Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from D-fructose

Article abstract of DOI:10.1016/j.tet.2005.09.043

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-D- fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4- O-benzyl-5-deoxy-1,2-O-isopropylidene-β-D-fructopyranose (8), after treatment under modified Garegg's c

Full text of DOI:10.1016/j.tet.2005.09.043

Tetrahedron 61 (2005) 11697–11704
Polyhydroxylated pyrrolidines, III. Synthesis of new protected
2,5-dideoxy-2,5-iminohexitols from D-fructose*
*
´
Isidoro Izquierdo, Marıa T. Plaza, Miguel Rodrıguez, Francisco Franco and Alicia Martos
´
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 18 July 2005; accepted 14 September 2005
Available online 25 October 2005
Abstract—The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-b-D-fructopyranose (6) was straightforwardly transformed
into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-D-fructopyranose (8), after treatment under modified Garegg’s
conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-a-L-sorbopyranose (7) with
lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford
the corresponding b-D-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the
acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was
transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-20,50-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrroli-
dine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate D2-pyrroline (16), or
only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and
(2R,3S,4R,5R)-3,4-dibenzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
followed by a further cyclization, could lead to pyrrolizi-
dines, which stereochemistry at C(1,2,3,7a) belonging to
that of the natural hyacinthacines.
In previous papers, we have reported on the highly
stereoselective synthesis of orthogonally protected deriva-
tives of 2,5-dideoxy-2,5-imino-D-glucitol (DGDP)1 and 2,5-
dideoxy-2,5-imino-D-mannitol (DMDP),2 from the cheap
and commercially available D-fructose. Both compounds
were shown to be excellent chiral key intermediates for the
preparation of natural3 and unnatural hyacinthacines,4
potent glycosidase inhibitors.5
Continuing with our efforts on the title topic, we describe
herein, the highly stereoselective synthesis of 22 together
with that of its C(2)-epimer (21) using a D-psicose derivative
(12) as key intermediate, which is available from D-fructose
as source of chirality and functionalization.
Figure 1 shows0the synthetic potentiality of (2R,3S,4R,5R)-3,4-
dibenzyloxy-2 -O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)pyrrolidine [22, 2,5-dideoxy-2,5-imino-D-altritol
(DALDP) displaying the retrosynthesis of a great variety
of hyacinthacines, recently isolated from different natural
sources,6 where clearly is shown that 22 must be considered
an appropriate chiral starting material for the synthesis of
such target molecules. Thus, protection interchange
between the hydroxyl groups at C(20)–C(50), carbon-chain
lengthening at C(20) (the original C(1) of D-fructose) in a
two more carbon atoms fragment suitably functionalised,
2. Results and discussion
In order to obtain the above mentioned intermediate 12, it
was necessary to prepare 3,4-di-O-benzyl-1,2-O-ispropyli-
dene-b-D-psicopyranose (4). This was initially attempted by
a well established protocol consisting in: partial deacetona-
tion of the already known 3-O-benzyl-1,2:4,5-di-O-iso-
propylidene-b-D-psicopyranose (1)7 to the corresponding
1,2-O-isopropylidene derivative (2), subsequent 4,5-O-di-n-
butylstannylation to the not characterized 3, and finally
regioselective ring opening by benzyl bromide (see
Scheme 1), but conversely to many other cases,1,8 where
the main product comes from the electrophilic attack of the
reagent at the oxygen with the equatorial disposition [O(4)],
no regioselectivity was observed and an unresolvable
mixture of the corresponding 3,4- (4) and 3,5-di-O-benzyl
(5) derivatives was produced in low yield. The use of any
* For Part II, see Ref. 2.
´
Keywords: D-fructose; Stereoselective sıntesis; Polyhydroxylated pyrroli-
dines; 2,5-Dideoxy-2,5-iminohexitols; DADP; DALDP.
*
Corresponding author. Tel.: C34 958 249583; fax: C34 958 243845;
e-mail: isidoro@ugr.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.043

11698
I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
Figure 1. Retrosynthesis of natural hyacinthacines.
other electrophilic reagent (BzCl, TBDMSCl, MEMCl, etc.)
also gave the same result.
These unexpected results could be explained if intermediate 3
would adopt a 3,6B conformation similar to that found in 1 (see
Fig. 2), and presuming that a Me2C!/n-Bu2Sn! change
must not be of great stereochemical significance. It can be
observed the oxygen atoms at C(4,5) adopt a parallel
disposition, in such a way that both can be attacked by the
electrophilic reagent giving 4 and 5, without regioselectivity.
On the basis of the above results a new synthetic route was
designed (see Scheme 2), consisting in the introduction of
the appropriate funtionalization and stereochemistry at C(5)
in 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-b-D-fructo-
pyranose (6)8b prior to the inversion of the configuration at
C(3). Thus, reaction of 6 under the Garegg’s conditions9
afforded the corresponding 5-deoxy-5-iodo-a-L-sorbo
derivative (7), which treatment with LiN3 in DMF effected
SN2 substitution to yield 5-azido-3-O-benzoyl-4-O-benzyl-
5-deoxy-1,2-O-isopropylidene-b-D-fructopyranose (8).
Scheme 1. Synthesis of 4 and 5 from 1. Reagents and conditions: (i) 75% aq
AcOH/45 8C, 2 h; (ii) n-Bu2SnO/MeOH/reflux; (iii) BnBr/DMF/110 8C.
Scheme 2. Synthesis of 12 from D-fructose. Reagents and conditions: (i) I2/
Ph3P/imidazole/MePh, reflux; (ii) LiN3/DMF/100 8C; (iii) MeOH/MeONa
(cat), rt; (iv) Dess–Martin/Cl2CH2, rt; (v) NaBH4/MeOH, 0 8C; (vi) NaH/
DMF/BnBr, rt.
Figure 2. ORTEP view of compound 1. Thermal ellipsoid enclosed 50% of
electron density.

I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
11699
Zemplen debenzoylation of 8 gave the 3-O-deprotected 9,
that was subsequently oxidized to 2,3-diulose 10, not totally
characterized but reduced to 5-azido-4-O-benzyl-5-deoxy-
1,2-O-isopropylidene-b-D-psicopyranose (11). The high
stereoselectivity found was in accordance with that
observed by Tipson et al. in the reduction of 1,2:4,5-di-O-
isopropylidene-b-D-erythro-2,3-hexodiulo-2,6-pyranose.10
Compound 11 was straightforwardly transformed into the
totally protected derivative 12.
According to Scheme 3, deacetonation of 12 in acid medium
gave 13, existing as az2:1 mixture of a- and b-pyranoses in
5C2 and 2C5 conformations, respectively, according to their
1H and 13C NMR data (see Tables 1 and 2).
Scheme 4. Synthesis of total and partially protected polyhydroxylated
pyrrolidines 17 and 18. Reagents and conditions: (i) Ph3P/THF, reflux;
(ii) NaCNBH3/THF/AcOH, 0 8C; (iii) Raney-Ni/H2/MeOH–THF;
(iv) n-Bu4NCFK 3 H2O/THF, then 10% Pd–C/H2/MeOH/HCl.
O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)-D1-pyr-
roline (16) in almost quantitative yield that could be
characterized, but decomposed on standing. Conventional
reduction of 16 with sodium cianoborohydride gave a 2:1
mixture of (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-
dibenzyloxy-20,50-di-O-tert-butyldiphenylsilyl-2,5-bis(hy-
droxymethyl)pyrrolidine (18). The absolute configuration at
the new generated stereogenic centre [C(5)] in 17, and hence
that of 18, was easily determined after recording their
1
optical, H and 13C NMR data. Thus, 18 was optically
inactive indicating the presence of a symmetry plane,
confirmed by the presence of half of the resonance signals in
its NMR spectra. On the other hand, hydrogenation of 14
under the presence of Raney-Ni occurred with high
stereoselectivity to afford only 18. Compound 18 was
totally O-deprotected to the already known12 2,5-dideoxy-
2,5-imino-D-allitol (19 DADP) as its hydrochloride salt.
Scheme 3. Synthesis of protected uloses 14 and 15. Reagents and
conditions: (i) aq 60% TFA, rt; (ii) TBDPSCl/imidazole//DMF, rt.
Attempt to protect 13 as its 1-O-tert-butyldiphenylsilyl
derivative under the conventional conditions (silylating
reagent/imidazole/DMF) resulted in the formation of
5-azido-3,4-di-O-benzyl-1-O-tert-butyldiphenylsilyl-5-
deoxy-a-D-psicopyranose (15, 70%) together with an
appreciable amount of the unexpected 5-azido-3,4-di-O-
benzyl-1,6-di-O-tert-butyldiphenylsilyl-5-deoxy-D-psicose
(14, 26%), that were separated by chromatographic means.
Following the above protocol but in 15 (see Scheme 5), the
intramolecular Staudinger/aza-Wittig reaction afforded the
expected D1-pyrroline 20 (TLC evidence) that could not be
characterized due to its instability, but reduced to give only
one compound identified as (2S,3S,4R,5R)-3,4-dibenzy-
loxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)-
pyrrolidine (21), whereas the catalytic hydrogenation of
15 gave the (2R,3S,4R,5R)-isomer (22). De-O-silylation
of 22 gave the corresponding 23, which analytical and
Compounds 14 and 15 were the key intermediates for the
synthesis of the target 2,5-dideoxy-2,5-iminohexitols (see
Scheme 4). In a first approach, submission of 14 to an
intramolecular tandem Staudinger/aza-Wittig reaction11
afforded the expected (3S,4R,5R)-3,4-dibenzyloxy-20,50-di-
1
Table 1. H RMN chemical shifts (d) and J (Hz) values for compound 13a and 13b
H-10
Compound
H-1
H-3
H-4
H-5
H-6ax
H-6eq
CH2Ph
CH2Ph
OH
0
0
13a
3.69d, J1,1
Z
Z
3.46d
3.58d, J3,4Z2.
5 Hz
4.22br s
3.31ddd, J4,5
Z
Z
4.07t, J5,6axZ
11.4 Hz, J6,ax,6eq
3.74dd
4.85d, 4.78d,
4.63s
11.6 Hz
2.5 Hz, J5,6eq
Z
JZ10.6 Hz
5.3 Hz
11.4 Hz
5.57br s,
2.11br s
13b
3.93d, J1,1
3.26d
3.74m
4.10br s
3.86m
3.92dd, J5,6ax
Z
3.74m
5.00d, 4.69d,
4.76d, 4.68d,
11.8 Hz
2.4 Hz, J6,ax,6eq
Z
JZ11.6 Hz
JZ11.9 Hz
12.4 Hz
Table 2. 13C RMN chemical shifts (d) values for compound 13a and 13b
Compound
C-1
C-2
C-3
C-4
C-5
C-6
CH2Ph
13a
13b
64.46
65.91
97.86
97.67
76.86a
76.46a
73.12a
75.26a
57.09
56.28
56.77
62.15
75.98, 72.27
74.89, 71.42
a Assignments may be interchanged.

11700
I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
absorption was non-corrected. All non-hydrogen atoms
were generated according to stereochemistry and refined
using a riding model in SHELXS97.
C19H26O6: MZ350.40 g molK1; triclinic; space group P-1;
˚
˚
˚
aZ5.881(10) A, bZ8.052(14) A, cZ10.490(18) A, aZ
67.714(2)8, bZ84.247(3)8, gZ78.551(3)8, VZ450.39(13)
A , ZZ1, rcalcdZ1.292 g cmK3
,
mZ0.095 mmK1
,
3
˚
F(000)Z180. Colourless crystal, dimensions 0.27!
0.13!0.07 mm3. A total of 5288 reflections were collected
with 2.108!q!28.368; 3885 independent reflections with
3644 having I!2s!(I); 233 parameters; R1Z0.0412;
wR2Z0.1018; GoofZ1.081; maximum residual electronic
3
densityZ0.481 eK1 A .
˚
Scheme 5. Synthesis of partially protected polyhydroxylated pyrrolidines
21 and 22. Reagents and conditions: (i) Ph3P/THF, reflux; (ii) NaCNBH3/
THF/AcOH, 0 8C; (iii) Raney-Ni/H2/MeOH; (iv) n-Bu4NCFK 3 H2O/THF.
Full data collection parameters and structural data are
available as supporting information. Crystallographic data
for the crystal structure have been deposited with the
Cambridge Crystallographic Data Centre, CCDC 269114.
Copies of this information may be obtained free of charge
from The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: C44 1223 336033; e-mail, deposit@ccdc.
cam.ac.uk; web, http://www.ccdc.cam.ac.uk).
spectroscopic data were consistent with the assigned
stereochemistry.
Comments merit the high stereoselectivity found in the
catalytic hydrogenation of 14 and 15 (see Fig. 3). Contrary
to that previously reported,13 where the authors stated that
the stereochemistry of five-membered ring system is
controlled by that at C(4), our results seemed to indicate
that the size of the substituent at C(50) must play an
important roll in the steric course of the reaction, since
either the presence, in 14, or absence, in 15, of bulky
TBDPS protecting group at C(50) makes either the bottom or
top face the preferable for the hydrogen attack, respectively.
4.2. General procedures
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. Solutions were dried over
MgSO4 before concentration under reduced pressure. The
1H 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
Micromass Mod. Platform II and Autospec-Q mass
spectrometers. Optical rotations were measured for solu-
tions in CHCl3 (1 dm tube) with a Jasco DIP-370 polari-
meter. TLC was performed on precoated E. Merck silica gel
60 F254 aluminium sheets with detection by charring with
H2SO4 or employing a mixture of 10% ammonium
molybdate (w/v) in 10% aqueous sulphuric acid containing
0.8% cerium sulphate (w/v) and heating. Column chromato-
graphy was performed on silica gel (E. Merck, 7734). The
no crystalline compounds, for which elemental analyses
were not obtained, were shown to be homogeneous by
chromatography and characterized by NMR spectroscopy
and FAB-HRMS with thioglycerol matrix.
Figure 3. Transition states for catalytic hydrogenation of 14 and 15.
3. Conclusions
D-fructose was an excellent chiral starting material for the
stereoselective synthesis of polyhydroxylated pyrrolidines
alkaloids. Highly diastereoselective hydrogenation of
protected 5-azido-5-deoxy-D-psicose derivatives was the
best synthetic route to the target molecules.
4.2.1. 3-O-benzyl-1,2-O-isopropylidene-b-D-psicopyra-
nose (2). A solution of 3-O-benzyl-1,2:4,5-di-O-isopropy-
lidene-b-D-psicopyranose7 (1, 3.50 g, 10 mmol) in 75%
aqueous acetic acid (50 mL) was heated at 45 8C for 2 h.
TLC (ether) then revealed a new slower running compound.
The mixture was concentrated and repeatedly codistilled
with water and then dissolved in ethanol (60 mL),
neutralized with solid K2CO3 and concentrated. Column
chromatography (1:1 ether/hexane) gave pure syrupy 2
(2.50 g, 79%); [a]2D7K90 (c 1); IR (neat): y 3484 and 3451
(OH), 3031 (aromatic), 1373 and 1245 (CMe2), 745 and
700 cmK1 (aromatic). 1H NMR (400 MHz): d 7.33 (m, 5H,
Ph), 4.86 and 4.69 (2d, 2H, JZ11.3 Hz, CH2Ph), 4.06 and
4. Experimental
4.1. Crystal structure determination
Single crystal of 1 was mounted on a Bruker-Smart Apex
˚
area detector diffractometer (Mo Ka lZ0.71073 A). The
cell parameters were determined from reflections taken
from one steps in phi angle) each at 20 s exposure. The
structures were solved using direct methods (SHELXS14)
and refined against F2 using the SHELXS12 software.14 The
0
0
3.80 (2d, 2H, J1,1 Z9.3 Hz, H-1,1 ), 3.96 (t, 1H, J3,4, J4,5
Z
0
3.5 Hz, H-4), 3.96 (dd, 1H, J5,6Z2 Hz, J6,6 Z12.3 Hz, H-6),
0
0
3.86 (dd, 1H, J5,6 Z2.3 Hz, H-6 ), 3.74 (m, 1H, H-5), 3.66

I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
11701
(br d, 1H, H-3), 2.60 (br s, 2H, HO-4,5), 1.47 and 1.35 (2s,
6H, CMe2). 13C NMR: d 137.15, 128.69, 128.38, and 128.16
(PhCH2), 112.06 (CMe2), 104.88 (C-2), 80.99 (C-3), 76.02
(C-1), 73.27 (CH2Ph), 69.28 and 67.43 (C-4,5), 65.33 (C-6),
26.78 and 26.29 (CMe2). HRMS: m/z 333.1319 [MCCNa].
For C16H22O6Na 333.1314 (deviationK1.5 ppm).
flash chromatography (hexane/1:1 ether/hexane) to afford
crystalline 9 (1.83 g, 97%); mp 76–78 8C (from ether/
hexane); [a]2D7K132 (c 0.9); n (KBr) 3521 (OH), 3039
(aromatic), 2099 (N3), 1373 (CMe2), 741 and 697 cmK1
1
(aromatic). H NMR (300 MHz): d 7.45–7.25 (m, 5H, Ph),
4.77 and 4.72 (2d, 2H, JZ11.6 Hz, CH2Ph), 4.19 and 3.99
0
0
(2d, 2H, J1,1 Z8.8 Hz, H-1,1 ), 3.93–3.86 (m, 3H, H-3,5,6),
3.76 (dd, 1H, J4,5Z3.5 Hz, J3,4Z90.5 Hz, H-4), 3.70 (dd, 1H,
4.2.2. 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-iso-
propylidene-a-L-sorbopyranose (7). To a solution of tri-
phenylphosphine (8.82 g, 33.62 mmol), imidazole (4.57 g,
67.20 mmol), and iodine (8.52 g, 23.57 mmol) in dry
toluene (120 mL) was added 3-O-benzoyl-4-O-benzyl-1,2-
O-isopropylidene-b-D-fructopyranose8b (6, 6.95 g, 17.79 mmol)
in the same solvent (50 mL) and the mixture heated at
110 8C for 2 h. TLC (3:2 ether/hexane) then revealed a
faster-running compound. The reaction mixture was cooled,
washed with 10% aqueous sodium thiosulphate and brine,
then concentrated. Column chromatography (1:3 ether/
hexane) afforded crystalline 7 (6.7 g, 76%); mp 166–168 8C
(from ether); [a]2D6K64.5 (c 1.1); IR (KBr): y 3033
(aromatic), 1727 (ester), 1382 and 1274 (CMe2), 713 and
0
0
J5,6 Z2.2 Hz, J6,6 Z12.8 Hz, H-6 ), 1.48 and 1.43 (2s, 6H,
CMe2). 13C NMR: d 137.62, 128.67, 128.16, and 127.98
(CH2Ph), 112.27 (CMe2), 105.76 (C-2), 79.59 (C-3), 72.73
and 72.01 (C-1 and CH2Ph), 68.23 (C-4), 62.17 (C-6), 59.41
(C-5), 26.72 and 26.27 (CMe2). Anal. Calcd for
C16H21N3O5: C, 57.30; H, 6.31; N, 12.53. Found: C,
57.15; H, 6.77; N, 12.05.
4.2.5. 5-Azido-4-O-benzyl-5-deoxy-1,2-O-isopropyli-
dene-b-D-psicopyranose (11). To a stirred suspension of
Dess–Martin periodinane (3.48 g, 8.18 mmol) in dry
CH2Cl2 (20 mL) was added dropwise a solution of 9
(1.83 g, 5.46 mmol) in the same solvent (15 mL) under Ar.
The mixture was stirred at room temperature for 1 h. TLC
(3:2, ether/hexane) then revealed the presence of a faster-
running product. The reaction mixture was filtered and the
filtrate washed with 10% aqueous Na2CO3, brine and water,
then concentrated. The residue was percolated (3:2 ether/
hexane) through a short column of silica gel to afford
fractions containing presumably ketone 10 [1.7 g, 93.4%;
IR: y (neat) 1753 cmK1], that was used in the next step.
1
693 cmK1 (aromatic). H NMR (300 MHz): d 8.10–8.07,
7.63–7.58, 7.49–7.44, and 7.17–7.10 (4m, 10H, 2 Ph), 5.30
(d 1H, J3,4Z8.8 Hz, H-3), 4.84 and 4.59 (2d, 2H, JZ
10.1 Hz, CH2Ph), 4.22–3.92 (m, 4H,0 H-4,5,6ax,6eq), 3.97
0
and 3.92 (2d, 2H, J1,1 Z9.3 Hz, H-1,1 ), 1.52 and 1.43 (2s,
6H, CMe2). 13C NMR (inter alia): d 165.56 (COPh), 112.52
(CMe2), 104.93 (C-2), 81.88 (C-3), 75.57 (C-1), 72.67 (C-4),
71.88 (CH2Ph), 66.20 (C-6), 26.77 and 26.30 (CMe2), and
25.57 (C-5). Anal. Calcd for C23H25IO6: C, 52.68; H, 4.81.
Found: C, 53.21; H, 5.04.
To a stirred and ice-water cooled solution of 10 (1.7 g,
5.1 mmol) in dry methanol (20 mL) NaBH4 (0.29 g,
7.5 mmol) was added portionwise. After 1 h, TLC (3:2
ether/hexane) showed no ketone 10 and the presence of a
new product of higher mobility. The reaction mixture was
neutralized with AcOH, concentrated and the residue was
dissolved in Cl2CH2, washed with water then concentrated.
Flash column chromatography (1:1 ether/hexane) afforded
crystalline 11 (1.51 g, 88%); mp 60–61 8C (from ether/
hexane); [a]2D4K117 (c 1); n (KBr) 3509 (OH), 3033
(aromatic), 2124 (N3), 1368 (CMe2), 744 and 693 cmK1
4.2.3. 5-Azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-
isopropylidene-b-D-fructopyranose (8). A stirred solution
of 7 (3 g, 5.72 mmol) and lithium azide (0.84 g, 17.1 mmol)
in dry DMF (25 mL) was heated at 100 8C for 6 h. TLC (3:2
ether/hexane) then revealed a lower-running compound.
The mixture was concentrated to a residue that was dis-
solved in ether (40 mL), washed with brine and concen-
trated. Flash column chromatography (1:1 ether/hexane) of
the residue afforded 8 (2.5 g, 99%) as a colourless syrup;
[a]2D6K127 (c 0.7); IR (neat): y 3033 (aromatic), 2105 (N3),
1724 (ester), 1372 (CMe2), 710 cmK1 (aromatic). 1H NMR
(300 MHz): d 8.08–8.06, 7.63–7.57, 7.49–7.44, and 7.22–
7.17 (4m, 10H, 2 Ph), 5.64 (d 1H, J3,4Z9.9 Hz, H-3), 4.65
1
(aromatic). H NMR (300 MHz): d 7.42–7.26 (m, 5H, Ph),
4.80 and 4.63 (2d, 2H, JZ11.8 Hz, CH2Ph), 4.17 and 4.08
0
0
(2d, 2H, J1,1 Z9.5 Hz, H-1,1 ), 3.96 (dd, 1H, J5,6axZ2.2 Hz,
J6ax,6eqZ12.8 Hz, H-6ax), 3.89 (t, 1H, J3,4, J4,5Z3.5 Hz,
H-4), 3.85–3.80 (m, 3H, H-3,5,6eq), 3.17 (br d, 1H, JOH,3
Z
and 4.58 (2d, 2H, JZ12.1 Hz, CH2Ph), 4.12 (dd, 1H, J4,5
3.8 Hz, H-4), 4.02 and 3.94 (2d, 2H, J1,1 Z9.3 Hz, H-1,1 ),
Z
8.8 Hz, OH), 1.45 and 1.36 (2s, 6H, CMe2). 13C NMR: d
137.48, 128.63, 128.08, and 127.77 (CH2Ph), 112.48
(CMe2), 105.70 (C-2), 73.72 (C-1), 73.26 (C-4), 70.83 (C-3),
70.43 (CH2Ph), 62.34 (C-6), 58.86 (C-5), 26.74 and 26.42
(CMe2). Anal. Calcd for C16H21N3O5: C, 57.30; H,
6.31; N, 12.53. Found: C, 57.50; H, 6.29; N, 12.63.
HRMS: m/z 358.1380 [MCCNa]. For C16H21N3O5Na
358.1379 (deviationK0.2 ppm).
0
0
0
0
4.00–3.94 (m, 2H, H-5,6), 3.76 (dd, 1H, J5,6 Z2 Hz, J6,6
Z
13 Hz, H-60), 1.47 and 1.37 (2s, 6H, CMe2). 13C NMR (inter
alia): d 165.80 (COPh), 112.22 (CMe2), 104.87 (C-2), 76.83
(C-3), 72.49 and 71.97 (C-1 and CH2Ph), 68.93 (C-4),
62.26 (C-6), 59.86 (C-5), 26.66 and 26.27 (CMe2). HRMS:
m/z 462.1640 [MCCNa]. For C23H25N3O6Na 462.1641
(deviationC0.3 ppm).
4.2.4. 5-Azido-4-O-benzyl-5-deoxy-1,2-O-isopropyli-
dene-b-D-fructopyranose (9). Compound 8 (2.47 g,
5.62 mmol) in anhyd. MeOH (50 mL) was treated with
0.5 M NaMeO in MeOH (10 mL) for 24 h. TLC (3:2 ether/
hexane) then revealed a slower-running compound. The
mixture was neutralized with AcOH, concentrated and the
residue was partitioned in Cl2CH2-water. The organic phase
was separated, concentrated and the residue submitted to
4.2.6. 5-Azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropyli-
dene-b-D-psicopyranose (12). To a stirred suspension of
NaH (60% oil dispersion, 0.27 g, 6.76 mmol) in dry DMF
(10 mL), compound 11 (1.51 g, 4.51 mmol) in the same
solvent (10 mL) was added at room temperature. After
15 min, the mixture was cooled (ice-water) benzyl bromide
(580 mL, 4.96 mmol) was added and the mixture was
allowed to reach room temperature, then left for 2 h. TLC

11702
I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
(3:2 ether/hexane) then showed the presence of a faster-
running compound. The mixture was poured into ice-water,
and extracted with ether (4!30 mL). The combined
extracts were washed with brine, water, and concentrated.
Flash column chromatography (1:3 ether/hexane) of the
residue gave 12 (1.37 g, 72%) as white crystals; mp 118–
1208 (from ether/hexane); [a]2D5K101 (c 1); n (KBr): 3031
(aromatic), 2103 (N3), 1377 (CMe2), 735 and 694 cmK1
Eluted second was 5-azido-3,4-di-O-benzyl-1-O-tert-butyl-
diphenylsilyl-5-deoxy-a-D-psicopyranose (15, 4.55 g, 70%)
as a colourless syrup; [a]D25K37 (c 1.4); n (neat) 3468 (OH),
2102 (N3), and 701 cmK1 (aromatic). 1H NMR (300 MHz):
d 7.75–7.25 (2m, 20H, 4 Ph), 5.40 (s, 1H, OH-2), 4.86 and
4.79 (2d, 2H, JZ10.7 Hz, CH2Ph), 4.69 (s, 2H, CH2Ph),
4.28 (br t, 1H, H-4), 4.10 (t, 1H, J5,6axZJ6ax,6eqZ11.3 Hz,
0
0
H-6ax), 3.96 and 3.60 (2d, 2H, J1,1 Z10.5 Hz, H-1,1 ), 3.90
1
(d, 1H, J3,4Z2.6 Hz, H-3), 3.78 (dd, 1H, J5,6eqZ5.0 Hz,
H-6eq), 3.36 (ddd, 1H, J4,5Z2.5 Hz, H-5), and 1.08 (s, 9H,
CMe3). 13C NMR (inter alia): d 98.52 (C-2), 77.32 and
73.97 (C-3,4), 75.92 and 72.59 (2 CH2Ph), 65.47 (C-1),
57.54 (C-5), 56.92 (C-6), 27.04 (CMe3) and 19.43 (CMe3).
Starting material (0.87 g,) was finally recovered.
(aromatic). H NMR (300 MHz): d 7.43–7.26 (m, 10H, 2
Ph), 4.86 and 4.76 (2d, 2H, JZ11.7 Hz, CH2Ph), 4.82 and
4.77 (2d, 2H, JZ9.2 Hz, CH2Ph), 4.14 and 3.98 (2d, 2H,
0
0
J1,1 Z9.8 Hz, H-1,1 ), 4.04 (t, 1H, J3,4, J4,5Z3.0 Hz, H-4),
3.87 (dd, 1H, J5,6axZ4.1 Hz, J6ax,6eqZ11.9 Hz, H-6ax),
3.80 (dd, 1H, J5,6eqZ6.0 Hz, H-6eq), 3.66 (d, 1H, H-3), 3.61
(m, 1H, H-5), 1.48 and 1.35 (2s, 6H, CMe2). 13C NMR: d
137.99, 137.68, 128.65, 128.54, 128.50, 128.26, 127.97, and
127.85 (CH2Ph), 111.39 (CMe2), 105.69 (C-2), 77.22 and
77.04 (C-3,4), 74.50 (C-1), 74.49 and 73.21 (CH2Ph), 62.01
(C-6), 56.47 (C-5), 27.20 and 26.03 (CMe2). Anal. Calcd for
C23H27N3O5: C, 64.93; H, 6.40; N, 9.88. Found: C, 64.49;
H, 6.90; N, 10.06.
4.2.9. (2R,3R,4S,5R)-(17) and (2R,3R,4S,5S)-3,4-Dibenzyl-
oxy-20,50-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)pyrrolidine (18). To a solution of 14 (418 mg,
0.48 mmol) in dry THF (10 mL) was added triphenylphos-
phine (250 mg, 0.95 mmol) and the mixture refluxed with
stirring for 5 h. TLC (1:2 ether/hexane) then revealed a
slower-running compound. The reaction mixture was
supported on silica gel previously treated with ether/
hexane/TEA 1:3:0.1 and chromatographed (1:3:0.1 eth0 er/
hexane/TEA) to afford (3S,4R,5R)-3,4-dibenzyloxy-2 ,50-
di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)-d2-
pyrroline (16, 380 mg, 97%). [a]2D4 K39 (c 1.3); n (neat)
3070, 3049, and 3031 (aromatic), 1659 (C]N), and
4.2.7. 5-Azido-3,4-di-O-benzyl-5-deoxy-D-psicopyranose
(13). A solution of 12 (1.37 g, 3.22 mmol) in 60% aqueous
TFA (5 mL) was kept at room temperature for 2 h. TLC
(ether) then revealed two nearby and slower running
compounds. The mixture was concentrated and repeatedly
codistilled with water and then dissolved in dichloro-
methane, washed with 10% aqueous sodium carbonate and
water, then concentrated. Flash column chromatography
(1:1 ether/hexane) gave pure syrupy 13 (1.05 g, 85%)
1
701 cmK1 (aromatic). H NMR (300 MHz): d 7.72–7.20
(3m, 30H, 6 Ph), 4.83 (br d, 1H, J3,4Z5.8 Hz, H-3), 4.72 and
4.63 (2d, 2H, JZ11.2 Hz, CH2Ph), 5.57 and 4.51 (2d, 2H,
JZ11.7 Hz, CH2Ph), 4.61–4.54 (m, 2H, H-20a,20b), 4.25
(m, 1H, H-5), 4.17 (dd, 1H, J4,5Z1.9 Hz, H-4), 3.87 (dd,
1
asw2:1 mixture of its a and b-anomers, respectively. H
and 13C NMR data (400 Hz), see Tables 1 and 2. HRMS:
m/z 408.1538 [MCCNa]. For C20H23N3O5Na 408.1535
(deviationK0.6 ppm).
1H, J5,5 aZ3.5 Hz, J5 a,5 bZ10.5 Hz, H-50a), 3.81 (dd, 1H,
0
0
0
J5,5 bZ4.1 Hz, H-50b), 1.06 and 1.03 (2s, 18H, 2 CMe3). 13C
0
NMR (inter alia): d 176.40 (C-2), 82.29, 77.63 and 73.23
(C-3,4,5), 73.39 and 71.89 (2 CH2Ph), 64.03 and 62.81
(C-20,50), 27.01 (2 CMe3), 19.33 and 19.27 (2 CMe3).
Compound 16 decomposed on standing.
4.2.8. Silylation of (13). To an ice-water cooled and stirred
solution of 13 (4.90 g, 12.7 mmol) in dry DMF (30 mL)
were added imidazole (1 g, 14.7 mmol) and tert-butylchloro-
diphenylsilane (3.7 mL, 14.5 mmol) and the mixture was
left at room temperature for 20 h. TLC (ether) then showed
a complex mixture. MeOH (1 mL) was added and after
15 min the reaction mixture was diluted with water
(100 mL) and extracted with ether (2!40 mL), then
concentrated to a residue that was submitted to flash-
chromatography (1:6, ether/hexane/ether) to afford first
5-azido-3,4-di-O-benzyl-1,6-di-O-tert-butyldiphenylsilyl-
To a stirred and ice-water cooled solution of 16 (340 mg,
0.41 mmol) in THF (5 mL) containing acetic acid (50 mL),
NaCNBH3 (70 mg, 1.11 mmol) was added portionwise.
After 15 min, the reaction mixture was allowed to reach
room temperature. TLC (3:2 ether/hexane) then showed two
slower-running compounds. The reaction mixture was
slightly basified by addition of aqueous ammonia solution,
then concentrated to a residue that was partitioned into
ether/water, the organic phase was separated and concen-
trated. Column chromatography (1:3:0.1 ether/hexane/
TEA) afforded first 17 (145 mg, 43%) as a colourless
syrup. [a]2D9C19 (c 1.5); n (neat) 3070, 3049, and 701 cmK1
5-deoxy-D-psicose (14, 2.31 g, 26%) as a colourless syrup;
[a]2D6K1.2, [a] C7 (c 1.2); n (neat) 2101 (N3), 1735
26
405
(ketone), and 701 cmK1 (aromatic). 1H NMR (300 MHz): d
1
0
7.70–7.00 (4m, 30H, 6 Ph), 4.58 and 4.49 (2d, 2H, J1,1
Z
(aromatic). H NMR (300 MHz): d 7.70–7.20 (3m, 30H, 6
Ph), 4.69 and 4.61 (2d, 2H, JZ11.9 Hz, CH2Ph), 4.52 and
18.6 Hz, H-1,10), 4.45 and 4.39 (2d, 2H, JZ11.8 Hz,
CH2Ph), 4.45 and 4.33 (2d, 2H, J1,1 Z11.3 Hz, CH2Ph),
0
4.42 (2d, 2H, JZ12.0 Hz, CH2Ph), 4.11 (t, 1H, J3,4ZJ4,5
Z
4.20 (d, 1H, J3,4Z3 Hz, H-3), 3.92 (q, 1H, H-5), 3.82 (dd,
0
0
0
4.4 Hz, H-4), 3.94 (dd, 1H, J5,5 aZ6.9 Hz, J5 a,5 bZ10.2 Hz,
H-50a), 3.93 (dd, 1H, J2,3Z6.4 Hz, H-3), 3.82 (dd, 1H,
0
1H, J4,5Z7.2 Hz, H-4), 3.73 (t, 10H, J5,6ZJ6,6 Z6.4 Hz, H-
J5,5 bZ7.4 Hz, H-50b), 3.70 (dd, 1H, J2,2 aZ4.6 Hz,
0
6), 3.71 (t, 1H, J5,6 Z6.7 Hz, H-6 ), and 1.06 (s, 9H, CMe3).
0
0
13C NMR (inter alia): d 206.67 (C-2), 81.77 (C-3), 79.43
(C-4), 73.27 (2 CH2Ph), 69.11 (C-6), 64.55 (C-1), 62.94
(C-5), 26.81 (CMe3) and 19.36 (CMe3). HRMS: m/z
884.3896 [MCCNa]. For C52H59N3O5NaSi2 884.3891
(deviationK0.6 ppm).
0
0
0
J2 a,2 bZ10.7 Hz, H-20a), 3.66 (dd, 1H, J2,2 bZ4.4 Hz,
H-20b), 3.45 (dt, 1H, H-5), 3.33 (dt, 1H, H-2), 1.90 (br s, 1H,
NH), 1.09 and 1.06 (2s, 18H, 2 CMe3). 13C NMR (inter
alia): d 80.49 (C-3), 78.00 (C-4), 73.23 and 72.18 (2
CH2Ph), 64.58 (C-20), 63.72 (C-50), 61.70 (C-2), 61.20 (C-5),

I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
11703
27.09 and 27.07 (2 CMe3), and 19.39 (2 CMe3). Anal. Calcd
for C52H61NO4Si2: C, 76.15; H, 7.50; N, 1.71. Found: C,
75.87; H, 7.34; N, 2.05.
To a stirred and ice-water cooled solution of 20 (815 mg,
1.41 mmol) in THF (15 mL) containing acetic acid
(180 mL), NaCNBH3 (273 mg, 4.35 mmol) was added
portionwise. After 1 h, the reaction mixture was allowed
to reach room temperature. TLC (ether) then showed a non-
mobile compound. The reaction mixture was concentrated
and the residue dissolved in EtAcO and washed with brine,
then concentrated. Column chromatography (10:1 ether/
methanol) gave 21 (335 mg, 41%) as a colourless syrup.
[a]2D7C32 (c 1.6). n (neat) 3338 (OH), 3069, 3031, and
Eluted second was 18 (77 mg, 23%) as a colourless syrup. n
(neat) 3070, 3048, 3030 and 701 cmK1 (aromatic). 1H NMR
(300 MHz): d 7.70–7.21 (2m, 30H, 6 Ph), 4.51 and 4.47 (2d,
4H, JZ12.4 Hz, 2 CH2Ph), 3.81 (br d, 2H, J2,3ZJ4,5
4.7 Hz, H-3,4), 3.76 (dd, 2H, J2,2 aZJ5,5 aZ4.5 Hz,
Z
0
0
J2 a,2 bZJ5 a,5 bZ10.5 Hz, H-20a,50a), 3.71 (dd, 2H,
0
0
0
0
1
J2,2 bZJ5,5 bZ4.4 Hz, H-20b,50b), 3.41 (br q, 2H, H-2,5),
1.95 (br s, 1H, NH), and 1.03 (s, 18H, 2 CMe3). 13C NMR
(inter alia): d 78.43 (C-3,4), 71.87 (2 CH2Ph), 64.47 (C-20,50),
63.07 (C-2,5), 27.05 (2 CMe3), and 19.35 (2 CMe3). Anal.
Calcd for C52H61NO4Si2: C, 76.15; H, 7.50; N, 1.71. Found:
C, 76.43; H, 7.46; N, 1.67.
701 cmK1 (aromatic). H NMR (300 MHz): d 7.70–7.20
0
0
(2m, 20H, 4 Ph), 4.68 and 4.56 (2d, 2H, JZ11.7 Hz,
CH2Ph), 4.60 and 4.48 (2d, 2H, JZ11.9 Hz, CH2Ph), 4.03
0
(t, 1H, J2,3ZJ3,4Z4.3 Hz, H-3), 3.92 (dd, 1H, J2,2 a
Z
Z
6.6 Hz, J2 a,2 bZ10.2 Hz, H-20a), 3.86 (dd, 1H, J2,2 b
0
0
0
7.3 Hz, H-20b), 3.80 (dd, 1H, J4,5Z6.1 Hz, H-4), 3.51 (dd,
1H, J5,5 aZ3.5 Hz, J5 a,5 bZ10.5 Hz, H-50a), 3.46 (dd, 1H,
0
0
0
J5,5 bZ3.5 Hz, H-50b), 3.38 (m, 1H, H-2), 3.32 (m, 1H,
0
4.2.10. Hydrogenation of 14. Compound 14 (1.76 g,
2.04 mmol) in MeOH/THF (2:1 v/v, 60 mL) was hydro-
genated at 60 psi over wet Raney-Ni (3 g) for 5 h. TLC (3:1
ether/hexane) then revealed the presence of a slower-
running compound. The catalyst was filtered off, washed
with MeOH, and the combined filtrate and washings were
concentrated to a residue that was submitted to column
chromatography (1:3:0.1 ether/hexane/TEA) to afford 18
(1.06 g, 73%).
H-5), 2.28 (br s, 1H, NH), and 1.08 (s, 9H, CMe3). 13C NMR
(inter alia): d 80.89 (C-4), 78.47 (C-3), 73.23 and 72.58 (2
CH2Ph), 62.96 (C-20,50), 61.46 (C-2), 61.09 (C-5), 27.05
(CMe3), and 19.32 (CMe3). Anal. Calcd for C36H43NO4Si:
C, 74.32; H, 7.45; N, 2.41. Found: C, 74.48; H, 7.43; N,
2.28.
4.2.13. Hydrogenation of 15. Compound 15 (3.3g,
5.3 mmol) in MeOH (40 mL) was hydrogenated at 60 psi
over wet Raney-Ni (3 g) for 20 h. TLC (15:1 ether/
methanol) then revealed the presence of a slower-running
compound. The catalyst was filtered off, washed with
MeOH, and the combined filtrate and washings were con-
centrated to a residue that was submitted to column
chromatography (ether/15:1 ether/methanol) to afford
crystalline (2R,3S,4R,5R)-3,4-dibenzyloxy-20-O-tert-butyl-
diphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22, 1.9 g,
62%); mp 92–948 (from ether); [a]2D7C16 (c 1); n (KBr)
3270 (OH, NH), 3087, 3030, and 700 cmK1 (aromatic). 1H
NMR (400 MHz): d 7.68–7.62 and 7.44–7.25 (2m, 20H, 4
Ph), 4.56 and 4.49 (2d, 2H, JZ11.8 Hz, CH2Ph), 4.52
(s, 2H, CH2Ph), 3.86 (t, 1H, J3,4, J4,5Z4.5 Hz, H-4), 3.78 (br
t, 1H, J2,3Z5.2 Hz, H-3), 3.52 (br d, 2H, H-20,20), 3.49–3.39
(m, 4H, H-2,5,50a,50b), 2.05 (br s, 2H, NH,OH), and 1.05 (s,
9H, CMe3). 13C NMR (inter alia): d 78.71 (C-3), 78.59
(C-4), 72.28 and 71.83 (2 CH2Ph), 65.46 (C-20), 62.72 and
61.50 (C-2,5), 62.05 (C-50), 27.00 (CMe3), and 19.34
(CMe3). Mass spectrum (LSIMS): m/z 582.3038 [MCCH]
for C36H44NO4Si 582.3040 (deviation C0.2 ppm). Anal.
Calcd for C36H43NO4Si: C, 74.32; H, 7.45; N, 2.41. Found:
C, 74.35; H, 7.29; N, 2.22.
4.2.11. (2R,3R,4S,5S)-3,4-dihydroxy-2,5-bis(hydroxy-
methyl)pyrrolidine hydrochloride [2,5-dideoxy-2,5-
imino-D-allitol (DADP, 19)]. Compound 18 (990 mg,
1.2 mmol) in THF (25 mL), was treated with a solution of
tetra-n-butylammonium fluoride trihydrate (915 mg,
2.9 mmol) for 1 h at room temperature TLC (ether) then
showed the presence of a non mobile compound. The
reaction mixture was concentrated and the residue dissolved
in AcOEt and washed with brine, then concentrated.
Column chromatography (ether/5:1:0.1 ether/methanol/
NH4OH) of the residue afford fractions containing 3,4-
dibenzyloxy derivative of 18 (NMR evidence), contamin-
ated with tetra-n-butylammonium hydroxide, that was
subsequently hydrogenated in MeOH (15 mL) and concd
HCl (5 drops) over 10% Pd–C (200 mg) in an H2 atmosphere
for 24 h. TLC (5:1:0.1 ether/methanol/NH4OH) then
showed the presence of a compound of lower mobility.
The catalyst was filtered off, washed with MeOH and the
combined filtrate and washings concentrated to a residue
that was repeatedly washed with Cl2CH2 to yield 19
hydrochloride (90 mg, 38%) as a colourless foam. 1H NMR
(300 MHz, MeOH-d4)): d 4.10 (m, 2H, H-3,4), 3.86 (dd, 2H,
J2,2 aZJ5,5 aZ3.9 Hz, J2 a,2 bZ J5 a,5 bZ12.0 Hz H-20a,50a),
0
0
0
0
0
0
3.77 (dd, 2H, J2,2 bZ J5,5 bZ5.7 Hz, H-20b,50b), and 3.59
(m, 2H, H-2,5). 130C NMR: d 72.44 (C-3,4), 66.21 (C-2,5),
and 59.46 (C-20,5 ).
0
0
4.2.14. (2R,3R,4S,5R)-3,4-dibenzyloxy-2,5-bis(hydroxy-
methyl)pyrrolidine (23). Compound 22 (110 mg, 0.2 mmol)
in THF (10 mL), was treated with a solution of tetra-n-
butylammonium fluoride trihydrate (120 mg, 0.4 mmol) for
2 h at room temperature. TLC (5:1:0.1 ether/methanol/
TEA) then showed the presence of a more polar compound.
The reaction mixture was concentrated and the residue
submitted to column chromatography (5:1:0.1 ether/methanol/
TEA) to yield 23 (50 mg, 73%) as a colourless syrup;
[a]2D6K3 (c 1). 1H NMR (400 MHz): d 7.24–7.15 (m, 10H, 2
Ph), 4.50–4.40 (m, 4H, 2 CH2Ph), 3.92 (br s, 2H, OH,NH),
3.70 (br d, 1H, J2,7Z2.7 Hz, H-3 or H-4), 3.62–3.55 and
3.43–3.30 (2m, 6H, H-4 or H-3, H-20a,20b,50a,50b, H-5 or
4.2.12. (2S,3S,4R,5R)-3,4-Dibenzyloxy-20-O-tert-butyldi-
phenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (21).
Treatment of 15 (1.2 g, 1.93 mmol) in dry THF (30 mL)
with triphenylphosphine (760 mg, 2.9 mmol) as above for
7 h, afforded after work-up and column chromatograph0y
(2:1 ether/hexane/ether) (3S,4R,5R)-3,4-dibenzyloxy-2 -
O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)-d2-pyrro-
line (20, 850 mg, 77%) as an unstable pale yellow syrup,
that was not characterized but used in the next step.

11704
I. Izquierdo et al. / Tetrahedron 61 (2005) 11697–11704
H-2), and 3.05 (m, 1H, H-5 or H-2). 13C NMR (inter alia): d
78.52 and 77.74 (C-3,4), 72.11 and 71.97 (2 CH2Ph), 70.16
and 62.38 (C-2,5), 62.51 and 62.42 (C-20,50). Mass spectrum
(LSIMS): m/z 366.1680 [MCCNa] for C20H25NO4Na
366.1681 (deviationC0.2 ppm).
Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077. (c) Watson,
A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265. (d) Asano, N. Glycobiology
2003, 13, 93R.
6. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.;
Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald,
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Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1. (c) Yamashita, T.;
Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.;
Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002, 65, 1875.
7. Elliott, R. D.; Niwas, S.; Riordan, J. M.; Montgomery, J. A.;
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Acknowledgements
´
The authors are deeply grateful to Ministerio de Educacion
y Cultura (Spain) (Project PPQ2002-01303) and Junta de
´
Andalucıa (Group CVI-250) for financial support and for
two grants (F. Franco and A. Martos).
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