Diastereoselective syntheses of 1-deoxyhomonojirimycin and two new 1,5,6-trideoxy-1,5-iminoheptitols with d-allo- and l-talo-configuration

Article abstract of DOI:10.1016/j.tetasy.2006.07.022

The synthesis of 1-deoxyhomonojirimycin 2, as well as two new diastereomers, namely 1,5,6-trideoxy-1,5-imino-d-allo-heptitol 3 and 1,5,6-trideoxy-1,5-imino-l-talo-heptitol 4, is described. Compound 2 was obtained from 1,2:5,6-di-O-isopropylidene-α-d-gluco

Full text of DOI:10.1016/j.tetasy.2006.07.022

Tetrahedron: Asymmetry 17 (2006) 2006–2014
Diastereoselective syntheses of 1-deoxyhomonojirimycin
and two new 1,5,6-trideoxy-1,5-iminoheptitols
with D-allo- and L-talo-configuration
*
´
Geraldine Le Bouc, Christine Thomassigny and Christine Greck
Universite´ de Versailles St-Quentin-en-Yvelines, Institut Lavoisier de Versailles-UMR CNRS 8180, 45 Av. des Etats Unis,
78035 Versailles Cedex, France
Received 7 June 2006; accepted 19 July 2006
Abstract—The synthesis of 1-deoxyhomonojirimycin 2, as well as two new diastereomers, namely 1,5,6-trideoxy-1,5-imino-D-allo-hepti-
tol 3 and 1,5,6-trideoxy-1,5-imino-L-talo-heptitol 4, is described. Compound 2 was obtained from 1,2:5,6-di-O-isopropylidene-a-D-gluco-
furanose—while 3 and 4 were obtained from 1,2:5,6-di-O-isopropylidene-a-D-allofuranose. These compounds were transformed in a few
steps to the corresponding b-ketoesters 12 and 18, respectively, which were hydrogenated diastereoselectively in the presence of chiral
ruthenium complexes with total control of the C-5 stereogenic centre. The resulting b-hydroxyesters 13, 19a and 19b are key intermedi-
ates for the syntheses of the 1,5,6-trideoxy-1,5-iminoheptitols 2, 3 and 4, respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
heptitols with L-ido,8a–e,9 D-galacto,10 D-talo and L-allo11
configuration have been reported.
The importance of polyhydroxylated piperidines is mostly
due to their powerful activity as competitive inhibitors of
glycosidases. They have several applications as potential
therapeutics and in agrochemistry, and are notably used
for the treatment of human diseases, such as diabetes, can-
cer or viral infections.1 The number of derivatives prepared
in the literature2 since the elucidation of the structure of the
first natural iminosugar nojirimycin in 19683 is a reflection
of the interest of such compounds. Especially, the inhibi-
tion mechanism is still under study4 and could help to
understand the interactions in the sugar/enzyme complex.5
Several modifications of the natural inhibitors have been
reported and tested in order to examine the structure–activ-
ity relationship. In particular, iminosugars bearing a func-
tionalised chain at the C-5 position have been prepared
over the last few years, such as carbonyl analogues of
1-deoxynojirimycin6 and 1,5-dideoxy-1,5-iminoalditols.7
Several syntheses of the C-6 homologue 2 of the known
1-deoxynojirimycin 1 have been described.8 Biological eval-
uations have shown that the N-hydroxyethyl derivative of 2
is a potent inhibitor towards b-glucosidase and b-galactos-
idase.8e Preparations of other 1,5,6-trideoxy-1,5-imino-
In a previous report, we proposed the obtention of 1-deoxy-
homonojirimycin 2 from the b-ketoester 7.8f Herein we
report, the total synthesis of compound 2 from 1,2:5,6-di-
O-isopropylidene-a-D-glucofuranose 8 and the first diaste-
reoselective syntheses of 1-deoxyhomoiminosugars 3 and
4 with D-allo and L-talo configuration, respectively, from
1,2:5,6-di-O-isopropylidene-a-D-allofuranose 9 (Scheme 1).
H
N
H
N
HO
HO
HO
HO
OH
OH
OH
OH
OH
1
2
H
H
N
HO
N
HO
HO
OH
HO
OH
OH
4
3
Scheme 1.
*
The configuration of every asymmetric carbon atom is
central to the activity of the inhibitor. In particular, the
Corresponding author. Tel.: +33 1392 54474; fax: +33 1392 54452;
e-mail: greck@chimie.uvsq.fr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.022

G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
2007
three contiguous centres C-2, C-3 and C-4 of the homoimi-
nosugars could be obtained from the parent carbohydrate
derivative. The 1,5,6-trideoxy-1,5-iminoheptitols 2, 3 and
4 could be obtained by the cyclisation of azide 5 by acidic
hydrolysis and reductive amination.8fAzide 5 could be
obtained from alcohol 6 via an activation–nucleophilic
substitution with inversion of configuration. The ester
function of 6 is a precursor of the primary alcohol of 5.
The control of the C-5 hydroxylated stereogenic centre is
essential, in the way that it will induce the stereochemistry
of the C-5 carbon atom of the piperidine ring. b-Ketoester
7 bearing a furanose moiety is a direct precursor of
b-hydroxyester 6, which could be obtained as a single dia-
stereomer by hydrogenation in the presence of a chiral
ruthenium catalyst.12 Compound 7 can be derived from
the protected furanoses 8 or 9 (Scheme 2).
silylation of the primary alcohol function of 14 with tert-
butyldiphenylsilyl chloride in pyridine in the presence of
4-dimethylaminopyridine as a catalyst, led to silyl ether
15 in 68% yield while the starting material was recovered
in 26% yield. The secondary alcohol at C-5 was then acti-
vated as the corresponding methyl sulfonate ester, which
was too unstable to be purified and hence was used as
the crude product for the next step. Nucleophilic displace-
ment with sodium azide led to azide 16 with inversion of
configuration at the C-5 stereogenic centre, giving the
(5R) diastereomer. Tentative hydrolysis of 16 in a mixture
of TFA–H2O (3/2), followed by hydrogenolysis at 5 or
10 atm did not lead to the corresponding piperidine. Prior
treatment with tetrabutylammonium fluoride, in order to
remove the silyl groups, was necessary. Acidic treatment
of the obtained diol followed by the action of hydrogen
at room temperature and under atmospheric pressure in
the presence of platinum oxide led to a crude product
whose further purification over Amberlyst A-26 (OHꢀ)
exchange resin afforded 1-deoxyhomonojirimycin 2 in
75% yield for the three steps. The structure of the
homologated iminosugar was confirmed by the transfor-
mation into its hydrochloride form by treatment with a
methanolic solution of chlorhydric acid, and then compar-
ison with the NMR data and specific rotation given in the
literature.8a
2. Results and discussion
The synthesis of 1-deoxyhomonojirimycin 2 was developed
using diol 10 as the starting material (Scheme 3). Com-
pound 10 was obtained in two steps from 1,2:5,6-di-O-iso-
propylidene-a-D-glucofuranose 8 by protection of the
hydroxyl function as a tert-butyldimethylsilyl ether and
selective deprotection of the cyclic ketal at the 5,6-posi-
tion.13 Metaperiodate oxidation of 10 led to the corre-
sponding aldehyde, which was not isolated, and was
directly oxidised into carboxylic acid 11. Treatment of 11
with carbonyl diimidazole and with the magnesium salt
of monomethylmalonate, using the Masamune proce-
dure,14 afforded b-ketoester 12 without epimerisation at
C-4. Hydrogenation of 12 at an atmospheric pressure, in
the presence of the (R)-BinapRuBr2 catalyst15 gave
(5S)-hydroxy derivative 13 in 99% yield. We have previ-
ously described the important role played by the tert-butyl-
dimethylsilyl protecting group at C-3 leading to an
excellent diastereomeric excess higher than 99% in favour
of the (5S) diastereomer.12
Following a similar synthetic route, the ribosyl acid 17,
derived from commercial 1,2:5,6-di-O-isopropylidene-a-D-
allofuranose 9 in four steps,16 was used as starting material
for the preparation of piperidines 3 and 4. The Masamune
protocol was applied to this acid and the formation of the
b-ketoester 18 with a yield of 58% was allowed. Catalytic
hydrogenations under an atmospheric pressure allowed us
to obtain the two b-hydroxyester epimers at C-5 in good
yields: the use of the (R)-BinapRuBr2 complex gave 19a
in excellent diastereoisomeric excess (>99%), whereas the
use of the enantiomeric catalyst (S)-BinapRuBr2 produced
19b with 99% de (Scheme 4).
Reduction of the ester functionality in 13 with lithium alu-
minium hydride in tetrahydrofuran, led to diol 14 in 66%
yield. A side product corresponding to the cleavage of
the silyl ether at C-3 was identified in low yield. Selective
No substrate induction operated in this case, contrary to
what we had observed for the hydrogenation of 14, when
the C-3 tert-butyldimethylsilyl ether and the b-ketoester
side chain were in a cis relationship.
H
N
N
3 H
OH
H
HO
O
O
HO
O
MeO2C
O
HO
OH
O
HO
OH
O
HO
5
6
O
O
H
H
O
O
O
MeO2C
O
O
O
O
HO
HO
7
8 : D-gluco configuration
9 : D-allo configuration
Scheme 2. Retrosynthetic analysis of piperidines 2–4.

2008
G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
OH
H
HO
O
O
HO2C
O
O
ii)
i)
O
O
O
TBDMSO
TBDMSO
10
11
OH
O
H
H
O
MeO2C
MeO2C
O
O
iii)
iv)
O
O
TBDMSO
TBDMSO
N
12
13
OH
H
3 H
O
O
TBDPSO
O
RO
O
vi)
vii)
2
O
O
TBDMSO
TBDMSO
v)
14 R=H
15 R=TBDPS
16
Scheme 3. Reagents and conditions: (i) NaIO4, H2O/EtOH, 16 h, rt then CrO3, H2SO4, 16 h, rt, 77%; (iv) Im2CO, THF, 8 h, rt then (MeO2C–CH2–CO2–)2-
Mg2+, 24 h, rt, 51%; (iii) H2, [(R)-BinapRuBr2], 1 atm, 24 h, 40 ꢁC, 99%, de >99%; (iv) 5.0 equiv LiAlH4, THF, 2 h, rt, 66%; (v) 2.0 equiv TBDPSCl, 4-
DMAP, py, 12 h, rt, 68%; (vi) (a) MsCl, DCM/py, 3 h, 45 ꢁC, 100%; (b) NaN3, DMF, 12 h, 130 ꢁC, 77%; (vii) (a) TBAF, THF, 1 h, rt; (b) TFA, H2O, 2 h,
rt; (c) H2, PtO2, 1 atm, 12 h, rt; (d) Amberlyst A-26 (OHꢀ); 75%.
OH
H
O
MeO2C
O
O
H
ii)
O
BnO
19a
OH
O
O
MeO2C
HO2C
O
O
i)
O
O
BnO
BnO
iii)
17
H
18
O
MeO2C
O
O
BnO
19b
Scheme 4. Reagents and conditions: (i) Im2CO, THF, 16 h, rt then (MeO2C–CH2–CO2–)2Mg2+, 24 h, rt, 58%; (ii) H2, [(R)-BinapRuBr2], 1 atm, 24 h,
45 ꢁC, 88%, de >99%; (iii) H2, [(S)-BinapRuBr2], 1 atm, 24 h, 45 ꢁC, 80%, de >99%.
Two diastereomers 19a and 19b have been used separately
for the transformation into iminosugars derivatives 3 and
4, respectively (Scheme 5). Reduction in the presence of
1.5 equiv of lithium aluminium hydride led to diols 20a
or 20b, whose primary alcohol function was selectively pro-
tected as a triisopropylsilyl ether. Activation of the remain-
ing hydroxyl with methanesulfonyl chloride gave 22a or
22b, both stable enough to be isolated as oily compounds.
These sulfonates have been used directly in the substitution
step, leading to the azides 23a or 23b, respectively, with
inversion of configuration at the C-5 centres. As the preli-
minary attempts at direct cyclisation of 23 have failed, we
decided to remove first the triisopropylsilyl ether. Treat-
ment of 23a with tetrabutylammonium fluoride led to alco-
hol 24a in 80% yield. In our first attempt, the hydrolysis of
the isopropylidene acetal of 24a was run in aqueous TFA
and the reaction mixture containing the hemiacetal was
directly subjected to hydrogenation using platinum oxide.
Under these conditions, reduction of the azide, cleavage
of the benzyl ether and cyclisation occurred simulta-
neously. However the major product isolated was the N-tri-
fluoroacetamide of 3. To avoid its formation, the solvents
of the reaction mixture were evaporated after the acidic
hydrolysis of 24a, while the crude product was treated
under a hydrogen atmosphere in the presence of platinum
oxide at 20 bar. The expected homoiminosugar 3 was
obtained together with a small amount of the C-3 benzyl-
ated piperidine. The crude mixture was hydrogenolysed
in the presence of catalytic palladium on carbon under
acidic conditions. The purification over Amberlyst A-26
(OHꢀ) gave the iminosugar derivative 3, via alcohol 24a.
The application of a similar method to 23b produced
homoiminosugar 4, through a transformation to the
alcohol 24b.

G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
R1
2009
R2
R1
R2
H
H
O
O
19a
or 19b
ii)
i)
HO
O
TIPSO
O
O
O
BnO
20a
BnO
R1= OH, R2=H
R1= H, R2=OH
R1= OH, R2=H
b R1= H, R2=OH
21a
b
iii)
iv)
22a R1= OMs, R2=H
b R1= H, R2=OMs
23a R1= H, R2=N3
R1= N3, R2=H
b
N3
H
O
H
HO
N
vi)
v)
HO
O
23a
HO
OH
O
BnO
OH
24a
3
N3
H
N
H
O
HO
vi)
v)
HO
O
23b
HO
OH
O
BnO
OH
24b
4
Scheme 5. Reagents and conditions: (i) 1.5 equiv LiAlH4, THF, 1 h, 0 ꢁC to rt, 20a: 92%, 20b: 78%; (ii) 1.2 equiv TIPSCl, Im., DMF, 1 h, rt, 21a: 90%,
21b: 85%; (iii) MsCl, DCM/py, 2.5 h, 45 ꢁC, 22a: 92%, 22b: 73%; (iv) NaN3, DMF, 3 h, 110 ꢁC, 23a: 77%, 23b: 76%; TBAF, THF, 1 h 30 min, rt, 24a: 80%,
24b: 100%; (vi) (a) TFA, H2O, 2 h, 40 ꢁC; (b) H2, PtO2, 20 bar, 12 h, rt; (c) H2, Pd/C, 5 bar, 24 h, rt; (d) Amberlyst A-26 (OHꢀ); 3: 80%, 4: 51%.
The structures of iminosugars 3 and 4 have been confirmed
by transformation into their hydrochloride forms by treat-
ment with a methanolic solution of hydrochloride acid, and
then comparison with the NMR data and specific rotation
given in the literature.11
polarimeter (1 dm cell). NMR spectra were recorded on a
Brucker AC 200 or Avance 300 apparatus with chemical
shift values (d) in parts per million downfield from tetra-
methylsilane. Microanalyses were performed by the Service
de Microanalyse of University Pierre et Marie Curie, Paris,
France or by the ICSN, Gif-sur-Yvette, France.
3. Conclusion
4.2. 3-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-a-D-
xylo-furanuronic acid 11
In conclusion, we have prepared homologated 1-deoxyno-
jirimycin 2 from the protected a-D-xylo-furanuronic acid
11 in 10 steps with an overall yield of 13%, and the two
A solution of imidazole (3.5 g) in dry DMF (30 mL) was
added to commercial 1,2:5,6-di-O-isopropylidene-a-D-glu-
cofuranose (5.0 g, 19.2 mmol). tert-Butyldimethylsilyl chlo-
ride (3.5 g, 23.0 mmol) was then added. The reaction
mixture was stirred under argon for 16 h. The reaction
was diluted with water (10 mL) and extracted with Et2O
(5 · 8 mL). The organic layer was washed with brine, dried
over MgSO4, filtered and the solvents were evaporated.
Purification by column chromatography (SiO2, AcOEt/
pentane 3:7) gave the silylated intermediate (7.0 g, 98%)
1,5,6-trideoxy-1,5-iminoheptitols
3
and
4
from the
protected a-D-ribo-furanuronic acid 17, with overall yields
of 19% and 9%, respectively. In particular, the catalytic
hydrogenation of b-ketoesters bearing sugar moieties, led
to the corresponding b-hydroxyesters with excellent diaste-
reoselectivities, allowing the control of the configuration at
C-5 of the homoiminosugars.
whose NMR data were similar with those of the litera-
25
4. Experimental
4.1. General
ture;13a ½aꢁD ¼ ꢀ17 (c 1.3, DCM). This intermediate was
retaken with an aqueous solution of AcOH (80%,
100 mL). The mixture was stirred for 16 h at room temper-
ature. The solvent was then removed. Purification by col-
umn chromatography (SiO2, AcOEt/pentane 3:7) gave 10
Solvents were distilled according to Ref. 17. The bis-(2-
methylallyl)-cycloocta-1,5-diene–ruthenium(II)
complex
(5.1 g, 81%) whose NMR data are similar to those in the
25
and (R)-2,20-bis(diphenylphosphino)-1,10-binaphthyl are
from Acros. Flash chromatography was performed on
silica gel chromagel 60 ACC 35–70 lm. Analytical TLC:
aluminium-backed silica gel Merck 60 F254. Optical
rotations were measured at 25 ꢁC on a Perkin–Elmer 241
literature;13b ½aꢁD ¼ ꢀ19 (c 1.0, DCM).
A solution of NaIO4 (13.0 g, 60.8 mmol) in H2O/EtOH
(170 mL/85 mL) was added dropwise to a solution of 10
(15.5 g, 46.4 mmol) in H2O (44 mL). The reaction mixture

2010
G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
was stirred at room temperature for 16 h. The solvents
were then evaporated. The crude aldehyde was obtained
as a white oil and then dissolved in acetone (345 mL).
The solution was then cooled to 0 ꢁC. Jones reagent, pre-
pared with CrO3 (7.1 g, 71.1 mmol) in H2O (19 mL) and
H2SO4 95% (6.4 mL), was added dropwise to the solution.
The reaction mixture was stirred at room temperature for
16 h. Isopropanol (16 mL) was then added. The solution
was filtered and neutralised by the addition of a saturated
aqueous solution of NaHCO3 (150 mL). The solvents were
then evaporated. The aqueous layer was washed with
AcOEt (50 mL), acidified to pH 1 with an aqueous solution
of HCl (2 M, 70 mL) and extracted with AcOEt
(2 · 100 mL, 4 · 50 mL). The combined organic layers
were dried over MgSO4, filtered and the solvents evapo-
diene–ruthenium(II) complex (0.02 equiv, 1.6 mg) and
(R)-2,20-bis(diphenylphosphino)-1,10-binaphthyl (0.02 equiv,
3.4 mg) in degassed acetone (0.3 mL) was added a methan-
olic solution of hydrogen bromide (0.15–0.18 M,
0.04 equiv). The reaction mixture was stirred for 1 h. The
solvents were evaporated and the b-ketoester 12 (100 mg,
0.3 mmol) in freshly distilled degassed MeOH (0.6 mL)
cannulated to the catalyst. The reaction mixture was stirred
for 24 h at 40 ꢁC under a hydrogen atmosphere. The sol-
vents were evaporated and a purification by column chro-
matography (SiO2, Et2O/pentane 1:3) gave 13 (100 mg,
25
99%, de >99%); ½aꢁD ¼ ꢀ18 (c 1.6, DCM); 1H NMR
(200 MHz, CDCl3): d = 0.14 (s, 3H, Me), 0.17 (s, 3H,
Me), 0.90 (s, 9H, tBu), 1.32 (s, 3H, Me), 1.47 (s, 3H,
Me), 2.60 (m, 2H, H-6 and H-60), 3.26 (d, 1H,
J = 2.3 Hz, OH), 3.70 (s, 3H, COOMe), 4.12 (dd, 1H,
J = 6.9 and 4.9 Hz, H-4), 4.26 (d, 1H, J = 4.9 Hz, H-3),
4.37 (m, 2H, H-2 and H-5), 5.97 (d, 1H, J = 5.3 Hz,
H-1); 13C NMR (50 MHz, CDCl3): d = ꢀ5.19 (SiMe),
ꢀ4.52 (SiMe), 17.80 (CMe3), 25.57, 26.44, 26.92 (CMe2
and CMe3), 38.05 (C-6), 51.71 (OMe), 67.10 (C-5), 77.63
(C-3), 81.56 (C-4), 85.86 (C-2), 104.74 (C-1), 111.99
(CMe2), 171.76 (CO). Anal. Calcd for C17H32O7Si: C,
54.23; H, 8.57. Found: C, 54.14; H, 8.67.
rated. Purification by column chromatography (SiO2,
25
AcOEt/pentane 3:7) gave 11 (11.3 g, 77%); ½aꢁD ¼ ꢀ48 (c
0.8, DCM); 1H NMR (200 MHz, CDCl3): d = 0.08 (s,
3H, Me), 0.12 (s, 3H, Me), 0.86 (s, 9H, tBu), 1.34 (s, 3H,
Me), 1.49 (s, 3H, Me), 4.41 (d, 1H, J = 3.5 Hz, H-2), 4.53
(d, 1H, J = 3.1 Hz, H-3), 4.81 (d, 1H, J = 3.1 Hz, H-4),
6.08 (d, 1H, J = 3.3 Hz, H-1), 7.30–8.20 (broad signal,
1H, OH); 13C NMR (50 MHz, CDCl3): d = ꢀ5.32 (SiMe),
ꢀ4.98 (SiMe), 17.84 (CMe3), 25.48, 26.42, 27.09 (CMe2 and
CMe3), 76.36 (C-3), 81.01 (C-4), 84.87 (C-2), 105.85 (C-1),
113.02 (CMe2), 171.14 (CO). Anal. Calcd for C14H26O6Si:
C, 52.80; H, 8.23. Found: C, 52.68; H, 8.42.
4.5. 3-O-tert-Butyldimethylsilyl-6-deoxy-1,2-O-isopropyl-
idene-b-L-ido-hepto-1,4-furanose 14
4.3. Methyl 3-O-tert-butyldimethylsilyl-6-deoxy-1,2-O-iso-
propylidene-5-oxo-a-D-xylo-heptofuranuronate 12
A solution of LiAlH4 (5.0 equiv, 2.4 mmol, 92 mg) in dry
THF (2.5 mL) was added slowly (period over 5–10 min)
to a mixture of 13 (0.5 mmol, 183 mg) in dry THF
(2.5 mL) at 0 ꢁC under argon. The reaction mixture was
stirred for 2 h at room temperature. MeOH (1 mL) was
added slowly, followed by a saturated aqueous solution
of NH4Cl (10 mL). The crude was extracted with AcOEt
(4 · 5 mL), the organic layer dried over MgSO4, filtered
and the solvents evaporated. Purification by column chro-
Carbonyldiimidazole (9.6 g, 59.3 mmol) was added to a
solution of 11 (15.7 g, 49.4 mmol) in dry THF (330 mL).
The reaction mixture was stirred at room temperature for
8 h. The magnesium salt of monomethylmalonate (14.3 g,
55.4 mmol) was added and the reaction mixture and stirred
over 24 h. The solvents were evaporated and the residue
was treated with an aqueous solution of HCl (2 M) to
obtain pH 1. The aqueous layer was extracted with DCM
(4 · 80 mL). The combined organic layers were washed
with a saturated aqueous solution of NaHCO3, dried over
MgSO4, filtered and the solvents evaporated. Purification
matography (SiO2, Et2O/pentane 3:1) gave diol 14 (111 mg,
25
66%); ½aꢁD ¼ ꢀ28 (c 1.1, DCM); 1H NMR (200 MHz,
CDCl3): d = 0.14 (s, 3H, Me), 0.17 (s, 3H, Me), 0.90 (s,
9H, tBu), 1.32 (s, 3H, Me), 1.49 (s, 3H, Me), 1.80 (m,
2H, H-6 and H-60), 2.69 (broad s, 1H, OH), 3.21 (broad
s, 1H, OH), 3.86 (m, 2H, H-7 and H-70), 4.04 (dd, 1H,
J = 4.8 and 3.0 Hz, H-4), 4.14 (m, 1H, H-5), 4.23 (d, 1H,
J = 3.1 Hz, H-3), 4.38 (d, 1H, J = 3.7 Hz, H-2), 5.97 (d,
1H, J = 3.7 Hz, H-1); 13C NMR (75 MHz, CDCl3):
d = ꢀ4.50 (SiMe), ꢀ4.00 (SiMe), 17.43 (CMe3), 25.20,
25.29, 25.99, 26.49, 29.90 (CMe2 and CMe3), 34.63 (C-6),
60.38 (C-7), 69.56 (C-5), 76.77 (C-3), 82.36 (C-4), 85.33
(C-2), 104.25 (C-1), 111.55 (CMe2). Anal. Calcd for
C16H32O6Si: C, 55.14; H, 9.25. Found: C, 55.23; H, 9.63.
by column chromatography (SiO2, Et2O/pentane 1:5) gave
25
12 as white crystals (9.4 g, 51%); mp 78.5 ꢁC; ½aꢁD ¼ ꢀ104
1
(c 1.4, DCM); H NMR (300 MHz, CDCl3): d = 0.04 (s,
3H, Me), 0.10 (s, 3H, Me), 0.86 (s, 9H, tBu), 1.33 (s, 3H,
Me), 1.47 (s, 3H, Me), 3.47 (d, 1H, J = 17.1 Hz, H-6),
3.72 (s, 3H, COOMe), 3.81 (d, 1H, J = 17.1 Hz, H-60),
4.37 (d, 1H, J = 3.6 Hz, H-2), 4.49 (d, 1H, J = 3.3 Hz, H-
3), 4.63 (d, 1H, J = 3.3 Hz, H-4), 6.06 (d, 1H, J = 3.3 Hz,
H-1); 13C NMR (50 MHz, CDCl3): d = ꢀ5.30 (SiMe),
ꢀ5.16 (SiMe), 17.91 (CMe3), 25.48, 25.62, 26.46, 27.04
(CMe2 and CMe3), 47.70 (C-6), 52.08 (OMe), 77.98 (C-
3), 84.95 (C-2), 85.98 (C-4), 105.97 (C-1), 112.63 (CMe2),
167.52 (COOMe), 202.26 (CO). Anal. Calcd for
C17H30O7Si: C, 54.52; H, 8.07. Found: C, 54.43; H, 8.24.
4.6. 3-O-tert-Butyldimethylsilyl-7-O-tert-butyldiphenylsilyl-
6-deoxy-1,2-O-isopropylidene-b-L-ido-hepto-1,4-furanose 15
tert-Butyldiphenylsilyl chloride (2.0 equiv, 726 lL) and 4-
DMAP (catalytic amount) were added to a solution of 14
(490 mg, 1.4 mmol) in pyridine (10 mL). The reaction mix-
ture was stirred for 3 h under argon. The overall was reta-
ken with water (15 mL) and extracted with Et2O
(4 · 10 mL). The organic layer was washed with an aque-
ous solution of CuSO4 (5%, 3 · 10 mL), water (15 mL),
4.4. Methyl 3-O-tert-butyldimethylsilyl-6-deoxy-1,2-O-iso-
propylidene-b-L-ido-heptofuranuronate 13
The catalyst was prepared under argon according to the
following procedure: To bis-(2-methylallyl)-cycloocta-1,5-

G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
2011
then dried over MgSO4, filtered and the solvents were evap-
orated. A purification by column chromatography (SiO2,
Et2O/pentane 1:4) gave the expected product 15 (560 mg,
mixture was extracted with Et2O (4 · 2 mL). The combined
organic layers were dried over MgSO4, filtered and the sol-
vents were evaporated. Purification by column chromato-
graphy (SiO2, AcOEt) led to the expected diol (121 mg,
88%). This diol (121 mg, 0.46 mmol) was stirred in a solu-
tion of TFA in water (3/2, 5 mL) at 40 ꢁC for 2 h. PtO2
(10.6 mg, 0.046 mmol) was added under hydrogen atmo-
sphere. The reaction was stirred at room temperature for
12 h. The catalyst was filtered over Celite and washed with
MeOH. The solvents were evaporated. The crude product
was dissolved in water (5 mL), washed with DCM (2 mL)
then the solvents were evaporated. Purification over
Amberlyst A-26 (OHꢀ) eluting with an aqueous solution
of NH4OH (2.5%) gave the expected piperidine 2 (70 mg,
75% from 16). The specific rotation was measured on the
68%) and the unreacted starting material (127 mg, 26%);
25
mp 69.3 ꢁC; ½aꢁD ¼ ꢀ18 (c 1.0, DCM); 1H NMR
(200 MHz, CDCl3): d = 0.14 (s, 3H, Me), 0.18 (s, 3H,
Me), 0.91 (s, 9H, tBu), 1.05 (s, 9H, tBu), 1.33 (s, 3H,
Me), 1.49 (s, 3H, Me), 1.82 (m, 2H, H-6 and H-60), 3.30
(s, 1H, OH), 3.87 (m, 2H, H-7 and H-70), 4.09 (m, 1H,
H-4), 4.25 (m, 2H, H-5 and H-3), 4.38 (d, 1H,
J = 5.6 Hz, H-2), 5.99 (d, 1H, J = 5.6 Hz, H-1), 7.38–7.67
(m, 10H, Ar); 13C NMR (50 MHz, CDCl3): d = ꢀ5.11
(SiMe), ꢀ4.52 (SiMe), 17.86 (CMe3), 19.15 (CMe3),
25.65, 26.43, 26.54, 26.82, 26.95 (CMe2 and CMe3), 35.78
(C-6), 60.98 (C-7), 67.62 (C-5), 77.49 (C-3), 82.75 (C-4),
85.90 (C-2), 104.75 (C-1), 111.78 (CMe2), 127.64–133.66
(Ar). Anal. Calcd for C32H50O6Si2: C, 65.49; H, 8.59.
Found: C, 65.67; H, 8.72.
hydrochloride form of the piperidine after treatment with
25
a methanolic solution of HCl; ½aꢁD ¼ þ33 (c 0.8, MeOH)
25
{lit.8a ½aꢁD ¼ þ30 (c 0.55, MeOH)}.
4.7. 5-Azido-3-O-tert-butyldimethylsilyl-7-O-tert-butyldi-
phenylsilyl-5,6-dideoxy-1,2-O-isopropylidene-a-D-gluco-
hepto-1,4-furanose 16
4.9. Methyl 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-5-
oxo-a-D-ribo-heptofuranuronate 18
Compound 17 (10 g, 25.5 mmol) was treated according to
the same procedure as for 12 with a reaction time of 16 h
for the formation of the intermediate acylimidazolide. Puri-
Methanesulfonyl chloride (3.2 mmol, 245 lL) was added to
a solution of 15 (528 mg, 0.9 mmol) in a mixture of pyri-
dine/DCM (1/2, 20 mL). The overall mixture was then
warmed at 45 ꢁC for 3 h. Then a saturated aqueous solu-
tion of NaHCO3 was added until neutrality, and the aque-
ous layer was extracted with Et2O (5 · 15 mL). The organic
layer was washed with an aqueous solution of CuSO4 (5%,
2 · 25 mL), water (30 mL), dried over MgSO4, filtered and
the solvents evaporated. The crude product has been intro-
duced directly into the next step.
fication by column chromatography (SiO2, AcOEt/pentane
25
1:3) gave 18 (5.2 g, 58%) as a colourless oil; ½aꢁD ¼ þ76 (c
1
1.3, DCM); H NMR (300 MHz, CDCl3): d = 1.37 (s, 3H,
CMe2), 1.60 (s, 3H, CMe2), 3.54 (d, 1H, J = 16.2 Hz, H-6),
3.65 (d, 1H, J = 16.2 Hz, H-60), 3.71 (s, 3H, OMe), 3.94
(dd, 1H, J = 4.3 and 8.9 Hz, H-3), 4.53–4.72 (m, 3H, H-
2, H-4, CHHAr), 4.77 (d, 1H, J = 12.1 Hz, CHHAr),
5.79 (d, 1H, J = 3.5 Hz, H-1), 7.3–7.4 (m, 5H, Ar); 13C
NMR (75 MHz, CDCl3): d = 26.57, 26.96 (CMe2), 45.75
(C-6), 52.34 (OMe), 72.48 (CH2Ar), 78.04 (C-2), 79.08
(C-3), 82.58 (C-4), 104.36 (C-1), 113.79 (CMe2), 128.14,
128.51, 136.96 (Ar), 167.40 (C-7), 200.62 (C-5). Anal. Calcd
for C18H22O7: C, 61.71; H, 6.33. Found: C, 61.42; H, 6.26.
The mesylate was retaken in DMF (15 mL) under argon.
Sodium azide (1.2 equiv, 70 mg) was added and the reac-
tion mixture was warmed at 130 ꢁC for 12 h. After cooling,
water (15 mL) was added. The aqueous layer was extracted
with Et2O (4 · 10 mL). The combined organic layers were
dried over MgSO4, filtered and the solvents were evapo-
4.10. Methyl 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-b-L-
talo-heptofuranuronate 19a and methyl 3-O-benzyl-6-deoxy-
1,2-O-isopropylidene-a-D-allo-heptofuranuronate 19b
rated. Purification by column chromatography (SiO2,
25
Et2O/pentane 1:9) gave 16 (424.0 mg, 77%); ½aꢁ ¼ ꢀ6 (c
1.6, DCM); 1H NMR (200 MHz, CDCl3): dD= 0.19 (s,
6H, 2 Me), 0.94 (s, 9H, tBu), 1.06 (s, 9H, tBu), 1.33 (s,
3H, Me), 1.48 (s, 3H, Me), 1.76 (m, 1H, H-6), 2.29 (m,
1H, H-60), 3.85 (m, 4H, H-4, H-5, H-7 and H-70), 4.29
(d, 1H, J = 2.0 Hz, H-3), 4.39 (d, 1H, J = 3.7 Hz, H-2),
5.89 (d, 1H, J = 3.5 Hz, H-1), 7.39–7.70 (m, 10H, Ar);
13C NMR (50 MHz, CDCl3): d = ꢀ5.21 (SiMe), ꢀ4.52
(SiMe), 17.99 (CMe3), 19.15 (CMe3), 25.81, 26.34, 26.79,
26.89 (CMe2 and CMe3), 34.92 (C-6), 55.80 (C-5), 60.16
(C-7), 75.22 (C-3), 82.32 (C-4), 85.11 (C-2), 104.95 (C-1),
111.81 (CMe2), 127.64–135.60 (Ar). Anal. Calcd for
C32H49N3O5Si2: C, 62.81; H, 8.07. Found: C, 62.24; H,
8.30.
Following the procedure described for 12, b-ketoester 18
(100 mg, 0.3 mmol) was reacted with the catalyst prepared
with either (R)-2,20-bis(diphenylphosphino)-1,10-binaph-
thyl or (S)-2,20-bis(diphenylphosphino)-1,10-binaphthyl to
give, respectively, after purification by column chromato-
graphy (SiO2, AcOEt/pentane 1:1), 19a or 19b.
Compound 19a: colourless oil (88 mg, 88%), de >99%;
25
1
½aꢁD ¼ þ72 (c 0.8, DCM); H NMR (200 MHz, CDCl3):
d = 1.36 (s, 3H, CMe2), 1.59 (s, 3H, CMe2), 2.52–2.78
(m, 3H, H-6, H-60, OH), 3.71 (s, 3H, OMe), 3.96 (m, 2H,
H-3, H-4), 4.16 (m, 1H, H-5), 4.59 (m, 2H, H-2, CHHAr),
4.77 (d, 1H, J = 11.8 Hz, CHHAr), 5.75 (d, 1H,
J = 3.6 Hz, H-1), 7.30–7.42 (m, 5H, Ar); 13C NMR
(75 MHz, CDCl3): d = 26.46, 26.79 (CMe2), 38.73 (C-6),
51.80 (OMe), 66.23 (C-5), 72.31 (CH2Ar), 77.28 (C-3),
77.57 (C-2), 80.42 (C-4), 104.19 (C-1), 113.08 (CMe2),
128.01, 128.42, 137.41 (Ar), 172.63 (C-7). Anal. Calcd for
C18H24O7: C, 61.35; H, 6.86. Found: C, 61.38; H, 6.87.
4.8. 1,5,6-Trideoxy-1,5-imino-D-gluco-heptitol 2
Tetra-N-butyl ammonium fluoride (TBAF) 1 M in THF
(1.1 mL) was added to a solution of 16 (329 mg, 0.5 mmol)
in THF (2.3 mL). The reaction mixture was stirred for 1 h.
A saturated aqueous solution of NH4Cl was added and the

2012
G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
Compound 19b: pale yellow oil (80 mg, 80%), de >99%;
argon. Triisopropylsilyl chloride (180.4 mg, 0.9 mmol)
was added. The reaction solution was stirred for 1 h. The
reaction mixture was retaken with water (1 mL) and ex-
tracted with Et2O (3 · 3 mL). The combined organic layers
were washed with brine (3 mL), dried over MgSO4, filtered
and the solvents evaporated. Purification by column chro-
25
1
½aꢁD ¼ þ110 (c 0.6, DCM); H NMR (200 MHz, CDCl3):
d = 1.36 (s, 3H, CMe2), 1.59 (s, 3H, CMe2), 2.56 (m, 2H,
H-6, H-60), 2.79 (br, 1H, OH), 3.70 (s, 3H, OMe), 3.92
(dd, 1H, J = 4.4 and 8.8 Hz, H-3), 4.07 (m, 1H, H-4),
4.34 (m, 1H, H-5), 4.58 (m, 2H, H-2, CHHAr), 4.77 (d,
1H, J = 11.5 Hz, CHHAr), 5.74 (d, 1H, J = 3.7 Hz, H-1),
7.35 (m, 5H, Ar); 13C NMR (75 MHz, CDCl3):
d = 26.60, 26.87 (CMe2), 36.90 (C-6), 51.84 (OMe), 67.34
(C-5), 72.08 (CH2Ar), 77.23 (C-3), 77.67 (C-2), 79.92
(C-4), 104.10 (C-1), 113.11 (CMe2), 128.05, 128.08
128.46, 137.23 (Ar), 172.38 (C-7). Anal. Calcd for
C18H24O7: C, 61.35; H, 6.86. Found: C, 60.93; H, 7.01.
matography (SiO2, Et2O/pentane 1:1) gave 21a as a colour-
25
less oil (337 mg, 90%); ½aꢁD ¼ þ67 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 1.07 (m, 21H, i-Pr3Si), 1.37 (s, 3H,
CMe2), 1.59 (s, 3H, CMe2), 1.76 (m, 1H, H-6), 1.94 (m, 1H,
H-60), 3.02 (br s, 1H, OH), 3.88 (m, 1H, H-7 or H-5), 3.99
(m, 4H, H-3, H-4, H-5 or H-7, H-70), 4.57 (m, 1H, H-2),
4.62 (d, 1H, J = 11.8 Hz, CHHAr), 4.78 (d, 1H,
J = 11.7 Hz, CHHAr), 5.77 (d, 1H, J = 3.8 Hz, H-1), 7.36
(m, 5H, Ar); 13C NMR (75 MHz, CDCl3): d = 11.82
(Si(CHMe2)3), 17.96 (Si(CHMe2)3), 26.57, 26.86 (CMe2),
36.30 (C-6), 62.32 (C-7), 68.80 (C-5), 72.33 (CH2Ar),
77.44 (C-3), 77.64 (C-2), 81.39 (C-4), 104.29 (C-1), 112.88
(CMe2), 127.88, 127.99, 128.38, 137,77 (Ar). Anal. Calcd
for C26H44O6Si: C, 64.96; H, 9.23. Found: C, 64.91; H,
9.21.
4.11. 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-b-L-talo-
hepto-1,4-furanose 20a and 3-O-benzyl-6-deoxy-1,2-O-iso-
propylidene-a-D-allo-hepto-1,4-furanose 20b
A mixture of 19a (1.1 g, 3.1 mmol) in dry THF (16.2 mL)
was slowly added via cannula to a solution of LiAlH4
(176.3 mg, 4.6 mmol) in dry THF (10.5 mL) at 0 ꢁC under
argon. The reaction was stirred for 1 h at room tempera-
ture. The mixture was quenched by dropwise addition of
aqueous solution of HCl (2 M) until neutrality. The crude
product was extracted with DCM (4 · 5 mL). The com-
bined organic layers were washed with brine (5 mL), dried
over MgSO4, filtered and the solvents evaporated. Purifica-
The same procedure with 20b gave 21b as a colourless oil
25
(318 mg, 85%); ½aꢁD ¼ þ64 (c 2.0, DCM); 1H NMR
(200 MHz, CDCl3): d = 1.07 (m, 21H, i-Pr3Si), 1.36 (s,
3H, CMe2), 1.60 (s, 3H, CMe2), 1.77 (m, 2H, H-6, H-60),
3.33 (br s, 1H, OH), 3.95 (m, 4H, H-3, H-4, H-7, H-70),
4.18 (m, 1H, H-5), 4.59 (m, 2H, H-2, CHHAr), 4.77 (d,
1H, J = 11.9 Hz, CHHAr), 5.75 (d, 1H, J = 3.7 Hz, H-1),
7.31–7.35 (m, 5H, Ar); 13C NMR (75 MHz, CDCl3):
d = 11.77 (Si(CHMe2)3), 17.95 (Si(CHMe2)3), 26.63, 26.89
(CMe2), 34.16 (C-6), 62.45 (C-7), 69.88 (C-5), 72.06
(CH2Ar), 76.84 (C-3), 77.91 (C-2), 81.25 (C-4), 104.02 (C-
1), 112.82 (CMe2), 127.87, 128.07, 128.35, 137.65 (Ar).
Anal. Calcd for C26H44O6Si: C, 64.96; H, 9.23. Found:
C, 64.96; H, 9.51.
tion by column chromatography (SiO2, AcOEt) gave 20a as
25
white crystals (924 mg, 92%); mp 104.1 ꢁC; ½aꢁD ¼ þ101
1
(c 0.9, DCM); H NMR (300 MHz, CDCl3): d = 1.37 (s,
3H, CMe2), 1.60 (s, 3H, CMe2), 1.84 (m, 2H, H-6, H-60),
2.22 (br s, 2H, 2OH), 3.87 (m, 4H, H-3, H-5, H-7, H-70),
4.00 (dd, 1H, J = 2.7 and 8.8 Hz, H-4), 4.59 (m, 2H, H-2,
CHHAr), 4.78 (d, 1H, J = 11.9 Hz, CHHAr), 5.75 (d,
1H, J = 3.6 Hz, H-1), 7.32–7.38 (m, 5H, Ar); 13C NMR
(75 MHz, CDCl3): d = 26.55, 26.85 (CMe2), 36.20 (C-6),
60.91 (C-7), 69.46 (C-5), 72.34 (CH2Ar), 77.58, 77.60
(C-2, C-3), 80.98 (C-4), 104.18 (C-1), 113.21 (CMe2),
128.10, 128.49, 137.44 (Ar). Anal. Calcd for C17H24O6:
C, 62.95; H, 7.46. Found: C, 63.15; H, 7.76.
4.13. 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-5-O-
methanesulfonyl-7-O-triisopropylsilyl-b-L-talo-hepto-
1,4-furanose 22a and 3-O-benzyl-6-deoxy-1,2-O-isopropyl-
idene-5-O-methanesulfonyl-7-O-triisopropylsilyl-
a-D-allo-hepto-1,4-furanose 22b
The same procedure with 19b gave 20b: white crystals (783
25
mg, 78%); mp 83.6 ꢁC; ½aꢁD ¼ þ113 (c 1.0, DCM); 1H
NMR (200 MHz, CDCl3): d = 1.35 (s, 3H, CMe2), 1.58
(s, 3H, CMe2), 1.78 (m, 2H, H-6, H-60), 2.84 (br s, 2H,
2OH), 3.78 (dd, 2H, J = 5.3–5.9 Hz, H-7, H-70), 3.94 (dd,
1H, J = 16 Hz, H-3), 4.07 (m, 2H, H-4, H-5), 4.57 (m,
2H, H-2, CHHAr), 4.74 (d, 1H, J = 11.4 Hz, CHHAr),
5.72 (d, 1H, J = 3.5 Hz, H-1), 7.29 (m, 5H, Ar); 13C
NMR (75 MHz, CDCl3): d = 26.60, 26.85 (CMe2), 33.75
(C-6), 61.49 (C-7), 71.00 (C-5), 72.10 (CH2Ar), 77.28
(C-3), 77.68 (C-2), 80.35 (C-4), 104.01 (C-1), 113.15
(CMe2), 128.14, 128.50, 137.20 (Ar). Anal. Calcd for
C17H24O6: C, 62.95; H, 7.46. Found: C, 63.12; H, 7.69.
Methanesulfonyl chloride (0.2 mL, 2.3 mmol) was added to
a solution of 21a or 21b (318.6 mg, 0.7 mmol) in a mixture
of pyridine/DCM (1/2, 14 mL). The reaction mixture was
warmed to 45 ꢁC for 2.5 h for 21a or 1.5 h for 21b. A
saturated aqueous solution of NaHCO3 was added until
neutrality. The overall solution was extracted with Et2O
(4 · 10 mL). The combined organic layers were washed
with an aqueous solution of CuSO4 (5%, 4 · 15 mL), water
(15 mL), dried over MgSO4, filtered and the solvents were
evaporated. Compound 22 (a or b) has been introduced
directly into the next step. Purification by column chroma-
tography (SiO2, DCM) has allowed us to obtain the pure
compounds for analysis.
4.12. 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-7-O-triiso-
propylsilyl-b-L-talo-hepto-1,4-furanose 21a and 3-O-benzyl-
6-deoxy-1,2-O-isopropylidene-7-O-triisopropylsilyl-a-D-allo-
hepto-1,4-furanose 21b
25
Compound 22a: pale yellow oil (341 mg, 92%); ½aꢁD ¼ þ41
1
(c 0.8, DCM); H NMR (300 MHz, CDCl3): d = 1.07 (m,
21H, i-Pr3Si), 1.36 (s, 3H, CMe2), 1.58 (s, 3H, CMe2),
2.08 (m, 2H, H-6, H-60), 3.07 (s, 3H, SO2Me), 3.84 (m,
3H, H-3, H-7, H-70), 4.16 (dd, 1H, J = 3.7 and 8.8 Hz,
A solution of imidazole (142.3 mg, 2.1 mmol) in dry DMF
(1.2 mL) was added to 20a (252.8 mg; 0.8 mmol) under

G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
2013
H-4), 4.57 (m, 1H, J = 3.9–4.1 Hz, H-2), 4.62 (d, 1H,
J = 11.1 Hz, CHHAr), 4.74 (d, 1H, J = 11.1 Hz, CHHAr),
5.06 (m, 1H, H-5), 5.77 (d, 1H, J = 3.6 Hz, H-1), 7.29–7.38
(m, 5H, Ar); 13C NMR (75 MHz, CDCl3): d = 11.93
(Si(CHMe2)3), 17.99 (Si(CHMe2)3), 26.56, 26.88 (CMe2),
34.95 (C-6), 38.62 (SO2Me), 58.9 (C-7), 72.34 (CH2Ar),
77.44 (C-2), 78.41 (C-3), 78.65 (C-5), 79.17 (C-4), 104.05
(C-1), 113.14 (CMe2), 127.97, 128.29, 128.35, 137.38 (Ar).
Anal. Calcd for C27H46O8SSi: C, 58.03; H, 8.30. Found:
C, 58.51; H, 8.13.
CHHAr), 4.78 (d, 1H, J = 12.1 Hz, CHHAr), 5.76 (d,
1H, J = 3.5 Hz, H-1), 7.33–7.39 (m, 5H, Ar); 13C NMR
(75 MHz, CDCl3): d = 11.91 (Si(CHMe2)3), 18.00
(Si(CHMe2)3), 26.52, 26.87 (CMe2), 34.22 (C-6), 57.40
(C-5), 59.56 (C-7), 72.26 (CH2Ar), 76.21 (C-2), 78.26 (C-3),
80.63 (C-4), 104.05 (C-1), 113.15 (CMe2), 127.94, 128.07,
128.48, 137.31 (Ar). Anal. Calcd for C26H43N3O5Si: C,
61.75; H, 8.57. Found: C, 61.59; H, 8.64.
4.15. 5-Azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-
a-D-allo-hepto-1,4-furanose 24a and 5-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene-b-L-talo-hepto-1,4-furanose
24b
25
Compound 22b: pale yellow oil (270 mg, 73%); ½aꢁD ¼ þ61
1
(c 1.7, DCM); H NMR (300 MHz, CDCl3): d = 1.06 (m,
21H, i-Pr3Si), 1.36 (s, 3H, CMe2), 1.59 (s, 3H, CMe2),
2.03 (m, 2H, H-6, H-60), 3.00 (s, 3H, SO2Me), 3.83 (m,
2H, H-7, H-70), 3.99 (dd, 1H, J = 4.4 and 8.8 Hz, H-3),
4.27 (dd, 1H, J = 2.2, 8.8 Hz, H-4), 4.58 (m, 2H, H-2,
CHHAr), 4.75 (d, 1H, J = 11.4 Hz, CHHAr), 5.13 (m,
1H, H-5), 5.73 (d, 1H, J = 3.7 Hz, H-1), 7.29–7.36 (m,
5H, Ar); 13C NMR (75 MHz, CDCl3): d = 11.88
(Si(CHMe2)3), 17.96 (Si(CHMe2)3), 26.57, 26.89 (CMe2),
34.16 (C-6), 38.18 (SO2Me), 59.12 (C-7), 72.14 (CH2Ar),
77.27 (C-3), 77.52 (C-2), 79.05, 79.12 (C-5, C-4), 103.81
(C-1), 113.32 (CMe2), 128.01, 128.43, 137.17 (Ar). Anal.
Calcd for C27H46O8SSi: C, 58.03; H, 8.30. Found: C,
57.94; H, 8.17.
TBAF 1 M in THF (1.2 mL) was added to a solution of
23a or 23b (507.4 mg, 1.0 mmol) in THF (4.4 mL). The
reaction mixture was stirred for 1.5 h. A saturated aqueous
solution of NH4Cl was added until neutrality and the mix-
ture was extracted with Et2O (5 · 10 mL). The combined
organic layers were dried over MgSO4, filtered and the
solvents were evaporated. Purification by column chromato-
graphy (SiO2, Et2O/pentane 3:2) gave 24a or 24b.
25
Compound 24a: 281 mg, 80%; ½aꢁD ¼ þ152 (c 2.1, DCM);
1H NMR (300 MHz, CDCl3): d = 1.37 (s, 3H, CMe2), 1.60
(s, 3H, CMe2), 1.70 (m, 3H, H-6, H-60,OH), 3.76 (m, 2H,
H-7, H-70), 3.93 (dd, 1H, J = 4.3 and 8.6 Hz, H-3), 3.99
(m, 1H, H-5), 4.24 (dd, 1H, J = 3.1 and 8.5 Hz, H-4),
4.57 (d, 1H, J = 11.6 Hz, CHHAr), 4.60 (m, 1H, H-2),
4.76 (d, 1H, J = 11.6 Hz, CHHAr), 5.78 (d, 1H,
J = 3.7 Hz, H-1), 7.34–7.38 (m, 5H, Ar); 13C NMR
(75 MHz, CDCl3): d = 26.62, 26.91 (CMe2), 32.63 (C-6),
59.62 (C-7), 60.10 (C-5), 72.13 (CH2Ar), 77.49 (C-3),
77.69 (C-2), 80.67 (C-4), 103.89 (C-1), 113.24 (CMe2),
128.10, 128.46, 137.15 (Ar). Anal. Calcd for C17H23N3O5:
C, 58.44; H, 6.64; N, 12.03. Found: C, 58.34; H, 6.53; N,
11.92.
4.14. 5-Azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-
7-O-triisopropylsilyl-a-D-allo-hepto-1,4-furanose 23a and 5-
azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-7-O-tri-
isopropylsilyl-b-L-talo-hepto-1,4-furanose 23b
Sodium azide (74.2 mg, 1.1 mmol) was added to a solution
of 22a (177.3 mg, 0.3 mmol) in DMF (5 mL) under argon.
The reaction mixture was warmed to 110 ꢁC for 3 h. After
cooling, water (5 mL) was added. The aqueous layer was
extracted with Et2O (4 · 3 mL). The combined organic
layers were dried over MgSO4, filtered and the solvents
evaporated. Purification by column chromatography
(SiO2, DCM) gave 23a.
25
Compound 24b: 350 mg, 100%; ½aꢁD ¼ þ97 (c 2.0, DCM);
1H NMR (300 MHz, CDCl3): d = 1.37 (s, 3H, CMe2), 1.65
(s, 3H, CMe2), 2.01 (m, 2H, H-6, H-60), 3.57 (m, 1H, H-5),
3.80 (m, 2H, H-7, H-70), 3.87 (dd, 1H, J = 4.2 and 8.8 Hz
H-3), 4.12 (dd, 1H, J = 2.9 and 8.8 Hz, H-4), 4.60 (m,
2H, H-2, CHHAr), 4.79 (d, 1H, J = 11.8 Hz, CHHAr),
5.76 (d, 1H, J = 3.7 Hz, H-1), 7.34 (m, 5H, Ar); 13C
NMR (75 MHz, CDCl3): d = 26.52, 26.87 (CMe2), 33.70
(C-6), 57.84 (C-5), 59.14 (C-7), 72.33 (CH2Ar), 77.30 (C-
2), 78.23 (C-3), 80.34 (C-4), 104.00 (C-1), 113.29 (CMe2),
128.12, 128.21, 128.54, 137.17 (Ar). Anal. Calcd for
C17H23N3O5: C, 58.44; H, 6.64; N, 12.03. Found: C,
58.37; H, 6.62; N, 12.19.
25
Compound 23a: colourless oil (124 mg, 77%); ½aꢁD ¼ þ105
1
(c 1.4, DCM); H NMR (200 MHz, CDCl3): d = 1.07 (m,
21H, i-Pr3Si), 1.37 (s, 3H, CMe2), 1.60 (s, 3H, CMe2),
1.76 (m, 2H, H-6, H-60), 3.80 (m, 2H, H-7, H-70), 3.93
(dd, 1H, J = 4.4 and 8.5 Hz, H-3), 4.11 (m, 1H, H-5),
4.22 (dd, 1H, J = 2.9 and 8.6 Hz, H-4), 4.56 (m, 2H, H-2,
CHHAr), 4.74 (d, 1H, J = 11.6 Hz, CHHAr), 5.78 (d,
1H, J = 3.7 Hz, H-1), 7.37 (m, 5H, Ar); 13C NMR
(75 MHz, CDCl3): d = 11.93 (Si(CHMe2)3), 17.99
(Si(CHMe2)3), 26.65, 26.93 (CMe2), 33.05 (C-6), 59.43
(C-5), 59.54 (C-7), 72.09 (CH2Ar), 77.51 (C-3), 77.83 (C-2),
81.09 (C-4), 103.97 (C-1), 113.14 (CMe2), 128.00, 128.41,
137.36 (Ar). Anal. Calcd for C26H43N3O5Si: C, 61.75; H,
8.57. Found: C, 61.54; H, 8.41.
4.16. 1,5,6-Trideoxy-1,5-imino-D-allo-heptitol 3
Azide 24a (123.3 mg, 0.3 mmol) was stirred for 2 h at 40 ꢁC
in a solution of TFA in water (3/2, 3.8 mL). The solvents
were eliminated and the residue retaken in MeOH
(3.8 mL). PtO2 (8.0 mg, 0.03 mmol) was added and the
reaction mixture hydrogenolysed at room temperature for
12 h to 20 bar. The catalyst was filtered over Celite and
washed with MeOH. The solvents were then evaporated.
The crude was dissolved in EtOH (4 mL). Concentrated
The same procedure with 22b led to 23b: colourless oil
25
(122 mg, 76%); ½aꢁD ¼ þ48 (c 1.1, DCM); 1H NMR
(200 MHz, CDCl3): d = 1.08 (m, 21H, i-Pr3Si), 1.37 (s,
3H, CMe2), 1.59 (s, 3H, CMe2), 1.96 (m, 2H, H-6, H-60),
3.66 (m, 1H, H-5), 3.87 (m, 3H, H-3, H-7,s H-70), 4.09
(dd, 1H, J = 2.6 and 8.8 Hz, H-4), 4.59 (m, 2H, H-2,

2014
G. Le Bouc et al. / Tetrahedron: Asymmetry 17 (2006) 2006–2014
Zhong, Z.; Ichikawa, Y.; Porco, J. A., Jr.; Wong, C.-H. J.
Am. Chem. Soc. 1991, 113, 6187–6196; (i) Jespersen, T. M.;
Bols, M.; Sierks, M. R.; Skrydstrup, T. Tetrahedron 1994, 50,
13449–13460, and references cited therein.
HCl (3.5 mL) and Pd/C (353 mg) were then added. The
mixture was stirred under a hydrogen atmosphere (5 bars)
at room temperature for 24 h. Purification over Amberlyst
A-26 (OHꢀ) eluting with an aqueous solution of NH4OH
(2.5%), gave the expected piperidine 3 (49.9 mg, 80%).
The specific rotation was measured on the hydrochloride
form of the piperidine after treatment with a methanolic
6. (a) Kilonda, A.; Compernolle, F.; Toppet, S.; Hoornaert, G.
J. Tetrahedron Lett. 1994, 35, 9047–9050; (b) Compernolle,
F.; Joly, G.; Peeters, K.; Toppet, S.; Hoornaert, G. Tetra-
hedron 1997, 53, 12739–12754; (c) Shilvock, J. P.; Hsia, K. Y.;
Nash, R. J.; Lloyd, J. D.; Winters, A. L.; Asano, N.; Fleet, G.
W. J. Tetrahedron: Asymmetry 1998, 9, 4157–4164.
7. (a) Rassu, G.; Pinna, L.; Spanu, P.; Culeddu, N.; Casiraghi,
G.; Fava, G. G.; Ferrari, M. B.; Pelosi, G. Tetrahedron 1992,
48, 727–742; (b) Chen, Y.; Vogel, P. J. Org. Chem. 1994, 59,
2487–2496; (c) Baudat, A.; Picasso, S.; Vogel, P. Carbohydr.
Res. 1996, 281, 277–284; (d) Picasso, S.; Chen, Y.; Vogel, P.
Carbohydr. Lett. 1994, 1, 1–8; (e) Lundt, I.; Madsen, R.
Synthesis 1995, 787–794.
25
25
solution of HCl; ½aꢁD ¼ þ19 (c 0.1, MeOH) {lit.11 ½aꢁD
¼
ꢀ18 (c 1.6, MeOH) for its enantiomer}.
4.17. 1,5,6-Trideoxy-1,5-imino-L-talo-heptitol 4
Azide 24b (178.5 mg, 0.5 mmol) was treated as for 24a
to give 4 (46.0 mg, 51%). The specific rotation was mea-
sured on the hydrochloride form of the piperidine after
25
treatment with a methanolic solution of HCl; ½aꢁD ¼ þ24
25
´
´
´
8. (a) Szolcsanyi, P.; Gracza, T.; Koman, M.; Pronayova, N.;
(c 0.6, MeOH) {lit.11 ½aꢁD ¼ ꢀ24:1 (c 0.5, MeOH) for its
Liptaj, T. Tetrahedron: Asymmetry 2000, 11, 2579–2597; (b)
enantiomer}.
´
´
´
Szolcsanyi, P.; Gracza, T.; Koman, M.; Pronayova, N.;
Liptaj, T. Chem. Commun. 2000, 471–472; (c) Saha, N. N.;
Desai, V. N.; Dhavale, D. D. Tetrahedron 2001, 57, 39–46; (d)
Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem.
2001, 66, 1065–1074; (e) Dhavale, D. D.; Matin, M. M.;
Sharma, T.; Sabharwal, S. G. Bioorg. Med. Chem. 2003, 11,
3295–3305; (f) Thomassigny, C.; Barroso, M. T.; Greck, C.
Lett. Org. Chem. 2005, 2, 316–318.
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