Proline catalyzed direct diastereoselective 6-enolexo aldolization: Toward the synthesis of the imino sugar DNJ

Article abstract of DOI:10.1016/j.tetasy.2010.10.024

A l-proline catalyzed direct diastereoselective 6-enolexo aldolization reaction of differentiating dialdehydes derived from tartaric acid is presented. This organocatalytic approach provides high levels of syn-selectivity (dr >10:1) with the stereocontrol

Full text of DOI:10.1016/j.tetasy.2010.10.024

Tetrahedron: Asymmetry 21 (2010) 2703–2708
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Tetrahedron: Asymmetry
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Proline catalyzed direct diastereoselective 6-enolexo aldolization: toward
the synthesis of the imino sugar DNJ
⇑
Indresh Kumar , Chandrashekhar V. Rode
Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 September 2010
Accepted 26 October 2010
A L-proline catalyzed direct diastereoselective 6-enolexo aldolization reaction of differentiating dialdehy-
des derived from tartaric acid is presented. This organocatalytic approach provides high levels of syn-
selectivity (dr >10:1) with the stereocontrolled C–C bond formation between C4 and C5 intramolecularly,
which can serve to synthesize imino-sugar skeleton quickly.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
HO
O
O
N
O
O
enolendo
The aldol reaction is one of the important C–C bond forming
reactions in organic chemistry, and several asymmetric and cata-
lytic variants have been developed.1 Recently, direct asymmetric
aldol reaction catalyzed by small organic molecules, such as pro-
line and its derivatives through an enamine intermediate, have
been studied; in particular, intermolecular aldol reaction has been
extensively explored by several research groups.2 Regarding the
direct intramolecular aldol reaction, there are two modes of cycli-
zation, in which the enolendo mode remained as the first organo-
catalytic reaction,3 while the enolexo mode of cyclization
remained undeveloped until the first report from List et al. in
2003.4 In the case of the enolendo mode of cyclization, the enamine
C–C bond constitutes a part of newly formed cyclic skeleton, while
in the case of the enolexo mode of cyclization the enamine C–C
bond does not constitute the part of ring system as shown in
Figure 1. However, the later mode of cyclization reaction is mainly
suitable for the asymmetric desymmetrization of meso-
compounds.5
Imino-sugars are biologically active compounds consisting of
polyhydroxy piperidine and pyrrolidine skeletons.6 Such com-
pounds have been the subject of extensive interest over the past
three decades, several comprehensive reviews and accounts on
their synthesis and glycosidase inhibitors activities have been
published.7 Some of these imino-sugars have already been tested
and approved for the treatment of diabetes,8 Gauchers disease,9
HIV infection,10 viral infections,11 and cancer.12 They have also
been used as chemical probes, in combination with protein crys-
tallography and kinetic studies, to provide further insight into the
aldolization
(1971)
(2003)
n
n
n
O
N
OH
n
O
O
O
enolexo
aldolization
n
n
Figure 1. Enolendo and enolexo mode of cyclization.
glycosidase mechanism.13,7b Although the quest for stronger gly-
cosidase inhibitors has been the driving force for the synthetic ef-
forts dedicated to this class of compound,14 it is probable that
several of their biological properties are not related to their abil-
ity to inhibit glycosidase (Fig. 2).15
OH OH
OH
OH OH
OH
HO
HO
HO
HO
HO
HO
NH
N
NH
2
1
3
L-deoxyidonojirimycin
1-deoxynojirimycin (DNJ)
castanospermine
Figure 2. Some important imino-sugars.
During our continued studies on the direct aldol reactions for
the synthesis of important biological skeletons,16 we realized that
the issue of differentiating between two C@O groups of a dialde-
hyde using organocatalysts has not been explored much, except
for the cross-aldol reactions developed by MacMillan and others.17
Our aim was to differentiate between two intramolecular aldehyde
⇑
Corresponding author. Tel.: +91 20 2590 2349; fax: + 91 20 2590 3260.
E-mail address: cv.rode@ncl.res.in (C.V. Rode).
Present address: College of Sciences, Shri Mata Vaishno Devi University, Katra 182
320, J&K, India.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.024

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I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 21 (2010) 2703–2708
moieties by creating a well defined stereocenter at the
a
-position
OTBS
OTBS
of one of the aldehydes, which will eventually address the
matched–mismatched concept defined by Enders18a and Houk.18b
With this idea in mind, a new retrosynthetic approach was de-
signed for the synthesis of polyhydroxylated piperidines via the
proline catalyzed direct diastereoselective enolexo-aldolization of
dialdehydes differentiating at C4 and C5; a key step of this ap-
proach is shown in Scheme 1. Following this approach, the con-
struction of two new stereogenic centers with complete stereo-
control via a C–C bond formation can be achieved. To the best of
our knowledge, none of the approaches reported in the literature
provide access to these imino sugars through the intramolecular
stereo-controlled bond formation between C4 and C5, while the
intermolecular variant is already known.19
O
O
O
O
OH
(a)
Ref. 20
8
NCbz
OH
9
7
(b)
(b)
X
OH OH
O
O
O
O
O
O
N
Cbz
OH
11
10
Scheme 2. Reagents and conditions: (a) (i) IBX (3 equiv), EtOAc, 4 h, quantitative,
(ii) ethanolamine 6 (1.1 equiv), Pd/C (10%), MeOH, H2, 24 h, (iii) CbzCl (1.2 equiv),
CH2Cl2/H2O (1:1), Na2CO3 (2.2 equiv), 0 °C, 2 h, 85% after three steps; (b) TBAF (1 M
solution in dry THF, 2 M equiv), dry THF, 0 °C to rt 3 h, 90% yield.
O
O
OH OH
OH OH
5
4
O
O
O
O
HO
HO
3
NPg
NPg
NH
1
2
Next, we used tosyl as a protecting group and compound 12 was
easily prepared from alcohol 7 using a similar sequence of reac-
tions with 86% isolated yield. The TBS-deprotection was then car-
ried out with TBAF solution to give key diol compound 5 in 90%
yield. In order to prepare dialdehyde compound 4 for the direct
6-enolexo aldolization as a key step for the synthesis of the core
structure of imino sugars, the oxidation of compound 5 was carried
out using IBX (5.0 equiv) in EtOAc under reflux conditions for 5 h.
This reaction was monitored by TLC and after the complete con-
sumption of diol 5; the reaction was cooled, after which IBX was
filtered and washed with saturated NaHCO3. The crude dialdehyde
compound 4 was then used for direct aldolization without any
1
4
5
HO
HO
CO2H
CO2H
O
O
OH
OTBS
OH
+
H2N
6
7
L-(+)-Tartaric acid 8
Scheme 1. New retrosynthetic analysis of the imino sugar DNJ.
2. Results and discussion
purification. The key aldolization step was carried out using L-pro-
From the retrosynthetic analysis, we started with L-(+)-tartaric
line (15 mol %) as an organocatalyst at rt for 20 h in CHCl3/DMSO
(3:1) as solvent, followed by in situ reduction with NaBH4/MeOH
at the same temperature. The solvent system CHCl3/DMSO (3:1)
was found to be better for this reaction after examining several sol-
vent systems, in which dehydration proceeds slower when com-
pared to other solvent systems. The resulting crude aldol adduct
was purified over flash column chromatography using EtOAc/Pet
ether as eluting solvents to give aldol product 13 with 70% yield
along with 19% of the corresponding dehydrated product 14 after
three steps. The removal of protecting groups from 13 under sim-
acid 8 because of its stereochemical similarity with deoxynojirimy-
cin 1 at C2 and C3. Initially, 8 was converted into known alcoholic
compound 7 by following the reported procedure.20 Compound 7
was oxidized quantitatively using IBX (o-iodoxy benzoic acid) at
reflux for 4 h using EtOAc as a solvent21 and the crude aldehyde
was further used for the reductive amination with ethanolamine
6 using Pd/C (10%) under hydrogen atmosphere for 12 h, followed
by in situ protection of the resulting secondary amine with CbzCl
under biphasic basic conditions22 to give compound 9 with 85%
isolated yield after three consecutive steps. The TBS-deprotection
of compound 9 under standard Corey’s method23 provided cyclic
carbamate 11 instead of diol 10, similar to a key synthon of type
5 (Scheme 2).
ilar known conditions gives direct access to L-deoxyidonojirimycin
2,24 (Scheme 3).
The 1H and 13C NMR spectroscopic data showed the agreement
with the cyclization with dr (>10:1), 13C NMR showed two signals
OTBS
O
OH
OH
O
O
(a)
(b)
OH
7
NTs
NTs
O
12
5
(c)
OH OH
OH
O
O
O
O
O
O
O
(d)
deprotection
+
2
NTs
NTs
14 19%
Scheme 3. Reagents and conditions: (a) (i) ethanolamine 6 (1.1 equiv), Pd/C (10%), MeOH, H2, 24 h, (ii) TsCl (1.2 equiv), CH2Cl2/H2O (1:1), Na2CO3 (2.2 equiv), 0 °C, 2 h, 86%
NTs
O
4
13 (dr >10:1) 70%
after three steps; (b) TBAF (1 M, 1.5 equiv), dry THF, 0 °C to rt 4 h, 90%; (c) IBX (5 equiv), EtOAc, reflux, 5 h; (d) (i)
MeOH, rt, 2 h, 70% of 13 (dr >10;1)and 19% of 14 after three steps.
L-proline (15 mol %), CHCl3/DMSO (3:1), rt, 20 h, (ii) NaBH4,

I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 21 (2010) 2703–2708
2705
at d 44.35 and 59.57 in 13C–DEPT for –CH2 and four signals at d
58.10, 70.35, 73.75, and 79.96 for –CH of the corresponding cy-
clized compound 13. For compound 14, the 1H NMR showed an
alkene proton at d 5.72 and two –CH2 in the 13C–DEPT at d
47.97, 63.92 and alkene carbon –CH at d 114.49 and the other
two –CH at d 74.99, and 76.07. In order to confirm the stereo-
chemical outcome of this 6-enolexo aldol reaction, the aldol prod-
uct 13 was transformed into its corresponding diacetyl derivative
15 by treating with AcCl (2.5 equiv) in dry CH2Cl2/pyridine at 0 °C
for 2 h, and isolated as almost a single diastereomer confirmed by
1H and 13C NMR in 84% yield after chromatographic purification.
Similarly, compound 14 was converted into its corresponding
acetyl derivative 16 in 89% isolated yield after purification
(Scheme 4).
OAc
OAc
H
H
β
α
4
O
O
α
β
2
5
3
H
1
NTs
H
α
H
β
H
15
O
O
O
H
O
H
N
N
O
O
O
O
OAc OAc
O
NTs
NTs
(a)
O
O
O
13
NTs
O
15
N
OAc
O
Ts
N
H
O
O
N
NTs
O
(b)
O
Me
O
O
Me
14
H
O
NTs
O
O
O
H
16
B
A
Me
anti-enamine
Me
syn-enamine
Scheme 4. Reagents and conditions: (a) AcCl (2.5 equiv), dry CH2Cl2/pyridine (1:1),
0 °C, 2 h, 84% (b) AcCl (1.1 equiv), dry CH2Cl2/pyridine (1:1), 0 °C, 2 h, 89%.
more favored
less favored
The exact stereochemistry of diacetyl derivative 15 was deter-
mined and explained by NOSEY experiments, which showed that
the direct diastereoselective 6-enolexo aldolization was highly
syn-selective. The proton at C5 showed a strong NOE-correlation
with the proton at C4 as well as with the proton Hb at C1 (strong),
which confirmed the correlation of Hb at C5 and that all these
protons were on the same side of the ring. Whereas, the two pro-
OH OH
NTs
OH OH
NTs
O
O
O
O
syn-outcome
anti-outcome
major
minor
a
tons of –CH2OAc at C6 showed a correlation with the H protons
Figure 3. Structural elucidation by NOE correlation and predicted transition states.
of C1 and C3, hence attributing the syn-selectivity. This stereo-
chemical outcome can be explained by the two different transi-
tion states A and B with respect to the fixed stereochemistry at
C2 and C3. The Ri-facial attack on the acceptor aldehyde by the
enamine nucleophile proceeds through the energetically less fa-
vored syn-enamine intermediate A leading to the formation of
the minor anti-product, while the major syn-product outcome of
this reaction can be explained through the energetically more
favored anti-enamine intermediate B (Fig. 3). The syn-selective
pounds with different stereochemistry at C2 and C3 while the
stereochemistry at C4 and C5 can be controlled with the aldol reac-
tion catalyzed by proline, which is available in both D- and L-forms.
Further studies toward this direction are currently in progress in
our laboratory.
outcome of this L-proline catalyzed direct diastereoselective 6-
4. Experimental
enolexo aldolization reaction was confirmed through the single
crystal X-ray structure of –NCbz derivative 17 of the cyclized
product 13.
4.1. General methods
All the reagents were used as supplied. The reactions involving
hygroscopic reagents were carried out under an argon atmosphere
using oven-dried glassware. THF was distilled from sodium-benzo-
phenone 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 spectra were recorded on Perkin–Elmer FT-IR 16 PC spec-
trometer. The NMR spectra were recorded on a Bruker system
(200 MHz for 1H and 75 MHz for 13C). The chemical shifts are re-
ported using the d (delta) scale for 1H and 13C spectra. Choices of deu-
terated solvents (CDCl3, D2O) are indicated below. LC–MS was
recorded using electrospray ionization technique. All the organic ex-
tracts were dried over sodium sulfate and concentrated under aspi-
rator 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 temperature is referred as rt.
3. Conclusion
In conclusion, we have demonstrated a new approach to the
imino sugar skeleton, in which the proline catalyzed diastereose-
lective 6-enolexo aldol reaction differentiating between the dialde-
hydes was
a key step. This aldolization proceeds via high
diastereoselectivity (dr >10:1) with syn-selectivity as confirmed
by the NOSY-correlation of the corresponding diacetyl derivative
as well as the single crystal X-ray structure of the cyclized product.
The syn-stereochemical outcome of the reaction was explained by
two energetically different transition states. This is the first organ-
ocatalytic approach for the stereo-controlled C–C bond formation
between C4 and C5 intramolecularly to provide quick synthesis
of the imino sugar skeletons. Using this approach, the synthesis
of other imino-sugar analogs can be carried out starting from com-

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I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 21 (2010) 2703–2708
4.2. Benzyl ((4S,5S)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl(2-hydroxyethyl) carbamate (9)
4.5. N-(2-Hydroxyethyl)-N-(((4S,5S)-5-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl-4-methylbenzenesulfona-
mide (5)
A mixture of 7 (1.1 g, 3.98 mmol) and IBX (3.33 g, 11.94 mmol)
in EtOAc (60 mL) was heated at reflux for 4 h at 80 °C and was fol-
lowed by TLC. The reaction temperature was brought to rt and fil-
tered. The filtrate was washed with 20% solution of NaHCO3
(2 ꢀ 20 mL). The organic layer was dried over Na2SO4 and the sol-
vent was removed under reduced pressure to give aldehyde com-
pound, which was used for reductive amination without
purification. For this, a solution of aldehydic compound (1.0 g,
3.64 mmol) and ethanol amine 6 (0.25 g, 4.0 mmol) in MeOH
(20 mL), was added Pd/C (40 mg, 10 mol %) at rt and the resulting
solution was stirred further for 12 h under hydrogen atmosphere
followed by TLC. The reaction mixture was filtered to remove Pd/
C and concentrated under reduced pressure to give a slightly yellow
liquid that was dissolved in CH2Cl2 (20 mL). To the resulting solu-
tion was added a solution of Na2CO3 (0.85 g, 8.2 mmol) in water
(20 mL) and CbzCl [0.682 g, 1.14 mL (50 % solution in toluene),
4.0 mmol] at 0 °C and the mixture was stirred for a further 2 h at
the same temperature. The organic layer was separated and the
aqueous layer was extracted with dichloromethane (2 ꢀ 20 mL).
The combined organic extracts were dried over Na2SO4 and evapo-
rated in vacuo. The residue was purified by chromatography on sil-
ica gel eluting with hexane: ethyl acetate solution to give 9 (1.53 g,
To a solution of compound 12 (0.5 g, 1.10 mmol) in dry THF
(5 mL) was added tetra-n-butylammonium fluoride (2.22 mL,
2.22 mmol, 1 M in THF) at 0 °C and the mixture was stirred further
for an additional 3 h at the same temperature. The solvent was evap-
orated and the residue was taken in EtOAc (10 mL) and stirred with
water (3 mL), after which the organic layer was separated and dried
over Na2SO4, and evaporated under reduced pressure. The crude
material was column chromatographed over silica gel to give diol
5 (0.34 g, 90% yield). ½a D25
ꢁ
¼ ꢂ32:0 (c 1, CHCl3), 1H NMR (200 MHz,
CDCl3): d = 1.36 (s, 3H), 1.38 (s, 3H), 2.39 (s, 3H), 2.80–3.12 (m,
3H), 3.38–3.93 (m, 8H), 4.14–4.25 (m, 1H), 7.28 (d, J = 7.9 Hz , 2H),
7.65 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3): d = 21.28, 26.69,
26.78 (overlapped), 52.18 (dept), 53.12 (dept), 61.17 (dept), 61.80
(dept), 76.80, 79.31, 109.21, 127.15, 129.68, 135.01, 143.67. LC–MS
(ESI-TOF): m/z [M+H]+ 360.03, [M+Na]+ 382.03.
4.6. (3aS,6S,7R,7aS)-6-(Hydroxymethyl)-2,2-dimethyl-5-tosyl-
hexahydro-[1,3]dioxolo[4,5-c]pyridine-7-ol (13)
A mixture of 5 (0.50 g, 1.39 mmol) and IBX (1.94 g, 6.95 mmol) in
EtOAc (30 mL) was heated at reflux for 5 h at 80 °C, followed by TLC.
The reaction temperature was brought to rt and filtered. The filtrate
was washed with 20% solution of NaHCO3 (2 ꢀ 20 mL), the organic
layer was dried over Na2SO4 and the solvent was removed under re-
ducedpressure. Theresultingcrudeoxidizedproduct4 wasusedfur-
ther for the cyclization without purification. This slightly yellow
material 4 was dissolved in CHCl3/DMSO (3:1, 8 mL) at rt followed
85% yield after three steps) as a colorless liquid. ½a D25
¼ ꢂ16:2 (c 1,
ꢁ
CHCl3), 1H NMR (200 MHz, CDCl3): d = 0.07 (m, 6H), 0.85 (m, 9H),
1.38 (m, 6H), 3.07–3.48 (m, 3H), 3.53–3.89 (m, 7H), 3.99–4.31 (m,
1H), 5.13 (s, 2H), 7.33 (s, 5H). 13C NMR (75 MHz, CDCl3):
d = ꢂ5.73, ꢂ5.67 (overlapped), 18.10, 25.61, 26.65, 26.81 (over-
lapped), 48.35, 52.88, 59.61, 64.10, 68.45, 78.91, 80.15, 108.76,
127.98, 128.13, 128.43, 136.39, 156.87. Anal. Calcd for C23H39NO6-
Si: C, 60.89; H, 8.67; N, 3.09. Found: C, 60.83; H, 8.61; N, 3.13.
by the addition of L-proline (0.030 g, 20 mol %). The resulting solu-
tion was further stirred for 20 h at the same temperature followed
by the addition of 5 mL of MeOH and in situ reduction with NaBH4
(0.065 g, 1.66 mmol, slight excess) for 2 h. The reaction mixture
was evaporated in vacuo and poured into cold water (15 mL), fol-
lowedby the extractionwithEtOAc (4 ꢀ 20 mL). The combinedreac-
tionmixture wasdriedover Na2SO4 and concentrated underreduced
pressure; the resulting mass was purified by flash column chroma-
tography to give 13 (0.348 g, 70%) and 14 (0.089 g, 19%) with com-
4.3. (3aS,8aS)-7-(2-Hydroxyethyl)-2,2-dimethyltetrahydro-
[1,3]dioxolo[4,5-e][1,3]oxazepin-6(7H)-one (11)
To a solution of compound 9 (0.5 g, 1.10 mmol) in dry THF
(5 mL) was added tetra-n-butylammonium fluoride (2.22 mL,
2.22 mmol, 1 M in THF) at 0 °C and the mixture was stirred for
an additional 3 h at the same temperature. The solvent was evap-
orated and the residue was taken in EtOAc (10 mL) and stirred with
water (3 mL), after which the organic layer was separated and
dried over Na2SO4, and evaporated under reduced pressure. The
crude material was column chromatographed over silica gel to give
diols 10 (<5% yield) and 11 (0.255 g, 85% yield). For 11:
bined 89% yield after three steps. 13: ½a D25
¼ þ9:25 (c 0.5, MeOH),
ꢁ
1H NMR (400 MHz, CDCl3/D2O): d = 1.34 (s, 3H), 1.40 (s, 3H), 1.83
(br s, 2H, –OH, exchangeable), 2.41 (s, 3H), 3.04–3.16 (m, 2H),
3.55–3.60 (m, 1H), 3.69–3.76 (s, 1H), 3.86–3.90 (m, 1H), 4.00–4.04
(m, 1H), 4.16–4.23 (m, 1H), 4.36–4.41 (m, 1H), 7.30 (d, J = 8.0 Hz,
2H), 7.74 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): d = 21.52,
26.48, 26.68 (overlapped), 44.35 (dept), 58.10, 59.57 (dept), 70.35,
73.75, 79.96, 111.45, 126.99, 130.01, 137.17, 144.04. LC–MS (ESI-
TOF): m/z [M+H]+ 358.03, [M+Na]+ 379.99.
½
a 2D5
ꢁ
¼ ꢂ17:8 (c 1, CHCl3), 1H NMR (200 MHz, CDCl3): d = 1.48 (s,
6H), 3.03–3.95 (m, 11H), 2.69 (br s, 1H, –OH), 3.25–3.95 (m, 8H),
4.05–4.19 (m, 1H), 4.32–4.41 (m, 1H). 13C NMR (75 MHz, CDCl3):
d = 26.81, 26.89 (overlapped), 47.19, 52.27, 69.87, 66.81, 79.92,
87.21, 108.66, 155.89.
4.7. ((3aS,7aS)-2,2-Dimethyl-5-tosyl-3a,4,5,7a-tetrahydro-[1,3]
dioxolo[4,5-c]pyridine-6-yl)methanol (14)
4.4. N-(((4S,5S)-5-((tert-Butyldimethylsiloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl)-N-(2-hydroxyethyl)-4-
methylbenzenesulfonamide (12)
½
a 2D5
ꢁ
¼ þ291:4 (c 1, CHCl3), 1H NMR (200 MHz, CDCl3): d = 1.29
(s, 3H), 1.37 (s, 3H), 2.43 (s, 3H), 3.24–3.40 (m, 2H), 3.45–3.58 (m,
1H), 4.01 (m, 1H), 4.35 (dd, J = 14.2 Hz,1H), 5.72 (s, 1H), 7.33 (d,
J = 8.0 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d = 21.49, 26.40, 26.60 (overlapped), 47.97 (dept), 63.92 (dept),
74.99, 76.07, 113.38, 114.49, 126.87, 129.89, 134.47, 137.75,
144.45. LC–MS (ESI-TOF): m/z [M+H]+ 340.19, [M+Na]+ 362.20.
Similar to the previous preparation using tosyl as protecting
group, 86% after three steps from 7. Compound 12: ½a D25
¼ ꢂ22:2
ꢁ
(c 1, CHCl3), 1H NMR (200 MHz, CDCl3): d = 0.08 (s, 6H), 0.89 (s,
9H), 1.35 (s, 3H), 1.38 (s, 3H), 2.40 (s, 3H), 2.90–3.07 (m, 2H),
3.45–3.61 (m, 2H), 3.65–3.89 (m, 5H), 4.20–4.29 (m, 1H), 7.28 (d,
J = 8.1 Hz , 2H), 7.67 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d = ꢂ5.61, ꢂ5.46 (overlapped), 18.27, 21.37, 25.82, 26.69, 26.91
(overlapped), 52.49, 53.24, 61.42, 63.23, 78.41, 79.27, 109.32,
127.23, 129.65, 135.54, 143.51. LC–MS (ESI-TOF): m/z [M+H]+
474.17, [M+Na]+ 496.14.
4.8. ((3aS,6S,7R,7aR)-7-Acetoxy-2,2-dimethyl-5-tosylhexahydro-
[1,3]dioxolo[4,5-c]pyridine-6-yl)methyl acetate (15)
To a solution of compound 13 (0.5 g, 1.40 mmol) in pyridine: dry
CH2Cl2 (1:1, 6 mL) was added AcCl (2.5 equiv) at 0 °C and stirred for

I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 21 (2010) 2703–2708
2707
an additional 2 h at the same temperature. The reaction was mon-
itored by TLC and the solvent was evaporated at reduced pressure.
The crude mixture was washed with aqueous CuSO4 solution and
extracted with EtOAc (2 ꢀ 10 mL), dried over Na2SO4, and evapo-
rated in vacuo. The crude material was column chromatographed
over silica gel gave diacetyl compound 15 (0.53 g, 84% yield).
Crystal data for 17 (C17H23NO6): M = 337.36, Crystal dimensions
0.59 ꢀ 0.19 ꢀ 0.02 mm3, monoclinic, space group P21, a = 5.9264
(18), b = 17.946(6), c = 16.598(5) Å, b = 91.282(7)°, V = 1764.8(9)
Å3; Z = 4; T = 297(2) K,
q l (Mo-K ) = 0.096
calcd = 1.270 gcmꢂ3
, a
mmꢂ1, F(0 0 0) = 720, 2hmax = 46.00°, 18,905 reflections collected,
4907 unique, 3248 observed (I > 2 (I)) reflections, 173 refined
r
½
a 2D5
ꢁ
¼ þ13:95 (c 1, CHCl3), 1H NMR (400 MHz, CDCl3): d = 1.33 (s,
parameters, R value 0.2020, wR2 = 0.4396 (all data R = 0.2425,
wR2 = 0.4600), S = 1.528, minimum and maximum transmission
0.9454 and 0.9981, respectively, maximum and minimum residual
electron densities +0.858 and ꢂ1.053 e Åꢂ3. CCDC No 800567.
3H), 1.42 (s, 3H), 2.02 (s, 3H), 2.15 (s, 3H), 2.45 (s, 3H), 3.01–3.07
(m, 1H), 3.20–3.26 (m, 1H), 3.59–3.64 (m,1H), 4.16–4.20 (m, 1H),
4.21–4.26 (m, 1H), 4.31–4.36 (m, 1H), 4.79–4.84 (m, 2H), 7.32 (d,
J = 8.0 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d = 20.72, 20.75 (overlapped), 21.48, 26.42, 26.48 (overlapped),
43.85 (dept), 53.62, 59.11 (dept), 70.36, 73.74, 76.72, 111.61,
126.97, 129.79, 137.26, 143.98, 169.59, 170.60. LC–MS (ESI-TOF):
m/z [M+H]+ 442.12, [M+Na]+ 464.09.
Acknowledgments
One of the authors, I.K. thanks CSIR, New Delhi for senior re-
search fellowship. We also thank specially Dr. Rajmohan for exten-
sive NMR studies and Dr. S. R. Bahdbhade for the X-ray structure
study.
4.9. ((3aS,7aS)-2,2-Dimethyl-5-tosyl-3a,4,5,7a-tetrahydro-
[1,3]dioxolo[4,5-c]pyridine-6-yl)methyl acetate (16)
References
Similar to the previous method using AcCl (1.1 equiv) (85% yield
from 14). Compound 16: ½a D25
ꢁ
¼ þ187:7 (c 1, CHCl3), 1H NMR
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