A glycal approach towards an efficient and stereodivergent synthesis of polyhydroxypyrrolidines

Article abstract of DOI:10.1016/j.tet.2005.11.037

A stereo-defined synthesis of two diastereomers of polyhydroxypyrrolidines from 3,4,6-tri-O-benzyl-d-glucal 4 involving a cleavage-recyclization strategy is reported. Hemiacetal 7 obtained from glucal 4, upon reduction with LiAlH ₄ afforded dio

Full text of DOI:10.1016/j.tet.2005.11.037

Tetrahedron 62 (2006) 1877–1885
A glycal approach towards an efficient and stereodivergent
synthesis of polyhydroxypyrrolidines*
*
Vipin Kumar and Namakkal G. Ramesh
Department of Chemistry, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India
Received 15 July 2005; revised 2 November 2005; accepted 17 November 2005
Available online 13 December 2005
Dedicated to Professor K. K. Balasubramanian on the occasion of his 66th birthday
Abstract—A stereo-defined synthesis of two diastereomers of polyhydroxypyrrolidines from 3,4,6-tri-O-benzyl-D-glucal 4 involving a
cleavage–recyclization strategy is reported. Hemiacetal 7 obtained from glucal 4, upon reduction with LiAlH4 afforded diol 8. Selective
acetylation of 8 to 11, followed by Mitsunobu cyclization yielded the diversely protected polyhydroxypyrrolidine 12. Oxidation of 11 and
subsequent stereoselective reduction led to 20, the C-5 epimer of 11, which upon Mitsunobu cyclization gave polyhydroxypyrrolidine 21.
Selective deprotection of the acetyl groups of 12 and 21 were carried out using Na2CO3 in MeOH. Polyhydroxypyrrolidines 12 and 21 upon
heating with an excess of Mg in MeOH underwent simultaneous N-detosylation and deacetylation to afford amino alcohols 15 and 24,
respectively, in quantitative yield. Catalytic hydrogenation of 15 and 24 provided quantitatively the polyhydroxypyrrolidines 2 and 3,
respectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Several carbohydrate-based3,5 as well as a few chemo-
enzymatic4 and asymmetric6 syntheses of DMDP analogues
2 and 3 have been reported. However, a more general
approach towards various diastereomers of polyhydroxy-
pyrrolidines, especially a stereodivergent route proceeding
through a common intermediate, still remains a challenging
task. The well-defined multichiral architecture of carbo-
hydrates as well as their structural resemblance to aza sugars
provides unique advantages of a ‘chiral pool’ strategy
over others. Among the carbohydrate based approaches,
D-mannitol has been the choice of chiral synthon by several
groups, for the synthesis of 2.3a,b,d–h Surprisingly, glycals
have hardly been used in the synthesis of polyhydroxy-
pyrrolidines, despite their ready availability. Herein we
report an efficient stereodivergent synthesis of two
diastereomers of polyhydroxypyrrolidines, 2 and 3,
from tri-O-benzyl-D-glucal 4 in seven and nine steps,
respectively, in high yields.
Naturally occurring 3,4-dihydroxy-2,5-bis(hydroxymethyl)-
pyrrolidine (DMDP) 1 (Fig. 1) and its analogues constitute a
realm of important functional molecules that have drawn
considerable attention by virtue of their potent and varied
biological activities. These compounds are known to be
selective inhibitors of glycosidases, and hence are expected
to have potential chemotherapeutic utilities such as
antidiabetic, anticancer and anti-HIV properties.2 DMDP 1
is a strong inhibitor of a- and b-glucosidases but shows
weak inhibition against a-fucosidase.3b,4b,d Contrastingly,
polyhydroxypyrrolidine 2 shows mild inhibitory action
against a- and b-glucosidases but is a strong inhibitor of
a-fucosidase.3b Compound 3, a C-5 epimer of DMDP,
exhibits a broad spectrum of inhibition against a- and
b-glucosidases and a-mannosidase. Significantly, while
compound 3 is a selective inhibitor of a-galcatosidase
(and not b-galactosidase), naturally occurring DMDP 1 is
totally inactive against galactosidases.4b,d This varied
biological significance has provided a great impetus
worldwide for the synthesis of DMDP and its analogues.3–7
* See Ref.1
Keywords: Azasugars; Glycosidase inhibitors; Polyhydroxypyrrolidines;
Glycals; Mitsunobu cyclization.
*
Corresponding author. Tel.: C91 11 26596584; fax: C91 11 26581102/
26582037; e-mail: ramesh@chemistry.iitd.ac.in
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.037

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V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
2. Results and discussion
to Et3N in aq THF provided the required material, namely,
3,4,6-tri-O-benzyl-2-deoxy-2-(p-toluenesulfonamido)-a-D-
glucopyranose 7 in 83% yield.8 The next step in our
synthetic sequence was the reduction of the hemiacetal 7 to
the corresponding diol 8. Even though structurally similar
compounds have been readily reduced using NaBH4,5a,9
surprisingly compound 7 was robust to reduction with
NaBH4 under various conditions (entries 1–3; Table 1).
Other reagents such as NaBH4/CeCl3$7H2O, Bu4NBH4,
LiAlH4 also failed to reduce 7 at room temperature (entries
4–7; Table 1). The reason for the reluctance to reduction,
under mild conditions, may presumably be due to an initial
formation of a very highly stable complex such as 9 (Fig. 2).
After extensive experimentation, reduction of 7 to 8 was
successfully accomplished in quantitative yield by heating 7
with 3 equiv of LiAlH4 in THF at reflux (entry 9, Table 1).10
Acetylation of 8 with excess Ac2O in the presence of a
catalytic amount of DMAP afforded the diacetate 10 in 65%
yield. However, selective protection of the primary
hydroxyl group of 8 is an essential requisite in our synthetic
approach to polyhydroxypyrrolidine 12. This was con-
veniently achieved by using 0.9 equiv of Ac2O at K15 8C in
the presence of a catalytic amount of DMAP. Monoacetate
11 was isolated in 66% along with 16% of unreacted diol 8,
which could be readily separated and re-used. The mono
acetylation thus avoids the need for expensive TBDMSCl or
trityl chloride that are commonly used for the selective
protection of primary hydroxyl group. Intramolecular
cyclization of 11 proceeded smoothly under Mitsunobu
conditions, with complete inversion of configuration at C-5,
to afford 12 in 88% yield (Scheme 2).
Danishefsky et al. have earlier reported a two step
synthesis of 3,4,6-tri-O-benzyl-2-deoxy-2-sulfonamido-a-D-
glucopyranose 5 from tri-O-benzyl-D-glucal 4.8 However, the
synthetic utility of this compound has not been explored
much. It occurred to us that the hemiacetal 5 would be an
ideal substrate for a stereo-defined synthesis of polyhydroxy-
pyrrolidines via the cleavage of O–C1 bond followed by ring
closure through the nitrogen (Scheme 1).
Scheme 1.
Thus, iodonium di-sym-collidine perchlorate-promoted
stereoselective iodosulfonamidation of 3,4,6-tri-O-benzyl-
D-glucal 4 with p-toluenesulfonamide afforded 3,4,6-tri-O-
benzyl-2-deoxy-2-iodo-1-deoxy-1-(p-toluenesulfonamido)-
a-D-mannopyranose 6 in 78% yield (Scheme 2).8 Sub-
sequently, we have found that N-iodosuccinimide (NIS) is
a convenient alternative to iodonium di-sym-collidine
perchlorate in the above reaction; iodo compound 6
was obtained in an isolated yield of 90%. Exposure of 6
Table 1. Reduction of hemiacetal (7) under various conditions
Entry
Reagent
Condition
Conversion
of 7 (%)
1
2
3
4
5
6
7
NaBH4/MeOH
10 equiv, room
temperature, 30 min
0
0
0
0
0
0
0
NaBH4/MeOH–THF 1.5 equiv, room
temperature, 4 h
NaBH4/MeOH–THF 10 equiv, room
temperature, 16 h
NaBH4/CeCl3$7H2O 10 equiv, room
temperature, 17 h
Bu4NBH4/THF
LiAlH4/THF
LiAlH4/THF
1.1 equiv, room
temperature, 12 h
1.1 equiv, room
temperature, 10 h
2 equiv, room
temperature, 6.5 h
3 equiv, reflux, 5 h
3 equiv, reflux, 10 h
8
9
LiAlH4/THF
LiAlH4/THF
60
100a
a Yield is also 100% (see experimental details).
Scheme 2. Reagents and conditions: (a) I(sym-collidine)2ClO4 (1.6 equiv),
˚
p-toluenesulfonamide (1.27 equiv), molecular sieves 4 A, CH2Cl2, 0 8C,
0.5 h, 78%; (b) NIS (1.1 equiv), p-toluenesulfonamide (1.1 equiv),
˚
molecular sieves 4 A, CH2Cl2, 0 8C, 0.5 h, 90%; (c) Et3N (2 equiv),
Figure 2.
THF–H2O (5/2), rt 4 h, 83%; (d) LiAlH4 (3 equiv), THF, reflux, 10 h 100%;
(e) Ac2O (4 equiv), cat. DMAP, pyridine, rt, 2 h, 65%; (f) Ac2O (0.9 equiv),
cat. DMAP, pyridine, K15 8C, 2.25 h, 11Z66%, 8Z16%; (g) Ph3P
(1.3 equiv), DEAD (1.5 equiv), THF, 0 8C, 15 min, 88%.
The stereochemistry at C-5 of 12 was confirmed by a two-
step transformation into a C2-symmetric tetra-O-benzyl
derivative 14. Deacetylation of 12 (Na2CO3 in MeOH, 93%)

V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
1879
to 13 followed by benzylation using NaH and benzyl
chloride afforded 14 in 60% yield whose 13C NMR
spectrum displayed signals corresponding to only half the
number of carbon atoms (Scheme 3).
suited in our case. Though a few scattered reports are
available,12 only one example has been so far reported for
N-detosylation of an unactivated sulfonamide using Mg in
MeOH and that too under sonication.12b In our case,
N-detosylation occurred smoothly even without sonication.
On the other hand, exposure of 12 to 32% HBr in AcOH, did
not bring about the expected N-detosylation, but interest-
ingly took a different course to afford the tetra acetyl
derivative 16 (Scheme 4).13 The formation of 16 may be
visualized by initial debenzylation of the hydroxyl groups
followed by their acetylation under the reaction conditions.
Scheme 3. Reagents and conditions: (a) Na2CO3 (3 equiv), MeOH, rt, 12 h,
93%; (b) NaH (1.2 equiv), BnCl (1.2 equiv), DMF, rt, 6 h, 60%.
Our next attempt was the synthesis of 3 (C-5 epimer of 2),
which requires the inversion of configuration at C-5 of 11. It
was envisaged that iodination of 11 to 17 followed by an
intramolecular SN2 displacement of the iodine by the
nitrogen would lead to 21. However, when 11 was treated
with triphenylphosphine/I2/imidazole (Garegg’s reagent),
17 was not formed. Instead, a facile intramolecular
cyclization occurred to afford 12 in 60% yield, with the
spectral data and specific rotation identical to those obtained
from Mitsunobu cyclization (Scheme 5). Garegg’s reagent
has found wide applications in the halogenation of alcohols,
dehydration, didehydoxylation, epoxide formation,
reduction of nitro group to nitrile14 etc. We are not aware
of this reagent combination being used for such an
intramolecular cyclization. This protocol thus provides a
synthetic alternative to Mitsunobu cyclization in the present
case.
One-step global deprotection of 12 to 2 was attempted using
Na/liquid NH3. Even though the reaction was successful,
isolation of the water-soluble 2 from the reaction mixture
was tedious and time-consuming. Hence, a two-step
procedure was followed. Simultaneous N-detosylation and
deacetylation of 12 were carried out by heating with
20 equiv of Mg in MeOH for 1 h at reflux. Catalytic
hydrogenation of the resulting amino alcohol 15 over Pd/C
in ethanol afforded the polyhydroxypyrrolidine 2 in
quantitative yield (over two steps) (Scheme 4). The specific
rotation {[a]2D8 K12 (c 0.20, H2O)} and spectral data
(1H and 13C NMR) of the polyhydroxypyrrolidine obtained
were consistent with the literature values for the free base 2
reported by Dureault et al.3f Different data were reported by
Dureault et al. {[a]D K13 (c 1, H2O); 1H NMR (D2O) d 4.37
(2H, d), 3.87–4.10 (6H, m); 13C NMR (D2O) d 77.2, 65.4,
60.0.}3f and by Zou et al. {[a]D C9.6 (c 0.57, H2O);
1H NMR (D2O) d 3.76 (2H, d), 3.43 (2H, dd), 3.36 (2H, dd),
3.02 (2H, dt); 13C NMR (D2O) d 79.93, 64.41, 63.33.}3d for
free base 2. More confusingly, the data reported by Dureault
et al. for free base 23f and by Zou et al. for its HCl salt3d
were identical. It should be pointed out that in all the earlier
literature reports, invariably acidic reagents and/or resins
have been used in the final deprotection step to obtain the
polyhydroxypyrrolidine 2. In our case, the reactions and
work-up (especially the deprotecting steps) have been
carried out under completely neutral conditions. The
formation of HCl salt is thus extremely unlikely and that
the data reported in this manuscript may unambiguously
provide the correct one for the free base 2.
Scheme 5. Reagents and conditions: (a) PPh3 (4 equiv), I2 (3 equiv),
imidazole (4 equiv), toluene, reflux, 45 min, 60%.
In order to epimerize the C-5 centre of 11, an oxidation–
reduction route was followed. Oxidation of 11 with PDC
proceeded smoothly to afford the carbonyl compound 18,
which was found to exist preferentially in its cyclic form 19,
as evident from the absence of ketone C]O signal in its 13
C
NMR spectrum and appearance of a quaternary carbon
signal at d 88.97 (due to C-5 carbon). Selective reduction of
19 to 20 was then attempted with NaBH4 at room
temperature. The outcome of the initial reaction was not
very encouraging, with the epimeric alcohols 11 and 20
obtained in equal proportions (entry 1, Table 2). In order to
achieve stereoselective reduction of 19 to 20, various
reagent combinations were tried under different conditions,
but most of them either provided 11 and 20 in equal
proportions or preferably 11 (entries 2–4, Table 2).
However, with NaBH4/CeCl3$7H2O, at K78 8C, stereo-
selective reduction in favour of 20 could be realized in a
ratio of 4:1 (entry 6, Table 2). The epimeric alcohols 11 and
20 could be readily separated by column chromatography.
Mitsunobu cyclization of 20 provided protected polyhy-
droxypyrrolidine 21 in 70% yield (Scheme 6). The
stereochemistry at C-5 of 21 was confirmed as before by
converting it to the tetra-O-benzyl derivative 23 whose 13C
NMR spectrum displayed signals corresponding to same
number of carbon atoms (Scheme 7).
Scheme 4. Reagents and conditions: (a) Mg (20 equiv), MeOH, reflux, 1 h,
100%; (b) H2, 5% Pd–C, 30 8C, 13 h, 100%; (c) 32% HBr in AcOH, EtOAc,
rt, 72 h, 51%.
It is worth mentioning here that among the various reagents
available for N-detosylation,11-13 Mg in MeOH12 was best

1880
V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
Table 2. Stereoselective reduction of 19 under various conditions
two diastereomers of polyhydroxypyrrolidines could be
obtained in high yields from a common intermediate,
which is not the case in most of the carbohydrate based
approaches reported so far. The diverse protection of 12 and
21 assumes synthetic significance and provides a handle for
selective deprotection, which may find applications in the
synthesis of other complex natural products. Extension of
this methodology to other glycals would make this a much
more general approach to these classes of compounds.
During the course of our synthesis, we have demonstrated
that Garegg’s protocol provides a synthetic alternative to
Mitsunobu cyclization in ideal cases. We have also shown
that Mg in MeOH is a very convenient and simple reagent for
N-detosylation of even unactivated sulfonamides, which may
provide a synthetically useful protocol in organic chemistry.
Entry
Reagent
Condition
Ratioa
11:20
1
2
NaBH4/CH2Cl2–MeOH 1 equiv, room
temperature, 30 min
1.2 equiv, room
50:50
60:40
Bu4NBH4/CH2Cl2
temperature, 15 min
1.2 equiv, 0 8C, 30 min
3
4
5
Bu4NBH4/CH2Cl2
NaBH4/CH2Cl2–MeOH 1 equiv, K25 8C, 1 h
NaBH4/CeCl3$7H2O
MeOH
NaBH4/CeCl3$7H2O
MeOH
60:40
50:50
35:65
1 equiv, 0 8C, 20 min
6
3.6 equiv, K78 8C, 5 h
20:80b
a Diastereomeric ratio was determined using NMR spectra.
b Isolated yield of 11Z16%; 20Z60%.
4. Experimental
4.1. General
All solvents were purified using standard procedures. Thin-
layer chromatography (TLC) was performed on Merck
precoated silica gel aluminium plates. Flash column
chromatography was performed on 230–400 mesh silica
gel. Optical rotations were recorded on an Autopol II and
Autopol V (Rudolph Research Flanders, New Jersey)
instrument.0 All the rotations were measured at 589 nm
(sodium D line). Melting points of the compounds are
uncorrected. IR spectra were taken within the range 4000–
400 cmK1 as KBr pellets on a Nicolet (Madison, USA) FT-
Scheme 6. Reagents and conditions: (a) PDC (6 equiv), CH2Cl2, reflux, 8 h,
83%; (b) NaBH4 (3.6 equiv), CeCl3$7H2O (1.2 equiv), MeOH, K78 8C,
5 h, 20Z60%, 11Z16%; (c) Ph3P (1.3 equiv), DEAD (1.5 equiv), THF,
0 8C, 15 min, 70%.
1
IR spectrophotometer (Model Protege 460). All the H and
13C NMR spectra were recorded on 300 MHz Bruker
Spectrospin DPX FT NMR. Chemical shifts are reported as
d values (ppm) relative to internal standard Me4Si.
Elemental analyses were performed on a Perkin Elmer
2400 series II analyzer. Mass spectra were recorded using
Waters Micro Mass Q-TOF instrument.
4.1.1.
1-(p-toluenesulfonamido)-a-D-mannopyranose
3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-deoxy-
(6).
Procedure A: using I(sym-collidine)2ClO4. To a suspension
of tri-O-benzyl glucal 4 (4.91 g, 11.80 mmol), p-toluene-
˚
sulfonamide (2.56 g, 14.98 mmol) and powdered 4 A
molecular sieves (4.91 g) in dry CH2Cl2 (20 mL) was
added I(sym-collidine)2ClO4 (8.85 g, 18.88 mmol) under
15
Scheme 7. Reagents and conditions: (a) Na2CO3 (6 equiv), CH2Cl2–
MeOH, rt, 51 h, 90%; (b) NaH (1.2 equiv), BnCl (1.2 equiv), DMF, rt, 6 h,
60%; (c) Mg (20 equiv), MeOH, reflux, 1 h, 100%; (d) H2, 5% Pd–C, 30 8C,
12 h, 100%.
a N2 atmosphere and stirred at 0 8C. When the reaction was
complete (TLC, 30 min), the solid was filtered and the
filtrate was diluted with ether (300 mL). The combined
organic layer was washed with saturated Na2S2O3
(200 mL), CuSO4 (200 mL), NaCl (2!200 mL), dried
over sodium sulfate and concentrated. Flash chromato-
graphy (5:1 hexane/ethyl acetate) of the resulting residue
provided 6 (6.56 g, 78%) as a white solid.
Finally, the parent polyhydroxypyrrolidine 3 was obtained
in two steps from 21 as before in quantitative yield. The
spectral data and optical rotation {[a]2D8 C22.7 (c 0.14,
H2O)} of 3 were consistent with the literature values {[a]D23
C25.7 (c 4.00, H2O),4d [a]D20 C25.1 (c 1.5, H2O)5b} for the
free base.
Procedure B: using NIS. To a suspension of tri-O-benzyl
glucal 4 (3.33 g, 8.00 mmol), p-toluenesulfonamide (1.50 g,
˚
8.80 mmol) and powdered 4 A molecular sieves (3.50 g) in
3. Conclusion
dry CH2Cl2 (15 mL) was added NIS (1.98 g, 8.80 mmol)
under a N2 atmosphere and stirred at 0 8C. When
the reaction was complete (TLC, 30 min), the solid was
filtered and the filtrate was diluted with CH2Cl2 (300 mL).
The combined organic layer was washed with saturated
In conclusion, we have developed a simple and stereo-
divergent route to two diastereomers of polyhydroxypyrro-
lidines from readily available 3,4,6-tri-O-benzyl-D-glucal 4.
The salient feature of our methodology is that stereo-defined

V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
1881
Na2S2O3 (200 mL), water (200 mL), dried over sodium
sulfate and concentrated. Flash chromatography (5:1,
hexane/ethyl acetate) of the resulting residue provided 6
(5.14 g, 90%) as a white solid, mp 120–122 8C; [Found: C,
57.38; H, 5.10; N, 1.78. C34H36O6NSI requires C, 57.22; H,
5.05; N, 1.96%]; [a]2D8 K21.2 (c 0.99, CHCl3); nmax(KBr)
3254, 3030, 2863, 1496, 1453, 1432, 1358, 1325, 1157,
1103, 1041, 1027, 697 cmK1; dH (300 MHz, CDCl3)7.73(2H,
d, JZ8.2 Hz, SO2Ar), 7.33–7.25 (13H, m, Ph), 7.16–7.11
(4H, m, SO2Ar, Ph), 5.58 (2H, br s, NH, H-1), 4.66 (2H, t,
JZ10.8 Hz, CH2Ph), 4.56–4.52 (2H, m, CH2Ph), 4.46–4.35
(3H, m), 3.82 (1H, t, JZ7.6 Hz), 3.54–3.44 (2H, m),
3.14–3.07 (2H, m), 2.33 (3H, s, Me); dC (75 MHz, CDCl3)
143.7, 138.1, 137.8, 137.3, 129.5, 128.2, 128.0, 127.7, 127.5,
127.2, 83.5, 77.1, 74.8, 74.6, 73.2, 73.0, 71.2, 67.5, 31.3, 21.4.
HRMS (ESI): [MCNa]C, found 628.2336. C34H39O7NSNa
requires 628.2345.
4.1.4. 1,5-Di-O-acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-(p-
toluenesulfonamido)-D-glucitol (10). To a stirred solution
of 8 (0.51 g, 0.84 mmol) in pyridine (1 mL) was added
DMAP (0.015 g, 0.126 mmol) and acetic anhydride
(0.32 mL, 3.37 mmol). The reaction mixture was allowed
to stir for 2 h at room temperature, quenched with 100 mL
of 10% HCl and extracted with ethyl acetate (3!50 mL).
The combined organic layer was then washed with brine
(100 mL), dried over sodium sulfate and concentrated. Flash
chromatography (6:1 hexane/ethyl acetate) of resulting
residue provided 10 (0.38 g, 65%) as colourless gummy
liquid; [a]2D8 C2.8 (c 2.01, CHCl3); nmax(KBr) 3431, 3030,
2925, 1740, 1631, 1366, 1231, 1162, 1092, 1048, 699 cmK1
;
dH (300 MHz, CDCl3) 7.71 (2H, d, JZ7.9 Hz, SO2Ar),
7.31–7.20 (17H, m, SO2Ar, Ph), 5.19 (1H, d, JZ4.5 Hz, H-1),
5.06 (1H, d, JZ8.5 Hz, NH exchangeable with D2O), 4.76
(1H, d, JZ11 Hz), 4.67 (1H, d, JZ11.2 Hz), 4.51 (3H, m),
4.44 (1H, d, JZ11 Hz), 3.85–3.73 (6H, m), 3.55 (1H, dd,
JZ10.2, 5.4 Hz), 2.37 (3H, s, SO2C6H4Me), 2.03 (3H, s,
CHOCOMe), 1.72(3H, s, CH2OCOMe); dC (75 MHz, CDCl3)
170.1, 169.8, 143.0, 137.8, 137.6, 137.2, 129.4, 128.1, 127.6,
127.4,126.8,77.9, 76.5, 74.7, 74.2, 72.8, 72.4, 67.8, 63.1, 53.1,
21.2, 20.8, 20.2; HRMS (ESI): [MCNa]C, found: 712.2516.
C38H43O9NSNa requires 712.2556.
4.1.2. 3,4,6-Tri-O-benzyl-2-deoxy-2-(p-toluenesulfon-
amido)-a-D-glucopyranose (7). To a stirred solution of 6
(4.06 g, 5.69 mmol) in THF (60 mL) and H2O (24 mL) at
room temperature was added triethylamine (1.58 mL,
11.38 mmol). After 4 h, saturated NaCl solution (250 mL)
was added and the resulting mixture was extracted with
ether (4!100 mL). The combined organic layer was dried
over sodium sulfate and concentrated to give a white solid,
which on recrystallization (THF/hexane) provided pure 7
(2.85 g, 83%) as a white solid, mp 178 8C (decomp.);
[Found: C, 67.76; H, 6.28; N, 1.87. C34H37O7NS requires C,
67.66; H, 6.13; N, 2.32%]; [a]2D8 C23.8 (c 0.79, THF);
nmax(KBr) 3284, 3031, 2912, 1451, 1327, 1160, 1140, 1072,
1048, 1028, 700 cmK1; dH (300 MHz, CDCl3) 7.72 (2H, d,
JZ8.2 Hz, SO2Ar), 7.30–7.08 (17H, m, SO2Ar, Ph), 5.01
(1H, br s, H-1), 4.88 (1H, d, JZ9.1 Hz, NH exchangeable
with D2O), 4.74–4.67 (3H, m), 4.57–4.41 (3H, m), 3.96 (1H,
d, JZ9.1 Hz), 3.70–3.42 (5H, m), 2.88 (1H, br s, OH
exchangeable with D2O), 2.35 (3H, s, Me); dC (75 MHz,
CDCl3) 142.7, 138.2, 138.0, 137.7, 129.3, 128.1, 127.9,
127.8, 127.5, 127.1, 126.7, 91.5, 79.8, 78.3, 75.1, 74.6, 73.2,
69.6, 68.8, 57.8, 21.3; HRMS (ESI): [MCNa]C, found
626.2225. C34H37O7NSNa requires 626.2188.
4.1.5. 1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-(p-toluene-
sulfonamido)-D-glucitol (11). To a stirred solution of 8
(1.74 g, 2.87 mmol) in pyridine (3 mL) was added DMAP
(0.035 g, 0.287 mmol). After the reaction mixture was cooled
to K15 8C, acetic anhydride (0.24 mL, 2.58 mmol) dissolved
in pyridine (2 mL) was added dropwise during the course of
1.25 h. After complete addition, the reaction mixture was
stirred for an additional 1 h at K15 8C, then quenched
with 10% HCl (200 mL) and extracted with ethyl acetate
(4!75 mL). The combined organic layer was washed with
brine (3!100 mL), dried over sodium sulfate and concen-
trated. Flash chromatography (5:1 hexane/ethyl acetate) of the
resulting residue provided 11 (1.23 g, 66%) as colourless
gummy liquid along with unreacted 8 (0.28 g, 16%).
Compound 11. [a]D28 C6.2 (c 1.10, CHCl3); nmax (KBr)
3442, 3030, 2921, 2856, 2361, 1739, 1631, 1227, 1158,
1097, 766, 699 cmK1; dH (300 MHz, CDCl3) 7.72 (2H, d,
JZ8.1 Hz, SO2Ar), 7.34–7.19 (17H, m, SO2Ar, Ph), 5.15
(1H, d, JZ7.4 Hz, NH exchangeable with D2O), 4.76 (1H, d,
JZ11.2 Hz), 4.68 (1H, d, JZ11.2 Hz), 4.56–4.45 (4H, m,
2!CH2Ph), 3.97 (1H, dd, JZ12.6, 3.6 Hz), 3.93–3.88 (2H,
m), 3.83–3.80 (1H, m), 3.76 (1H, d, JZ7.2 Hz), 3.66 (1H, t,
JZ6.9 Hz), 3.59 (1H, dd, JZ9.5, 3.6 Hz), 3.48 (1H, dd,
JZ9.5, 5.0 Hz), 2.59 (1H, d, JZ5.9 Hz, OH exchangeable
with D2O), 2.37 (3H, s, SO2C6H4Me), 1.75 (3H, s, COMe); dC
(75 MHz, CDCl3) 170.4, 143.1, 137.8, 137.6, 137.3, 129.4,
128.2, 127.7, 126.8, 78.1, 74.5, 74.1, 73.1, 71.2, 70.6, 63.4,
53.3, 21.2, 20.3; HRMS (ESI): MHC, found: 648.2623.
C36H42O8NS requires 648.2631.
4.1.3. 3,4,6-Tri-O-benzyl-2-deoxy-2-(p-toluenesulfon-
amido)-D-glucitol (8). In a flame dried 250 mL three-
necked round bottomed flask 7 (5.96 g, 9.88 mmol) was
dissolved in dry THF (90 mL) under a N2 atmosphere. To
this, LAH (1.13 g, 29.64 mmol) was added and the reaction
was heated at reflux for 10 h. The reaction mixture was then
quenched with 2 M HCl (250 mL) and extracted with
CHCl3 (4!100 mL). The combined organic layer was dried
over sodium sulfate and concentrated to yield 8 (5.98 g,
quantitative) as colourless gummy liquid. The compound
was pure enough (NMR) and does not require further
purification; [a]D28 K3.0 (c 1.95, THF); nmax(KBr) 3397,
3030, 2922, 1453, 1328, 1157, 1097, 737, 698; dH
(300 MHz, CDCl3) 7.71 (2H, d, JZ7.7 Hz, SO2Ar),
7.33–7.20 (17H, m, SO2Ar, Ph), 5.31 (1H, d, JZ8.0 Hz,
NH exchangeable with D2O), 4.72 (1H, d, JZ11.2 Hz),
4.62 (1H, d, JZ11.2 Hz), 4.54–4.46 (4H, m, 2!CH2Ph),
3.83–3.74 (2H, m), 3.64–3.57 (m, 3H), 3.49–3.46 (2H,
m), 3.32–3.24 (1H, m), 2.68 (1H, d, JZ5.6 Hz, OH
exchangeable with D2O), 2.36 (3H, s, Me), 2.17 (1H, dd,
JZ4.4, 3.0 Hz, OH exchangeable with D2O); dC (75 MHz,
CDCl3) 143.1, 137.8, 137.6, 129.4, 128.2, 127.7, 126.8,
78.4, 78.2, 74.6, 73.8, 73.1, 71.0, 70.8, 62.2, 55.5, 21.2;
4.1.6. (2S,3R,4R,5S)-2-(Acetoxymethyl)-3,4-di-O-benzyl-
5-(benzyloxymethyl)-N-(p-toluenesulfonamido)pyrro-
lidine (12). Procedure A: using Mitsunobu conditions. In a
flame dried 100 mL three-necked round bottomed flask
was taken 11 (2.21 g, 3.42 mmol) and dissolved in dry

1882
V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
THF (15 mL) under a N2 atmosphere. PPh3 (1.16 g,
4.45 mmol) was then added and the reaction mixture was
cooled to 0 8C. DEAD (0.81 mL, 5.13 mmol) was injected
into the reaction mixture dropwise. After the reaction was
over (15 min, as indicated by TLC), the reaction was
stopped and the solvent was evaporated. Flash chromato-
graphy (6:1 hexane/ethyl acetate) of resulting residue
provided 12 (1.89 g, 88%) as colourless gummy liquid.
temperature and allowed to stir for 6 h. The reaction
mixture was then quenched with water (10 mL) and
extracted with ethyl acetate (3!50 mL). The combined
organic layer was then washed with brine (100 mL), dried
over sodium sulfate and concentrated. Flash chromatog-
raphy (8:1 hexane/ethyl acetate) of resulting residue
provided 14 (0.034 g, 60%) as colourless gummy liquid;
[a]2D8 K27.9 (c 0.42, CHCl3); nmax(KBr) 3030, 2925, 2870,
2360, 1769, 1722, 1604, 1454, 1367, 1207, 1102, 1027, 738,
698 cmK1; dH (300 MHz, CDCl3) 7.68 (2H, d, JZ7.9 Hz,
SO2Ar), 7.38–7.12 (22H, m, Ph), 4.63 (2H, d, JZ11.9 Hz),
4.55 (2H, d, JZ11.9 Hz), 4.46–4.45 (2H, m), 4.32 (2H, d,
JZ11.9 Hz), 4.26 (2H, d, JZ11.9 Hz), 3.94 (2H, br s), 3.86
(2H, dd, JZ9.8, 3.8 Hz), 3.63 (2H, d, JZ9.8 Hz), 2.28 (3H,
s, Me); dC (75 MHz, CDCl3) 142.7, 138.4, 138.2, 129.1,
128.7, 128.2, 128.0, 127.4, 127.1, 126.3, 80.7, 73.1, 72.9,
67.1, 58.4, 21.3; HRMS (ESI): [MCNa]C, found:
700.2701. C41H43O6NSNa requires 700.2709.
Procedure B: using Garegg’s reagent. A mixture of
11 (0.200 g, 0.309 mmol), PPh3 (0.324 g, 1.236 mmol),
imidazole (0.840 g, 1.236 mmol) and iodine (0.235 g,
0.927 mmol) in toluene (5 mL) was stirred under reflux at
a bath temperature of 120 8C for 45 min, after which the
reaction mixture was cooled to room temperature. Saturated
NaHCO3 solution (10 mL) was added and the mixture was
stirred for 5 min. Compound was extracted with chloroform
(3!75 mL), and washed with saturated Na2S2O3 solution
(100 mL). The combined organic layer was dried over
sodium sulfate and concentrated. Flash chromatography
(6:1 hexane/ethyl acetate) of the resulting residue provided
12 (0.116 g, 60%) as colourless gummy liquid; [a]2D8 K21.4
(c 1.26, CHCl3); nmax(KBr) 2925, 2854, 1740, 1454, 1243,
1219, 1155, 1128, 764, 698 cmK1; dH (300 MHz, CDCl3)
7.67 (2H, d, JZ8.1 Hz, SO2Ar), 7.28–7.17 (15H, m, Ph),
7.11–7.08 (2H, m, SO2Ar), 4.61–4.55 (3H, m), 4.53 (1H, d,
JZ11.7 Hz), 4.47 (1H, d, JZ8.4 Hz), 4.37 (1H, dd,
JZ11.8, 3.9 Hz), 4.30 (1H, d, JZ11.8 Hz), 4.23–4.18
(3H, m), 4.00–3.94 (2H, m), 3.87 (1H, dd, JZ9.9, 3.9 Hz),
3.64 (1H, d, JZ9.9 Hz), 2.33 (3H, s, SO2C6H4Me), 1.71
(3H, s, COMe); dC (75 MHz, CDCl3) 169.9, 143.0, 138.2,
137.7, 129.3, 128.3, 128.0, 127.6, 127.5, 127.1, 126.9, 80.2,
80.0, 73.3, 72.9, 66.8, 61.4, 58.2, 56.8, 21.3, 20.6; HRMS
(ESI): MHC, found: 630.2552. C36H40O7NS requires
630.2525.
4.1.9. (2S,3R,4R,5S)-3,4-Di-O-benzyl-5-(benzyloxy-
methyl)-2-(hydroxymethyl)pyrrolidine (15). In a flame
dried 50 mL three-necked round bottomed flask was taken
activated Mg turnings (0.252 g, 10.50 mmol) and further
flame dried under a N2 atmosphere. Compound 12 (0.330 g,
0.525 mmol) dissolved in dry MeOH (7 mL) was transferred
into the reaction flask and heated at reflux for 1 h. After this
time, MeOH was evaporated, water (400 mL) was added to
the reaction mixture and stirred for 15 min. Compound was
then extracted with chloroform (4!100 mL), dried over
sodium sulfate and concentrated to obtain 15 (0.227 g,
100%) as colourless gummy liquid. The compound was pure
enough (NMR) and does not require further purification;
[a]2D8 K6.1 (c 0.79, THF); nmax(KBr) 3397, 3030, 2924,
2871, 1769, 1722, 1605, 1454, 1377, 1103, 1028, 738,
698 cmK1; dH (300 MHz, CDCl3) 7.33–7.23 (15H, m, Ph),
4.59–4.53 (5H, m), 4.39 (1H, d, JZ11.8 Hz), 4.06 (2H, d,
JZ4.1 Hz), 3.78 (1H, dd, JZ11.8, 4.5 Hz), 3.71–3.55 (4H,
m), 3.48 (1H, dd, JZ9.3, 4.5 Hz), 1.90 (2H, br s, NH, OH
exchangeable with D2O); dC (75 MHz, CDCl3) 137.9,
137.4, 137.1, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8,
127.7, 127.6, 81.8, 80.8, 73.3, 72.4, 72.3, 67.3, 61.0, 60.0,
59.1; HRMS (ESI): MHC, found: 434.2332. C27H32O4N
requires 434.2331.
4.1.7. (2S,3R,4R,5S)-3,4-Di-O-benzyl-5-(benzyloxy-
methyl)-2-(hydroxymethyl)-N-(p-toluenesulfonamido)-
pyrrolidine (13). To a stirred solution of 12 (0.050 g,
0.079 mmol) in MeOH (1 mL) at room temperature was
added Na2CO3 (0.025 g, 0.237 mmol). After completion of
the reaction (12 h, as indicated by TLC), the solid was
filtered and MeOH was evaporated to obtain 13 (0.043 g,
93%) as colourless viscous liquid. The compound was pure
enough (NMR) and does not require further purification;
[a]2D8 K26.6 (c 0.70, CHCl3); nmax(KBr) 3351, 3258, 2924,
1616, 1333, 1160, 1110, 758, 698 cmK1; dH (300 MHz,
CDCl3) 7.72 (2H, d, JZ7.9 Hz, SO2Ar), 7.30–7.18 (15H, m,
Ph), 7.01 (2H, d, JZ3.8 Hz, SO2Ar), 4.70–4.50 (5H, m),
4.30–4.10 (4H, m), 3.99 (1H, d, JZ10 Hz), 3.85–3.77 (3H,
m), 3.57 (1H, d, JZ10 Hz), 2.69 (1H, br s, OH exchange-
able with D2O), 2.32 (3H, s, Me); dC (75 MHz, CDCl3)
143.2, 138.0, 137.7, 137.5, 137.0, 129.3, 128.3, 127.9,
127.6, 127.3, 127.1, 126.8, 81.3, 81.2, 73.3, 73.1, 72.6, 66.2,
61.0, 59.8, 58.2, 21.3; HRMS (ESI): [MCNa]C, found:
610.2220. C34H37O6NSNa requires 610.2239.
4.1.10. (2S,3R,4R,5S)-3,4-Dihydroxy-2,5-bis(hydroxy-
methyl)pyrrolidine (2). Five percentage palladium on
charcoal (0.270 g) was taken up in a 50 mL three-necked
round bottomed flask. Compound 15 (0.090 g, 0.208 mmol)
dissolved in ethanol (4 mL) was added to the reaction flask.
H2 gas was then bubbled slowly into reaction mixture for
13 h at 30 8C, after which time the reaction mixture was
filtered and ethanol was evaporated. Recrystallization of the
resulting residue (MeOH/ethyl acetate) yielded
2
(0.034 g, 100%) as a white solid; [a]2D8 K12 (c 0.20,
H2O); dH (300 MHz, D2O) 4.22 (2H, br s), 3.95–3.74 (6H,
m); dC (75 MHz, D2O) 78.3, 66.4, 61.1.
4.1.8. (2S,3R,4R,5S)-3,4-Di-O-benzyl-2,5-bis(benzyloxy-
methyl)-N-(p-toluenesulfonamido)pyrrolidine (14). To a
solution of 13 (0.050 g, 0.085 mmol) in DMF (1 mL) at 0 8C
was added NaH (0.004 g as 60% in mineral oil;
0.102 mmol) and benzyl chloride (0.012 mL, 0.102
mmol). Reaction mixture was then brought to room
4.1.11. (2S,3R,4R,5S)-3,4-Di-O-(acetyl)-2,5-bis(acetoxy-
methyl)-N-(p-toluenesulfonamido)pyrrolidine (16). To a
stirred, 0 8C cooled, 32% HBr in AcOH (5 mL), 12 (0.200 g,
0.318 mmol) dissolved in ethyl acetate (2 mL) was added in
four portions over a period of 2 h. Then reaction mixture
was allowed to stir for 72 h at room temperature, after which

V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
1883
time it was cooled to 0 8C, quenched with saturated
NaHCO3 solution (10 mL) and extracted with chloroform
(4!50 mL). The combined organic layer was washed with
water, dried over sodium sulfate and concentrated. Flash
chromatography (3:1 hexane/ethyl acetate) of the resulting
residue provided 16 (0.079 g, 51%) as colourless gummy
liquid; [a]2D8 K5.7 (c 0.34, CHCl3); nmax(KBr) 2924, 2361,
1745, 1643, 1371, 1223, 1158, 1100, 1055, 771 cmK1; dH
(300 MHz, CDCl3) 7.72 (2H, d, JZ7.7 Hz, SO2Ar), 7.30
(2H, d, JZ7.7 Hz, SO2Ar), 5.42 (2H, d, JZ4.2 Hz, H-2, H-
5), 4.36 (4H, m, 2!CH2OCOMe), 4.17 (2H, d, JZ11.5 Hz,
H-3, H-4), 2.43 (3H, s, SO2C6H4Me), 2.07 (6H, s,
2!CHOCOMe), 1.88 (6H, s, 2!CH2OCOMe); dC
(75 MHz, CDCl3) 170.2, 169.7, 143.8, 136.8, 129.7,
127.0, 72.5, 60.5, 55.9, 21.4, 20.5; HRMS (ESI): MHC,
found: 486.1432. C21H28O10NS requires 486.1434.
(4H, m), 3.94–3.73 (5H, m), 3.62 (1H, d, JZ8.6 Hz), 3.47
(1H, t, JZ8.6 Hz), 3.24 (1H, dd, JZ9.3, 4.0 Hz), 2.37 (4H,
s, SO2C6H4Me, OH), 1.82 (3H, s, COMe); dC (75 MHz,
CDCl3) 170.3, 143.3, 138.2, 137.7, 137.6, 132.1, 131.9,
129.6, 128.3, 128.2, 127.9, 127.8, 126.9, 78.9, 77.2, 75.3,
75.0, 73.2, 71.6, 69.3, 63.3, 52.4, 21.4, 20.4; HRMS (ESI):
MHC, found: 648.2650. C36H42O8NS requires 648.2631.
4.1.14. (2S,3R,4R,5R)-2-(Acetoxymethyl)-3,4-di-O-ben-
zyl-5-(benzyloxymethyl)-N-(p-toluenesulfonamido)pyr-
rolidine (21). Following a similar procedure as for
compound 12, 1.14 g (1.77 mmol) of 20 provided 21
(0.77 g, 70%) as white crystalline solid, mp 84 8C; [a]D28
K4.2 (c 1.42, THF); nmax(KBr) 3028, 2907, 1744, 1455,
1348, 1216, 1161, 1080, 1031, 739, 667 cmK1; dH
(300 MHz, CDCl3) 7.72 (2H, d, JZ7.8 Hz, SO2Ar), 7.29–
7.18 (15H, m, Ph), 7.00 (2H, m, SO2Ar), 4.60–4.53 (2H, m,
CH2Ph), 4.47 (1H, d, JZ11.9 Hz), 4.41–4.31 (3H, m), 4.24
(2H, m), 4.04 (1H, m), 3.88–3.84 (1H, dd, JZ12.5, 5.8 Hz),
3.78–3.71 (3H, m), 3.68–3.64 (1H, m), 2.34 (3H, s,
SO2C6H4Me), 1.96 (3H, s, COMe); dC (75 MHz, CDCl3)
170.4, 143.7, 138.0, 137.4, 136.9, 133.3, 129.5, 128.3,
128.1, 127.8, 127.5, 127.3, 81.1, 79.9, 73.2, 72.1, 71.0, 70.5,
64.1, 62.3, 59.7, 21.4, 20.7; HRMS (ESI): MHC, found:
630.2532. C36H40O7NS requires 630.2525.
4.1.12. Oxidation of 11 to 19 using PDC. To a flame dried
100 mL three-necked round bottomed flask, was added 11
(0.70 g, 1.08 mmol) dissolved in dry dichloromethane
(15 mL) under a N2 atmosphere. To this, PDC (2.44 g,
6.48 mmol) was added and the reaction mixture heated at
458C for 8 h, after which time the residue was filtered
through a G-4 sintered filter and washed with more
dichloromethane (100 mL). The organic layer was washed
with 10% HCl (2!75 mL) and saturated NaHCO3
(100 mL). The organic layer was dried over sodium sulfate
and concentrated. Flash chromatography (6:1 hexane/ethyl
acetate) of resulting residue provided 19 (0.58 g, 83%) as
colourless gummy liquid; [a]2D8 K18.7 (c 1.48, CHCl3);
nmax(KBr) 3445, 3030, 2923, 2856, 2361, 1740, 1455,
1347, 1242, 1159, 1091, 738, 699, 666 cmK1; dH
(300 MHz, CDCl3) 7.82 (2H, d, JZ7.5 Hz, SO2Ar),
7.31–7.20 (17H, m, SO2Ar, Ph), 4.71–4.47 (6H, m,
3!CH2Ph), 4.30–4.16 (4H, m), 3.90–3.76 (4H, m), 2.40
(3H, s, SO2C6H4Me), 1.84 (3H, s, COMe); dC (75 MHz,
CDCl3) 170.1, 143.2, 137.7, 137.0, 129.5, 129.0, 128.2,
128.0, 127.9, 127.6, 127.4, 127.1, 126.9, 88.9, 82.0,
79.5, 73.7, 73.4, 73.1, 63.0, 56.0, 21.3, 20.6; HRMS
(ESI): [MCNa]C, found: 668.2306. C36H39O8NSNa
requires 668.2294.
4.1.15. (2S,3R,4R,5R)-3,4-Di-O-benzyl-5-(benzyloxy-
methyl)-2-(hydroxymethyl)-N-(p-toluenesulfonamido)-
pyrrolidine (22). To a stirred solution of 21 (0.070 g,
0.11 mmol) in dichloromethane (1 mL), was added MeOH
(1 mL) and Na2CO3 (0.070 g, 0.67 mmol) at room tem-
perature. After completion of the reaction (51 h, TLC), the
reaction mixture was filtered and MeOH was evaporated to
obtain 22 (0.059 g, 90%) as colourless viscous liquid.
The compound was pure enough (NMR) and does not
require further purification; [a]2D8 K11.1 (c 0.67, CHCl3);
nmax(KBr) 3464, 3030, 2924, 2870, 2359, 1733, 1496, 1454,
1343, 1216, 1162, 1089, 1045, 1028, 751, 698, 669 cmK1
;
dH (300 MHz, CDCl3) 7.66 (2H, d, JZ7.7 Hz, SO2Ar),
7.33–7.18 (15H, m, Ph), 7.05 (2H, br s, SO2Ar), 4.53–4.25
(7H, m), 3.88–3.82 (3H, m), 3.70–3.59 (4H, m), 3.27 (1H, br
s, OH exchangeable with D2O), 2.36 (3H, s, Me); dC
(75 MHz, CDCl3) 143.8, 137.6, 136.9, 133.5, 129.6, 128.5,
128.4, 128.2, 128.1, 127.9, 127.7, 82.3, 80.1, 73.4, 72.4,
71.8, 70.0, 63.5, 62.8, 62.6, 21.5; HRMS (ESI): [MCNa]C,
found: 610.2249. C34H37O6NSNa requires 610.2239.
4.1.13. 1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-(p-
toluenesulfonamido)-L-iditol (20). To a K78 8C cooled
solution of 19 (0.97 g, 1.50 mmol) in MeOH (3 mL) was
added CeCl3$7H2O (0.67 g, 1.80 mmol) and the mixture
allowed to stir for 1 h. After 1 h, NaBH4 (0.205 g,
5.40 mmol) was added in portions over a period of 4.5 h.
The reaction was stirred for an additional 30 min, at
K78 8C. It was then brought to room temperature, MeOH
was evaporated and saturated NH4Cl (100 mL) was added to
quench the reaction. The solution was extracted with
chloroform (3!75 mL). The combined organic layer was
washed with brine (200 mL), dried over sodium sulfate and
concentrated. Flash chromatography (5:1 hexane/ethyl
acetate) of resulting residue provided 20 (0.584 g, 60%) as
white crystalline solid along with 11 (0.155 g, 16%).
Compound 20, mp 104 8C; [a]2D8 K2.8 (c 0.35, THF);
nmax(KBr) 3443, 2922, 2853, 2359, 1728, 1638, 1452, 1332,
1159, 1091, 768, 699 cmK1; dH (300 MHz, CDCl3) 7.73
(2H, d, JZ7.9 Hz, SO2Ar), 7.33–7.21 (17H, m, SO2Ar, Ph),
5.09 (1H, d, JZ9.1 Hz, NH exchangeable with D2O), 4.83
(1H, d, JZ10.8 Hz), 4.76 (1H, d, JZ10.8 Hz), 4.51–4.43
4.1.16. (2R,3R,4R,5S)-3,4-Di-O-benzyl-2,5-(benzyloxy-
methyl)-N-(p-toluenesulfonamido)pyrrolidine (23).
Following a similar procedure as for compound 14,
0.050 g (0.085 mmol) of 22 provided 23 (0.034 g, 60%) as
colourless gummy liquid; [a]2D8 K3.8 (c 0.26, CHCl3);
nmax(KBr) 3030, 2361, 2335, 1737, 1646, 1454, 1350, 1162,
1090, 737, 697, 667 cmK1; dH (300 MHz, CDCl3) 7.67 (2H,
d, JZ7.5 Hz, SO2Ar), 7.29–7.24 (18H, m, Ph), 7.15 (2H, m,
Ph), 6.94 (2H, d, JZ4.2 Hz, SO2Ar), 4.53–4.39 (6H, m),
4.15 (2H, s), 4.04 (1H, dd, JZ4.9, 3.2 Hz), 4.00 (1H, s),
3.89–3.72 (6H, m), 2.29 (3H, s, Me); dC (75 MHz, CDCl3)
143.5, 138.2, 137.6, 133.3, 129.4, 128.2, 127.9, 127.6,
127.1, 81.6, 80.5, 73.4, 73.2, 72.6, 71.0, 70.7, 68.7, 64.5,
61.6, 21.4; HRMS (ESI): [MCNa]C, found: 700.2695.
C41H43O6NSNa requires 700.2709.

1884
V. Kumar, N. G. Ramesh / Tetrahedron 62 (2006) 1877–1885
4. (a) Dax, K.; Peinsipp, R.; Stutz, A. E. Tetrahedron Lett. 1997,
38, 225–226. (b) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.;
Siuzdak, G.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119,
8146–8151. (c) Legler, G.; Korth, A.; Berger, A.; Ekhart, C.;
Gradnig, G.; Stutz, A. E. Carbohydr. Res. 1993, 250, 67–77. (d)
Liu, K. K.-C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.;
Wong, C. H. J. Org. Chem. 1991, 56, 6280–6289.
4.1.17. (2S,3R,4R,5R)-3,4-Di-O-benzyl-5-(benzyloxy-
methyl)-2-(hydroxymethyl)pyrrolidine (24). Following a
similar procedure as for compound 15, 0.316 g
(0.502 mmol) of 21 provided 24 (0.217 g, quantitative) as
colourless gummy liquid; [a]2D8 C11.3 (c 0.53, CHCl3);
nmax(KBr) 3380, 3030, 2922, 2857, 1649, 1453, 1364, 1251,
1095, 912, 743, 698 cmK1; dH (300 MHz, CDCl3)
7.31–7.24 (15H, m, Ph), 4.58–4.49 (5H, m), 4.41 (1H, d,
JZ11.6 Hz), 4.06 (1H, dd, JZ5.1, 2.0 Hz), 3.92 (1H, dd,
JZ4.6, 2.0 Hz), 3.87 (1H, dd, JZ11.8, 4.4 Hz), 3.78 (1H,
dd, JZ11.6, 4.4 Hz), 3.61–3.57 (2H, m), 3.35 (2H, t,
JZ4.9 Hz), 2.36 (2H, br s, NH, OH exchangeable with
D2O); dC (75 MHz, CDCl3) 138.0, 137.5, 128.3, 127.6, 86.2,
84.6, 73.1, 71.9, 71.5, 70.7, 63.1, 61.5, 60.9; HRMS (ESI):
MHC, found: 434.2368. C27H32O4N requires 434.2331.
Spectral data of 24 were consistent with the literature values
reported by Wong et al.5i
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4.1.18. (2R,3R,4R,5S)-3,4-Dihydroxy-2,5-bis(hydroxy-
methyl)pyrrolidine (3). Following a similar procedure as
for compound 2, 0.252 g (0.582 mmol) of 24 using 1.512 g
of 5% palladium on charcoal for 12 h at 30 8C provided
0.094 g of 3 (quantitative); [a]2D8 C22.7 (c 0.14, H2O); dH
(300 MHz, D2O) 4.17 (1H, br t), 3.99 (1H, br t), 3.92–3.71
(5H, m), 3.50 (1H, quintet, JZ4.0 Hz,); dC (75 MHz, D2O):
78.4, 77.0, 69.1, 65.4, 61.7, 59.3; dC (75 MHz, MeOH-d4): d
76.2, 74.8, 66.7, 62.1, 59.6, 57.1.
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Acknowledgements
7. (a) Moreno-Vargas, A. J.; Robina, I.; Petricci, E.; Vogel, P.
J. Org. Chem. 2004, 69, 4487–4491. (b) Yu, C.-Yi.; Asano, N.;
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We are grateful to the Department of Science and
Technology, New Delhi for financial support (SP/S1/
G-19/2000). V.K. thanks the Council of Scientific and
Industrial Research, New Delhi for a research fellowship.
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