Polyhydroxylated pyrrolidines. Part 2: Highly stereoselective synthesis of partially protected DMDP derivatives from D-fructose

Article abstract of DOI:10.1016/S0957-4166(02)00369-5

The readily available 3,4-di-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose 2 was straightforwardly transformed into 5-azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-D-fructopyranose 4, after treatment under modified Garegg's conditions followed by reaction of the resulting 3,4-di-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-L-sorbopyranose 3 with sodium azide in DMF. Cleavage of the acetonide of 4 to afford 6 followed by regioselective O-tert-butyldiphenylsilylation at C(1)OH afforded 7. Hydrogenation of 7 proceeded with high stereoselectivity yielding 3,4-di-O-benzyl-1-O-tert-butyldiphenylsilyl-2,5-dideoxy-2,5-imino-D-mannitol 1, confirmed by its O-desilylation to 8. Compound 1 was subjected to different N-protection reactions to afford the corresponding N-allyl (1a), N-benzyl (1b), and N-tert-butyloxycarbonyl (1c) derivatives.

Full text of DOI:10.1016/S0957-4166(02)00369-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1503–1508
Polyhydroxylated pyrrolidines. Part 2: Highly stereoselective
synthesis of partially protected DMDP derivatives from
D-fructose
Isidoro Izquierdo,* Mar´ıa T. Plaza and Francisco Franco
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 23 May 2002; accepted 8 July 2002
Abstract—The readily available 3,4-di-O-benzyl-1,2-O-isopropylidene-b-
into 5-azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-b- -fructopyranose 4, after treatment under modified Garegg’s condi-
-sorbopyranose 3 with sodium
D-fructopyranose 2 was straightforwardly transformed
D
tions followed by reaction of the resulting 3,4-di-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-a-
L
azide in DMF. Cleavage of the acetonide of 4 to afford 6 followed by regioselective O-tert-butyldiphenylsilylation at C(1)OH
afforded 7. Hydrogenation of 7 proceeded with high stereoselectivity yielding 3,4-di-O-benzyl-1-O-tert-butyldiphenylsilyl-2,5-
dideoxy-2,5-imino-D-mannitol 1, confirmed by its O-desilylation to 8. Compound 1 was subjected to different N-protection
reactions to afford the corresponding N-allyl (1a), N-benzyl (1b), and N-tert-butyloxycarbonyl (1c) derivatives. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Continuing with these efforts, we describe herein the
highly stereoselective synthesis, starting from the same
hexulose, of those isomeric and partially protected
polyhydroxypyrrolidines derived from the natural gly-
In two previous papers, we reported on the highly
stereoselective synthesis, starting from the cheap and
commercially available
D
-fructose, of appropriately
cosidase inhibitor, 2,5-dideoxy-2,5-imino-D-mannitol
protected polyhydroxypyrrolidines, such as those
(DMDP).4
derived
from
2,5-dideoxy-2,5-imino-D-glucitol
(DGDP),1 and later on the use of DGDP as an excel-
lent chiral key intermediate for the synthesis2 of two
isomeric analogues [7a-epi-hyacinthacine A2 (7-
deoxyalexine) and 5,7a-diepi-hyacinthacine A3] of the
recently isolated3 hyacinthacines, which are potent gly-
cosidase inhibitors.
Retrosynthetic analysis (Fig. 1) shows the potential of 1
in the preparation of polyhydroxylated pyrrolizidines
(australine and hyacinthacines A2 and A3), where it can
be clearly seen that an adequately protected DMDP 1 is
an excellent chiral starting material for the synthesis of
such target molecules. Thus, chain extension at C(5%)
Figure 1. Retrosynthesis of polyhydroxylated pyrrolizidines.
* Corresponding author. E-mail: isidoro@platon.ugr.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00369-5

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I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1503–1508
(originally C(6) of
D
-fructose) by a suitably functional-
Catalytic (Raney nickel) hydrogenation of 7 caused
reduction of the 5-azido group to the corresponding
5-amino function which internally condensed with the
carbonyl group at C(2) to produce a D2-pyrroline (A,
not isolated but detected by TLC) which is finally
hydrogenated to the expected partially O-protected
pyrrolidine 1. The (R)-configuration of the new C(2)
stereogenic center in 1, could be easily determined
through its O-desilylation to 8, whose 1H and 13C
NMR spectra were consistent with its C2-symmetry
(Scheme 2).
ized two carbon fragment, followed by further cycliza-
tion, could lead to pyrrolizidines which stereochemistry
at C(7a) belonging to that of the australine series.
2. Results and discussion
According to Scheme 1, the reaction of 3,4-di-O-ben-
zyl-1,2-O-isopropylidene-b-
-fructopyranose1 2 under
D
modified Garreg’s conditions,5 caused the slow substi-
tution of the C(5) hydroxyl group, with concomitant
inversion of configuration, to afford the corresponding
The high stereoselectivity found in the hydrogenation
of 7, where 1 was the only pyrrolidine detected and
isolated, merits comment. The formation of 1 could be
explained, according to our results1 and those of other
authors,8 by the addition of hydrogen to the same
b-face occupied by the substituent next to the NꢀC
bond, giving a product with the C(2)- and C(3)-sub-
stituents in a trans-disposition (see Fig. 2).
5-deoxy-5-iodo-a- -sorbo derivative 3, which had the
L
same analytical and spectroscopic data to those previ-
ously reported.6 Treatment of 3 with sodium azide in
N,N-DMF effected SN2 substitution to yield 5-azido-
2,3-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-
D-
fructopyranose 4.6
In order to shorten the synthesis, an attempt to trans-
form 2“4 in a one-pot reaction, by treatment of the
former with CBr4/Ph3P/NaN3/DMF/110°C,7 resulted in
the isolation of 5, the 5-bromo-5-deoxy analogue of 3
and 4, both in low yield.
Cleavage of the acetonide group of 4 by treatment with
70% aqueous trifluoroacetic acid afforded 5-azido-2,3-
di-O-benzyl-5-deoxy-b- -fructopyranose 6. Reaction of
D
6 with tert-butyldiphenylchlorosilane took place selec-
tively at the primary hydroxyl group affording the
corresponding 1-O-silylated derivative 7. Compounds 6
and 7 existed as only one anomer (13C NMR data).
Figure 2. Proposed stereochemistry for the hydrogenation
pathway of intermediate D2-pyrroline (A).
Scheme 1. Synthesis of protected 5-azido-5-deoxy-
(ii) NaN3/DMF/D; (iii) CBr4/Ph3P/NaN3/DMF/D.
D
-fructose derivative 4. Reagents and conditions: (i) Ph3P/I2/imidazole/DMF/D;
Scheme 2. Synthesis of protected pyrrolidine 1. Reagents and conditions: (i) 70% aq. TFAA; (ii) TBDPSCl/DMF/imidazole; (iii)
Raney-Ni/H2; (iv) AllBr/K2CO3/Me2CO/rt; (iv) BnBr/K2CO3/Me2CO/rt; (iv) (t-BuOCO)2O/TEA/Cl2CH2; (v) t-Bu4N+F−·3H2O/
THF.

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1503–1508
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I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1503–1508
Table 2. 13C NMR chemical shifts (l) for compounds 1, 1a–c, and 5–8
a
Compd
C-1
–
C-2
63.31b
C-2%
C-3
C-4
C-5
C-5%
C-6
–
PhCH2
Me3C
27.00
26.92
26.90
Me3C Me2C
Me2C
1
62.96c
60.97
61.31
85.77d
83.36
83.45
85.10d
86.11
86.07
63.23b
67.95
68.01
62.10c
59.96
60.04
72.10,
72.01
71.89,
71.35
71.91,
71.36,
51.01
71.53,
71.43
76.17,
75.52
75.74,
72.68
75.66,
72.72
72.07
19.38
19.26
19.21
–
–
–
–
–
–
1a
1b
–
67.21
66.35
–
–
–
1ce
5
–
65.47
105.48
97.96
98.21
63.51
64.78
81.66
84.21
66.69
48.16
59.92
60.22
63.51
62.01
–
28.31,
26.92
–
19.31
–
–
71.55
65.68
65.89
–
–
83.84b
78.93b
79.07b
85.48
79.73b
75.38b
75.24b
85.48
–
64.00
61.51
61.17
–
–
112.56
26.19,
26.16
–
6
–
–
–
–
–
–
–
7
–
–
26.86
–
19.34
–
–
–
8
62.30
62.30
a Signals for the phenyl groups are not included.
b Interchangeable assignments.
c Interchangeable assignments.
d Interchangeable assignments.
e Signal for CO at 155.67 ppm.
3. Experimental
3.1. General
water, then concentrated. Column chromatography (2:3
ether–hexane) afforded crystalline 3 (3 g, 48%); mp
93–94°C (lit.6 mp 85–87°C). Compound 3 had the same
optical and spectroscopy data to those previously
reported.6
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. Solutions were dried
over MgSO4 before concentration under reduced pres-
3.3. 5-Azido-3,4-di-O-benzyl-5-deoxy-1,2-O-isopropyli-
dene-b-D-fructopyranose 4
1
sure. The H and 13C NMR spectra were recorded with
Bruker AMX-300, AM-300, and ARX-400 spectrome-
ters 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 solutions in CHCl3 (1 dm tube) with a
Jasco DIP-370 polarimeter. TLC was performed on
precoated E. Merck silica gel 60 F254 aluminum sheets
with detection by employing a mixture of 10% ammo-
nium molybdate (w/v) in 10% aqueous sulphuric acid
containing 0.8% cerium sulphate (w/v) and heating.
Column chromatography 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.
A stirred solution of 3 (2.93 g, 5.7 mmol) and sodium
azide (1.52 g, 23.4 mmol) in dry DMF (50 mL) was
heated at 100°C for 5 days. TLC (1:1 ether–hexane)
then revealed a slightly more polar compound. The
mixture was concentrated to a residue that was dis-
solved in ether (40 mL), washed with brine and concen-
trated. Column chromatography (1:4 ether–hexane) of
the residue afforded 4 (2.05 g, 85%), which had the
same optical and spectroscopy data to those previously
reported.6
3.4. 3,4-Di-O-benzyl-5-bromo-5-deoxy-1,2-O-isopropyli-
dene-a-L-sorbopyranose 5 and 4
To a stirred solution of 2 (1.7 g, 4.25 mmol) in dry
DMF (30 mL) were added triphenylphosphine (1.67 g,
6.38 mmol), carbon tetrabromide (2.12 g, 6.38 mmol),
and sodium azide (0.83 g, 12.8 mmol). The mixture was
heated at 110°C overnight. TLC (2:1 ether–hexane)
then revealed a complex mixture. The solvent was
3.2. 3,4-Di-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropyli-
dene-a-L-sorbopyranose 3
To a solution of triphenylphosphine (6.43 g, 24.55
mmol), imidazole (3.24 g, 49.08 mmol) and iodine (6.22
g, 24.55 mmol) in dry DMF (50 mL) was added 3,4-di-
eliminated
and
the
residue
dissolved
in
dichloromethane (30 mL) and washed with water, then
concentrated. Column chromatography (1:4 ether–hex-
ane“ether) afforded first crystalline 5 (150 mg); mp
77–80°C; [h]2D4 −16° (c 1.1). For NMR data, see Tables
1 and 2. Anal. calcd for C23H27BrO5: C, 59.61; H, 5.87.
Found: C, 60.11; H, 5.99%. Eluted second was 4 (150
mg).
O-benzyl-1,2-O-isopropylidene-b-
D
-fructopyranose1
2
(4.91 g, 12.27 mmol) and the mixture heated at 110°C
for 2 days. TLC (2:1 ether–hexane) then revealed a less
polar product. The solvent was evaporated under vac-
uum and the residue dissolved in ether (50 mL) and
washed with 10% aqueous sodium thiosulphate and

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1503–1508
1507
3.5. 5-Azido-3,4-di-O-benzyl-5-deoxy-b-
D
-fructopyran-
mixture was concentrated and the residue dissolved in
dichloromethane (10 mL) and washed with water. The
organic phase was separated and concentrated. Column
chromatography [7:1 ether–methanol, 0.1% Et3N] of
the residue yielded crystalline (2R,3R,4R,5R)-3,4-diben-
ose 6
A solution of 4 (570 mg, 1.34 mmol) in 70% aqueous
trifluoroacetic acid (2 mL) was kept at room tempera-
ture for 5 h. TLC (2.1 ether–hexane) then revealed a
more polar product. The mixture was concentrated and
repeatedly co-distilled with water and then dissolved in
CH2Cl2 and concentrated. The residue was purified by
zyloxy-2,5-bis(hydroxymethyl)pyrrolidine
8 (30 mg,
56%); mp 80–81°C; [h]D27 +25 (c 1). For NMR data, see
Tables 1 and 2. Anal. calcd for C20H25NO4: C, 69.94;
H, 7.34; N, 4.08. Found: C, 69.70; H, 6.97; N, 4.21%.
chromatography on silica gel and (2:1 ether–hexane) to
film
max
yield syrupy 6 (450 mg, 87%), [h]2D7 −47 (c 1.4); w
3.9. (2R,3R,4R,5R)-N-Allyl-3,4-dibenzyloxy-2%-O-tert-
3484 and 3446 (OH), 3082 and 3030 (aromatic), 2102
(N3), 740 and 697 cm−1 (aromatic). For NMR data, see
Tables 1 and 2. Mass spectrum (LSIMS): m/z 408.1536
[M++Na] for C20H23N3NaO5 408.1535 (deviation –0.2
ppm).
butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 1a
To a solution of 1 (460 mg, 0.8 mmol) in dry acetone
(10 mL) was added anhydrous potassium carbonate
(540 mg) and the mixture sonicated for 15 min, then
allyl bromide (250 mL, 3 mmol) was added and the
mixture was stirring at room temperature. After 12 h
TLC (ether) revealed the presence of a less polar com-
pound. The mixture was filtered and the solid thor-
oughly washed with acetone and the filtrate and
washings concentrated to a residue that was partitioned
in dichloromethane/water. The organic phase was sepa-
rated and concentrated to a residue that was submitted
3.6. 5-Azido-3,4-di-O-benzyl-1-O-tert-butyldiphenylsilyl-
5-deoxy-b-D-fructopyranose 7
To a stirred, ice-water cooled solution of 6 (4.49 g, 11.6
mmol) in dry DMF (30 mL) were added imidazole (840
mg, 12.3 mmol) and tert-butylchlorodiphenylsilane (3.2
mL, 12.3 mmol) and the mixture was left at room
temperature 12 h. TLC (2:1 ether–hexane) then revealed
a less polar product. The mixture was concentrated and
the residue dissolved in ether (15 mL) and the resulting
solution was washed with brine and concentrated.
Column chromatography purification (1:2 ether–hex-
ane) of the residue afforded pure 7 (5.2 g, 72%) as a
to chromatography (1:1 ether–hexane) to give 1a as a
film
colorless syrup (425 mg, 86%); [h]2D2 +22 (c 1); w
3458
max
(OH), 3031 and 3020, 736 and 700 cm−1 (aromatic). For
NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z 644.3170 [M++Na] for C39H47NNaO4Si
644.3172 (deviation +0.3 ppm).
film
max
viscous syrup; [h]2D7 −27 (c 1); w
3469 (OH), 3068 and
3030 (aromatic), 2102 (N3), 738 and 700 cm−1 (aro-
matic). For NMR data, see Tables 1 and 2. Mass
spectrum (LSIMS): m/z 646.2716 [M++Na] for
C36H41N3NaO5Si 646.2713 (deviation −0.4 ppm).
3.10. (2R,3R,4R,5R)-N-Benzyl-3,4-dibenzyloxy-2%-O-
tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine
1b
3.7. Hydrogenation of 7
To a solution of 1 (211 mg, 0.36 mmol) in dry acetone
(4 mL) was added anhydrous potassium carbonate (250
mg) and the mixture sonicated for 15 min, then benzyl
bromide (160 mL, 1.4 mmol) was added and the mixture
was left at room temperature with stirring. After 5 h
TLC (2:1 ether–hexane) revealed the presence of a less
polar product. The mixture was filtered and the solid
thoroughly washed with acetone and the filtrate and
washings concentrated to a residue that was submitted
to chromatography (1:1 ether–hexane) to give 1b as a
colorless syrup (240 mg, quantitative); [h]2D7 −12 (c 1).
For NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z HRMS 694.3328 [M++Na] for
C43H49NNaO4Si 694.3329 (deviation +0.1 ppm).
Compound 7 (5.18 g, 8.3 mmol) in MeOH (50 mL) was
hydrogenated at 50 psi over wet Raney nickel (2.5 g)
for 4 h. TLC (ether) then revealed the presence of a
slower-running compound (presumably the D2-pyrro-
line) together with a non-mobile compound. The
hydrogenation was continued for additional 20 h, when
TLC (ether) indicated the presence of only the above-
mentioned non-mobile compound. The catalyst was
removed by filtration and washed with MeOH. The
combined filtrate and washings were concentrated to a
residue that was submitted to column chromatography
(ether with 0.1% Et3N) to afford (2R,3R,4R,5R)-3,4-
dibenzyloxy - 2% - O - tert - butyldiphenylsilyl - 2,5 - bis(hy-
droxymethyl)pyrrolidine (1, 4.6 g, 97%) as a colorless
syrup; [h]2D5 +11 (c 1). For NMR data, see Tables 1 and
2. Mass spectrum (LSIMS): m/z 604.2854 [M++Na] for
C36H43NNaO4Si 604.2859 (deviation +0.8 ppm).
3.11. (2R,3R,4R,5R)-3,4-Dibenzyloxy-N-tert-butyloxy-
carbonyl-2%-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)pyrrolidine 1c
3.8. O-Desilylation of 1
To an ice-water cooled, stirred solution of 1 (224 mg,
0.39 mmol) in dry dichloromethane (3 mL), TEA (62
mL, 0.46 mmol) and di-tert-butyl dicarbonate (92 mg,
0.42 mmol) were added and the mixture was left at
room temperature. After 5 h TLC (ether) revealed the
presence of a faster-running compound. The reaction
mixture was quenched with dry methanol (0.3 mL),
Compound 1 (86 mg, 0.14 mmol) in THF (3 mL), was
treated with a solution of tetra-n-butylammonium
fluoride trihydrate (70 mg, 0.22 mmol) for 2 h at room
temperature. TLC (ether/methanol, 20:1) then showed
the presence of a more polar product. The reaction

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I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1503–1508
then supported on silica gel and chromatographed (1:1
625–628; (f) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda,
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1999, 65; 437–439; (h) Ikeda, K.; Takahashi, M.; Nishida,
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Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N.
Carbohydr. Res. 2000, 323, 73–80. For previous syntheses,
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Rollin, P.; Yang, J.; Holman, G. D. Carbohydr. Res. 2001,
333, 327–334. In this paper, compound 3 was mistakenly
named with the b-L-sorbo configuration.
7. Beaupere, D.; Stasik, B.; Uzan, R.; Demailly, G. Carbo-
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8. (a) Liu, K. K.-C.; Kajimoto, T.; Chen, L.; Zhong, Z.;
Ichikawa, Y.; Wong, C.-H. J. Org. Chem. 1991, 56, 6280–
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ether–hexane) to afford 1c (250 mg, quantitative) as a
film
colorless syrup; [h]2D7 −5 (c 1); w
3441 (OH), 3065 and
max
3031 (aromatic) 1693 (CO), 737 and 699 cm−1 (aro-
matic). For NMR data, see Tables 1 and 2. Mass
spectrum (LSIMS): m/z HRMS 704.3384 [M++Na] for
C41H51NNaO6Si 704.3383 (deviation −0.2 ppm).
Acknowledgements
The authors are deeply grateful to Ministerio de Educa-
cio´n y Cultura (Spain) for financial support (Project
PB98-1357) and for a grant (F. Franco).
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