A facile and stereoselective synthesis of the C-2 epimer of (+)-deacetylanisomycin

Article abstract of DOI:10.1016/j.tetasy.2011.01.021

A short, simple and efficient synthesis of the C-2 epimer of (+)-deacetylanisomycin starting from d-mannitol, utilizing an epoxide opening with a Grignard reagent and acid catalysed unusual intramolecular 5-endo-tet cyclization as key steps has been repor

Full text of DOI:10.1016/j.tetasy.2011.01.021

Tetrahedron: Asymmetry 22 (2011) 190–194
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A facile and stereoselective synthesis of the C-2 epimer of
(+)-deacetylanisomycin
⇑
K. Sridhar Reddy, B. Venkateswara Rao
Organic III division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short, simple and efficient synthesis of the C-2 epimer of (+)-deacetylanisomycin starting from D-man-
nitol, utilizing an epoxide opening with a Grignard reagent and acid catalysed unusual intramolecular 5-
endo-tet cyclization as key steps has been reported.
Received 29 November 2010
Accepted 26 January 2011
Available online 2 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
RO
OH
RO
OH
MeO
MeO
Pyrrolidines are found in a number of biologically active natural
and unnatural compounds.1 Amongst them, polyhydroxylated pyr-
rolidines such as (ꢀ)-anisomycin 1 (Fig. 1) and its derivatives have
drawn considerable interest over last three decades. Anisomycin 1
is an antibiotic and was first isolated from the fermentation broths
of Streptomyces griseolous and Streptomyces roseochromogens by So-
bin and Tanner in 1954.2 Later it was also isolated from Streptomy-
ces sp. SA3079 and No. 638.3 The structure and relative
stereochemistry of 1 were determined by chemical studies4 and
X-ray crystallographic analysis5 and later the absolute stereochem-
istry of 1 was established as being (2R,3S,4S).6
N
N
R1
R1
R=Ac R1=H
ent-1
R=Ac R1=H
1
ent-1a R=R1=H
1a R=R1=H
ent-1b R=H R1=Cbz
1b R=H R1=Cbz
RO
OH
RO
OH
MeO
MeO
N
H
N
H
ent-2
R=Ac
Anisomycin 1 was found to exhibit selective and potent activi-
ties against pathogenic protozoa and certain strains of fungi7 and it
is currently being used in clinical trials for the treatment of amoe-
bic dysentery and vaginitis. More recently it was reported that
anisomycin 1 had been identified as an antitumor substance show-
ing in vitro cytotoxicity against human tumour lines, such as mam-
malian cell lines HBL 100, RAS A and MCF 7 in the nanomolar
region.3,8 Both anisomycin 1 and its deacetylderivative 1a have
been used as fungicides in the eradication of bean mildew and
for the inhibition of other pathogenic fungi in plants.9 Recently
some derivatives of 1 have also shown potent inhibitory activity
2
R=Ac
ent-2a R=H
2a R=H
Figure 1. The structure of (ꢀ)-anisomycin 1 and its derivatives.
ses have been reported for 1 and its analogues, many of them have
drawbacks, such as long reaction sequences and poor stereoselec-
tivity. Therefore, any approach which gives enantiomerically pure
compound is important for making analogues to evaluate their
biological activity. In continuation of our efforts in the synthesis
of polyhydroxylated pyrrolidine alkaloids and azasugars,13 we
herein report the stereoselective synthesis of a C-2 epimer of
(+)-deacetylanisomycin 2a whose absolute stereochemistry is
(2R,3R,4R) from the inexpensive and readily available chiral pool
against a
-rhamnosidase and some other glycosidases.10 Some chi-
ral polyhydroxylated pyrrolidines have also been used as catalysts/
ligands in asymmetric synthesis.11
starting material, D-mannitol. So far, one stereoselective synthesis
has been reported for 2a.12d However, the present method consti-
tutes a novel approach for the synthesis of this compound
(Schemes 1 and 2).
2. Results and discussion
Due to promising biological activity and structural features of
1, several strategies for the synthesis of (ꢀ)-anisomycin 112,13f
and its analogues have been developed. Although several synthe-
1,2:3,4:5,6-Tri-O-isopropylidene-
D-mannitol obtained from
D-mannitol was treated with H5IO6 to give the corresponding alde-
hyde and immediate reduction of the resultant crude aldehyde with
NaBH4 gave arabinitol derivative 3.14 Treatment of 3 with MsCl/
Et3N gave 4, which upon further treatment with NaN3 in DMF
⇑
Corresponding author. Tel.: +91 40 27193003; fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.021

K. S. Reddy, B. V. Rao / Tetrahedron: Asymmetry 22 (2011) 190–194
191
O
O
O
b
c
NHR
d
OR
N3
O
O
O
O
O
O
O
O
O
6 R=H
7 R=Cbz
3 R=H
4 R=Ms
5
a
O
O
g
h
e
NHCbz
NHCbz
O
RO
O
HO
O
8 R=H
9 R=Ts
f
10
O
HO
OH
j
k
2a
NHCbz
MeO
OH
O
N
Cbz
MeO
11 R=H
12 R=Ms
13
i
Scheme 1. Reagents and conditions: (a) MsCl, Et3N, DCM, 0 °C to rt, 1 h; (b) NaN3, DMF, 90 °C, 12 h, 83% for two steps; (c) Pd/C, MeOH, rt, 3 h; (d) CbzCl, Na2CO3, THF, 2 h, 81%
for two steps; (e) 50% aq AcOH, rt, overnight, 84%; (f) p-TsCl, Et3N, 10 mol % Bu2SnO, DCM, 0 °C to rt, 1 h; 93%; (g) K2CO3, MeOH, 30 min, 90%; (h) 4-bromoanisole, Mg, I2/CuCN
(cat.), ꢀ78 °C, 2 h, 79%; (i) MsCl, Et3N, DCM, rt, 1 h; (j) TFA, DCM, 0 °C to rt, 2 h, 79%; (k) Pd/C, MeOH, rt, overnight, 90%.
O
O
OH
(1:1)
TFA: DCM
MeO
NHCbz
CbzHN
OMs O
MeO
12
5-endo opening of the epoxide
HO
OH
MeO
MeO
OMe
MeO
N
N
Cbz
Cbz
14
13
Scheme 2.
yielded azido derivative 5. Reduction of the azido functionality
with Pd/C in MeOH gave amine 6, which upon in situ treatment
with CbzCl/Na2CO3 afforded compound 7. Selective hydrolysis of
7 with 50% aq AcOH gave diol 8. The regioselective tosylation of 8
provided 9, which upon further treatment with K2CO3/MeOH
yielded epoxide 10. The reaction of 10 with p-methoxyphenylmag-
nesium bromide in the presence of a catalytic amount of I2/CuCN
gave 11. Compound 11 was converted into mesyl derivative 12.
It should be noted that the treatment of 12 with TFA gave the cyc-
lised product 13 directly with double inversion of configuration,
whose NMR did not match with (+)-N-benzyloxycarbonyl deacety-
lanisomycin ent-1b based on a comparison with the reported
values.13f To further confirm the stereochemistry at the newly
formed stereogenic centre the cyclised product 13 was converted
into dimethoxy compound 14, whose 1H NMR spectra were in
agreement with the reported values.15 Compound 13 was
subjected to hydrogenation in the presence of Pd/C, which resulted
in the formation of 2a. The specific rotation of the C-2 epimer of
(+)-deacetylanisomycin 2a was ½a D25
ꢁ
¼ þ18 (c 0.8, MeOH), {lit12d
½
a 2D5
ꢁ
¼ þ20 (c 1, MeOH)}. The retention of configuration can be ex-
plained by the epoxide intermediate, which might have undergone
cyclization via an unusual 5-endo-tet mode.16
3. Conclusion
In conclusion, we have developed a new, short and efficient syn-
thetic approach for the C-2 epimer of (+)-deacetylanisomycin 2a
from D-mannitol, utilizing a stereoselective intramolecular in situ
5-endo-tet opening of an epoxide. The application of the above
strategy for the synthesis of important pyrrolidine and piperidine
molecules is currently in progress.

192
K. S. Reddy, B. V. Rao / Tetrahedron: Asymmetry 22 (2011) 190–194
with diethyl ether (3 ꢂ 80 mL). The combined organic extracts
4. Experimental
were washed with water (50 mL) brine (30 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure and purified
by column chromatography (ethyl acetate/hexane 1:12) to afford
5 (5.5 g, 83% from 5) as a liquid. Rf (20% ethyl acetate/hexane)
Moisture and oxygen sensitive reactions were carried out under
a nitrogen atmosphere. All the solvents and reagents were purified
by standard techniques. TLC was performed on Merck Kiesel gel 60,
F254 plates (layer thickness 0.25 mm). Column chromatography
was performed on silica gel (60–120 and 100–200 mesh) using
ethyl acetate, hexane chloroform and methanol as eluents. Melting
points were determined on a Fisher John’s melting point apparatus
and are uncorrected. IR spectra were recorded on a Perkin–Elmer
RX-1 FT-IR system. 1H NMR (400, 300 and 200 MHz) and 13C
NMR (75 and 100 MHz) spectra were recorded on the correspond-
ing MHz. 1H NMR data are expressed as chemical shifts in ppm fol-
lowed by multiplicity (s—singlet; d—doublet; t—triplet; q—quartet;
m—multiplet), number of proton(s) and coupling constant(s) J (Hz).
13C NMR chemical shifts are expressed in ppm. Optical rotations
were measured with JASCO P-2000 digital polarimeter. Accurate
mass measurement was performed on Q STAR mass spectrometer
(Applied Biosystems, USA).
0.6; ½a 2D5
ꢁ
¼ þ63:4 (c 1.5, CHCl3); IR mmax 666, 841, 917, 979, 1056,
1155, 1214, 1375, 1448, 1734, 2098, 2882, 2932, 2987 cmꢀ1
;
1H
NMR (300 MHz, CDCl3) d 4.02–4.12 (m, 2H), 3.89–3.99 (m, 2H),
3.72 (t, 1H, J = 8.05 Hz), 3.63 (dd, 1H, J = 2.1, 13.1 Hz), 3.26 (dd,
1H, J = 4.7, 13.1 Hz), 1.43 (s, 3H), 1.37 (s, 6H), 1.30 (s, 3H); 13C
NMR (300 MHz, CDCl3) d 109.8, 109.5, 79.7, 77.5, 77.1, 67.8, 51.7,
27.0, 26.8, 26.7, 25.2; ESI/MS (m/z) 230 (MꢀN2).
4.3. Benzyl ((4S,40R,5R)-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolan)-5-yl) methylcarbamate 7
To a solution of compound 5 (4.2 g, 16.3 mmol) in MeOH
(30 mL) was added a catalytic amount of 10% Pd/C then the flask
was purged with H2 and the solution was hydrogenated for 24 h.
The reaction mixture was filtered through a Celite bed, after which
MeOH was removed from the reaction mixture in vacuo. The crude
residue was dissolved in DCM (40 mL), and to it were added
Na2CO3 (2.07 g, 19.5 mmol) and CbzCl (2.3 mL, 16.3 mmol) drop-
wise at 0 °C. After being stirred for 1 h at room temperature, the
reaction mixture was diluted with CHCl3 (50 mL). The organic layer
was washed with water (30 mL), brine (20 mL), and dried over
Na2SO4. Evaporation of the solvent under reduced pressure and
purification by silica gel column chromatography (ethyl acetate/
hexane 1:6) afforded 7 (4.83 g, 81%) as pale yellow liquid. Rf (30%
4.1. ((4S,40R,5R)-2,2,20,20-Tetramethyl-4,40-bi(1,3-dioxolan)-5-
yl)methanol 3
To a solution of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol
(10 g, 33.0 mmol) in dry ether (150 mL) was added periodic acid
(9.8 g, 42.88 mmol) portion wise at 0 °C under a nitrogen atmo-
sphere. After stirring for 6 h at room temperature, the reaction
mixture was filtered and the filtrate concentrated under reduced
pressure to give the aldehyde, which was used in the next step
without any purification.
To the above aldehyde in dry MeOH (40 mL) was added NaBH4
(1.44 g, 38.0 mmol) portionwise at 0 °C under a nitrogen atmo-
sphere. After being stirred for 1 h at room temperature, satd aq NH4Cl
was added to the reaction mixture, followed by MeOH concentrated
under reduced pressure and the residue was extracted with ethyl
acetate (3 ꢂ 100 mL). The combined organic extracts were washed
with brine (50 mL), dried over anhydrous Na2SO4, concentrated un-
der reduced pressure and purified by column chromatography (ethyl
acetate/hexane 1:4) to afford 3 (5.2 g, 68%, based on recovery of start-
ethylacetate/hexane) 0.5; ½a D25
¼ ꢀ2:8 (c 1.8, CHCl3); IR mmax 844,
ꢁ
1080, 1153, 1239, 1375, 1458, 1530, 1724, 2362, 2884, 2938,
2987, 3357 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.22–7.35 (m, 5H),
;
5.21 (br s, 1H), 5.02–5.12 (dd, J = 11.3, 2H), 4.06–4.14 (m, 1H),
3.87–4.01 (m, 3H), 3.44–3.57 (m, 3H), 1.39 (s, 3H) 1.36 (s, 3H),
1.34 (s, 3H), 1.32 (s, 3H); 13C NMR (300 MHz, CDCl3) d 156.3,
136.5, 128.4, 127.9, 109.8, 109.4, 79.4, 78.9, 76.7, 67.7, 66.6, 43.0,
26.9, 26.8, 26.5, 25.1; ESI/MS (m/z) 388 (M++Na); HRMS calcd for
C19H27NO6Na 388.1736, found 388.1730.
ing material as
¼ ꢀ1:1 (c 1.0, CHCl3); IR (neat) mmax 841, 1062, 1156, 1213,
1375, 2881, 2934, 2987, 3481 cmꢀ1 1H NMR (300 MHz, CDCl3) d
a syrup. Rf (40% ethyl acetate/hexane) 0.5;
4.4. Benzyl ((4R,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl) methylcarbamate 8
½ ꢁ
a 2D5
;
4.12 (dd, 1H, J = 5.6, 8.1 Hz), 3.91–4.03 (m, 3H), 3.63–3.79 (m, 3H),
2.20 (br s, 1H), 1.41 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H);
13C NMR (300 MHz, CDCl3) d 109.7, 109.3, 80.8, 78.4, 76.8, 67.7,
62.6, 26.8, 26.8, 26.5, 25.1; FABMS (m/z) 233 (M++1); HRMS calcd
for C11H20O5Na 233.1388, found 233.1398.
Compound 7 (3.8 g, 10.3 mmol) was stirred at room tempera-
ture in 50% AcOH (38 mL). After stirring overnight at the same tem-
perature, the reaction mixture was neutralized with aq NaHCO3,
and extracted with ethyl acetate (2 ꢂ 100 mL). The combined or-
ganic extracts were washed with brine (30 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure and purified
by column chromatography (ethyl acetate/hexane 1:1.2) to afford
8 (2.84 g, 84% based on recovery of starting material) as white crys-
4.2. (4S,40R,5R)-5-(Azidomethyl)-2,2,20,20-tetramethyl-4,40-
bis(1,3-dioxolane) 5
talline solid. Rf (80% ethyl acetate/hexane) 0.5; ½a D25
¼ ꢀ17:5 (c 1.0,
ꢁ
To a stirred solution of 3 (6.2 g, 26.6 mmol) in dry DCM (60 mL)
was added Et3N (3.5 mL, 26.6 mmol) at 0 °C under a nitrogen atmo-
sphere. After 5 min of stirring, methanesulfonylchloride (2.1 mL,
26.6 mmol) was added dropwise to the reaction mixture and al-
lowed to stir at room temperature for 1 h, then the reaction mix-
ture was extracted with CHCl3 (100 mL). The organic extract was
washed with water (50 mL), brine (30 mL), dried over Na2SO4
and evaporation of the solvent under reduced pressure afforded
4 as a liquid, which was carried onto the next step without any
purification.
To the above mesylate derivative 4 in dry DMF (30 mL) was
added NaN3 (2.6 g, 40.0 mmol) under a nitrogen atmosphere at
room temperature. The reaction was slowly heated to 90 °C and
stirred for 12 h, the reaction mixture was allowed to cool room
temperature, poured into ice cold water (40 mL) and extracted
CHCl3); IR mmax 698, 741, 883, 1049, 1158, 1245, 1374, 1457, 1531,
1695, 2855, 2924, 3357 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.29–
;
7.40 (m, 5H), 5.39 (br s, 1H), 4.97–5.24 (dd, J = 12.6, 2H), 4.03–
4.13 (m, 1H), 3.46–3.85 (m, 6H), 2.72 (br s, OH), 1.93 (br s, OH),
1.36 (m, 6H); 13C NMR (300 MHz, CDCl3) d 157.3, 136.1, 128.5,
128.2, 128.1, 109.0, 78.8, 77.2, 72.8, 67.1, 64.2, 42.6, 26.9, 26.8;
ESI/MS (m/z) 348 (M++Na); HRMS calcd for C16H23NO6Na
348.1423, found 348.1436.
4.5. (R)-2-((4R,5R)-5-((Benzyloxycarbonylamino)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-2-hydroxyethyl 4-
methylbenzenesulfonate 9
To a stirred solution of 8 in DCM (2.2 g, 6.7 mmol) were
added Et3N (1.0 mL, 6.7 mmol), Bu2SnO (168 mg, 0.67 mmol) and

K. S. Reddy, B. V. Rao / Tetrahedron: Asymmetry 22 (2011) 190–194
193
p-toluenesulfonylchloride in DCM (1.38 g, 6.7 mmol) at 0 °C under
a nitrogen atmosphere. After stirring for 1 h at room temperature,
the reaction mixture was extracted with CHCl3 (100 mL). The or-
ganic extract was washed with water (30 mL), brine (30 mL), dried
over anhydrous Na2SO4, concentrated under reduced pressure and
purified by column chromatography (ethyl acetate/hexane 1:8) to
give 9 (3.0 g, 93%) as a liquid. Rf (20% ethyl acetate/hexane) 0.4;
78.8, 73.2, 66.9, 55.1, 42.9, 39.4, 27.0, 26.9; ESI/MS (m/z) 415.9
(M++1); HRMS calcd for C23H29NO6Na 438.1892, found 438.1879.
4.8. (2R,3R,4R)-Benzyl 3,4-dihydroxy-2-(4-methoxybenzyl)-
pyrrolidine-1-carboxylate 13
To a stirred solution of 11 (0.62 g, 1.49 mmol) in dry DCM
(10 mL) was added Et3N (0.24 mL, 1.79 mmol) at 0 °C under a
nitrogen atmosphere. After stirring for 5 min methanesulfonyl-
chloride (0.12 mL, 1.64 mmol) was added dropwise to the reaction
mixture and allowed to stir at room temperature for 1 h. The reac-
tion mixture was then extracted with CHCl3 (50 mL). The organic
extract was washed with water (30 mL), brine (20 mL), dried over
Na2SO4 and evaporation of the solvent under reduced pressure
afforded 12 as a liquid, which was used in the next step without
any purification.
½
a 2D5
ꢁ
¼ ꢀ32:3 (c 1.2, CHCl3); IR mmax 699, 860, 1000, 1100, 1248,
1375, 1458, 1519, 1718, 2362, 2854, 2925, 3339 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 7.77–7.82 (m, 2H), 7.23–7.34 (m, 7H), 5.30
(br s, 1H), 5.02–5.14 (dd, J = 12.0, 2H), 4.15–4.22 (dd, 1H, J = 1.8,
10.1 Hz), 3.90–4.05 (m, 2H), 3.80 (br s, OH), 3.65–3.75 (m, 1H),
3.33–3.5 (m, 3H), 2.43 (s, 3H) 1.29 (s, 6H); 13C NMR (300 MHz,
CDCl3) d 157.3, 136.1, 128.5, 128.2, 128.1, 128.0, 127.8, 109.0,
80.0, 78.7, 76.4 72.8, 67.1, 64.2, 50.9, 42.6, 29.7, 26.9, 26.8; ESI/
MS (m/z) 480 (M++1); HRMS calcd for C23H29NO8NaS 502.1511,
found 502.1512.
To the above mesylate derivative 12 in DCM (5 mL) was added
trifluoroacetic acid (5 mL) at 0 °C. After stirring for 1 h, the reaction
mixture was concentrated under reduced pressure, after which
benzene (10 mL) was added to the residue and the solvents were
removed under reduced pressure. The crude residue was dissolved
in ice cold water and extracted with ethyl acetate (40 mL). The or-
ganic extract was dried over Na2SO4, and the solvent evaporated
under reduced pressure and purified by column chromatography
(ethyl acetate/hexane 3.5:1) to afford 13 (0.42 g, 79%) as a liquid.
4.6. Benzyl ((4R,5S)-2,2-dimethyl-5-((R)-oxiran-2-yl)-1,3-
dioxolan-4-yl) methylcarbamate 10
To a stirred solution of monotosylate derivative 9 (2.8 g,
5.83 mmol) in dry MeOH (25 mL) was added K2CO3 (0.80 g,
5.83 mmol) under a nitrogen atmosphere. After being stirred for
30 min at room temperature, the MeOH was evaporated under re-
duced pressure while keeping the temperature of water bath be-
low 30 °C. The residue was extracted with CHCl3 (100 mL). The
organic extract was washed with water (30 mL), brine (30 mL),
dried over anhydrous Na2SO4, concentrated under reduced pres-
sure and purified by column chromatography (ethyl acetate/hex-
ane 1:4) to give 10 (1.6 g, 90%) as a liquid. Rf (40% ethyl acetate/
Rf (70% ethyl acetate/hexane) 0.4; ½a D25
¼ þ13:7 (c 1.1, CHCl3); IR
ꢁ
mmax 749, 815, 1032, 1178, 1244, 1511, 1611, 2928, 3326 cmꢀ1
;
NMR (400 MHz, CDCl3): d 7.28–7.539 (m, 5H), 7.11–7.16 (m, 1H),
6.98–7.03 (m, 1H), 6.74–6.81 (m, 2H), 5.04–5.19 (m, 2H), 4.05–
4.10 (m, 1H), 3.89–3.96 (m,1H), 3.79–3.87 (m, 2H), 3.74 (s, 3H),
3.05–3.33 (m, 2H), 2.89 (dd, 1H J = 13.1, 10.2 Hz), 2.24 (br s, 2H,
2OH); 13C NMR (300 MHz, CDCl3) d 162.7, 157.9, 155.4, 155.2,
136.5, 136.2, 130.6, 130.4, 130.1, 128.4, 128.0, 127.9, 127.7,
113.9, 78.3, 77.6, 75.3, 74.9, 67.3, 66.8, 66.5, 66.4, 55.1, 52.6,
52.1, 36.8, 35.7; ESI/MS (m/z) 380 (M++Na); HRMS calcd for
hexane) 0.5; ½a 2D5
¼ ꢀ4:5 (c 1.3, CHCl3); IR mmax 698, 744, 856,
ꢁ
986, 1081, 1155, 1242, 1375, 1455, 1528, 1711, 2361, 2934,
2987, 3343 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.28–7.39 (m, 5H),
;
5.05–5.19 (m, 3H), 4.01–4.11 (m, 1H), 3.38–3.55 (m, 3H), 3.03–
3.11 (m, 1H), 2.81–2.90 (m, 1H), 2.6–2.73 (m, 1H), 1.41 (s, 3H),
1.40 (s, 3H); 13C NMR (300 MHz, CDCl3) d 156.4, 136.3, 129.8,
128.4, 128.0, 109.9, 78.5, 77.4, 66.8, 51.3, 45.4, 42.7, 26.9, 26.5;
ESI/MS (m/z) 308 (M++1); HRMS calcd for C16H21NO5Na
330.1317, found 330.1328.
C20H23NO5Na 380.1473, found 380.1489.
4.9. (2R,3R,4R)-2-(4-Methoxybenzyl)pyrrolidine-3,4-diol 2a
To a stirred solution of compound 13 (0.050 g, 0.13 mmol) in
MeOH a catalytic amount Pd/C (10 mol %) was added, then the
flask was purged with H2 and the solution hydrogenated for 24 h.
The reaction mixture was filtered through a Celite bed then the
solution was concentrated under vacuum and purified by column
chromatography (methanol/chloroform 1:19) to afford 2a
(0.026 g, 90%) as a syrup. Rf (5% Methanol/chloroform) 0.3.;
4.7. Benzyl ((4R,5R)-5-((R)-1-hydroxy-2-(4-
methoxyphenyl)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)
methylcarbamate 11
½
a 2D5
ꢁ
¼ þ18 (c 0.8, CHCl3); {lit.12d
½
a 2D5
ꢁ
¼ þ20 (c 1, MeOH)} IR mmax
To a stirred solution of 10 (1 g, 3.25 mmol) in dry THF (10 mL)
were added CuCN (5 mg) and (p-methoxyphenyl) magnesium bro-
mide {freshly prepared with Mg (312 mg, 13.0 mmol), p-bromo
anisole (1.22 mL, 9.8 mmol) and I2 (3 mg) in dry THF (5 mL)} drop-
wise at ꢀ78 °C under a nitrogen atmosphere. After stirring for 2 h
at the same temperature, the reaction mixture was quenched with
satd aq NH4Cl at 0 °C, concentrated under reduced pressure and the
residue was extracted with ethyl acetate (3 ꢂ 50 mL). The com-
bined organic extracts were washed with brine (30 mL), dried over
anhydrous Na2SO4, concentrated under reduced pressure and puri-
fied by column chromatography (ethyl acetate/hexane 1:4) to af-
ford 11 (1.02 g, 76%) as a syrup. Rf (30% ethyl acetate/hexane)
752, 820, 1031, 1177, 1244, 1458, 1512, 1608, 2852, 2922,
3300 cmꢀ1 1H NMR (300 MHz, CDCl3): 7.20 (2H, d, J = 8.3), 6.84
;
(2H, d, J = 8.3 Hz), 3.96–4.05 (m, 2H), 3.77 (s, 3H), 2.93–3.26 (m,
5H), 2.76–2.90 (m, 2H), 2.61 (m, 1H); 13C NMR (300 MHz, CDCl3)
d 158.4, 130.3, 129.4, 114.2, 82.5, 75.6, 62.3, 55.2, 40.9, 36.5; ESI/
MS (m/z) 224 (M++1); HRMS calcd for C12H18 N O3 224.1286, found
224.1278.
4.10. (2R,3R,4R)-Benzyl3,4-dimethoxy-2-(4-methoxybenzyl)-
pyrrolidine-1-carboxylate 14
0.5; ½a 2D5
ꢁ
¼ ꢀ12:7 (c 1.0, CHCl3); IR mmax 517, 699, 754, 1036,
To a solution of the above diol (13 mg, 0.036 mmol) in THF
(5 mL) was added NaH (2 mg, 95%, 0.08 mmol) and MeI in THF
(0.4 v/v%, 1 mL) at 0 °C. After being stirred for 1 h at 0 °C and then
for 40 min at rt and refluxed for 2 h, the reaction mixture was di-
luted with NH4Cl solution (10 mL) and extracted with ethyl acetate
(20 mL ꢂ 3). The extract was dried over MgSO4, the solvent evapo-
rated under reduced pressure and purified by column chromatog-
raphy (ethyl acetate/hexane 1:3) to afford 14 (12 mg, 87%) as a
1086, 1246, 1513, 1703, 2934, 2987, 3359 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.28–7.37 (m, 5H), 7.13–7.30 (m, 2H), 6.82–
6.87 (m, 2H), 5.25 (br s, 1H), 4.90–5.13 (dd, J = 12.2, 2H), 3.99–
4.08 (m, 1H), 3.77 (m, 4H), 3.39–3.58 (m, 3H), 2.99 (dd, 1H,
J = 2.2, 13.5 Hz), 2.63 (dd, 1H, J = 8.1, 13.7 Hz), 2.44 (br s, OH),
1.40 (s, 3H), 1.39 (s, 3H); 13C NMR (300 MHz, CDCl3) d 158.3,
156.8, 136.3, 130.5, 129.2, 128.4, 128.1, 128.0, 113.9, 108.8, 79.1,

194
K. S. Reddy, B. V. Rao / Tetrahedron: Asymmetry 22 (2011) 190–194
liquid. Rf (50% ethyl acetate/hexane) 0.5; ½a D25
¼ þ30:2 (c 1.3,
ꢁ
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CHCl3); IR mmax 841, 1062, 1155, 1212, 1375, 2880, 2934, 2987,
3480 cmꢀ1 1H NMR (300 MHz/CDCl3): 7.46–7.28 (m, 5H), 7.20
;
(d, J = 7.5 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.83 (dd, J = 10.0,
4.6 Hz, 2H), 5.25–5.09 (m, 2H), 3.98 and 3.67 (rotamers, m, 1H),
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(m/z) 386 (M++1).
Acknowledgements
K.S.R. thanks CSIR, New Delhi, for the research fellowship and
also thanks Dr. J. S. Yadav and Dr. A. C. Kunwar, for their support
and encouragement. We also thank DST (SR/S1/OC-14/2007),
New Delhi for the financial assistance.
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