Asymmetric synthesis of 1,4-dideoxy-1,4-imino-D-ribitol via stereoselective addition of allylphenylsulfone to an aryl N-sulfinylimine

Article abstract of DOI:10.1016/S0957-4166(02)00033-2

Asymmetric synthesis of 1,4-dideoxy-1,4-imino-D-ribitol was achieved utilizing the stereoselective addition of allylphenylsulfone to a chiral N-sulfinyl-2-furfuryl imine and ring-closing metathesis reactions as key steps.

Full text of DOI:10.1016/S0957-4166(02)00033-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3409–3415
Asymmetric synthesis of 1,4-dideoxy-1,4-imino-
D
-ribitol via
stereoselective addition of allylphenylsulfone to an aryl
N-sulfinylimine†
Ramaiah Kumareswaran and Alfred Hassner*
Department of Chemistry, Bar Ilan University, Ramat Gan 52 900, Israel
Received 3 January 2002; accepted 22 January 2002
Abstract—Asymmetric synthesis of 1,4-dideoxy-1,4-imino-D-ribitol was achieved utilizing the stereoselective addition of
allylphenylsulfone to a chiral N-sulfinyl-2-furfuryl imine and ring-closing metathesis reactions as key steps. © 2002 Published by
Elsevier Science Ltd.
1. Introduction
offer a highly versatile entry into azasugar 1. Since
pyrroline 2 possesses fixed stereochemistry at C(2), we
envisaged that stereoselective dihydroxylation followed
by oxidative cleavage of the 2-aryl ring and functional
group manipulations should provide the targeted struc-
ture 1. We herein describe the synthesis of N-Boc-(2S)-
2-furyl-3-pyrroline 2a, following a modification of our
earlier procedure5 (using BOC protection in this case)
and its further elaboration to azasugar 1.
The core structure of an azasugar may contain various
heterocyclic ring systems such as polyhydroxy-pyrro-
lidines, piperidines or indolizidines. Because of their
ability to mimic carbohydrates in various biological
processes, azasugars are found to have activities against
cancer, diabetes and viral infections.2 There have been a
number of synthetic efforts to reach these targets both
from carbohydrate3 and non-carbohydrate starting
materials,4 but many of these routes suffer from exces-
sive length and/or lack of selectivity. It is to be noted
that asymmetric routes to azasugars require the incor-
poration of three or four stereogenic centers consisting
of three to four hydroxyl substituents.
2. Results and discussion
Our synthesis commenced with the stereoselective addi-
tion of lithiated allylphenylsulfone carbanion not bear-
ing any additional functions, to non-racemic sulfinyl-
imine 36 (Eq. (1)). Allylphenylsulfone was deprotonated
Retrosynthetic analysis (Scheme 1) shows that non-
racemic (2S)-2-aryl-3-pyrrolines of the type 2 would
HO
OH
SO2Ph
Ar
Ar
N
Ar
N
H
N
H2N
OH
O
R
O
R
1
2
H
O
SO2Ph
+
S
p-Tol
N
Ar
Scheme 1.
* Corresponding author. Fax: 972-3-5351250; e-mail: hassna@mail.biu.ac.il
†
Stereochemistry 93. For part 92, see: Ref. 1.
0957-4166/01/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00033-2

3410
R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 3409–3415
with lithium diisopropylamide (LDA) in THF at
−100°C, followed by the addition of the sulfinylimine 3
in THF. The reaction was complete within 2 min to
afford 4 as a 1:2 mixture of two diastereomers, which
were not separable by column chromatography. Vary-
ing the reaction conditions did not improve the
diastereoselectivity. The diastereomeric ratio was deter-
mined by integration of the a-sulfonyl proton of both
Lewis acids as reported in some examples in the litera-
ture.7
With 5 and 7 in hand, our next goal was to convert
them to 1. Monoallylation of 7 using allyl bromide in
the presence of K2CO3 gave 9 (Scheme 3). Further,
reductive removal of the sulfonyl group with SmI2 to
produce 10 followed by Boc protection of the amine
function set the stage for a metathesis ring closure to
obtain the targeted pyrroline ring. Treatment of 11 with
5 mol% of Grubbs catalyst8 [Cl2(Pcy3)2RuꢀCHPh] in
1
isomers in the H NMR spectrum. In the major isomer
the proton appeared as a dd (J=9.9, 2.7 Hz) and in the
minor isomer as a dd with J=9.9, 3.3 Hz.
(1)
Removal of the sulfonyl group in 4 by treatment with
TFA afforded chromatographically separable diastereo-
mers 5 and 6 (Scheme 2) with the diastereomeric ratio
elucidated as above for the isomers of 4. In order to
determine the absolute configuration at the carbon a to
the amino function, we intended to isomerize the dou-
ble bond in 5 and 6 independently. Exposure of 5 and
6, respectively, to a catalytic amount of tert-BuOK
afforded 7 and 8, whose specific rotations (+31 and
−13), though of opposite direction, were not of the
same magnitude, confirming primarily the fact that they
are indeed epimers with respect to C(4). Careful analy-
CH2Cl2 at room temperature afforded pure pyrroline
2a as a mixture of two carbamate rotamers.
Dihydroxylation on 2a under standard reaction condi-
tions using a catalytic amount of OsO4 in conjunction
with NMO (N-methylmorpholine oxide) in a three sol-
vent system afforded 12 as a single isomer (Scheme 3).
The observed selectivity can be explained by the pres-
ence of the b-oriented C2-furyl group which allows the
osmylation to take place only from the a-face purely on
steric grounds. Protection of the diol as its isopropyl-
idine derivative gave the expected 13. The assigned
structure was deduced from 2D COSY, NOESY and
HMQC experimental data. Having incorporated the
vicinal hydroxyl groups in a stereoselective manner at
positions C(3) and C(4), our attention was directed
towards converting the 2-furyl group at C(2) into a
hydroxymethyl function. In our hands, oxidation of the
furyl ring using a catalytic amount of RuCl3×H2O9 and
1
sis of the H NMR spectrum of 6 indicated that it was
contaminated with nearly 7% of isomerized products 7
and/or 8. Presumably the major contaminant was 7
(derived from the major product 5 as indicated by the
reduced negative rotation of 8 compared to (+)-7). The
isomerization during sulfone addition could not be
avoided by reducing the amount of base or by adding
SO2Ph
SO2Ph
Fur-2
SO2Ph
Fur-2
SO2Ph
Fur-2
TFA, MeOH
0oC, 2 h
O
+
+
S
N
H
4
Fur-2
H2N
H2N
H2N
p-Tol
~ (7%)
6
(-)-5 (major, 62%)
(+)- inseparable
SO2Ph
t-BuOK, THF
(-)-5
0oC, 2 h
H2N
Fur-2
(+)-7
SO2Ph
Fur-2
SO2Ph
t-BuOK, THF
0oC, 2 h
+
(+)-6
H2N
H2N
Fur-2
(+)-7 (minor)
(-)-8 (major)
(-)
Scheme 2.

R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 3409–3415
3411
SO2Ph
Fur-2
Br
SO2Ph
Fur-2
SmI2-THF, HMPA
-20oC, 20 min
K2CO3, CH3CN
0oC- rt, 3 days
H2N
N
H
9
7
[Ru]=, CH2Cl2
rt, 2.5 h
N-TBCBT, CH2Cl2
rt, Overnight
Fur-2
N
Fur-2
O
N
N
Fur-2
H
Boc
Boc
2a
10
11
O
HO
OH
Fur-2
1. Cat. RuO2, NaIO4
2,2- DMP, Cat.p-TSA
CH2Cl2, rt, 30 min
Cat. OsO4, NMO
Fur-2
HO
t-BuOH, CH3CN, CCl4
35 min
2. CH2N2, Et2O
t-BuOH, THF, H2
O
N
N
6 h
Boc
13
Boc
12
O
O
OH
Cl
O
O
1. 80% aq. TFA
DIBAL-H, Et2O
-78oC, 15 min
CO2Me
24 h, rt
2. aq. HCl
N
N
H2
N
OH
OH
Boc
Boc
14
15
1.HCl
Scheme 3.
5 equiv. of NaIO4 followed by treatment with diazo-
methane gave 14 in only poor yield. On the other
hand, oxidation using a catalytic amount of RuO2×
H2O10 and 5 equiv. of NaIO4 followed by esterification
using diazomethane improved the yield of 14 to 82%.
Reduction of the ester using 5 equiv. of DIBAL-H in
ether at −78°C gave the alcohol 15 in high yield.
Stirring 15 at room temperature in 80% aq. TFA for 24
h then effected global deprotection to afford our target
compound 1 as the trifluoroacetate salt. Treatment of
this trifluoroacetate salt with aq. NaOH followed by
chromatographic purification on Dowex-H+ afforded
the free base 1, which was converted (vide Section 2)
into 1·HCl. The specific rotation of 1·HCl in compari-
son with the literature value3d indicated it to be 94%
enantiomerically pure. Since the dihydroxylation of 2a
had proceeded with near 100% stereoselectivity, we
attribute the presence of 3% of enantiomer due either to
minor contamination of 2a with its enantiomer or
partial racemization in one of the synthetic steps.
MeOH. Flash column chromatography was done on
Merck silica gel 60 (230–400 mesh), and pre-coated
Merck silica gel plates (60F-25H) were used for TLC.
1
Unless otherwise mentioned H and 13C NMR spectra
were recorded in CDCl3 on a Bruker AM-300 spec-
trometer. COSY, NOESY and HMQC spectra were
recorded on a Bruker AM-600 spectrometer. Coupling
constants were determined directly from 1H NMR spec-
tra. Mass spectra (CI) were recorded at 60–70 eV.
Optical rotations were measured on a Perkin–Elmer
141 polarimeter with path length of 0.1 dm. Chiral
sulfinylimine 3 was prepared following the Davis
procedure.6
3.2. Preparation of (+)-(Ss,3S,4R)-3-phenylsulfonyl-4-
(2-furyl)-4-[N-(p-tolylsulfinyl) amino]-but-1-ene 4
In a two-necked, round-bottomed flask equipped with
an argon inlet, rubber septum and a stirring bar was
placed diisopropylamine (0.36 mL, 2.64 mmol) in THF
(4 mL). At −50°C, n-BuLi (1.6 M in hexane, 1.5 mL,
2.4 mmol) was added dropwise and stirred for 15 min
at the same temperature. The flask was further cooled
to −100°C and a solution of allylphenylsulfone (436 mg,
2.4 mmol) in THF (10 mL) was added dropwise. After
20 min a solution of sulfinylimine 3 (466 mg, 2 mmol)
in THF (5 mL) was added dropwise along the sides of
the flask and after 2 min, TLC analysis indicated
consumption of the starting material. The reaction was
quenched by adding saturated aq. NH4Cl (1 mL) and
extracted thoroughly with dichloromethane (3×30 mL).
The combined organic extract was washed with brine,
3. Experimental
3.1. General
All air- and moisture-sensitive reactions were carried
out in flame-dried, argon-flushed, two-necked flasks
sealed with rubber septa, and the dry solvents and
reagents were introduced with
a syringe. Tetra-
hydrofuran (THF) was freshly distilled from sodium/
benzophenone. Reactions with cooling at −100°C were
performed using a mixture of liquid nitrogen and

3412
R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 3409–3415
dried (MgSO4) and concentrated. Purification by flash
column chromatography (40% EtOAc in hexane)
yielded 4 (795 mg, 96%) as an inseparable mixture of
two diastereomers in a 1:2 ratio: mp 70°C; [h]2D5 +79 (c
0.9, CHCl3); 1H NMR (CDCl3) For the major
diastereomer l 7.86 (tt, 2H, J=7,1.2 Hz), 7.69 (d, 2H,
J=8.1 Hz), 7.63 (tt, 1H, J=6.9, 2.7 Hz), 7.54 (tt, 2H,
J=6.6, 1.2 Hz), 7.35 (dd, 1H, J=4, 1.8 Hz), 7.28 (d,
2H, J=8.1 Hz), 6.46 (d, 1H, exchangeable with D2O,
J=3.3 Hz), 6.36 (dd, 1H, J=2.7, 1.2 Hz), 6.27 (dd, 1H,
J=3.3, 1.8 Hz), 5.92 (dt, 1H, J=17.1, 9.9 Hz), 5.46, (br
d, 1H, J=3 Hz), 5.29 (dd, 1H, J=10.8, 1.5 Hz), 4.95
(d, 1H, J=17.1 Hz), 4.24 (dd, a-sulfonyl proton from
the major isomer, J=9.9, 2.7 Hz), 4.04 (dd, a-sulfonyl
proton from the minor isomer, J=9.9, 3.3 Hz) 2:1
ratio, 2.4 (s, 3H). 13C NMR l 151.43, 150.22, 142.74,
141.7, 134.19, 130.06, 129.89, 129.56, 127.03, 126.45,
125.8, 125.66, 110.9, 109.32, 73, 53.05, 21.74.
mixture was stirred at the same temperature for 2 h,
when complete disappearance of 5 with appearance of a
polar spot on TLC was observed. Cold water (1 mL)
was added to quench the reaction and the mixture was
extracted thoroughly with CH2Cl2 (3×20 mL). The
combined organic extract was washed with brine, dried
(MgSO4) and concentrated under reduced pressure.
Purification of the crude mass by flash column chro-
matography (50% EtOAc in hexane) afforded 7 as a
pale yellowish oil (284 mg, 90%): [h]2D5 +31 (c 1, CHCl3);
1H NMR (CDCl3) l 7.71 (dd, 2H, J=7.5, 3 Hz), 7.52
(tt, 1H, J=7.5, 3 Hz), 7.44 (tt, 2H, J=7.5, 3 Hz), 7.24
(q, 1H, J=7.3 Hz), 7.0 (br s, 1H), 6.18 (br d, 2H, J=2
Hz), 5.14 (br s, 1H), 2.57 (br s, 2H, exchangeable with
D2O), 1.95 (d, 3H, J=7.3 Hz); 13C NMR (CDCl3) l
154.11, 143.58, 142.13, 141.78, 140.56, 133.22, 129.29,
128.07, 110.69, 106.91, 48.14, 14.71. HRMS observed
mass=278.082072 (for MH+ calculated mass=
278.085090).
3.3. (−)-(3S,4R)-4-Amino-3-phenylsulfonyl-4(2-furyl)but-
1-ene 5
3.5. (−)-(4R)-N-(2-Propenyl)-3-phenylsulfonyl-4-(2-
furyl)-2(E)-butenyl amine 9
Into a single-necked, round-bottomed flask equipped
with a stirring bar and a rubber septum was placed 4
(794 mg, 1.9 mmol) in MeOH (10 mL) at 0°C under an
Ar atmosphere. Trifluoroacetic acid (0.5 mL, 6.43
mmol) was added dropwise and the resultant solution
was stirred at the same temperature for 2 h until
complete disappearance of the starting material. The
reaction mixture was then concentrated and the resid-
ual oil was dissolved in CH2Cl2 and transferred into a
beaker. The beaker was immersed in an ice bath and a
satd aq. NaHCO3 was added until the pH rose to 8.
The contents of the beaker were transferred into a
separatory funnel and the mixture was extracted with
CH2Cl2 (3×25 mL). The combined organic extract was
washed with brine, dried (MgSO4) and concentrated.
Purification of the crude product by flash column chro-
matography (45% EtOAc in hexane) afforded the major
isomer 5 as a viscous oil (348 mg, 66%). The minor
isomer 6 (166 mg) obtained upon elution with the same
solvent system was found to be contaminated with a
minor amount of the isomerized product. This impure
isomer was not further studied. The major isomer 5
In a single-necked, round-bottomed flask equipped with
a magnetic stirring bar and a rubber septum was placed
K2CO3 (455 mg, 3.3 mmol) in CH3CN (2 mL) at 0°C
under an Ar atmosphere. Solutions of amine 7 (457 mg,
1.65 mmol) in CH3CN (4 mL) and allyl bromide (240
mg, 1.98 mmol) in CH3CN (1 mL) were added succes-
sively. The reaction mixture was brought to room tem-
perature and stirred for 3 days, when complete
disappearance of 7 with appearance of a non-polar spot
on TLC was observed. Cold water (1 mL) was added to
quench the reaction and the mixture was extracted
thoroughly with CH2Cl2 (3×20 mL). The combined
organic extract was then washed with brine, dried
(MgSO4) and concentrated. Purification of the crude
product by flash column chromatography (14% EtOAc)
afforded pure 9 (408 mg, 78%): [h]2D5 −13 (c 2.3, CHCl3);
1H NMR (CDCl3) l 7.67 (dt, 2H, J=8.4, 3 Hz), 7.5 (tt,
1H, J=7.5, 3 Hz), 7.4 (tt, 2H, J=7.5, 3 Hz), 7.26 (q,
1H, J=7 Hz), 6.98 (dd, 1H, J=6, 2 Hz), 6.1 (dd, 1H,
J=6, 2 Hz), 6.08 (dd, 1H, J=6, 2 Hz), 5.8 (ddt, 1H,
J=17.1, 10.5, 5.7 Hz), 5.15 (ddt, 1H, J=17.1, 2, 0.6
Hz), 5.07 (dq, 1H, J=10.5, 2 Hz), 4.88 (s, 1H), 3.17
(dddt, 2H, J=17, 12.2, 6, 1.5 Hz), 2.19 (br s, 1H,
exchangeable with D2O), 2.02 (d, 3H, J=7 Hz); 13C
NMR (CDCl3) l 151.95, 142.21, 141.22, 140.39, 139.9,
135.65, 132.25, 128.32, 127.32, 116.09, 109.77, 106.79,
52.7, 49.2, 14.22. HRMS observed mass=317.107283
(for MH+ calculated mass=317.108565).
1
showed [h]2D5 −32 (c 0.9, CHCl3); H NMR (CDCl3) l
7.88 (dd, 2H, J=8.7, 0.72 Hz), 7.64 (tt, 1H, J=7.5, 2
Hz), 7.53 (tt, 2H, J=7.5, 2 Hz), 7.28 (dd, 1H, J=5.8,
0.6 Hz), 6.28 (dd, 1H, J=3, 1.5 Hz), 6.24 (dd, 1H,
J=5.8, 3 Hz), 6.05 (dt, 1H, J=17.1, 10.2 Hz), 5.28 (dd,
1H, J=9, 3 Hz), 5.06 (d, 1H, J=2.1 Hz), 4.8 (dd, 1H,
J=17.1, 3 Hz), 3.93 (dd, 1H, J=9, 3 Hz), 2.03 (br s,
2H, exchangeable with D2O); 13C NMR (CDCl3) l
154.25, 141.8, 137.67, 133.82, 129.3, 128.91, 125.59,
125.45, 110.3, 106.6, 72.52, 48.92. HRMS observed
mass=278.084419 (for MH+ calculated mass=
278.085090).
3.6. (+)-(4S)-N-(2-Propenyl)-4-(2-furyl)-2(Z)-butenyl
amine 10
To a stirred solution of 9 (180 mg, 0.57 mmol) in
SmI2–THF solution (0.1 M, 22.5 mL) at −20°C under
Ar atmosphere was added HMPA (2 mL) dropwise.
The resulting mixture was stirred at the same tempera-
ture for 20 min and then quenched with aq. NH4Cl (1
mL). THF was removed under reduced pressure and
extracted with EtOAc (3×25 mL). The combined
organic extract was washed with brine, dried (MgSO4)
3.4. (+)-(4R)-4-Amino-3-phenylsulfonyl-4(2-furyl)-2(E)-
butene 7
To a stirred solution of amine 5 (316 mg, 1.14 mmol) in
THF (6 mL) at 0°C under an Ar atmosphere was added
tert-BuOK (5 mg) in one portion and the resultant

R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 3409–3415
3413
and concentrated. Purification of the crude by flash
column chromatography (15% EtOAc in hexane)
afforded pure 10 (60 mg, 59%) as an oil: [h]2D5 +22.6 (c
1.5, CHCl3); 1H NMR (CDCl3, 600 MHz) l 7.35 (dd, 1H,
J=1.8, 0.6 Hz), 6.3 (dd, 1H, J=3, 1.8 Hz), 6.17 (dt, 1H,
J=3, 1 Hz), 5.92 (ddt, 1H, J=17.4, 10, 6 Hz), 5.69 (dqd,
1H, J=10.8, 6.6, 1.2 Hz), 5.55 (tq, 1H, J=10.8, 1.8 Hz),
5.18 (dq, 1H, J=17.4, 1.8 Hz), 5.11 (dq, 1H, J=10.8, 1.8
Hz), 4.67 (d, 1H, 10.8 Hz), 3.24 (qdt, 2H, J=18, 6, 1.4
Hz), 1.7 (dd, 3H, J=6.6, 1.8 Hz); 13C NMR (CDCl3) l
156.04, 142.09, 136.87, 130.04, 127.53, 116.74, 110.4,
106.22, 52.31, 49.94, 13.65. HRMS observed mass=
177.118442 (for M+ calculated mass=177.115364).
mmol) in t-BuOH, THF and H2O (0.6, 0.2, 0.1 mL,
respectively) at room temperature under an Ar atmo-
sphere. Osmium(VIII) oxide (3 mg, 0.012 mmol) was then
added in one portion. A THF (1 mL) solution of 2a (155
mg, 0.6 mmol) was added dropwise and the resultant
mixture was stirred for 6 h. The reaction mixture was
passed through a thick pad of silica gel to remove the
colored mass and washed with EtOAc (50 mL). Washing
of the filtrate with brine, drying (MgSO4) and evaporation
followed by flash column chromatographic purification
afforded pure 12 as a colorless solid (148 mg, 92%): mp
75–77°C; [h]2D5 −15.7 (c 1.15, CHCl3); 1H NMR (CDCl3)
l 7.32 (d, 1H, J=3 Hz), 6.3 (t, 1H, J=3 Hz), 6.18 (br
s, 1H), 4.69 and 4.75 (2 br s, 1H), 4.45 (q, 1H, J=5.7
Hz), 4.2 (t, 1H, J=3.6 Hz), 3.74 (dd, 1H, J=11.1, 6 Hz),
3.49 (br s, 1H), 3.17 (br s, 2H, exchangeable with D2O),
1.4 and 1.3 (2s, 9H); 13C NMR (CDCl3) l (carbonyl peak
was not seen due to line broadening) 154.75, 141.72,
110.32, 107.07, 80.26, 76.78 and 75.53, 70.58 and 69.9,
60.69, 50.4, 28.2. HRMS observed mass=270.133424 (for
MH+ calculated mass=270.134148).
3.7. (−)-(4S)-N-Boc-N-(2-propenyl)-4-(2-furyl)-2(Z)-
butenyl amine 11
In a single-necked flask equipped with a rubber septum
and an argon inlet was placed freshly prepared tert-
butoxycarbonyloxybenzotriazole11 (282 mg, 1.2 mmol)
under an Ar atmosphere at room temperature. A CH2Cl2
(3 mL) solution of 10 (177 mg, 1 mmol) was added
dropwise and the mixture was stirred overnight. Removal
of the solvent under reduced pressure followed by
chromatographic purification (11% EtOAc in hexane)
afforded 11 (221 mg, 80%) as a mixture of two rotamers:
[h]2D5 −25 (c 1, CHCl3); 1H NMR (CDCl3) l 7.34 (m, 1H),
6.29 (m, 1H), 6.17 (m, 1H), 5.62–5.8 (m, 4H), 4.96 (m,
2H), 1.7 and 1.75 (2d, 3H, J=7 Hz), 1.46 and 1.45 (2s,
9H); 13C NMR (CDCl3) l (carbonyl peak was not seen
due to line broadening)155.24 and 153.72, 141.8, 135.23,
129.31 and 128.88, 126.6 and 125.83, 115.38, 110.1, 107.87
and 107.6, 79.87, 54.99 and 50.1, 46.96, 28.4, 17.83 and
13.45. HRMS observed mass=278.173345 (for MH+
calculated mass=278.175619).
3.10. (−)-(2R,3R,4S)-N-Boc-2-(2-furyl)-3,4-isopropyli-
denedioxypyrrolidine 13
In a single-necked flask equipped with an argon inlet, a
rubber septum and magnetic stirring bar was placed
p-TSA (3 mg) under an Ar atmosphere at room temper-
ature. A solution of 12 (85 mg, 0.32 mmol) in CH2Cl2
(3 mL) followed by 2,2-dimethoxypropane (0.156 mL,
1.28 mmol) were introduced by syringe. After stirring for
30 min, the solvent was removed under reduced pressure
and the residue was purified by flash column chromatog-
raphy (20% EtOAc in hexane) to afford pure 13 (82 mg,
83%) as a mixture of two rotamers: [h]2D5 −41.3 (c 0.8,
1
CHCl3); H NMR (CDCl3, 600 MHz) For the major
3.8. (−)-(2S)-N-Boc-2-(2-furyl)-3,4-dehydropyrrolidine
2a
rotamer l 7.34 (d, 1H, J=1.5 Hz), 6.31 (dd, 1H, J=3,1.5
Hz), 6.13 (d, 1H, J=3 Hz), 5.02 (br s, 1H), 4.87 (t, 1H,
J=5.5 Hz), 4.8 (d, 1H, J=6 Hz), 3.9 (dd, 1H, J=13, 1.5
Hz), 3.58 (dd, 1H, J=12.5, 5 Hz), 1.4 (s, 9H), 1.52 and
1.33 (2s, 6H) and for the minor isomer l 7.34 (d, 1H,
J=1.5 Hz), 6.31 (dd, 1H, J=3,1.5 Hz), 6.2 (d, 1H, J=3
Hz), 5.22 (br s, 1H), 4.84 (t, 1H, J=5.5 Hz), 4.8 (d, 1H,
J=6 Hz), 3.88 (d, 1H, J=13, 1.5 Hz), 3.53 (dd, 1H,
J=12.5, 4.5 Hz), 1.46 (s, 9H), 1.5 and 1.3 (2s, 6H); 13C
NMR (CDCl3) (carbonyl peak was not seen due to line
broadening) l 154.33, 142.19, 111.91, 110.22, 106.85 and
106.58, 84.16 and 83.54, 80.07 and 79.86, 78.92, 61.22 and
60.74, 52.38 and 51.84, 29.7, 26.87, 24.96. HRMS
observed mass=309.157261 (for M+ calculated mass=
309.157623).
In a two-necked flask equipped with a magnetic stirring
bar, rubber septum and an argon inlet was placed Grubbs
catalyst (25 mg, 0.03 mmol) under an Ar atmosphere. A
solution of 11 (167 mg, 0.6 mmol) in CH2Cl2 (2 mL) was
introduced by syringe and the resultant pink colored
solution was stirred for 2.5 h when TLC analysis indicated
the total disappearance of 11. The reaction mixture was
exposed to air and concentrated. Purification of the crude
product by flash column chromatography (10% EtOAc
in hexane) afforded pure 2a (130 mg, 92%) as a mixture
1
of two rotamers: [h]D25 −101.8 (c 1.6, CHCl3); H NMR
(CDCl3) l 7.35–7.29 (m, 1H), 6.32–6.14 (m, 2H), 5.97–
5.91 (m, 1H), 5.74–5.72 (m, 1H), 5.6 and 5.49 (2 br, 1H),
4.26–4.22 (m, 2H), 1.45 and 1.35 (2s, 9H); 13C NMR
(CDCl3) l 174, 154.24 and 153.99, 141.71 and 141.41,
127.75, 126.45, 110.24, 106.81 and 106.31, 79.68, 61.16
and 60.98, 53.41 and 52.95, 28.46 and 28.26. HRMS
observed mass=235.120955 (for M+ calculated mass=
235.120844).
3.11. (−)-(2S,3R,4S)-N-Boc-2-carbomethoxy-3,4-iso-
propylidinedioxypyrrolidine 14
To a well stirred mixture of CH3CN (3.2 mL), CCl4 (2
mL) and H2O (3.2 mL) were added sequentially NaIO4
(691 mg, 3.25 mmol) and RuO2·H2O (8.6 mg, 0.065
mmol). The mixture was stirred vigorously at room
temperature. After 30 min, the resulting mixture was
treated with 13 (201 mg, 0.65 mmol) in CH3CN (2 mL).
The solution turned black during 5 min and enough
NaIO4 was added in small portions to turn the color to
3.9. (−)-(2R,3R,4S)-N-Boc-2-(2-furyl)pyrrolidine-3,4-
diol 12
In a single-necked flask equipped with a magnetic stirring
bar and a rubber septum was placed NMO (72 mg, 0.612

3414
R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 3409–3415
light green. The mixture was diluted with water and
extracted with EtOAc (3×20 mL). The combined
organic extract was washed sequentially with 20% aq.
NaHSO3 until colorless and then with brine and dried
(MgSO4), and the solvent was evaporated under
reduced pressure. The crude acid was dissolved in Et2O,
cooled to 0°C and treated with an ethereal solution of
diazomethane until a slight yellow color persisted. The
excess diazomethane was quenched with acetic acid.
The resulting solution was concentrated under reduced
pressure and the crude ester was purified by flash
column chromatography (25% EtOAc in hexane) on
silica gel to afford pure 14 (160 mg, 82%): [h]2D5 −9.4 (c
(Dowex 50x, 80–100, H+ form, eluted with 0.5 M aq.
NH4OH) to give 1,4-dideoxy-1,4-imino- -ribitol which
was dissolved in water (3 mL) and the pH of the
solution was adjusted to 4 with dilute aq. HCl to
D
afford, after freeze drying, 1,4-dideoxy-1,4-imino-D-
ribitol hydrochloride 1 (64 mg, 75%): mp 130–132°C;
[h]2D0 +53.9 (c 1, H2O) [lit.3d [h]D20 +57.6 (c 0.59, H2O)]
1H NMR (D2O, 600 MHz) l 4.37 (td, C2H, J=4.2, 1.9
Hz), 4.19 (dd, C3H, J=8.4, 4.2 Hz), 3.96 (dd, C5H,
J=12.6, 3.4 Hz), 3.82 (dd, C5%H, J=12.6, 6 Hz), 3.62
(m, C4H), 3.49 (dd, C1H, J=13, 4.2 Hz), 3.36 (dd,
C1%H, J=13, 2 Hz); 13C NMR (D2O) l 50.66, 59.04,
62.84, 70.46, 72.21.
1
0.85, CHCl3); H NMR (CDCl3) l 4.74–4.7 (m, 2H),
4.58 (br s, 1H), 4.4 (br s, 1H), 3.83 (dd, 1H, J=16.2,
12.6 Hz), 3.76 (s, 3H), 3.57 (td, 1H, J=12.6, 4.2 Hz),
1.49, 1.48 and 1.32 (3s, 6H), 1.47 and 1.42 (2s, 9H); 13C
NMR (CDCl3) l 199.17, 171.2, 112.54, 83.27 and 82.49,
80.53, 79.57 and 78.6, 66.36 and 65.81, 52.42 and 52.32,
51.96, 28.32 and 28.24, 26.91 and 26.85, 25. HRMS
observed mass=301.150730 (for M+ calculated mass=
301.152538).
Acknowledgements
Support of this research by a grant from the US–Israel
Binational Science Foundation and from the Marcus
Center for Medicinal and Pharmaceutical Chemistry is
gratefully acknowledged. We thank Dr. H. E. Gottlieb
for valuable help with NMR spectra.
3.12. (2R,3R,4S)-N-Boc-2-hydroxymethyl-3,4-isopropyl-
idinedioxypyrrolidine 15
In a two-necked flask equipped with an argon inlet,
magnetic stirring bar and a rubber septum was placed
ester 14 (135 mg, 0.45 mmol) in Et2O (6 mL) under an
Ar atmosphere at −78°C. DIBAL-H (1 M solution in
hexanes, 2.25 mL, 2.25 mmol) was added dropwise and
stirred for 15 min. Water (1 mL) was added to quench
the reaction. The mixture was diluted with DCM (30
mL) and filtered through a pad of anhydrous MgSO4.
The filtrate was dried (MgSO4) and concentrated.
Purification of the crude by flash column chromatogra-
phy (40% EtOAc in hexane) afforded pure 15 (98 mg,
80%) as a mixture of two rotamers: [h]2D5 −19.4 (c 1.77,
References
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1
CHCl3); H NMR (CDCl3, 600 MHz) For the major
rotamer l 4.79 (d, 1H, J=6 Hz), 4.78 (dt, 1H, J=6, 1.5
Hz), 4.62 (dd, 1H, J=6, 1.5 Hz), 4.15 (t, 1H, J=5 Hz),
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5 Hz), 3.52 (dd, 1H, J=13, 5 Hz), 1.52 (s, 3H), 1.47 (s,
9H), 1.35 (s, 3H); For the minor rotamer l 4.84 (dt,
1H, J=6, 1.5 Hz), 4.79 (d, 1H, J=6 Hz), 4.62 (dd, 1H,
J=6, 1.5 Hz), 4.01 (t, 1H, J=5 Hz), 3.81 (br d, 1H,
J=4 Hz), 3.79 (dd, 1H, J=13, 5 Hz), 3.6 (dd, 1H,
J=13, 6 Hz), 1.52 (s, 3H), 1.48 (s, 9H), 1.35 (s, 3H); 13
C
NMR (CDCl3) (carbonyl peak was not seen due to line
broadening) l 112, 82.43, 80.68, 79.33, 65.57, 63.81,
53.05, 28.75, 27.43, 25.43. HRMS observed mass=
274.165627 (for MH+ calculated mass=274.165448).
3.13. (+)-1,4-Dideoxy-1, 4-imino
1·HCl
D-ribitol hydrochloride
5. Kumareswaran, R.; Balasubramanian, T.; Hassner, A.
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stirred at room temperature under an Ar atmosphere
for 24 h. TLC analysis indicated the absence of starting
material. The solvent was removed and the resulting
trifluoroacetate salt was neutralized with dilute aq.
NaOH and purified by ion exchange chromatography
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3415
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