Convenient route to enantiopure substituted butyrolactones: application in a formal synthesis of both enantiomers of enterolactone

Article abstract of DOI:10.1016/j.tet.2007.08.103

A simple route for the synthesis of enantiopure substituted γ-butyrolactones involving a highly diastereoselective alkylation of an enantiomerically pure substituted latent succinate ester is described. This route provides entry into both enantiomers of 3,4-disubstituted butyrolactones from a single enantiomer, 2,3-di-O-cyclohexylidine-R-(+)-glyceraldehyde. The synthetic potential of this methodology has been demonstrated by a formal synthesis of both enantiomers of enterolactone.

Full text of DOI:10.1016/j.tet.2007.08.103

Tetrahedron 63 (2007) 11710–11715
Convenient route to enantiopure substituted butyrolactones:
application in a formal synthesis of both enantiomers
of enterolactone
*
Manju Ghosh
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur 700032, Kolkata, India
Received 8 May 2007; revised 13 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—A simple route for the synthesis of enantiopure substituted g-butyrolactones involving a highly diastereoselective alkylation of an
enantiomerically pure substituted latent succinate ester is described. This route provides entry into both enantiomers of 3,4-disubstituted
butyrolactones from a single enantiomer, 2,3-di-O-cyclohexylidine-R-(+)-glyceraldehyde. The synthetic potential of this methodology has
been demonstrated by a formal synthesis of both enantiomers of enterolactone.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
with them, considerable attention has been focussed7 on
the development of efficient methodologies for the stereo-
controlled construction of substituted butyrolactones.
Herein, we report a stereocontrolled route that provides ac-
cess to disubstituted as well as trisubstituted butyrolactones
in enantiomerically pure form. The strategy is illustrated
with a formal synthesis of both enantiomers of entero-
lactone.8
Natural products containing substituted butyrolactone as the
core structure are of considerable interest due to their impor-
tant biological profile.1 The lignan2 lactones such as entero-
lactone 1 and arctigenin 2 are classic examples of bioactive
disubstituted butyrolactones. Recent investigations by Lin
and co-workers3 have shown that enterolactone 1 inhibits
breast and colon cancer and suppresses the growth of pros-
tate cancer cells. Arctigenin 2 and its analogs have also
been shown4 to be potent inhibitors of HIV-type 1 integrase.
Roccellaric acid 35 and nephrosteranic acid 45c,6 are repre-
sentative examples of bioactive trisubstituted butyrolac-
tones. Due to interesting biological activities associated
2. Results and discussion
We envisaged that the enantiopure and differentially pro-
tected succinate 6 (Scheme 1) would be an ideal synthon
for sequential introduction of two different substituents
based on enolate alkylation prior to its transformation to bu-
tyrolactone. Diastereoselection during alkylation of the ester
6 might be expected to arise through p-face discrimination
of the metal enolate, which would possibly be chelated
with the dioxolane ring. The ester 6 was prepared by
catalytic hydrogenation of the unsaturated ester 5, which
O
O
OMe
OH
OH
O
O
OMe
OH
OH
1
2
R2
O
R2
O
R1
O
R1
O
O
O
i
R3
Me
COOH
Me
COOH
95%
O
O
COOEt
COOEt
C13H27
C11H23
5
6, R3 = H
ii 67%
7, R3 = 3-OMeC6H4CH2
3
4
R1, R2 = -(CH2)5-
Keywords: Asymmetric synthesis; Diastereoselection; Lactones; Lignans.
* Tel.: +91 33 2473 4971; fax: +91 33 2473 2805; e-mail:
basundhara9763@yahoo.com
Scheme 1. (i) H2, 10% Pd/C, EtOH; (ii) LDA, THF/HMPA, 3-
MeOC6H4CH2Br, ꢀ78 ꢁC to rt.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.103

M. Ghosh / Tetrahedron 63 (2007) 11710–11715
11711
5
O
OEt
ref. 9
H
65% (2 steps)
O
E
R2
O
R1
O
O
R2
R2
O
R1
O
R1
H
H
+
Figure 1.
CO2Et
CO2Et
70%
R2
9
in turn was obtained from 2,3-di-O-cyclohexylidene-R-(+)-
glyceraldehyde following the literature procedure.9 Alkyl-
ation of the enolate generated (LDA) from the ester 6 with
3-methoxy benzyl bromide proceeded smoothly but non-
stereoselectively to give a 1:1 mixture of the alkylated
products 7 in 85% yield. The distant chiral center thus
failed to induce any diastereoselectivity during enolate
alkylation.
8
i
78%
R2
i
R1
O
R1
O
O
H
O
H
R3
Ar
Ar
R3
H
H
We next considered the possibility of inducing diastereo-
selectivity through alkylation of ester having a b substituent
such as the readily available latent succinate 8 or 9. Houk
and co-workers10 proposed a model to predict the stereo-
chemical outcome during addition of an electrophile to
a-chiral C–C double bonds. According to this model, elec-
trophiles add through an orientation (Fig. 1) in which the
small substituent (H in the present case) of the chiral center
lies onto the side of the double bond minimizing the 1,3-
allylic strain between the small substituent and the substitu-
ent (OEt or the enolate O) on the double bond giving rise to
the anti-Felkin product. Fleming and co-workers11 have
extensively investigated the addition of various electrophiles
to a-chiral C–C double bond including alkylation of a-chiral
enolates, which in accord with Houk’s model yielded the
anti-Felkin product predominantly irrespective of the E/Z
geometry of the olefin. Based on the above findings, we
predicted that alkylation of the enolate of the ester 8 or 912
would take place preferentially from the face of the smallest
group (H atom in this case) present in the chiral center to
produce predominantly 10 and 11, respectively. Once the
diastereomerically pure compound is obtained, the vinyl
group can either be removed through oxidation to a carboxy-
lic acid followed by decarboxylation or modified to provide
a desired substituent in the lactone to be prepared. With this
background, the esters 8 and 9 were prepared as a chromato-
graphically separable mixture (1:1) in 65% yield in two steps
from the ester 5 according to the procedure9 developed
earlier in this laboratory. Alkylation of lithium enolate gen-
erated from the ester 8 with 3-methoxy benzyl bromide
afforded the ester 10 along with the other diastereoisomer
in a 5:1 ratio. The pure ester 10 was obtained in 70% yield
after column chromatography. The gross structure of the
product 10 was easily determined from spectroscopic data.
The stereochemical assignment to 10 is based on its transfor-
mation to the trans-disubstituted lactone 18 (Scheme 2).
Similarly, alkylation of the enolate of the ester 9 gave the
alkylated product 11 along with the other diastereomers
in a ratio of approximately 5:1. The pure diastereoisomer
11 was obtained in 78% yield after chromatographic
separation.
10, R3 = CO2Et
12, R3 = CH2OH
iii 84%
11, R3 = CO2Et
ii
95%
ii
87%
13, R3 = CH2OH
iii 74%
HO OH
HO OH
H
H
HO
Ar
HO
Ar
H
H
14
15
iv 87%
R2
H
O
R1
H
H
R
vi
51%
O
O
Ar
Ar
H
16, R1, R2 = H, OH
18, R = CO2H
19, R = H
v
vii
75%
17, R1, R2 = O
84%
For structures 8 - 13, R1, R2 = -(CH2)5
For structures 10 - 19, Ar = 3-MeOC6H4
-
Scheme 2. (i) LDA, THF/HMPA, 3-MeOC6H4CH2Br, ꢀ78 ꢁC to rt; (ii)
LiAlH4, THF, rt; (iii) HOAc/H2O, rt; (iv) NaIO4, CH3CN/H2O; (v) Jones
oxidation; (vi) RuCl3$xH2O, NaIO4, CH3CN/CCl4/H2O and then Jones
reagent; (vii) toluene, reflux.
as delineated in Scheme 2. The ester 10 was reduced with
lithium aluminum hydride in diethyl ether to produce the al-
cohol 12 in 95% yield. Acid catalyzed deketalization of the
spiroketal in 12 afforded the triol 14 in 84% yield. Periodate
cleavage of the vicinal diol in 14 afforded a 1:1 mixture of
lactol epimers 16 in 87% yield. The lactol 16 without further
purification was directly oxidized with Jones reagent to
afford the disubstituted lactone 17, [a]2D5 +15.2 (c 1.8,
CHCl3) in 75% yield. Following a similar sequence the ester
11 was converted to the enantiomer of the lactone 17, [a]D25
ꢀ15.5 (c 2.4, CHCl3), through oxidation of the ent-lactol 16,
which in turn was obtained from periodate cleavage of the
diastereoisomeric triol 15. Thus, both the enantiomers of
the disubstituted lactone 17 can be obtained from 2,3-di-
O-cyclohexylidine R-(+)-glyceraldehyde.
After successfully attaining reasonably good level of stereo-
control during alkylation, we next focused on the transfor-
mation of the ester 10 to the trans-disubstituted lactone 17

11712
M. Ghosh / Tetrahedron 63 (2007) 11710–11715
We next planned to introduce the second benzyl substituent
through alkylation of the enolate of the lactone 17 toward the
synthesis of enterolactone 1. Unfortunately, attempted alkyl-
ation of the enolate of the lactone 17 produced an insepara-
ble mixture of several products. We thus decided to convert
the vinyl group to the corresponding acid. The lactone 17
was subjected to RuO4 oxidation producing, instead of the
expected lactonic acid 18, an intractable mixture of prod-
ucts. The lactonic acid 18 could finally be obtained in 51%
yield from the lactol 16 through a sequence of RuO4 and
Jones oxidation. The coupling constant (J¼9.3 Hz)13 of
the hydrogen at C-3, which appeared as a doublet at
d 3.36, indicated that the benzyl group and the carboxylic
acid group are trans to each other. This confirmed that the
vinyl group and the benzyl group in the ester 10 are trans to
each other. Refluxing a toluene solution of the carboxylic
acid 18 for 16 h effected smooth decarboxylation giving
4. Experimental
4.1. General
All reactions were carried out under a blanket of nitrogen. A
usual work up of the reaction mixture consists of extraction
with diethyl ether, washing with brine, drying over anhy-
drous Na2SO4, and removal of the solvent in vacuo. Column
chromatography was carried out with silica gel (60–120
mesh). Petroleum ether refers to the fraction having bp
60–80 ꢁC. Peak positions in 1H and 13C NMR spectra are in-
dicated in parts per million downfield from internal TMS in
d units. NMR spectra were taken in CDCl3 at 300 MHz for
1H and 75 MHz for 13C. 13C peaks’ assignment is based
on DEPT experiment. IR spectra for liquids were recorded
as neat.
1
rise to b-arylmethyl g-butyrolactone 19.14 The H and 13C
4.1.1. Ethyl 3-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]propa-
noate 6. A solution of the unsaturated ester 5 (800 mg,
3.33 mmol) in ethanol (8 mL) was stirred magnetically in
the presence of 10% Pd/C as catalyst in an atmosphere of hy-
drogen for 5 h. The catalyst was filtered off and the solvent
was removed in vacuo to afford the ester 6 (770 mg, 95%) as
a colorless liquid; [a]2D5 ꢀ5.2 (c 1.5, CHCl3); IR: nmax
NMR spectra of the lactone 19 prepared in this way are com-
parable to those reported in the literature.8j In general, b-aryl-
methyl butyrolactones are intermediates to vast number of
lignan lactones. For example, the lactone 19 obtained in this
way, having [a]D23 +6.5 (c, CHCl3) [lit.8j [a]2D5 +6.15 (c 1.86,
CHCl3)] has been converted to (ꢀ)-enterolactone 1 in two
steps. Similarly, the ent-lactone 17 obtained from the ester 9
has been converted to the enantiomer of the lactone 19,
[a]2D5 ꢀ5.9 (c 0.8, CHCl3) [lit.8e [a]2D5 ꢀ6.76 (c 1.04,
CHCl3)]. The ent-lactone 19 has been converted to (+)-entero-
lactone.8e Thus, a formal synthesis of the both enantiomers of
enterolactone 1 from a single enantiomer, 2,3-di-O-cyclo-
hexylidine R-(+)-glyceraldehyde has been achieved.
1738 cmꢀ1; H NMR: d 1.24 (3H, t, J¼7.2 Hz), 1.37 (3H,
1
br s), 1.57 (10H, m), 1.79–1.89 (2H, m), 2.32–2.48 (2H,
m), 3.52 (1H, t, J¼7.5 Hz), 3.99–4.15 (3H, m); 13C NMR:
d 14.3 (CH3), 23.9 (CH2), 24.1 (CH2), 29.0 (CH2), 30.6
(CH2), 35.2 (CH2), 36.6 (CH2), 60.5 (CH2), 68.8 (CH2),
74.6 (CH), 109.5 (C), 173.2 (CO); HRMS (ESI): calcd for
C13H22O4Na (M+Na)+, 265.1416; found, 265.1417.
The synthesis of trisubstituted butyrolactone can be illus-
trated as delineated in Scheme 3. The ester 11 was hydro-
lyzed with aqueous ethanolic potassium hydroxide under
reflux. The resulting alkaline solution was heated at 80 ꢁC
with 80% aqueous acetic acid to afford after chromatograph-
ic purification the trisubstituted lactone 20 in 75% yield. The
vinyl group in the lactone 20 is a latent carboxylic acid while
the hydroxymethyl group at C-5 can be elaborated to the de-
sired alkyl chain. Thus, the route depicting the synthesis of
the trisubstituted lactone 20 from 2,3-di-O-cyclohexyl-
idine-R-(+)-glyceraldehyde will be of great significance
for the synthesis of lactones such as 3 and 4 with carboxylic
acid as one of the substituents.
4.1.2. Ethyl 3-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-2-(3-
methoxybenzyl)propanoate 7. To a magnetically stirred so-
lution of LDA [prepared from n-BuLi (1 mL, 1.64 mmol,
1.6 M in hexane)] and diisopropyl amine (0.29 mL,
2 mmol) in THF (4 mL)], cooled to ꢀ78 ꢁC, was added a so-
lution of the ester 6 (200 mg, 0.82 mmol) in THF (1 mL).
After addition is complete, the temperature of the bath was
slowly raised to ꢀ30 ꢁC. The reaction mixture was again
cooled to ꢀ78 ꢁC. HMPA (0.25 mL) followed by 3-methoxy
benzyl bromide (329 mg, 1.64 mmol) was added to it. Stir-
ring was continued for 4 h at ꢀ78 ꢁC. The reaction mixture
was then quenched by addition of saturated aqueous ammo-
nium chloride. Usual work up of the reaction mixture with
diethyl ether followed by column chromatography [petro-
leum ether/ethyl acetate (9:1)] afforded an inseparable
diastereoisomeric mixture (1:1) of the ester 7 (200 mg,
67%); [a]2D5 ꢀ4.4 (c 2.8, CHCl3); IR: nmax 1732, 1601,
OH
H
i
75%
O
11
1585 cmꢀ1 1H NMR (of the mixture): d 1.14 (3H, t,
;
Ar
O
J¼7.2 Hz), 1.35 (2H, br s), 1.52–1.65 (8H, m), 1.9–2.1
(1H, m), 2.71–2.79 (2H, m), 2.91 (2H, m), 3.43 (1H, t,
J¼6.9 Hz), 3.75 (3H, s), 3.94–4.07 (4H, m), 6.73 (3H, m),
7.16 (1H, t, J¼7.8 Hz); 13C NMR: d 14.15 (CH3), 14.18
(CH3), 23.8 (CH2), 23.9 (CH2), 24.01 (CH2), 24.05 (CH2),
25.2 (CH2), 35.1 (CH2), 35.2 (CH2), 35.6 (CH2), 35.8
(CH2), 36.60 (CH2), 36.63 (CH2), 44.1 (CH), 44.8 (CH),
55.1 (CH3), 60.4 (CH2), 69.04 (CH2), 69.08 (CH2), 73.7
(CH), 73.8 (CH), 109.4 (C), 109.6 (C), 111.84 (CH),
111.86 (CH), 114.6 (CH), 121.37 (CH), 121.39 (CH),
129.34 (CH), 129.37 (CH), 140.42 (C), 140.5 (C), 159.6
(C), 175.06 (CO), 175.2 (CO); HRMS (ESI): calcd for
C21H30O5Na (M+Na)+, 385.1991; found, 385.1998.
20
Scheme 3. (i) KOH, EtOH/H2O, reflux then HOAc/H2O, reflux.
3. Conclusion
We have developed a simple route for the construction of
both enantiomers of 3,4-disubstituted butyrolactones. This
route has been extended to the synthesis of a trisubstituted
butyrolactone. The potential of the strategy has been
illustrated by a formal enantiodivergent synthesis of both
enantiomers of enterolactone 1 from R-(+)-2,3-di-O-cyclo-
hexylidine glyceraldehyde.

M. Ghosh / Tetrahedron 63 (2007) 11710–11715
11713
4.1.3. (2S,3S)-Ethyl 2-(3-methoxybenzyl)-3-[(2S)-1,4-
dioxaspiro[4.5]dec-2-yl]pent-4-enoate 10. Following the
above procedure, the enolate of the ester 8 (400 mg,
1.5 mmol) generated with LDA [prepared from n-BuLi
(1.87 mL, 3 mmol, 1.6 M in hexane) and diisopropyl amine
(0.53 mL, 3.8 mmol)] was alkylated with 3-methoxy benzyl
bromide (600 mg, 3 mmol) to afford after column chromato-
graphy (petroleum ether/ether (9:1)] the ester 10 (410 mg,
70%) as colorless oil; [a]2D5 +14.9 (c 1.2, CHCl3); 1H
NMR: d 1.04 (3H, t, J¼7 Hz), 1.50–1.65 (10H, m), 2.47
(1H, m), 2.66 (1H, dd, J¼13, 11 Hz), 2.83–2.98 (3H, m),
3.63 (1H, t, J¼7.6 Hz), 3.77 (3H, s), 3.93–4.08 (3H, m),
5.16 (1H, dd, J¼15, 1.8 Hz), 5.31 (1H, dd, J¼10, 1.8 Hz),
5.73–5.86 (1H, m), 6.74–6.88 (3H, m), 7.15 (1H, t,
J¼7.8 Hz); 13C NMR: d 13.0 (CH3), 23.8 (CH2), 24.1
(CH2), 25.3 (CH2), 34.7 (CH2), 35.8 (CH2), 37.4 (CH2),
49.2 (CH), 49.5 (CH), 55.2 (CH3), 60.3 (CH2), 66.9 (CH2),
75.6 (CH), 108.5 (C), 111.8 (CH), 114.6 (CH), 120.2
(CH2), 121.4 (CH), 129.3 (CH), 134.6 (CH), 139.9 (C),
158.5 (C), 173.7 (CO). HRMS (ESI): calcd for
C23H32O5Na (M+Na)+, 411.2148; found, 411.2147.
(CH3), 61.4 (CH2), 67.4 (CH2), 74.5 (CH), 109.7 (C),
111.0 (CH), 114.9 (CH), 118.9 (CH2), 121.6 (CH), 129.5
(CH), 136.1 (CH), 142.1 (C), 159.5 (C). HRMS (ESI): calcd
for C21H30O4Na (M+Na)+, 369.2042; found, 369.2046.
4.1.6. (2R,3R)-2-(3-Methoxybenzyl)-3-[(2S)-1,4-dioxa-
spiro[4.5]dec-2-yl]pent-4-en-1-ol 13. Following the above
procedure, the ester 11 (270 mg, 0.7 mmol) was reduced
with lithium aluminum hydride (29 mg, 0.76 mmol) to af-
ford the hydroxy compound 13 (210 mg, 87%); [a]2D5 +4.2
1
(c 2, CHCl3); H NMR: d 1.25–1.68 (10H, m), 2.0 (1H, br
s), 2.19 (1H, s), 2.32–2.47 (2H, m), 2.83 (1H, m), 3.46
(1H, dd, J¼5.1, 11.7 Hz), 3.58 (1H, t, J¼8.1 Hz), 3.71
(1H, dd, J¼3, 11.6 Hz), 3.79 (3H, s), 3.96 (1H, dd,
J¼5.7, 8.2 Hz), 4.09 (1H, m), 5.15–5.20 (2H, m), 5.55–
5.67 (1H, m), 6.72–6.79 (3H, m), 7.18 (1H, t, J¼8 Hz);
13C NMR: d 24.1 (CH2), 24.2 (CH2), 25.2 (CH2), 34.6
(CH2), 35.6 (CH2), 36.6 (CH2), 45.6 (CH), 50.4 (CH),
55.2 (CH), 62.2 (CH2), 69.2 (CH2), 76.1 (CH), 110.3
(C), 111.4 (CH), 115.0 (CH), 118.9 (CH2), 121.8 (CH),
129.4 (CH), 136.3 (CH), 142.8 (C), 159.7 (C). HRMS
(ESI): calcd for C21H30O4Na (M+Na)+ 369.2042; found,
369.2040.
4.1.4. (2R,3R)-Ethyl 2-(3-methoxybenzyl)-3-[(2S)-1,4-
dioxaspiro[4.5]dec-2-yl]pent-4-enoate 11. The enolate of
the ester 9 (400 mg, 1.5 mmol) generated on treatment
with LDA [prepared from n-BuLi (1.86 mL, 3 mmol,
1.6 M in hexane) and diisopropyl amine (0.53 mL,
3.75 mmol)] was alkylated with 3-methoxy benzyl bromide
(600 mg, 3 mmol) to afford after chromatography [petro-
leum ether/ether (9:1)] the ester 11 (405 mg, 78%) as color-
less oil; [a]2D5 +7.9 (c 1.5, CHCl3); 1H NMR: d 1.01 (3H, t,
J¼7.2 Hz), 1.32 (3H, br s), 1.51 (7H, m), 2.56–2.88 (4H, m),
3.58 (1H, t, J¼7.2 Hz), 3.70 (3H, s), 3.88–4.03 (4H,
m), 5.07–5.13 (2H, m), 5.47–5.60 (1H, m), 6.64–6.72 (3H,
m), 7.08 (1H, t, J¼7.8 Hz); 13C NMR: d 14.5 (CH3), 24.3
(CH2), 24.4 (CH2), 25.6 (CH2), 35.0 (CH2), 35.6 (CH2),
36.8 (CH2), 49.8 (CH), 51.5 (CH), 55.5 (CH3), 60.6 (CH2),
68.5 (CH2), 76.2 (CH), 110.5 (C), 112.2 (CH), 114.9 (CH),
119.8 (CH2), 121.8 (CH), 129.5 (CH), 134.9 (CH), 141.9
(C), 159.9 (C), 174.5 (CO). HRMS (ESI): calcd for
C23H32O5Na (M+Na)+, 411.2148; found, 411.2144.
4.1.7. (2S,3S,4S)-5-(3-Methoxyphenyl)-3-vinylpentane-
1,2,4-triol 14. A solution of the hydroxy compound 12
(200 mg, 0.58 mmol) in aqueous acetic acid (5 mL, 80%)
was stirred at rt for 18 h. The reaction mixture was diluted
with ethyl acetate (10 mL). The entire mass was transferred
into a separatory funnel and washed successively with 10%
aqueous NaOH (3ꢂ3 mL) and brine (2ꢂ5 mL), dried, and
concentrated in vacuum. The residual mass was chromato-
graphed [petroleum ether/ethyl acetate (2:3)] to afford the
triol 14 (130 mg, 84%); [a]2D5 +7.3 (c 1.0, CHCl3); 1H
NMR: d 1.94–2.00 (1H, br s), 2.14–2.22 (2H, m), 2.45
(1H, dd, J¼10, 14 Hz), 2.77 (1H, dd, J¼4.5, 14 Hz), 3.42–
3.73 (6H, m), 3.77 (3H, s), 3.98 (1H, br s), 5.06 (1H, dd,
J¼1.8, 17.4 Hz), 5.18 (1H, dd, J¼1.8, 10.2 Hz), 5.93 (1H,
m), 6.70–6.75 (3H, m), 7.18 (1H, t, J¼7.5 Hz); 13C NMR:
d 35.5 (CH2), 44.7 (CH), 48.7 (CH), 61.5 (CH2), 65.8
(CH2), 70.8 (CH), 111.3 (CH), 115.10 (CH), 115.13 (CH),
118.6 (CH2), 121.6 (CH), 129.5 (CH), 136.7 (CH), 142.3
(C), 159.7 (C). HRMS (ESI): calcd for C15H22O4Na
(M+Na)+, 289.1416; found, 289.1418.
4.1.5. (2S,3S)-2-(3-Methoxybenzyl)-3-[(2S)-1,4-dioxa-
spiro[4.5]dec-2-yl]pent-4-en-1-ol 12. A solution of the ester
10 (225 mg, 0.6 mmol) in diethyl ether (5 mL) was added
to a magnetically stirred suspension of lithium aluminum
hydride (24 mg, 0.64 mmol) in diethyl ether (5 mL) at rt.
The reaction mixture was stirred at rt for 4 h. On cooling to
0 ꢁC, the reaction mixture was quenched by sequential addi-
tion of water (25 ml), aqueous sodium hydroxide (75 ml,
15%), and water (75 ml). Stirring was continued for addi-
tional 15 min. The precipitated white solid was filtered
out. The filtrate after drying was concentrated and the resid-
ual mass was chromatographed [petroleum ether/ether (4:1)]
to afford the hydroxy compound 12 (190 mg, 95%); [a]D25
4.1.8. (2S,3R,4R)-5-(3-Methoxyphenyl)-3-vinylpentane-
1,2,4-triol 15. Following the above procedure deketalization
of the dioxolane derivative 13 (210 mg, 0.6 mmol) was
achieved to afford the triol 15 (120 mg, 74%); [a]2D5 +9.8
1
(c 2.2, CHCl3); H NMR: d 2.25 (2H, m), 2.47 (1H, br t),
2.79 (1H, m), 3.37–3.45 (2H, m), 3.51–3.70 (6H, m), 3.76
(3H, s), 5.12 (2H, m), 5.52–5.61 (1H, m), 6.70–6.77 (3H,
m), 7.16 (1H, t, J¼7.5 Hz); 13C NMR: d 33.9 (CH2), 43.2
(CH2), 48.3 (CH), 55.3 (CH3), 62.5 (CH2), 71.7 (CH),
111.3 (CH), 115.1 (CH), 119.2 (CH2), 121.6 (CH), 129.5
(CH), 135.8 (CH), 142.7 (C), 159.7 (C). HRMS (ESI): calcd
for C15H22O4Na (M+Na)+, 289.1416; found, 289.1417.
1
+15.9 (c 1.0, CHCl3); H NMR: d 1.20–1.60 (10H, m),
1.97 (1H, br s), 2.18 (1H, m), 2.31 (1H, m), 2.64 (1H, dd,
J¼9, 13.8 Hz), 2.75 (1H, br s), 2.83 (1H, dd, J¼5.7,
13.8 Hz), 3.48 (1H, m), 3.65 (1H, t, J¼7.8 Hz), 3.77 (3H,
s), 3.98 (1H, t, J¼7.8 Hz), 4.37–4.41 (1H, m), 5.05–5.25
(2H, m), 5.91–6.00 (1H, m), 6.72–6.79 (3H, m), 7.18 (1H,
t, J¼7.8 Hz); 13C NMR: d 24.1 (CH2), 25.2 (CH2), 35.1
(CH2), 35.4 (CH2), 35.9 (CH2), 46.3 (CH), 46.6 (CH), 55.2
4.1.9. (3S,4S)-4-(3-Methoxybenzyl)-tetrahydro-3-vinyl-
furan-2-ol 16. To a solution of the triol 14 (110 mg,
0.41 mmol) in aqueous acetonitrile (4 mL, 60%), NaIO4
(175 mg, 0.82 mmol) was added. The resulting suspension
was stirred at rt for 1.5 h. Usual work up of the reaction

11714
M. Ghosh / Tetrahedron 63 (2007) 11710–11715
mixture with diethyl ether afforded the lactol 16 (85 mg,
87%) as a 1:1 diastereoisomeric mixture; 1H NMR:
d 2.23–2.53 (3H, m), 2.84 (1H, dt, J¼4, 10 Hz), 3.51 (1H,
t, J¼8.4 Hz), 3.70 (3H, s), 3.83 (1H, t, J¼7.2 Hz), 4.02
(1H, t, J¼8.4 Hz), 5.02–5.28 (3H, m), 5.66–5.75 (1H, m),
6.60–6.66 (3H, m), 7.10 (1H, t, J¼7.8 Hz); 13C NMR:
d 37.8 (CH2), 38.2 (CH2), 42.8 (CH), 47.1 (CH), 55.5
(CH3), 57.4 (CH3), 72.4 (CH2), 73.1 (CH2), 99.9 (CH),
103.7 (CH), 118.8 (CH), 114.8 (CH), 117.7 (CH2), 118.8
(CH2), 121.4 (CH), 129.8 (CH), 134.2 (CH), 137.1 (CH),
142.0 (C), 142.1 (C), 160.1 (C). HRMS (ESI): calcd for
C14H18O3Na (M+Na)+, 257.1154; found, 257.1140.
toluene (2 mL) was heated under reflux for 16 h. Removal
of toluene in vacuum afforded the lactone 19 (7 mg, 84%);
[a]2D5 +6.03 (c 1.0, CHCl3); 1H NMR: d 2.29 (1H, dd,
J¼6.9, 17.4 Hz), 2.61 (1H, dd, J¼7.8, 17.4 Hz), 2.73–2.90
(3H, m), 3.80 (3H, s), 4.04 (1H, dd, J¼6.6, 9 Hz), 4.34
(1H, t, J¼7.2 Hz), 6.69–6.79 (3H, m), 7.23 (1H, t,
J¼7.8 Hz); 13C NMR: d 34.4 (CH2), 37.2 (CH), 39.1
(CH2), 55.3 (CH3), 72.8 (CH2), 112.0 (CH), 114.8 (CH),
121.1 (CH), 129.9 (CH), 139.9 (C), 160.0 (C), 177.0 (CO).
HRMS (ESI): calcd for C12H14O3Na (M+Na)+, 229.0840;
found, 229.0841.
4.1.13. (R)-5-Hydroxymethyl-(R)-3-(3-methoxybenzyl)-
(R)-4-vinyl-dihydro-furan-2-one 20. The ester 11
(100 mg, 0.25 mmol) was heated under reflux with a solution
made by dissolving KOH (70 mg, 1.25 mmol) in ethanol
(5 mL) and water (0.5 mL) for 4 h. On cooling to rt, an aque-
ous solution of acetic acid (2 mL, 80%) was added and the
resulting acidic solution was refluxed for another 4 h. The
reaction mixture on cooling was neutralized by adding
powdered sodium bicarbonate portionwise till evolution of
carbon dioxide ceased. Usual work up of the reaction mix-
ture with diethyl ether followed by column chromatography
[petroleum ether/ethyl acetate (7:3)] afforded the lactone
20 (50 mg, 75%); [a]2D5 +51.6 (c 1.2, CHCl3); IR: nmax
4.1.10. (3S,4S)-4-(3-Methoxybenzyl)-dihydro-3-vinyl-
furan-2(3H)-one 17. Jones reagent was added to a magneti-
cally stirred ice-cold solution of the lactol 16 (50 mg,
0.2 mmol) in acetone (1 mL) till the color of the reagent per-
sisted. The reaction mixture was extracted with diethyl ether
(3ꢂ4 mL). The combined extract was washed sequentially
with 2% aqueous NaOH (2 mL) and brine (4 mL), dried,
and concentrated. The residual mass was chromatographed
[petroleum ether/ether (5:1)] to afford the lactone 17
(35 mg, 75%); [a]2D5 +6.8 (c 1.8, CHCl3); IR: nmax
1774 cmꢀ1 1H NMR: d 2.58–2.74 (2H, m), 2.87–3.00
;
(2H, m), 3.80 (3H, s), 3.94 (1H, t, J¼9.0 Hz), 4.27 (1H, t,
J¼9 Hz), 5.33 (2H, m), 5.76 (1H, m), 6.74 (3H, m), 7.23
(1H, t, J¼7.8 Hz); 13C NMR: d 37.6 (CH2), 43.4 (CH),
49.8 (CH), 55.3 (CH3), 71.2 (CH2), 111.9 (CH), 114.8
(CH), 120.3 (CH2), 121.1 (CH), 129.9 (CH), 131.8 (CH),
139.3 (C), 160.0 (C), 176.7 (CO). HRMS (ESI): calcd for
C14H16O3Na: (M+Na)+ 255.0997; found, 255.0993.
1
1770 cmꢀ1; H NMR: d 2.27 (1H, br), 2.80 (2H, m), 3.00
(2H, m), 3.50 (1H, dd, J¼4.5, 12.6 Hz), 3.77 (3H, s), 3.84
(1H, br d, J¼12.6 Hz), 4.14 (1H, m), 5.06–5.15 (2H, m),
5.48–5.57 (1H, m), 6.76 (3H, m), 7.17 (1H, t, J¼7.8 Hz);
13C NMR: d 34.4 (CH2), 46.1 (CH), 48.1 (CH), 55.5
(CH3), 61.7 (CH2), 82.8 (CH), 112.6 (CH), 115.6 (CH),
119.9 (CH2), 122.3 (CH), 129.8 (CH), 135.0 (CH), 139.4
(C), 160.0 (C), 177.3 (CO); HRMS (ESI): calcd for
C15H18O4Na (M+Na)+, 285.1103; found, 285.1101.
4.1.11. (3R,4S)-4-(3-Methoxybenzyl)-tetrahydro-2-oxo-
furan-3-carboxylic acid 18. Sodium metaperiodate
(107 mg, 0.5 mmol) was added to a magnetically stirred so-
lution of the lactol 16 (50 mg, 0.2 mmol) in carbon tetrachlo-
ride (0.6 mL), acetonitrile (0.6 mL), and water (1.2 mL). A
catalytic amount of RuCl3$xH2O (2 mg) was added to this
suspension and stirring was continued for 3 h. The reaction
mixture was diluted with diethyl ether (10 mL) and filtered
through a plug of cotton. The filtrate on drying was concen-
trated in vacuum. The residual mass was dissolved in ace-
tone (1 mL) and to it was added Jones reagent drop wise
till the color of the reagent persisted. The reaction mixture
was extracted with diethyl ether (3ꢂ4 mL). The combined
extract was washed with water (3 mL) and then with satu-
rated aqueous sodium bicarbonate (2ꢂ2 mL). The organic
extract was discarded. The combined alkaline extract on
cooling to 0 ꢁC was acidified with 12 N HCl. Usual work
up of the acidic solution with diethyl ether afforded the
acid 18 (30 mg, 51%); [a]2D5 +20.4 (c 0.9, CHCl3); IR: nmax
Acknowledgements
Financial support from the Department of Science and Tech-
nology, Government of India through Grant no. SR/WOS-A/
CS-16/2004 is gratefully acknowledged. The author thanks
Professor Subrata Ghosh of this Department for valuable
advice.
References and notes
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1776, 1732 cmꢀ1
;
1H NMR: d 2.79 (1H, dd, J¼8,
13.6 Hz), 2.97 (1H, dd, J¼5.4, 13.5 Hz), 3.24–3.31 (1H,
m), 3.36 (1H, d, J¼9.3 Hz), 3.79 (3H, s), 4.03 (1H, t,
J¼8.7 Hz), 4.42 (1H, t, J¼8.7 Hz), 6.78 (3H, m), 7.23
(1H, t, J¼7.8 Hz); 13C NMR: d 37.7 (CH2), 41.3 (CH),
51.3 (CH), 55.4 (CH3), 71.5 (CH2), 112.5 (CH), 114.8
(CH), 121.3 (CH), 130.1 (CH), 138.4 (C), 160.0 (C), 171.2
(CO), 172.3 (CO). HRMS (ESI): calcd for C13H14O5Na
(M+Na)+, 273.0739; found, 273.0735.
4.1.12. (S)-4-(3-Methoxybenzyl)-dihydrofuran-2(3H)-
one 19. A solution of the acid 18 (10 mg, 0.036 mmol) in
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11715
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