Asymmetric synthesis of a 3,4-substituted pyrrolidine by l-proline catalyzed direct enolexo aldolization

Article abstract of DOI:10.1016/j.tetasy.2007.05.004

The asymmetric synthesis of a 3,4-substituted N-tosyl pyrrolidine has been achieved by using l-proline catalyzed 5-enolexo aldolization with high enantio and diastereoselectivity.

Full text of DOI:10.1016/j.tetasy.2007.05.004

Tetrahedron: Asymmetry 18 (2007) 1210–1216
Asymmetric synthesis of a 3,4-substituted pyrrolidine
by L-proline catalyzed direct enolexo aldolization
Indresh Kumar,a S. R. Bhideb and C. V. Rodea,*
aHomogeneous Catalysis Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
bDivision of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 12 April 2007; accepted 2 May 2007
Available online 15 June 2007
Abstract—The asymmetric synthesis of a 3,4-substituted N-tosyl pyrrolidine has been achieved by using L-proline catalyzed 5-enolexo
aldolization with high enantio and diastereoselectivity.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
This led us to propose a new strategy for the synthesis of
1-imino-sugars, which are several times more potent than
2 towards b-glycosidases. Poly-hydroxylated nitrogen
heterocyclic compounds with piperidine, pyrrolidine, pyrr-
olizidine, and indolizidine skeletons (e.g., nojirimycin 1,
1-deoxynojirimycin 2, fagomine 3, swainsonine 4, and syn-
thetic isofagomine 5) have been shown to be specific and
potent inhibitors of glycosidases.7 In particular, the devel-
opment of synthetic methods to create a pyrrolidine skele-
ton has been of longstanding importance in synthetic
chemistry.8 With the continuation of our program on the
direct diastereoselective intermolecular and intramolecular
aldol reaction catalyzed by L-proline for the synthesis of
The aldol reaction has emerged as one of the most powerful
and efficient carbon–carbon bond forming reactions in
organic synthesis. Many efforts have been devoted to the
development of the catalytic asymmetric aldol reaction
using ‘preformed and stereo defined stable enolates’.1 Over
the last few years, the direct asymmetric aldol reaction has
received a great deal of interest because of its atom econ-
omy and involvement of unmodified carbonyl units for
‘in situ generated labile enolates’ using biocatalysts,2 metal
catalysis,3 and organo-catalysis4 under mild conditions.
The main attention has been focused on the use of a small
organic molecule such as proline as an organo-catalyst for
the direct asymmetric aldol reaction due to its ready avail-
ability in both L- or D-forms and its importance from both
a synthetic as well as mechanistic point of view.5 Recently,
List et al. have shown the first direct 6-enolexo aldolization
in high enantioselectivity for the synthesis of b-hydroxy
cyclohexane carbonyl derivatives (Scheme 1).6
OH OH
OH OH
OH
OH
HO
HO
HO
OH
NH
NH
N
R
3
4
1 R=OH, nojirimycin
(-)-swainsonine
2 R=H, deoxy nojirimycin
fagomine
CO2H
6-enolexo
OH
aldolization
of an aldehyde
N
H
OHC
OHC
OH
OHC
(10 mol%)
HO
HO
OH
Dry DCM, rt
HO
95% yield,
99% ee
NH
HO
N
Ts
Scheme 1.
5
6
epiisofagomine
*
Corresponding author. Tel.: +91 20 25892349; fax: +91 20 25893260;
e-mail: cv.rode@ncl.res.in
Figure 1.
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.05.004

I. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 1210–1216
1211
amino polyols and amino sugars,9 we herein report the syn-
thesis of a 3,4-substituted pyrrolidine ring in high enantio-
and diastereoselective ratios through a direct 5-enolexo
aldolization catalyzed by L-proline (Fig. 1).
OH
O
OH
O
O
O
(a)
(c)
+
O
H2N
13
N
Cbz
12
14
2. Results and discussion
OAc
OAc
HO
TBSO
Initially, we started the synthesis of the core structure of
the isofagomine alkaloids using a diastereoselective ap-
proach with 6-enolexo aldolization and the retrosynthetic
analysis is shown in Scheme 2. The direct diastereoselective
6-enolexo aldolization catalyzed by L-proline is the key step
of this approach. The main challenge of this approach is to
discriminate between two aldehyde groups by putting a
well-defined stereocenter at the active methylene position
of one of the aldehyde groups; so that proline catalyzed
highly diastereoselective 6-enolexo aldolization can occur
via an enamine intermediate with another aldehyde func-
tionality. The already existing stereogenic center in synthon
9 may have some impact on the diastereoselective outcome
of the direct aldolization reaction. In the retrosynthetic
analysis, compound 10 was visualized as a key intermedi-
ate, which can be oxidized to dialdehyde 9 for the further
step of aldolization.
OAc
OAc
(b)
N
N
Cbz
Cbz
15
16
(d)
(d)
OTBS
OH
TBSO
OH
O
O
N
HO
N
Cbz
17
10
Scheme 3. Reagents and conditions: (a) (i) Pd/C (10 mol %), MeOH, H2
(1 atm) rt, 12 h; (ii) CbzCl (1.2 equiv), Na2CO3 (2.2 equiv), DCM–H2O
(1:1), 0 ꢁC, 3 h, 85% for two steps; (b) (i) p-TSA, MeOH, rt, 8 h; (ii) AcCl
(2.2 equiv), DCM–pyridine (1:1), 0 ꢁC, 3 h, 83% yield after two steps. (c)
TBSCl (1.1 equiv), imidazole, dry DCM, 0 ꢁC, 4 h, 92% yield; (d) K2CO3
(cat.), MeOH, rt, 30 min, 93% yield.
The first task was to prepare the suitably protected inter-
mediate 10. Hence, we started from (R)-glyceraldehyde
12; which was easily prepared from commercially available
D-mannitol.10 Reductive amination of glyceraldehyde 12
was carried out with 3-aminopropanol 13, for 12 h at rt
under a hydrogen atmosphere followed by protection with
CbzCl under biphasic basic conditions to provide a
Cbz-protected alcohol 14 with 85% yield after two steps.11
Acetonide deprotection of 14 using p-TSA/MeOH at rt,
followed by protection with AcCl (2.1 equiv) in pyridine/
DCM gave diacetyl derivative 15 in 83% yield after two
steps.
two steps from compound 16 by the cleavage of N-Cbz,
followed by protection with benzyl bromide to provide
compound 18 in 87% yield after two steps. The deprotec-
tion of –OAc groups from 18 was carried out with K2CO3-
(cat.)/MeOH at rt to provide diol compound 19 in 92%
yield. The resulting diol 19 was then subjected to oxidation
under different (IBX, DMP, or Swern) conditions. Unfor-
tunately, all these attempts for the oxidation of compound
19 to the dialdehyde gave a complex reaction mixture
which indicated that the b-amino-dialdehyde formed dur-
ing the oxidation was unstable due to the amino benzyl
moiety (Scheme 4).
The secondary alcohol of compound 15 was protected with
1.1 equiv of TBSCl/imidazole in dry DCM at 0 ꢁC for 4 h
to provide TBS-protected compound 16 in 92% yield.
The acetyl deprotection of compound 16 was carried out
with a catalytic amount of K2CO3/MeOH at rt12 and sur-
prisingly, we obtained compound 17 as a cyclic carbamate
instead of diol 10. Even though the –OBn group is not a
good leaving group, the formation of six member cyclic
carbamate might be the driving force for this reaction
(Scheme 3).
These unsuccessful attempts prompted us to find a new
protecting group and a tosyl group was considered to be
the most suitable candidate. Compound 21 was prepared
following the same route described for compound 16 in
Scheme 3. The acetyl deprotection of compound 21 was
carried out with the standard procedure to provide com-
pound 22 in high yield. The oxidation of compound 22
was carried out with IBX (5.0 equiv) under reflux condi-
tions13 and the resulting oxidized product was used for di-
rect aldolization without any purification. The direct aldol
To overcome this problem, we used benzyl as a protecting
group on the amino functionality. This was carried out in
OH OH
O
O
OH OH
O
OH
O
O
HO
PgO
PgO
O
O
N
H
N
N
N
Pg
Glyceraldehyde
Pg
Pg
5
9
10
11
12
Scheme 2. New retrosynthetic approach for 1-imino-sugar.

1212
I. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 1210–1216
OAc
OH
OH
AcO
OH
OH
OAc
TBSO
OH
(b)
(a)
OAc
(a)
(b)
24
16
N
N
N
Ts
Ts
Bn
18
6
25
OH
TBSO
Scheme 6. Reagents and conditions: (a) PTA (cat.), MeOH, rt, 30 min.
quantitative yield; (b) AcCl (2.1 equiv), DCM–pyridine (1:1), 0 ꢁC, 3 h,
87% yield.
(c)
Oxidation
Complex reaction
mixture
N
Bn
19
indicated by H and 13C NMR (Scheme 6). The reaction
1
is highly selective, and the stereochemistry of the product
was determined by NOESY experiments. The observed
NOE correlations between the proton at C-4 and the two
proton of –CH2OAc, Hb at C-5 (strong), as well as Hb at
C-2 (week); and that between Hb at C-2 and the proton
Scheme 4. Reagents and conditions: (a) (i) Pd/C (10 mol %), MeOH, H2
(1 atm), rt; (ii) BnBr (1.2 equiv), Na2CO3 (2.2 equiv), DCM–H2O (1:1),
reflux, 3 h, 87% in two steps; (b) K2CO3 (cat.), MeOH, rt, 30 min, 92%
yield; (c) IBX, DMP or Swern oxidation conditions.
reaction was carried out with L-proline (20 mol %) at 5 ꢁC
for 16 h in CHCl3–DMSO (3:1), followed by in situ reduc-
tion with NaBH4/MeOH at the same temperature to give a
AcO
OH
OAc
β
1
stable diol, whose H and 13C NMR spectral data showed
H
β
4
2
H
the cyclization. However this product shows four –CH2
groups in 13C-DEPT NMR. A detail interpretation of the
spectral data showing four –CH2 at d = 48.88, 57.38,
59.40, 66.39 in 13C NMR indicates the attachment of these
methylenes to the heteroatom which was possible for the
product having five membered ring. We found that a 1,2-
TBS migration occurred under –OAc deprotection (mild
basic) conditions and gave compound 23 with a TBS-group
on the primary hydroxyl group. This upon oxidation fol-
lowed by 5-endolexo cyclization gave a 3,4-substituted pyr-
rolidine ring with high dr 9:1 (1H NMR) and ee = 90%
(major), 18% (minor) of each diastereomer (chiral HPLC,
OD-H column) (Scheme 5).
N
α
H
Ts
A
HO2C
OTBS
N
H
TBSO
HO
N
H
O
O
N
O
Ts
same side
sterically hindered
N
Ts
B
HO2C
TBSO
H
N
TBSO
N
In order to confirm the structure and stereochemical out-
come of the aldol product, a further transformation was
carried out with the TBS-deprotection of 24 using PTA
(cat)/MeOH14 to quantitatively give triol 6. Compound 6
was protected with AcCl (2.1 equiv) in DCM/pyridine at
0 ꢁC for 4 h to give the corresponding diacetyl product
25, which was isolated as the almost pure diastereomer as
OH
Ts
N
O
H
O
opposite side
Favored
N
O
Ts
C
Figure 2.
OH
OH
O
OH
OAc
TBSO
OH
O
O
TBSO
(a)
(b)
OAc
(c)
12
+ 13
N
N
N
1,2 TBS migration
occured
Ts
Ts
Ts
20
21
22
OH
OTBS
OH
OH
O
OH
TBSO
TBSO
HO
TBSO
(e)
(d)
(d, e)
N
N
N
N
Ts
Ts
Ts
Ts
24
1-Imino sugar
23
analog
dr 9:1, ee 90%, 18%
Scheme 5. Reagents and conditions: (a) (i) Pd/C (10 mol %), MeOH, H2 (1 atm) rt, 12 h; (ii) TsCl (1.2 equiv), Na2CO3 (2.2 equiv), DCM–H2O (1:1), 0 ꢁC,
3 h, 83% in two steps; (b) (i) p-TSA, MeOH, rt, 8 h; (ii) AcCl (2.2 equiv), DCM–pyridine (1:1), 0 ꢁC, 3 h; (iii) TBSCl (1.1 equiv), imidazole, dry DCM,
0 ꢁC, 4 h, 73% yield in three steps; (c) K2CO3 (cat.), MeOH, rt, 30 min, 89% yield; (d) IBX (5.0 equiv), EtOAc, reflux, 4.5 h; (e) (i) L-proline (15 mol %),
CHCl3–DMSO (3:1), 5 ꢁC, 16 h; (ii) NaBH4, MeOH, 5 ꢁC, 2 h, 65% yield after three steps.

I. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 1210–1216
1213
of –CH2OAc at C-3 in A allowed syn-selectivity to be
attributed.
duced pressure to give a slightly yellowish liquid that was
diluted in DCM (20 ml). To the resulting solution was added
a solution of Na2CO3 (2.68 g, 25.36 mmol) in water (20 ml)
and CbzCl (2.15 g, 12.694 mmol) at 0 ꢁC and the mixture
was stirred further for 2 h at the same temperature. The or-
ganic layer was separated and the aqueous layer was ex-
tracted with dichloromethane (2 · 20 ml). The combined
organic extracts were dried over Na2SO4 and evaporated
in vacuo. The residue was purified by chromatography on
silica gel eluting with hexane–ethyl acetate (8:2–6:4) to give
14 (3.15 g, 85% yield in two steps) as a colorless liquid:
½aꢀD ¼ ꢁ7:6 (c 1, CHCl3), H NMR (200 MHz, CDCl3):
d = 1.28 (s, 3H), 1.35 (s, 3H), 1.72 (m, 2H), 3.15–3.25 (m,
1H), 3.51 (m, 6H), 3.88–4.05 (m, 1H), 4.19 (m, 1H), 5.10
(s, 2H), 7.30 (s, 5H). 13C NMR (75 MHz, CDCl3):
d = 25.09, 26.85, 30.06, 44.95, 49.85, 58.76, 67.14, 67.34
(overlapping signals), 74.92, 109.18, 127.83, 128.03,
128.46, 136.32, 156.89. Anal. Calcd for C17H25NO5: C,
63.14; H, 7.79; N, 4.33. Found: C, 63.09; H, 7.82; N, 4.39.
The high syn-selectivity of the reaction can be explained by
two different transition states during cyclization, in transi-
tion state B, the bulky –OTBS group and imminium-ion
are on the same side and suffer from steric hindrance while
in transition state C, these groups are on opposite sides and
so are without steric hindrance. This means C is energeti-
cally more favored than B giving the syn outcome of this
reaction (Fig. 2). Hence, the –OTBS group, due to its bulk-
iness plays an important role in directing the stereochemis-
try at C-4 to give syn outcome of the reaction.
25
1
3. Conclusion
In conclusion, we have demonstrated the synthesis of poly-
hydroxylated 3,4-substituted pyrrolidine skeleton having
one quaternary center using direct 5-enolexo aldolization
with high diastereo- and enantioselectivity. 1,2-TBS migra-
tion, which occurred in the intermediate steps, directed the
cyclization in a 5-enolexo fashion, as well as controlling the
stereochemical outcome of the L-proline catalyzed reaction.
The synthesis of the core structure of 1-imino-sugars using
6-enolexo aldolization in a diastereoselective fashion will be
reported in due course.
4.3. Benzyl (2S)-3-acetoxy-2-hydroxypropyl 3-acetoxy-
propylcarbamate 15
A solution of 15 (1.2 g, 3.71 mmol) in MeOH (25 ml) was
stirred with a catalytic amount of p-TSA at rt for 8 h fol-
lowed by TLC. After completion of the reaction, MeOH
was evaporated under reduced pressure to give a pasty resi-
due. This was used further by dissolving in DCM–pyridine
(1:1) solvents (14 ml) at 0 ꢁC followed by the addition of
the solution of AcCl (0.62 g, 2.1 mmol) in 5 ml dry DCM
at the same temperature for 25 min and stirred additionally
for 3 h. The reaction mixture was poured into ice water and
extracted with (3 · 20 ml) DCM. The combined organic
extracts were dried over Na2SO4 and evaporated under
reduced pressure. The residue was further purified by col-
4. Experimental
4.1. General methods
All reagents were used as supplied. The reactions involving
hygroscopic reagents were carried out under argon atmo-
sphere using oven-dried glassware. THF was distilled from
sodium-benzophenone ketyl prior to use. Reactions were
followed by TLC using 0.25 mm Merck silica gel plates
(60F-254). Optical rotation values were measured using
JASCO P-1020 digital polarimeter using Na light. IR spec-
tra were recorded on Perkin–Elmer FT-IR 16 PC spec-
trometer. The NMR spectra were recorded on a Bruker
umn chromatography to give 15 (1.13 g, 83% in two steps)
25
as a pasty liquid: ½aꢀ ¼ ꢁ5:0 (c 1, CHCl3), 1H NMR
(200 MHz, CDCl3): d D= 1.80–2.10 (m, 8H), 3.30–3.45 (m,
4H), 3.95–4.10 (m, 5H), 5.09 (s, 2H), 7.31 (s, 5H). 13C
NMR (75 MHz, CDCl3): d = 20.54, 27.39, 45.80, 51.05,
61.74, 66.04, 67.37, 68.87, 127.65, 127.91, 128.32, 136.03,
157.17, 170.77. Anal. Calcd for C18H25NO7: C, 58.84; H,
6.86; N, 3.81. Found: C, 58.91; H, 6.79; N, 3.91.
1
system (200 MHz for H and 75 MHz for 13C). The chem-
1
ical shifts are reported using the d (delta) scale for H and
13C spectra. Choices of deuterated solvents (CDCl3, D2O)
are indicated below. LC–MS was recorded using the elec-
trospray ionization technique. All the organic extracts were
dried over sodium sulfate and concentrated under aspirator
vacuum at room temperature. Column chromatography
was performed using (100–200 and 230–400 mesh) silica
gel obtained from M/s Spectrochem India Ltd. Room tem-
perature is referred as rt.
4.4. Benzyl (2S)-3-acetoxy-2-tert-butyldimethylsilyloxy-
propyl 3-acetoxypropylcarbamate 16
To a stirred solution of compound 15 (1.2 g, 3.26 mmol)
and imidazole (0.267 g, 3.91 mmol) with a catalytic amount
of DMAP in dry DCM (8 ml) was added a solution of
TBSCl (0.591 g, 3.92 mmol) in dry DCM (5 ml) at 0 ꢁC
for 10 min. The resulting mixture was stirred for a further
2 h at the same temperature followed by 1 h at rt. This
reaction was quenched by 20% aqueous solution of NaH-
CO3. The organic layer was separated and the aqueous
layer was extracted with dichloromethane (2 · 10 ml).
The combined extracts were dried over Na2SO4 and the
solvent was evaporated in vacuo. The residue was purified
by chromatography on silica gel eluting with hexane–ethyl
4.2. Benzyl {[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}(3-
hydroxypropyl)carbamate 14
To a stirred solution of (R)-glyceraldehyde 12 (1.5 g,
11.5 mmol) and 3-aminopropanol 13 (1.0 g, 13.84 mmol)
in MeOH (25 ml), was added Pd/C (120 mg, 10 mol %) at
rt. The resulting solution was stirred further for 12 h under
a hydrogen atmosphere followed by TLC. The reaction mix-
ture was filtered to remove Pd/C and concentrated under re-
acetate (9:1) to give 16 (1.45 g, 92% yield) as a colorless
25
liquid. ½aꢀ ¼ ꢁ9:2 (c 1, CHCl3), 1H NMR (200 MHz,
CDCl3): dD= 0.01 (t, 6H), 0.85 (s, 9H), 1.75–2.05 (m, 8H),

1214
I. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 1210–1216
3.09–3.19 (m, 1H), 3.23–3.70 (m, 4H), 3.89–4.18 (m, 4H),
5.10 (s, 2H), 7.32 (s, 5H). 13C NMR (75 MHz, CDCl3):
d = ꢁ5.19, 17.69, 20.60, 25.49, 27.40, 46.01, 51.13, 61.74,
66.09, 67.10, 68.53, 127.73, 128.09, 128.32, 136.30,
155.93, 170.66. LC–MS (ESI-TOF): m/z [M+H]+ 482.23.
Anal. Calcd for C24H39NO7Si: C, 59.85; H, 8.16; N, 2.91.
Found: C, 59.79; H, 8.11; N, 2.95.
1H NMR (200 MHz, CDCl3): d = 0.02 (s, 6H), 0.85 (s,
9H), 1.63–1.77 (m, 2H), 2.44–2.76 (m, 4H), 3.41–3.58 (m,
3H), 3.65–3.85 (m, 4H), 7.30 (s, 5H). 13C NMR
(75 MHz, CDCl3): d = ꢁ5.59, 18.06, 25.70, 28.60, 52.86,
56.48, 59.07, 62.18, 65.40, 69.02, 127.04, 128.21, 128.98,
138.18. Anal. Calcd for C19H35NO3Si: C, 64.54; H, 9.98;
N, 3.96. Found: C, 64.43; H, 9.93; N, 3.98.
4.5. (5S)-5-tert-Butyldimethylsilyloxy-3-(3-hydroxypropyl)-
1,3-oxazinan-2-one 17
4.8. N-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-N-(3-
hydoxypropyl)-4-methylbenzenesulfonamide 20
To a stirred solution of compound 16 (1.0 g, 2.01 mmol) in
distilled MeOH (10 ml) was added K2CO3 (cat.) at ambient
temperature, and the reaction was followed by TLC. The
starting material was completely consumed within half an
hour. The solvent was evaporated under reduced pressure
and the residue was purified by passing through the small
To a stirred solution of (R)-glyceraldehyde 12 (2.0 g,
15.36 mmol)
and
3-aminopropanol
13
(1.38 g,
118.44 mmol) in MeOH (32 ml) was added Pd/C (150 mg,
10 mol %) at rt. The resulting solution was stirred further
for 12 h under a hydrogen atmosphere followed by TLC.
The reaction mixture was filtered to remove Pd/C and con-
centrated under reduced pressure to give a slightly yellowish
liquid that was diluted in DCM (20 ml). To the resulting
solution was added a solution of Na2CO3 (3.58 g,
33.81 mmol) in water (20 ml) and tosyl chloride (3.50 g,
118.37 mmol) at 0 ꢁC and the mixture was stirred further
for 2 h at the same temperature. The organic layer was sep-
arated and the aqueous layer extracted with dichlorometh-
ane (3 · 20 ml). The combined organic extracts were dried
over Na2SO4 and the solvent was evaporated in vacuo.
The residue was purified by chromatography on silica gel
eluting with hexane–ethyl acetate (8:2 to 7:3) to give 20
(4.38 g, 83% yield in two steps) as a colorless liquid:
pad of silica giving compound 17 (0.56 g, 93% yield) as a
25
colorless liquid. ½aꢀD ¼ ꢁ5:3 (c 1, CHCl3), 1H NMR
(200 MHz, CDCl3): d = 0.12 (s, 6H), 0.89 (s, 9H), 1.77
(m, 2H), 3.25–3.75 (m, 8H), 4.42 (m, 1H). 13C NMR
(75 MHz, CDCl3): d = ꢁ5.20, 17.92, 25.32, 29.76, 45.52,
50.83, 60.13, 66.94, 72.31, 152.86. LC–MS (ESI-TOF):
m/z [M+H]+ 290.13. Anal. Calcd for C13H27NO4Si: C,
53.94; H, 9.40; N, 4.84. Found: C, 53.87; H, 9.32; N, 4.90.
4.6. 3-{[(2S)-3-Acetoxy-2-tert-butyldimethylsilyloxy-
propyl](benzyl)amino}propyl acetate 18
25
1
To a stirred solution of compound 16 (1.5 g, 3.11 mmol) in
distilled MeOH (7 ml) was added Pd/C (32 mg, 10 mol %)
at rt. The resulting mixture was hydrogenated under an
atmospheric pressure of hydrogen for 3 h, and the reaction
was followed by TLC. The resulting mixture was filtered
and solvent removed in vacuo to give an oily product that
was taken in dichloromethane (10 ml). To the resulting
solution was added a solution of Na2CO3 (0.726 g,
6.85 mmol) in water (10 ml) and benzyl bromide (0.64 g,
3.37 mmol) and the mixture was refluxed for 3 h. The
organic layer was separated and the aqueous layer
extracted with dichloromethane (2 · 10 ml). The combined
extracts were dried over Na2SO4 and the solvent was evap-
orated under reduced pressure. The residue was chromato-
½aꢀD ¼ ꢁ11:0 (c 1, CHCl3), H NMR (200 MHz, CDCl3):
d = 1.28 (s, 3H), 1.35 (s, 3H), 1.79 (m, 2H), 2.39 (s, 3H),
2.97 (m, 1H), 3.14 (m, 1H), 3.32–3.48 (m, 2H), 3.60–3.72
(m, 3H), 4.05 (dd, J = 8.4, 6.3 Hz, 1H), 4.26 (m, 1H), 7.28
(d, J = 8.0 Hz, 2H, Ar), 7.66 (d, J = 8.3 Hz, 2H, Ar). 13C
NMR (75 MHz, CDCl3): d = 21.22, 25.09, 26.52, 31.09,
46.50, 51.80, 58.67, 67.23, 74.88, 109.45, 126.95, 129.57,
135.60, 143.38. LC–MS (ESI-TOF): m/z [M+H]+ 344.14,
[M+Na]+ 366.12. Anal. Calcd for C16H25NO5S: C, 55.96;
H, 7.34; N, 4.08. Found: C, 55.89; H, 7.28; N, 4.15.
4.9. (2S)-3-Acetoxy-2-tert-butyldimethylsilyloxypropyl-N-
(3-acetoxypropyl)-4-methylbenzenesulfonamide 21
graphed over silica gel to give compound 18 (1.18 g, 87% in
Following the previous preparation procedure for 16:
25
25
1
two steps) as a colorless liquid. ½aꢀD ¼ ꢁ12:2 (c 1, CHCl3),
½aꢀD ¼ þ5:25 (c 1, CHCl3), H NMR (200 MHz, CDCl3):
d = 0.06 (s, 6H), 0.85 (s, 9H), 1.85 (m, 2H), 2.01 (s, 3H),
2.05 (s, 3H), 2.41 (s, 3H), 3.06–3.32 (m, 4H), 3.69 (d,
J = 4.3 Hz, 0.5H), 3.95–4.04 (m, 3H), 4.07–4.16 (m, 2H),
4.20 (d, J = 4.1 Hz, 0.5H), 7.29 (d, J = 8.0 Hz, 2H, Ar),
7.66 (d, J = 8.3 Hz, 2H, Ar). 13C NMR (75 MHz, CDCl3):
d = ꢁ4.89, 17.76, 20.66, 21.29, 25.52, 27.49, 47.56, 51.73,
61.61, 65.88, 69.57, 127.13, 129.62, 135.83, 143.46, 170.40,
170.63 (overlapping). LC–MS (ESI-TOF): m/z [M+H]+
502.14, [M+Na]+ 524.13. Anal. Calcd for C23H39NO7SSi:
C, 55.06; H, 7.84; N, 2.79. Found: C, 55.01; H, 7.79; N, 2.83.
1H NMR (200 MHz, CDCl3): d = 0.01 (s, 6H), 0.82 (s, 9H),
1.73 (m, 2H), 1.92 (s, 3H), 1.96 (s, 3H), 2.47 (m, 4H), 3.52
(d, J = 13.5 Hz, 1H, –NCH2Ar), 3.58 (d, J = 13.5 Hz, 1H,
–NCH2Ar), 3.80–3.95 (m, 2H), 4.01 (t, J = 6.4 Hz, 2H),
4.17 (dd, J = 10.5, 2.5 Hz, 1H), 7.32 (s, 5H). 13C NMR
(75 MHz, CDCl3): d = ꢁ4.82, 17.93, 20.90, 25.60, 26.21,
51.23, 57.63, 59.78, 62.33, 67.21, 69.13, 126.91, 128.12,
128.76, 139.09, 170.68. Anal. Calcd for C23H39NO5Si: C,
63.12; H, 8.98; N, 3.20. Found: C, 63.07; H, 8.91; N, 3.26.
4.7. (2S)-2-tert-Butyldimethylsilyloxy-3-[benzyl(3-hydroxy-
propyl)amino]propanol 19
4.10. (2S)-2-Hydroxy-3-tert-butyldimethylsilyloxypropyl-N-
(hydroxypropyl)-4-methylbenzenesulfonamide 23
Similar to the acetyl deprotection of compound 16, depro-
tection of 18 followed by chromatographic purification
To a stirred solution of compound 21 (1.5 g, 2.98 mmol) in
distilled MeOH (12 ml) was added K2CO3 (cat.) at ambient
temperature, followed by TLC. The starting material was
over silica gel gave compound 19 (1.12 g, 92% yield from
25
1.5 g of 18) as a pasty liquid. ½aꢀD ¼ ꢁ13:4 (c 1, CHCl3),

I. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 1210–1216
1215
used within half an hour. The solvent was evaporated un-
der reduced pressure and the residue purified by passing
through a small pad of silica gel to give compound 23
D2O): d = 2.09 (m, 1H), 2.41 (s, 3H), 3.06 (m, 2H) 3.15–
3.68 (m, 6H), 7.30 (d, J = 8.0 Hz, 2H, Ar), 7.68 (d,
J = 8.3 Hz, 2H, Ar). 13C NMR (75 MHz, CDCl3/D2O):
d = 21.39, 42.35, 48.75 (dept), 57.09 (dept), 59.85 (dept),
65.93 (dept), 79.82, 127.41, 129.49, 132.74, 143.55. Anal.
Calcd for C13H19NO5S: C, 51.81; H, 6.35; N, 4.65. Found:
C, 51.78; H, 6.31; N, 4.68.
(1.10 g, 89% yield) as
a
colorless pasty liquid.
25
1
½aꢀD ¼ ꢁ7:5 (c 1, CHCl3), H NMR (200 MHz, CDCl3):
d = 0.04 (s, 6H), 0.86 (s, 9H), 1.80 (m, 2H), 2.40 (s, 3H),
2.68 (br s, 2H, exchangeable) 2.98–3.105 (m, 1H), 3.15–
3.31 (m, 3H), 3.54–3.88 (m, 5H), 7.29 (d, J = 8.0 Hz, 2H,
Ar) 7.62 (d, J = 8.3 Hz, 2H, Ar). 13C NMR (75 MHz,
CDCl3): d = ꢁ5.53, 18.11, 21.39, 25.73, 31.17, 47.35,
52.53, 58.98, 64.64, 70.89, 127.19, 129.69, 135.52, 143.51.
LC–MS (ESI-TOF): m/z [M+H]+ 418.11, [M+Na]+
440.09. Anal. Calcd for C19H35NO5SSi: C, 54.64; H, 8.45;
N, 3.35. Found: C, 54.57; H, 8.39; N, 3.41.
4.13. {(3R,4S)-3-Hydroxy-N-[(4-methylphenyl)sulfonyl]pyr-
rolidine-3,4-diyl}bis(methylene)diacetate 25
To a stirred solution of 6 (0.35 g, 1.16 mmol) and in dry
DCM/pyridine (1:1) (8 ml) was added a solution of acetyl
chloride (0.19 g, 2.43 mmol) in dry DCM (2.5 ml) at 0 ꢁC
for 30 min. The combined reaction mixture was stirred
for 2 h at the same temperature and then poured into the
cold water (10 ml), which was further extracted with
DCM (2 · 10 ml). The combined organic extracts were
dried over Na2SO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography
to give diacetyl derivative 25 with 87% yield as a single
diastereomer as confirmed by 1H and 13C NMR.
4.11. (3R,4S)-3-Hydroxy-4-(hydroxymethyl)-N-[4-methyl-
phenylsulfonyl]pyrrolidin-3-yl-methyl-tert-butyldimethylsilyl-
ether 24
A mixture of 23 (0.80 g, 1.91 mmol) and IBX (2.67 g,
9.57 mmol) in EtOAc (38 ml) was heated at reflux for
4.5 h at 80 ꢁC, followed by TLC. The reaction temperature
was brought to rt and filtered. The filtrate was washed with
20% sol of NaHCO3 (3 · 20 ml). The organic layer was
dried over Na2SO4 and the solvent was removed under re-
duced pressure. The resulting crude oxidized product was
used for the cyclization without purification. This slight
yellowish material was dissolved in CHCl3–DMSO (3:1,
12 ml) at 5 ꢁC, followed by the addition of L-proline
(0.032 g, 15 mol %). The resulting solution was stirred for
a further 16 h at the same temperature followed by the
addition of 5 ml of MeOH and in situ reduction with
NaBH4 (0.075 g, slight excess) for 2 h. The reaction mix-
ture was evaporated in vacuo and poured into cold water
(15 ml), followed by the extraction with EtOAc
(4 · 20 ml). The combined reaction mixture was dried over
Na2SO4 and concentrated under reduced pressure; the
resulting pasty mass was purified by flash column chroma-
20
1
½aꢀD ¼ þ2:9 (c 0.5, CHCl3), H NMR (400 MHz, CDCl3):
d = 2.00 (s, 3H), 2.07 (s, 3H), 2.31 (m, 1H) 2.42 (s, 3H),
3.09 (t, J = 9.8 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 3.42
(d, J = 11.0 Hz, 1H), 3.56 (t, J = 8 Hz, 1H), 3.98 (d,
J = 12.2 Hz, 1H), 4.00 (dd, J = 7.0, 10.5 Hz, 1H), 4.15 (d,
J = 12.2 Hz, 1H), 4.20 (dd, J = 7.0, 11.3 Hz, 1H), 7.32
(d, J = 8.0 Hz, 2H, Ar), 7.69 (d, J = 8.2 Hz, 2H, Ar). 13C
NMR (75 MHz, CDCl3): d = 20.66, 20.75 (overlapping),
21.51, 43.46, 49.56 (dept), 58.12 (dept), 61.24 (dept),
67.73 (dept), 127.55, 129.78, 133.24, 143.89, 170.78,
171.04. LC–MS (ESI-TOF): m/z [M+H]+ 386.38,
[M+Na]+ 408.39. Anal. Calcd for C17H23NO7S: C, 52.97;
H, 6.01; N, 3.63. Found: C, 52.97; H, 6.05; N, 3.69.
Acknowledgments
tography to give 24 (0.51 g, 65% yield after three steps) as a
25
The authors gratefully acknowledge the help from Dr. P.
R. Rajmohanan (center NMR faculty, NCL) for NOE
experiments. One of the authors, Indresh Kumar thanks
CSIR, New Delhi, for the award of senior research
fellowship.
white solid at low temperature. ½aꢀD ¼ ꢁ5:1 (c 0.5, MeOH),
1H NMR (400 MHz, CDCl3/D2O): d = 0.06 (s, 6H), 0.87
(s, 9H), 1.63 (br s, 1H, exchangeable), 2.11 (m, 1H), 2.42
(s, 3H), 3.06 (d, J = 10.8 Hz, 1H), 3.12 (m, 1H), 3.40 (d,
J = 10.5 Hz, 1H), 3.47–3.53 (m, 3H), 3.60–3.63 (m, 2H),
7.31 (d, J = 8.0 Hz, 2H, Ar), 7.69 (d, J = 8.3 Hz, 2H,
Ar). 13C NMR (75 MHz, CDCl3): d = ꢁ5.74, 17.98,
21.36, 25.60, 44.53, 48.89 (dept), 57.39 (dept), 59.40 (dept),
66.41 (dept), 80.38, 127.48, 129.54, 132.88, 143.50. LC–MS
(ESI-TOF): m/z [M+H]+ 416.09, [M+Na]+ 438.08. Anal.
Calcd for C19H33NO5SSi: C, 54.91; H, 8.00; N, 3.37.
Found: C, 54.83; H, 7.92; N, 3.44.
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