Diastereoselective synthesis of β-piperonyl-γ-butyrolactones from Morita-Baylis-Hillman adducts. highly efficient synthesis of (±)-yatein, (±)-podorhizol and (±)-epi-podorhizol

Article abstract of DOI:10.1590/S0103-50532010001200021

Starting from a Morita-Baylis-Hillman adduct we describe a simple and very efficient method for the diastereoselective preparation of hydroxylated β-piperonyl-γ-butyrolactones. To exemplify the efficiency of this approach we also describe a highly efficie

Full text of DOI:10.1590/S0103-50532010001200021

J. Braz. Chem. Soc., Vol. 21, No. 12, 2327-2339, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman
Adducts. Highly Efficient Synthesis of ( )-Yatein, ( )-Podorhizol and ( )-epi-Podorhizol
Giordano Trazzi, Marcelo Fabiano André and Fernando Coelho*
Instituto de Química, Universidade Estadual de Campinas, CP 6154,
13083-970 Campinas-SP, Brazil
Descrevemos nesse trabalho um método simples e eficiente para a preparação diastereosseletiva
de b-piperonil-g-butirolactonas hidroxiladas, a partir de um aduto de Morita-Baylis-Hillman.
Para exemplificar a eficiência dessa abordagem descrevemos também as sínteses das lignanas
biologicamente ativas, ( )-yateína, ( )-podorizol e ( )-epi-podorizol.
Starting from a Morita-Baylis-Hillman adduct we describe a simple and very efficient method
for the diastereoselective preparation of hydroxylated b-piperonyl-g-butyrolactones. To exemplify
the efficiency of this approach we also describe a highly efficient synthesis for the biologically
active lignans ( )-yatein, ( )-podorhizol and ( )-epi-podorhizol.
Keywords: Morita-Baylis-Hillman, lignans, diastereoselectivity
Introduction
plant Kadsura coccinea and presents a moderate nitric
oxide inhibitory activity.8 Beilschmin A (5) was isolated
from the stems of chinese plant Beilschmiedia tsangii. This
lignan was found to exhibit significant in vitro cytotoxicity
against P-388 and HT-29 cell lines, with IC50 values of
1.2 and 5.0 mg mL-1, respectively.9 The most prominent
member of the aryltetralin lignan class is podophyllotoxin
(6). This compound and some analogues have been isolated
from American Mayapple (Podophyllum peltatum).10
Podophyllotoxin (6) has long been known to possess anti-
mitotic activity with early clinical trials showing it to be
highly efficacious but also quite toxic. Driven by the desire
to enhance this biological profile, there have been many
synthetic modifications to the podophyllotoxin structure,
including the generation of potent anticancer agents. It is
possible to include the following agents, as the actually
marketed medicines Etoposide and Teniposide.10
The structural diversity and complexity associated with
biological effects exhibit by lignans have stimulated the
development of several synthetic approaches to prepare
them, both in racemic and enantiomeric pure forms.11 Most
of the synthetic methodologies are based on a b-aryl-g-
butyrolactone. This key intermediate is very important in
the synthesis of butyrolactone lignans, which are used as
plataform for the preparation of other lignans.12
Lignans are natural products originated from a coupling
reaction between C6-C3 units (phenylpropionate). These
secondary metabolites are widely encountered in plant
kingdom and present a huge structural diversity normally
associated with interesting biological effects, such as anti-
tumoral, fungicide and anti-viral.1,2 Furthermore, they also
show other biological activities against insects and some
vertebrates (Figure 1).3
Trachelogenin amide A (1, Figure 1) is a dibenzyl-
butane lignan, isolated from the leaves and stems of
Trachelospermum jasminoides. This plant is used in chinese
folk medicine to treat rheumatic arthralgia, aching of
loins and knees, and traumatic injuries.4 Actaelactone (2,
Figure 1), is a dibenzylbutyrolactone lignan isolated from
back cohosh (Actaea racemosa).5 Actaealactone showed
antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl
(DPPH) free-radical assay, with an IC50 value of 26 µmol L-1.
It also exhibited a small stimulating effect on the growth
of MCF-7 breast cancer cells. 9a-Angloyloxypinoresinol
(3) has displayed inhibitory activity against HIV reverse
transcriptase and was isolated from the roots and
rhizomes of the chinese plant Ligularia kanaitizensis.6,7
Kadsuralignan J (4) was isolated from roots of the chinese
Some years ago, Enders et al.13 elegantly demonstrated
that hydroxylated b-aryl-g-butyrolactone is a central
*e-mail: coelho@iqm.unicamp.br

2328
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
O
HO
O
OH
OMe
MeO
HO
O
O
NH2
OH
O
H
O
HO
O
O
O
H
OH
H
H
HO
OMe
OH
MeO
OMe
OH
Actaelactone (2)
(dibenzylbutyrolactone lignan)
Trachelogenin amide (1)
(dibenzylbutane lignan)
9α-Angloyloxypinoresinol (3)
(furofuran lignan)
O
OH
O
O
OH
O
MeO
MeO
O
O
MeO
O
O
O
O
OCH3
MeO
O
MeO
MeO
OMe
MeO
OMe
Beilschmin A (5)
Kadsuralignan J (4)
(dibenzocyclooctadiene lignan)
Podophillotoxin (6)
(substituted tetrahydrofuran lignan)
(aryltetralin lignan)
Figure 1. Types and examples of biological active lignans.
Ar
O
H
OH
H
O
O
O
O
OH
OH
R
Ar1
O
R
furofuran lignan
O
Ar2
R1
Substituted
β-butyrolactone
R
O
O
dibenzyilbutanediols
OH
R1
butyrolactone lignan
OH
O
O
O
R
O
R
R1
R1
O
aryltetralone lignan
butyrolactone lignan
O
R1
dibenzylcyclooctadiene
lignan
Figure 2. b-Aryl-g-butyrolactone as key intermediates for lignans synthesis.
intermediate from which several different types of lignans
can be synthesized (Figure 2).13,14
functionalized b-hydroxy-a-methylene carbonyl
derivatives.15,16 The adducts formed in this reaction have
been used as substrate for the synthesis of natural products
and drugs.17
Results and Discussion
Some years ago we reported, for the first time, a
strategy which allowed the preparation of b-aryl-g-
butyrolactone using Morita-Baylis-Hillman adduct as
Morita-Baylis-Hillman is an amazing chemical
transformation capable of efficiently providing highly

Vol. 21, No. 12, 2010
Trazzi et al.
2329
OH
OH
O
OH
O
O
O
O
O
O
O
O
O
CN
O
O
7a/b
syn-hydroxylated
butyrolactone (8)
anti-hydroxylated
butyrolactone (9)
O
O
O
O
OH
Regioisomeric
lactone (10)
Scheme 1. Butyrolactones from Morita-Baylis-Hillman adducts.
O
O
O
intermediates.14 This simple and straightforward strategy
provided access to syn- and anti-hydroxylated b-aryl-g-
butyrolactone (8 and 9, respectively) in good yield. The
diastereoselectivity for the syn isomer was acceptable
(4:1), but for the anti was very poor (1:1.5). In this
case, the presence of regioisomeric lactone 10 was also
detected, thus compromising the whole efficiency of the
synthetic methodology (Scheme 1).
O
O
R
O
R1
O
O
H3CO
OCH3
H3CO
OCH3
OCH3
OCH3
Yatein (11)
R1 = OH, R = H, Podorhizol (12)
R1 = H; R = OH, epi-Podorhizol (13)
Basically, a diastereoselective Michael addition of a
cyanide to the double bond of a Morita-Baylis-Hillman
gave 7a/b, as a mixture of diastereoisomers. Reduction
of the ester group followed by basic hydrolysis of the
nitrile group and in situ cyclisation, afford the desired
butyrolactones in good yield. Unfortunately, this strategy
had two major drawbacks. The first one was concerning
the poor diastereoselectivity observed for the anti
isomer. This isomer is particularly important for the
synthesis of aryltetralin lactones, such as podophillotoxin.
Second, an undesired regioisomeric butyrolactone (10) is
formed, which renders the chromatographic separation
laborious.
Withtheaimof overcoming aforementioneddrawbacks,
we describe herein an alternative diastereoselective
approach for the preparation of syn- and anti-hydroxylated
b-aryl-g-butyrolactone. To demonstrate the versatility of our
aproach we also describe a highly efficient total synthesis of
( )-yatein (11), ( )-podorhizol (12) and ( )-epi-podorhizol
(13) (Figure 3).
Figure 3. Lignans from a Morita-Baylis-Hillman addduct.
Yatein (11) is a biologically active butyrolactone lignan.
This natural compound has strong insect feeding deterrent,18
and anti-viral activity.19 Podorhizol (12) presents a moderate
anti-tumor activity,20 while epi-podorhizol (13) shows
antibacterial activity.21
Hydroxylated b-aryl-g-butyrolactones can be prepared
from a Morita-Baylis-Hillman using the synthetic strategy
depicted in scheme below (Scheme 2).
Thebutyrolactonescanbepreparedbydirectoxidationof
lactol 14, which in turn can be synthesized in one step from
cyanide-ester 7, using reductive conditions. The preparation
of 7 can be secured by a diastereoselective Michael addition
reaction with a suitable Morita-Baylis-Hillman adduct, such
as 16. Based on our previous results, we anticipated good
diastereoselective control could be achieved in the Michael
step, mainly in the preparation of the syn diastereoisomer.14
In order to improve the diastereoselectivity in the
preparation of anti isomer, we thought that b-ketoesters 15
OH
O
OH
OH
Ar
O
Ar
Ar
CN
O
O
OH
O
7
Ar
O
OH
O
14
cis/trans-(8/9)
O
O
16
Ar
O
Ar = 3,4-Methylenedioxyphenyl
CN
15
Scheme 2. Retrosynthetic approach for the preparation of hydroxylated butyrolactones from Morita-Baylis-Hillman adduct.

2330
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
H
OH
O
H
CH2CN
O
H
H
CH2CN
O
O
O
Ar
Ar
OH
CO2CH3
CN
CO2CH3
anti-7
A
Scheme 3. Stereochemical racionalization to obtain anti isomer 7.
OH
O
O
OH O
O
O
O
O
O
a
O
b
O
O
CN
7a/b (syn: anti; 1: .1.5)
Piperonal
16
Scheme 4. Preparation of cyanide 7. Reagents and conditions: (a) methyl acrylate (30 equiv.), DABCO, [bmim]PF6, ultrasound, 80 h, 89%; (b) NaCN,
NH4Cl, DMF:H2O (3:1), 12 h, 87%.
Table 1. Preparation of b-keto ester 15
could be used as substrate in a diastereoselective reduction
step. Based on a careful conformational analysis of 15,
we likely assume that A is the most stable conformer
(Scheme 3). We can thus expect that hydride attack should
preferentially occur on the less hindered side, leading to
the anti diastereoisomer as the major product.
O
O
OH
O
O
[O]
+
Ar
O
Ar
O
Ar
CN
CN
CN
15
17
7a/b
Ar= 3,4-Methylenedioxyphenyl
Taking in to account these preliminary considerations,
we commenced with the synthesis of b-hydroxy-ester 16
by coupling of methyl acrylate with piperonal. Electron-
rich aldehyde piperonal is very resistant to Morita-Baylis-
Hillman reaction and normally rate, conversion and yield
are very low. Searching to circumvent this problem we
carried out a reaction using an excess of acrylate (30 equiv.)
in the presence of catalytic amount of an ionic liquid
[bmim]PF6 (1-butyl-3-methylimidazolium hexafluoro-
phosphate) and ultrasound. Under these conditions, adduct
16 was obtained after 80 h, in 89% yield (Scheme 4).
Michael addition reaction between sodium cyanide
and adduct 16 afforded 7 in 87% yield but in a poor
diastereoisomeric ratio (syn:anti; 1:1.5), as previously
observed (Scheme 4).
The mixture was easily characterized by measuring the
coupling constant (J) of the carbinolic proton in 1H NMR
spectrum. A doublet resonance at 5.10 ppm (J 4.4 Hz)
was attributed to the syn diastereomer, while the doublet
resonance at 4.95 ppm (J 7.6 Hz) was attributed to the
anti isomer. The spectral data are consistent with those
previously reported in literature.14
The preparation of b-ketoester 15 was unexpectedly
troublesome. We tested several different oxidizing reagents.
The results are summarized in Table 1.
Depending on experimental conditions used the
b-ketoester 15 was contaminated with the decarboxylation
product 17 (entries 1 and 2, Table 1). It is known that
hypervalent reagent can hydrolyse esters and acetals.23
Then, we believe that the large excess of 2-iodoxybenzoic
acid (IBX) used in the reaction has favored the hydrolysis of
Entry
Reaction conditions
IBX/CH3CN (reflux)c
time
Products, (%)a,b
15 + 17, 55
15 + 17, 40
15, 55
1
2
3
4
5
6
12 h
12 h
12 h
12 h
8 h
IBX (3 equiv.)/AcOEt (reflux)
IBX (1.2 equiv.)/AcOEt (reflux)
IBX (1.2 equiv.)/acetone
PDC/CH2Cl2, r.t.
15, 45
15, 65
CrO3-H2SO4/acetone, 0 °C
15-20 min
15, 94
a Yields refer to isolated and purified products; b all spectral data (1H NMR,
13C NMR, IR, HRMS) are compatible with the proposed structures; c see
reference 22.
our keto ester, which subsequently loss CO2. The best result
was achieved when Jones reagent was used in acetone at
0 °C.24 Under these conditions, b-ketoester 15 was obtained
as a sole product in 94% yield (entry 6, Table 1).
Having ketoester 15 in our hands, we subjected it to
a set of different reductive conditions. The results are
summarized in Table 2.
In all cases, diastereoselectivity was better than that
achieved by conjugate addition of cyanide to the double
bond of Morita-Baylis-Hillman adduct. Moreover,
the highest selectivity was attained when employing
NaBH4 at room temperature and using methanol as
solvent (syn:anti;1:10). The difference between the
diastereoselectivity for the oxidation-reduction approach
and the Michael addition of sodium cyanide Michael
addition is remarkable (Figure 4). After a simple
chromatographic purification, anti-( )-7b was obtained
as a sole diastereoisomer in 75% yield. To accomplish
our goal, it was necessary to protect the secondary

Vol. 21, No. 12, 2010
Trazzi et al.
2331
Table 2. Diastereoselective reduction of b-keto ester 17
A dichloromethane solution of 18 was then treated with
a solution of diisobutylaluminium hydride (DIBAL-H)
(3 equiv.), at -78 °C for 3 h to give the lactol 14 in
91% (Scheme 5). DIBAL-H reduces the ester group
to the primary alcohol and nitrile to an imine, which
is quenched at this stage. During the aqueous workup,
imine is hydrolyzed to the aldehyde, which reacts with
the alcohol to give lactol 14 (Scheme 5). The NMR
analysis of lactol 14 was tedious, since the temporary
appearance of a third stereogenic center excessively
complicates the spectrum. Thus, 14 was directly treated
with tetrapropylammonium perruthenate (TPAP) in
the presence of N-methylmorpholine-N-oxide (NMO)
and molecular sieve (MS, 4 Å) to afford silylated anti-
butyrolactone 19 in 92%.28
O
O
OH
O
OH O
[H]
+
Ar
O
Ar
O
Ar
O
CN
( )-15
Ar= 3,4-Methylenedioxyphenyl
CN
CN
(anti)- -7b
(syn)- -7a
Entry
Reaction conditions
time (h)
Products, %a,b
syn:anti ratio
1
2
3
4
5
NaBH4/CH2Cl2/ -63 °Cc
NaBH4/CH2Cl2/ r.t.
3
3
7a/b, -, -
7a/b, 56, 1:7.5
7a/b, 75, 1:10
7a/b, 45, 1:427
7a/b, 50, 1:3
NaBH4/MeOH/ r.t.
1.5
12
2
NaBH4/i-PrOH/ r.t.
PhMe2SiH, HMPA, 0 °Cd
aYields refer to isolated and purified products; b all spectral data (1H NMR,
13C NMR, IR, HRMS) are compatible with the proposed structures; c see
reference 25; (d) see reference 26.
Removal of the protecting group with tetra-n-
butylammonium fluoride (TBAF) in MeOH gave anti-b-
piperonyl-g-butyrolactone 9 in 94% (Scheme 5).
hydroxyl group of anti-cyanide 7b. Then, compound 7b
was treated with tert-butyldimethylsilyl chloride (TBSCl)
and imidazole in anhydrous dimethylformamide (DMF)
to afford the silylether 18 in 78% yield.
All spectroscopic data are compatible with the proposed
structure. The anti-b-piperonyl-g-butyrolactone 9 was
prepared in a highly diastereoselective approach in 36%
overall yield, in 8 steps starting from piperonal.
Figure 4. Determining the stereochemical ratio of cyano-ester 7a/b. A. Diastereoisomeric ratio (syn:anti; 1:2) obtained by direct addition of cyanide on the
double bond of the adduct. Signal centered at 5.08 ppm was atributted to the syn isomer (J 2.8 and 5.1 Hz), while that centered at 4.92 ppm (J 3.5 and 7.8 Hz)
was atributted to the anti one. In both cases the minor coupling constants are due to the coupling with the hydroxyl hydrogen. B. Diastereoisomeric ratio
obtained just after ketoester reduction with NaBH4.
OR
OTBS
OTBS
OH
R
O
O
O
O
O
O
R
O
O
c,d
b
a
O
O
CN
CN
O
OH
18b; R = CO2CH3
14b
anti-( )-7b; R = CO2CH3
19b, R = OTBS
9, R = H
Scheme 5. Diastereoselective preparation of anti-butyrolactone. Reagents and conditions: (a) TBSCl, imidazole, DMF (drops), 18 h, r.t., 78%; (b) DIBAL-H,
CH2Cl2, -78 °C, 3 h, 91%; (c) TPAP, NMO, MS (4 Å), 1 h, 92%; (d) TBAF, MeOH, 0 °C, 2 h, 95%.

2332
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
OR
OTBS
OTBS
OH
R
R
O
O
O
O
O
O
R
O
O
c-e
b
a
O
CN
X
syn/anti-( )-18a/b - (4:1)
R = CO2CH3
16; R = CO2CH3
20; R = CO2CH3
14a, R = TBS, X = OH
19a, R = TBS, X = =O
syn-( )-8, R = H; X = =O
Scheme 6. Diastereoselective preparation of syn-butyrolactone 8a. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, r.t., 2 h, 95%; (b) KCN,
NH4Cl, DMF:H2O (3:1), 18 h, 83%; (c) DIBAL-H, CH2Cl2, -78 °C, 3 h, 91%; (d) TPAP, NMO, MS (4 Å), 1 h, 92%; (e) TBAF, MeOH, 0 °C, 2 h, 95%.
TBS
Ar
TBS
Ar
TBS
Ar
To demonstrate the feasibility of this strategy we also
prepared syn-butyrolactone (8), using a similar synthetic
sequence. To direct the diastereoselectivity towards the
formation of the syn isomer, the secondary hydroxyl group
of Morita-Baylis-Hillman adduct should be protected
before the cyanide addition. The enhanced presence of
the silyl group alters the course of the Michael addition
leading to the syn isomer as the major product (Scheme 6).
Initially adduct 16 was silylated to afford the silyl ether
20 in 95%. Michael addition reaction yielded cyanide-
esters 18a/b as a mixture of diastereoisomers in which
the syn isomer is the major one (4:1). This stereochemical
ratio is certainly defined during the protonation of the
enol intermediate formed after the addition of cyanide
(Scheme 7). This protonation should likely occur in the
enol face in opposite to the silyl group. However, the
preference for this face seems to be not so high. A careful
analysis of the proposed conformers clearly shows that
we have a steric enhancement in both faces, although one
side (opposite to TBDS group) being most accessible
than other. This observation can explain the moderate
selectivity attained.
O
OH
O
O
O
O
H+
HCN
O
O
O
CN
CN
)-syn
(
OTBS
H
Ar
NCH2C
OH
OH
NCH2C
H
OCH3
OCH3
Ar
OTBS
Ar = 3,4-Methylenedioxyphenyl
enol formed as intermediate
Scheme 7. Explaining the diastereoselectivity observed during the Michael
addition over the silylated Morita-Baylis-Hillman (MBH) adduct.
however, only slight enrichment of the mixture in favor
of the syn isomer was realized. DIBAL-H reduction
afford the lactol, which was immediately oxidized to the
corresponding silylated lactone in 84% yield over two steps.
The silyl group was removed to provide syn-hydroxylated
b-piperonyl-g-butyrolactone (8) in 95%. Unfortunately,
lactone syn was already contaminated with a small
amount of the anti isomer (7:1). The syn-butyrolactone
was prepared in an overall yield of 56% in 7 steps from
piperonal.
The optimized synthetic sequence was now employed
for the synthesis of ( )-yatein (11), ( )-podorhizol (12) and
( )-epi-podorhizol (13), through a common intermediate.
We made several attempts to separate these
diasteroisomers by column chromatography at this stage,
OTBS
O
O
O
O
O
b
a
O
O
O
O
O
O
O
( )-21
syn-( )-19b
c
H3CO
OCH3
OCH3
( )-Yatein (11)
O
O
R1
R
O
O
H3CO
OCH3
OCH3
R = OH, R1 = H, Podorhizol (12)
R = H; R1 = OH, epi-Podorhizol (13)
Scheme 8. Reagents and conditions: (a) Pd/C 5%, H2, 60 psi, 4 h, r.t., 92%; (b) LDA, THF, -78 °C, then bromide 22, 6 h, 80%; (c) LDA, THF, -78 °C,
aldehyde, 1 h, chromatographic separation, 80%.

Vol. 21, No. 12, 2010
Trazzi et al.
2333
To perform the lignan syntheses we have decided to
use the sequence depicted in Scheme 8. Hydrogenolysis
of 19b in the presence of hydrogen and palladium on
carbon at 60 psi provide b-piperonyl-g-butyrolactone
21, after 4 h, in 92% yield. Alkylation of 21 with the
3,4,5-trimethoxybenzyl bromide (22)29 in the presence
of LDA at -78 °C gave ( )-yatein (11) in 80% yield
(Scheme 8). To synthesize podorhizol and epi-podorhizol
we simply change the electrophile at the condensation
step. Instead of bromide we use commercially available
3,4,5-trimethoxy-benzaldehyde in an aldolic condensation.
The diastereoisomers (1:1 ratio) were easily separated
by column chromatography, as previously reported
(Scheme 6).30 All spectroscopic data for epimeric lignans
are completely compatible to those available in literature.31
The lignans were prepared in 6 steps from Morita-
Baylis-Hillman adduct 16. ( )-Yatein (11) was prepared
in 49% overall yield. ( )-Podorhizol (12) and ( )-epi-
podorhizol (13) were prepared both in 6 steps from Morita-
Baylis-Hillman adduct 16 in 24.5 and 24% overall yield,
respectively. All spectroscopic data are compatible with
the proposed structures.
flame ionization detector, using a HP-5 capillary (cross
linked 5% phenyl methyl siloxane, 28 m) column or by
NMR. Manipulations and reactions were not performed
under a dry atmosphere or employing dry solvents,
unless otherwise specified. Purifications and separations
by column chromatography were performed on silica
gel, using normal or flash chromatography. Thin-layer
chromatography (TLC) visualization was achieved by
spraying with 5% ethanolic phosphomolybdic acid and
heating. Morita-Baylis-Hillman reactions were sonicated
in an UNIQUE model GA 1000 ultrasonic bath (1000 W,
25 kHz). Ice was added occasionally to avoid increasing
the temperature of the water of the ultrasonic bath, which
was maintained between 30 and 40 °C. Reagents were
purchased fromAldrich,Acros or Lancaster, and were used
without prior purification.
( )-Methyl 2-[1,3-benzodioxol-5-yl(hydroxy)methyl]prop-
2-enoate (16)
A mixture of piperonal (12 g, 79.9 mmol), methyl
acrylate (54 mL, 0.6 mol), 1-methyl-3-butylimidazolium
hexafluorophosphate [bminPF6] (0.23 g, 0.79 mmol) and
1,4-diazabicyclo[2.2.2]octane (DABCO) (5.83 g, 52 mmol)
was kept in an ultrasound bath for 20 h. Next, a new portion
of methyl acrylate was added (54 mL, 0.6 mol) and the
reaction was kept on the ultrasound for 20 h. This procedure
was repeated twice to complete 80 h. The reaction medium
was then evaporated and the acrylate was almost totally
recuperated. The crude was diluted with dichloromethane
(100 mL), washed with distilled water (100 mL) and brine
(50 mL). The organic phase was dried over Na2SO4 and
the solvent was removed under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:AcOEt, 4:1, v/v) to provide 16.8 g of adduct 16
in 89% yield, as yellow tinged oil, which crystalise on
standing. mp 40-42 °C; IR nmax/cm-1 3490, 2954, 2897,
1703, 1630, 1487, 1438, 1295, 1246, 1037 (film); 1H NMR
(CDCl3, 300 MHz) d 6.85-6.74 (m, 3H aromatics), 6.32
(d, 1H, J 0.9 Hz), 5.93 (s, 2H), 5.86 (d, 1H, J 0.9 Hz),
5.46 (d, 1H, J 5.3 Hz), 3.71 (s, 3H), 3.06 (d, 1H, J 5.3 Hz,
exchangeable with D2O); 13C NMR (CDCl3, 75.4 MHz)
d 166.8, 147.8, 147.2, 141.9, 135.3, 120.2, 108.2, 107.2,
101.1, 72.9, 51.9; HRMS (70 eV, m/z) Calc. for C12H12O5:
236.06847. Found: 236.0685.
Conclusions
In summary we have described an alternative and
efficient strategy for the synthesis of lignans from Morita-
Baylis-Hillman adduct. This simple and straighforward
sequence allows the diastereoseletive synthesis of anti
and syn hydroxylated b-piperonyl-g-butyrolactone in
good overall yield. As far as we know this is the first
report concerning the total synthesis of lignans from a
Morita-Baylis-Hillman adduct. Due to the ease to which
different Morita-Baylis-Hillman adducts were obtained,
this approach can be used to furnish lignans of greater
molecular diversity. Finally, we have demonstrated that
Morita-Baylis-Hillman adducts can be considered as a
valuable substrate to prepare lignans.
Experimental
General
1
The H and 13C NMR spectra were recorded with a
Varian GEMINI BB at 300 and 75.4 MHz and Bruker
at 250 and 62.5 MHz, respectively, or on an Inova
Instrument at 500 and 125 MHz, respectively. The mass
spectra were recorded using a HP model 5988A GC/MS
with a High Resolution Autospec/EBE. IR were obtained
with a Nicolet model Impact 410. Diastereoselectivities
were determined from GC analysis on a HP6890 with
( )-Methyl 2-[(tert-butyldimethylsilyloxy)(1,3-benzodioxol-
5-yl)methyl]prop-2-enoate (20)
To a solution of 16 (3 g, 12.7 mmol) in dichloromethane
(100 mL) was added, at 0 °C and under an inert gas

2334
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
atmosphere, Et3N (3.5 mL, 25.5 mmol) and TBSOTf
(3.5 mL, 16.5 mmol). The resulting solution was stirred
at room temperature for 1 h. After that, the reaction
medium was diluted with dichloromethane (100 mL)
and the organic phase was washed a saturated solution
of NaHCO3 (200 mL) and distilled water (100 mL). The
organic phase was dried over anhydrous Na2SO4 and the
solvent was removed under reduced pressure. The residue
was purified by flash silica gel column chromatography
(hexane: AcOEt, 9:1, v/v) to provide 20 (4.35 g), in 98%
yield, as a viscous oil. IR nmax/cm-1 2954, 2888, 2860,
2833, 1720, 1634, 1495, 1438, 1246, 1152, 1070, 1041
14.9; HRMS (ESI, m/z) Calc. for C13H13NO5: 263.07937.
Found: 263.07892.
( )-Methyl 3-(tert-butyldimethyl silyloxy)-3-(1,3-
benzodioxol-5-yl)-2-(cyanomethyl)propanoate (18a/b)
To a solution of 20 (4.45 g, 12.7 mmol) in a mixture of
dimethylformamide and water (4:1) was added potassium
cyanide (2.79 g, 42.8 mmol) and ammonium chloride
(2.29 g, 42.8 mmol). The resulting mixture was stirred at
room temperature for 12 h. After that, the medium was
diluted with distilled water (200 mL) and the aqueous
phase was extracted twice with ethyl acetate (100 mL
each). The combined organic phases were washed with
distilled water (2 × 100 mL) and brine (100 mL). After
removal of the solvent under reduced pressure, the residue
was purified by flash silica gel column chromatography
(hexane:AcOEt, 4:1, v/v) to afford 3.69 g of a colorless
viscous oil, in 83% yield, as a mixture of diastereoisomer
(anti:syn; 1:4). IR nmax/cm-1 2954, 2924, 2883, 2854, 2241,
1
(film); H NMR (CDCl3, 300 MHz) d 6.85-6.79 (m, 2H
aromatics), 6.70 (d, 1H, J 8.4 Hz), 6.22 (dd, 1H, J 1.7 and
1.2 Hz), 6.05 (dd, 1H, J 1.7 and 1.7 Hz), 5.92 (d, 1H,
J 1.5 Hz), 5.91 (d, 1H, J 1.5 Hz), 5.51 (bs, 1H), 3.67 (s,
3H), 0.9 (s, 9H), 0.04 (s, 3H), -0,10 (s, 3H); 13C NMR
(CDCl3, 75.4 MHz) d 166.3, 147.3, 146.7, 136.6, 120.6,
107.7, 107.4, 100.9, 72.3, 51.6, 25.7, 18.1, -4.9, -5.13;
HRMS (ESI, m/z) Calc. for C18H26O5Si: 350.15495.
Found: 294.09234 [M-57]+.
1
1735, 1444, 1492, 1248, 1076, 1040 (film); H NMR
(CDCl3, 300 MHz) d 6.90-6.60 (m, 3H aromatics), 5.97
(bs, 2H), 5.10 (d, 1H, J 4.3 Hz, diastereoisomer syn), 4.82
(d, 1H, J 7.6 Hz, diastereoisomer anti), 3.78 (s, 3H, anti),
3.76 (s, 3H, syn), 3.05-2.70 (m, 2H), 2.50-2.36 (m, 1H),
0.97 (s, 9H, syn), 0.96 (s, 9H, anti), 0.01 (s, 3H, anti),
0.0 (s, 3H, syn), -0.02 (s, 3H, anti), -0.25 (s, 3H, syn);
13C NMR (CDCl3, 75.4 MHz) diastereoisomer syn: d 170.7,
147.7, 147.3, 133.9, 119.3, 118.5, 108.1, 106.3, 73.9, 52.3,
51.4, 25.6, 17.9, 14.2, -4.7, -5.4; diastereoisomer anti:
d 171.3, 148, 147.8, 133.8, 120.9, 117.6, 108.1, 106.5, 74.8,
52.3, 51, 25.5, 17.9, -4.7, -5.5; HRMS (EI, m/z) Calc. for
C19H27NO5Si: 377.16585. Found: 377.16319.
( )-Methyl 3-(1,3-benzodioxol-5-yl)-2-(cyanomethyl)-3-
hydroxypropanoate (7a/b)
To a solution of 16 (3 g, 12.7 mmol) in a mixture of
dimethylformamide and water (3:1) was added potassium
cyanide (2.79 g, 42.8 mmol) and ammonium chloride
(2.29 g, 42.8 mmol). The resulting mixture was stirred at
room temperature for 12 h. After that, the medium was
diluted with distilled water (200 mL) and the aqueous phase
was extracted twice with ethyl acetate (100 mL each). The
organic phases were combined and washed with distilled
water (2 × 100mL) and brine (100 mL). The organic phase
was then dried over Na2SO4 and the solvent removed under
reduced pressure. The residue was purified by flash silica
gel column chromatography (hexane:AcOEt, 7:3, v/v) to
give 7a/b (2.51 g), in 75% yield, as a viscous tinged yellow
oil, in a mixture of diastereoisomers (anti:syn; 1.5:1).
mp 50-52 °C; IR nmax/cm-1 3459, 2958, 2901, 2251, 1736,
1487, 1434, 1239, 1037 (film); 1H NMR (CDCl3, 300 MHz)
d 6.85-6.75 (m, 3H aromatics), 5.97 (s, 2H), 5.09 (dd, 1H,
J 2.9 and 5.1Hz, syn diastereoisomer), 4.90 (dd, 1H, J 3.5
and 7.7 Hz, anti diastereoisomer), 3.79 (s, 3H), 3.72 (s,
3H), 3.10-2.92 (m, 2H), 3.08-3.03 (m, 1H), 3.03-3.0 (m,
1H), 2.82 (dd, 1H, J 9 and 17 Hz, CH2CN, anti), 2.62 (d,
1H, J 4.4 Hz, CH2CN, syn), 2.56 (d, 1H, J 4.9 Hz, CH2CN,
syn), 2.42 (dd, 1H, J 8 and 17 Hz, CH2CN, anti); 13C NMR
(CDCl3, 75.4 MHz) d 171.8, 171.5, 148.2, 147.9, 147.6,
133.9, 133.3, 120, 119.9, 118, 117.1, 108.4, 108.3, 106.3,
106.1, 101.3, 101.2, 73.7, 72.6, 52.7, 52.6, 49.4, 48.8, 16.9,
( )-Methyl 3-(1,3-benzodioxol-5-yl)-2-(cyanomethyl)-3-
oxopropanoate (15)
To a solution of 7a/b (0.5 g, 1.9 mmol) in acetone
(50 mL) was added drop by drop, at 0 °C, a freshly
prepared solution of the Jones reagent24 (5 mL). The
reaction was monitored by TLC until the complete
disappearance of the starting material. If necessary a
tiny amount of the Jones reagent was added again. After
the completion, an excess of isopropanol was added and
the mixture was stirred just to become green. Then, the
reaction was diluted with ethyl acetate (150 mL) and
the organic phase was washed with water (2 × 150 mL)
and brine (150 mL). The organic phase was dried over
Na2SO4 and removed under reduced pressure. The residue
was purified by flash silica gel column chromatography
(hexane:AcOEt, 1:1, v/v) to give 15 in 94% yield, as a

Vol. 21, No. 12, 2010
Trazzi et al.
2335
tinged yellow viscous oil. IR nmax/cm-1 2970, 2953, 2238,
1740, 1679, 1437, 1254, 1037 (film); H NMR (CDCl3,
75 MHz) d 171.6, 148.2, 147.9, 133.2, 120, 117.4, 108.4,
106.3, 101.3, 73.7, 52.8, 48.9, 17.1; HRMS (EI, m/z) Calc.
for C19H27NO5Si: 377.16585. Found: 377.16319.
1
500 MHz) d 7.65 (d, 1H, J 3 Hz), 7.48 (s, 1H), 6.90 (d,
1H, J 3 Hz), 6.05 (s, 2H), 4.65 (apt, 1H, J 12 Hz), 3.75 (s,
3H), 3.18-2.95 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 189,
167.3, 153, 148.6, 129.5, 126, 117.3, 108.5, 108.1, 102.2,
53.4, 49.5, 16.9; HRMS (EI, m/z) Calc. for C13H11NO5:
261.06372. Found: 261.063351.
anti-( )-4-[1,3-Benzodioxol-5-yl(tert-butyldimethyl
silyloxy)methyl]tetrahydrofuran-2-ol (14b)
To a solution of cyano-ester 18b (0.18 g, 0.48 mmol)
in anhydrous dichloromethane (15 mL), at –78 °C, in an
inert gas atmosphere, was added diisobutyl aluminum
hydride (DIBAL-H, 1 mol L-1 solution in toluene,
1.56 mL, 1.56 mmol). The resulting mixture was stirred
at -78 °C after 3 h. Then, a saturated solution of sodium
acetate was added at -78 °C and the reaction was warmed
at room temperature. After that, the reaction was dropped
over a mixture of ethyl acetate (15 mL) and saturated
solution of ammonium chloride (5 mL) and stirred after
1 h. The resulting gel was filtered over a pad of Celite®.
The cake was washed with an additional amount of ethyl
acetate (25 mL). The combined organic phases were
dried over Na2SO4 and the solvent was removed under
reduced pressure. The residue was purified by flash silica
gel column chromatography (hexane:AcOEt, 7:3, v/v) to
afford 0.155 g of 14b, in 91% yield, as a viscous light
yellow oil. IR nmax/cm-1 3411, 2953, 2925, 2884, 2855,
anti-( )-Methyl 3-(1,3-benzodioxol-5-yl)-2-(cyanomethyl)-
3-hydroxypropanoate (7b)
To a stirred solution of ketoester 15 (0.173 g,
0.67 mmol) in methanol (3 mL) was added, at 0 °C, sodium
borohydrate (0.025 g, 0.66 mmol). The reaction was stirred
at room temperature for 90 min. The solvent was then
removed under reduced pressure and the residue was diluted
with ethyl acetate (30 mL). The organic phase was washed
with distilled water (2 × 30 mL) and a saturated solution of
ammonium chloride (30 mL). The organic phase was then
filtered over a pad of Celite® and dried over Na2SO4. The
solvent was removed under reduced pressure. The residue
was purified by flash silica gel column chromatography
to provide 7b, in 75% yield, as a colorless oil and high
diastereoisomeric purity (anti:syn;10:1). IR nmax/cm-1 3462,
2958, 2916, 2247, 1736, 1602, 1504, 1489 (film); 1H NMR
(CDCl3, 500 MHz) d 6.87 (m, 3H), 6.0 (s, 2H), 4.95 (d,
1H, J 7.5 Hz), 3.80 (s, 3H), 3.08-3.03 (m, 1H), 2.62 (dd,
1H, J 9 and 17 Hz), 2.42 (dd, 1H, J 8 and 17 Hz); 13C NMR
(CDCl3, 75 MHz) d 171.3, 148.2, 147.9, 133.2, 120, 117,
108.4, 108.1, 106.3, 101.3, 52.8, 48.9, 17.1; HRMS (EI,
m/z) Calc. for C13H13NO5: 263.07937. Found: 263.07921.
1
1491, 1437, 1237, 1074, 1045 (film); H NMR (CDCl3,
250 MHz) d 6.90-6.60 (m, 3H), 5.95 (s, 2H), 5.60-5.30
(m, 1H), 4.70-4.30 (m, 1H), 4.20-3.40 (m, 2H), 4.15 (bs,
1H), 3.05 (bs, 1H), 2.90-2.40 (m, 1H), 2.20-1.40 (m, 2H),
0.92-0.82 (2s, 2 × 9H), 0.10-0.0 (2s, 2 × 3H), -0.12 -
-0.26 (2s, 2 × 3H); 13C NMR (CDCl3, 62.5 MHz) d 147.6,
147.5, 146.8, 146.7, 138, 137.9, 119.8, 119.6, 107.7,
107.6, 106.7, 106.6, 100.9, 98.7, 98.6, 77.4, 77.2, 70.3,
69.6, 47.4, 46.2, 25.7, 25.6, 18.03, 18, -4.48, -5.1, -5.2;
HRMS (ESI, m/z) Calc. for C18H28O5Si + Na: 375.1604
[M + Na]+. Found: 375.1557 [M + Na]+.
anti-( )-Methyl 3-(tert-butyldimethyl silyloxy)-3-(1,3-
benzodioxol-5-yl)-2-(cyanomethyl)propanoate (18b)
To a mixture of cyano-ester 7b (0.27 g, 1 mmol), tert-
butyldimethylsilyl chloride (0.2 g, 1.3 mmol) and imidazole
(0.17 g, 2.5 mmol), under an inert gas atmosphere, was
added 2 drops of anhydrous DMF. The resulting mixture
was vigorously stirred for 18 h, at room temperature. After
that, the reaction was diluted with ethyl acetate (25 mL). The
organic phase was washed with distilled water (25 mL) and
brine(25mL).Aftersolventremoval, theresiduewaspurified
by flash silica gel column chromatography (hexane:AcOEt,
70:30) to provide 18b, in 78% yield, as a colorless viscous
oil. IR nmax/cm-1 2949, 2925, 2888, 2851, 2251, 1740, 1491,
anti-( )-4-[1,3-Benzodioxol-5-yl(tert-butyldimethyl
silyloxy)methyl]dihydrofuran-2(3H)-one (19b)
To a solution of lactol 14b (0.18 g, 0.52 mmol) in
anhydrous dichloromethane (20 mL), at room temperature
under an inert gas atmosphere, was added molecular
sieves (4 Å, 0.27 g), N-Methyl morpholine (NMO,
0.12 g, 1.04 mmol) and tetrapropylammonium ruthenate
(TPAP, 0.0184 g, 0.04 mmol). The resulting mixture was
stirred after 1 h. Then the crude was filtered over a pad of
Celite® and the solvent removed under reduced pressure.
The residue was purified by flash silica gel column
chromatography to afford 0.165 g of 19b, in 92% yield,
as colorless viscous oil. IR nmax/cm-1 2953, 2929, 2892,
1
1442, 1241, 1172, 1086, 1033 (film); H NMR (CDCl3,
500 MHz) d 6.80-6.60 (m, 3H), 5.96 (s, 2H), 4.85 (d, 1H,
J 7.6 Hz), 3.76 (s, 3H), 2.98 (m, 1H), 2.33 (d, 2H, J 6.4 Hz),
0.92 (s, 9H), 0.02 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3,

2336
Diastereoselective Synthesis of b-Piperonyl-g-Butyrolactones from Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
1
2851, 1777, 1491, 1437, 1241, 1172, 1078, 1033, 1008
(film); 1H NMR (CDCl3, 250 MHz) d 6.80-6.65 (m, 3H),
5.95 (s, 2H), 4.48 (d, 1H, J 6.8 Hz), 4.28 (m, 2H), 2.76
(m, 1H), 2.31 (m, 1H), 0.87 (s, 9H), 0.03 (s, 3H), -0.22 (s,
3H); 13C NMR (CDCl3, 62.5 MHz) d 176.7, 147.8, 147.2,
136.1, 119.4, 108, 106.3, 101, 75.5, 70, 44.1, 31.2, 25.7,
17.9, -4.53, -5.26; HRMS (ESI, m/z) Calc. for C18H26O5Si:
351.1648 [M + H]+. Found: 351.1628 [M + H]+.
1769, 1487, 1438, 1248, 1037 (film); H NMR (CDCl3,
300 MHz) d 6.75 (d, 1H, J 7.8 Hz), 6.63 (d, 1H, J 1.7 Hz),
6.59 (dd, J 1.7 and 7.8 Hz), 5.94 (s, 2H), 4.33 (dd, 1H,
J 6.8 and 9.2 Hz), 4.02 (dd, 1H, J 6.0 and 9.2 Hz), 2.80 (m,
1H), 2.69 (m, 2H), 2.60 (dd, 1H, J 8.0 and 17 Hz), 2.27
(dd, 1H, J 6.8 and 17 Hz); 13C NMR (CDCl3, 75.4 MHz)
d 176.5, 147.8, 146.2, 131.7, 121.5, 108.7, 108.3, 100.9,
72.5, 38.7, 37.3, 34.2; HRMS (EI, m/z) Calc. for C12H12O4:
220.07356. Found: 220.07341.
anti-( )-4-[1,3-Benzodioxol-5-yl(hydroxy)methyl]
dihydrofuran-2(3H)-one (7b)
Preparation of ( )-yatein (11)
To a solution of 19b (0.1 g, 0. 38 mmol) in methanol
(5 mL) was added, at 0 °C and in an inert gas atmosphere,
tetrabutylammonium fluoride (solution 1 mol L-1 in THF,
0.45 mL, 0.45 mmol). The resulting mixture was stirred
at the same temperature after 2 h. Then, the solvent was
removed under reduced pressure and the residue was diluted
with ethyl acetate (25 mL). The organic phase was washed
with distilled water (2 × 10 mL) and brine (10 mL) and dried
over anhydrous Na2SO4.After solvent removal, the residue
was purified by flash silica gel column chromatography
to give 7b as colorless viscous oil, in 95% yield.
IR nmax/cm-1 3429, 2900, 1771, 1492, 1444, 1248, 1040
(film); 1H NMR (CDCl3, 250 MHz) d 6.90-6.70 (m, 3H),
5.95 (s, 2H), 4.38 (d, 1H, J 8.0 Hz), 4.16 (dd, 1H, J 7.8
and 9.3 Hz), 4.03 (dd, 1H, J 6.4 and 9.3 Hz), 2.20-2.40
(m, 2H); 13C NMR (CDCl3, 62.5 MHz) d 177.4, 148,
147.5, 135.8, 119.6, 108.2, 106.2, 101.2, 74.4, 69.9, 42.4,
30.7; HRMS (EI, m/z) Calc. for C12H12O5: 236.06847.
Found: 236.06831.
To a solution of 21 (0.12 g, 0.54 mmol) in anhydrous
THF (5 mL), at –78 °C and in an inert gas atmosphere, was
added a freshly prepared 1mol L-1 LDA solution (0.6 mL,
0.6 mmol). The temperature was raised until the room one
and then the system was cooled again to -78 °C and stirred
for 30 min.After that, a solution of 5-(bromomethyl)-1,2,3-
trimethoxybenzene (0.71 g, 2.72 mmol) in anhydrous THF
(0.5 mL) was added. The final mixture was stirred after 6 h.
Then, a saturated solution of ammonium chloride (1 mL)
was added and the reaction was extracted with ethyl acetate
(30 mL). The organic phase was washed with distilled water
(20 mL), brine (20 mL) and dried over anhydrous Na2SO4.
After solvent removal, the residue was purified by flash
silica gel column chromatography (hexane:AcOEt, 8:2,
v/v) to provide ( )-yatein (11) as a fluid tinged yellow oil,
in 80% yield. IR nmax/cm-1 2994, 2941, 2839, 1768, 1593,
1507, 1486, 1458, 1417, 1331, 1245, 1127, 1037, 1017
(film); 1H NMR (CDCl3, 300 MHz) d 6.68 (d, 1H, J 6.9 Hz),
6.47 (dd, 1H, J 1.6 and 6.9 Hz), 6.44 (bs, 1H), 6.35 (s, 2H),
5.92 (m, 2H), 4.18 (dd, 1H, J 7.1 and 9.3 Hz), 3.90-3.84
(m, 1H), 3.84 (s, 3H), 3.82 (s, 6H), 2.95-2.85 (m, 2H),
2.70-2.40 (m, 4H); 13C NMR (CDCl3, 62.5 MHz) d 178.1,
153, 147.7, 146.2, 136.7, 133.1, 131.3, 121.4, 108.6, 108.2,
106.2, 101, 71.4, 60.9, 56.1, 46.5, 41, 38.4, 35.3; HRMS
(EI, m/z) Calc. for C22H24O7: 400.15220. Found: 400.15198.
( )-4-(1,3-Benzodioxol-5-ylmethyl)dihydrofuran-2(3H)-
one (21)
To a solution of 18a/b (0.55 g, 1.57 mmol) in methanol
(50 mL) was added 5% Pd/C (0.034 g, 0.16 mmol)
and two drops of concentrated hydrochloric acid. The
resulting mixture was placed in a hydrogenation bottle,
which was maintained in a shaker equipment, under
hydrogen pressure (60 psi, 4 atm) after 4 h. Then, the
mixture was neutralized with solid sodium bicarbonate
and filtered over a pad of Celite®. The cake was washed
with ethyl acetate (10 mL). The combined organic
phases were removed and the crude was redissolved in
ethyl acetate (50 mL). The organic phase was washed
with distilled water (25 mL), brine (25 mL) and finally
dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure. The residue was purified by
flash silica gel column chromatography to afford 21, as a
yellow tinged fluid oil, in 92% yield. IR nmax/cm-1 2909,
Preparation of ( )-podorhizol (12) and ( )-epi-podorhizol
(13)
To a solution of 21 (0.1 g, 0.44 mmol) in anhydrous
THF (5 mL), at –78 °C and under an inert gas atmosphere,
was added a solution of freshly prepared lithium
diisopropylamine (LDA, 0.2 mol L-1, 0.26 mL, 0.42 mmol).
The resulting solution was allowed to warm to 0 °C
during 30 min. After the solution was cooled again to
-78 °C and stirred after 30 min. Then a solution of
3,4,5-trimethoxybenzaldehyde (0.08 g, 0.44 mmol) in
anhydrous THF (2 mL) was added. The resulting solution
was stirred after 1 h, at -78 °C. Then the reaction was

Vol. 21, No. 12, 2010
Trazzi et al.
2337
quenched with a saturated solution of ammonium chloride
(10 mL) and warmed to the room temperature. The medium
was extracted with ethyl acetate (30 mL) and the organic
phase was washed with distilled water (2 × 10 mL) and
dried over anhydrous Na2SO4. The isomers were separated
by flash silica gel column chromatography (CH2Cl2:MeOH,
98:2, v/v) to afford 12 and 13 in a combined yield of 80%.
( )-Podorhizol (12): Yield: 41%; mp 123-125 °C
(124-126 °C)29; IR nmax/cm-1 3500, 1762, 1590, 1490
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1
(KBr); H NMR (300 MHz, CDCl3) d 6.47 (s, 2H), 6.59
(d, 1H, J 7.7 Hz), 6.30 (dd, 1H, J 7.8 and 1.5 Hz), 6.22 (d,
1H, J 1.5 Hz), 5.92 (dd, 2H, J 1.4 and 1.4 Hz), 5.25 (d, lH,
J 2.9 Hz), 4.39 (dd, lH, J 8.7 and 8.0 Hz), 3.97 (dd, lH,
J 8.7 and 8.9 Hz), 3.83 (s, 3H, 3.82 (s, 6H), ca. 2.80 (m,
lH), 2.62 (dd, lH, J 6.1 and 2.9 Hz), 2.47 (dd, lH, J 13.7
and 7.7 Hz), 2.25 (dd, lH, J 3.7 and 8.1Hz); 13C NMR
(75.4 MHz, CDCl3) d 178.3, 153.4 (2 × C), 147.9, 146.3,
137.6, 136.8, 131.5, 121.5, 108.6, 107.9, 102.6, 101.1, 72.8,
72.1, 60.8, 56.2 (2 × OCH3), 52.8, 39.4, 36.4
( )-epi-Podorhizol (13): Yield: 39%; mp 132-133 °C
(133-134 °C)29; IR29c max/cm-1 3500, 3010, 2780, 1760,
n
1600, 1510, 1490, 1230, 1120, 925 (film-CHCl3); 1H NMR
(300 MHz, CDCl3) d 6.66 (d, 1H, J 8.2 Hz), 6.65(s, 2H),
6.34 (dd, 1H, J 8.21 and 7 Hz), 6.33(d, 1H, J 1.7Hz), 5.92
(dd, 2H, J 1.4 and 1.4 Hz,-OCH2O-) ,4.79 (d, 1H, J 7.9 Hz),
4.18 (dd, 1 H, J 9.3 and 7.8 Hz), 3.92 (dd, 1H, J 9.3 and
8.4 Hz), 3.88 (s, 6H), 3.83 (s, 3H), 2.62 (dd, 1H, J 9.1 and
7.8 Hz), ca. 2.50 (m, lH), 2.20 (dd, 1H, J 13.8 and 8.9 Hz),
2.12 (dd, 1H, J 13.7 and 5.4Hz); 13C NMR (125 MHz,
CDCl3) d 178.7, 153.8 (2 × C), 148.1, 146.6, 138.7, 135.8,
131.6, 121.5, 108.7, 108.4, 104.1 (2 × C), 101.1, 74.7, 72,
61, 56 (2 × C), 51.7, 38.9, 38.3.
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Acknowledgments
G. T. and M. F. A. thank FAPESP and CAPES for
fellowships, respectively. F. C. thanks CNPq for a research
fellowship.Authors thank CNPq and FAPESP for financial
support and Prof. C. H. Collins for English revision.
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Submitted: April 24, 2010
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