same conditions as for compound 11 afforded
the expected azasugar 12 in 71% yield as a
brown oil.
The direct cleavage of the diol group in 12
to a hydroxymethyl derivative 3 by consecu-
tive reactions with sodium periodate and
sodium borohydride failed. N-Protection of
the azasugar 12 by reaction with ethyl
triflouracetate21 was unsuccessful. However,
the Fmoc-derivative 18 was obtained in 70%
For the synthesis of (3R,4S)-4[(1S,2R)-
1,2,3-trihydroxypropyl]pyrrolidin-3-ol (26) the
target compound was obtained from 25 by
catalytic reduction of a nitro group followed
by reductive amination with the masked sugar
aldehyde (Scheme 3). According to the litera-
ture, 25 could be obtained from diacetone- -
D
glucose which in the first step was oxidized
with dry DMSO and acetic acid to give the
furan-3-ulose 2123 which after conversion to
2224 was treated again with the same reagent
for the elimination reaction to give 2324 prior
to the conversion to 25.25,26 Although good
yields were obtained of 25, the main problem
in this route was sulfur-by-products formed in
the two steps where DMSO was used. The
sulfur-by-products poisoned the catalyst in the
reductive amination reaction and thereby in-
activating it. The problem was partially solved
by extensive-column chromatography after the
synthesis of 22 and again after the synthesis of
23. Even then, the Pd–C catalyst had to be
exchanged several times in order to get a
complete intramolecular reductive amination
reaction. To avoid DMSO in the synthesis of
25, diacetone- -glucose (20) was oxidized by a
D
complex of CrO3–acetic anhydride and dry
pyridine27 and another route was followed to
obtain 25 from 21. The methylene derivative
24 was obtained in a Wittig reaction using
MePPh3Br and n-BuLi in dry THF.19 The
nitro group was introduced in a radical reac-
tion with AgNO2 and I2 and subsequent re-
duction of the resulting double bond26
afforded 25. Using this route for the synthesis
of 25, the azasugar 26 was obtained in 90%
yield in the subsequent catalytic reduction re-
action of the nitro group and reductive amino
alkylation in the one-pot reaction using Pd–C
and hydrogen.
Scheme 3. (a) DMSO/Ac2O; (b) CrO3/Py/Ac2O/CH2Cl2; (c)
MeNO2/t-BuOK/DMF; (d) CH3P(C6H5)3Br/n-BuLi/THF; (e)
(1) AgNO2/I2/Et2O; (2) NaBH4/EtOH; (3) Amberlite IR-
120(H+); (f) (1) NaBH4/EtOH; (2) Amberlite IR-120(H+); (g)
H2/200 psi/Pd–C/H2O.

V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
119
5-O-(tert-Butyldimethylsilyl)-3-C-cyano-3-
deoxy-1,2-O-isopropylidene-h- -ribo-pento-
3. Summary
D
furanose (9).—A solution of 5-O-(tert-
butyldimethylsilyl)-3-C-cyano-1,2-O-isopro-
In the present investigation we have demon-
strated a new methodology of synthesizing
1-aza analogues of furanose sugars. The key
step is an intramolecular reductive aminoalky-
lation reaction of 3-C-aminomethyl aldosug-
ars using hydrogen and Pd–C. The amino
group in turn is obtained in the same reaction
prior to the aminoalkylation by reduction of
azido, cyano and nitro groups when the alde-
hydo group in the sugar is masked as a hemi-
acetal. It is believed this methodology of
synthesizing azasugars will be generally
applicable.
pylidene-3-O-(phenyloxythiocarbonyl)-a- -
D
xylo-pentofuranose17 (8) (490 mg, 1 mmol),
a,a%-azobisisobutironitrile (AIBN, 37.5 mg,
0.25 mmol) in dry oxygen free toluene (25
mL) was stirred for 15 min while N2 was
bubbled through the mixture. Then (n-
Bu)3SnH (0.53 mL, 2 mmol) was added. The
flask was heated in an oil bath at 70 °C for 4
h under N2. On cooling to rt, water (10 mL)
was added and the emulsion was evaporated
to dryness in vacuo. The residue was chro-
matographed on a silica gel column with
EtOAc (5–10%, v/v) in cyclohexane to afford
two compounds: 9 (239 mg, 76%): Rf 0.32
4. Experimental
(50%
EtOAc–cyclohexane);
1H
NMR
(CDCl3): l 0.07, 0.09 (2s, 6 H, [CH3]2Siꢀ), 0.90
(s, 9 H, ꢀ[CH3]3), 1.37, 1.59 (2s, 6 H, ꢀ[CH3]2),
3.35 (dd, 1 H, J 4.7, 9.5 Hz, H-3), 4.10 (m, 2
H, H-5), 4.55 (dd, 1 H, J 2.1, 9.8 Hz, H-4),
5.05 (t, 1 H, J 3.8 Hz, H-2), 6.05 (d, 1 H, J 3.3
Hz, H-1); 13C NMR (CDCl3): l −4.9
([CH3]2Siꢀ), 18.7 (ꢀC[CH3]3), 26.3 (ꢀ[CH3]3),
26.8, 27.0 (ꢀ[CH3]2), 35.8 (C-3), 61.2 (C-5),
79.9 (C-4), 80.3 (C-2), 105.7 (C-1), 113.5
(ꢀC[CH3]2), 115.8 (CN); and compound 10 (48
mg, 15%): Rf 0.41 (50% EtOAc–cyclohexane);
1H NMR (CDCl3): l 0.07, 0.09 (2s, 6 H,
[CH3]2Siꢀ), 0.90 (s, 9 H, ꢀ[CH3]3), 1.37, 1.59
(2s, 6 H, ꢀ[CH3]2), 3.48 (d, 1 H, J 4.8 Hz,
H-3), 4.05 (dd, 1 H, J 7.9, 10.2 Hz, H-5), 4.20
(dd, 1 H, J 4.8, 10.0 Hz, H-5), 4.58 (m, 1 H,
H-4), 5.10 (d, 1 H, J 4.1 Hz, H-2), 6.20 (d, 1
H, J 3.6 Hz, H-1); 13C NMR (CDCl3): l −4.9
([CH3]2Siꢀ), 18.6 (ꢀC[CH3]3), 26.2 (ꢀ[CH3]3),
26.8, 27.0 (ꢀ[CH3]2), 40.4 (C-3), 62.6 (C-5),
78.1 (C-4), 83.0 (C-2), 105.7 (C-1), 113.2
(ꢀC[CH3]2), 116.5 (CN).
General.—NMR spectra were recorded on
a Bruker AC-300 FT NMR spectrometer at
1
300 MHz for H NMR and at 75.5 MHz for
13C NMR. Internal standards used in 1H
NMR spectra were Me4Si (l 0.00) for CDCl3,
CD3OD, Me2SO-d6 and 1,4-dioxane (l 3.75)
for D2O; in 13C NMR were CDCl3 (l 77.0),
CD3OD (l 49.0), Me2SO-d61(l 39.5) and 1,4-
dioxane (l 67.2) for D2O. H COSY experi-
ment for compound 12 was recorded on an
1
Varian Unity Inova at 500 MHz. H NMR
steady-state NOE difference spectroscopy ex-
periments were carried out on compounds 9
and 10 with a Bruker AC-250 spectrometer.
Accurate ion mass determination was per-
formed on a Kratos MS-50-RF equipped with
FAB source. The [M+H]+ ions were peak-
matched using ions derived from the glycerol
matrix. Thin-layer chromatography (TLC)
analyses were carried out using TLC plates 60
F254 purchased from Merck and were visual-
ized in UV light (254 nm) and/or with a 5%
solution of H2SO4 in MeOH for sugar deriva-
tives and/or with a ninhydrin spray reagent
(0.3 g ninhydrin in 100 mL butan-1-ol and 3
mL HOAc) for azasugars and its derivatives.
The silica gel (0.063–0.200 mm) used for
column chromatography was purchased from
Merck. All solvents were distilled before use.
The reagents used were purchased from
Aldrich, Sigma or Fluka.
3-C-Cyano-3-deoxy- -ribo-pentofuranose
D
(11).—A solution of nitrile 9 (1.0 g, 3.2 mmol)
in 70% HOAc (20 mL) was heated at 100 °C
for 24 h. After allowing the mixture to cool,
water was added (20 mL) and the aq solution
was extracted with CH2Cl2 (3×15 mL). The
water layer was evaporated under vacuum.
The residue was purified by chromatography
on a silica-gel column with 10% (v/v) MeOH
in CH2Cl2 to give the mixture of pyranose and

120
V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
1 H, H-3), 3.40–3.95 (m, 7 H, 3×OH,
furanose forms of 11 (331 mg, 65%) as a
colorless oil: 1H NMR (Me2SO-d6): l 3.18 (dd,
1 H, J 5.0, 9.5 Hz, H-3), 3.25–3.80 (m, 5 H,
3×OH, H-5), 4.08 (m, 1 H, H-4), 5.10 (m, 1
H, H-2), 5.90 (m, 1 H, H-1); 13C NMR
(Me2SO-d6): l 40.0, 39.9 (C-3), 64.8, 64.3 (C-
5), 68.3, 65.9 (C-4), 81.6, 76.6 (C-2), 103.3,
95.9 (C-1), 119.2, 119.4 (CN).
CH2N3, H-5), 4.08 (m, 2 H, H-2, H-4), 5.10 (s,
13
1 H, H-1); C NMR (Me2SO-d6): l 44.1, 36.7
(C-3), 50.8, 48.5 (CH2N3), 65.3, 64.6 (C-5),
76.1, 69.1 (C-4), 81.9, 76.1 (C-2), 103.0, 94.0
(C-1).
(3R,4S)-4-[(1S)-1,2-Dihydroxyethyl]pyrro-
lidin-3-ol (12).—The 10% Pd–C (315 mg) was
suspended in a solution of water (25 mL) with
11 or 17 (2 mmol). The mixture was kept at
200 psi H2 at rt for 24 h and filtered through
Celite® which was further washed by 100 mL
of water. The combined water solutions were
evaporated in vacuo. The residue was purified
by silica-gel column chromatography (0–30%
(v/v) aq NH3 in dioxane) to give 12 as a
brownish oil, 194 mg (66%) from 11, 209 mg
(71%) from 17: Rf 0.24 (50% aq NH3–1,4-
3-C-Azidomethyl-3-deoxy-5-O-(tert-butyl-
dimethylsilyl)-1,2-O-isopropylidene-h- -ribo-
D
pentofuranose (15).—Compound 1418 (1.5 g,
3.8 mmol) and 10 equiv of NaN3 or 1.1 equiv
of dimethylammonium azide in DMF (20 mL)
were heated with stirring at 95 °C for 1.5 h.
The mixture was evaporated to dryness in
vacuo. The residue was dissolved in a mixture
of CH2Cl2 (20 mL) and water (20 mL). The
organic layer was washed with water (3×15
mL), dried over Na2SO4 and evaporated to
give a syrup which was purified on a silica-gel
column with 10–50% (v/v) EtOAc in cyclo-
1
dioxane); H NMR (D2O): l 2.15 (m, 1 H,
H-4), 2.65 (dd, 1 H, J 7.3, 11.8 Hz, H-5), 2.89
(dd, 1 H, J 2.8, 12.5 Hz, H-2), 3.00 (dd, 1 H,
J 5.4, 12.4 Hz, H-5), 3.20 (m, 1 H, H-2),
3.50–3.70 (m, 3 H, CH[OH]CH2OH), 4.40
(dt, 1 H, J 3.2, 5.1 Hz, H-3), 4.79 (m, 4 H,
1
hexane to yield 15 (540 mg, 45%); H NMR
(CDCl3): l 0.07, 0.09 (2s, 6 H, [CH3]2Siꢀ), 0.90
(s, 9 H, ꢀ[CH3]3), 1.37, 1.59 (2s, 6 H, ꢀ[CH3]2),
2.51 (m, 1 H, H-3), 3.65 (dd, 1 H, J 5.5, 12.2
Hz, CH2N3), 3.80 (dd, 1 H, J 9.8, 12.2 Hz,
CH2N3), 3.96 (dd, 2 H, J 3.9, 4.9 Hz, H-5),
4.08 (m, 1 H, H-4), 4.92 (t, 1 H, J 4.2 Hz,
13
3×OH, NH); C NMR (D2O): l 48.0 (C-4),
50.5 (C-5), 54.1 (C-2), 64.9 (CH2OH), 72.8
(CH), 74.1 (C-3); HRMS (FAB) m/z 148.0962
([MH]+ [C6H14NO3]=148.0974).
13
H-2), 6.05 (d, 1 H, J 3.8 Hz, H-1); C NMR
N - Fmoc - (3R,4S) - 4 - [(1S) - 1,2 - dihydroxy-
ethyl]pyrrolidin-3-ol (18).—(3R,4S)-4-[(1S)-
1,2-Dihydroxyethyl]pyrrolidin-3-ol (12, 500
mg, 3.42 mmol) was dissolved in a suspension
of 10% aq NaHCO3 (15 mL) in dioxane (15
mL). 9-Fluorenylmethyl chloroformate (1.3 g,
5.1 mmol) was added. The resulting solution
was stirred at rt for 18 h, treated with water
(50 mL) and extracted with CH2Cl2 (3×75
mL). The combined organic layers were dried
(Na2SO4) and evaporated under diminished
pressure to give an oil which was purified by
silica-gel column chromatography with cyclo-
hexane–EtOAc (0–25%, v/v) followed by
CH2Cl2–MeOH (25%) to afford 18 (880 mg,
70%): Rf 0.47 (10% MeOH–CH2Cl2); 1H
NMR (CD3OD): l 2.23 (br,s, 1 H, H-4), 3.25
(m, 2 H, H-5), 3.45–3.65 (m, 5 H, H-2,
CH[OH]CH2OH), 4.23 (m, 1 H, CH [Fmoc]),
4.40 (m, 3 H, CH2 [Fmoc], H-3), 4.85 (br,s, 3
H, 3×OH), 7.25–7.83 (m, 8 H, Fmoc); 13C
NMR (CD3OD): l 45.7, 45.9 (C-4), 46.3, 46.5
(C-5), 46.8 (Fmoc), 51.6, 51.8 (C-2), 63.9 (C-
(CDCl3): l −4.9([CH3]2Siꢀ), 18.7 (ꢀC[CH3]3),
26.2 (ꢀ[CH3]3), 26.8, 27.2 (ꢀ[CH3]2), 45.8 (C-3),
48.2 (CH2N3), 63.6 (C-5), 80.4 (C-2), 81.3
(C-4), 105.4 (C-1), 112.4 (ꢀC[CH3]2); and 3-C-
azidomethyl-3-deoxy-1,2-O-isopropylidene-a-
1
D
-ribo-pentofuranose (16, 270 mg, 31%); H
NMR (CDCl3): l 1.37, 1.59 (2s, 6 H, ꢀ[CH3]2),
1.98 (br,s, 1 H, OH), 2.32 (m, 1 H, H-3), 3.38
(dd, 1 H, J 6.5, 12.0 Hz, CH2N3), 3.65 (m, 2
H, CH2N3, H-5), 3.94 (m, 2 H, H-4, H-5), 4.73
(t, 1 H, J 4.2 Hz, H-2), 5.84 (d, 1 H, J 3.7 Hz,
H-1); 13C NMR (CDCl3): l 26.3, 26.6
(ꢀ[CH3]2), 43.8 (C-3), 47.7 (CH2N3), 61.9 (C-
5), 80.4 (C-2), 80.9 (C-4), 104.8 (C-1), 112.2
(ꢀC[CH3]2).
3-C-Azidomethyl-3-deoxy- -ribo-pentofura-
D
nose (17).—This was synthesized as a mixture
of pyranose and furanose forms from the mix-
ture of 3:2 15 and 16 (810 mg, 2.9 mmol) by
the same methodology as described for the
synthesis of 11; yield 450 mg (82%) of a
1
colorless oil: H NMR (Me2SO-d6): l 2.41 (m,

V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
121
psi. The solution was filtered through Celite®
and washed thoroughly with water and evapo-
rated in vacuo giving the title compound 26
(93 mg, 90%) as a brown foam, which could
be purified by silica-gel column chromatogra-
phy (0–30% (v/v) aq NH3 in dioxane): Rf 0.10
3), 66.4 (Fmoc), 69.4, 70.1, 70.6, 70.7
(CH[OH]CH2OH), 118.8, 123.9, 126.0, 126.6,
140.4, 143.0, 154.5 (Fmoc); FAB-MS m/z 370
[M+H+].
N-Fmoc-(3R,4R)-4-(hydroxymethyl)pyrro-
lidin-3-ol (19).—A cooled solution of com-
pound 18 (724 mg, 1.96 mmol) in EtOH (10
mL) was added to a solution of NaIO4 (461
mg, 2.16 mmol) in water (5 mL) while stirring.
After 30 min, NaBH4 (217 mg, 5.86 mmol)
was added. After 30 min the resulting solution
was diluted with water (10 mL) and extracted
with CH2Cl2 (3×50 mL). The combined or-
ganic layers were dried (Na2SO4) and evapo-
rated under diminished pressure to give pure
19 (660 mg, 99%): Rf 0.52 (10% MeOH–
1
(50% aq NH3–1,4-dioxane); H NMR (D2O):
l 2.57 (sep, 1 H, J 3.7 Hz, H-4), 3.10 (dd, 1 H,
J 7.0, 12.0 Hz, H-5), 3.16 (dd, 1 H, J 2.7, 12.5
Hz, H-2), 3.32 (dd, 1 H, J 5.4, 12.4 Hz, H-5),
3.50–3.70 (m, 5 H, H-2, ꢀCH[OH]CH[OH]-
CH2OH), 4.57 (td, 1 H, J 3.1, 5.3 Hz, H-3),
13
4.78 (m, 5 H, NH, 4×OH); C NMR (D2O):
l 47.9 (C-4), 48.5 (C-5), 53.6 (C-2), 63.3
(CH2OH), 71.3, 71.4 (ꢀCH[OH]CH[OH]ꢀ),
73.5 (C-3); HRMS (FAB) m/z 178.1078
([MH]+ [C7H16NO4]=178.1079).
1
CH2Cl2); H NMR (CDCl3): l 2.30 (br.s, 1 H,
H-4), 3.20 (m, 1 H, H-5), 3.32 (m, 1 H, H-5),
3.40–3.70 (m, 5 H, H-2, CH2OH, CH
[Fmoc]), 4.20–4.38 (m, 5 H, CH2 [Fmoc], H-3,
2×OH), 7.25–7.83 (m, 8 H, [Fmoc]). 13C
NMR (CDCl3): l 46.4, 46.6 (C-4), 47.2, 47.5
(C-5), 48.2 (Fmoc), 52.4, 52.8 (C-2), 62.4 (C-
3), 67.4 (Fmoc), 71.8, 72.6 (CH2OH), 119.9,
125.0, 126.0, 127.7, 141.2, 143.8, 155.2
(Fmoc); FAB-MS m/z 340 [M+H]+.
References
1. Bols, M. Acc. Chem. Res. 1998, 31, 1–8.
2. Ichikawa, Y.; Igarashi, Y.; Ichicawa, M.; Suhara, Y. J.
Am. Chem. Soc. 1998, 120, 3007–3018.
3. Ichikawa, Y.; Igarashi, Y.; Ichicawa, M. Tetrahedron
Lett. 1995, 36, 1767–1770.
4. Jaeger, E.; Biel, J. H. J. Org. Chem. 1965, 30, 740–744.
5. Lee, Y. H.; Kim, H. K.; Youn, I. K.; Chae, Y. B. Bioorg.
Med. Chem. Lett. 1991, 1, 287–290.
6. Sørensen, M. D.; Khalifa, N. M.; Pedersen, E. B. Synthe-
sis 1999, 1937–1943.
(3R,4R)-4-(Hydroxymethyl)pyrrolidin-3-ol
(3).—A mixture of compound 19 (520 mg,
1.53 mmol) and Et3N (0.65 mL, 4.70 mmol) in
MeCN (30 mL) was stirred at 60 °C for 15 h.
The solvent was removed in vacuo and the
residue was dissolved in CH2Cl2 (10 mL)–wa-
ter (30 mL) and washed with CH2Cl2 (2×30
mL). The water layer was concentrated under
diminished pressure to yield 3 (171 mg, 95%):
7. Bols, M.; Persson, M. P.; Butt, W. M.; Jørgensen, M.;
Christensen, P.; Hansen, L. T. Tetrahedron Lett. 1996, 37,
2097–2100.
8. Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39,
5841–5844.
9. Bols, M.; Hansen, S. U. Acta Chem. Scand. 1998, 52,
1214–1222.
10. Ichikawa, Y.; Makino, K. Tetrahedron Lett. 1998, 39,
1
Rf 0.41 (50% aq NH3 –1,4-dioxane); H NMR
8245–8248.
11. Kowollik, W.; Janairo, G.; Voelter, W. J. Org. Chem.
1988, 53, 3943–3947.
12. Bashyal, B. P.; Fleet, G. W. J.; Gough, M. J.; Smith, P.
W. Tetrahedron 1987, 43, 3083–3093.
13. Farr, R. A.; Holland, A. K.; Huber, E. W.; Peet, N. P.;
Weintraub, P. M. Tetrahedron 1994, 50, 1033–1044.
14. Moravcova, J.; Capkova, J.; Stanek, J. Carbohydr. Res.
1994, 263, 61–66.
15. Yoshimura, Y.; Sano, T.; Matsuda, A.; Ueda, T. Chem.
Pharm. Bull. 1988, 36, 162–167.
16. Calvo-Mateo, A.; Camarasa, M.-J.; Diaz-Ortiz, A.; de las
Heras, F. G. J. Chem. Soc., Chem. Commun. 1988, 1114–
1115.
17. Calvo-Mateo, A.; Camarasa, M.-J.; Diaz-Ortiz, A.; de las
Heras, F. G. Tetrahedron 1988, 44, 4895–4903.
18. Lin, T.-S.; Zhu, J.-L.; Dutschman, G. E.; Cheng, Y.-C.;
Prusoff, W. H. J. Med. Chem. 1993, 36, 353–362.
19. Acton, E. M.; Goerner, R. N.; Uh, H. S.; Ryan, K. J.;
Henry, D. W. J. Med. Chem. 1979, 22, 518–525.
(CD3OD): l 2.20 (m, 1 H, H-4), 2.74 (dd, 1 H,
J 5.7, 11.4 Hz, H-5), 2.85 (dd, 1 H, J 3.1, 12.1
Hz, H-2), 3.10 (dd, 1 H, J 5.2, 12.0 Hz, H-5),
3.20–3.28 (m, 1 H, H-2), 3.45–3.60 (m, 2 H,
CH2OH), 4.15 (td, 1 H, J 3.3, 5.1 Hz, H-3),
13
4.79 (m, 3 H, 2×OH, NH); C NMR (D2O):
l 73.5 (C-3), 61.9 (CH2OH), 54.3 (C-2), 50.7
(C-5), 48.1 (C-4); HRMS (FAB) m/z 118.0868
([MH]+ [C5H12NO2]=118.0864).
(3R,4S) - 4 - [(1S,2R) - 1,2,3 - Trihydroxypro-
pyl]pyrrolidin-3-ol
(26).—3-Deoxy-3-C-ni-
-allose (25, 130 mg, 0.58 mmol)
tromethyl-
D
was dissolved in 10 mL of water, and 10%
Pd–C (46 mg) was added. The solution was
hydrogenated in an autoclave for 24 h at 200

122
V.V. Filiche6 et al. / Carbohydrate Research 333 (2001) 115–122
20. Titova, I. E.; Poplavskii, V. S.; Koldobskii, G. I.; Niko-
laev, V. D.; Erussalimsky, G. B. Khim. Geterotsikl. Soed.
1986, 1086–1089.
21. Rosowsky, A.; Forsch, R. A.; Bader, H.; Freisheim, J. H.
J. Med. Chem. 1991, 34, 1447–1454.
22. Hebert, N.; Davis, P. W.; DeBaets, E. L.; Acevado, O. L.
Tetrahedron Lett. 1994, 35, 9509–9512.
23. Mazur, A.; Tropp, E.; Engel, R. Tetrahedron 1984, 40,
3949–3956.
24. Albrecht, H. P.; Moffat, J. G. Tetrahedron Lett. 1970, 13,
1063–1066.
25. Garg, N.; Hossain, N.; Plavec, J.; Chattopadhyaya, J.
Tetrahedron 1994, 50, 4167–4178.
26. Szarek, W. A.; Jewell, J. S.; Szczerek, I.; Jones, K. N.
Can. J. Chem. 1969, 47, 4473–4476.
27. Garegg, P. J.; Samuelsson, B. Carbohydr. Res. 1978, 67,
267–270.
.