A practical route to partially protected pyrrolidines as precursors for the stereoselective synthesis of alexines

Article abstract of DOI:10.1016/S0008-6215(00)00319-0

Either 3-O-benzoyl- (2a) or 3-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose (2b) were regioselectively O-benzylated at C-4 to give 4a and 4b, respectively, which were transformed into 5-azido-3-O-benzoyl-4-O-benzyl- (6a) and 5-azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-L-sorbopyranose (6b) by nucleophilic displacement of the corresponding 5-O-mesyl derivatives 5a and 5b by sodium azide in DMF, respectively. Compound 6b was also prepared from 4b in one step by the Mitsunobu methodology. Deacetonation of 6a and 6b gave the partially protected free azidouloses 8a and 8b, respectively, that were protected as their 1-O-TBDPS derivatives 9a and 9b. Hydrogenation of 9b over Raney nickel gave stereoselectively (2R,3R,4R,5S)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis (hydroxymethyl)pyrrolidine (12) which was identified by transformation into the well known (2R,3R,4R,5S)-3,4-dihydroxy-2,5-bis(hydroxymethyl)pyrrolidine (1, DGDP).

Full text of DOI:10.1016/S0008-6215(00)00319-0

www.elsevier.nl/locate/carres
Carbohydrate Research 330 (2001) 401–408
Note
A practical route to partially protected pyrrolidines as
precursors for the stereoselective synthesis of alexines
Isidoro Izquierdo Cubero,* Maria T. Plaza Lo´pez-Espinosa, Rafael Robles D´ıaz,
Francisco Franco Montalba´n
Department of Organic Chemistry, Faculty of Pharmacy, Uni6ersity of Granada, E-18071 Granada, Spain
Received 12 October 2000; accepted 6 December 2000
Abstract
Either 3-O-benzoyl- (2a) or 3-O-benzyl-1,2-O-isopropylidene-b-
zylated at C-4 to give 4a and 4b, respectively, which were transformed into 5-azido-3-O-benzoyl-4-O-benzyl- (6a) and
5-azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-a- -sorbopyranose (6b) by nucleophilic displacement of the
D
-fructopyranose (2b) were regioselectively O-ben-
L
corresponding 5-O-mesyl derivatives 5a and 5b by sodium azide in DMF, respectively. Compound 6b was also
prepared from 4b in one step by the Mitsunobu methodology. Deacetonation of 6a and 6b gave the partially
protected free azidouloses 8a and 8b, respectively, that were protected as their 1-O-TBDPS derivatives 9a and 9b.
Hydrogenation of 9b over Raney nickel gave stereoselectively (2R,3R,4R,5S)-3,4-dibenzyloxy-2%-O-tert-
butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) which was identified by transformation into the well known
(2R,3R,4R,5S)-3,4-dihydroxy-2,5-bis(hydroxymethyl)pyrrolidine (1, DGDP). © 2001 Elsevier Science Ltd. All rights
reserved.
Keywords:
D-Fructose; Stereoselective synthesis; Polyhydroxypyrrolidines
alexine type, since it contains the appropriate
chiral information and can be easily trans-
formed into the adequately protected
(2R,3R,4R,5S)-3,4-dihydroxy-2,5-bis(hydroxy-
The pyrrolizidine skeleton 1-aza-bicyclo-
[3.3.0]octane is the basic framework of a
group of alkaloids isolated from both plant
and animal sources such as alexine, australine
methyl)pyrrolidine (2,5-dideoxy-2,5-imino- -
D
and casuarine. Alexine,
a
tetrahydroxy-
glucitol, DGDP, 1), a versatile key intermedi-
ate, which after two carbon-chain lengthening
at C-6 (C-5% when the heterocyclic nomencla-
ture is used) and subsequent cyclization would
provide the required polyhydroxypyrrolizidine
bicyclic system.
pyrrolizidine isolated from Alexa leiopetala by
Nash et al.1 in 1988 shows inhibitory activity
against glycosidase and could then be of use
as chemotherapeutic agents.2 According to the
retrosynthetic scheme (Scheme 1),
D-fructose
could be considered a suitable chiral starting
material for the synthesis of compounds of
Compound 1 has been previously prepared
from 5-azido-5-deoxy-
L
-sorbose and 5-keto- -
D
fructose, respectively, by chemoenzymatic ap-
proaches.3,4 However, this does not allow the
suitable protection for the synthesis of alexine
compounds. With this objective in mind, a
* Corresponding author. Tel.: +34-958-243846; fax: +34-
958-243845.
E-mail address: isidoro@platon.ugr.es (I. Izquierdo
Cubero).
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00319-0

402
I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
Scheme 1. Retrosynthetic scheme for the preparation of alexine and 7-deoxyalexine from
D-fructose.
Treatment of 8a with tert-butylchloro-
diphenylsilane–imidazole in DMF afforded 5-
azido - 3 - O - benzoyl - 4 - O - benzyl - 1 - O - tert-
synthesis of adequately protected 1, starting
from a readily available 3-O-substituted
derivative of 1,2-O-isopropylidene-b- -fructo-
D
butyldiphenylsilyl-5-deoxy-a- -sorbopyranose
L
pyranose is now reported.
(9a) in quantitative yield. Hydrogenation of
9a over 10% Pd–C gave the corresponding
pyrroline 10a, characterized through its 5%-O-
acetyl derivative 11a. An attempt to continue
the hydrogenation of 10a to the pyrrolidine
stage was unsuccessful and only an extensive
decomposition was observed. On the basis of
this results, a change of protective group at
C-3 was considered and 3-O-benzyl-1,2-O-iso-
Reaction of 3-O-benzoyl-4-O-benzyl-1,2-O-
isopropylidene-b-
D
-fructopyranose5 (4a) with
methanesulfonyl chloride gave the corre-
sponding 5-O-methanesulfonyl derivative 5a
that was subsequently transformed into the
related 5-azido-3-O-benzoyl-4-O-benzyl-5-de-
oxy-1,2-O-isopropylidene-a- -sorbopyranose
L
(6a) by treatment with sodium azide in DMF.
The acidic removal of the 1,2-O-isopropyli-
dene group afforded crystalline 5-azido-3-O-
propylidene-b-
-fructopyranose (2b)7 was
D
used as chiral starting material. O-Benzylation
at C-4 of 2b was carried out via its 4,5-O-stan-
nylene derivative 3 by regioselective ring open-
ing with benzyl bromide at the oxygen in
equatorial position to give the corresponding
3,4-di-O-benzyl derivative 4b, straightfor-
wardly transformed into 5-azido-3,4-di-O-
benzoyl-4-O-benzyl-5-deoxy-a- -sorbopyranos
L
2
e (8a). The C5 conformation and a configura-
tion of 8a were reasonably assigned on the
13
basis of its C NMR spectrum which showed
a single signal for C-2 at l 97.13. The HO-1 in
8a was protected as its O-tert-butyldiphenylsi-
lyl ether 9a before hydrogenation to the inter-
mediate pyrrolidine, since it has been
reported6 that decomposition takes place in an
analogous compound when a free hydroxyl
group was present at the same position
(Scheme 2).
benzyl-5-deoxy-1,2-O-isopropylidene-a- -sorbo
L
pyranose (6b) through the 5-O-mesyl deriva-
tive 5b as above. Compound 6b was also
synthesized from 6a by Zemple´n debenzoyla-
tion to 7 followed by 3-O-benzylation and
finally, in order to shorten the synthesis, by a
Mitsunobu reaction on 4b with hydrogen
azide.8 Deacetonation of 6b in acidic medium
gave 5-azido-3,4-di-O-benzyl-5-deoxy-a- -sor-
L
bopyranose (8b), which enantiomer has been
reported.9 As in the case of 8a, compound 8b
existed as only one anomer (13C NMR)
(Scheme 3).
Chemoselective protection at C-1 of 8b to
give the azidohexulose 9b, as above, followed
by catalytic hydrogenation over Raney nickel
allowed the formation of the corresponding
aminocarbonyl sugar that rearranged in a fast
process to its cyclic imine intermediate 10b
which was finally hydrogenated in a highly
stereocontrolled manner to afford (2R,3R,
4R,5S) - 3,4 - dibenzyloxy - 2% - O - tert - butyldi-
phenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine
Scheme 2.

I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
403
Scheme 3.
(12) in accordance with results previously re-
ported.3a,c,10 The configuration of 12, as well
as that of its easier to handle N-Cbz derivative
13, were established on the basis of its analyt-
ical and spectroscopic data and by total de-
protection to the known DGDP 1.3,4,11,12
Compound 13 is an interesting molecule,
since depending on whether the chain length-
ening occurred, either at C-1 or C-6, the target
compounds would belong either to the alexine
or australine series.
propylidene-b-
-fructopyranose5 (4a, 5.1 g,
D
12.3 mmol) and triethylamine (2 mL, 14.4
mmol) in dry CH2Cl2 (50 mL) was added
dropwise methanesulfonyl chloride (1 mL, 13
mmol), and the mixture was maintained at rt
overnight. TLC (2:1 ether–hexane) then re-
vealed a faster-running compound. Methanol
(1 mL) was added, and after 1 h the mixture
was concentrated and the residue dissolved in
CH2Cl2 (30 mL), washed with water, then
concentrated. Column chromatography (1:1
CH2Cl2–ether) afforded crystalline 5a (4.2 g,
70%), mp 156–158 °C (from ether); [h]D25
−
143° (c 1.7); IR (KBr): w 1723 (CꢀO, benzoate)
1. Experimental
1
and 1378 cm−1 (CMe2); H NMR: l 8.07–
8.05, 7.65–7.59, 7.50–7.45, and 7.23–7.09 (4
m, 10 H, aromatic), 5.60 (d, 1 H, J3,4 10.2 Hz,
H-3), 5.22 (m, 1 H, H-5), 4.71 and 4.51 (2 d,
2 H, J 11.5, PhCH2), 4.10 (dd, 1 H, J5,6a 1.1,
J6a,6e 13.3 Hz, H-6a), 4.07 (dd, 1 H, J4,5 3.2
Hz, H-4), 4.05 and 3.96 (2 d, 2 H, J1,1% 9.3 Hz,
H-1,1%), 4.02 (dd, 1 H, J5,6e 1.9 Hz, H-6e), 3.08
(s, 3 H, Ms), 1.49, and 1.40 (2 s, 6 H, CMe2);
13C NMR: l 165.85 (CO), 136.84, 133.59,
129.92, 129.44, 128.64, 128.45, 128.05, and
127.98 (aromatic), 112.38 (CMe2), 104.77 (C-
2), 76.85 and 75.16 (C-3,5), 72.70 and 71.89
(PhCH2, C-1), 68.43 (C-4), 63.30 (C-6), 39.23
(Ms), 26.55 and 26.29 (CMe2). Anal. Calcd for
C24H28O9S: C, 58.52; H, 5.73; S, 6.51. Found:
C, 58.54; H, 5.87; S, 6.43.
General methods.—Melting points were de-
termined with a Gallenkamp apparatus and
are uncorrected. Solutions were dried over
MgSO4 before concentration under reduced
1
pressure. The H and 13C NMR spectra were
recorded with Bruker AMX-300, AM-300,
and ARX-400 spectrometers for solutions in
CDCl3 (internal Me4Si). IR spectra were
recorded with a Perkin–Elmer 782 instrument
and mass spectra with a Hewlett–Packard
HP-5988-A and Fisons mod. Platform II and
VG Autospec-Q mass spectrometers. Optical
rotations were measured for solutions in
CHCl3 (1-dm tube) with a Jasco DIP-370 po-
larimeter. TLC was performed on precoated
E. Merck Silica Gel 60 F254 aluminum sheets
with detection by charring with H2SO4.
Column chromatography was performed on
Silica Gel (E. Merck, 7734). The noncrys-
talline compounds, for which elemental analy-
ses were not obtained were shown to be
homogeneous by chromatography and charac-
terized by NMR spectroscopy and FAB-
HRMS with thioglycerol matrix.
5-Azido-3-O-benzoyl-4-O-benzyl-5-deoxy-
1,2 - O - isopropylidene - h -
L
- sorbopyranose
(6a).—A stirred solution of 5a (4 g, 8.13
mmol) and NaN3 (1.05 g, 16.2 mmol) in dry
DMF (30 mL) was heated at 80 °C for 15 h.
TLC (2:1 ether–hexane) then revealed a
faster-running compound. The mixture was
concentrated to a residue that was dissolved in
ether (40 mL), washed with brine and concen-
trated. Column chromatography (1:1 ether–
hexane) of the residue afforded crystalline 6a
(3 g, 84%), mp 97–98 °C (from ether–hex-
ane); [h]2D6 −222° (c 1.4); IR (KBr): w 2109
3-O-Benzoyl-4-O-benzyl-1,2-O-isopropyli-
dene-5-O-methanesulfonyl-i- -fructopyranose
D
(5a).—To an ice-water cooled and stirred so-
lution of 3-O-benzoyl-4-O-benzyl-1,2-O-iso-

404
I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
[h]2D3 −197° (c 1); IR (KBr): w 3528 and 3259
(OH), 2107 (N3), and 1717 cm−1 (CꢀO, ben-
zoate); 13C NMR: l 166.17 (CO), 137.22,
133.77, 130.03, 129.11, 128.69, 128.37, 128.23,
and 127.94 (aromatic), 97.13 (C-2), 79.11 (C-
3), 75.58 (PhCH2), 72.54 (C-4), 65.33 (C-1),
61.70 (C-5), and 60.80 (C-6). Anal. Calcd for
C20H21N3O6: C, 60.14; H, 5.30; N, 10.52.
Found: C, 59.98; H, 5.73; N, 10.47.
(N3), 1724 (CꢀO, benzoate), 1383 and 1374
1
cm−1 (CMe2); H NMR: l 8.10–8.02, 7.63–
7.58, 7.50–7.45, and 7.19–7.08 (4 m, 10 H,
aromatic), 5.31 (d, 1 H, J3,4 9.7 Hz, H-3), 4.76
and 4.62 (2 d, 2 H, J 10.5, PhCH2), 3.97 and
3.91 (2 d, 2 H, J1,1% 9.3 Hz, H-1,1%), 3.84–3.64
(m, 4 H, H-4,5,6a,6e), 1.50 and 1.42 (2 s, 6 H,
CMe2); 13C NMR: l 165.74 (CO), 137.29,
133.63, 129.93, 129.40, 128.69, 128.35, 128.20,
and 127.90 (aromatic), 112.48 (CMe2), 104.44
(C-2), 80.12 (C-3), 75.47 (PhCH2), 71.69 (C-
1), 71.39 (C-4,5), 61.52 (C-6), 26.73 and 26.25
(CMe2). Anal. Calcd for C23H25N3O6: C,
62.86; H, 5.73; N, 9.56. Found: C, 63.10; H,
6.09; N, 9.58.
5-Azido-3-O-benzoyl-4-O-benzyl-1-O-tert-
butyldiphenylsilyl-5-deoxy-h- -sorbopyranose
L
(9a).—To a stirred solution of 8a (1.82 g, 4.6
mmol) in dry DMF (7 mL) were added imida-
zole (340 mg,
5
mmol) and tert-
butylchlorodiphenylsilane (1.3 mL, 5 mmol)
and the mixture was left at rt 5 h. TLC (2:1
ether–hexane) then revealed a faster-running
compound. The mixture was concentrated and
the residue dissolved in ether (30 mL) and the
resulting solution was washed with brine and
concentrated. Column chromatography (1:4
ether–hexane) of the residue afforded pure 9a
(2.24 g, 96%) as a syrup; [h]2D2 −85.5° (c 1.2);
IR (film): w 3511 (OH), 3074 (aromatic), 2110
(N3), 1733 (CꢀO, benzoate), and 709 cm−1
5-Azido-4-O-benzyl-5-deoxy-1,2-O-isopropy-
lidene-h- -sorbopyranose (7).—Compound 6a
L
(2 g, 4.5 mmol) in anhyd MeOH (15 mL) was
treated with 0.1 M NaOMe in MeOH (5 mL)
overnight. TLC (2:1 ether–hexane) then
showed the absence of 6a and the presence of
a slower-running compound. The mixture was
neutralized with AcOH, and after the usual
work-up the resulting residue was chro-
matographed (1:5“1:1 ether–hexane) to af-
ford syrupy 7 (1.4 g, 92%); [h]2D7 −145° (c 1);
IR (film): w 3483 (OH), 3068 and 3036 (aro-
matic), 2110 (N3), 1385 and 1373 (CMe2), 733
1
(aromatic); H NMR: l 8.09–8.02 and 7.70–
7.15 (2 m, 20 H, aromatic), 5.16 (dd, 1 H, J3,4
9.5, J3,OH 1 Hz, H-3), 4.82 and 4.69 (2 d, 2 H,
J 10.6 Hz, PhCH2), 4.12 (t, 1 H, J4,5 9.5 Hz,
H-4), 4.04 (d, 1 H, HO-2), 3.86 (d, 2 H, J5,6
8.6 Hz, H-6,6), 3.77 (q, 1 H, H-5), 3.73 and
3.61 (2 d, 2 H, J1,1% 10.5 Hz, H-1,1%), and 1.09
(s, 9 H, CMe3); 13C NMR (inter alia): l 165.60
(COPh), 96.90 (C-2), 79.44 (C-3), 75.50
(PhCH2), 72.34 (C-4), 65.90 (C-1), 61.77 (C-
5), 60.70 (C-6), 26.82 (CMe3), and 19.30
(CMe3). HRMS: m/z 660.25067 [M+Na]+.
For C36H39N3NaO6Si 660.25058 (deviation −
0.1 ppm).
1
and 698 cm−1 (aromatic); H NMR: l 7.45–
7.28 (m, 5 H, PhCH2), 4.94 and 4.68 (2 d, 2
H, J 10.8, PhCH2), 4.15 and 3.94 (2 d, 2 H,
J1,1% 8.8 Hz, H-1,1%), 3.73–3.51 (2 m, 5 H,
H-3,4,5,6a,6e), 1.49 and 1.45 (2 s, 6 H, CMe2);
13C NMR: l 137.91, 128.58, 128.26, and
128.06 (PhCH2), 112.49 (CMe2), 105.41 (C-2),
82.76 (C-3), 75.36 (C-1), 72.04 (C-4), 71.95
(PhCH2), 61.47 (C-6), 60.93 (C-5), 26.68 and
26.35 (CMe2). HRMS: m/z 358.13777 [M+
Na]+. For C16H21N3NaO5 358.13789 (devia-
tion 0.3 ppm).
Hydrogenation of 9a.—Compound 9a (1.89
g, 3 mmol) in MeOH–ether (50 mL) was
hydrogenated at 69 KPa over 10% Pd–C (0.3
g) overnight. TLC (1:0.1 ether–triethylamine)
then revealed the presence of only a slower-
running compound. The catalyst was filtered
off, washed with MeOH–ether, and the com-
bined filtrate and washings were concentrated
to give (3R,4R,5S)-3-benzoyloxy-4-benzyloxy-
2%-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)-1-pyrroline (10a, 1.64 g, 94%) as a
clear syrup, that was characterized through its
5%-O-acetate (11a). Thus, conventional acetyl
5-Azido-3-O-benzoyl-4-O-benzyl-5-deoxy-h-
-sorbopyranose (8a).—A solution of 6a (2.75
L
g, 6.3 mmol) in 70% aq TFA (10 mL) was
kept at rt 5 h. TLC (2:1 ether–hexane) then
revealed a slower-running compound. The
mixture was diluted with water and the precip-
itated 8a was collected by filtration, washed
with water and finally air-dried (2.43 g, quan-
titative). An aliquot was chromatographed
(1:1“2:1 ether–hexane) to afford pure 8a
(100 mg), mp 97–98 °C (from ether–hexane);

I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
405
3,4-di-O-Benzyl-1,2-O-isopropylidene-5-O-
methanesulfonyl-i- -fructopyranose (5b).—
ation of 10a (100 mg, 0.17 mmol) in dry
CH2Cl2 (6 mL) with Ac2O (0.5 mL) and tri-
ethylamine (0.6 mL) gave, after usual work-up
and column chromatography (1:1 ether–hex-
ane), pure 11a (65 mg, 60%) as a colorless
syrup; [h]2D2 −47° (c 1.8); IR (film): w 1744
(CꢀO, acetate), 1728 (CꢀO, benzoate), and
D
To an ice-water cooled and stirred solution of
4b (5.26 g, 13 mmol) and triethylamine (5.2
mL, 37.6 mmol) in dry CH2Cl2 (25 mL) was
added dropwise methanesulfonyl chloride
(1.67 mL, 17.2 mmol), and the mixture was
maintained at rt overnight. TLC (3:1 ether–
hexane) then revealed a faster-running com-
pound. MeOH (1 mL) was added and after 1
h the mixture was concentrated and the
residue dissolved in CH2Cl2 (30 mL) washed
with water and concentrated. Column chro-
matography (1:3“1:2 ether–hexane) afforded
crystalline 5b slightly impurified that was re-
crystallized (1:9 ether–hexane) giving pure
compound (4.6 g, 74%), mp 78–80 °C; [h]D27
−109° (c 1.1); IR (KBr): w 3064 and 3032
(aromatic), 1385 and 1375 (CMe2), 738 and
1
1659 cm−1 (CꢀN); H NMR (inter alia): l
6.26 (s, 1 H, H-3), 4.88 and 4.67 (2 d, 2 H, J
12 Hz, PhCH2), 2.00 (s, 3 H, Ac), and 1.00 (s,
13
9 H, CMe3); C NMR: l 174.92 (C-2), 171.00
(COMe), 165.64 (COPh), 80.86 and 80.34 (C-
3,4), 72.07 (PhCH2), 71.88 (C-5), 62.95 and
62.59 (C-2%,5%), 26.73 (CMe3), 21.09 (COMe),
and 19.16 (CMe3). HRMS: m/z 658.26005
[M+Na]+. For C38H41NNaO6Si 658.26009
(deviation 0.1 ppm).
3,4-di-O-benzyl-1,2-O-isopropylidene-i-
fructopyranose (4b).—To a solution of 3-O-
benzyl-1,2-O-isopropylidene-b- -fructopyranos
D-
1
697 cm−1 (aromatic); H NMR: l 7.34 (m, 10
D
H, 2 PhCH2), 5.14 (m, 1 H, H-5), 4.98 and
4.66 (2 d, 2 H, J 11.4 Hz, PhCH2), 4.80 and
4.67 (2 d, 2 H, J 10.7 Hz, PhCH2), 4.01 (dd, 1
H, J4,5 3.2 Hz, H-4), 4.00 (bd, 1 H, H-6a), 3.99
and 3.94 (2 d, 2 H, J1,1% 8.6 Hz, H-1,1%), 3.93
(dd, 1 H, J5,6e 1.9, J6a,6e 13.4 Hz, H-6e), 3.74
(d, 1 H, J3,4 9.8 Hz, H-3), 3.04 (s, 3 H, Ms),
1.48 and 1.44 (2 s, 6 H, CMe2); 13C NMR: l
137.97, 137.34, 128.61, 128.56, 128.50, 128.45,
128.40, 128.31, 128.27, 128.10, 127.83, 127.79,
and 127.75 (aromatic), 112.32 (CMe2), 105.64
(C-2), 77.95, 77.52, and 74.66 (C-3,4,5), 75.45
(C-1), 72.93 and 71.73 (2 PhCH2), 62.74 (C-6),
39.03 (Ms), 26.99 and 26.14 (CMe2). Anal.
Calcd for C24H30O8S: C, 60.23; H, 6.31.
Found: C, 59.87; H, 6.60.
e7 (2b, 8 g, 25 mmol) in anhyd MeOH (70 mL)
was added dibutyltin oxide (6.6 g, 26.5 mmol)
and the suspension was heated for 2 h under
reflux, then concentrated to afford the 3,4-
dibutylstannylene derivative 3 as a solid foam
that was dried under vacuum over P2O5
overnight. A solution of 3 in dry DMF (60
mL) was treated with BnBr (6 mL, 51 mmol)
and heated at 110 °C for 4 h. TLC (ether) then
revealed a main faster-running product. Evap-
oration of the solvent gave a residue, a solu-
tion of which in ether was washed with brine
and water, then concentrated. Column chro-
matography (1:3 ether–hexane) of the residue
afforded 4b (5.7 g, 55%) as syrup; [h]2D6 −82°
(c 1); IR (film): w 3500 (OH), 3030 and 3020
(aromatic), 1385 and 1375 (CMe2), 710 and
5-Azido-3,4-di-O-benzyl-5-deoxy-1,2-O-iso-
propylidene-h- -sorbopyranose (6b).—(a) A
L
1
680 cm−1 (aromatic); H NMR: l 7.37 (m, 10
stirred solution of 5b (4 g, 8 mmol) and NaN3
(690 mg, 10.6 mmol) in dry DMF (30 mL)
was heated at 100 °C for 2 days. TLC (3:1
ether–hexane) then revealed a faster-running
compound. The mixture was concentrated to a
residue that was dissolved in ether (40 mL),
washed with brine and concentrated. Column
chromatography (1:4 ether–hexane) of the
residue afforded syrupy 6b (3.36 g, 98%); [h]D25
−107° (c 1.2); IR (film): w 3067 and 3035
(aromatic), 2109 (N3), 1384 and 1373 (CMe2),
H, 2 CH2Ph), 4.99 and 4.67 (2 d, 2 H, J 11.5
Hz, PhCH2), 4.77 and 4.55 (2 d, 2 H, J 11.8
Hz, PhCH2), 4.06 (dd, 1 H, H-4), 4.05 and
3.95 (2 d, 2 H, J1,1% 8.6 Hz, H-1,1%), 3.91–3.80
(m, 2 H, H-6a,6e), 3.66 (d, 1 H, J3,4 9.6 Hz,
H-3), 1.49 and 1.42 (2 s, 6 H, CMe2); 13C
NMR: l 138.38, 137.73, 128.64, 128.42,
128.07, 127.98, 127.83, and 127.71 (CH2Ph),
111.96 (CMe2), 105.64 (C-2), 76.93 and 71.68
(C-3,4,5), 75.13 (C-1), 71.88 and 71.59 (2
PhCH2), 60.35 (C-6), 27.06 and 26.15 (CMe2).
HRMS: m/z 423.17835 [M+Na]+. For
C23H28NaO6 423.17836 (deviation 0.0 ppm).
1
736 and 696 cm−1 (aromatic); H NMR: l
7.41–7.31 (m, 10 H, 2 PhCH2), 4.98 and 4.67
(2 d, 2 H, J 11.5 Hz, PhCH2), 4.90 (s, 2 H,

406
I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
PhCH2), 4.93 and 4.67 (2 d, 2 H, J 11.3 Hz,
PhCH2), 3.91 (t, 1 H, J3,4=J4,5 =9.2 Hz, H-4),
3.76–3.37 (m, 7 H, H-1,1%,3,5, 6,6%, OH-2), and
2.15 (t, 1 H, J1,OH 6.5 Hz, OH-1); 13C NMR: l
137.78, 137.41, 128.76, 128.74, 128.72, 128.65,
128.58, 128.53, 128.49, 128.39, 128.27, and
128.04 (aromatic), 97.72 (C-2), 81.63 (C-3),
78.93 (C-4), 75.78 and 75.54 (2 PhCH2), 65.53
(C-1), 61.91 (C-5), and 60.95 (C-6). Anal.
Calcd for C20H23N3O5: C, 62.32; H, 6.01; N,
10.90. Found: C, 62.60; H, 6.19; N, 11.12.
5-Azido-3,4-di-O-benzyl-1-O-tert-butyl-
PhCH2), 3.93 and 3.85 (2 d, 2 H, J1,1% 8.6 Hz,
H-1,1%), 3.86 (dt, 1 H, J5,6e 1.6, J4,5 =J5,6a=9.3
Hz, H-5), 3.79–3.58 (m, 3 H, H-4,6a,6e), 3.44
(d, 1 H, J3,4 9.3 Hz, H-3), 1.51 and 1.47 (2 s,
6 H, CMe2); 13C NMR: l 137.90, 137.87,
128.56, 128.29, 128.01, 127.94, and 127.90
(aromatic), 112.47 (CMe2), 105.30 (C-2), 82.56
(C-3), 78.64 (C-4), 75.75 and 75.47 (2 PhCH2),
71.57 (C-1), 61.94 (C-5), 61.28 (C-6), 27.16 and
26.19 (CMe2). HRMS: m/z 448.18493 [M+
Na]+. For C23H27N3NaO5 448.18484 (devia-
tion −0.2 ppm).
(b) Compound 6b was also obtained in
quantitative yield from 7 (1.31 g, 3.9 mmol) by
treatment with NaH (187 mg, 7.8 mmol) and
BnBr (0.7 mL, 5.8 mmol) in dry THF (15 mL),
after usual work-up.
diphenylsilyl - 5 - deoxy - h -
L
- sorbopyranose
(9b).—To a stirred solution of 8b (5 g, 13
mmol) in dry DMF (25 mL) were added imi-
dazole (968 mg, 14.5 mmol) and tert-
butylchlorodiphenylsilane (3.7 mL, 14.5
mmol) and the mixture was left at rt 20 h. TLC
(1:4 ether–hexane) then revealed a faster-run-
ning compound. The mixture was concen-
trated and the residue dissolved in ether (30
mL) and the resulting solution was washed
with brine and concentrated. Column chro-
matography (1:6 ether–hexane) of the residue
afforded pure 9b (8.5 g, quantitative) as a
syrup; [h]2D6 −33° (c 1.6); IR (film): w 3525
(OH), 3070, 3051, and 3034 (aromatic), 2114
(c) To a stirred solution of 4b (400 mg, 1
mmol) in dried CHCl3 (6 mL), triphenylphos-
phine (390 mg, 1.5 mmol) and a 1 M solution
of hydrogen azide (2 mL) in the same solvent
were added. The resulting mixture was cooled
(ice-water) and diethyl azodicarboxylate
(DEAD) (0.24 mL, 1.5 mmol) was added
dropwise. The solution was allowed to warm
slowly to rt. After 2 h, more HN3 solution (2
mL, 2 mmol), PPh3 (390 mg, 1.5 mmol) and
DEAD (0.24 mL, 1.5 mmol) were added and
the mixture left at rt overnight. TLC (3:1
ether–hexane) then showed the absence of 4b
and the presence of 6b. The reaction mixture
was supported on silica gel and chro-
matographed as above to afford pure 6b (340
mg, 80%) according to its analytical and spec-
troscopic data.
1
(N3), 741 and 699 cm−1 (aromatic); H NMR:
l 7.67–7.13 (3 m, 20 H, aromatic), 4.95 and
4.91 (2 d, 2 H, J 10.8 Hz, PhCH2), 4.89 and
4.57 (2 d, 2 H, J 11.2 Hz, PhCH2), 3.95 (t, 1 H,
J3,4=J4,5 =9.3 Hz, H-4), 3.78 (dd, 1 H, J5,6e 7,
J6a,6e 10.9 Hz, H-6e), 3.73 (t, 1 H, J5,6a 9.7 Hz,
H-6a), 3.66 and 3.48 (2 d, 2 H, J1,1% 10.1 Hz,
H-1,1%), 3.62 (dt, 1 H, H-5), 3.54 (s, 1 H,
HO-2), 3.49 (d, 1 H, H-3), and 1.07 (s, 9 H,
CMe3); 13C NMR (inter alia): l 98.00 (C-2),
81.91 (C-3), 78.94 (C-4), 75.88 and 75.51 (2
PhCH2), 65.92 (C-1), 62.12 (C-5), 60.90 (C-6),
26.88 (CMe3), and 19.34 (CMe3). HRMS: m/z
646.27126 [M+Na]+. For C36H41N3NaO5Si
646.27132 (deviation 0.1 ppm).
Hydrogenation of 9b.—Compound 9b (3.21
g, 5.14 mmol) in MeOH (40 mL) was hydro-
genated at 345 KPa over wet Raney nickel
(Fluka, 2.6 g) for 4 h. TLC (ether) then re-
vealed the presence of a slower-running com-
pound. 13C NMR analysis of an aliquot
indicated the formation of only pyrroline 10b
(C-2 at 176.41 ppm). The hydrogenation was
continued for additional 15 h, when TLC
5-Azido-3,4-di-O-benzyl-5-deoxy-h- -sorbo-
L
pyranose (8b).—A solution of 6b (3.36 g, 7.9
mmol) in 70% aq trifluoroacetic acid (10 mL)
was kept at rt for 24 h. TLC (3:1 ether–hex-
ane) then revealed a slower-running com-
pound. The mixture was concentrated and
repeatedly co-distilled with water and then
dissolved in CH2Cl2 and concentrated.
Column chromatography (1:1 ether–hexane)
gave crystalline 8b (2.41 g, 78.4%), mp 76–
78 °C, [h]2D8 −49° (c 1), lit. for the
D
enan-
tiomer 72–75 °C;9 [h]D22 +46° (c 0.5);9 IR
(KBr): w 3500 and 3280 (OH), 3070 and 3030
(aromatic), 2130 (N3), 750 and 700 cm−1 (aro-
1
matic); H NMR: l 7.41–7.28 (m, 10 H, 2
PhCH2), 4.94 and 4.90 (2 d, 2 H, J 10.7 Hz,

I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
407
2 H, PhCH2), 4.50 and 4.38 (2 d, 2 H, J 12.7
Hz, PhCH2), 4.38–3.70 (m, 8 H), 2.63 (bs, 1
H, OH), and 1.02 (s, 9 H, CMe3); 13C NMR
(inter alia): l 156.98 (CONꢁ), 82.60 (C-3),
80.08 (C-4), 72.29 and 71.78 (2 PhCH2), 67.52
(ꢂNCOOCH2Ph), 64.59 (C-2), 63.15 (C-5),
63.03 and 62.64 (C-2%,5%), 26.95 (CMe3), and
19.28 (CMe3). HRMS: m/z 738.32257 [M+
Na]+. For C44H49NNaO6Si 738.32269 (devia-
tion 0.2 ppm).
(ether) indicated the presence of a new and
slower-running compound. The catalyst was
filtered off, washed with MeOH, and the com-
bined filtrate and washings were concentrated
to a residue that was subjected to column
chromatography
(ether)
to
afford
(2R,3R,4R,5S) - 3,4 - dibenzyloxy - 2% - O - tert-
butyldiphenylsilyl - 2,5 - bis(hydroxymethyl)-
pyrrolidine (12, 2.9 g, 97%) as a colorless
syrup; [h]2D5 +26° (c 1.3); IR (film): w 3374
(OH), 3088, 3070 and 3034 (aromatic), and
(2R,3R,4R,5S) - 3,4 - Dibenzyloxy - N-
benzyloxycarbonyl - 2,5 - bis(hydroxymethyl)-
pyrrolidine (14).—To a stirred solution of 13
(500 mg, 0.7 mmol) in THF (6 mL) was added
a solution of tetrabutylammonium fluoride tri-
hydrate (400 mg, 1.3 mmol) in the same sol-
vent (5 mL) under Ar and the mixture was
kept at rt overnight. TLC (2:1 ether–hexane)
then showed the presence of a slower-running
compound. The solvent was evaporated and
the residue dissolved in ether (20 mL) washed
with water and concentrated. Column chro-
matography (4:1 ether–hexane) gave pure 14
1
701 cm−1 (aromatic); H NMR: l 7.70–7.23
(2 m, 20 H, aromatic), 4.62 and 4.44 (2 d, 2 H,
J 11.8 Hz, PhCH2), 4.54 and 4.48 (2 d, 2 H, J
11.7 Hz, PhCH2), 4.10 (dd, 1 H, J3,4 2.1, J4,5
5.3 Hz, H-4), 4.04 (dd, 1 H, J2,3 4.9 Hz, H-3),
3.94–3.79 (m, 4 H, H-2%a,2%b,5%a,5%b), 3.33 (bq,
1 H, J5,5%a=J5,5%b=4.4 Hz, H-5), 3.22 (bq, 1
H, J2,2%a=J2,2%b=4.5 Hz, H-2), 2.53 (bs, 2 H,
NH and OH), and 1.06 (s, 9 H, CMe3); 13C
NMR: l 138.14, 137.63, 135.74, 135.72,
133.40, 133.31, 129.87, 128.71, 128.56, 128.10,
127.85, and 127.63 (aromatic), 86.94 (C-3),
84.84 (C-4), 72.10 and 71.64 (2 PhCH2), 65.33
(C-2), 63.91 (C-2%), 61.71 (C-5%), 61.39 (C-5),
26.97 (CMe3), and 19.41 (CMe3). HRMS: m/z
604.28595 [M+Na]+. For C36H43NNaO4Si
604.28591 (deviation −0.1 ppm).
(2R,3R,4R,5S) - 3,4 - Dibenzyloxy - N-
benzyloxycarbonyl-2%-O-tert-butyldiphenylsilyl-
2,5-bis(hydroxymethyl)pyrrolidine (13).—To
an ice-water cooled and stirred solution of 12
(2.88 g, 4.25 mmol) in MeOH (35 mL) and
triethylamine (2.3 mL, 16.6 mmol) was added
dropwise benzyl chloroformiate (0.9 mL, 6.1
mmol) and the mixture was allowed to reach
rt. After 2 h, TLC (ether) revealed the pres-
ence of 12 together with two new compounds
of higher mobility, being the main one that
with lower Rf value. Additional triethylamine
(2.3 mL, 16.6 mmol) and benzyl chloroformi-
ate (0.9 mL, 6.1 mmol) were necessary to
complete the reaction. The mixture was con-
centrated and the residue supported on silica
gel and chromatographed (1:1 ether–hexane)
(304 mg, 92%) as a colorless syrup; [h]2D6 −4°,
22
405
[h]
−19° (c 0.8); IR (film): w 3390 (OH),
3067 and 3032 (aromatic), 1698 (CONꢁ), 741
1
and 698 cm−1 (aromatic); H NMR: l 7.40–
7.27 (m, 15 H, aromatic), 5.13 (s, 2 H,
ꢂNCOOCH2Ph), 4.72–3.60 (3 m, 12 H), 2.85
and 2.71 (2 bs, 2 H, OH-2%,5%); 13C NMR
(inter alia): l 156.36 (CONꢁ), 82.01 (C-3,4),
72.92 and 72.41 (2 PhCH2), 67.64
(ꢂNCOOCH2Ph), 63.66 (C-2,5), 62.16 and
61.51 (C-2%,5%). HRMS: m/z 500.20481 [M+
Na]+. For C28H31NNaO6 500.20491 (deviation
0.2 ppm).
(2R,3R,4R,5S) - 3,4 - Dihydroxy - 2,5 - bis-
(hydroxymethyl)pyrrolidine hydrochloride (15)
and the free base (1).—To a solution of 14
(300 mg, 0.2 mmol) in MeOH (25 mL) were
added 10% Pd–C (150 mg) and concd HCl
(three drops). The mixture was kept under H2
(345 KPa) for 14 h. TLC (ether) then revealed
the absence of 14. The catalyst was removed
by filtration and the filtrate concentrated to a
residue that was dissolved in EtOH and perco-
lated through a short column of silica gel to
afford 15 (120 mg, quantitative) as a thick
to give 13 (2.4 g, 68%) as a colorless syrup;
22
[h]2D2 +10°, [h]
+26° (c 0.8); IR (film): w
405
3444 (OH), 3066 and 3032 (aromatic), 1706
syrup; [h]2D4 −3.4° (c 1, MeOH); H NMR
1
1
(CONꢁ), 738 and 699 cm−1 (aromatic); H
NMR: l 7.65–7.10 (m, 25 H, aromatic), 5.04
and 4.98 (2 d, 2 H, J 12.3 Hz, PhCH2), 4.60 (s,
(MeOH-d4): l 4.28 (bs, 1 H, H-3), 4.11 (bt, 1
H, J 3 Hz, H-4), 4.04–3.82 (m, 5 H, H-

408
I. Izquierdo Cubero et al. / Carbohydrate Research 330 (2001) 401–408
Derome, A. E.; Hamor, T. A.; Scofield, A. M.; Watkin,
D. J. Tetrahedron Lett. 1988, 29, 2487–2490.
2. (a) Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L.
R. Cancer Res. 1988, 48, 1091–1094. (b) Ratner, L. AIDS
Res. Hum. Retro6iruses 1992, 8, 165–173.
3. (a) Liu, K. K. -C.; Kajimoto, T.; Chen, L.; Zhong, Z.;
Ichikawa, Y.; Wong, C. -H. J. Org. Chem. 1991, 56,
6280–6289. (b) Legler, G.; Korth, A.; Berger, A.; Ekhart,
C.; Gradnig, G.; Stu¨tz, A. E. Carbohydr. Res. 1993, 250,
67–77. (c) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.;
Siuzdak, G.; Wong, C. H. J. Am. Chem. Soc. 1997, 119,
8146–8151.
2,2%a,2%b,5%a,5%b), 3.61 (bq, 1 H, J 4 Hz, H-5);
13C NMR (MeOH-d4): l 76.26 and 74.77 (C-
3,4), 67.11 and 63.42 (C-2,5), 59.54 and 57.15
(C-2%,5%).
A solution of 15 (120 mg) in MeOH (5 mL)
was deionized using Amberlite IRA-400 resin
(OH− form). Evaporation of the solvent gave
pure 1 (90 mg, 92%); [h]2D6 +25° (c 1, MeOH),
lit. [h]2D2 +27.6 (c 1.3, MeOH);4 1H and 13C
NMR (D2O) data for 1 were in accordance
with those previously published3a,11,12, respec-
tively.
4. Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59,
3175–3185.
5. Izquierdo, I.; Plaza, M.-T.; Tornel, P. L. An. Quim. 1988,
84C, 340–343.
6. Furneaux, R. H.; Tyler, P. C.; Whitehouse, L. A. Tetra-
hedron Lett. 1993, 34, 3609–3612.
7. Izquierdo, I.; Plaza, M.-T. An. Quim. 1990, 86, 554–560.
8. Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61,
5546–5556.
9. Kuzuhara, H.; Kimura, M.; Emoto, S. Carbohydr. Res.
1975, 45, 245–255.
10. Kajimoto, T.; Chen, L.; Liu, K. K.-C.; Wong, C.-H. J.
Am. Chem. Soc. 1991, 113, 6678–6680.
11. Fechter, M. H.; Gradnig, G.; Berger, A.; Mirtl, C.;
Schmid, W.; Stu¨tz, A. E. Carbohydr. Res. 1998, 309,
367–374.
12. Yu, J.; Choi, S. Y.; Lee, S.; Yoon, H. J.; Jeong, S.; Mun,
H.; Park, H.; Schultz, P. G. Chem. Commun. 1997, 1957–
1958.
Acknowledgements
The authors are deeply grateful to the Min-
isterio de Educacio´n y Cultura (Spain) for
financial support (Proposal PB98-1357) and
for a grant (F. Franco Montalba´n).
References
1. Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
.