A new approach to (+)-anisomycin

Article abstract of DOI:10.1016/j.tetasy.2005.08.039

An efficient approach to enantiomerically pure (+)-deacetylanisomycin 2a and a formal synthesis of (+)-anisomycin 2 (11% overall yield in 10 steps) have been achieved through simple and good yielding reactions, starting from 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol 3. Grignard reaction and intramolecular cyclisation reactions are key steps in the strategy.

Full text of DOI:10.1016/j.tetasy.2005.08.039

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16(2005) 3154–3159
A new approach to (+)-anisomycinI
J. Santhosh Reddy, A. Ravi Kumar and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 20 June 2005; revised 26August 2005; accepted 29 August 2005
Abstract—An efficient approach to enantiomerically pure (+)-deacetylanisomycin 2a and a formal synthesis of (+)-anisomycin 2
(11% overall yield in 10 steps) have been achieved through simple and good yielding reactions, starting from 1,2:3,4:5,6-tri-O-iso-
propylidene-D-mannitol 3. Grignard reaction and intramolecular cyclisation reactions are key steps in the strategy.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Anisomycin 1 is an antibiotic that was isolated from the
fermentation broth filtrates of Streptomyces griseolous
and Streptomyces roseochromogens by Sobin and Tan-
ner at Pfizer, Inc. in 1954.1 Its structure and relative ste-
reochemistry were confirmed by chemical studies2 and
X-ray crystallographic analysis.3 The absolute stereo-
chemistry of this alkaloid (Fig. 1) were firmly established
as (2R,3S,4S) by chemical correlation with L-tyrosine.4
The diverse biological activity of anisomycin is due to
the presence of a chiral pyrrolidine skeleton.8 The activ-
ity and structural features of 1 has attracted the atten-
tion of several synthetic organic chemists.9,10 Few
routes have given good stereoselectivity, while others
have an inherent problem in separating unwanted iso-
mers. In continuation of our interest in the synthesis
of biologically active chiral pyrrolidines,11 we undertook
the synthesis of the unnatural isomer, (+)-anisomycin 2.
Herein, we report a strategy where all the three centers
of the (+)-anisomycin 2 were fixed from the inexpensive
and readily available chiral pool starting material, D-
mannitol. So far, three syntheses are reported for (+)-
anisomycin 2.10 Two of the approaches10a,b are nonste-
reoselective and low yielding while the other10c prepared
(+)-anisomycin, but with 88–90% ee. Previously, (+)-
anisomycin 2 was synthesized from (+)-N-benzyloxycar-
bonyl deacetylanisomycin 2b in three steps.10c There-
fore, our approach mainly deals with the synthesis of
(+)-(2S,3R,4R) deacetylanisomycin 2a and its Cbz
derivative 2b as outlined below.
Anisomycin 1 possesses a strong and selective activity
against pathogenic protozoa and fungi, and has been
used successfully in the clinics for the treatment of Tri-
chomonas vaginitis and for amoebic dysentery.5 Both
anisomycin 1 and its deacetyl derivative 1a have been
used as fungicides in the eradication of bean mildew
and for the inhibition of other pathogenic fungi in
plants.6 Anisomycin 1 was found to inhibit peptide bond
formation on eukaryotic ribosomes.7
OH
RO
OH
RO
MeO
MeO
1,2:3,4:5,6-Tri-O-isopropylidene-D-mannitol 3, a fully
protected form of D-mannitol was treated with H5IO6
to give aldehyde12 4 and immediate reduction of the
resultant crude aldehyde 4 with NaBH4 gave arabinitol
derivative 5. Treatment of 5 with benzyl bromide/NaH
furnished benzyl ether derivative 6. Selective hydrolysis
of 6 with 50% aq AcOH gave diol 7. Regioselective tosyl-
ation of 7 gave 8, which on further treatment with
K2CO3/MeOH yielded epoxide 9. Reaction of 9 with
p-methoxyphenylmagnesium bromide in the presence
of a catalytic amount of I2/CuI gave 10. Compound
N
N
H
R'
1
R=Ac
1a R=H
2 R=Ac, R'=H
2a R=R'=H
2b R=H, R'=Cbz
Figure 1. The structure of (ꢀ)-anisomycin 1 and (+)-anisomycin 2.
q IICT Communication Number: 050314.
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40
*
27160512; e-mail: venky@iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.039

J. S. Reddy et al. / Tetrahedron: Asymmetry 16 (2005) 3154–3159
3155
O
O
O
O
O
O
O
a
b
c
OH
OBn
H
O
O
O
O
O
O
O
O
O
O
O
O
3
4
5
6
O
O
O
g
f
i
cd
OBn
OBn
OBn
RO
O
OR
O
O
MeO
HO
O
e
7 R=H
10 R=H
9
h
8 R=Ts
11 R=Ms
O
O
O
j
l
OBn
OR
OBn
NH
O
k
NH
O
N3
O
MeO
MeO
R
MeO
m,n
Boc
13 R=H
15 R=H
12
h
14 R=Boc
16 R=Ms
OH
OH
HO
AcO
MeO
MeO
ref. 10c
N
N
R
H
2a R=H
o
2
2b R=Cbz
Reagents and conditions: (a) ref. 12; (b) NaBH4, MeOH, rt, 3 h, 67% for two steps; (c) NaH, BnBr, DMF,
0 o
o
C−
rt, overnight, 84%; (d) 50% aq. AcOH, rt, overnight, 84%; (e) p-TsCl, Et3N, DCM, 0 C, 16 h; (f)
o
K2CO3, MeOH, 30 min, 71% for two steps; (g) 4-Bromo anisole, Mg, I2/CuI (cat.), 0
rt
C− , overnight,
o
86%; (h) MsCl, Et3N, DCM, rt, 1 h; (i) NaN3, [18-Crown-6], DMSO, 65 C, 24 h, 83% for two steps; (j)
LiAlH4, THF, 0 oC−rt, overnight; (k) (Boc)2O, Et3N, THF, rt, 6 h, 81% for two steps; (l) Li/liq.NH3, -78 oC,
o
o
30 min, 83%; (m) TFA, DCM, 0 C−rt, 10 h; (n) Et3N, MeOH, 0 C−rt, 5 h; (o) Cbz-Cl, Na2CO3, THF, 2 h,
69% for four steps.
10 on treatment with MsCl/Et3N gave 11, which on fur-
ther treatment with NaN3/[18-crown-6] in DMSO13
yielded azido derivative 12. Reduction of the azido func-
tionality with LiAlH4/THF gave amine 13, which on
in situ treatment with (Boc)2O/Et3N afforded compound
14. Removal of benzyl group in 14 was achieved using
Li/liq. NH3 to give 15. Compound 15 was converted
to corresponding mesyl derivative 16 with MsCl/Et3N,
which without purification treated with TFA followed
by Et3N to give (+)-deacetyl anisomycin 2a. Further
treatment of 2a with Cbz–Cl gave (+)-N-benzyloxy-
carbonyl deacetylanisomycin 2b,9a,c,e,k whose melting
point, 1H NMR and IR were in agreement with the
ylanisomycin 2a, has been achieved from D-mannitol,
which also helps in making compound 2 in good quan-
tities for the complete evaluation of its biological
activity.
4. Experimental
TLC was performed on Merck Kiesel gel 60, F254 plates
(layer thickness 0.25 mm). Column chromatography
was performed on silica gel (60–120 mesh) using ethyl
acetate and hexane mixture as eluent. Melting points
were determined on a Fisher JohnÕs melting point appa-
ratus and are uncorrected. IR spectra were recorded on
reported values. The specific rotation of (+)-N-benzyl-
25
1
oxycarbonyl deacetylanisomycin 2b is ½aŠ ¼ þ7:9 (c
a Thermo Nicolet nexus 670 FT-IR systems. H NMR
D
25
0.45, MeOH) {lit.9e for (ꢀ)-isomer is ½aŠ ¼ ꢀ8:2
(300 MHz) and 13C NMR (75 MHz) spectra were
recorded on Bruker Avance-300 MHz spectrometer.
1H NMR (400 MHz) spectra were recorded on a Varian
Unity-400 MHz spectrometer. Optical rotations were
measured with Horiba-SEPA-300 digital polarimeter.
FABMS were recorded on a VG AUTOSPEC M251
(Micromass) at 70 eV using a direct inlet system. EI-
mass spectrum was recorded on a VG 7070 H (Micro-
mass) spectrometer. HRMS were recorded on a Q
STAR XL HYBRID (PE SEIEX) spectrometer. Chiral
D
(c 5.97, MeOH)}.
3. Conclusion
Since 2b had previously been transformed into (+)-
anisomycin 2,10c the present work offers an alternative
route to the enantiomerically pure unnatural isomer 2.
A good yielding approach to the synthesis of (+)-deacet-

3156
J. S. Reddy et al. / Tetrahedron: Asymmetry 16 (2005) 3154–3159
HPLC followed by LC–MS was carried out on AGI-
LENT-1100 SERIES spectrometer.
70.68, 67.57, 27.05, 26.59, 25.23; FABMS (M++1):
323; HRMS calcd for C18H26O5Na+: 345.1680, found:
345.1677.
4.1. 2,3:4,5-Di-O-isopropylidene-D-arabinitol 5
4.3. 1-O-Benzyl-2,3-O-isopropylidene-D-arabinitol 7
To a solution of 1,2:3,4:5,6-tri-O-isopropylidene-D-man-
nitol 3 (12.5 g, 41.4 mmol) in dry ether (180 mL) was
added periodic acid (12.26g, 53.80 mmol) portionwise
at 0 ꢁC under a nitrogen atmosphere. After stirring for
6h at room temperature, the reaction mixture was fil-
tered through a pad of Celite, and the filtrate concen-
trated under reduced pressure to give crude arabinose
derivative 4, which was used in the next step without
any purification.
The fully protected compound 6 (2.5 g, 7.76mmol) was
stirred at room temperature in 50% acetic acid (25 mL).
After stirring overnight at the same temperature, the
reaction mixture was neutralized with aq NaHCO3,
and extracted with ethyl acetate (2 · 100 mL). The com-
bined organic extracts were washed with brine (20 mL),
dried over anhydrous Na2SO4, concentrated under
reduced pressure and purified by column chromatography
(ethyl acetate/hexane) (1:1) to afford 7 (1.4 g, 84%
25
D
To the above arabinose derivative 4 in dry MeOH
(40 mL) was added NaBH4 (1.81 g, 47.86mmol) por-
tionwise at 0 ꢁC under a nitrogen atmosphere. After
being stirred for 3 h at room temperature, saturated aq
NH4Cl was added to the reaction mixture, MeOH con-
centrated under reduced pressure and residue extracted
with ethyl acetate (3 · 100 mL). The combined organic
extracts were washed with brine (50 mL), dried over
anhydrous Na2SO4, concentrated under reduced pres-
sure and purified by column chromatography (ethyl ace-
based on SM recovery) as a pale yellow syrup. ½aŠ ¼
ꢀ1:4 (c 1.065, CHCl3) [>99% enantiomeric excess was
determined from chiral HPLC using Chiralcel OB-H
column (5% i-propanol/n-hexane, flow rate = 1 mL/min,
k = 225 nm)]; IR mmax (KBr, cmꢀ1): 860, 1083, 1216,
1375, 1453, 1638, 2357, 2926, 2985, 3427; 1H NMR
(300 MHz, CDCl3): d 7.24–7.38 (m, 5H), 4.59 (s, 2H),
4.02 (dt, 1H, J = 4.5, 7.5 Hz), 3.68–3.78 (m, 3H), 3.58–
3.67 (m, 2H), 3.53 (dd, 1H, J = 7.5, 9.0 Hz), 3.33 (br s,
OH), 2.08 (br s, OH), 1.36(s, 3H), 1.35 (s, 3H); FABMS
(M++1): 283; HRMS calcd for C15H22O5Na+: 305.1377,
found: 305.1364.
tate/hexane) (1:11) to afford 5 (4.5 g, 67% based on
25
recovery of SM 3) as a yellowish oil. ½aŠ ¼ ꢀ1:1 (c
D
1.14, CHCl3); IR mmax (film, cmꢀ1): 845, 905, 1069,
1157, 1218, 1377, 1455, 2882, 2932, 2987, 3488; 1H
NMR (400 MHz, CDCl3): d 4.12 (dd, 1H, J = 5.4,
8.6Hz), 3.91–4.03 (m, 3H), 3.63–3.79 (m, 3H), 2.25
(dd, 1H, J = 4.7, 8.6Hz), 1.41 (s, 3H) 1.38 (s, 3H),
1.36(s, 3H), 1.33 (s, 3H); 13C NMR (75 MHz, CDCl3,
proton decoupled): d 109.82, 109.39, 80.82, 78.68,
76.87, 67.88, 62.72, 26.92, 26.88, 26.60, 25.15; FABMS
(M++1): 233; HRMS calcd for C11H20O5Na+:
255.1208, found: 255.1220.
4.4. 1-O-Benzyl-2,3-O-isopropylidene-4-oxiranyl-D-
arabinitol 9
To a stirred solution of 7 in CH2Cl2 (1.3 g, 4.6mmol)
were added Et3N (1.92 mL, 13.82 mmol) and p-toluene-
sulfonylchloride (0.87 g, 4.6mmol) at 0 ꢁC under a
nitrogen atmosphere. After stirring for 16h at room
temperature, the reaction mixture was extracted with
CHCl3 (150 mL). The organic extract was washed with
water (30 mL), brine (30 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure, and then
carried to the next step without any purification.
4.2. 1-O-Benzyl-2,3:4,5-di-O-isopropylidene-D-
arabinitol 6
To a stirred suspension of NaH (1.03 g, 25.86mmol) in
dry DMF (20 mL) was added a solution of 5 (3 g,
12.93 mmol) in dry DMF (10 mL) dropwise at 0 ꢁC
under a nitrogen atmosphere. After stirring at room
temperature for 15 min, benzyl bromide was added
and the reaction mixture stirred overnight, quenching
with saturated aq NH4Cl at 0 ꢁC and extracted with
ether (2 · 100 mL). The combined organic extracts
were washed with brine (30 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure and
purified by column chromatography (ethyl acetate/hex-
To a stirred solution of monotosylate derivative 8 in
dry MeOH (8 mL) was added K2CO3 (1.14 g,
8.25 mmol) under a nitrogen atmosphere. After being
stirred for 30 min at room temperature, the MeOH
was evaporated under reduced pressure keeping the
temperature below 30 ꢁC. The residue was extracted
with CHCl3 (100 mL). The organic extract was washed
with water (20 mL), brine (20 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure
and purified by column chromatography (ethyl ace-
tate/hexane) (1:11) to give 9 (860 mg, 70%) as a color-
25
ane) (1:24) to afford pure 6 (3.5 g, 84%) as a pale yel-
less oil. ½aŠ ¼ ꢀ4:0 (c 0.22, CHCl3); IR mmax (film,
D
25
low oil. ½aŠ ¼ þ6:1 (c 0.95, CHCl3); IR mmax (film,
cmꢀ1): 858, 915, 1085, 1247, 1374, 1454, 1625, 2865,
cmꢀ1): 844,D1057, 1083, 1152, 1214, 1249, 1474, 1637,
2875, 2933, 2987; 1H NMR (400 MHz, CDCl3): d
7.18–7.34 (m, 5H), 4.60 (d, 1H, J = 11.7 Hz), 4.57 (d,
1H, J = 11.7 Hz), 4.07 (m, 2H), 3.94–4.02 (m, 1H),
3.89 (dd, 1H, J = 4.7, 7.8 Hz), 3.68–3.73 (m, 2H),
3.54 (dd, 1H, J = 5.5, 10.6Hz), 1.39 (s, 3H), 1.37 (s,
3H), 1.31 (s, 3H), 1.29 (s, 3H); 13C NMR (75 MHz,
CDCl3, proton decoupled): d 138.18, 128.28, 127.67,
127.52, 109.76, 109.57, 79.75, 77.74, 77.17, 73.45,
2924, 2988; H NMR (300 MHz, CDCl3): d 7.24–7.33
1
(m, 5H), 4.57 (s, 2H), 4.07–4.13 (m, 1H), 3.57–3.63
(m, 3H), 2.99–3.03 (m, 1H), 2.77 (t, 1H, J = 4.5 Hz),
2.62 (dd, 1H, J = 3.0, 5.2 Hz), 1.41 (s, 3H), 1.40 (s,
3H); 13C NMR (75 MHz, CDCl3, proton decoupled):
d 137.92, 128.37, 127.66, 110.09, 78.09, 73.61, 70.52,
51.73, 44.93, 26.95, 26.69; FABMS (M++1): 283;
HRMS calcd for C15H20O4Na+: 287.1259, found:
287.1266.

J. S. Reddy et al. / Tetrahedron: Asymmetry 16 (2005) 3154–3159
3157
4.5. (2R,3R,4R)-1-O-Benzyl-2,3-O-isopropylidene-
5-(4-methoxyphenyl) pentane-1,2,3,4-tetrol 10
2H, J = 8.7 Hz), 6.81 (d, 2H, J = 8.7 Hz), 4.5 (d, 1H,
J = 11.7 Hz), 4.47 (d, 1H, J = 11.7 Hz), 4.19–4.24 (m,
1H), 3.83 (dd, 1H, J = 2.1, 8.0 Hz), 3.79 (s, 3H), 3.58
(dd, 1H, J = 4.3, 9.5 Hz), 3.42 (dd, 1H, J = 5.8,
9.5 Hz), 3.24 (dt, 1H, J = 2.1, 7.3, 14.6Hz), 2.99 (dd,
2H, J = 5.1, 7.3 Hz), 1.49 (s, 3H), 1.377 (s, 3H); FABMS
(M+): 397; HRMS calcd for C22H27O4N3Na+: 420.1899,
found: 420.1919.
To a stirred solution of 9 (550 mg, 2.08 mmol) in dry
THF (10 mL), CuI (10 mg) was added (p-methoxyphen-
yl)magnesium bromide {freshly prepared with Mg
(252 mg, 10.4 mmol), p-bromo anisole (0.78 mL,
6.24 mmol) and I2 (5 mg) in dry THF (5 mL)} dropwise
at 0 ꢁC under nitrogen atmosphere. After stirring over-
night at room temperature, the reaction mixture was
quenched with saturated aq NH4Cl at 0 ꢁC, THF was
removed under reduced pressure and the residue
extracted with ethyl acetate (3 · 50 mL). The combined
organic extracts were washed with brine (30 mL), dried
over anhydrous Na2SO4, concentrated under reduced
pressure and purified by column chromatography (ethyl
4.7. (2R,3R,4S)-1-O-Benzyl-4-(tert-butoxycarbonyl)-
amino-2,3-O-isopropylidene-5-(4-methoxyphenyl)
pentane-1,2,3-triol 14
To a suspension of LiAlH4 (94 mg, 2.46mmol) in dry
THF (4 mL) was added compound 12 (490 mg,
1.23 mmol) in dry THF (6mL) dropwise at 0 ꢁC under
a nitrogen atmosphere. After overnight stirring at
room temperature, the reaction mixture was quenched
with water (0.5 mL), 15% aq NaOH (0.5 mL) and
water (1.5 mL) successively at 0 ꢁC. After 10 min of
stirring, (Boc)2O (0.85 mL, 3.70 mmol) was added
and the reaction continued for 6h at room tempera-
ture. The reaction mixture was then extracted with
ethyl acetate (80 mL). The organic extract was washed
with water (30 mL), brine (20 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure,
and purified by column chromatography (ethyl ace-
acetate/hexane) (1:9) to afford 10 (670 mg, 86%) as a
25
pale brown oil. ½aŠ ¼ þ13:2 (c 0.68, CHCl3); IR mmax
D
(film, cmꢀ1): 818, 1035, 1084, 1172, 1245, 1297, 1372,
1454, 1511, 1613, 2358, 2923, 2986, 3448; 1H NMR
(300 MHz, CDCl3): d 7.22–7.33 (m, 5H), 7.12 (d, 2H,
J = 8.7 Hz), 6.78 (d, 2H, J = 8.7 Hz), 4.55 (s, 2H),
3.99–4.13 (m, 1H), 3.76(s, 3H), 3.70–3.79 (m, 1H),
3.51–3.65 (m, 3H), 2.92 (dd, 1H, J = 3.0, 13.6Hz), 2.6
(dd, 1H, J = 7.5, 13.6Hz), 2.52 (br s, OH), 1.40 (s,
3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3, proton
decoupled): d 158.21, 137.46, 130.46, 129.80, 128.34,
127.73, 113.81, 109.08, 80.87, 78.28, 73.50, 73.16,
70.79, 55.13, 38.88, 26.96, 26.86; FABMS (M+): 372;
HRMS calcd for C22H28O5Na+: 395.1834, found:
395.1828.
tate/hexane) (1:15) to give 14 (450 mg, 81% based on
25
recovery of SM 12) as a pale yellow oil. ½aŠ ¼ ꢀ4:3
D
(c 0.33, CHCl3); IR mmax (film, cmꢀ1): 818, 857, 1039,
1086, 1169, 1247, 1368, 1511, 1584, 1611, 1712, 2930,
1
2981, 3448; H NMR (300 MHz, CDCl3): d 7.08–7.25
4.6. (2R,3R,4S)-4-Azido-1-O-benzyl-2,3-O-isopropyl-
idene-5-(4-methoxyphenyl) pentane-1,2,3-triol 12
(m, 7H), 6.76 (d, 2H, J = 9.0 Hz), 4.79 (d, 1H,
J = 9.8 Hz), 4.45 (s, 2H), 3.85 (m, 3H), 3.74 (s, 3H),
3.46(d, 2H), 2.7–2.88 (m, 2H), 1.42 (s, 3H), 1.39 (s,
9H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3, proton
decoupled): d 158.21, 155.63, 138.12, 130.26, 130.03,
128.27, 127.48, 113.83, 108.98, 79.36, 76.33, 73.32,
69.69, 55.18, 50.85, 38.90, 28.33, 27.01, 26.80; FABMS
(M++1): 472; HRMS calcd for C27H37O6N+: 472.2699,
found: 472.2720.
To a stirred solution of 10 (620 mg, 1.66 mmol) in dry
CH2Cl2 (10 mL) was added Et3N (0.7 mL, 4.99 mmol)
at 0 ꢁC under a nitrogen atmosphere. After 5 min of stir-
ring, methanesulfonylchloride (0.17 mL, 2.16mmol)
was added dropwise to the reaction mixture and allowed
to stir at room temperature for 1 h, the reaction mixture
was extracted with CHCl3 (100 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 11 as a yellow oil, which was
carried to the next step without any purification.
4.8. (2R,3R,4S)-4-(tert-Butoxycarbonyl)amino-2,3-O-
isopropylidene-5-(4-methoxyphenyl) pentane-1,2,3-
triol 15
To a solution of lithium (14 mg, 2.01 mmol) in liquid
NH3 (50 mL) was added a solution of benzyl ether 14
(190 mg, 0.40 mmol) in dry THF (5 mL) at ꢀ78 ꢁC.
After stirring for 30 min at ꢀ78 ꢁC, the reaction mixture
was slowly warmed to room temperature for 2 h to
evaporate the ammonia. The reaction mixture was neu-
tralized with aq NH4Cl, and concentrated under
reduced pressure. The residue was extracted with ethyl
acetate (2 · 30 mL). The combined organic extracts were
washed with brine (20 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure and puri-
fied by column chromatography (ethyl acetate/hexane)
To a stirred solution of above mesylate derivative 11 in
dry DMSO (10 mL) were added [18-crown-6] (438 mg,
1.66 mmol) and NaN3 (539 mg, 8.3 mmol) under nitro-
gen atmosphere at room temperature, the reaction was
slowly heated to 65 ꢁC, after being stirred for 24 h, the
reaction mixture was allowed to room temperature,
poured in to ice cold water (20 mL), and extracted with
ethyl acetate (3 · 50 mL). The combined organic
extracts were washed with brine (20 mL), dried over
anhydrous Na2SO4, concentrated under reduced pres-
sure and purified by column chromatography (ethyl ace-
tate/hexane) (1:49) to afford 12 (550 mg, 83% from 10)
(1:3) to give 15 (128 mg, 83%) as a sticky syrup.
25
25
as a pale yellow oil. ½aŠ ¼ þ16:9 (c 0.69, CHCl3); IR
½aŠ ¼ ꢀ11:5 (c 0.3, CHCl3); IR mmax (film, cmꢀ1): 816,
D
D
mmax (film, cmꢀ1): 812, 852, 1036, 1092, 1172, 1246,
1299, 1373, 1454, 1511, 1612, 2109, 2924, 2989; 1H
NMR (400 MHz, CDCl3): d 7.25–7.3 (m, 5H), 7.11 (d,
898, 1039, 1168, 1246, 1369, 1459, 1511, 1612, 1705,
1
2854, 2925, 3447; H NMR (300 MHz, CDCl3): d 7.1
(d, 2H, J = 8.8 Hz), 6.77 (d, 2H, J = 8.8 Hz), 4.71 (d,

3158
J. S. Reddy et al. / Tetrahedron: Asymmetry 16 (2005) 3154–3159
1H, J = 9.6Hz), 3.78–3.94 (m, 2H), 3.79 (s, 3H), 3.58–
3.66 (br s, 2H), 2.79 (d, 2H, J = 8.0 Hz), 2.1–2.2 (br s,
1H), 1.41 (s, 3H), 1.37 (s, 9H), 1.36(s, 3H); 13C NMR
(75 MHz, CDCl3, proton decoupled): d 158.21, 155.94,
130.11, 129.71, 113.84, 108.77, 79.59, 77.94, 77.39,
61.80, 65.14, 50.83, 38.79, 28.24, 26.97, 26.89; FABMS
(M++1): 382; HRMS calcd for C20H31O6Na+:
404.2049, found: 404.2053.
Acknowledgements
J.S.R. and A.R.K. thank UGC and CSIR, New Delhi,
for the research fellowships. We also thank Dr. J. S.
Yadav and Dr. A. C. Kunwar, for their support and
encouragement.
References
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column chromatography (ethyl acetate/hexane) (1:1) to
afford 2b (58 mg, 69% from 15) as a white solid. Mp:
125–126 ꢁC [(lit.9e mp 127–129 ꢁC for (ꢀ)-isomer)];
25
½aŠ ¼ þ7:9 (c 0.45, MeOH) {lit.9e for (ꢀ) isomer
D
25
is ½aŠ ¼ ꢀ8:2 (c 5.97, MeOH)}; IR9c (KBr, cmꢀ1):
D
816, 966, 1033, 1101, 1178, 1245, 1302, 1357, 1423,
1511, 1611, 1673, 2854, 2925, 3030, 3050, 3600–3150;
1H NMR9e (400 MHz, CDCl3): d 7.30–7.52 (5H, m),
7.01–7.24 (2H, unresolved), 6.79 (2H, br s), 5.16 (2H,
br s), 4.23 (1H, br s), 4.03 (1H, br s), 3.95 (1H, br s),
3.78 (3H, s), 3.60 (1H, dd, J = 11.4, 5.7 Hz), 2.99–3.51
(2H, unresolved), 2.89 (1H, dd, J = 13.6, 9.3 Hz),
1.79–2.02 (2H, unresolved); EIMS9e (M+ꢀ121): 236;
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380.1471.
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