Synthesis of the dimethyl ester of 1-deoxy-L-idonojirimycin-1- methylenphosphonate: A new approach to iminosugar phosphonates

Article abstract of DOI:10.1080/07328300600731990

1-Methylenphosphonate-1-deoxy-L-idonojirimycin (1) has been synthesized starting from commercially available tetrabenzyl glucose, the key steps being substitution of the hydroxyl group at C-5 of compound 7 with an azido group, stereoselective reaction of

Full text of DOI:10.1080/07328300600731990

Journal of Carbohydrate Chemistry, 25:151–162, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600731990
Synthesis of the Dimethyl
Ester of 1-Deoxy-
L-Idonojirimycin-1-
Methylenphosphonate:
A New Approach to
Iminosugar Phosphonates
Barbara La Ferla, Piergiuliano Bugada, and Francesco Nicotra
Department of Biotechnology and Bioscience, University of Milano Bicocca,
Milano, Italy
1-Methylenphosphonate-1-deoxy-L-idonojirimycin (1) has been synthesized starting
from commercially available tetrabenzyl glucose, the key steps being substitution
of the hydroxyl group at C-5 of compound 7 with an azido group, stereoselective
reaction of the aldehyde at C-1 of compound 10 with dimethyl methylenephosphonate
anion, conversion of the azide into an amino group, and finally cyclization of the
aminoalcohol 12.
Keywords Carbohydrate analogs, Iminosugars, Phosphonates, Inhibitors
Received October 6, 2005; accepted November 10, 2005.
Address correspondence to Barbara La Ferla, Department of Biotechnology and Bio-
science, University of Milano Bicocca, Piazza della Scienza 2, I-20126 Milano, Italy.
E-mail: barbara.laferla@unimib.it
151

B. La Ferla et al.
152
INTRODUCTION
Naturally occurring iminosugars are known to be potent inhibitors of
carbohydrate processing enzymes such as glycosidases and glycosyltrans-
ferases,[1] which are involved in many biological and pathological process.
This has suggested their used in a wide range of potential therapeutic
applications,[2–6] and has stimulated synthetic chemists to develop new and
more efficient synthetic strategies for the preparation of new, more potent and
selective iminosugar derivatives. Due to the great interest in these compounds,
a great number of novel structures have been synthesized so far, nonetheless,
there are only very few examples of iminosugar phosphonates.[7] In this work
we report the synthesis of a new compound 1-deoxy-L-idonojirimycin-1-methy-
lenphosphonate using a novel approach to iminosugar phosphonates.
RESULTS AND DISCUSSION
Our synthetic route started from tetrabenzyl glucose 2. In order to introduce a
nitrogen atom at C-5, which was required for the generation of the iminosu-
gars, the following synthetic scheme was elaborated (Sch. 1): acetolysis and
basic hydrolysis of the acetate afforded compound 3, which in turn was
reduced to the corresponding alditol, which was protected as isopropylidene
derivative 4. Protection of the primary hydroxyl group at C-1 as acetate (5)
and cleavage of the isopropylidene group followed by protection of the
primary hydroxyl group at C-6 as t-butyldiphenylsilyl ether afforded
compound 7 with a free hydroxyl group at C-5. The free hydroxyl group of 7
was exploited for the introduction of the nitrogen atom; its substitution with
an azide through a Mitsunobu reaction afforded compound 8 with inversion
of configuration at C-5. In order to introduce the methylenephosphonate
moiety, the acetylated primary hydroxyl group at C-1 was selectively depro-
tected and oxidized to the corresponding aldehyde 10, and then subjected to
a nucleophilic attack using lithium methylenedimethyl phosphonate. The
reaction afforded compound 11 as an inseparable mixture of diastereoisomers
1
in a ratio of R/S ¼ 23:77, determined by H NMR spectroscopy. Only after
reduction with thiphenylphosphine in water/THF the corresponding major
amine 12 was obtained as pure product in 51% yield over the two steps.
The absolute configuration of the newly formed stereocenter was attributed
to the cyclized product and is discussed later on. Compound 12 was then
cyclized through an intramolecular Mitsunobu reaction, affording, after
removal of the silyl protection, pure compound 14 in 58% yield over the two
steps. Final debenzylation afforded the dimethyl ester of 1-deoxy-L-idonojiri-
mycin-1-methylenphosphonate (1). 1H NMR spectroscopic analysis of
compound 14 allowed us to determine the absolute configuration of the C(2)
stereocenter formed during the additon of the phosphonate group. The

Phosphonate Derivative of 1-Deoxy-L-Idonojirimycin
153
Scheme 1: Reagents and conditions. a) Ac2O/TFA 4/1 then NaOH 4M; b) Na, MeOH; c)
NaBH4, EtOH; d) 2,2-dimethoxypropane, camphor-10-sulfonic acid, CH3CN (91% over four
steps); e) Ac2O, pyridine, DMAP, CH2Cl2 (96%); f) H2O, CSA, CH3CN, 608C (96%); g) TBDPSCl,
imidazole, CH2Cl2 (95%); h) (PhO)2PON3, PPh3, DIAD, THF (71%); i) MeONa, MeOH (91%);
j) Dess-Martin periodinane, CH2Cl2; k) CH3PO(OMe)2, BuLi, THF, 2788C (62% over two steps);
l) PPh3, H2O, THF, 608C (51%); m) PPh3, DIAD, THF; n) TBAF, THF (58% over two steps);
o) Pd(OH)2/C, H2, MeOH/AcOH 98%.
values of the coupling constants (J3,2 ¼ 8.5 Hz, J4,3 ¼ 8.0 Hz, and J5,4 ¼ 9.0 Hz)
(Fig. 1) were indicative of a trans-diaxial disposition of the protons, thus indi-
4
cating a C1 conformation; moreover, the diaxial disposition of C(2)-H/C(3)-H
allowed to determine the absolute configuration (R) of C(2).
Biological evaluation of compound 1 in a variety of glycosidase inhibition
assay is in due course.
EXPERIMENTAL
General Remarks
All solvents were dried with molecular sieves for at least 24 h prior to use.
Thin layer chromatography (TLC) was performed on silica gel 60 F254 plates

B. La Ferla et al.
154
Figure 1: Conformation and coupling constants values of compound 13.
(Merck) with detection using UV light when possible, or by charring with a
solution of concd. H2SO4/EtOH/H2O (5:45:45) or a solution of (NH4)6Mo7O24
(21 g), Ce(SO4)2 (1 g), concd. H2SO4 (31 mL) in water (500 mL). Flash column
1
chromatography was performed on silica gel 230–400 mesh (Merck). H, 13C
NMR, and 31P spectra were recorded at 258C with a Varian Mercury
400 MHz instrument using CDCl3 as the solvent unless otherwise stated.
Chemical shift assignments, reported in ppm, are referenced to the
corresponding solvent peaks. Mass spectra were recorded with a MALDI2
Kompakt Kratos instrument, using gentisic acid (DHB) as the matrix.
Optical rotations were measured at rt using a Kru¨ss P3002 electronic polari-
2
meter and are reported in units of 1021 deg cm
21. Elemental analyses
.
g
.
were performed using a Perkin-Elmer Series II Analyzer 2400.
2,3,4-Tri-O-benzyl-D-glucopyranose (3). Compound 2 (2.5 g, 4.62 mmol),
was cooled to 08C under an inert atmosphere, and a solution of Ac2O/TFA
4/1 (30 mL) was slowly added. The reaction was left stirring at 08C. After
3 h ice-cold water was added (50 mL), and after 15 min the reaction mixture
was neutralized by a slow addition at 08C of NaOH 4M. The mixture was
then extracted with AcOEt (3 ꢀ 100 mL), the combined organic layers were
dried over Na2SO4, and the solvent was eliminated under reduced
pressure. The crude was dissolved in dry MeOH (10 mL) and a catalytic
amount of Na was added. After 15 min the reaction mixture was neutralized
with amberlite IR 120-Hþ, filtered, and evaporated, affording known
compound 3[8] as mixture of diastereoisomers. Crude 3 was directly used
for the following step.
2,3,4-Tri-O-benzyl-5,6-O–isopropylidene-D-glucitol (4). Crude compound
3 was dissolved in EtOH (30 mL) and NaBH4 (1.17 g, 31 mmol) was added in
five portions. After 3 h the solvent was removed under reduced pressure and
the solid residue was suspended in a saturated solution of Na2CO3 (30 mL).
The suspension was stirred for 20 min and then extracted with EtOAc

Phosphonate Derivative of 1-Deoxy-L-Idonojirimycin
155
(3 ꢀ 30 mL), the combined organic layers were dried over Na2SO4, and the
solvent was eliminated under reduced pressure. The crude was dissolved in
dry CH3CN (10 mL) under inert atmosphere, and 2,2-dimethoxypropane
(1.2 mL, 10.07 mmol) and a catalytic amount of camphor-10-sulfonic acid
were added. After 1 h the reaction was neutralized with triethylamine and
the solvent was removed under reduced pressure. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate v/v 7/3), yielding 4
(3.48 g, 91% from 2) as a colorless oil. [a]2D0 þ1.2 (c 0.4 CHCl3); 1H NMR:
d ¼ 1.33 (s, 3 H, CH3iPr), 1.42 (s, 3 H, CH3iPr), 3.50 [m, 1 H, C(1a)-H], 3.70–
3.78 [m, 3 H, C(2)-H, C(3)-H, C(1b)-H], 3.93–3.97 [m, 2 H, C(4)-H, C(6a)-H],
4.03 [dd, 1 H, J ¼ 8.0 Hz, J ¼ 7.2 Hz, C(6b)-H], 4.22 [bdt, 1 H, J ¼ 7.2 Hz,
J ¼ 4.0 Hz, C(5)-H], 4.61–4.68 (m, 4 H, 4CHPh), 4.75 (d, 1 H, J ¼ 11.2 Hz,
CHPh), 4.83 (d, 1 H, J ¼ 11.6 Hz, CHPh), 7.19–7.34 (m, 15 H, CHAr) ppm.
13C NMR: d ¼ 25.38, 26.97 (2 CH3iPr), 61.87, 66.20 [C(1), C(6)], 73.30, 74.33,
75.05 (3CH2Ph), 77.44, 78.33, 78.83, 79.88 [C(2), C(3), C(4), C(5)], 108.5
(CqiPr), 127.9–128.7 (CHAr), 138.1, 138.2, 138.3 (CqAr) ppm. MS (MALDI-
TOF): m/z 515 [M þ Na]þ, 531 [M þ K]þ; C30H36O6 (492.25): Calcd.; C, 73.15;
H, 7.37. found; C, 72.95; H, 7.21.
1-O-Acetyl-2,3,4-tri-O-benzyl-5,6-O–isopropylidene-D-glucitol
(5).
Compound 4 (183 mg, 0.37 mmol) was dissolved in CH2Cl2 (2 mL) and
pyridine (6 equiv., 2.22 mmol, 176 mg, 179 mL), DMAP (0.1 equiv., 0.04 mmol,
5 mg), and acetic anhydride (3 equiv., 1.11 mmol, 114 mg, 105 mL) were added.
The solution was stirred at rt for 1 h, and then HCl (5%, 2 mL) was added. The
two layers were separated, and the aqueous layer was extracted with CH2Cl2
(3 ꢀ 5 mL). The combined organic layers were dried over Na2SO4. The
solvent was eliminated under reduced pressure, and the residue was purified
by flash chromatography (petroleum ether/ethyl acetate v/v 10/1), yielding
5 (189 mg, 96%) as colorless oil. [a]2D0 þ 7.0 (c 1.0 CHCl3); H NMR: d ¼ 1.23
1
(s, 3 H, CH3iPr), 1.33 (s, 3 H, CH3iPr), 1.93 (s, 3H, CH3Ac), 3.58 [dd, 1 H,
J ¼ 6.1 Hz, J ¼ 4.1 Hz, C(4)-H], 3.79 [ddd, 1 H, J ¼ 9.4 Hz, J ¼ 5.9 Hz,
J ¼ 3.3 Hz, C(2)-H], 3.83–3.87 [m, 2 H, C(3)-H, C(6a)-H], 3.92 [bt, 1 H,
J ¼ 7.6 Hz, C(6b)-H], 4.00 [dd, 1 H, J ¼ 12.0 Hz, J ¼ 5.9 Hz, C(1a)-H], 4.12
[ddd, 1 H, J ¼ 11.3 Hz, J ¼ 6.8 Hz, J ¼ 4.2 Hz, C(5)-H], 4.25 [dd, 1 H,
J ¼ 12.0 Hz, J ¼ 3.4 Hz, C(1b)-H], 4.51 (d, 1 H, J ¼ 11.6 Hz, CHPh), 4.55
(d, 1 H, J ¼ 11.3 Hz, CHPh), 4.57 (d, 1 H, J ¼ 11.3 Hz, CHPh), 4.58 (d, 1 H,
J ¼ 11.6 Hz, CHPh), 4.64 (d, 1 H, J ¼ 11.3 Hz, CHPh), 4.73 (d, 1 H,
J ¼ 11.3 Hz, CHPh), 7.19–7.24 (m, 15 H, CHAr) ppm. 13C NMR:
d ¼ 21.43(CH3Ac), 25.43, 26.97 (2 CH3iPr), 64.23, 66.21 [C(1), C(6)], 73.35,
74.47, 74.95 (3CH2Ph), 77.36, 77.54, 78.53, 79.33 [C(2), C(3), C(4), C(5)],
108.5 (CqiPr), 127.9–132.4 (CHAr), 138.2, 138.4, 138.4 (CqAr), 170.9 (C55O)
ppm. MS (MALDI-TOF): m/z 557 [M þ Na]þ, 573 [M þ K]þ; C32H38O7
(534.26): Calcd; C, 71.89; H, 7.16. Found; C, 71.95; H 7.20.

B. La Ferla et al.
156
1-O-Acetyl-2,3,4-tri-O-benzyl-D-glucitol (6). Compound
5
(1.07 g,
2.01 mmol) was dissolved in CH3CN (10 mL), and then H2O (500 mL) and
CSA (0.1 equiv., 0.2 mmol, 50 mg) were added. The mixture was stirred at
608C for 20 min, and then NaHCO3 (sat. sol., 5 mL) was added. The two
layers were separated, and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 5 mL). The combined organic layers were dried over Na2SO4.
The solvent was eliminated under reduced pressure, and the residue was
purified by flash chromatography (petroleum ether/ethyl acetate v/v 8/2),
yielding 6 (944 mg, 96%) as colorless oil. [a]2D0 þ11.2 (c 0.9 CHCl3); H NMR:
1
d ¼ 1.89 (s, 3 H, CH3Ac), 2.22–2.28 (m, 1 H, OH), 3.27 (d, 1 H, J ¼ 5.6 Hz,
OH), 3.55–3.58 [m, 1 H, C(6a)-H], 3.64–3.67 [m, 3 H, C(3)-H, C(4)-H, C(6b)-
H], 3.73–3.75 [m, 1 H, C(5)-H], 3.84–3.87 [m, 1 H, C(2)-H], 4.11 [dd, 1 H,
J ¼ 11.5 Hz, J ¼ 5.9 Hz, C(1a)-H], 4.19 [dd, 1 H, J ¼ 11.5 Hz, J ¼ 4.8 Hz,
C(1b)-H], 4.51–4.61 (m, 6 H, 6CHPh), 7.15–7.26 (m, 15 H, CHAr) ppm. 13C-
NMR: d ¼ 21.37 (CH3Ac), 63.78, 63.89 [C(1), C(6)], 72.06 [C(5)], 73.61, 74.01,
74.17 (3CH2Ph), 76.62, 76.88, 78.20 [C(2), C(3), C(4)], 128.2–128.7 (CHAr),
137.6, 137.7, 137.9 (3CqAr), 170.8 (C55O) ppm. MS (MALDI-TOF): m/z 518
[M þ Na]þ, 534 [M þ K]þ; C29H34O7 (494.23): Calcd: C, 70.43; H, 6.93. Found:
C, 70.29; H, 7.03.
1-O-Acetyl-2,3,4-tri-O-benzyl-6-O–t-butyldiphenylsilyl-D-glucitol (7).
Compound 6 (944 mg, 1.93 mmol) was dissolved, under inert atmosphere,
in dry CH2Cl2 (10 mL), and imidazole (3 equiv., 5.79 mmol, 394 mg) and
tert-butyldiphenylchlorosilane (1.5 equiv., 2.90 mmol, 741 mL) were added.
The solution was stirred at rt overnight, and then CH3OH (1 mL) and
H2O (10 mL) were added. The two layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 ꢀ 10 mL). The combined organic layers
were dried over Na2SO4. The solvent was eliminated under reduced
pressure, and the residue was purified by flash chromatography (petroleum
ether/ethyl acetate v/v 9/1), yielding 7 (1.35 g, 95%) as colorless oil. [a]D20
21.7 (c 1.4 CHCl3); 1H NMR: d ¼ 1.09 (s, 9 H, CH3tBu), 1.98 (s, 3 H,
CH3Ac), 2.85 (d, 1 H, J ¼ 5.2 Hz, OH), 3.82–3.88 [m, 4 H, C(3)-H, C(4)-H,
C(6a)-H, C(6b)-H], 3.90–3.98 [m, 2 H, C(2)-H, C(5)-H], 4.17 [dd, 1 H,
J ¼ 11.9 Hz, J ¼ 6.1 Hz, C(1a)-H], 4.35 [dd, 1 H, J ¼ 11.8 Hz, J ¼ 3.4 Hz,
C(1b)-H], 4.55 (s, 2 H, CH2Ph), 4.61 (d, 1 H, J ¼ 11.4 Hz, CHPh), 4.64
(d, 1 H, J ¼ 10.9 Hz, CHPh), 4.67 (d, 1 H, J ¼ 10.9 Hz, CHPh), 4.69 (d, 1 H,
J ¼ 11.4 Hz, CHPh), 7.24–7.67 (m, 25 H, CHAr) ppm. 13C-NMR: d ¼ 19.75
(CqtBu), 21.39 (CH3Ac), 27.36 (CH3tBu), 64.53, 65.19 [C(1), C(6)], 72.05
[C(5)], 73.50, 73.54, 74.72 (3CH2Ph), 77.33, 77.48, 78.52 [C(2), C(3), (4)],
127.8–130.0 (CHAr), 133.2, 133.3 (2CqAr), 135.7, 135.8 (CHAr), 138.1,
138.2, 138.2 (3CqAr), 170.8 (C55O) ppm. MS (MALDI-TOF): m/z 756
[M þ Na]þ, 772 [M þ K]þ; C45H52O7Si (732.35): calcd: C, 73.74; H, 7.15.
Found: C, 73.94; H, 7.22.

Phosphonate Derivative of 1-Deoxy-L-Idonojirimycin
157
1-O-Acetyl-5-azido-2,3,4-tri-O-benzyl-6-O–t-butyldiphenylsilyl-5-deoxy-
D-iditol (8). Compound 7 (189 mg, 0.258 mmol) was dissolved, under inert
atmosphere, in dry THF (2 mL). PPh3 (3 equiv., 0.774 mmol, 203 mg) was
added and the mixture was cooled to 08C. DIAD (3 equiv., 0.774 mmol,
150 mL) and diphenyl phosphoryl azide (3.2 equiv., 0.826 mmol, 180 mL) were
slowly added. The mixture was stirred at rt overnight, and then the solvent
was evaporated and the crude product was purified by flash chromatography
(petroleum ether/ethyl acetate v/v 9/1), yielding 8 (139 mg, 71%) as colorless
oil. [a]2D0 þ12.5 (c 0.9 CHCl3); 1H NMR: d ¼ 1.07 (s, 9 H, CH3tBu), 1.98
(s, 3 H, CH3Ac), 3.49–3.52 [m, 1 H, C(5)-H], 3.59 [dd, 1 H, J ¼ 10.3 Hz,
J ¼ 4.9 Hz, C(6a)-H], 3.72–3.84 [m, 4 H, C(2)-H, C(3)-H, C(4)-H, C(6b)-H],
4.23–4.26 [m, 2 H, C(1a)-H, C(1b)-H], 4.48 (d, 1 H, J ¼ 11.5 Hz, CHPh), 4.55–
4.58 (m, 2 H, 2CHPh), 4.65 (d, 1 H, J ¼ 11.9 Hz, CHPh), 4.66 (d, 1 H,
J ¼ 11.1 Hz, CHPh), 4.73 (d, 1 H, J ¼ 11.5 Hz, CHPh), 7.18–7.65 (m, 25 H,
CHAr) ppm. 13C NMR: d ¼ 19.54 (CqtBu), 21.34 (CH3Ac), 27.20 (CH3tBu),
63.51, 64.38 [C(1), C(6)], 63.88 [C(5)], 72.79, 75.06, 75.06 (3CH2Ph), 75.84,
77.69, 78.83 [C(2), C(3), C(4)], 127.9–130.0 (CHAr), 132.9, 133.1 (2CqAr),
135.7, 135.8 (CHAr), 137.7, 137.8, 138.0 (3CqAr), 170.7 (C55O) ppm. IR
(n/cm21): 1739.78 (C55O), 2099.80 (N3); MS (MALDI-TOF): m/z 780
[M þ Na]þ, 796 [M þ K]þ; C45H51N3O6Si (757.35): Calcd: C, 71.30; H, 6.78; N
5.54. Found; C, 71.50; H, 6.62; N, 5.39.
5-Azido-2,3,4-tri-O-benzyl-6-O–t-butyldiphenylsilyl-5-deoxy-D-iditol (9).
Compound 8 (130 mg, 0.172 mmol) was dissolved in dry CH3OH (2 mL) and
Na (cat.) was added. The mixture was stirred at rt for 30 min and then was neu-
tralized with amberlite IR 120-Hþ. After filtration the solvent was eliminated
under reduced pressure and the residue was purified by flash chromatography
(petroleum ether/ethyl acetate v/v 8/2), yielding 9 (112 mg, 91%) as colorless
oil. [a]2D0 þ9.3 (c 1.3 CHCl3); H NMR: d ¼ 1.09 (s, 9 H, CH3tBu), 3.60–3.67
1
(m, 3 H), 3.72 [dd, 1 H, J ¼ 10.4 Hz, J ¼ 5.2 Hz], 3.79–3.86 (m, 3 H), 3.92 [dd,
1 H, J ¼ 7.1 Hz, J ¼ 4.2 Hz], 4.54 (d, 1 H, J ¼ 11.4 Hz, CHPh), 4.59 (d, 1 H,
J ¼ 11.7 Hz, CHPh), 4.62–4.65 (m, 2 H, 2CHPh), 4.68 (d, 1 H, J ¼ 11.2 Hz,
CHPh), 4.75 (d, 1 H, J ¼ 11.4 Hz, CHPh), 7.20–7.67 (m, 25 H, CHAr) ppm.
13C NMR: d ¼ 19.57 (CqtBu), 27.22 (CH3tBu), 61.68, 64.21 [C(1), C(6)], 63.69
[C(5)], 72.70, 75.00, 75.07 (3CH2Ph), 77.80, 78.44, 79.40 [C(2), C(3), C(4)],
128.0–128.8 (CHAr), 130.0, 130.1 (CHAr), 133.0, 133.1 (2CqAr), 135.8–135.9
(CHAr), 137.9, 137.9, 138.0 (3CqAr) ppm. IR: 2100.0, (N3), 3455.9 (OH); MS
(MALDI-TOF): m/z 739 [M þ Na]þ, 755 [M þ K]þ; C43H49N3O5Si (715.34):
Calcd: C, 72.14; H, 6.90; N, 5.87. Found C, 71.99; H, 6.82; N, 5.50.
5-Azido-2,3,4-tri-O-benzyl-6-O–t-butyldiphenylsilyl-5-deoxy-D-idose (10).
Compound 9 (826 mg, 1.15 mmol) was dissolved in CH2Cl2 (10 mL) and Dess
Martin Periodinane (1.5 equiv., 1.73 mmol, 734 mg) was added. The mixture

B. La Ferla et al.
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was stirred at rt for 30 min, then quenched with a saturated aqueous solution of
NaHCO3(5 mL) and a 10% aqueous solution of Na2S2O3 (5 mL). The mixture
was stirred for 1 h, and then the two layers were separated and the organic
layer was washed with a saturated solution of NaHCO3 (2 ꢀ 10 mL) and
brine (1 ꢀ 10 mL). The organic layer was dried over Na2SO4 and solvent was
eliminated under reduced pressure. The crude product was used for the next
step without further purification. [a]2D0 þ20.0 (c 1.0 CHCl3); 1H NMR:
d ¼ 1.09 (CH3tBu), 3.56–3.61 [m, 1 H, C(5)-H], 3.71 [dd, 1 H, J ¼ 10.5 Hz,
J ¼ 7.0 Hz, C(6a)-H], 3.77 [dd, 1 H, J ¼ 10.5 Hz, J ¼ 4.4 Hz, C(6b)-H], 3.89
[bt, 1 H, C(4)-H], 3.92–3.96 [m, 2 H, C(2)-H, C(3)-H], 4.48 (s, 2 H, CH2Ph),
4.51–4.54 (m, 2 H, 2CHPh), 4.62 (d, 1 H, J ¼ 11.0 Hz, CHPh), 4.83 (d, 1 H,
J ¼ 11.9 Hz, CHPh), 7.26–7.67 (m, 25 H, CHAr), 9.66 [s, 1 H, C(1)-H] ppm.
13C NMR: d ¼ 19.60 (CqtBu), 27.22 (CH3tBu), 64.09 [C(5)], 64.15 [C(6)],
73.40, 74.42, 74.65 (3CH2Ph), 77.12, 79.92, 80.96 [C(2), C(3), C(4)], 127.9–
130.1 (CHAr), 132.9, 133.0 (2CqAr), 135.8, 135.9 (CHAr), 137.0, 137.3, 137.5
(3CqAr), 200.6 [C(1)] ppm. IR: 1728.6 (C55O), 2100.7, (N3); MS (MALDI-
TOF): m/z 737 [M þ Na]þ, 753 [M þ K]þ; C43H47N3O5Si (713.33): Calcd: C,
72.34; H, 6.64; N, 5.89. Found; C, 72.00; H, 6.72; N, 5.55.
(2R/S,3R,4S,5R,6S) Dimethyl 6-Azido-3,4,5-tris-benzyloxy-7-t-butyldi-
phenylsilanyloxy-2-hydroxy-heptylphosphonate (11). In a flame-dried
vessel, BuLi (2.30 mmol, 1.6 M in hexane, 1.44 mL) was diluted with dry
THF (10 mL), and at 2788C dimethyl methyl phosphonate (2.30 mmol,
254 mL) was slowly added. The mixture was stirred at 2788C for 30 min,
and then 10 (1.15 mmol) dissolved in dry THF (8 mL) was added. The
mixture was stirred at 2788C for 1 h, then quenched with NH4Cl (1 M,
4 mL). CH2Cl2 (10 mL) was added, and the two layers were separated. The
organic layer was washed with NH4Cl 1M (1 ꢀ 10 mL) and H2O
(2 ꢀ 10 mL). The organic phase was dried over Na2SO4, and the solvent
was eliminated under reduced pressure. The crude was purified by flash
chromatography (petroleum ether/ethyl acetate v/v 4/6), yielding an inse-
parable mixture of two diasteroisomers (R/S 23/77, 597 mg, 62% over two
steps) as colorless oil.
(2S,3R,4S,5R,6S) Dimethyl 6-Amino-3,4,5-tris-benzyloxy-7-t-butyldi-
phenylsilanyloxy-2-hydroxy-heptylphosphonate (12). The mixture 11
(381 mg, 0.455 mmol) was dissolved in THF (8 mL). PPh3 (2 equiv.,
0.909 mmol, 239 mg) and H2O (25 equiv., 11.38 mmol, 205 mL) were added,
and the mixture was stirred at 608C for 18 h. The solvent was evaporated
and the crude product was purified by flash chromatography (AcOEt to
AcOEt/CH3OH v/v 15/1), yielding pure 12 (190 mg) (yield 51%) as a colorless
oil. [a]2D0 þ2.7 (c 1.0 CHCl3); 1H NMR: d ¼ 1.07 (s, 9 H, CH3tBu), 1.91 [ddd, 1 H,
J ¼ 18.9 Hz, J ¼ 15.3 Hz, J ¼ 3.3 Hz, C(1a)-H], 2.10 [ddd, 1 H, J ¼ 16.0 Hz,

Phosphonate Derivative of 1-Deoxy-L-Idonojirimycin
159
J ¼ 15.3 Hz, J ¼ 9.6 Hz, C(1b)-H], 3.14–3.16 [m, 1 H, C(6)-H], 3.51 [dd, 1 H,
J ¼ 9.6 Hz, J ¼ 7.4 Hz, C(7a)-H], 3.63–3.72 [m, 2 H, C(3)-H, C(7b)-H], 3.66
(d, 3 H, JH,P ¼ 5.7 Hz, OCH3), 3.69 (d, 3 H, JH,P ¼ 5.6 Hz, OCH3), 3.81 [dd, 1
H, J ¼ 6.1 Hz, J ¼ 3.1 Hz, C(5)-H], 4.11 [bt, 1 H, C(4)-H], 4.30–4.36 [m, 1 H,
C(2)-H], 4.48 (d, 1 H, J ¼ 11.1 Hz, CHPh), 4.54 (d, 1 H, J ¼ 11.2 Hz, CHPh),
4.70 (s, 2 H, CH2Ph), 4.76 (d, 1 H, J ¼ 11.2 Hz, CHPh), 4.81 (d, 1 H,
J ¼ 11.1 Hz, CHPh), 7.20–7.65 (m, 25 H, CHAr) ppm. 13C NMR: d ¼ 19.68
1
(CqtBu), 27.37 (CH3tBu), 30.19 [d, JC,P ¼ 139.5 Hz, C(1)], 52.67, 52.74
2
(OCH3), 53.70 [C(6)], 66.4 [d, JC,P ¼ 4.6 Hz, C(2)], 66.98 [C(7)], 74.57, 74.78,
74.87 (3CH2Ph), 78.97, 81.17, 81.31 [C(3), C(4), C(5)], 127.8–129.9 (CHAr),
133.5, 133.6 (2CqAr), 135.8 (CHAr), 138.3, 138.4, 138.5 (3CqAr) ppm. IR:
3349.6, 3361.7 (NH2, OH); MS (MALDI-TOF): m/z 812 [M þ H]þ, 834
[M þ Na]þ, 850 [M þ K]þ; C46H58NO8PSi (811.37): calcd. C, 68.04; H, 7.20; N,
1.72. Found C, 67.97; H, 7.03; N, 1.85.
(2R,3S,4S,5R,6S) Dimethyl [3,4,5-Tris-benzyloxy-6-(t-butyldiphenylsi-
lanyloxymethyl)-
piperidin-2-yl]-methylenephosphonate
(13).
Compound 12 (227 mg, 0.280 mmol) was dissolved under inert atmosphere
in dry THF (3 mL), and then PPh3 (2 equiv., 0.559 mmol, 147 mg) was
added. The solution was cooled at 08C, and then DIAD (2 equiv.,
0.559 mmol, 108 mL) was slowly added. The mixture was stirred for 18 h
at rt, and then the solvent was removed under reduced pressure and the
crude was purified by flash chromatography (ethyl acetate), yielding an
inseparable mixture of 13 and triphenylphosphine oxide, which was sub-
jected to NMR analysis. 1H NMR (400 MHz, CDCl3, 258C): d ¼ 1.09 (s, 9 H,
CH3tBu), 1.69 (ddd, 1 H, JH,P ¼ 15.6 Hz, J ¼ 14.9 Hz, J ¼ 10.0 Hz, CHP), 2.44
(bdd, 1 H, JH,P ¼ 20.1 Hz, J ¼ 14.6 Hz, CHP), 3.11 [bt, 1 H, J ¼ 8.8 Hz, C(3)-H],
3.31 [bt, 1 H, J ¼ 9.4 Hz, C(2)-H], 3.38–3.41 [m, 1 H, C(6)-H], 3.62–3.67 [m,
1 H, C(4)-H], 3.68 (d, 3 H, JH,P ¼ 10.9 Hz, OCH3), 3.71 (d, 3 H, JH,P ¼ 11.1 Hz,
OCH3), 3.75–3.79 [m, 2 H, C(5)-H, CHOH], 4.01 (bt, 1 H, CHOH), 4.34 (d, 1 H,
J ¼ 11.5 Hz, CHPh), 4.38 (d, 1 H, J ¼ 11.5 Hz, CHPh), 4.59 (d, 1 H,
J ¼ 11.9 Hz, CHPh), 4.66 (d, 1 H, J ¼ 11.7 Hz, CHPh), 4.82 (d, 1 H,
J ¼ 11.7 Hz, CHPh), 4.94 (d, 1 H, J ¼ 11.9 Hz, CHPh), 7.10–7.71 (m, CHAr)
ppm. 13C NMR: d ¼ 19.62 (CqtBu), 27.24 (CH3tBu), 28.47 (d, 1JC,P ¼ 139.6 Hz,
2
3
CH2P), 49.46 [d, JC,P ¼ 5.4 Hz, C(2)], 52.72 (d, JC,P ¼ 6.1 Hz, OCH3), 52.94
3
(d, JC,P ¼ 6.1 Hz, OCH3), 56.40 [C(6)], 60.75 (CH2OTBDPS), 75.60, 75.77,
4
75.79 (3CH2Ph), 80.51 [C(5)], 83.52 [d, JC,P ¼ 1.1 Hz, C(4), 83.77 [d,
3JC,P ¼ 16.9 Hz, C(3)], 127.8–128.7 (CHAr), 129.9, 130.0 (CHAr), 132.1–132.3
(CHAr), 132.2, 133.2, 133.5, 133.6 (4CqAr), 135.7, 135.8 (CHAr), 138.1, 138.3,
138.8 (3CqAr).
(2R,3S,4S,5R,6S) Dimethyl (3,4,5-Tris-benzyloxy-6-hydroxymethyl-
piperidin-2-yl)-methylenephosphonate (14). Compound 13 was dissolved

B. La Ferla et al.
160
in dry THF (3 mL), and then TBAF (0.560 mmol, 1 M in THF, 560 mL) was
added. The mixture was stirred at rt overnight and then quenched with
buffer phosphate (3 mL). The two layers were separated, and the aqueous
layer was extracted with AcOEt (3 ꢀ 5 mL). The combined organic layers
were dried over Na2SO4. The solvent was eliminated under reduced pressure,
and the residue was purified by flash chromatography (ethyl acetate to ethyl
acetate/methanol v/v 9/1), yielding 14 (90 mg, 58% over two steps) as colorless
oil. [a]2D0 þ10.1 (c 1.3 CHCl3); 1H NMR: d ¼ 1.62 (ddd, 1 H, J ¼ 15.5 Hz,
J ¼ 15.3 Hz, J ¼ 10.3 Hz, CHP), 2.30 (ddd, 1 H, J ¼ 18.2 Hz, J ¼ 15.1 Hz,
J ¼ 2.1 Hz, CHP), 3.02–3.10 [m, 1 H, C(2)-H], 3.14 [bt, 1 H, J ¼ 8.5 Hz, C(3)-
H], 3.39 [bdt, 1 H, J ¼ 10.5 Hz, J ¼ 5.4 Hz, J ¼ 5.4 Hz, C(6)-H], 3.70 [dd, 1 H,
J ¼ 9.0 Hz, J ¼ 8.0 Hz, C(4)-H], 3.71 (d, 3 H, J ¼ 10.9 Hz, OCH3), 3.72 (d, 3 H,
J ¼ 10.9 Hz, OCH3), 3.77 [dd, 1 H, J ¼ 9.0 Hz, J ¼ 5.6 Hz, C(5)-H], 3.77–3.80
(m, 1 H, CHOH), 3.86 (bt, 1 H, J ¼ 10.5 Hz, CHOH), 4.59 (d, 1 H, J ¼ 11.2 Hz,
CHPh), 4.66 (s, 2 H, CH2Ph), 4.76 (d, 1 H, J ¼ 10.9 Hz, CHPh), 4.90 (d, 1 H,
J ¼ 10.9 Hz, CHPh), 4.91 (d, 1 H, J ¼ 11.2 Hz, CHPh), 7.28–7.33 (m, 15 H,
1
CHAr) ppm. 13C NMR: d ¼ 27.27 (d, JC,P ¼ 140.3 Hz, CH2P), 48.90
[d, 2JC,P ¼ 4.6 Hz, C(2)], 52.85 (d, 3JC,P ¼ 6.1 Hz, OCH3), 52.97
3
(d, JC,P ¼ 6.1 Hz, OCH3), 54.99 [C(6)], 58.58 (CH2OH), 73.09, 75.29, 75.90
(3CH2Ph), 81.31 [C(5)], 83.19 [d, 3JC,P ¼ 16.1 Hz, C(3)], 83.61 [d,
4JC,P ¼ 2.3 Hz, C(4)], 127.9–128.7 (CHAr), 138.1, 138.3, 138.7 (3CqAr) ppm.
MS (MALDI-TOF): m/z 556 [M þ H]þ, 578 [M þ Na]þ, 594 [M þ K]þ;
C30H38NO7P (555.24): Calcd: C; 64.85; H, 6.89; N, 2.52. Found; C, 64.69; H,
6.77; N, 2.61.
1-Deoxy-L-idonojirimycin-1-methylenphosphonate (1). Compound 14
(50 mg, 0.09 mmol) was dissolved in MeOH (3 mL); a catalytic amount of
Pd(OH)2 and acetic acid (1 mL) were added and then the reaction mixture
was stirred under H2 overnight. The catalyst was filtered through a pad
of Celite (eluting with MeOH) and then the solvent was evaporated
under reduced pressure to afford pure compound 1 (26 mg, 98% yield) as
an amorphous solid. [a]D20 222.4 (c 1.0 MeOH); 1H NMR (D2O): d ¼ 2.32
(ddd, 1 H, J ¼ 19.4 Hz, J ¼ 16.3 Hz, J ¼ 6.6 Hz, CHP), 2.61 (ddd, 1 H,
J ¼ 20.4 Hz, J ¼ 16.3 Hz, J ¼ 5.8 Hz, CHP), 3.16–3.28 [m, 2 H, C(2)-H,
C(6)-H], 3.44–3.51 [m, 2 H, C(3)-H, C(4)-H], 3.66 (d, 3 H, J ¼ 11.1 Hz,
OCH3), 3.67 (d, 3 H, J ¼ 11.1 Hz, OCH3), 3.74–3.79 (m, 2 H, CH2OH),
3.84–3.90 [m,
1
H, C(5)-H] ppm. 13C NMR (D2O): d ¼ 25.10
(d, 1JC,P ¼ 141.8 Hz, CH2P), 54.33 [d, 2JC,P ¼ 6.0 Hz, C(2)], 56.11
3
3
(d, JC,P ¼ 6.9 Hz, POCH3), 56.18 (d, JC,P ¼ 6.9 Hz, POCH3), 56.53 [C(6)],
3
58.67 (CH2OH), 70.88 [C(5)], 73.09 [d, JC,P ¼ 11.3 Hz, C(3)], 76.20 [C(4)]
ppm. 31P NMR (D2O): d ¼ 39.11 ppm; MS (MALDI-TOF): m/z 286
[M þ H]þ; C9H20NO7P (285.10): calcd: C, 37.90; H, 7.07, N, 4.91. Found;
C, 38.01; H, 6.84; N, 5.03.

Phosphonate Derivative of 1-Deoxy-L-Idonojirimycin
161
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