Synthesis of intermediates in the formation of hydroxy piperidines and 2-azido lactones from d-erythrose

Article abstract of DOI:10.1016/j.tetasy.2008.02.003

A new stereodivergent synthesis towards piperidine iminosugar and azido lactones is described. The reaction of ethylidene-d-erythrose with amide sulfur ylides gave two isomeric trans-epoxyamides which were converted to 2-azido derivatives. Hydrolysis of the allo isomer gave 2-azido-1,4-lactone while the manno isomer gave the open chain epoxyamide. The latter gave a DMJ derivative in two steps. Direct hydrolysis of ethylidene epoxyamides gave the 3,6-anhydro glyconamides.

Full text of DOI:10.1016/j.tetasy.2008.02.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 721–729
Synthesis of intermediates in the formation of hydroxy piperidines
and 2-azido lactones from D-erythrose
*
´
´
M. Soledad Pino-Gonzalez and Noe Ona
˜
Departamento de Bioquı´mica, Biologı´a Molecular, Inmunologı´a y Quı´mica Orga´nica, Facultad de Ciencias,
Universidad de Ma´laga, 29071 Ma´laga, Spain
Received 24 January 2008; accepted 1 February 2008
Available online 10 March 2008
Abstract—A new stereodivergent synthesis towards piperidine iminosugar and azido lactones is described. The reaction of ethylidene-D-
erythrose with amide sulfur ylides gave two isomeric trans-epoxyamides which were converted to 2-azido derivatives. Hydrolysis of the
allo isomer gave 2-azido-1,4-lactone while the manno isomer gave the open chain epoxyamide. The latter gave a DMJ derivative in two
steps. Direct hydrolysis of ethylidene epoxyamides gave the 3,6-anhydro glyconamides.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
starting from a ribose derivative, which gave an unique
2,3-epoxyamide. Now, our objective is to extend the strat-
egy to different monosaccharides, in order to develop short
and efficient routes to prepare different iminosugars. The
use of a tetrose as a starting material would lead to piper-
idine iminosugars.
Hydroxylated piperidines have attracted increasing interest
as synthetic targets because of their important activity as
medicinally active compounds.1 These carbohydrate mim-
ics are among the most known iminosugars. Deoxyman-
nojirimycin (DMJ) 1, isolated from natural sources,2 has
been shown to inhibit a-L-fucosidase, a-D-mannosidase
and a-D-glucosidase activities,3 and therefore various
methods have been developed to improve its synthesis.4
Later, it has been reported that l-allo-DNJ (l-deoxyallono-
jirimycin) 2 is a better inhibitor than DMJ of both plant
and lysosomal a-mannosidases.5 Although several efficient
syntheses towards these piperidines have been described,
most of them involve long processes.6
2. Results and discussion
Herein we report the synthesis of potential precursors of
DMJ and l-allo-DNJ derivatives. We envisioned a retro-
synthetic strategy whereby the starting monosaccharide
might have the proper configuration in order to obtain
both the D-manno and l-allo piperidine frameworks. Ethyl-
idene-D-erythrose 3 was the monosaccharide derivative
chosen (Scheme 1). The reaction of its epimer, ethylidene
D-threose, with ylide 4 (R = Me) was described to be mod-
erately stereoselective, yielding the two trans-isomers in a
3:2 rate, and (2R,3S) being the configuration of the pre-
dominant isomer.11a,c In a similar way, ethylidene-D-ery-
throse should lead to a mixture of stereoisomers with a
predictable configuration of the predominant (2S,3R)-iso-
mer. Previous configurational studies have been carried
out for other epoxyamides.11a,b,d,e In other cases,11f,g con-
figuration was assigned by comparison with NMR data
of related compounds obtained by Sharpless asymmetric
epoxidation.
On the other hand, 2-azido lactones can have several appli-
cations. They have been shown to be key compounds in the
synthesis of pyrrolidine iminosugars.7 Some of these
hydroxylated pyrrolidines showed selective inhibition of
glycosidases.8 In addition, 2-azido lactones are masked
amino acids and can be useful for novel amino acid prepa-
ration.9a Finally, they may be related to 2-azido monosac-
charides, which allow greater selectivity for glycosylation
reactions.9b
In previous papers,10 we have described a methodology to
synthesize iminosugar derivatives with different ring sizes
Ethylidene D-erythrose 3, obtained by periodate oxidation
of ethylidene D-glucose 5,12 was converted by the
*
Corresponding author. E-mail: pino@uma.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.003

722
M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
H
N
H
N
HO
HO
OH
OH
HO
HO
OH
OH
2
1
R´´O
R´O
R´´O
R´O
OR´
N3
OR´
N3
R´O
R´O
CONR2
CONR2
R´O
R´O
R´O
R´O
OR´
OR´
S
R
R
S
O
O
CONR2
CONR2
Me2S=CHCONR2
+
4
O
OH
O
CHO
3
Scheme 1. Retrosynthetic scheme for preparing piperidine iminosugars.
corresponding sulfur ylides (R = Et, Bn), generated in situ,
in the trans epoxides 6a,b and 7a,b, respectively, in a 3:2
rate (a:b, approximately by 1H NMR), (Scheme 2).
Whereas in the case of R = Et, the isomers could not be
separated, for R = Bn column chromatography allowed
us to isolate both isomers 7a and 7b. A similar isomer ratio
was obtained for R = Me. In order to have a separate
configurational assignment, we hydrolyzed the mixture of
stereoisomers 6a,b with periodic oxidation in water. The
resulting mixture gave a negative rotatory power,11d reveal-
ing the configuration of the predominant epoxyamide as
(2S,3R)-6a. Configurational determination of these struc-
tures is described in the text by chemical transformations.
The best results in the epoxide opening of 6a,b were ob-
tained with sodium azide in DMF, with catalytic AcOH,
to regioselectively give the 2-azido derivatives 8a and 8b.
Other attempts were made with NaN3/MgSO4/MeOH,
but reaction times were longer and mixtures with the 3-
azido isomers were obtained.
With the appropriate stereoisomers 8 in hand, the next step
was to find adequate protection. Diols 8a and 8b were benz-
ylated to give 9a and 9b. However hydrolysis of the ethyl-
idene group of 9a and 9b, with AcOH or TFA, did not give
the desired acyclic products in appreciable yield. Under
mild conditions, the starting material was recovered. A bet-
ter result was observed with AmberlystÒ 15 in methanol
(40–60 °C), although the open chain product 11 could only
be isolated from isomer 9b. Hydrolysis of 9a under analo-
gous conditions gave lactone 10. At rt, hydrolysis was
incomplete and product 9a was recovered.
OH
OH
O
O
O
The different behaviour of isomers 9a and 9b in the hydro-
lysis can be explained by the high steric hindrance that the
manno isomer presents in the transition state towards the
lactone. The cyclization is avoided by nearby groups with
a cis relationship.
OH
5
NaIO4,
NaOH, H2O
3
The acyclic compound 11 was treated with tosyl chloride to
give tosylated 12. Hydrogenation of the azido group in 12,
with subsequent cyclization, allowed us to obtain a piperi-
dine amide derivative 13. The NMR data of 13 showed val-
ues in accordance with a DMJ derivative. The large value
of J4,3 = J4,5 = 9.1 Hz, clearly requires the trans-diaxial
relationship of these protons,13 thus indicating the 4C1 con-
formation and confirming the D-manno configuration.
These results are in agreement with the conformational
analysis carried out by computational molecular modelling
Me2SCH2CONR2. Cl,
50% aq. NaOH
O
O
O
OH
OH
O
+
S
R
S
R
3:2
O
O
CONR2
CONR2
6a R = Et
7a R = Bn
6b R = Et
7b R = Bn
Scheme 2. Synthesis of ethylidene-D-erythrose 3 and trans-epoxyamides.

M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
723
similar to the experimental values. Consequently, there is
no doubt about the configurational assignment.
Reduction of the amide group with Super-HydrideÒ gave
2,4-di-O-benzyl-1-deoxymannojirimycin 14 (Scheme 3).
In order to study the influence of the neighbouring groups
in the hydrolysis of the acetal, we prepared the acetyl deriv-
atives 16a and 16b (Scheme 4). The results were analogous
to those of the benzylated products 9a and 9b. The acetyl-
ated compound 16a, after treatment with Amberlyst 15 in
MeOH at 50–60 °C, gave lactone 17. Under the same con-
ditions, compound 16b gave tetrol 18 (Scheme 4).
The formation of the deprotected lactone 17 allowed us to
test the absolute configuration of the isomers obtained. The
mixture of isomers 7a,b could lead to lactones with D-allo
or D-manno configuration. The known 2-azido-2-deoxy-
D-mannono-1,4-lactone8b showed a positive specific rota-
tion and different NMR data15 (J3,4 = 2.8 and J4,5
=
9.4 Hz, manno), to those obtained by us [J3,4 = 0 (anti)
and J4,5 = 4.8 Hz] besides negative specific rotation. Thus,
lactone 17 formed from 16a should have the allo
configuration.
At first, experiments were performed with mixtures of iso-
mers (a,b) in higher amounts, but the polarities of the iso-
meric products were sometimes inverted in relation to the
starting isomers, thus complicating the isolation and char-
acterization of these compounds. In order to correlate each
isomer with its product, reactions had to be repeated with
each isomer separately.
Figure 1. Preferred conformation of compound 13.
as can be seen in Figure 1.14 The theoretical coupling con-
stants, obtained by molecular modelling calculations, are
HO
O
OR
O
BnO
O
Amberlyst®15
MeOH, 50 ºC
N3
O
RO
CONEt2
BnO
N3
NaN3
8a: R = H
BnBr, TBAI
NaH
10
6a,b
AcOH
9a: R = Bn
DMF
Δ
RO
HO
O
OBn
N3
OR
N3
Amberlyst®15
MeOH, 50 ºC
O
BnO
RO
CONEt2
CONEt2
8b: R = H
11: R = H
TsCl
CH2Cl2, py
BnBr, TBAI
NaH
12: R = Ts
9b: R = Bn
H2, Pd/C
MeOH
60 psi
H
H
N
Et2NOC
BnO
N
HO
Super-H®
(1M, THF)
BnO
OBn
OBn
OH
OH
14
13
Scheme 3. Synthesis of azido lactone 10 and 2,4-di-O-benzyl-1-deoxymannojirimicyn 14.

724
M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
Scheme 4. Synthesis of azido lactone 17 and azido tetrol 18.
An alternative route involved the deprotection of the acetal
before epoxide opening. Epoxides 7a,b were benzylated
and the new products 19a,b treated with acid resin. How-
ever, acetal hydrolysis of 19a,b gave subsequent cyclization
through intramolecular epoxide opening. Thus, 3,6-anhy-
dro derivatives 20a,b were obtained, after purification, in
approximately 5:3 ratio (1H NMR), (Scheme 5). Acetyl-
ation of 20a,b gave two isomers 21a and 21b which could
be separated by column chromatography and identified,
the more polar isomer being the predominant product. If
we assume the predominant absolute configuration in the
starting epoxyamides mixture 7a,b, as 2S,3R, and consider
the regioselective and stereospecific cyclization processes,
we must assign the a configuration to the more polar prod-
uct. In fact, 19a showed J3,4 = 3.76 and J4,5 = 4.30, com-
patible values for an a-configuration, compared with
other analogous products.11c,16
The definitive confirmation of the structures 21a and 21b
was given by their hydrolysis using TFA–H2O (2:1). The
a-compound was the one that could lactonize to give bicy-
clic 22, while the b-isomer, under the same conditions gave
the deacetylated 20b. 13C NMR data of 22 were compared
with that of the known debenzylated compound,17 confirm-
ing the a-configuration.
3. Conclusion
In conclusion, we have developed a new synthesis of 2,4-di-
O-benzyl-1-deoxymannojirimycin 14 from an inexpensive
starting material. In addition, we have obtained new a-azi-
do lactones 10 and 17, which can be converted into other
glycosidase inhibitors or novel amino acids. Structural
assignments have been verified by NMR data with bidi-
mensional experiments, and by chemical transformations
to give products with verifiable stereochemistry. We are
currently developing other routes, with different protecting
groups, in order to increase the yields and obtain the D-allo
piperidine derivatives.
4. Experimental
4.1. General
Reactions were monitored by thin layer chromatography
(TLC) on E. Merck Silica Gel plates (0.25 mm) and
visualized using UV light (254 nm) and/or heating with
7% ethanolic phosphomolybdic acid solution. Flash
chromatography was performed on E. Merck Silica Gel
(60, particle size 0.040–0.063 mm). NMR spectra were
recorded on a Bruker Avance-400 or WP200SY spec-
trometers at room temperature. Chemical shifts (ppm)
are reported relative to the residual solvent peak. Multiplic-
Scheme 5. Hydrolysis of ethylidene epoxyamides 19a,b and structural
confirmation of the predominant isomer.

M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
725
ities are designated as singlet (s), doublet (d), triplet (t) and
multiplet (m). Coupling constants J are expressed in Hertz
units. Equatorial and axial protons are named as He an Ha.
NMR assignments were undertaken based on two-dimen-
sional COSY and gHMQC experiments. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. High
resolution mass spectra (HRMS) were recorded with a
Micromass AutoSpecQ instrument of the University of
Granada.
d 4.55 (m, 5H, 2CH2–Ph, CHCH3), 4.07 (dd, J5,6e = 5.4,
J6a,6e = 10.4, 1H, H-6e), 3.87 (d, 1H, J2,3 = 2.4, H-2),
3.59 (ddd, J3,4 = 3.7, J5,6a = J4,5 = 10.3, 1H, H-5), 3.50
(dd, 1H, H-3), 3.46 (dd, 1H, H-4), 3.37 (t, 1H, H-6a),
1.29 (d, 3H, CH3). 13C NMR (100 MHz, CDCl3): 168.2
(CO), 126–137 (Ph), 98.6 (CHCH3), 78.0 (C-4), 70.3
(C-6), 63.3 (C-5), 57.8 (C-3), 50.9 (C-2), 49.3 and 48.5
(CH2Ph),20.3 (CHCH3). EM: 292 [Mꢂ91]+, 91 (100%).
HRMS (FAB): [M+H]+ calcd for C22H26NO5, 384.1811;
found, 384.1825.
4.2. 2,3-Anhydro-N,N-diethyl-4,6-O-ethylidene-D-altro-
hexonamide 6a and 2,3-anhydro-N,N-diethyl-4,6-O-ethyl-
idene-D-gluco-hexonamide 6b
4.4. 2-Azido-N,N-diethyl-4,6-O-ethylidene-D-allo-hexon-
amide 8a and 2-azido–N,N-diethyl-4,6-O-ethylidene-D-
manno-hexonamide 8b
To a solution of 3 (960 mg, 6.56 mmol) in dichloromethane
(16 mL) were added the sulfonium salt 4 (R = Et) (1.64 g,
7.74 mmol) and 50% aqueous NaOH (8 mL). The reaction
mixture was stirred at room temperature and monitored by
TLC. After 30 min, water (24 mL) was added and the or-
ganic phase separated. The aqueous phase was extracted
with tert-butylmethyl ether (3 ꢀ 25 mL) and the organic
layers were washed with water, dried over MgSO4 and
evaporated in vacuo to obtain an irresoluble mixture 6a,b
as a white solid (1.44–1.53 g, 85–90%), in a 3:2 isomer ratio
To a solution of the epoxyamide mixture obtained above
6a,b (1.02 g, 3.9 mmol) in DMF (22 mL) were added
NaN3 (0.39 g, 6 mmol) and AcOH (0.26 mL). The reaction
mixture was heated (95 °C) with stirring under argon and
monitored by TLC. After 5 h, the reaction mixture was
eluted with AcOEt and washed with aq NH4Cl and then
with water. The organic layer was dried over MgSO4 and
the solvents were evaporated in vacuo. Purification by col-
umn chromatography gave 425 mg of 8a, 375 mg of 8b and
57 mg of mixtures (72% yield). Compound 8a had Rf 0.7
(AcOEt). 1H NMR (200 MHz, CDCl3): d 4.60 (q, 1H,
CH–CH3), 4.22 and 4.13 (2 dd, 2H, H-3, H-6e), 3.98 (d,
1H, H-2), 3.78 (m, H-5), 3.40 (m, 6H, H-2, H-4, H-6a
and CH2CH3), 1.28 (d, 3H, H–CH3), 1.20 and 1.15 (2t,
2 ꢀ 3H, 2CH2CH3). 13C NMR (50 MHz, CDCl3): d 168.1
(CO), 98.0 (CHCH3), 79.8 (C-4), 75.3 (C-3), 69.4 (C-6),
64.2 (C-5), 54.6 (C-2), 41.8 and 40.4 (NCH2), 20.0
(CHCH3), 13.7 and 12.3 (2CH2CH3). HRMS (FAB):
[M+Na]+ calcd for C12H22N4O5Na, 325.1487; found,
1
(1H NMR). Rf: 0.3 (ethyl acetate) H NMR (400 MHz,
CDCl3) two isomers (a,b): d 4.66 (m, J = 4.8, 2H, 2
OCHCH3), 4.10 (m, J5,6e = 5.4, J6e,6a = 10.7, 2 ꢀ 1H, He-
6a,6b), 3.77 (d, J2,3 = 1.8, 1H, H-2b), 3.74 (d, J2,3 = 2.1,
1H, H-2a), 3.75 and 3.72 (2m, J5,6a = 10.2, 2 ꢀ 1H, H-5a,
b), 3.58–3.30 (m, 2 ꢀ 8H, 4, 3, H-6a, OH and
2 ꢀ 2CH2CH3), 1.25 (at, 2 ꢀ 3H, CHCH3), 1.18 (m,
2 ꢀ 3H, 2CH2CH3) and 1.07 (m, 2 ꢀ 3H, 2CH2CH3). 13C
NMR (100 MHz, CDCl3): d 166.6 (CO), 98.7 and 98.6
(CHCH3), 79.3 and 78.3, (C-4b, C-4a), 63.5 and 61.9,
(C-5a, C-5b), 2 ꢀ 70.4 (C-6a, C-6b), 57.4 and 56.8 (C-3a,
C-3b), 50.9 and 50.7 (C-2b, C-2a), 41.6, 41.5, 40.7 and
40.7 (CH2CH3) 20.3 (CHCH3), 14.5, 14.5, 12.8 and 12.7
(CH2CH3). HRMS (FAB): [M+H]+ calcd for
C12H22NO5, 260.1499; found, 260.1505.
1
325.1489. Compound 8b had Rf 0.5 (AcOEt). H NMR
(200 MHz, CDCl3): d 4.62 (q, 1H, CH–CH3), 4.32 (d,
1H, H-3), 4.10 (d + m, 2H, H-2 and H-6e), 3.82 (m, 1H,
H-5), 3.35 (m, 6H, H-4, H-6a and 2CH2CH3), 1.22 (d,
3H, CH–CH3), 1.12 and 1.03 (2t, 2 ꢀ 3H, 2CH2CH3).
13C NMR (50 MHz, CDCl3): d 168.7 (CO), 98.7 (CHCH3),
79.7 (C-4), 70.2 (C-6), 68.0 (C-3), 59.7 (C-5), 56.7 (C-2),
42.3 and 41.1 (NCH2), 20.0 (CHCH3), 14.1 and 12.5
(2CH2CH3). HRMS (FAB): [M+Na]+ calcd for
C12H22N4O5Na, 325.1487; found, 325.1490.
4.3. 2,3-Anhydro-N,N-dibenzyl-4,6-O-ethylidene-D-altro-
hexonamide 7a and 2,3-anhydro-N,N-dibenzyl-4,6-O-ethyl-
idene-D-gluco-hexonamide 7b
The same procedure performed to obtain compound 6a,b
was followed with 3 (796 mg, 5.45 mmol) and 4 (R = Bn)
(2.20 g, 6.55 mmol), obtaining 7a,b as a white solid
(1.77 g, 85%), in a 3:2 isomer relation (1H NMR). A small
portion was purified by column chromatography at atmo-
spheric pressure to give the two pure isomers. Compound
4.5. 2-Azido-3,5-di-O-benzyl-N,N-diethyl-4,6-O-ethylidene-
D-allo-hexonamide 9a and 2-azido-3,5-di-O-benzyl-N,N-
diethyl-4,6-O-ethylidene-D-manno-hexonamide 9b
To a solution of 8a (250 mg, 0.82 mmol) in THF (8 mL),
with stirring at 0 °C, were added 66 mg of 60% NaH (min-
eral oil), 0.2 mL of BnBr and 30 mg of tetrabutyl ammo-
nium iodide. The reaction was monitored by TLC (1:1,
hexane/ethyl acetate) and left for 34 h at rt. Then, solvents
were evaporated and the residue was extracted with dichlo-
romethane. The solution was washed with aq 5% NaOH
and water, dried over MgSO4 and concentrated giving a
residue which was purified by column chromatography to
give 9a (298 mg, 75%). Rf: 0.7 (2:1, hexane/ethyl acetate).
1H NMR (400 MHz, CDCl3): d 7.10–7.40 (m, 10H, 2Ph),
4.75 (d, 1H, CH2Ph), 4.67 (q, 1H, CHCH3), 4.45–4.60
(m, 3H, CH2Ph), 4.20 (m, 3H), 3.90 (m, 2H), 3.44 (m,
7a: Rf: 0.22 (3:2, hexane/ethyl acetate) mp: 138 °C,
22
½aꢁD ¼ ꢂ0:3 (c 2.25, CH2Cl2). 1H NMR (200 MHz,
CDCl3): d 4.55 (m, 5H, 2CH2–Ph, CH–CH3), 4.10 (dd,
J5,6e = 5.4, J6e,6a = 10.9, 1H, H-6e), 3.89 (d, J2,3 = 2.4,
1H, H-2), 3.78 (ddd, J3,4 = 3.7, J4,5 = 10.3, 1H, H-5),
3.52 (dd, 1H, H-3), 3.32 (t, 1H, H-6a), 3.29 (dd, 1H, H-
4), 1.25 (d, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
168.9 (CO), 126–136 (Ph), 98.6 (CHCH3), 78.4 (C-4), 70.5
(C-6), 61.8 (C-5), 57.3 (C-3), 50.8, (C-2), 49.4 and 48.8
(CH2Ph), 20.3 (CHCH3). EM: 292 [Mꢂ91]+, 91 (100%).
Compound 7b: Rf: 0.16 (3:2, hexane/ethyl acetate).
22
1
½aꢁD ¼ ꢂ0:1 (c 2, CH2Cl2). H NMR (200 MHz, CDCl3):

726
M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
2H, CH2CH3, H-6a), 3.20 (m, 2H, CH2CH3), 2.92 (m, 1H,
CH2CH3), 1.32 (d, 3H, CHCH3), 1.04 (t, 3H, CH2CH3),
0.81 (t, 3H, CH2CH3). 13C NMR (50 MHz, CDCl3): d
168.2 (CO), 127–138 (Ph), 99.7 (CHCH3), 80.2 and 79.9
(C-4, C-3), 74.8 and 71.8 (2CH2Ph), 69.7 and 69.3 (C-5,
C-6), 57.7 (C-2), 42.5 and 41.9 (2CH2CH3), 20.6 (CHCH3),
13.1 and 14.5 (2CH2CH3). HRMS (FAB): [M+Na]+ calcd
for C26H34N4O5Na, 505.2427; found, 505.2432. The same
procedure as described above was used with 8b (400 mg,
1.31 mmol) in THF (13 mL), with the addition of 105 mg
of 60% NaH, 0.32 mL of BnBr and 50 mg of tetrabutyl
ammonium iodide. After 72 h, the reaction mixture was
worked up as above and the product purified by column
chromatography to give 9b (411 mg, 65%). Rf: 0.65 (2:1,
hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3): d
7.10–7.40 (m, 10H, 2Ph), 4.64 (q, 1H, CHCH3), 4.53 (d,
1H, CH2Ph), 4.36 (t, 2H, CH2Ph), 4.1–4.3 (m, 4H, CH2Ph)
3.70 (m, 2 H), 3.6–3.0 (m, 5H, CH2CH3), 1.28 (d, 3H,
CHCH3), 1.10 and 1.02 (2t, 2 ꢀ 3H, CH2CH3). 13C
NMR (100 MHz, CDCl3): d 168.2 (CO), 127–138 (Ph),
99.7 (CHCH3), 78.6 and 76.9 (C-4, C-3), 74.8 and 71.8
(2CH2Ph), 69.6 and 68.5 (C-5, C-6), 56.7 (C-2), 42.5 and
41.9 (CH2CH3), 20.6 (CHCH3), 14.7 and 13.0 (2CH2CH3).
HRMS (FAB): [M+Na]+ calcd for C26H34N4O5Na,
505.2427; found, 505.2433.
4.7. Tosylation of compound 11
A solution of diol 11 (310 mg, 0.68 mmol) in CH2Cl2
(4 mL) with pyridine (0.1 mL) and tosyl chloride (388 mg,
3 mmol) was kept at rt for 1 d, to give compound 12
(333 mg, 80%) after work-up and purification by column
chromatography. Rf: 0.5 (3:2 hexane/ethyl acetate). 1H
NMR (400 MHz, CDCl3): d 7.80–7.00 (m, 14H, Ph), 4.55
(d, J = 11.8, 1H, CH2Ph), 4.45 (t, J = 11.8, 2H, CH2Ph),
4.15 (m, J = 11.8, J = 9.7, 3H, CH2, H-3), 4.05 (d,
J = 11.3, 1H), 3.96 (d, J = 9.6, 1H, H-2), 3.70 (d, J = 9.1,
1H, H-4), 3.50 (m, 1H, H-5), 3.40–3.10 (m, 4H, 2CH2CH3),
2.35 (s, 3H, CH3 of Ts), 1.06 (m, 6H, CH2CH3). 13C NMR
(100 MHz, CDCl3): d 168.0 (CO), 145.0–127.5 (Ph), 76.4
and 76.3 (C-3, C-5), 74.5 and 71.6 (2CH2Ph), 69.4 (C-6),
69.1 (C-4), 56.2 (C-2), 42.3 and 41.3 (2CH2CH3), 21.6
(CH3 of Ts), 14.7 and 12.9 (2CH2CH3).
4.8. 1,5-Dideoxy-1,5-imino-2,4-di-O-benzyl-N,N-diethyl-D-
mannopyranosiduronamide 13
To a vessel with tosylated compound 12 (290 mg,
0.47 mmol) under an argon atmosphere were added meth-
anol (10 mL) and a catalytic amount of Pd/C. The mixture
is purged and maintained under hydrogen atmosphere at rt
(by a H2 filled balloon). After 2 h the reaction is complete.
The mixture was filtered over CeliteTM and purified by col-
umn chromatography to give piperidine 13 as a white solid
4.6. Hydrolysis of 9a and 9b. 2-Azido-2-deoxy-3,5-di-O-
benzyl-D-allono-1,4-lactone 10 and 2-azido-3,5-di-O-
benzyl-N,N-diethyl-D-manno-hexonamide 11
(180 mg, 90%), mp: 143–144 °C. Rf: 0.6 (9:1, ethyl acetate/
27
methanol). ½aꢁD ¼ ꢂ83 (c 1.1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 7.30 (m, 10H, Ph), 4.77 (d,
J = 10.7, 1H, CH2Ph), 4.57 (d, J = 11.8, 1H, CH2Ph),
4.54 (2d, 2H, CH2Ph), 3.82 (t, J3,4 = J4,5 = 9.1, 1H, H-4),
3.71 (br s, 1H, H-2), 3.61 (ddd, J3,2 = 3.2, J3,4 = 9.1,
J3,OH = 9.1, 1H, H-3), 3.58–3.13 (4m, 4H, 2CH2CH3),
3.36 (d, J4,5 = 9.1, 1H, H-5), 3.16 and 2.53 (2d,
J1e,1a = 15.0, 2H, 1-He and 1-Ha), 1.11 and 1.10 (at,
2 ꢀ 3H, 2CH2CH3). 13C NMR d (100 MHz, CDCl3):
171.1 (CO), 139.1, 138.4 and 128.9–127.9 (Ph), 81.5 (C-
4), 78.1 (C-2), 75.9 (C-3), 59.4 (C-5), 75.6 and 71.9
(CH2Ph), 46.5 (C-1), 42.6 and 41.3 (CH2CH3), 15.0 and
13.4 (CH2CH3). HRMS (FAB): [M+H]+ calcd for
C24H33N2O4, 413.2443; found, 413.2440.
The benzylated 9a (330 mg, 0.68 mmol) or 9b (124 mg,
0.25 mmol) was dissolved in MeOH, separately, and stirred
with AmberlystÒ 15 at 50–60 °C. After 1 d, reaction mix-
tures were filtered, the resin washed with MeOH and the
solvent evaporated, giving residues, which were purified
by column chromatography. Compound 9a gave lactone
10 (186 mg, 71%) and compound 9b gave diol 11 (70 mg,
60%). Lactone 10 had Rf: 0.6 (1:1, hexane/ethyl acetate).
27
1
½aꢁD ¼ þ11 (c 1.8, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.30–7.10 (m, 10H, Ph), 4.67, 4.62, 4.53 and 4.43 (m + d,
J = 9.8, 4H, 2CH2Ph), 4.62 (d, J4,5 = 3.2, 1H, H-4), 4.37 (d,
J3,2 = 5.9, 1H, H-3), 4.11 (d, 1H, H-2), 3.67 (m, 1H, H-5),
3.58 (m, 2H, H-6). 13C NMR (100 MHz, CDCl3): d 171.7
(CO), 136.6 (2C) and 128.7–127.8 (Ph), 84.3 (C-4), 78.0
(C-5), 75.2 (C-3), 73.4 and 72.3 (2CH2Ph), 60.3 (C-6),
59.5 (C-2). HRMS (FAB): [M+Na]+ calcd for
C20H21N3O5Na, 406.1378; found, 406.1374. Compound
4.9. 2,4-Di-O-Benzyl-1-deoxymannojirimicin 14
To a stirred solution of piperidine 13 (35 mg, 0.08 mmol) in
THF (1.5 mL), with an ice bath and under an argon atmo-
sphere, was added Super-HydrideÒ, 1 M in tetrahydro-
furan (0.6 mL, 0.6 mmol). The reaction was left at rt for a
day and then, more hydride was added (0.2 mL, 0.2 mmol).
After 2 d, TLC indicated the conversion of the starting
material to a more polar product. Then, the mixture was
diluted with MeOH, treated with acid resin, filtered and
concentrated. The residue was purified by column chroma-
tography to obtain pure 14 (20 mg, 69%). Rf: 0.2 (9:1, ethyl
1
11 had Rf: 0.3 (3:2 hexane/ethyl acetate). mp: 115 °C. H
NMR d (400 MHz, CDCl3): 7.40–7.10 (m, 10H, Ph), 4.64
(d, J = 11.8, 1H, CH2Ph), 4.52 (d, J = 11.3, 1H CH2Ph),
4.35 (d, 1H, CH2Ph, J = 11.8), 4.27 (d, 1H, J2,3 = 9.7, H-
3), 4.18 (d, J = 11.3, 1H, CH2Ph), 4.06 (d, 1H, H-2), 3.97
(d, J4,5 = 8.6, 1H, H-4), 3.95 (m, J6a,5 = 3.8, H-6a), 3.89
(dd, J6a,6b = 11.8, J6b,5 = 2.7, H-6b), 3.40–3.50 and 3.24
27
1
(2m, 4H + 1H, H-5 and 2NCH2), 1.06 (2t, 6H, CH2CH3).
13C NMR d (100 MHz, CDCl3): 168.4 (CO), 138.0–127.0
(Ph), 78.1 and 76.8 (C-3, C-5), 74.7 and 71.3 (2 CH2Ph),
70.3 (C-4), 60.9 (C-6), 56.5 (C-2), 41.5 and 42.5
(2CH2CH3), 13.1 and 14.9 (2CH2CH3). HRMS (FAB):
[M+H]+ calcd for C24H33N4O5, 457.2451; found, 457.2459.
acetate/methanol). ½aꢁ ¼ ꢂ5:5 (c 0.7, CH2Cl2). H NMR
(400 MHz, CDCl3): dD7.32 (m, 10H, Ph), 4.90, 4.70, 4.63
and 4.51 (4d, J = 10.9 and 11.6, 4H, 2CH2Ph), 3.85 (dd,
J = 3.7 and 10.9, 1H, H-6), 3.75 (br s, 1H, H-2), 3.67 (m,
2H, H-3 and H-6), 3.50 (t, J3,4 = J4,5 = 9.8, 1H, H-4),
3.27 (dd, J1e,2 = 3.0, J1e,1a = 14.6, 1H, 1-He), 2.62 (d, 1H,

M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
727
H-1a), 2.60 (m, 1H, H-5). 13C NMR (100 MHz, CDCl3): d
138, 137 and 129–127, 78, 77 and 75 (C-2, C-3 and C-4), 74
and 71 (CH2Ph), 62 and 60 (C-5 and C-6), 45 (C-1). HRMS
(FAB): [M+Na]+ calcd for C20H25NO4Na, 366.1681;
found, 366.1683.
J5,4 = J5,6e = 10.2, H-5), 4.39 (d, 1H, H-2), 4.32 (d,
0
J = 17.2, 2H, CH2Ph), 4.17 (dd, 1H, J6;6 ¼ 10:2, H-6e),
3.97 (d, J = 14.5, 1H, CH2Ph), 3.89 (dd, 1H, H-4), 3.33
(t, 1H, H-6a), 1.99 and 1.67 (2s, 2 ꢀ 3H, 2CH3CO), 1.20
(d, J = 4.8, 3H, CHCH3). 13C NMR (100 MHz, CDCl3):
d 169.8, 168.5 and 168.1 (3CO), 136.6, 135.7 and 129.0–
126.3 (2Ph), 99.5 (CHMe), 75.9 (C-4), 68.7 (C-3), 67.3
(C-6), 61.6 (C-5), 55.4 (C-2), 49.5 and 49.2 (2NCH2),
20.6, 20.2 and 20.1 (2CH3CO, CHCH3). HRMS (FAB):
[M+Na]+ calcd for C26H30N4O7Na, 533.2013; found,
533.2016. Compound 16a had Rf: 0.65 (3:2 hexane/ethyl
4.10. 2-Azido-N,N-dibenzyl-4,6-O-ethylidene-D-allo-hexon-
amide 15a and 2-azido-N,N-dibenzyl-4,6-O-ethylidene-D-
manno-hexonamide 15b
To a stirred solution of the epoxy amide mixture 7a,b
(530 mg, 1.38 mmol) in DMF (7.8 mL) were added NaN3
(138 mg, 2.12 mmol) and AcOH (0.09 mL). The mixture
was heated (95 °C) under an argon atmosphere and moni-
tored by TLC. After 2.5 h, the reaction mixture was eluted
with AcOEt and washed with aq NH4Cl and then with
water. The organic layer was dried (MgSO4) and the sol-
vents were evaporated in vacuo. Purification by column
chromatography gave 235 mg of 15a and 218 mg of 15b
(77% yield). Isomers 15a and 15b could be separated by
column chromatography. 15a had Rf: 0.4 (3:2 hexane/ethyl
25
1
acetate). ½aꢁD ¼ ꢂ37 (c 1, CH2Cl2). H NMR (200 MHz,
CDCl3): d 7.40–7.00 (m, 10H, 2Ph), 5.44 (dd, J3,4 = 2.2,
J2,3 = 8.8, 1H, H-3), 5.02 (d, J = 14.6, 1H, CH2Ph), 4.96
(ddd, J5,6e = 5.1, J5,4 = J5,6a = 10.2, 1H, H-5), 4.59 (m,
2H, CH2Ph and OCHCH3), 4.36 (2d, J = 8.8, 16.8, 2H,
CH2Ph and H-2), 4.20 (dd, J6a,6e = 10.2, 1H, H-6e), 4.08
(d, J = 14.6, 1H, CH2Ph), 3.94 (dd, 1H, H-4), 3.27 (t,
1H, H-6a), 1.91 and 1.78 (2s, 2 ꢀ 3H, 2CH3CO), 1.20 (d,
J = 5.1, 3H, CHCH3). 13C NMR (100 MHz, CDCl3): d
169.6, 168.8 and 168.0 (3CO), 136.7, 135.5 and 129.1–
126.3 (2Ph), 99.2 (OCHMe), 77.7 (C-4), 70.8 (C-3), 67.5
(C-6), 63.6 (C-5), 56.1 (C-2), 49.4 and 48.9 (2NCH2),
20.54, 20.48 and 20.2 (2CH3CO, CHCH3). HRMS
(FAB): [M+Na]+ calcd for C26H30N4O7Na, 533.2012;
found, 533.2016.
25
1
acetate), ½aꢁD ¼ ꢂ171 (c 1, CH2Cl2). H NMR (400 MHz,
CDCl3): d 7.40–7.10 (m, 10H, 2Ph), 4.74 and 4.52 (2d,
J = 15.0 and 16.6, 2H, CH2Ph), 4.40 (m, 3H, CHCH3
and CH2Ph), 4.21 (dd, J2,3 = 2.7, J3,4 = 8.8, 1H, H-3),
4.12 (d, 1H, H-2), 4.07 (dd, J5,6a = 5.4, J6a,6e = 10.2, 1H,
H-6e), 3.73 (ddd, 1H, H-5), 3.38 (t, 1H, H-4), 3.32 (t,
J5,6e = J6a,6e = 10.2, 1H, H-6a). 13C NMR (50 MHz,
CDCl3): d 170.1 (CO), 136–126 (Ph), 98.6 (CHCH3), 79.1
(C-4), 78.4 (C-3), 69.8 (C-6), 66.4 (C-5), 54.2 (C-2), 49.8
and 48.0 (2CH2Ph), 20.3 (CHCH3). HRMS (FAB):
[M+Na]+ calcd for C22H26N4O5Na, 449.1801; found,
4.12. 2-Azido-2-deoxy-D-allono-1,4-lactone 17 and 2-azido-
N,N-dibenzyl-D-manno-hexonamide 18
The acetylated 16a (97 mg, 0, 19 mmol) was dissolved in
MeOH and stirred with AmberlystÒ 15 at 60 °C. After
1 d, the reaction mixture was filtrated, the resin washed
with MeOH and the solvent evaporated, giving a residue
which was washed with hexane (2 mL) and further purified
449.1798. Compound 15b had Rf: 0.3 (3:2 hexane/ethyl ace-
25
tate). ½aꢁD ¼ þ40 (c 0.8, CH2Cl2). 1H NMR (200 MHz,
CDCl3): d 7.40–7.10 (m, 10H, 2Ph), 4.80 (d, J = 15.0,
1H, CH2Ph), 4.63 (m, 2H, OCHCH3 and CH2Ph), 4.47
(m, 3H, H-3 and CH2Ph), 4.27 (d, J2,3 = 9.1, 1H, H-2),
4.10 (dd, J5,6e = 5.4, J6a,6e = 10.7, 1H, H-6e), 3.85 (ddd,
1H, H-5), 3.57 (dd, J3,4 = 1,1, J4,5 = 9.7, 1H, H-4), 3.42
(t, J5,6a = J6a,6e = 10.7, 1H, H-6a), 2.52 (br s, OH), 1.22
(d, 3H, CHCH3). 13C NMR (100 MHz, CDCl3): d 170.9
(CO), 136–126 (Ph), 98.9 (CHCH3), 79.5 (C-4), 70.4 (C-
6), 68.8 (C-3), 60.2 (C-5), 57.8 (C-2), 50.5 and 49.5
(2CH2Ph), 20.3 (CHCH3). HRMS (FAB): [M+Na]+calcd
for C22H26N4O5Na, 449.1801; found, 449.1806.
by column chromatography to give lactone 17 (30 mg,
20
77%). Rf: 0.45 (ethyl acetate). ½aꢁD ¼ ꢂ3:5 (c 1.3, MeOH).
1H NMR (400 MHz, D2O): d 4.58 (d, J2,3 = 5.91, 1H, H-3),
4.54 (d, 1H, H-2), 4.38 (d, J4,5 = 4.8 Hz, 1H, H-4), 3.74
0
(1H, ddd, H-5), 3.54 (dd, J5,6 = 4.3 Hz, J6;6 ¼ 11:8 Hz,
1H, H-6), 3.48 (dd, J5;6 ¼ 5:9 Hz, 1H, H-60), 13C NMR
0
(100 MHz, D2O): d 174.7 (CO), 86.8 (C-4), 69.8 (C-5),
68.4 (C-6), 61.5 (C-3), 60.5 (C-2). HRMS (FAB):
[M+Na]+, calcd for C6H9N3O5Na, 226.0440; found,
226.0441. The same procedure was followed with isomer
16b (67 mg, 0.13 mmol) to give tetrol 18 (36 mg, 69%).
Rf: 0.45 (ethyl acetate). 1H NMR (400 MHz,
CDCl3 + CD3OD): d 4.83 and 4.62 (2d, J = 15.0, 17.2,
2 ꢀ 1H, CH2Ph), 4.27 and 4.15 (2m, 4 H), 3.61 (m), 3.0
(m). 13C NMR d (100 MHz, CDCl3 + CD3OD): 170.9
(CO), 136.0, 135.6 and 130–126 (Ph), 71.1, 69.95 and
69.88 (3C, C-5, C-4, C-3), 63.6 (C-6), 57.8 (C-2), 48.8 and
45.8 (NCH2). HRMS (FAB): [M+Na]+ calcd for
C20H24N4O5Na, 423.1645; found, 423.1644.
4.11. 3,5-Di-O-Acetyl-2-azido-N,N-dibenzyl-4,6-O-ethyl-
idene-D-altro-hexonamide 16a and 3,5-di-O-acetyl-2-azido-
N,N-dibenzyl-4,6-O-ethylidene-D-gluco-hexonamide 16b
Diols 15a or 15b (40 mg, 0.09 mmol) were stirred in pyri-
dine (1 mL) with acetic anhydride (0.3 mL) in an ice bath
for 5 h. The reactions were left at rt overnight. Ice was
added and a white precipitate was formed in both cases.
The precipitates were filtered and washed, and according
to their NMR data, pure diacetylated products 16a
(57 mg, 95%) or 16b (53 mg, 88%) were, respectively, ob-
4.13. 2,3-Anhydro-N,N-dibenzyl-5-O-benzyl-4,6-O-ethyl-
idene-D-altro-hexonamide 19a and 2,3-anhydro-N,N-dibenz-
yl-5-O-benzyl-4,6-O-ethylidene-D-gluco-hexonamide 19b
tained. Compound 16b had Rf: 0.7 (3:2, hexane/ethyl ace-
25
tate). ½aꢁD ¼ ꢂ21 (c 0.9, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 7.40–7.10 (m, 10H, 2Ph), 5.56 (dd, J3,4 = 1.6,
J2,3 = 10.2, 1H, H-3), 5.11 (d, J = 14.5, 1H, CH2Ph), 4.60
(m, 2H, CH2Ph, CHMe), 4.50 (dt, 1H, J5,6a = 5.4,
Benzylation of epoxyamides 7a,b (160 mg, 0.42 mmol) in
THF (2 mL), HNa (16 mg, 0.67 mmol), TBAI (1/10 equiv)
and BnBr (0.05 mL) gave compounds 19a,b (159 mg, 80%).

728
M. S. Pino-Gonza´lez, N. On˜a / Tetrahedron: Asymmetry 19 (2008) 721–729
1H NMR (200 MHz, CDCl3): d 7.40–7.00 (m, 2 ꢀ 15H,
2 ꢀ 3Ph), 4.75–4.25 (m, 2 ꢀ 7H, 2 ꢀ 3CH2Ph, 2CHCH3),
4.10 (2dd, 2 ꢀ 1H, J6e,6a = 10.7, J6e,5 = 4.8, H-6e), 3.81
(d, 1H, J2,3 = 2.15, H-2 isomer a), 3.78 (d, 1H,
J2,3 = 2.15, H-2 isomer b), 3.54 (m, 2 ꢀ 2H, H-3 and H-
5), 3.30 (m, 2 ꢀ 2H, H-4 and H-6a), 1.21 and 1.18 (2d,
2 ꢀ 3H, 2CHCH3). 13C NMR (100 MHz, CDCl3): d
167.5 (2CO), 137.3–135.9 and 129.0–126.6 (Ph), 98.7 and
98.6 (CHCH3), 77.5, 76.5, 72.5, 72.1, 70.0, 69.6, 68.7 and
68.5 (2 ꢀ 4 C, C-4, C-5, C-6 and CH2Ph), 57.6 and 57.1
(C-3a, C-3b), 50.9 and 50.5 (C-2a, C-2b), 49.1, 48.6 and
48.4 (4C, one double, 2 ꢀ 2NCH2Ph), 20.2 (2CHCH3).
HRMS (FAB): [M+Na]+ calcd for C29H31NO5Na,
496.2099; found, 496.2098.
7.05 (m, 15H, Ph), 5.68 (d, J2,3 = 9.7, 1H, H-2), 5.60 (dd,
J3,4 = 3.8, J4,5 = 4.3, 1H, H-4), 4.77 (2d, J = 15.4, 16.7,
2H, CH2Ph), 4.55 (d, J = 11.3, 1H, CH2Ph), 4.51 (dd,
1H, H-3), 4.42–4.27 (3d, 3H, CH2Ph), 4.24 (m, 1H, H-5),
0
3.95 (dd, J5,6 = 7.5, J6;6 ¼ 8:1, 1H, H-6), 3.67 (dd,
J5;6 ¼ 7:5, 1H, 60-H), 1.98 and 2.06 (2s, 2 ꢀ 3H, CH3CO).
0
13C NMR (100 MHz, CDCl3): d 169.8, 169.6 and 168.5 (3
CO), 137.0, 136.4 and 136.0 (3 quat. Ph), 128–127 (Ph),
78.9 (C-3), 77.6 (C-5), 72.7 (CH2Ph), 70.4 (C-4), 69.2 (C-
6), 66.7 (C-2), 49.8 and 47.9 [N(CH2Ph)2], 20.6 and 20.4
(2CH3CO). HRMS (FAB): [M+Na]+ calcd for
C31H33NO7Na, 554.2154; found, 554.2154.
4.16. Hydrolysis of compounds 21a and 21b. 3,6-Anhydro-5-
O-benzyl-D-mannono-1,4-lactone 22
4.14. 3,6-Anhydro-5-O-benzyl-N,N-dibenzyl-D-mannon-
amide 20a and 3,6-anhydro-5-O-benzyl-N,N-dibenzyl-D-
allonamide 20b
To a small amount of 21a was added TFA/H2O (2:1) and
the mixture was stirred at 50 °C for a day. Then, solvents
were evaporated and the residue was characterized by
NMR spectroscopy, giving lactone 22. The same procedure
was followed with 21a giving the deacetylated 20. Lactone
22 was purified by column chromatography. Rf: 0.2 (1:1,
hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3): d
7.36 (m, 5H, Ph), 4.91 (t, 1H, J3,4 = J4,5 = 3.8, H-4), 4.71
and 4.58 (2d, J = 11.3, 2H, CH2Ph), 4.62 (dd, 1H, H-3),
4.38 (d, J2,3 = 5.4, 1H, H-2), 4.25 (ddd, 1H, H-5), 4.08
To a solution of epoxyamides 19a,b (300 mg, 0.634 mmol)
in methanol was added AmberlystÒ 15. The mixture was
stirred and heated (45–50 °C). After 24 h, resin was filtered
and the solution concentrated in vacuo to give a syrup,
which was purified by column chromatography. NMR
data showed this to be an irresoluble mixture of com-
pounds 20a,b (180 mg, 63%) Rf: 0.3 (2:1), 0.5 (1:1) (hex-
1
0
(dd, J5,6 = 7.5, J6;6 ¼ 8:6, 1H, H-6) and 3.74 (t,
ane/ethyl acetate). H NMR (400 MHz, CDCl3), mixture
J5;6 ¼ 8:6, 1H, 60-H). 13C NMR (50 MHz, CDCl3): d
0
of isomers, d 7.45–7.15 (m, 15H, Ph), 5.17 (d, 1H, CH2Ph,
J = 15.28), 5.06 (m, 2H, CH2Ph), 4.97 (d, 1H, CH2Ph,
J = 17.1), 4.73–4.57 (m, 5H, CH2Ph), 4.49 (t, 1H,
J = 4.1, isomer a), 4.38 (t, 1H, J = 5.3, isomer b), 4.32–
4.4 and 4.00–3.80 (2m). 13C NMR (100 MHz, CDCl3): d
173.9 and 172.3, (2C@O), 137–126 (2 ꢀ 3Ph), 84.6 and
83.7 (C-3a, 3b), 78.7 and 78.3 (C-5a, 5), 72.7 and 72.4
(C-4a, 4b), 70.8, 70.3, 70.2, 69.7 and 69.3 (2 ꢀ 2CH2O,
C-2b), 65.9 (C-2a), 49.4, 49.0, 48.2 and 48.1 (2 ꢀ 2 CH2N).
174.4 (CO), 136.7 and 129.0–128.0 (Ph), 78.2 (C-4), 76.7
(2C, C-5 and C-3), 72.8 (CH2Ph), 69.6 (C-6) and 69.2 (C-
2). HRMS (FAB): [M+Na]+ calcd for C13H14O5Na,
273.0739; found, 273.0740.
Acknowledgements
We are grateful to Professor George W. J. Fleet, University
of Oxford, for kindly providing us with NMR data of 2-
azido-2-deoxy-D-mannono-1,4-lactone. This research was
4.15. 2,4-Di-O-Acetyl-3,6-anhydro-5-O-benzyl-N,N-dibenz-
yl-D-mannonamide 21a and 2,4-di-O-acetyl-3,6-anhydro-5-
O-benzyl-N,N-dibenzyl-D-allonamide 21b
´
supported with funds from the Direccion General de Inves-
´
´
´
tigacion Cientıfica y Tecnica of Spain (Ref. CTQ2004-
´
´
08141) and from the Consejerıa de Educacion y Ciencia,
To a solution of the mixture of isomers 20a,b (145 mg,
0.32 mmol) in CH2Cl2 (5 mL) and pyridine (5 mL) was
added 1.5 equiv of acetyl chloride. After a day, work-up
as usual gave, after evaporation of the solvent, a residue
that was purified to give pure 21b, less polar, (47 mg) and
pure 21a, more polar, (62 mg). (65% yield). Compound
21b had Rf: 0.5 (2:1, hexane/ethyl acetate). 1H NMR d
(400 MHz, CDCl3): d 7.35–7.05 (m, 15H, Ph), 5.45 (m,
2H, H-2 and H-4), 4.79 (d, J = 15.0, 1H, CH2Ph), 4.56–
4.34 (3d, 3H, CH2Ph), 4.32 (t, J2,3 = J3,4 = 4.3, 1H, H-3),
4.24 (d, J = 15.0, 1H, CH2Ph), 4.11 (m, 1H, H-5), 3.88
´
Junta de Andalucıa (FQM-158).
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0
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