Stereoselective synthesis of oxazolidines from 2-amino-2-deoxy-D-allose derivatives and their reactivity with nucleophiles

Article abstract of DOI:10.1016/S0957-4166(00)00498-5

The use of 2-amino-2-deoxy-D-allose in the synthesis of oxazolidines is described. The reaction takes place with total stereoselectivity in the preparation of both simple oxazolidines (from aldehydes as reagent) and bicyclic oxazolidines (from chlorocarbonyl compounds and keto-acids as reagents). The reactivity of the obtained oxazolidines with hydride and alkylmagnesium chlorides is also described.

Full text of DOI:10.1016/S0957-4166(00)00498-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 135–147
Stereoselective synthesis of oxazolidines from
2-amino-2-deoxy-
D
-allose derivatives and their reactivity with
nucleophiles†
Jose´ M. Vega-Pe´rez,* Margarita Vega, Eugenia Blanco and Fernando Iglesias-Guerra
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad de Sevilla, E-41071 Seville, Spain
Received 11 December 2000; accepted 18 December 2000
Abstract—The use of 2-amino-2-deoxy-D-allose in the synthesis of oxazolidines is described. The reaction takes place with total
stereoselectivity in the preparation of both simple oxazolidines (from aldehydes as reagent) and bicyclic oxazolidines (from
chlorocarbonyl compounds and keto-acids as reagents). The reactivity of the obtained oxazolidines with hydride and alkylmagne-
sium chlorides is also described. © 2001 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
ral oxazolidines obtained via condensation with chiral
b-aminoalcohols.
The highly stereoselective condensation of carbonyl
compounds (mainly aldehydes) with chiral b-aminoal-
cohols is of considerable interest as the 1,3-oxazolidines
obtained are important chiral intermediates used in
numerous asymmetric transformations. Neelakatan2
described the synthesis and stereochemistry of these
heterocycles (obtained by reaction between ephedrine
and aromatic aldehydes) in 1971. Since then, numerous
research groups have concentrated on broadening their
use as chiral adjutants.
Meyers et al.13 described the asymmetric synthesis of
bicyclic compounds having an oxazolidine ring fused to
one of lactam, by condensation of the keto-acid with
chiral b-aminoalcohols, generating in the process a new
chiral centre with high stereoselectivity, the final
diastereoisomeric excess depending on the nature of the
precursor aminoalcohol substituents and their configu-
ration, and on the cyclisation procedure used.14–17
The addition of hydrides to lactams with different
substituents in the angular position gives different com-
pounds depending on the nature of the hydride. Thus,
the addition of lithium aluminium hydride yields the
totally reduced compound, and in all cases, the
configuration18 of the lactam stereocentre is retained.
Diastereoselective addition of nucleophilic agents to the
amino-bearing carbon gives an attractive approach to
the asymmetric synthesis of chiral amines with good
stereochemical control. Numerous works have been
published on this topic, aimed partly at obtaining new
chiral nitrogenated compounds (optically active
amines,3,4 a-aminoaldehydes,5 etc.) and partly at a
deeper understanding of the addition mechanism and
the factors affecting the degree of stereoselection
obtained (groups present in the heterocycle, nature of
nucleophile used, solvent, temperature, etc.).6–8 At the
same time, various asymmetric transformations (Diels–
Alder cycloadditions,9 nucleophile addition,10,11 epoxi-
dations,12 etc.) have been carried out on
a,b-unsaturated carbonyl compounds derived from chi-
As part of our work, we have used 2-aminosugars with
gluco, allo and altro configurations as chiral starting
materials in the synthesis of different compounds (2-
aminoglycals,19 2-nitrosugars,20 and compounds with
potential anti-cancer activity21–23). In previous papers
we have described the synthesis of oxazolidines from
2-amino-2-deoxy-D-glucose derivatives with different
groups on C-(2) of the oxazolidine ring,1,24,25 and the
reactivity of these compounds with nucleophiles.26
Herein, we describe the stereoselective synthesis of oxa-
zolidines and bicyclic oxazolidines from 2-amino-2-
* Corresponding author. Tel./fax: +34 95 4556737; e-mail:
deoxy-
D
-allose derivatives 1–6, and their reactivity with
vega@fafar.us.es
†
Oxazolidines from sugars, part 5. For part 4, see Ref. 1
hydrides and alkylmagnesium chlorides.
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00498-5

136
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
2. Results and discussion
derivatives 3 and 4 with aldehydes. The products, 11–
16, present a stereogenic centre on C-(2) of the oxazol-
idine ring formed (Scheme 3). The reaction was carried
out with 3 or 4 and the aldehyde in dichloromethane
The alkyl 2-acetamido-4,6-O-benzylidene-2-deoxy-2-N-
3-O-methylidene-b- -allopyranosides 7 and 8 were
obtained in good yield from the benzyl or dodecyl
D
,
containing 4 A molecular sieves. Compounds 11–16
2-acetamido-4,6-O-benzylidene-2-deoxy-b-D-allopyra-
were formed with complete stereoselectivity in these
reactions (the NMR spectra of the bulk reaction indi-
cated the presence of a single stereoisomer in each
case). NOE and NOESY experiments allowed us to
assign the (S)-configuration for the stereogenic centre
formed in these reactions. Compounds 3 and 4 were
obtained from the corresponding N-acetyl derivatives 1
and 2 by reduction with lithium aluminium hydride
under standard conditions.
nosides 127 and 228 by reaction with dibromomethane
under phase-transfer conditions, using a methodology
previously described by our research group for obtain-
ing oxazolidines derived from 2-amino-2-deoxy-D-
glucose25,26 (Scheme 1). The NMR spectra showed the
signals corresponding to the methylidene group, intro-
1
duced in the reaction. In the H spectra, a singlet at
5.13 ppm for compound 7 and a double doublet (AB
system) at 5.16 ppm for compound 8 were observed.
The 13C spectra showed signals at 80.5 and 79.8 ppm
for compounds 7 and 8, respectively.
We have also obtained the bicyclic oxazolidines 17–29
from compounds 5 and 6. In 17–29 the second cycle,
fused to the oxazolidine ring, was formed in the reac-
tion. These compounds had a trialkylamine structure
(bicyclic pyrrolidines 17–21) when a g-chlorocarbonyl
compound was used, or an N,N-dialkylamide structure
(bicyclic lactams 22–29), when a g- or d-keto-acid was
used in the condensation reaction.
The preparation of N-alkyloxazolidines and N-acyloxa-
zolidines, either mono- or disubstituted on C-(2) of the
oxazolidine ring, was carried out by reaction of the
alkyl
4,6-O-benzylidene-2-deoxy-2-ethylamino-b-
D-
allopyranosides 3 and 4 or the alkyl 2-amino-4,6-O-
benzylidene-2-deoxy-b-
-allopyranosides 527 and 621
D
with an aldehyde or ketone in the absence of an alkali.
The bicyclic pyrrolidines 17–21 were prepared by con-
densation of compounds 5 or 6 and the corresponding
g-chlorocarbonyl compound at room temperature in
dichloromethane in the presence of triethylamine
(Scheme 4), as described by Pedrosa et al.29 for the
reaction of (R)-phenylglycinol with dialkyl g- and d-
chloroketones. The g-chlorocarbonyl compounds used
in this study were an aldehyde, a methylketone, and a
phenylketone. The reaction times were longest when we
used 4-chlorobutyrophenone. The NMR spectra of the
bulk reaction indicated the presence of a single
stereoisomer in each case, and the condensation took
place with total diastereoselectivity. NOESY experi-
ments showed that the group on the angular carbon
always had the same spatial orientation (cis with
respect to H-1 of the sugar), independently of its nature
(R2=H, Me, Ph).
The synthesis of compound 10 was carried out from 5
in two steps (Scheme 2). The treatment of 5 with
acetone–dichloromethane (1:1) containing magnesium
sulphate as a dehydrating agent gave oxazolidine 9,
characterised by its mass spectrum {MS (CI) m/z 398
(100%) [M+H]+}. It was used without further purifica-
tion because of its low stability (oxazolidine X imine
equilibrium has been described for compounds with this
structure).2 The reaction of 9 with acetyl chloride/pyri-
dine in dichloromethane yielded compound 10 (65%
from 5). The NMR data confirm the presence of iso-
propylidene and acetyl groups, three singlets at 2.18,
1
1.58 and 1.47 ppm in the H spectrum, and 168.4, 96.9,
26.7, 24.3 and 23.8 ppm in the 13C spectrum.
We also synthesised another set of oxazolidines which
were obtained from the condensation of 2-ethylamino
Scheme 1.
Scheme 2. (i) Acetone/CH2Cl2/MgSO4. (ii) AcCl/Py/CH2Cl2.

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
137
The reaction of compounds 5 and 6 with g- and d-keto-
acids gave the bicyclic lactams 22–29 with total
stereoselectivity (NMR analysis of the crude reaction
mixture) and a configuration for the new stereogenic
centre with cis relationship between H-1 of the sugar
and the substituent on the bridgehead carbon (R2
group) in all compounds obtained (NOE and NOESY
experiments) (Scheme 5). When the reaction was carried
of the oxazolidine ring (Scheme 6). Compound 7 was
reduced more quickly than 10 and 11. The preparation
of 32 from 10 and LiAlH4/THF was carried out via 31,
characterised by its mass spectrum {MS (CI) m/z 498
1
[M+H]+ (10%)} and its H NMR (two singlets at 1.56
and 1.44 ppm corresponding to the isopropylidene
group, and two multiplets at 2.56 and 1.09 ppm corre-
sponding to the ethyl group). Stirring 31 for 48 h with
1
,
out in dichloromethane containing 4 A molecular
LiAlH4 gave the ring opened 32. The H NMR confir-
sieves30 (method A), only the bicyclic lactams 22, 24,
and 26 were obtained using 3-acetylpropionic acid or
4-acetylbutyric acid as reagents. The use of 3-benzoyl-
propionic acid, 4-benzoylbutyric acid, 2-carboxybenz-
aldehyde or 2-acetylbenzoic acid led to undesired com-
pounds. In some cases we detected the formation of a
non-cyclic amide, probably due to the lower reactivity
of the carbonyl group linked to an aromatic ring.
med the presence of the isopropyl group, with a multi-
plet at 3.16 ppm and a doublet at 0.96 ppm. Reaction
of 13 in toluene with tert-BuMgCl/THF over two days
led to compounds 34 (Scheme 6) as a stereoisomeric
mixture with a 76% diastereomeric excess.
The reaction of LiAlH4 and MeMgCl with the bicyclic
oxazolidines 17, 18 and 22 gave the compounds 35 and
36 (Scheme 7). Table 1 firstly shows that the reactions
carried out with simple oxazolidines are slower than
those with bicyclic oxazolidines having a bridgehead
substituent, R2. Secondly, it is notable that compounds
35 and 36 are epimers at C-(2) of the pyrrolidine ring
and, given that they are obtained from compounds 17
and 18 (or 22) stereochemically pure with the configura-
tion of the angular carbon of the bicyclic system per-
fectly defined, it is deduced that the reactions with
LiAlH4 and MeMgCl follow the same stereochemical
course. Various authors18,29,31 have demonstrated that
the reductive ring opening of the N,O-acetal moiety in
bicyclic pyrrolidines and bicyclic lactams takes place
with retention of the configuration of the bridgehead
We used another procedure13,14 (method B) in the
preparation of bicyclic lactams. A solution of com-
pound 5 or 6, the appropriate g- or d-keto-acid and
p-toluenesulphonic acid in toluene was heated under
reflux in a Dean–Stark apparatus to afford compounds
23, 25 and 27–29 after 12 h.
We have also studied the reaction of some oxazolidines
and bicyclic oxazolidines with lithium aluminium
hydride and alkylmagnesium chlorides, varying the
reaction conditions (Table 1). The reaction of com-
pounds 7, 10 and 11 with LiAlH4 in THF gave, respec-
tively, compounds 30, 32 and 33 by reductive opening
Scheme 3.
Scheme 4.

138
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
carbon of the bicyclic system. Consequently, we could
easily assign the absolute configurations of compounds
35 and 36. However, the LiAlH4 reduction of bicyclic
oxazolidines substituted with an aromatic ring at the
angular position (19, 21, 23, 25, 27, 28 and 29) led to
inseparable mixtures of products.
oxazolidine ring was an aryl group, the reaction led to
a mixture of products.
3. Experimental
3.1. General
In conclusion, we present a stereoselective procedure
for the synthesis of oxazolidines derived from alkyl
allopyranosides, with good yields, in which the 2-
Evaporations were conducted under reduced pressure.
Preparative chromatography was performed on Silica
Gel 60 (E. Merck). Kieselgel 60 F254 (E. Merck) was
used for TLC. Melting points are uncorrected. Optical
rotations were obtained on a Bellingham+Stanley Ltd
P-20 polarimeter at 25°C. Infrared (IR) spectra were
obtained on a Jasco FT/IR-410 spectrophotometer.
amino-2-deoxy-D-allose moiety acts as a good chiral
adjutant, both in the formation of simple oxazolidines
and in that of bicyclic pyrrolidines and bicyclic lactams.
The reactivity of the oxazolidines with lithium alu-
minium hydride and Grignard reagents depends heavily
on the C-(2) substituent of the oxazolidine ring. When
C-(2) was unsubstituted or substituted with an alkyl
group, the reaction took place with good stereoisomeric
control, whereas when the C-(2) substituent of the
Mass spectra were recorded on
a
Micromass
AUTOSPECQ mass spectrometer, CI at 150 eV, and
HR mass measurements with resolutions of 10,000.
NMR spectra were recorded at 25°C on a Bruker
Scheme 5. (i) Method A: CH2Cl2/molecular sieves/2 weeks (22, 24, 26). (ii) Method B: toluene/TsOH/reflux/12 hours (23, 25
27–29).
Table 1. Reaction of oxazolidines with LiAlH4 and RMgX
Entry
Oxazolidine
Reagent
Molar relationship
oxazolidine/reagent
Time reaction
(h)
Reaction
product
Yielda (%)
d.e.b (%)
1
2
3
4
5
6
7
8
9
7
LiAlH4
LiAlH4
LiAlH4
LiAlH4
t-BuMgCl
MeMgCl
MeMgCl
LiAlH4
LiAlH4
1:5
1:5
1:5
1:10
1:4
1:5
1:5
1:2
1:10
15
15
48
48
48
4
30
31c
32
33
34
35
35
36
36
70
72
56
53
68
71
76
94
78
—
—
—
—
76
72
84
100
80
10
10
11
13
17
17
18
22
72d
15
5
a Yields refer to compounds obtained in each reaction after isolation and purification.
b Determined by integration in 1H NMR spectra of reaction mixtures.
c Detected by MS and characterised by 1H NMR.
d Reaction at room temperature.

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
139
Scheme 6.
Scheme 7. (i) LiAlH4/THF/reflux.
1
AC-200 spectrometer at 200 MHz for H and 50 MHz
for 13C, and on a Bruker AMX-500 spectrometer at 500
1H, Jgem 11.6 Hz, OCHAHB
6
Ph), 4.40 (dd, 1H, J5,6e 5.0
Hz, J6e,6a 10.2 Hz, H-6e), 4.24 (t, 1H, J2,3=J3,4 2.6 Hz,
H-3), 4.07 (dt, 1H, J4,5=J5,6a 9.7 Hz, J5,6e 5.0 Hz, H-5),
3.78 (t, 1H, J5,6a=J6e,6a 10.2 Hz, H-6a), 3.62 (dd, 1H,
J3,4 2.6 Hz, J4,5 9.4 Hz, H-4), 2.7−2.5 (m, 3H, H-2,
MHz for H and 125 MHz for 13C. The chemical shifts
are reported in ppm on the l scale relative to TMS.
1
NCH2
NMR (50 MHz, CDCl3): l 137.2–126.3 (2Ph), 102.2
(PhCH), 99.9 (C-1), 79.5 (C-4), 71.4 (OCH2Ph), 69.1
(C-6), 65.1 (C-3), 63.2 (C-5), 61.6 (C-2), 40.5
(NCH2CH3), 15.3 (NCH2C
H3). HRMS (CI): [M+H]+,
6 CH3), 1.08 (t, 3H, J 7.1 Hz, NCH2CH6 3
). 13C
3.2. Alkyl 4,6-O-benzylidene-2-deoxy-2-ethylamino-
b-D-allopyranosides 3 and 4
6
6
A solution of alkyl 2-acetamido-4,6-O-benzylidene-2-
deoxy-b- -allopyranoside 1 or 2 (10.0 mmol) in dry
6
6
D
found 386.196060. C22H28NO5 requires 386.196748.
Anal. calcd for C22H27NO5: C, 68.55; H, 7.06; N, 3.63.
Found: C, 68.27; H, 7.01; N, 3.63.
THF (200 mL) was stirred under an argon atmosphere
at reflux, 1 M solution of lithium aluminium hydride in
THF (15.0 mmol) was added, and the reaction mixture
stirred under reflux overnight and then left to cool to
room temperature. Saturated aqueous sodium sulphate
solution (4.5 mL) was added dropwise. The solid was
removed by filtration and washed with anhydrous
THF. The filtrate was concentrated to dryness to give a
solid which was recrystallised from 96% ethanol.
3.2.2. 1-Dodecyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-b-D-allopyranoside 4. Yield 3.80 g (82%); mp
122–123°C; [h]D −60.6 (c 0.5, CH2Cl2); MS (CI) m/z
1
464 (100%) [M+H]+. H NMR (200 MHz, CDCl3): l
7.5–7.3 (m, 5H, Ph), 5.53 (PhCH6 ), 4.58 (d, 1H, J1,2 8.0
Hz, H-1), 4.35 (dd, 1H, J5,6e 5.0 Hz, J6e,6a 10.1 Hz,
H-6e), 4.23 (t, 1H, J2,3=J3,4 2.6 Hz, H-3), 4.03 (dt, 1H,
J5,6e 5.0 Hz, J4,5=J5,6a 9.7 Hz, H-5), 3.86 (m, 1H,
3.2.1. Benzyl 4,6-O-benzylidene-2-deoxy-2-ethylamino-b-
D
-allopyranoside 3. Yield 3.35 g (87%); mp 148–149°C;
[h]D −89.8 (c 0.5, CH2Cl2); MS (CI) m/z 386 (100%)
OCHA
3.57 (dd, 1H, J3,4 2.5 Hz, J4,5 9.4 Hz, H-4), 3.45 (m, 1H,
OCHAHBR), 2.7−2.5 (m, 3H, H-2, NCH2CH3), 1.6−1.2
[m, 20H, (CH2)10], 1.11 (t, 3H, J 7.1 Hz, NCH2CH3),
6 HBR), 3.74 (t, 1H, J5,6a=J6e,6a 10.2 Hz, H-6a),
[M+H]+. H NMR (200 MHz, CDCl3): l 7.5–7.3 (m,
1
10H, 2Ph), 5.56 (PhCH
6
), 4.91 (d, 1H, Jgem 11.6 Hz,
OCHAHBPh), 4.69 (d, 1H, J1,2 8.0 Hz, H-1), 4.56 (d,
6
6
6
6

140
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
0.86 (t, 3H, J 6.5 Hz, CH3). 13C NMR (50 MHz,
CDCl3): l 137.2−126.2 (Ph), 102.1 (CHPh), 100.7 (C-1),
79.6 (C-4), 70.2 (OCH2R), 69.1 (C-6), 65.1 (C-3), 63.1
(C-5), 61.7 (C-2), 40.6 (NCH2CH3), 31.8−22.6 [(CH2)10],
15.3 (NCH2C
H3), 14.1 (CH3). HRMS (CI): [M+H]+,
found 464.338053. C27H46NO5 requires 464.337599.
Anal. calcd for C27H45NO5: C, 69.94; H, 9.78; N, 3.02.
Found: C, 69.62; H, 9.83; N, 3.00.
3.4. Formation of N-acetyloxazolidine from benzyl
6
2-amino-4,6-O-benzylidene-2-deoxy-b-D-allopyranoside,
6
acetone and acyl chlorides
6
6
3.4.1. Benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-2-
N-3-O-isopropylidene-b- -allopyranoside 10. A solution
of benzyl 2-amino-4,6-O-benzylidene-2-deoxy-b-
D
D
-
allopyranoside 5 (1.0 g, 2.8 mmol) in dry acetone (100
mL) was stirred at room temperature for 3 h. Distilled
dichloromethane (100 mL) and anhydrous magnesium
sulphate (2.0 g) were added, and the suspension was
stirred for two weeks. Then, the reaction mixture was
filtered through a pad (4 cm diameter×0.5 cm height) of
kieselguhr and the solvent was evaporated to dryness.
The compound obtained, benzyl 2-amino-4,6-O-benzyl-
3.3. Formation of N-acetyloxazolidines from alkyl 2-
acetamido-4,6-O-benzylidene-2-deoxy-b-D-allopyranoside
and dibromomethane
3.3.1. Alkyl 2-acetamido-4,6-O-benzylidene-2-deoxy-2-
N-3-O-methylidene-b- -allopyranosides 7 and 8. To a
solution of the alkyl 2-acetamido-4,6-O-benzylidene-2-
deoxy-b- -allopyranoside 1 or 2 (2.5 mmol) in distilled
idene-2-deoxy-2-N-3-O-isopropylidene-b-D-allopyrano-
D
side 9 {MS (CI) m/z 398 (100%) [M+1]+}, was used
without further purification. To a solution of 9 in
distilled dichloromethane (100 mL) at 0°C, dry pyridine
(10 mL) and acetyl chloride (5.0 mmol) were added.
The reaction mixture was stirred overnight at room
temperature, and then poured into ice water. The
organic phase was washed successively with water, satu-
rated aqueous sodium bicarbonate solution, and
washed with further water. The solution was dried
(MgSO4), filtered, and evaporated to dryness. The solid
obtained was purified by column chromatography using
hexane–ethyl acetate (16:10) as the eluent, yielding 0.80
g (65%); mp 149–150°C; [h]D −53.9 (c 0.5, CH2Cl2); MS
(CI) m/z 440 (100%) [M+H]+. 1H NMR (200 MHz,
D
dichloromethane (50 mL), dibromomethane (50 mL),
50% aqueous sodium hydroxide solution (100 mL) and
tetrabutylammonium bromide (6.5 mg, 0.02 mmol)
were added. The reaction mixture was stirred vigor-
ously under reflux for 2 days, then cooled to room
temperature. The organic phase was washed with water
until neutral, dried (MgSO4), and the solvent was
removed under reduced pressure to give a solid which
was purified by flash chromatography on silica gel.
3.3.2. Benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-2-
N-3-O-methylidene-b-D-allopyranoside 7. Column chro-
matography using hexane–ethyl acetate (15:10) as
eluent yielded 0.85 g (83%); mp 86–87°C; [h]D −68.0 (c
0.5, CH2Cl2); MS (CI) m/z 412 (41%) [M+H]+. 1H
NMR (200 MHz, CDCl3): l 7.5–7.3 (m, 10H, Ph), 5.57
CDCl3): l 7.5–7.3 (m, 10H, 2Ph), 5.56 (s 1H, PhCH
4.89 (d, 1H, Jgem 11.7 Hz, OCHAHBPh), 4.65 (d, 1H,
J1,2 7.6 Hz, H-1), 4.59 (d 1H, Jgem 11.7 Hz,
OCHAHBPh), 4.5–4.4 (m, 2H, H-3, H-6e), 4.0–3.7 (m,
6 ),
6
6
4H, H-5, H-2, H-4, H-6a), 2.18 (s, 3H, CH3CO), 1.58,
1.47 [2s, 6H, OC(CH3)2N]. 13C NMR (50 MHz,
CDCl3): l 168.4 (CꢀO), 136.8–126.4 (2Ph), 102.8
(PhCH
Hz, OCHA
(d, 1H, Jgem 11.3 Hz, OCHAHB
6
), 5.13 (s, 2H, OCH2N), 4.92 (d, 1H, Jgem 11.3
HBPh), 4.64 (d, 1H, J1,2 7.4 Hz, H-1), 4.57
Ph), 4.5–4.4 (m, 2H,
6
(PhC
72.4 (C-3), 71.3 (OC
(C-2), 26.7, 23.8 [OC(C
calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19.
Found: C, 68.17; H, 6.66; N, 3.28.
6
H), 100.6 (C-1), 96.9 [OC
6
(CH3)2N], 76.8 (C-4),
H2Ph), 69.1 (C-6), 63.5 (C-5), 61.8
H3)2N], 24.3 (COCH3). Anal.
6
6
H-3, H-6e), 4.0–3.7 (m, 4H, H-2, H-4, H-5, H-6a), 2.14
(s, 3H, CH3). 13C NMR (50 MHz, CDCl3): l 169.3
6
6
(CꢀO), 136.7–126.3 (2Ph), 102.8 (PhC
6
H), 100.7 (C-1),
H2Ph),
80.5 (OCH2N), 76.6 (C-4), 76.4 (C-3), 71.9 (OC
6
69.0 (C-6), 63.6 (C-5), 60.0 (C-2), 22.6 (CH3). Anal.
calcd for C23H25NO6: C, 67.14; H, 6.12; N, 3.40.
Found: C, 66.91; H, 6.21; N, 3.41.
3.5. Formation of oxazolidine rings from alkyl 4,6-O-
benzylidene-2-deoxy-2-ethylamino-b-D-allopyranosides
and aldehydes
3.3.3. 1-Dodecyl 2-acetamido-4,6-O-benzylidene-2-de-
To a solution of the alkyl 4,6-O-benzylidene-2-deoxy-2-
ethylamino-b- -allopyranoside 3 or 4 (1.0 mmol) in
oxy-2-N-3-O-methylidene-b-
D
-allopyranoside 8. Column
D
,
chromatography using hexane–ethyl acetate (2:1) as
distilled dichloromethane (50 mL), containing 4 A
molecular sieves, the corresponding aldehyde (2.5
mmol) was added. The suspension was stirred until
completion of the reaction (1–2 weeks, TLC). The solid
was removed by filtration, washed with dichloro-
methane, and the organic phase was evaporated to
dryness.
eluent yielded 0.90 g (74%) as a syrup; MS (CI) m/z 490
1
(45%) [M+H]+; H NMR (250 MHz, CDCl3): l 7.5–7.3
(m, 5H, Ph), 5.55 (s, 1H, PhCH6 ), 5.16 (dd, 2H, Jgem
10.8 Hz, OCH2N), 4.51 (d, 1H, J1,2 7.5 Hz, H-1),
4.4–4.3 (m, 2H, H-3, H-6e), 4.0–3.7 (m, 5H, H-2, H-4,
H-5, H-6a, OCH6 AHBR), 3.47 (m, 1H, OCHAH6 BR), 2.19
(s, 3H, CH3CON), 1.6–1.2 [m, 20H, (CH2)10], 0.86 (m,
3H, CH3). 13C NMR (50 MHz, CDCl3): l 168.6 (CꢀO),
3.5.1. (S)-Benzyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-2-N-3-O-ethylidene-b-D-allopyranoside 11. Only
one stereoisomer was obtained, which was purified by
column chromatography using hexane–ethyl ether (4:1)
as eluent, yielding 0.25 g (61%); mp 85–86°C; [h]D
−104.6 (c 0.7, CH2Cl2); MS (CI) m/z 412 [M+H]+
136.4–125.7 (Ph), 101.8 (PhC
6
H), 101.2 (C-1), 79.8
(OCH2N), 76.0 (C-4), 75.7 (C-3), 69.9 (OCH2R), 68.4
(C-6), 62.8 (C-5), 59.3 (C-2), 31.3–22.1 [(CH2)10], 21.9
(C
490.316780. C28H44NO6 requires 490.316864.
6
H3CON), 13.6 (CH3). HRMS (CI): [M+H]+, found

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
141
1
(100%). H NMR (500 MHz, CDCl3): l 7.6–7.3 (m,
10H, 2Ph), 5.57 (s, 1H, PhCH), 4.90 (d, 1H, Jgem 12.2
Hz, OCHAHBPh), 4.66 (d, 1H, Jgem 12.2 Hz,
OCHAHBPh), 4.59 (d, 1H, J1,2 6.0 Hz, H-1), 4.4–4.3 (m,
2H, H-6e, OCH(CH3)N), 4.28 (dd, 1H, J2,3 5.5 Hz, J3,4
(NC
6
H2CH3), 33.5 {OCH[C
6
H(CH3)2]N}, 18.1, 17.4
6
{OCH[CH(C6 H3)2]N}, 14.4 (NCH2C6 H3). HRMS (CI):
6
[M+H]+, found 440.242266. C26H34NO5 requires
6
440.243699.
6
3.3 Hz, H-3), 4.00 (dt, 1H, J4,5=J5,6a 9.9 Hz, J5,6e 5.1
Hz, H-5), 3.94 (dd, 1H, J3,4 3.3 Hz, J4,5 9.7 Hz, H-4),
3.75 (t, 1H, J5,6a=J6e,6a 10.1 Hz, H-6a), 3.04 (t, 1H,
1,2=J2,3 5.8 Hz, H-2), 2.66 (q, 2H, J 7.2 Hz,
NCH2CH3), 1.33 [d, 3H, J 5.3 Hz, OCH(CH3)N], 1.11
(t, 3H, J 7.2 Hz, NCH2CH3
). 13C NMR (50 MHz,
CDCl3): l 137.4–126.3 (2Ph), 102.5 (PhCH), 102.4 (C-
1), 95.1 [OCH(CH3)N], 76.8 (C-4), 73.5 (C-3), 70.7
(OCH2Ph), 69.5 (C-6), 66.2 (C-2), 62.7 (C-5), 47.3
(NCH2CH3), 21.6 [OCH(CH3)N], 14.2 (NCH2CH3).
3.5.4. (S)-Benzyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-2-N-3-O-(trans-3-phenyl-2-propenylidene)-b-D-all-
opyranoside 14. Only one stereoisomer was obtained,
which was purified by column chromatography using
hexane–ethyl ether (7:1) as eluent, yielding 0.25 g
(50%); mp 120–121°C; [h]D −140.0 (c 0.2, CHCl3); MS
(CI) m/z 500 (100%) [M+H]+. 1H NMR (200 MHz,
CDCl3): l 7.5–7.3 (m, 15H, 3Ph), 6.65 (d, 1H, Jtrans 15.8
J
6
6
6
6
6
6
Hz, CHCHꢀCH
Hz, CHCHꢀCHPh), 5.56 (s, 1H, PhCH
Jgem 12.2 Hz, OCHAHBPh), 4.76 (d, 1H, J 6.5 Hz,
CHCHꢀCHPh), 4.65 (d, 1H, Jgem 12.2 Hz,
OCHAHBPh), 4.64 (d, 1H, J1,2 6.1 Hz, H-1), 4.4–4.3 (m,
2H, H-3, H-6e), 4.0–3.9 (m, 2H, H-4, H-5), 3.73 (t, 1H,
5,6e=J6e,6a 9.8 Hz, H-6a), 3.15 (t, 1H, J1,2=J2,3 5.9 Hz,
H-2), 2.72 (q, 2H, J 7.2 Hz, NCH2CH3), 1.09 (t, 3H, J
7.2 Hz, NCH2CH3
). 13C NMR (50 MHz, CDCl3): l
137.6–126.0 (3Ph), 133.4 (CHCHꢀCHPh), 129.0
(CHCHꢀCHPh), 102.6 (PhCH), 101.9 (C-1), 98.7
(CHCHꢀCHPh), 77.0 (C-4), 73.7 (C-3), 70.8 (OCH2Ph),
69.6 (C-6), 66.0 (C-2), 62.8 (C-5), 47.2 (NCH2CH3),
6
Ph), 6.09 (dd, 1H, Jtrans 15.8 Hz, J 6.6
6
6
6
6
6
), 4.90 (d, 1H,
Anal. calcd for C24H29NO5: C, 70.05; H, 7.10; N, 3.40.
Found: C, 70.35; H, 7.25; N, 3.37.
6
6
6
3.5.2. (S)-Benzyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-2-N-3-O-propylidene-b-
D
-allopyranoside 12. Only
J
one stereoisomer was obtained, which was purified by
column chromatography using hexane–ethyl ether
(45:10) as eluent, yielding 0.30 g (71%); mp 112–113°C;
[h]D −98.1 (c 1.0, CH2Cl2); MS (CI) m/z 426 (100%)
6
6
6
6
6
1
[M+H]+. H NMR (250 MHz, CDCl3): l 7.5–7.3 (m,
6
6
10H, 2Ph), 5.54 (s, 1H, PhCH
Hz, OCHAHBPh), 4.64 (d, 1H, Jgem 12.3 Hz,
OCHAHBPh), 4.54 (d, 1H, J1,2 6.7 Hz, H-1), 4.38 (dd,
1H, J5,6e 4.5 Hz, J6e,6a 9.7 Hz, H-6e), 4.3–4.2 [m, 2H,
H-3, OCH(CH2CH3)N], 3.9–3.8 (m, 2H, H-4, H-5),
3.72 (t, 1H, J5,6a=J6e,6a 9.7 Hz, H-6a), 2.98 (dd, 1H, J1,2
6.7 Hz, J2,3 5.3 Hz, H-2), 2.60 (m, 2H, NCH2CH3), 1.57
[m, 2H, OCH(CH2CH3)N], 1.09 (t, 3H, J 7.2 Hz,
NCH2CH3), 0.90 [t, 3H, J 7.5 Hz, OCH(CH2CH3)N].
13C NMR (50 MHz, CDCl3): l 137.5–126.4 (2Ph),
102.6 (PhCH), 102.4 (C-1), 99.7 [OCH(CH2CH3)N],
77.3 (C-4), 73.5 (C-3), 70.8 (OCH2Ph), 69.5 (C-6), 66.2
(C-2), 62.9 (C-5), 48.2 (NCH2CH3), 28.6
[OCH(CH2CH3)N], 14.5 (NCH2CH3), 8.9 [OCH-
(CH2CH3)N]. Anal. calcd for C25H31NO5: C, 70.56; H,
6
), 4.87 (d, 1H, Jgem 12.3
6
+
’
14.2 (NCH2C6 H3). HRMS (EI): [M] , found
6
6
499.235940. C31H32NO5 requires 499.235874.
6
3.5.5. (S)-1-Dodecyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-2-N-3-O-propylidene-b-D-allopyranoside 15. Only
6
one stereoisomer was obtained, which was purified by
column chromatography using hexane–ethyl ether (8:1)
as eluent, yielding 0.30 g (60%) as a syrup; MS (CI) m/z
6
6
6
504 (100%) [M+H]+. H NMR (200 MHz, CDCl3): l
1
6
6
7.5–7.3 (m, 5H, Ph), 5.53 (s, 1H, PhCH
J1,2 6.8 Hz, H-1), 4.35 (dd, 1H, J5,6e 4.5 Hz, J6e,6a 9.9
Hz, H-6e), 4.3–4.2 [m, 2H, H-3, OCH(CH2CH3)N],
4.0–3.8 (m, 3H, H-4, H-5, OCHAHBR), 3.70 (t, 1H,
5,6a=J6e,6a 9.9 Hz, H-6a), 3.46 (m, 1H, OCHAHBR),
2.88 (dd, 1H, J1,2 6.8 Hz, J2,3 5.1 Hz, H-2), 2.57 (m, 2H,
J 7.2 Hz, NCH2CH3), 1.7–1.6 [m, 2H, OCH(CH2
CH3)N], 1.5–1.3 [m, 20H, (CH2)10], 1.10 (t, 3H, J 7.2
Hz, NCH2CH3), 0.98 [t, 3H, 7.4 Hz, OCH
(CH2CH3
)N] 0.88 (m, 3H, CH3). 13C NMR (50 MHz,
CDCl3): l 137.2–126.4 (Ph), 103.8 (PhCH), 102.6 (C-1),
99.6 [OCH(CH2CH3)N], 77.3 (C-4), 73.7 (C-3), 70.3
(OCH2R), 69.5 (C-6), 66.2 (C-2), 62.7 (C-5), 48.0
(NCH2CH3), 31.9–22.6 [(CH2)10], 28.6 [OCH(CH2-
CH3)N], 14.5 (NCH2CH3), 14.1 (CH3), 8.9 [OCH(CH2-
6 ), 4.42 (d, 1H,
6
6
6
6
6
6
6
J
6
7.34; N, 3.29. Found: C, 70.36; H, 7.29; N, 3.38.
6
6
3.5.3. (S)-Benzyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
amino-2-N-3-O-isobutylidene-b-
D
-allopyranoside
13.
6
J
Only one stereoisomer was obtained, which was
purified by column chromatography using hexane–ethyl
ether (7:1) as eluent, yielding 0.25 g (57%) as a syrup;
MS (CI): m/z 440 (100%) [M+H]+. 1H NMR (500 MHz,
CDCl3): l 7.5–7.3 (m, 10H, 2Ph), 5.60 (s, 1H, PhCH
4.88 (d, 1H, Jgem 12.4 Hz, OCHAHBPh), 4.66 (d, 1H,
Jgem 12.4 Hz, OCHAHBPh), 4.55 (s, 1H, J1,2 7.0 Hz,
6
6
6
6
6
),
6
6
6
6
6
C6
H3)N]. HRMS (CI): [M+H]+, found 504.368496.
H-1), 4.39 (dd, 1H, J5,6e 5.0 Hz, J6e,6a 10.3 Hz, H-6e),
4.22 (dd, 1H, J2,3 4.9 Hz, J3,4 3.3 Hz, H-3), 4.02 {d, 1H,
C30H50NO5 requires 504.368899.
J 5.7 Hz, OCH
6
[CH(CH3)2]N}, 3.90 (dt, 1H, J4,5=J5,6a
3.5.6. (S)-1-Dodecyl 4,6-O-benzylidene-2-deoxy-2-ethyl-
9.8 Hz, J5,6e 5.0 Hz, H-5), 3.84 (dd,1H, J3,4 3.3 Hz, J4,5
9.6 Hz, H-4), 3.75 (t, 1H, J5,6a=J6e,6a 10.2 Hz, H-6a),
2.97 (dd, 1H, J1,2 7.0 Hz, J2,3 5.0 Hz, H-2), 2.58 (m, 2H,
amino-2-N-3-O-(2-phenylethylidene)-b-D-allopyranoside
16. Only one stereoisomer was obtained, which was
purified by column chromatography using hexane–ethyl
ether (10:1) as eluent, yielding 0.40 g (71%) as a syrup;
NCH2
3H, J 7.1 Hz, NCH2CH3
OCH[CH(CH3 2
) ]N}. 13C NMR (50 MHz, CDCl3): l
137.3–126.2 (2Ph), 103.2 (PhCH), 102.1 (C-1), 101.9
{OCH[CH(CH3)2]N}, 77.2 (C-4), 73.3 (C-3), 70.5
(OCH2Ph), 69.2 (C-6), 65.9 (C-2), 62.7 (C-5), 48.7
6
CH3), 1.64 {m, 1H, OCH[CH
6 (CH3)2]N}, 1.12 (t,
1
6
), 0.93, 0.92 {2d, 6H, J 6.7 Hz,
MS (CI) m/z 566 (100%) [M+H]+. H NMR (200 MHz,
6
CDCl3): l 7.5–7.2 (m, 10H, 2Ph), 5.51 (s, 1H, PhCH
4.51 [t, 1H, J 4.2 Hz, OCH(CH2Ph)N], 4.30 (d, 1H,
H-1), 4.17 (dd, 1H, J5,6e 4.5 Hz, J6e,6a 10.0 Hz, H-6e),
3.8–3.6 (m, 5H, H-3, H-5, H-4, H-6a, OCHAHBR), 3.20
6 ),
6
6
6
6
6

142
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
(m, 1H, OCHAHB
2.79 (dd, 1H, J1,2 7.1 Hz, J2,3 5.0 Hz, H-2), 2.45 (m, 2H,
NCH2CH3), 1.5–1.2 [m, 20H, (CH2)10], 1.02 (t, 3H, J
7.1 Hz, NCH2CH3
), 0.88 (m, 3H, CH3). 13C NMR (50
MHz, CDCl3): l 137.2–126.2 (2Ph), 103.8 (PhCH),
102.5 (C-1), 98.6 [OCH(CH2Ph)N], 77.3 (C-4), 73.8
(C-3), 70.4 (OCH2R), 69.4 (C-6), 66.1 (C-2), 62.8 (C-5),
47.9 (NCH2CH3), 41.3 [OCH(CH2Ph)N], 31.9–22.6
[(CH2)10], 14.5 (NCH2CH3), 14.1 (CH3). HRMS (EI):
6
R), 2.98 [m, 2H, OCH(CH2
6
Ph)N],
H-1), 4.39 (dd, 1H, J5,6e 4.3 Hz, J6e,6a 9.6 Hz, H-6e),
4.30 (dd, 1H, J2,3 4.5 Hz, J3,4 3.0 Hz, H-3), 3.9−3.7 (m,
6
3H, H-4, H-5, H-6a), 3.35 (m, 1H, CHA
1H, J1,2 7.5 Hz, J2,3 4.5 Hz, H-2), 2.65 (m, 1H,
CHAHBN), 1.8−1.7 [m, 4H, (CH2)2], 1.36 (s, 3H, CH3).
13C NMR (50 MHz, CDCl3): l 137.5−126.4 (Ph), 106.6
(OCN), 102.6 (PhCH), 101.4 (C-1), 77.6 (C-4), 71.7
(C-3), 70.9 (OCH2Ph), 69.6 (C-2), 69.3 (C-6), 62.8
6 HBN), 2.96 (dd,
6
6
6
6
6
6
6
6
6
(C-5), 55.6 (CH2N), 38.2, 24.4 [(CH2)2], 28.8 (CH3).
HRMS (EI): [M]+, found 423.205276. C25H29NO5
requires 423.204573. Anal. calcd for C25H29NO5: C,
70.90; H, 6.90; N, 3.31. Found: C, 70.63; H, 6.80; N,
3.35.
+
’
[M] , found 565.375782. C35H51NO5 requires
565.376724.
3.6. General procedure for the formation of bicyclic
pyrrolidines from alkyl 2-amino-4,6-O-benzylidene-2-
deoxy-b-
D
-allopyranosides and g-chlorocarbonyl
3.6.3. (2S)-2-Phenyl-2,3-propylen-(benzyl 2-amino-4,6-
compounds
O-benzylidene-2,3-dideoxy-b- -allopyranoside)[2,3-d][1,3]
D
oxazolidine 19. Only one stereoisomer was obtained,
which was purified by column chromatography using
hexane–diethyl ether (8:1) as eluent, yielding 0.15 g
(31%) (0.1 g of starting material was recovered); mp
162–163°C; [h]D −90.9 (c 0.5, CH2Cl2); MS (CI) m/z
486 (40%) [M+H]+. 1H NMR (200 MHz, CDCl3): l
To a solution of alkyl 2-amino-4,6-O-benzylidene-2-
deoxy-b- -allopyranoside 5 or 6 (1.0 mmol) in distilled
D
dichloromethane (15 mL), triethylamine (1.2 mmol)
and the corresponding g-chlorocarbonyl compound (1.2
mmol) were added. The solution was stirred at room
temperature until completion of the reaction (1–2
weeks, TLC). Then, the solids were removed by filtra-
tion and the solution was washed successively with
saturated aqueous solution of sodium bicarbonate and
water, dried (MgSO4), filtered, and the filtrate evapo-
rated to dryness. The solid obtained was purified by
flash chromatography on silica gel.
7.6−7.2 (m, 15H, 3Ph), 5.53 (s, 1H, PhCH
Jgem 11.9 Hz, OCHAHBPh), 4.49 (dd, 1H, J2,3 4.3 Hz,
J3,4 3.3 Hz, H-3), 4.32 (d, 1H, Jgem 11.9 Hz,
OCHAHBPh), 4.23 (dd, 1H, J5,6e 4.4 Hz, J6e,6a 9.6 Hz,
6 ), 4.67 (d, 1H,
6
6
H-6e), 4.08 (d, 1H, J1,2 7.6 Hz, H-1), 3.77 (dd, 1H, J3,4
3.3 Hz, J4,5 9.1 Hz, H-4), 3.67 (t, 1H, J5,6a=J6e,6a 9.9
Hz, H-6a), 3.6–3.5 [m, 2H, H-5, NCHA
(dd, 1H, J1,2 7.6 Hz, J2,3 4.4 Hz, H-2), 2.88 [m, 1H,
NCHAHB(CH2)], 2.22 (m, 1H, NCH2CHAHBCH2), 2.03
(m, 1H, NCH2CHAHBCH2), 1.8−1.7 (m, 2H, NCH2
CH2CH2
). 13C NMR (50 MHz, CDCl3): l 146.7−125.5
(Ph), 108.6 [OC(Ph)N], 102.7 (PhCH), 100.7 (C-1), 77.9
(C-4), 72.9 (C-3), 71.8 (OCH2Ph), 69.7 (C-2), 69.2
(C-6), 62.6 (C-5), 55.8 [NCH2(CH2)2], 42.6, 24.9
[NCH2(CH2)2]. Anal. calcd for C30H31NO5: C, 74.21;
6 HB(CH2)], 3.22
3.6.1. (2R)-2,3-Propylen-(benzyl 2-amino-4,6-O-benzyli-
6
6
dene-2,3-dideoxy-b-
D
-allopyranoside)[2,3-d][1,3]oxazolid-
6
ine 17. Only one stereoisomer was obtained, which was
purified by column chromatography using hexane–ethyl
acetate (27:10) as eluent, yielding 0.25 g (61%); mp
132–133°C; [h]D −80.0 (c 0.6, CHCl3); MS (CI) m/z 410
6
6
6
6
6
1
(100%) [M+H]+. H NMR (500 MHz, CDCl3): l 7.6−
6
7.3 (m, 10H, 2Ph), 5.55 (s, 1H, PhCH
OCHN), 4.92 (d, 1H, Jgem 11.8 Hz, OCHA
(d, 1H, Jgem 11.8 Hz, OCHAHBPh), 4.55 (d, 1H, J1,2 6.9
6
), 5.20 (dd, 1H,
H, 6.43; N, 2.88. Found: C, 74.07; H, 6.47; N, 2.88.
6
HBPh), 4.68
6
3.6.4. (2R)-2-Methyl-2,3-propylen-(1-dodecyl 2-amino-
Hz, H-1), 4.40 (dd, 1H, J5,6e 4.5 Hz, J6e,6a 10.5 Hz,
H-6e), 4.30 (dd, 1H, J2,3 4.7 Hz, J3,4 2.6 Hz, H-3),
3.8−3.7 (m, 3H, H-4, H-5, H-6a), 3.32 (dd, 1H, J1,2 6.9
4,6-O-benzylidene-2,3-dideoxy-b- -allopyranoside)[2,3-d]
D
[1,3]oxazolidine 20. Only one stereoisomer was
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (3:1) as eluent, yielding
0.40 g (80%); mp 56–57°C; [h]D −53.3 (c 0.5, CH2Cl2);
Hz, J2,3 4.7 Hz, H-2), 3.25 (m, 1H, CHA
1H, CHAHB
N), 2.2–1.7 [m, 4H, (CH2)2]. 13C NMR (50
MHz, CDCl3): 137.4−126.4 (Ph), 102.6 (PhCH), 100.6
(C-1), 99.3 (OCHN), 78.0 (C-4), 71.1 (OCH2Ph), 70.9
6 HBN), 2.64 (m,
6
1
6
MS (CI) m/z 502 (44%) [M+H]+. H NMR (200 MHz,
6
CDCl3): l 7.5–7.3 (m, 5H, Ph), 5.53 (s, 1H, PhCH6 ),
(C-3), 69.3 (C-6), 69.1 (C-2), 62.8 (C-5), 53.7 (CH2N),
32,8, 24,1 [(CH2)2]. HRMS (EI): [M]+, found
409.186911. C24H27NO5 requires 409.188923. Anal.
calcd for C24H27NO5: C, 70.40; H, 6.65; N, 3.42.
Found: C, 70.22; H, 6.68; N, 3.40.
4.49 (d, 1H, J1,2 7.5 Hz, H-1), 4.37 (dd, 1H, J5,6e 4.5 Hz,
J6e,6a 9.6 Hz, H-6e), 4.28 (t, 1H, J2,3=J3,4 4.4 Hz, H-3),
3.9–3.7 (m, 4H, H-4, H-5, H-6a, OCHA
1H, OCHAHBR), 3.32 [m, 1H, (CH2)2CHA
(dd, 1H, J1,2 7.5 Hz, J2,3 4.4 Hz, H-2), 2.63 [m, 1H,
(CH2)2CHAHBN], 1.8–1.6 [m, 4H, (CH2)CH2N], 1.48 [s,
6
HBR), 3.53 (m,
6
6
HBN], 2.86
6
6
3.6.2. (2R)-2-Methyl-2,3-propylen-(benzyl 2-amino-4,6-
3H, OC(CH3)N], 1.24 [m, 20H, (CH2)10], 0.86 (t, 1H, J
O-benzylidene-2,3-dideoxy-b- -allopyranoside)[2,3-d][1,3]
D
6.5 Hz, CH3). 13C NMR (50 MHz, CDCl3): l 137.2−
126.4 (Ph), 106.6 [OC
(C-1), 77.6 (C-4), 71.7 (C-3), 70.3 (OC
69.4 (C-6), 62.7 (C-5), 55.8 [(CH2)2C
oxazolidine 18. Only one stereoisomer was obtained,
which was purified by column chromatography using
hexane–ethyl acetate (2:1) as eluent, yielding 0.30 g
(71%); mp 122–123°C; [h]D −82.8 (c 0.4, CH2Cl2); MS
(CI) m/z 424 (100%) [M+H]+. 1H NMR (200 MHz,
6 (CH3)N], 102.6 (PhC6 H), 102.4
6
H2R), 69.7 (C-2),
H2N]; 38.2, 24.4
6
[(C6 H2)2CH2N], 31.9−22.7 [(CH2)10], 29.0 [OC(C6 H3)N],
14.1 (CH3). HRMS (CI): [M+H]+, found 502.353026.
C30H48NO5 requires 502.353249. Anal. calcd for
C30H47NO5: C, 71.82; H, 9.44; N, 2.79. Found: C,
71.59; H, 9.44; N, 2.72.
CDCl3): l 7.5−7.3 (m, 10H, 2Ph), 5.54 (s, 1H, PhCH
4.90 (d, 1H, Jgem 12.1 Hz, OCHAHBPh), 4.69 (d, 1H,
Jgem 12.1 Hz, OCHAHBPh), 4.61 (d, 1H, J1,2 7.5 Hz,
6 ),
6
6

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
143
3.6.5. (2S)-2-Phenyl-2,3-propylen-(1-dodecyl 2-amino-
4,6-O-benzylidene-2,3-dideoxy-b- -allopyranoside)[2,3-d]
(C
6
H2CH2CON), 33.5 (CH2C
6
H2CON), 26.8 (CH3).
D
Anal. calcd for C25H27NO6: C, 68.63; H, 6.22; N, 3.20.
Found: C, 68.44; H, 6.51; N, 3.14.
[1,3]oxazolidine 21. Only one stereoisomer was
obtained, which was purified by column chromatogra-
phy using hexane–diethyl ether (10:1) as eluent, yielding
0.35 g (62%); mp 90–91°C; [h]D +38.5 (c 0.5, CH2Cl2);
3.7.1.2. d-Lactam of (R)-benzyl 2-amino-4,6-O-benzyl-
idene-2-deoxy-2-N-3-O-(4-carboxy-1-methylbutylidene)-
b-D-allopyranoside 24. Only one stereoisomer was
1
MS (CI) m/z 564 (100%) [M+H]+. H NMR (500 MHz,
CDCl3): l 7.7–7.2 (m, 10H, 2Ph), 5.51 (s, 1H, PhCH
6
),
obtained, which was purified by column chromatogra-
phy using dichloromethane–methanol (150:1) as eluent,
yielding 0.65 g (72%); mp 88–89°C; [h]D −57.8 (c 0.5,
CH2Cl2); IR (KBr) 1663 cm−1; MS (CI) m/z 452 (57%)
4.49 (dd, 1H, J2,3 4.3 Hz, J3,4 3.2 Hz, H-3), 4.23 (dd,
1H, J5,6e 5.2 Hz, J6e,6a 10.3 Hz, H-6e), 3.94 (d, 1H, J1,2
7.7 Hz, H-1), 3.75 (dd, 1H, J3,4 3.2 Hz, J4,5 9.4 Hz,
H-4), 3.66 (t, 1H, J5,6a=J6e,6a 10.3 Hz, H-6a), 3.6–3.5
[M+H]+. H NMR (500 MHz, Me2CO-d6): l 7.5–7.2
1
[m, 3H, H-5, OCHA
1H, OCHAHBR), 3.14 (dd, 1H, J1,2 7.7 Hz, J2,3 4.4 Hz,
H-2), 2.89 [m, 1H, (CH2)2CHAHBN], 2.3–1.8 [m, 4H,
(CH2)2CH2N], 1.5–1.2 [m, 20H, (CH2)10], 0.87 (t, 1H, J
6.9 Hz, CH3). 13C NMR (50 MHz, CDCl3): l 146.9−
125.5 (2Ph), 108.5 (OCN), 102.7 (PhCH), 100.6 (C-1),
78.1 (C-4), 72.9 (C-3), 70.2 (OCH2R), 69.7 (C-2), 69.2
(C-6), 62.6 (C-5), 55.7 [(CH2)2CH2N], 42.6, 24.9
6
HBR, (CH2)2CHA
6
HBN], 3.24 (m,
(m, 10H, 2Ph), 5.70 (s, 1H, PhCH
12.7 Hz, OCHAHBPh), 4.74 (d, 1H, J1,2 6.7 Hz, H-1),
4.63 (d, 1H, Jgem 12.7 Hz, OCHAHBPh), 4.57 (dd, 1H,
J1,2 6.7 Hz, J2,3 4.8 Hz, H-2), 4.39 (dd, 1H, J2,3 4.8 Hz,
J3,4 3.2 Hz, H-3), 4.32 (dd, 1H, J5,6e 5.1 Hz, J6e,6a 10.2
Hz, H-6e), 4.04 (dd, 1H, J3,4 3.2 Hz, J4,5 9.6 Hz, H-4),
3.92 (dt, 1H, J4,5=J5,6a 9.9 Hz, J5,6e 5.1 Hz, H-5), 3.79
(t, 1H, J5,6a=J6e,6a 10.2 Hz, H-6a), 2.40 (m, 1H,
CH2CH2CHA
CHAHBCON), 1.9–1.6 (m, 3H, CH2
1.65 (m, 1H, CH2CHAHBCH2CON), 1.34 (s, 3H, CH3).
13C NMR (125 MHz, Me2CO-d6): l 169.5 (CꢀO),
139.0–127.3 (2Ph), 103.0 (PhCH), 101.2 (C-1), 96.2
(OCN), 77.4 (C-4), 73.3 (C-3), 70.7 (OCH2Ph), 69.9
(C-6), 64.3 (C-5), 60.0 (C-2), 34.7 (CH2CH2CH2CON),
29.1 (CH2CH2CH2CON), 15.5 (CH2CH2CH2CON),
6 ), 4.85 (d, 1H, Jgem
6
6
6
6
6
6
6
6
[(C6
H2)2CH2N], 31.9−22.6 [(CH2)10], 14.1 (CH3). HRMS
6
HBCON), 2.28 (m, 1H, CH2CH2-
(CI): [M+H]+, found 564.368739. C35H50NO5 requires
564.368899. Anal. calcd for C35H49NO5: C, 74.56; H,
8.76; N, 2.48. Found: C, 74.26; H, 8.56; N, 2.36.
6
6
CHAHBCH2CON),
6
6
6
3.7. Formation of g- and d-bicyclic lactams from alkyl
6
2-amino-4,6-O-benzylidene-2-deoxy-b-
D
-allopyranosides
6
and g- or d-keto-acids
6
6
26.0 (CH3). Anal. calcd for C26H29NO6: C, 69.16; H,
6.47; N, 3.10. Found: C, 69.13; H, 6.60; N, 2.99.
3.7.1. Method A. To a solution of benzyl 2-amino-4,6-
O-benzylidene-2-deoxy-b- -allopyranoside 5 (0.71 g,
D
2.0 mmol) in distilled dichloromethane (50 mL), con-
3.7.1.3. g-Lactam of (R)-1-dodecyl 2-amino-4,6-O-ben-
zylidene-2-N-3-O-(3-carboxy-1-methylpropylidene)-2-de-
oxy-b-D-allopyranoside 26. Only one stereoisomer was
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (22:10) as eluent, yield-
ing 1.35 g (87%); mp 72–73°C; [h]D −36.4 (c 0.4,
CHCl3); MS (CI) m/z 516 (72%) [M+H]+. 1H NMR
(200 MHz, Me2CO-d6): l 7.5–7.3 (m, 5H, Ph), 5.64 (s,
,
taining 4 A molecular sieves, 4-acetylbutyric acid (0.52
g, 4.0 mmol) was added, and the reaction mixture was
stirred for 2 weeks at room temperature. Then, the
solid was removed by filtration through a pad (4 cm
diameter×0.5 cm height) of kieselguhr, and the organic
phase was washed successively with water, saturated
aqueous solution of sodium bicarbonate and water,
dried (MgSO4), filtered, and the filtrate evaporated to
dryness.
1H, PhCH6 ), 4.64 (d, 1H, J1,2 7.5 Hz, H-1), 4.32 (dd,
1H, J5,6e 3.6 Hz, J6e,6a 9.3 Hz, H-6e), 4.23 (dd, 1H, J2,3
4.7 Hz, J3,4 2.3 Hz, H-3), 4.04 (dd, 1H, J1,2 7.5 Hz, J2,3
4.7 Hz, H-2), 3.9–3.6 (m, 4H, H-4, H-5, H-6a,
3.7.1.1. g-Lactam of (R)-benzyl 2-amino-4,6-O-benzyl-
idene-2-N-3-O-(3-carboxy-1-methylpropylidene)-2-de-
OCH
CH2CHA
6
AHBR), 3.50 (m, 1H, OCHAHB
6
R), 2.61 (m, 1H,
CHAHBCON),
oxy-b-
D
-allopyranoside 22. Only one stereoisomer was
6
HBCON), 2.3–2.1 (m, 3H, CH2
6
6
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (18:10) as eluent, yield-
ing 1.10 g (84%); mp 102–103°C; [h]D −28.8 (c 0.6,
CH2Cl2); IR (KBr) 1717 cm−1; MS (CI) m/z 438 (68%)
1.62 (s, 3H, CH3), 1.30 [m, 20H, (CH2)10], 0,90 (m, 3H,
CH3). 13C NMR (50 MHz, Me2CO-d6): l 178.6 (CꢀO),
138.7–127.0 (Ph), 102.6 (PhC6 H), 101.4 (C-1), 101.2
(OCN), 77.0 (C-4), 75.7 (C-3), 70.0 (OCH2R), 69.5
(C-6), 63.8 (C-5), 60.9 (C-2), 37.6 (CH2CH2CON), 33.3
(CH2CH2CON), 32.5–23.9 [(CH2)10], 27.0 (CH3), 14.3
’
[OCH2(CH2)10C6 H3]. HRMS (EI): [M] , found
1
[M+H]+. H NMR (500 MHz, Me2CO-d6): l 7.5–7.2
6
(m, 10H, 2Ph), 5.7 (s, 1H, PhCH
12.5 Hz, OCHAHBPh), 4.69 (d, 1H, J1,2 7.6 Hz, H-1),
4.66 (d, 1H, Jgem 12.5 Hz; OCHAHBPh), 4.35 (dd, 1H,
6
), 4.87 (d, 1H, Jgem
6
+
6
6
515.322745. C30H45NO6 requires 515.324689.
J5,6e 4.8 Hz, J6e,6a 10.0 Hz, H-6e), 4.29 (dd, 1H, J2,3 4.7
Hz, J3,4 3.3 Hz, H-3), 4.12 (dd, 1H, J1,2 7.6 Hz, J2,3 4.7
Hz, H-2), 3.97 (dd, 1H, J3,4 3.3 Hz, J4,5 9.5 Hz, H-4),
3.86 (dt, 1H, J4,5=J5,6a 9.7 Hz, J5,6e 4.8 Hz, H-5), 3.79
(t, 1H, J5,6a=J6e,6a 10.0 Hz, H-6a), 2.68 (m, 1H,
3.7.2. Method B. A solution of the alkyl 2-amino-4,6-O-
benzylidene-2-deoxy-b- -allopyranoside 5 or 6 (3.0
D
mmol), the g- or d-keto-acid (7.0 mmol) and p-toluene-
sulphonic acid (0.7 mmol) in toluene (150 mL) was
stirred under reflux using a Dean–Stark apparatus.
When TLC showed that all starting compound had
been consumed (ꢀ12 h), the reaction mixture was
evaporated to dryness. The evaporation residue was
dissolved in dichloromethane (200 mL), and the solu-
CH2CHA
1.41 (s, 3H, CH3). 13C NMR (125 MHz, Me2CO-d6): l
178.7 (CꢀO), 139.0–127.3 (2Ph), 102.9 (PhCH), 101.4
(OCN), 100.4 (C-1), 77.3 (C-4), 76.0 (C-3), 71.0
(OCH2Ph), 69.7 (C-6), 64.2 (C-5), 61.1 (C-2), 37.8
6 HBCON), 2.3–2,1 (m, 3H, CH6 2CHAH6 BCON),
6
6

144
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
tion was washed successively with water, saturated
aqueous sodium bicarbonate solution and water, then
dried (MgSO4), filtered, and the filtrate evaporated to
dryness. The solid obtained was purified by flash chro-
matography on silica gel.
1.55 g (90%) as a syrup; MS (CI): m/z 578 (38%)
1
[M+H]+. H NMR (500 MHz, CDCl3): l 7.6–7.3 (m,
10H, 2Ph), 5.53 (s, 1H, PhCH6 ), 4.39 (m, 1H, H-3), 4.33
(dd, 1H, J1,2 7.6 Hz, J2,3 4.6 Hz, H-2), 4.22 (dd, 1H,
J5,6e 5.3 Hz, J6e,6a 10.4 Hz, H-6e), 4.04 (d, 1H, J1,2 7.6
Hz, H-1), 3.80 (dd, 1H, J3,4 3.3 Hz, J4,5 9.5 Hz, H-4),
3.67 (t, 1H, J5,6a=J6e,6a 10.4 Hz, H-6a), 3.61 (m,
3.7.2.1. g-Lactam of (S)-benzyl 2-amino-4,6-O-ben-
zylidene-2-N-3-O-(3-carboxy-1-phenylpropylidene)-2-de-
OCHA
6
HBR), 3.52 (dt, 1H, J4,5=J5,6a 9.9 Hz, J5,6e 5.3
R), 2.74 (m, 1H,
oxy-b-
D
-allopyranoside 23. Only one stereoisomer was
Hz, H-5), 3.20 (m, OCHAHB
6
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (22:10) as eluent, yield-
ing 1.05 g (70%); mp 82–83°C; [h]D +54.5 (c 0.4,
CH2Cl2); IR (KBr) 1723 cm−1; MS (CI) m/z 500 (18%)
CH2CH6 AHBCON), 2.5–2.4 (m, 3H, CH6 2CHAH6 BCON),
0.86 (t, 3H, J 6.3 Hz, CH3). 13C NMR (125 MHz,
CDCl3): l 178.6 (CꢀO), 143.5–124.3 (2Ph), 102.7
(PhC
6 H), 102.4 (OCN), 99.1 (C-1), 76.9 (C-4), 76.1
1
[M+H]+. H NMR (500 MHz, Me2CO-d6): l 7.5–7.3
(C-3), 70.2 (OC6 H2R), 69.1 (C-6), 59.9 (C-5), 39.2
(m, 15H, 3Ph), 5.68 (s, 1H, PhCH
12.3 Hz, OCHAHBPh), 4.51 (t, 1H, J2,3=J3,4 3.4 Hz,
H-3), 4.4–4.3 (m, 2H, H-2, OCHAHBPh), 4.22 (dd, 1H,
6
), 4.70 (d, 1H, Jgem
(C6 H2CH2CON), 32.6 (CH2C6 H2CON), 31.9–22.7
6
[(CH2)10], 14.1 (CH3). HRMS (CI): [M+H]+, found
6
578.347048. C35H48NO6 requires 578.348164.
J5,6e 5.3 Hz, J6e,6a 10.3 Hz, H-6e), 4.18 (d, 1H, J1,2 7.7
Hz, H-1), 3.98 (dd, 1H, J3,4 3.4 Hz, J4,5 9.6 Hz, H-4),
3.72 (t, 1H, J5,6a=J6e,6a 10.3 Hz, H-6a), 3.47 (dt, 1H,
3.7.2.4. g-Lactam of (R)-benzyl 2-amino-4,6-O-benzyl-
idene-2-N-3-O-(2-carboxybenzylidene)-2-deoxy-b-D-allo-
J
4,5=J5,6a 9.9 Hz, J5,6e 5.3 Hz, H-5), 2.67 (m, 1H,
CH2CHAHBCON), 2.49 (m, 1H, CHAHBCH2CON),
2.4–2.3 (m, 2H, CHAHBCHAHB
CON). 13C NMR (125
MHz, Me2CO-d6): l 179.0 (CꢀO), 139.0–125.1 (3Ph),
103.1 (OCN), 102.8 (PhCH), 99.9 (C-1), 77.4 (C-4), 76.8
(C-3), 71.4 (OCH2Ph), 69.4 (C-6), 64.1 (C-5), 61.0
(C-2), 39.7 (CH2CH2CON), 32.9 (CH2CH2CON). Anal.
pyranoside 28. Only one stereoisomer was obtained,
which was purified by column chromatography using
hexane–ethyl acetate (28:10) as eluent, yielding 0.80 g
(57%); mp 182–183°C; [h]D −20.0 (c 0.6, CHCl3); IR
6
6
6
6
1
6
(KBr) 1720 cm−1; MS (CI) m/z 472 (100%) [M+H]+. H
6
NMR (500 MHz, CDCl3): l 7.8–7.3 (m, 14H, Ar), 6.14
6
6
(s, 1H, OCHN), 5.55 (s, 1H, PhCH
12.1 Hz, OCHAHBPh), 4.81 (d, 1H, J1,2 5.8 Hz, H-1),
4.70 (d, 1H, Jgem 12.1 Hz, OCHAHBPh), 4.58 (t, 1H,
6 ), 4.95 (d, 1H, Jgem
calcd for C30H29NO6: C, 72.13; H, 5.85; N, 2.80.
Found: C, 71.93; N, 6.17; H, 2.78.
6
6
J
1,2=J2,3 5.8 Hz, H-2), 4.5–4.4 (m, 2H, H-3, H-6e),
3.7.2.2. d-Lactam of (S)-benzyl 2-amino-4,6-O-benzyl-
idene-2-N-3-O-(4-carboxy-1-phenylbutylidene)-2-deoxy-
4.1–4.0 (m, 2H, H-4, H-6a), 3.78 (m, 1H, H-5). 13C
NMR (50 MHz, CDCl3): l 173.6 (CꢀO), 143.8–123.9
b-D
-allopyranoside 25. Only one stereoisomer was
(Ar), 102.5 (PhC6 H), 98.9 (C-1), 92.2 (OCN), 76.8 (C-4),
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (2:1) as eluent, yielding
1.10 g (71%); mp 154–155°C; [h]D −41.7 (c 0.2,
CH2Cl2); IR (KBr) 1673 cm−1; MS (CI) m/z 514 (40%)
76.6 (C-3), 70.7 (OC6 H2Ph), 69.5 (C-6), 63.6 (C-5), 59.4
(C-2). Anal. calcd for C28H25NO6: C, 71.32; H, 5.34; N,
2.97. Found: C, 71.05; H, 5.59; N, 2.66.
1
[M+H]+. H NMR (500 MHz, CDCl3): l 7.5–7.2 (m,
3.7.2.5. g-Lactam of (R)-benzyl 2-amino-4,6-O-benzyl-
idene-2-N-3-O-[1-(2-carboxyphenyl)ethylidene]-2-deoxy-b-
10H, 3Ph), 5.53 (s, 1H, PhCH
Hz, J2,3 5.0 Hz, H-2), 4.76 (d, 1H, Jgem 12.5 Hz,
OCHAHBPh), 4.46 (dd, 1H, J2,3 5.0 Hz, J3,4 3.2 Hz,
H-3), 4.38 (d, 1H, Jgem 12.5 Hz, OCHAHBPh), 4.30 (d,
6 ), 4.92 (dd, 1H, J1,2 6.8
D-allopyranoside 29. Only one stereoisomer was
6
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (34:10) as eluent, yield-
ing 1.30 g (90%); mp 107–108°C; [h]D −73.5 (c 0.5,
CHCl3); MS (CI) m/z 486 (65%) [M+H]+. 1H NMR
(200 MHz, CDCl3): l 7.8−7.3 (m, 14H, Ar), 5.52 (s, 1H,
6
1H, J1,2 6.8 Hz, H-1), 4.19 (dd, 1H, J5,6e 5.3 Hz, J5,6a
10.4 Hz, H-6e), 3.88 (dd, 1H, J3,4 3.2 Hz, J4,5 9.6 Hz,
H-4), 3.66 (t, 1H, J5,6a=J6e,6a 10.4 Hz, H-6a), 3.43 (dt,
1H, J4,5=J5,6a 9.9 Hz, J5,6e 5.3 Hz, H-5), 2.5–2.4 (m,
PhCH
(d, 1H, J1,2 7.3 Hz, H-1), 4.74 (d, 1H, Jgem 12.5 Hz,
OCHAHBPh), 4.5−4.4 (m, 2H, H-3, H-6e), 4.17 (dd, 1H,
6 ), 4.99 (d, 1H, Jgem 12.5 Hz, OCH6 AHBPh), 4.87
2H, CH2CH2CH2
HBCH2CON), 1.86 (m, 1H, CH2CHAHB
1.70 (m, 1H, CHAHBCH2CH2CON), 1.31 (m, 1H,
CHAHB
CH2CH2CON). 13C NMR (50 MHz, CDCl3): l
170.0 (CꢀO), 142.0–125.4 (3Ph), 102.7 (PhCH), 99.1
(C-1), 97.9 (OCN), 76.8 (C-4), 73.4 (C-3), 70.6
(OCH2Ph), 69.1 (C-6), 62.7 (C-5), 59.3 (C-2), 36.7
(CH2CH2CH2CON), 29.5 (CH2CH2CH2CON), 14.5
(CH2CH2CH2CON). Anal. calcd for C31H31NO6: C,
6
CON), 2.21 (m, 1H, CH2CHA
6 -
6
CH2CON),
6
6
J1,2 7.5 Hz, J2,3 3.0 Hz, H-2), 3.97 (m, 1H, H-5), 3.8−3.7
(m, 2H, H-4, H-6a), 1.56 (s, 3H, CH3). 13C NMR (50
MHz, CDCl3): l 175.2 (CꢀO), 149.2−123.1 (Ar), 102.5
6
6
(C-1), 100.4 (OCN), 98.3 (PhC
6
H), 76.7 (C-4), 76.6
6
(C-3), 70.4 (OC6 H2Ph), 69.2 (C-6), 63.1 (C-5), 62.5
6
6
(C-2), 26.7 (CH3). Anal. calcd for C29H27NO6: C, 71.74;
H, 5.61; N, 2.88. Found: C, 71.54;H, 5.85;N, 2.90.
6
72.50; H, 6.08; N, 2.73. Found: C, 72.25; H, 6.36; N,
2.55.
3.8. Reaction of oxazolidines 7, 10, 11, 18 and 22 with
lithium aluminium hydride
3.7.2.3. g-Lactam of (S)-1-dodecyl 2-amino-4,6-O-ben-
zylidene-2-N-3-O-(3-carboxy-1-phenylpropylidene)-2-de-
A solution of either 7, 10, 11, 18 or 22 (0.5 mmol) in
dry THF (30 mL) was heated under an argon atmo-
sphere at reflux with stirring. Lithium aluminium
hydride solution (1 M) in THF (1.0–5.0 mmol) was
oxy-b-D-allopyranoside 27. Only one stereoisomer was
obtained, which was purified by column chromatogra-
phy using hexane–ethyl acetate (3:1) as eluent, yielding

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
145
added, and the reaction mixture was stirred for 5–48 h
(see reaction conditions in Table 1) and was then left to
cool to room temperature. Saturated aqueous sodium
sulphate solution (0.3–1.5 mL) was added dropwise.
The solid was removed by filtration and washed with
anhydrous THF and the filtrate was then concentrated
to dryness, giving a solid which was purified by column
chromatography.
13C NMR (50 MHz, CDCl3): l 137.3–126.2 (Ph), 101.9
(PhCH), 99.2 (C-1), 79.2 (C-4), 71.3 (C-3), 70.9
(OCH2Ph), 69.3 (C-6), 62.8 (C-5), 61.0 (C-2), 49.5
[NCH(CH3)2], 40.1 (NCH2CH3), 21.4, 18.7,
[NCH(CH3)2], 16.6 (NCH2C
H3). HRMS (CI): [M+H]+,
6
6
6
6
6
6
found 428.242967. C25H34NO5 requires 428.243699.
3.8.4. Benzyl 4,6-O-benzylidene-2-deoxy-2-diethylamino-
b-D-allopyranoside 33. Obtained from compound 11
3.8.1. Benzyl 4,6-O-benzylidene-2-deoxy-2-ethylmethyl-
amino-b-D-allopyranoside 30. Obtained from compound
using the described conditions. Purified by column
chromatography using hexane–diethyl ether (2:1) as
eluent, yielding 0.11 g (53%) as a syrup; MS (CI) m/z
7 using the described conditions. Purified by column
chromatography using hexane–ethyl acetate–acetone
(10:10:1) as eluent, yielding 0.14 g (70%); mp 94–95°C;
[h]D −72.7 (c 0.2, CH2Cl2); MS (CI) m/z 400 [M+H]+
1
414 (100%) [M+H]+. H NMR (200 MHz, CDCl3): l
7.5–7.3 (m, 10H, 2Ph), 5.56 (s, 1H, PhCH
J1,2 8.0 Hz, H-1), 4.92 (d, 1H, Jgem 11.5 Hz,
OCHAHBPh), 4.59 (d, 1H, Jgem 11.5 Hz, OCHAHBPh),
6 ), 5.05 (d, 1H,
1
(100%). H NMR (200 MHz, CDCl3): l 7.5–7.3 (m,
6
6
10H, 2Ph), 5.56 (s, 1H, PhCH
H-1), 4.93 (d, 1H, Jgem 11.5 Hz, OCHA
1H, Jgem 11.5 Hz, OCHAHBPh), 4.38 (dd, 1H, J5,6e 4.8
6
), 5.06 (d, 1H, J1,2 8.4 Hz,
4,40 (dd, 1H, J5,6e 4.8 Hz, J6e,6a 10.1 Hz, H-6e), 4.24 (t,
1H, J2,3=J3,4 2.7 Hz, H-3), 3.98 (dt, 1H, J4,5=J5,6a 9.7
Hz, J5,6e 4.8 Hz, H-5), 3.77 (t, 1H, J5,6a=J6e,6a 10.1 Hz,
H-6a), 3.59 (dd, 1H, J3,4 2.7 Hz, J4,5 9.3 Hz, H-4),
6
HBPh), 4.61 (d,
6
Hz, J6e,6a 10.0 Hz, H-6e), 4.32 (t, 1H, J2,3=J3,4 2.6 Hz,
H-3), 3.99 (dt, 1H, J4,5=J5,6a 9.7 Hz, J5,6e 4.9 Hz, H-5),
3.77 (t, 1H, J5,6a=J6e,6a 10.0 Hz, H-6a), 3.56 (dd, 1H,
J3,4 2.6 Hz, J4,5 9.4 Hz, H-4), 2.8–2.6 (m, 3H, H-2,
2.9–2.7 (m, 5H, H-2, 2NCH2
Hz, 2NCH2CH3
). 13C NMR (50 MHz, CDCl3): l
137.3–126.2 (2Ph), 101.8 (PhCH), 99.7 (C-1), 79.6 (C-
4), 70.8 (OCH2Ph), 70.6 (C-3), 69.3 (C-6), 62.9 (C-5),
62.7 (C-2), 45.1 (2NCH2CH3), 13.9 (2NCH2CH3).
6 CH3), 1.00 (t, 6H, J 7.1
6
6
NCH
NCH2CH3
126.2 (2Ph), 101.7 (PhC
(OCH2Ph), 70.1 (C-3), 69.2 (C-6), 64.3 (C-5), 62.8
(C-2), 50.1 (NCH2CH3), 39.1 (NCH3), 13.2
(NCH2CH3). HRMS (EI): [M] , found 399.205079.
6
2CH3), 2.48 (s, 3H, NCH3), 1.03 (t, 3H, J 7.1 Hz,
). 13C NMR (50 MHz, CDCl3): l 137.2–
H), 99.4 (C-1), 79.5 (C-4), 70.8
6
6
6
6
+
’
6
HRMS (EI): [M] , found 413.220264. C24H31NO5
requires 413.220223.
6
6
+
’
6
3.8.5. (S) - Benzyl 4,6 - O - benzylidene - 2 - deoxy - 2 - (2-
methylpyrrolid-1-yl)-b-D-allopyranoside 36. Obtained
C23H29NO5 requires 399.204573. Anal. calcd for
C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C,
68.93; H, 7.23; N, 3.58.
from compound 18, using the described conditions.
Only one stereoisomer was obtained, which was
purified by column chromatography using hexane–ethyl
acetate (1:1) as eluent, yielding 0.20 g (94%); mp 66–
68°C; [h]D −60.0 (c 0.4, CH2Cl2); MS (CI) m/z 426
3.8.2. Benzyl 4,6-O-benzylidene-2-deoxy-2-ethylamino-2-
N-3-O-isopropylidene-b-D-allopyranoside 31. Obtained
[M+H]+ (100%). H NMR (200 MHz, CDCl3): l 7.5–
from compound 10 using the described conditions. MS
1
(CI) m/z 426 (55%) [M+H]+. 1H NMR (200 MHz,
7.3 (m, 10H, 2Ph), 5.57 (s, 1H, PhCH
8.4 Hz, H-1), 4.93 (d, 1H, Jgem 11.5 Hz, OCHA
4.59 (d, 1H, Jgem 11.5 Hz, OCHAHBPh), 4.41 (dd, 1H,
6
), 5.13 (d, 1H, J1,2
CDCl3): l 7.5–7.3 (m, 10H, 2Ph), 5.53 (s, 1H, PhCH
4.89 (d, 1H, Jgem 11.6 Hz, OCHAHBPh), 4.70 (d, 1H,
J1,2 7.2 Hz, H-1), 4.63 (d, 1H, Jgem 11.5 Hz,
OCHAHBPh), 4,42 (dd, 1H, J5,6e 4.8 Hz, J6e,6a 10.10 Hz,
6 ),
6
HBPh),
6
6
J5,6e 4.8 Hz, J6e,6a 10.0 Hz, H-6e), 4.22 (t, 1H, J2,3=J3,4
2.6 Hz, H-3), 4.00 (dt, 1H, J4,5=J5,6a 9.6 Hz, J5,6e 4.8
Hz, H-5), 3.78 (t, 1H, J5,6e=J6e,6a 10.0 Hz, H-6a), 3.62
(dd, 1H, J3,4 2.6 Hz, J4,5 9.3 Hz, H-4), 3.2–3.1 [m, 2H,
6
H-6e), 4.30 (t, 1H, J2,3=J3,4 3.2 Hz, H-3), 4.1–3.6 (m,
3H, H-4, H-5, H-6a), 3.24 (dd, 1H, J1,2 7.3 Hz, J2,3 3.4
Hz, H-2), 2.56 (m, 2H, NCH2
OC (CH3)2N], 1.09 (t, 3H, J 6.9 Hz, NCH2CH3
6
CH3), 1.56, 1.44 [2s, 6H,
).
NCH
NCHAHB
HBCH2), 1.4–1.3 (m, 1H, NCH2CHAHB
3H, J 6.1 Hz, CH3). 13C NMR (50 MHz, CDCl3): l
137.2–126.2 (2Ph), 101.7 (PhCH), 100.1 (C-1), 79.5
(C-4), 72.5 (C-3), 70.9 (OCH2Ph), 69.3 (C-6), 62.9
(C-5), 60.5 (C-2), 58.6 [NCH(CH3)], 48.5 (NCH2), 31.7,
6
(CH3), NCHA
CH2CH2), 1.8–1.6 (m, 3H, NCH2CHA
CH2), 1.04 (d,
6 HBCH2CH2], 2.9–2.7 (m, 2H, H-2,
6
6
6 -
6
6
3.8.3. Benzyl 4,6-O-benzylidene-2-deoxy-2-ethyliso-
propylamino-b- -allopyranoside 32. Obtained from com-
D
6
pound 10 using the described conditions. Purified by
column chromatography using hexane–ethyl acetate
(1:1) as eluent, yielding 0.12 g (56%) as a syrup; MS
(CI) m/z 428 (100%) [M+H]+. 1H NMR (200 MHz,
6
6
22.7 [(CH2)2], 20.2 (CH3). HRMS (CI): [M+H]+, found
426.228071. C25H32NO5 requires 426.228048. Anal.
calcd for C25H31NO5: C, 70.56; H, 7.34; N, 3.29.
Found: C, 70.28; H, 7.38; N, 3.29.
CDCl3): l 7.5–7.3 (m, 10H, 2Ph), 5.57 (s, 1H, PhCH
4.98 (d, 1H, J1,2 8.0 Hz, H-1), 4.93 (d, 1H, Jgem 11.3 Hz,
OCHAHBPh), 4.56 (d, 1H, Jgem 11.3 Hz, OCHAHBPh),
6 ),
6
6
4,40 (dd, 1H, J5,6e 4.9 Hz, J6e,6a 10.0 Hz, H-6e), 4.09 (t,
1H, J2,3=J3,4 2.7 Hz, H-3), 3.99 (dt, 1H, J4,5=J5,6a 9.7
Hz, J5,6e 4.9 Hz, H-5), 3.77 (t, 1H, J5,6a=J6e,6a 10.0 Hz,
H-6a), 3.62 (dd, 1H, J3,4 4.9 Hz, J4,5 9.4 Hz, H-4), 3.16
From compound 22, using the described conditions two
stereoisomers were obtained in 9:1 ratio (80% d.e. for
the (S)-isomer). The major isomer was isolated by
column chromatography using hexane–ethyl acetate
[m, 1H, NCH
Hz, H-2), 2.71 (m, 2H, NCH2
Hz, NCH2CH3), 0.96 [d, 6H, J 6.5 Hz, NCH(CH3 2
6
(CH3)2], 2.85 (dd, 1H, J1,2 8.0 Hz, J2,3 2.7
CH3), 1.00 (t, 3H, J 7.2
) ].
(1:1) as eluent, yielding 0.10 g (78%); HRMS (EI):
[M] , found 425.219021. C25H31NO5 requires
425.220223.
+
’
6
6
6

146
J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
3.9. Reaction of oxazolidines 13 and 17 with alkylmag-
nesium chlorides
When an identical reaction was carried out at room
temperature compound 35 was obtained with d.e. of
76%.
A solution of either 13 or 17 (0.5 mmol) in distilled and
dried toluene (30 mL) was stirred under an argon
atmosphere at reflux. The alkylmagnesium chloride
solution in THF (2.0–5.0 mmol) was added, and the
reaction mixture was stirred for 4–48 h (see reaction
conditions in Table 1). The reaction mixture was
diluted with toluene and washed with water, dried
(MgSO4), filtered and the filtrate concentrated to dry-
ness. The solid obtained was purified by column
chromatography.
Acknowledgements
We thank the DGICYT (Spain) for financial support
(grant PB97-0731), and Dr. Jose´ L. Espartero for his
collaboration in recording the NOE and NOESY
experiments.
References
3.9.1. Benzyl 4,6-O-benzylidene-2-deoxy-2-[ethyl(2,2-
1. Vega-Pe´rez, J. M.; Espartero, J. L.; Ruiz, F. J.; Alcudia,
F. Carbohydr. Res. 1993, 248, 95–106.
2. Neelakatan, L. J. Org. Chem. 1971, 36, 2256–2260.
3. Higashiyama, K.; Nakagawa, K.; Takahashi, H. Hetero-
cycles 1995, 41, 2007–2017.
dimethyl-1-isopropylprop-1-yl)-amino]-b-D-allopyranoside
34. From compound 13, using the described conditions,
the two stereoisomers were obtained in 7.4:1 ratio (76%
d.e.). Column chromatography allowed the purification
of the two stereoisomers but not their separation. Yield
4. Andre´s, C.; Nieto, J.; Pedrosa, R.; Villaman˜a´n, N. J.
1
0.17 mg (68%); MS (CI) m/z 498 [M+H]+ (10%). H
Org. Chem. 1996, 61, 4130–41435.
NMR (200 MHz, CDCl3) (for the major isomer): l
5. Muralidharan, K. R.; Mokhallalati, M. K.; Pridgen, L.
N. Tetrahedron Lett. 1994, 35, 7489–7492.
6. Wu, M.-J.; Pridgen, L. N. J. Org. Chem. 1991, 56,
1340–1344.
7. Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron
Lett. 1992, 33, 235–238.
7.6–7.3 (m, 10H, 2Ph), 5.57 (s, 1H, PhCH
J1,2 8.2 Hz, H-1), 4.98 (d, 1H, Jgem 11.3 Hz,
OCHAHBPh), 4.60 (d, 1H, Jgem 11.3 Hz, OCHAHBPh),
6 ), 5.10 (d, 1H,
6
6
4.43 (dd, 1H, J5,6e 4.9 Hz, J6e,6a 10.2 Hz, H-6e), 4.25 (t,
1H, J2,3=J3,4 2.6 Hz, H-3), 4.05 (dt, 1H, J4,5=J5,6a 9.9
Hz, J5,6e 4.8 Hz, H-5), 3.79 (t, 1H, J5,6e=J6e,6a 10.0 Hz,
H-6a), 3.62 (dd, 1H, J3,4 2.7 Hz, J4,5 9.7 Hz, H-4),
8. Takahashi, H.; Hsieh, B. C.; Higashiyama, K. Chem.
Pharm. Bull. 1990, 38, 2429–2431.
9. Hussain, A.; Wyatt, P. B. Tetrahedron 1993, 49, 2123–
2130.
3.1–2.9 (m, 3H, H-2, NCH2
(CH3)3CCHCH(CH3)2N], 2.15 [m, 1H, (CH3)3C-
CHCH(CH3)2N], 1.26 [d, 6H, J 7.0 Hz, (CH3)3C-
CHCH(CH3)2N], 1.2–1.0 [m, 12H, NCH2CH3
(CH3)3CCHCH(CH3)2N]. Anal. calcd for C30H43NO5:
6 CH3), 2.45 [d, 1H, J 3.0 Hz,
6
6
10. Cardani, S.; Poli, G.; Scolastico, C.; Villa, R. Tetrahedron
6
6 ,
1988, 44, 5929–5938.
11. Pridgen, L. N.; Mokhallalati, M. K.; Wu, M.-J. J. Org.
Chem. 1992, 57, 1237–1241.
6
C, 72.40; H, 8.71; N, 2.81. Found: C, 72.28; H, 8.68; N,
2.60.
12. Agami, C.; Couty, F.; Hamon, L.; Venier, O. J. Org.
Chem. 1997, 62, 2106–2112.
13. Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc.
1984, 106, 1146–1148.
14. Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–
9569.
3.9.2. (R) - Benzyl 4,6 - O - benzylidene - 2 - deoxy - 2 - (2-
methylpyrrolid-1-yl)-b-
D
-allopyranoside 35. From com-
pound 17, using the described conditions, the two
stereoisomers were obtained in 6:1 ratio (72% d.e. for
(R)-isomer). The major isomer was purified by column
chromatography using hexane–ethyl acetate (10:15) as
eluent, yielding 0.15 g (71%); mp 69–71°C; [h]D −100.0
15. Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J.
J. Org. Chem. 1989, 54, 4243–4246.
16. Royer, J.; Husson, H.-P. Heterocycles 1990, 36, 1493–
1496.
17. Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35,
2223–2226.
1
(c 0.3, CH2Cl2); MS (CI) m/z 426 [M+H]+ (100%). H
NMR (200 MHz, CDCl3): l 7.5–7.3 (m, 10H, 2Ph),
5.56 (s, 1H, PhCH
(d, 1H, Jgem 11.4 Hz, OCHA
11.4 Hz, OCHAHBPh), 4.40 (m, 2H, H-3, H-6e), 4.00
(dt, 1H, J4,5=J5,6a 10.0 Hz, J5,6e 5.1 Hz, H-5), 3.78 (t,
1H, J5,6e=J6e,6a 10.1 Hz, H-6a), 3.60 (dd, 1H, J3,4 2.5
6
), 4.96 (d, 1H, J1,2 8.0 Hz, H-1), 4.93
18. Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1991, 56,
2294–2296.
19. Iglesias-Guerra, F.; Candela, J. I.; Espartero, J. L.; Vega-
Pe´rez, J. M. Tetrahedron Lett. 1994, 35, 5031–5034.
20. Vega-Pe´rez, J. M.; Candela, J. I.; Iglesias-Guerra, F. J.
Org. Chem. 1997, 62, 6608–6611.
6
HBPh), 4.58 (d, 1H, Jgem
6
Hz, J4,5 9.4 Hz, H-4), 3.43 [m, 1H, NCH
[m, 3H, H-2, NCH2(CH2)2], 2.0–1.4 [m, 4H,
NCH2(CH2
)], 0.97 (d, 3H, J 6.3 Hz, CH3). 13C NMR
(50 MHz, CDCl3): l 137.2–126.3 (2Ph), 102.0 (PhCH),
99.5 (C-1), 79.4 (C-4), 70.8 (OCH2Ph), 69.2 (C-6), 66.6
(C-3), 62.6 (C-2), 62.5 (C-5), 53.6 [NCH(CH3)], 49.8
6 (CH3)], 3.0–2.8
6
21. Iglesias-Guerra, F.; Romero, I.; Alcudia, F.; Vega-Pe´rez,
6
J. M. Carbohydr. Res. 1998, 308, 57–62.
6
22. Iglesias-Guerra, F.; Candela, J. I.; Bautista, J.; Alcudia,
F.; Vega-Pe´rez, J. M. Carbohydr. Res. 1999, 316, 71–84.
23. Vega-Pe´rez, J. M.; Candela, J. I.; Blanco, E.; Iglesias-
Guerra, F. Tetrahedron 1999, 55, 9641–9650.
24. Vega-Pe´rez, J. M.; Espartero, J. L.; Ruiz, F. J.; Alcudia,
F. Carbohydr. Res. 1992, 232, 235–247.
6
6
(NCH2), 32.0, 22.4 [(CH2)2], 18.2 (CH3). Anal. calcd for
C25H31NO5: C, 70.56; H, 7.34; N, 3.29. Found: C,
70.48; H, 7.26; N, 3.25.

J. M. Vega-Pe´rez et al. / Tetrahedron: Asymmetry 12 (2001) 135–147
147
25. Vega-Pe´rez, J. M.; Espartero, J. L.; Alcudia, F. Carbo-
hydr. Res. 1992, 235, C5–C7.
26. Vega-Pe´rez, J. M.; Espartero, J. L.; Alcudia, F. J. Carbo-
29. Andre´s, J. M.; Herra´iz-Sierra, I.; Pedrosa, R.; Pe´rez-
Encabo, A. Eur. J. Org. Chem. 2000, 1719–1726.
30. Agami, C.; Couty, F.; Lequesne, C. Tetrahedron Lett.
1994, 35, 3309–3312.
hydr. Chem. 1993, 12, 477–486.
27. Gross, P. H.; Jeanloz, R. J. Org. Chem. 1967, 32, 2759–
2763.
28. Espartero, J. L. Ph.D., University of Seville, Spain, 1992.
31. Maury, C.; Wang, Q.; Gharbaoui, T.; Chiadmi, M.;
Tomas, A.; Royer, J.; Husson, H.-P. Tetrahedron 1997,
53, 3627–3636.
.
.