Heterolignanolides. Furo- and thieno-analogues of podophyllotoxin and thuriferic acid

Article abstract of DOI:10.1016/S0040-4020(01)00271-X

The conjugate addition-alkylation to 5H-furan-2-one followed by cyclization and controlled epimerizations have been applied to the synthesis of new furo- and thieno-lignan analogues. Podophyllotoxin and thuriferic acid heteroanalogues have been obtained by this methodology, as representative members of these families.

Full text of DOI:10.1016/S0040-4020(01)00271-X

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 3963±3977
Heterolignanolides. Furo- and thieno-analogues of
podophyllotoxin and thuriferic acid
p
Angel C. Ramos, Rafael Pelaez, Jose Luis Lopez, Esther Caballero, Manuel Medarde and
Â
Â
Arturo San Feliciano
  Â
Laboratorio de Quõmica Organica y Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, E-37007 Salamanca, Spain
Received 14 November 2000; revised 9 February 2001; accepted 28 February 2001
AbstractÐThe conjugate addition±alkylation to 5H-furan-2-one followed by cyclization and controlled epimerizations have been applied
to the synthesis of new furo- and thieno-lignan analogues. Podophyllotoxin and thurifericacid heteroanalogues have been obtained by this
methodology, as representative members of these families. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
1
Owing to their interest as antineoplasticagents and other
pharmacological activities,2 considerable work has been
completed on lignans and their derivatives. Their isolation
as natural products,3 their synthesis4 and the preparation of
different types of derivatives5 have been reviewed and two
general books on these compounds have also appeared.6
Podophyllotoxin and its semisyntheticderivative etoposide
7VP-16) are the best known of the lignan family.7
A large number of variations have been introduced in the
8,80-bis-phenylpropane skeleton, characteristic of these
compounds, but very little work has been directed to the
replacement of carbon atoms by heteroatoms or the replace-
ment of benzene rings by heteroaromaticrings. Such type of
analogue types have been called ªheterolignansº and have
been recently reviewed.8 Among heterolignans, azatoxin9
has been the most successful compound as an antineoplastic
agent and is now in clinical trials.
Figure 1. Structure of representative lignans and heterolignans 77-9 and 70-
90 numbering according to the general bis-phenylpropane skeleton of
lignans).
general method for the synthesis of heterolignans carrying
heterocyclic rings.12 In this paper, we present the appli-
cation of these methodologies to the synthesis of hetero-
There are many structural possibilities for heterolignans, as
can be deduced from the general structure in Fig. 1. As a
consequence, several different approaches can be employed
for their synthesis, either by adaptation of known method-
ologies for the synthesis of lignans or by the design of new
analogues of podophyllotoxins1,5,7 and the cytotoxic
13
thurifericacid carrying thieno, 5-methylthieno, furo and
5-methylfuro moieties instead of the 1,6-benzene ring.
8
syntheticstrategies.
In previous communications we reported a new procedure
for the synthesis of podophyllotoxin based on epimerization
reactions10 and the use of 2-heteroaryl-1,3-dithianes in the
conjugate addition±alkylation to 5H-furan-2-one,11 as a
2. Results and discussion
According to the retrosynthetic analysis depicted in Fig. 2,
the starting 2-heteroaryl-1,3-dithianes can be assembled
into the heterolignan skeleton by means of a conjugate
addition alkylation to 5H-furan-2-one, to produce after
cyclization and deprotection all-trans ketones. These can
Keywords: lignans; furans; thiophenes; antitumour compounds.
Corresponding author. Tel.: 134-923 294528; fax: 134-923 294515;
e-mail: medarde@gugu.usal.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00271-X

3964
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
chloride. The cyclization was carried out with the diastereo-
mericmixture or with the isolated erythro 3 or threo 4
isomers, always producing the all-trans lactones
5
7JH7 ±H8 and JH8 ± H8.10 Hz).18 Partial deprotection to 5e0,
from 314e, with tri¯uoroacetic acid and total deprotection
to 5e0, with tin tetrachloride was observed. Only SnCl4 can
be used for the cyclization of furyl derivatives due to the
decomposition produced when tri¯uoroacetic acid was
employed. Another characteristic of this reaction is the
observed lower reactivity of the threo isomers, which is in
agreement with a higher stability of the SnCl4±hydroxy-
lactone complex for less reactive threo isomers 4 than for
the more reactive erythro isomers 3.19
0
0
0
During the initial assays with 3a and tri¯uoroacetic acid,
besides the cyclized product 5a the carboxylic acid 13 was
isolated in moderate yields 7Fig. 4). The presence of the
lactone as a potential leaving group, the stabilization of
the intermediate cation by the aromatic ring and one sulfur
Figure 2. Syntheticstrategies for the synthesis of thieno- and furo-
analogues of podophyllotoxin and thurifericacid.
atom and the sterichindranec in the tetrasubstituted C
7
atom,20 could explain the unexpected transformation,
which has been also observed for other 1,3-dithianes in
similar structural arrangements.21
be used as intermediates in the synthesis of either the
thurifericacid or the podophyllotoxin analogues.
The ®rst syntheticstep, the conjugate addition to 5 H-furan-
2-one yielding lactones 2 proceeds in good yield, as
described in a preliminary paper.11 Consequently, the
whole process from dithianes 1 to the hydroxylactones 3
and 4 was attempted with the 2-thienyl- 7a), 5-methyl-2-
thienyl- 7b), 2-furyl- 7c) and 5-methyl-2-furyl- 7d) -1,3-
dithianes 7Fig. 3). Under the standard conditions,14 products
3 and 4 were obtained in very low yields due to the
inef®cient alkylation of the resulting enolate. A systematic
study on the in¯uence of temperature, time and added
lithium complexing agent 7TMEDA or HMPT) showed
that better conditions for the alkylation step are: tempera-
tures below 2408C for 4±5 h in the presence of two equiva-
lents of TMEDA. Higher temperatures or longer reaction
times led to the isolation of larger quantities of inter-
mediates 2 and the starting aldehydes. These facts can be
explained as a result of the retrocondensation of the alkyl-
ation products 3 and 4.
At this point, the deprotection of the carbonyl group at C7 to
ketoderivatives type 6 is required to follow the synthetic
route. The deprotection was carried out on 5a,5e using
HgO, yielding a 1:1 mixture of deprotected keto-lactone
6a,6e and the isomericketo-lactone 7a,7e. The use of longer
reaction time led to complete epimerization, as observed for
5a, which was converted into 7a after 60 h. If lower
temperatures were maintained during the addition of the
reagents 708C) and then allowed to slowly reach room
temperature, only the deprotected products 6a, 6b or 6e,
were isolated. On the other hand, when the reaction was
allowed to proceed from the beginning at room temperature
during 12 h, other products were also isolated, as was the
case for 15b, which was obtained together with 7b from 5b.
Such a transformation can be explained as depicted in Fig.
5. Pure 6a or 6e or deprotection mixtures 6a17a or 6e17e,
were transformed in re¯uxing acetic acid into pure 7.
The furo-derivatives 5c, 5d or 5f0 only yielded deprotected
products 6c, 6d or 6f0 without epimerized products, when
the reaction was carried out from the beginning at room
temperature. A quantitative epimerization to 7c or to 7d
was produced by treatment with TsOH in chloroform, the
replacement of re¯uxing HOAc by TsOH being required to
avoid the degradation of the furane ring. In this case 5d also
produced 15d when the treatment was extended for 12 h
7Fig. 5). The stereochemistry of compounds 6 and 7 can
be readily established from the values of chemical shifts
Using these optimized conditions, isolated yields increase to
become higher than 80% 7lower for compounds of type d),
with the erythro 3 as major and the threo 4 as minor reaction
products. The preference for the erythro products is that
usually observed for the conjugate addition±alkylation
using substituted 2-phenyl-1,3-dithianes as starting
materials in the synthesis of lignans. The relative con®gu-
rations of the reaction products can be readily established as
trans for the disubstituted lactone, on the basis of an anti
addition±alkylation process,15 and con®rmed by the chemi-
cal shift difference 7$0.3 ppm in trans isomers; <0.05 ppm
in cis stereoisomers) between both lactone protons 7H9 of
0
0
0
and coupling constants of H8, H7 and H8 7H7 is more
0
shielded in 6 d,4.3 ppm than in 7 d,4.8 ppm, JH8±H8
and JH7 ± H8 .10 Hz for 6).
0
0
0
the lignan skeleton). The relative con®guration of C7 for
3a±f and 4a±f is deduced by NMR spectral comparison
0
epimer epi-podorhizol 7d#4.95 ppm; J<6.6 Hz).16
Following our syntheticscheme, the reduction of ketones of
the picropodophyllotoxone type was carried out with
0
with podorhizol 7H7 : d.5.12 ppm; J<2.2 Hz) and its C7
LiAlH7tBuO)3 on 7a, 7c and 7e, which produced 2±3:1
22
mixtures of the desired alcohols 8a, 8c, 8e and the epimeric
alcohols 9a, 9c, 9e in low to moderate yield 733±63%). The
con®guration of the major reduction product was the result
of the attack from the less-hindered face in the expected
In spite of the low reactivity at position 3 of the heterocyclic
ring towards the alkylation,17 the synthesis of compounds
5a±f0 was completed with tri¯uoracetic acid or tin tetra-

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3965
Figure 3. Key: 7i) 7a) BuLi 1.6 M, THF, 2788C, 45 min; 7b) 5H-furan-2-one, THF, 2788C, 3 h; 7c) Ar±CHO, THF, TMEDA, 2408C, 3±48 h. 7ii) Method A:
TFA, benzene, 3 h; or Method B: SnCl4, CH2Cl2. 7iii) HgO, BF3´Et2O, THF±H2O 785:15), 08C to room temperature, 12 h. 7iv) Method C: HOAc, re¯ux; or
Method D: pTsOH, CHCl3, re¯ux. 7v) LiAlH7tBuO)3, THF, 4 h. 7vi) iPr2NEt, TBDMSTf, 08C, 4 h. 7vii) Method G: LiHMDS, THF, 2788C for 10 min to 08C
for 40 min, then HOAc; or Method H: LDA or tBuLi or NaNH2, THF, 2788C, 15±45 min, then HOAc. 7viii) TBAF, room temperature, 48 h.
preferred conformation of podophyllotoxone derivatives.23
Owing to the presence of the 3,4,5-trimethoxyphenyl ring in
the a-face and the complexation of the reagent with the
lactone moiety in the b-face, the reduction of the ketone
mainly produced the H7b isomer 8. The picropodophyllo-
toxin con®guration was established for 8 because of the
lower chemical shift 7,4.7 ppm) and higher coupling
constant 7about 7.8 Hz) for the H7, in comparison with
those 75.1 ppm, 2.2 Hz) for compounds 9 of the epipicro-
podophyllotoxin type.24
The protection of alcohols 819 as TBDMS derivatives was
directly carried out on the mixtures obtained from the reduc-
tion, due to the dif®culties in their separation. Fortunately,

3966
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
Figure 4. Proposed mechanism for the transformation of 3a into 13 under acidic conditions.
the silylation was diastereoselective towards the major
a-epimer, which has the hydroxyl group in a more acces-
sible pseudoequatorial disposition, without any observable
protection of the minor b-epimer, placed in hindered
pseudoaxial disposition and cis to the lactone ring. When
a less bulky reagent was used 8a19a yielded a mixture of
16117 7Fig. 6) in agreement with the proposed steric
hindrance for the selective protection of a-epimers 8 with
TBDMSCl.
alternative bases was also attempted, but no transfor-
mation was achieved 7NaNH2) or no stereoc hemic al
conversion and appearance 7tBuLi) of product 19 7Fig. 7)
was observed.
As it was pointed out in our preliminary paper, in spite of the
presence of the epimerized products with podophyllotoxin
con®guration 11 in the mixture of TBDMS derivatives, any
attempt to recover the free alcohols 12 resulted in the trans-
formation of these compounds into the hydroxyl derivatives
of the picropodophyllotoxin series 8. The ¯uoride anion
from the deprotection reagent was suf®ciently basic to
produce the undesired epimerization.27 The presence of
the thiophene or furan ring clearly affects the relative
stability of both stereoisomers of heteropodophyllotoxin
7trans-lactone) and heteropicropodophyllotoxin 7cis-
lactone) types in comparison with the natural carbocyclic
lignans. This in¯uence can be observed in the lower ratio
75:1 cis:trans) of the trans-lactone obtained in the kinetic
protonation of the enolate 71:1 mixture for natural lignans)
and the easier epimerization of the trans-lactones to the
cis-lactones.
Once the heteroanalogues with the picropodophyllotoxin
con®guration were prepared in a stereocontrolled process,
0
the well-known procedure for the epimerization at C8
according to the Kende methodology25 was applied on
thieno 10a and furo 10c. In standard experiments, from
pure 10a or 10c mixtures of 10a, 11a, or 10c, 11c in a 5:1
ratio were obtained. When the ethoxymethyl ether
derivative 16 was used, the picropodophyllotoxin con-
®guration predominated in the reaction mixture by a
7:1 ratio. During these experiments, the hydroxylated
derivative 18 was isolated 7Fig. 7),26 but its formation
was prevented by degasi®cation of the solvent. The use of
Figure 5. Proposed mechanism for the transformation of 5b,5d into 15b,15d with Hg21
.
Figure 6. Key: 7i) iPr2NEt, EOMCl, NaI, CH2Cl2, re¯ux, 12 h.
Figure 7. Structure of by-products 18 and 19.

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3967
Figure 8. Key: 7i) 1% KOH/MeOH, room temperature, 30 min; then HCl 2N. 7ii) Etheral CH2N2. 7iii) HCl dry stream, CH2Cl2, 1.5 h.
As the synthetic methodology to build up the heterocyclo-
lignanolide skeleton proved to be straightforward, we next
decided to prepare the heteroanalogues of thuriferic acid.
The preparation of these derivatives by means of basictreat-
ment of the keto-lactones is described in the literature:28
from podo- 78-80-trans-80-70-cis) or picropodo- 78-80-cis-
80-70-trans) -phyllotoxins the thurifericaicd 78 0-70-trans)
is readily obtained; whereas from isopicropodophyllotoxin
these compounds, in agreement with obtaining the same
0
0
products starting from both H8 ±H7 -trans isomers 6 and 7.
This relative con®guration is preserved during the basic
treatment, as no incorporation of deuterium was
0
detected in C8 when KOH treatment was carried out
in methanol-d4. The con®gurations for these compounds
were further con®rmed by preparing the trans±trans
0
choloroderivatives 22a, 22c, 22d JH8±H8 7,11.0 Hz) and
78-80-cis-80-70-cis) the epi-thurifericaicd 78
0-70-cis) is
JH8 ±H7 7,11.5 Hz).
0
0
produced. For the synthesis of the heterothuriferic acids
the ketolactones 6 and 7 can be used, because both stereo-
isomers should produce the thuriferic acid analogues,
provided no epimerization at C-80 takes place in the basic
medium 7Fig. 8).
The bioactivity evaluation of ®nal and intermediate products
6±11 and 20±22 is now in progress and will be published in
due course.
By KOH 71% in MeOH) treatment of either 6a±d or 7a±d,
followed by diazomethane methylation of acids 20a±d
7with or without previous puri®cation), the methyl hetero-
3. Conclusion
0
thuriferates 21a±d were obtained in all cases. The H8 ±H7
0
The methodology based on conjugated addition±alkyl-
ation±cyclization±deprotection, followed by key epimeri-
zations and other transformations has proven its utility in the
synthesis of different families of lignan analogues. The
stereocontrolled synthesis of furo- and thieno-analogues of
podophyllotoxins and thuriferic acid has been carried out in
few steps of medium to high yield.
coupling constants of 20d and 21d 72.6 and 2.9 Hz, respec-
tively) are relatively close to those observed for thuriferic
acid and its methyl ester 73.7 Hz), but compounds 20a±c
0
0
and 21a±c showed higher H8 ±H7 coupling constants 74.1±
5.0 Hz) closer to those of epi-thurifericaicd 75.4 Hz).
Nevertheless, the trans-con®guration was assigned to all

3968
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
4. Experimental
J1ˆ17.9, J2ˆ8.6 Hz); 2.74 72H, dt, J1ˆ14.3, J2ˆ3.4 Hz);
2.53 71H, dd, J1ˆ17.9, J2ˆ 8.6 Hz); 1.89±2.10 72H, m).
4.2.2. +^)+3R,4S)-4-[2-+2-thienyl)-1,3-dithian-2-yl]-3-[1R-
4.1. General procedure for the synthesis of 2-heteroaryl-
1,3-dithianes +1)
+3,4,5-trimethoxyphenyl)
hydroxymethyl]tetrahydro-
furan-2-one +3a). Mp 1568C. IR 7KBr): 3440, 1770, 1600,
1510 and 1130 cm21. EA: calc. for C22H26O6S3: C 54.8%; H
5.4%; found C 54.8%; H 5.4%. 1H-NMR 7CDCl3): 7.18 7dd,
J1ˆ5.2, J2ˆ1.3 Hz, H4); 7.06 7dd, J1ˆ3.6, J2ˆ1.3 Hz, H6);
To a magnetically stirred solution of the appropriate aryl-
carbaldehyde 70.021 mol) in 21 mL of CHCl3 cooled to 08C,
were successively added 1,3-propanedithiol 72.1 mL, 0.023
mol) and trimethylsilyl chloride 70.5 mL; 0.046 mol). The
reaction was maintained at room temperature overnight,
then quenched with NaOH 4% 7100 mL) and extracted
with CHCl3 72£20 mL). The combined organic layers
were washed with brine and dried over Na2SO4. Evaporation
of the solvent left a brown solid 1a±1d, that was puri®ed by
crystallization in EtOAc±hexane mixtures. Yield 82±90%.
0
0
6.82 7dd, J1ˆ5.2, J2ˆ3.6 Hz, H5); 6.39 7s, H2 ,6 ); 5.12 7d,
0
Jˆ2.9 Hz, H7 ); 4.80 7dd, J1ˆ9.6, J2ˆ2.6 Hz, H9a); 4.30 7dd,
J1ˆ9.6, J2ˆ8.1 Hz, H9b); 3.83 7s, 2£OMe); 3.82 7s, OMe);
0
3.18 7t, Jˆ2.9 Hz, H8 ); 2.91 7dt, J1ˆ8.1, J2ˆ2.9 Hz, H8);
2.77±1.80 7m, 6H). 13C-NMR 7CDCl3): 24.37±CH2±); 27.1
7SCH2); 27.57SCH2); 48.8780); 49.878); 56.1730,50OMe);
58.477); 60.68740OMe); 70.079); 73.9770); 102.6720,60);
127.175); 127.876); 129.074); 136.2710); 137.1740); 147.0
71); 153.2730,50); 178.5790).
4.2. General procedure for the synthesis of alcohol-
lactones 3 and 4 by conjugate addition±alkylation
4.2.3. 4-[2-+5-methyl-2-thienyl)-1,3-dithian-2-yl]tetra-
hydrofuran-2-one +2b). IR 7CHCl3): 1780, 1480, 1185,
To a solution of 2-heteroaryl-1,3-dithianes 1 70.1 M in dry
THF) at 2788C under argon, a 1.6 M solution of BuLi in
hexane 71.1 mol mol21) was added dropwise. After 45 min,
5H-furan-2-one 71.01 mol mol21, 1M in THF) in the dark,
was also added dropwise and allowed to react for 3 h. The
mixture was warmed to 2408C and the corresponding
benzaldehyde 71.5 mol mol21, 1 M in THF) and TMEDA
72 mol mol21) were added. After 3±48 h at 2408C the reac-
tion was quenched with a saturated NH4Cl solution and the
aqueous layer was extracted with EtOAc 7twice). The crude
product was puri®ed by ¯ash chromatography and crystal-
lization in EtOAc±hexane mixtures to yield 2, 3 and 4.
1
1035 and 930 cm21. MS m/z 7%): 300 7M1, 11). H-NMR
7CDCl3): 7.03 71H, d, Jˆ3.5 Hz); 6.65 71H, d, Jˆ3.5 Hz);
4.50 71H, dd, J1ˆ9.6, J2ˆ7.5 Hz); 4.29 71H, dd, J1ˆ9.6,
J2ˆ8.1 Hz); 3.10 71H, m); 2.64±3.02 74H, m); 2.43 73H,
s); 1.89±2.06 72H, m).
4.2.4. +^) +3R,4S)-4-[2-+5-methyl-2-thienyl)-1,3-dithian-
2-yl]-3-[1R-+3,4,5-trimethoxyphenyl) hydroxymethyl]-
tetrahydrofuran-2-one +3b). Mp 1828C. IR 7KBr): 3440,
1770, 1600, 1510 and 1130 cm21. EA: calc. for C23H28O6S3:
C 55.6%; H 5.7%; found C 55.5%; H 5.5%. 1H-NMR
0
0
7CDCl3): 6.87 7d, Jˆ3.4 Hz, H6); 6.49 7s, H2 ,6 ); 6.48 7d,
0
Jˆ3.4 Hz, H5); 5.13 7t, Jˆ3.7 Hz, H7 ); 4.80 7dd, J1ˆ9.3,
By this procedure representative reactions produced the
following results. 7a) From 1.00 g of 1a, 0.35 mL of 5H-
furan-2-one and 1.45 g of 3,4,5-trimethoxybenzaldehyde,
310 mg of 2a 722%) and 1.80 g of 3a 774%) were isolated.
7b) From 1.50 g of 1b, 0.49 mL of 5H-furan-2-one and
1.77 g of 3,4,5-trimethoxybenzaldehyde, 60 mg of 2b
73%), 2.13 g of 3b 762%) and 0.96 g of 4b 728%) were
isolated. 7c) From 1.95 g of 1c, 0.77 mL of 5H-furan-2-
one and 2.67 g of 3,4,5-trimethoxybenzaldehyde, 320 mg
of 2c 711%), 2.60 g of 3c 753%) and 1.20 g of 4c 724%)
were isolated. 7d) From 1.53 g of 1d, 0.56 mL of 5H-
furan-2-one and 1.91 g of 3,4,5-trimethoxybenzaldehyde,
350 mg of 2d 716%), 790 mg of 3d 724%) and 440 mg of
4d 713%) were isolated 7e). From 4.23 g of 1a, 1.48 mL of
5H-furan-2-one and 8.70 g of 4-benzyloxy-3,5-dimethoxy-
benzaldehyde, 2,20 g of 2a 736%) and 4.96 g of 3e 749%)
were isolated. 7f) From 2.03 g of 1c, 0.78 mL of 5H-furan-2-
one and 4.5 g of 4-benzyloxy-3,5-dimethoxybenzaldehyde,
1.10 g of 2c and 3.10 g of 3f14f 7ratio 7:3) were isolated
7only a small amount of 3f was puri®ed for characterization
purposes).
J2ˆ3.5 Hz, H9a); 4.32 7dd J1ˆ10.4, J2ˆ9.3 Hz, H9b); 3.85 7s,
0
2£OMe); 3.82 7s, OMe); 3.18 7d, Jˆ4.0 Hz, H8 ); 2.95±2.70
7m, H8); 2.77±1.80 7m, 6H); 2.35 7s, Me). 13C-NMR
7CDCl3):
15.2710);
24.27±CH2±);
27.07SCH2);
27.47SCH2); 48.6780); 49.778); 56.0730,50OMe); 58.577);
60.8740OMe); 69.979); 73.9770); 102.7720,60); 124.876);
129.175); 136.1710); 137.1740); 142.574); 143.771);
153.0730,50); 178.5790).
4.2.5. +^) +3R,4S)-4-[2-+5-methyl-2-thienyl)-1,3-dithian-
2-yl]-3-[1S-+3,4,5-trimethoxyphenyl) hydroxymethyl]-
tetrahydrofuran-2-one +4b). Mp 1728C. IR 7KBr): 3440,
1770, 1600, 1510 and 1130 cm21. EA: calc. for C23H28O6S3:
C 55.6%; H 5.7%; found C 55.5%; H 5.5%. 1H-NMR
7CDCl3): 7.03 7d, Jˆ3.6 Hz, H6); 6.62 7d, Jˆ3.6, H5); 6.52
0
0
0
7s, H2 ,6 ); 4.89 7m, H7 ); 4.60 7dd, J1ˆ9.5, J2ˆ2.5 Hz, H9a);
3.83 7s, 2£OMe); 3.82 7s, OMe); 3.77 7dd, J1ˆ10.3, J2ˆ
0
9.5 Hz, H9b); 3.36 7dd, J1ˆ4.7, J2ˆ2.9 Hz, H8 ); 2.90±2.86
7m, H8); 2.85±1.80 7m, 6H); 2.42 7s, Me). 13C-NMR
7CDCl3): 15.6710); 24.47±CH2±); 27.37SCH2); 27.4
7SCH2); 50.0780); 50.978); 56.2730,50OMe); 58.677); 60.9
740OMe); 68.279); 73.8770); 103.2720,60); 125.376); 129.5
75); 135.5710); 137.8740); 142.774); 143.871); 153.2730,50);
176.2790).
4.2.1. 4-[2-+2-thienyl)-1,3-dithian-2-yl]tetrahydrofuran-
2-one +2a). Mp 1228C 7hexane±EtOAc). IR 7CHCl3):
1780, 1480, 1180, 1030, 920 and 860 cm21. MS m/z 7%):
1
286 7M1, 15). H-NMR 7CDCl3): 7.35 71H, dd, J1ˆ5.2,
4.2.6. 4-[2-+2-furyl)-1,3-dithian-2-yl]tetrahydrofuran-2-
one +2c). Mp 708C 7hexane±EtOAc). IR 7CHCl3): 1790,
1500, 1480, 1180, 1030 and 950 cm21. MS m/z 7%): 270
J2ˆ1.1 Hz); 7.26 71H, dd, J1ˆ3.7 J2ˆ1.1 Hz); 7.02 71H,
dd, J1ˆ5.2, J2ˆ3.7 Hz); 4.51 71H, dd, J1ˆ9.7, J2ˆ
7.6 Hz); 4.28 71H, dd, J1ˆ9.7, J2ˆ7.6 Hz); 3.15 71H, m);
2.93 72H, ddd, J1ˆ15.7, J2ˆ10.6, J3ˆ3.0 Hz); 2.92 71H, dd,
1
7M1, 18). H-NMR 7CDCl3): 7.46 71H, d, Jˆ1.8 Hz); 6.64

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3969
71H, d, Jˆ3.3 Hz); 6.41 71H dd, J1ˆ3.3, J2ˆ1.8 Hz); 4.47
71H, dd, J1ˆ9.7, J2ˆ6.9 Hz); 4.31 71H, dd, J1ˆ9.7, J2ˆ
8.1 Hz); 3.18±3.35 71H, m); 2.87 71H, dd, J1ˆ18.0, J2ˆ
7.6 Hz); 2.86 72H, dt, J1ˆ14.4, J2ˆ3.5 Hz); 2.73 72H,
ddd, J1ˆ14.4, J2ˆ10.1, J3ˆ4.6 Hz); 2.52 71H, dd, J1ˆ
18.0, J2ˆ9.4 Hz); 1.98±2.05 72H, m).
4.2.11. +^) +3R,4S)-4-[2-+5-methyl-2-furyl)-1,3-dithian-
2-yl]-3-[1S-+3,4,5-trimethoxyphenyl) hydroxymethyl]-
tetrahydrofuran-2-one +4d). Mp 1628C 7hexane±EtOAc).
IR 7KBr) 3440, 1770, 1600, 1510 and 1130 cm21. EA: calc.
for C23H28O7S2: C 57.5%; H 5.9%; found C 57.6%; H 5.9%.
1H-NMR 7CDCl3): 6.56 7s, H2 ,6 ); 6.47 7brs, H5); 5.94 7brs,
0
0
0
H6); 4.95 7brs, H7 ); 4.42 7d, Jˆ9.8 Hz, H9a); 3.82 7s,
0
4.2.7. +^) +3R,4S)-4-[2-+2-furyl)-1,3-dithian-2-yl]-3-[1R-
+3,4,5-trimethoxyphenyl) hydroxymethyl]tetrahydro-
furan-2-one +3c). Mp 1728C. IR 7KBr): 3410, 1770, 1600,
1510 and 1130 cm21. EA: calc. for C22H26O6S2: C 58.6%; H
5.8%; found C 58.0%; H 5.9%. 1H-NMR 7CDCl3): 7.20 7d,
3£OMe); 3.70 7t, Jˆ9.8 Hz, H9b); 3.40 7m, H8 ); 3.10 7m,
H8); 2.80±1.80 7m, 6H); 2.25 7s, Me). 13C-NMR 7CDCl3):
13.4710); 24.37±CH2±); 26.97SCH2); 26.97SCH2); 47.2780);
49.978); 54.777); 55.8730,50OMe); 60.5740OMe); 67.979);
73.1770); 102.7720,60); 106.475); 113.176); 135.7710);
137.0740); 148.874); 152.7730,50); 153.071); 176.0790).
0
0
Jˆ1.8 Hz, H4); 6.50 7s, H2 ,6 ); 6.47 7d, Jˆ3.3 Hz, H6); 6.24
0
7dd, J1ˆ3.3, J2ˆ1.8 Hz, H5); 5.18 7m, H7 ); 4.70 7dd, J1ˆ
4.2.12. +^) +3R,4S)-3-[1R-+4-benzyloxy-3,5-dimethoxy-
phenyl)hydroxymethyl]-4-[2-+2-thienyl)-1,3-dithian-2-yl]-
tetrahydrofuran-2-one +3e). Mp 1528C. IR 7CHCl3): 3460,
1770, 1600, 1130 and 1010 cm21. EA: calc. for C28H30O6S3:
C 60.2%, H 5.4%; found C 60.5%, H 5.3%. 1H-NMR
7CDCl3): 7.50±7.27 7m, 5H, Ph); 7.15 7dd, J1ˆ4.6,
J2ˆ1.0 Hz, H4); 7.05 7dd, J1ˆ4.6, J2ˆ1.0 Hz, H6); 6.81
9.5, J2ˆ2.4 Hz, H9a); 4.33 7dd J1ˆ9.5, J2ˆ7.8 Hz, H9b); 3.86
0
7s, 2£OMe); 3.83 7s, OMe); 3.20 7t, Jˆ2.9 Hz, H8 ); 3.06 7m,
H8); 2.90±1.70 7m, 6H). 13C-NMR 7CDCl3): 24.57±CH2±);
27.17SCH2); 27.17SCH2); 45.5780); 50.078); 55.577);
56.2730,50OMe); 60.8740OMe); 69.879); 73.8770); 102.7
720,60); 110.375); 112.376); 136.3710); 136.3740); 143.374);
151.271); 153.3730,50); 178.5790).
0
0
0
7dd, J1ˆ4.6, J2ˆ3.5 Hz, H5); 6.39 7s, H2 ,6 ); 5.12 7m, H7 );
4.97 7s, CH2Ph); 4.74 7dd, J1ˆ9.5, J2ˆ2.5 Hz, H9a); 4.28 7dd
J1ˆ9.5, J2ˆ8.3 Hz, H9b); 3.78 7s, 2£OMe); 3.17 7t, Jˆ
4.2.8. +^) +3R,4S)-4-[2-+2-furyl)-1,3-dithian-2-yl]-3-[1S-
+3,4,5-trimethoxyphenyl) hydroxymethyl]tetrahydro-
furan-2-one +4c). Mp 1588C 7hexane±EtOAc). IR 7KBr):
3410, 1770, 1600, 1510 and 1430 cm21 EA: calc. for
C22H26O6S2: C 58.6%; H 5.8%; found C 60.0%; H 5.9%.
1H-NMR 7CDCl3): 7.40 7d, Jˆ1.7 Hz, H4); 6.62 7d, Jˆ
0
2.5 Hz, H8 ); 2.91 7dt, J1ˆ8.3, J2ˆ2.5 Hz, H8); 2.77±1.80
7m, 6H). 13C-NMR 7CDCl3): 24.37±CH2±); 27.47SCH2);
27.57SCH2); 49.1780); 49.978); 56.3730,50OMe); 58.377);
69.679); 74.3770); 75.170CH2Ph); 103.4720,60); 127.9
7OCH2Ph); 127.97OCH2Ph); 128.27OCH2Ph); 128.575);
128.576); 128.57OCH2Ph); 129.274); 136.3710); 138.0740);
147.371); 153.7730,50); 178.3790).
0
0
3.2 Hz, H6); 6.56 7s, H2 ,6 ); 6.37 7dd, J1ˆ3.2, J2ˆ1.7 Hz,
0
H5); 4.95 7m, H7 ); 4.50 7dd, J1ˆ10.1, J2ˆ2.7 Hz, H9a); 3.84
7s, 2£OMe); 3.82 7s, OMe); 3.71 7dd J1ˆ10.1, J2ˆ8.1 Hz,
0
H9b); 3.38 7dd, J1ˆ4.9, J2ˆ2.8 Hz, H8 ); 3.08 7m, H8); 2.95±
1.90 7m, 6H). 13C-NMR 7CDCl3): 24.57±CH2±); 27.3
7SCH2); 27.37SCH2); 47.6780); 49.978); 55.177); 56.1
730,50OMe); 60.8740OMe); 68.179); 73.4770); 103.0720,60);
110.775); 112.676); 135.4740); 135.5710); 143.574); 151.3
71); 153.1730,50); 176.0790).
4.2.13. +3R,4S)-3-[1R-+4-benzyloxy-3,5-dimethoxyphenyl)-
hydroxymethyl]-4-[2-+2-furyl)-1,3-dithian-2-yl]tetrahydro-
furan-2-one +3f). Mp 1588C. IR 7KBr): 3457, 1762, 1600
and 1190 cm21 EA: calc. for C28H30O7S2: C 62.0%, H 5.6%;
found C 61.6%; H 5.4%. 1H-NMR 7CDCl3): 7.50±7.20 7m,
0
0
5H, Ph); 7.20 7d, Jˆ1.8 Hz, H4); 6.50 7s, H2 ,6 ); 6.46 7d,
Jˆ3.3 Hz, H6); 6.24 7dd, J1ˆ3.3, J2ˆ1.8 Hz, H5); 5.20±
4.2.9. 4-[2-+5-methyl-2-furyl)-1,3-dithian-2-yl]dihydro-
furan-2-one +2d). IR 7CHCl3): 1780, 1610, 1485, 1185
and 850 cm21. MS m/z 7%): 284 7M1, 12). 1H-NMR
7CDCl3): 6.50 71H, d, Jˆ3.1 Hz); 5.97 71H, d, Jˆ3.1 Hz);
4.47 71H, dd, J1ˆ9.7, J2ˆ6.7 Hz); 4.31 71H, dd, J1ˆ9.7, J2ˆ
8.1 Hz); 3.21 71H, m); 2.87 71H, dd, J1ˆ17.6, J2ˆ7.7 Hz);
2.86 72H, ddd, J1ˆ14.3, J2ˆ8.0, J3ˆ4.3 Hz); 2.71 72H, dt,
J1ˆ14.3, J2ˆ4.3 Hz); 2.54 71H, dd, J1ˆ17.6, J2ˆ9.4 Hz);
2.29 73H, s); 1.92±2.10 72H, m).
0
5.17 7m, H7 ); 4.98 7s, CH2Ph); 4.63 7dd, J1ˆ9.4, J2ˆ
2.2 Hz, H9a); 4.29 7dd, J1ˆ9.4, J2ˆ7.9 Hz, H9b); 3.80 7s,
0
2£OMe); 3.20 7t, Jˆ2.6 Hz, H8 ); 3.06 7m, H8); 3.10±1.80
7m, 6H). 13C-NMR 7CDCl3): 24.47±CH2±); 27.07SCH2);
27.07SCH2); 45.4780); 50.278); 55.277); 56.1730,50OMe);
69.879); 73.5770); 74.870CH2Ph); 103.1720,60); 110.275);
112.076); 127.67Ph); 127.97Ph); 127.97Ph); 128.37Ph);
136.5710); 137.7740); 143.174); 151.371); 153.3730,50);
178.2790).
4.2.10. +^) +3R,4S)-4-[2-+5-methyl-2-furyl)-1,3-dithian-
2-yl]-3-[1R-+3,4,5-trimethoxyphenyl) hydroxymethyl]te-
trahydrofuran-2-one +3d). Mp 1448C. IR 7KBr) 3440,
4.3. Synthesis of lactones 5by cyclization of 3 and 4
1770, 1600, 1510 and 1130 cm21
. EA: calc. for
C23H28O7S2: C 57.5%; H 5.9%; found C 57.6%; H 5.9%.
Method A. To a solution of alcohol 70.1 M in benzene) was
added dropwise and with shaking tri¯uroacetic acid
725 mol mol21) in benzene and was kept for 3 h. It was
then neutralized with a saturated solution of NaHCO3 and
extracted in the usual manner with AcOEt. The crude
product was puri®ed by ¯ash chromatography and crystal-
lization in EtOAc±hexane mixtures.
1H-NMR 7CDCl3): 6.57 7s, H2 ,6 ); 6.36 7d, Jˆ3.1 Hz, H5);
0
0
0
5.85 7d, Jˆ3.1 Hz, H6); 5.30±5.20 7m, H7 ); 4.60 7dd, J1ˆ
9.5, J2ˆ2.5 Hz, H9a); 4.29 7dd, J1ˆ9.5, J2ˆ7.9 Hz, H9b);
0
3.87 7s, 2£OMe); 3.82 7s, OMe); 3.32 7d, Jˆ2.7 Hz, H8 );
3.10±3.00 7m, H8); 2.77±1.80 7m, 6H); 2.17 7s, Me).
13C-NMR 7CDCl3): 13.6 710); 24.5 7±CH2±); 26.9
7SCH2); 27.0 7SCH2); 45.3 780); 50.1 78); 55.6 77); 56.1
730,50OMe); 60.8 740OMe); 69.8 79); 73.8 770); 102.8
720,60); 106.4 75); 113.0 76); 136.2 710); 137.1 740); 148.9
74); 153.2 71); 153.2 730,50); 178.5 790).
Method B. To a solution of alcohol 70.1 M in CH2Cl2) was
added dropwise SnCl4 71.1 mol mol21, 1 M in CH2Cl2) and
left to react with stirring. Then, a saturated solution of
NaHCO3 was added and extracted in the usual manner

3970
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
with CH2Cl2. The crude product was puri®ed by ¯ash
chromatography and crystallization in EtOAc±hexane
mixtures.
7CDCl3): 15.4710); 23.47±CH2±); 29.47SCH2); 29.8
7SCH2); 44.2780); 45.178); 49.577); 55.7770); 56.1
730,50OMe); 60.8740OMe); 67.879); 105.7720,60); 125.175);
137.1740); 137.4710); 139.876); 140.074); 140.671);
153.1730,50); 174.7790).
4.3.1. +^) +4R,4aS,7aS)-8,8-+propylen-1,3-dithio)-4-+3,4,5-
trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]-
isobenzofuran-5-one +5a) and +^) +7S,8R)-8-+3,4,5-
trimethoxyphenyl)-3,4,7,8-tetrahydro-2H,6H-1,5-dithio-
cycloocta[2,3-g]benzothiopheno-7-carboxylic acid +13).
Following method A from 1.75 g of 3a, quantities of 1.15 g
of 5a 769%) and 276 mg of 13 718%) were obtained. Follow-
ing method B from 2.61 g of 3a, 2.20 g of 5a 788%) was
obtained.
4.3.3. +^) +4R,4aS,7aS)-8,8-+propylen-1,3-dithio)-4-+3,4,5-
trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrofuro[3,4-f]-
benzofuran-5-one +5c). Following method B from 2.00 g of
a mixture of 3c and 4c 72:1), 1.29 g of 5c 768%) was
obtained. Mp 2068C. IR 7KBr): 1770, 1600 and
1510 cm21. MS m/z 7%): 448 7M1, 100). EA: calc. for
C22H24O6S2: C 58.9%; H 5.4%; found C 60.0%; H 5.4%.
1H-NMR 7CDCl3): 7.31 7d, Jˆ2.7 Hz, H4); 6.47 7s, H2 ,6 );
5.95 7d, Jˆ2.7 Hz, H5); 4.56 7dd, J1ˆ8.9, J2ˆ7.5 Hz, H9a);
4.51 7dd, J1ˆ10.5, J2ˆ8.9 Hz, H9b); 3.92 7d, Jˆ10.2 Hz,
0
0
5a. Mp 2208C. IR 7CHCl3): 1780, 1600 and 1510 cm21. MS
m/z 7%): 464 7M1, 26). EA: calc. for C22H24O5S3: C 56.9%;
H 5.2%; found C 56.0%; H 5.0%. H-NMR 7CDCl3): 7.17
1
0
H7 ); 3.84 7s, OMe); 3.82 7s, 2£OMe); 3.24 7dd, J1ˆ13.7,
0
0
0
7d, Jˆ5.3 Hz, H4); 6.46 7s, H2 ,6 ); 6.40 7d, Jˆ5.3 Hz, H5);
J2ˆ10.2 Hz, H8 ); 3.02±2.95 7m, H8); 3.00±2.00 7m, 6H).
4.68 7dd, J1ˆ8.2, J2ˆ6.7 Hz, H9a); 4.53 7dd, J1ˆ10.6, J2ˆ
13C-NMR 7CDCl3): 24.67±CH2±); 27.77SCH2); 28.8
7SCH2); 41.2780); 44.578); 45.977); 50.9770); 56.1
730,50OMe); 60.8740OMe); 66.879); 105.3720,60); 110.275);
119.176); 136.3710); 137.1740); 142.774); 153.1730,50);
156.571); 174.2790).
0
8.3 Hz, H9b); 4.00 7d, Jˆ10.4 Hz, H7 ); 3.83 7s, OMe); 3.81
0
7s, 2£OMe); 3.46 7dd, J1ˆ13.7, J2ˆ10.4 Hz, H8 ); 3.30±
3.10 7m, H8); 3.00±2.00 7m, 6H). 13C-NMR 7CDCl3):
23.47±CH2±); 29.37SCH2); 29.77SCH2); 44.2780); 45.278);
49.377); 55.7770); 56.1730,50OMe); 60.8740OMe); 67.979);
105.7720,60); 125.975); 127.274); 136.9740); 137.4710);
139.876); 143.071); 153.1730,50); 174.5790).
4.3.4. +^) +4R,4aS,7aS)-2-methyl-8,8-+propylen-1,3-
dithio)-4-+3,4,5-trimethoxyphenyl)-4,4a,5,7,7a,8-hexahy-
drofuro[3,4-f]benzofuran-5-one +5d). Following method
B from 1.12 g of a mixture of 3d and 4d 72:1), 1.00 g of
5d 785%) was obtained. Mp 1248C. IR 7KBr): 1790, 1592
and 1239 cm21. MS m/z 7%): 462 7M1, 37). 1H-NMR
13. IR 7KBr): 3400±2500, 1710, 1680, 1600 and
1010 cm21. MS m/z 7%): 464 7M1, 100). 1H-NMR
7CDCl3): 7.22 7d, Jˆ5.0 Hz, H4); 6.87 7d, Jˆ5.0 Hz, H5);
0
0
0
0
0
6.22 7s, H2 ,6 ); 4.72 7d, Jˆ3.0 Hz, H7 ); 4.45 7d, Jˆ13.1 Hz,
7CDCl3): 6.46 7s, H2 ,6 ); 5.55 7s, H5); 4.58 7dd, J1ˆ9.0,
0
H9a); 3.88 7d, Jˆ3.0 Hz, H8 ); 3.78 7s, OMe); 3.72 7s,
J2ˆ7.3 Hz, H9a); 4.51 7dd, J1ˆ10.6, J2ˆ9.0 Hz, H9b); 3.85
0
2£OMe); 3.28 7d, Jˆ13.1 Hz, H9b); 2.80±1.90 7m, 6H).
13C-NMR 7CDCl3): 28.27±CH2±); 34.17SCH2); 34.4
7SCH2); 36.879); 42.3780); 52.3770); 56.1730,50OMe);
60.7740OMe); 105.3720,60); 124.778); 125.275); 128.874);
134.577); 135.2 710); 137.2740); 138.076); 140.171);
153.0730,50); 176.2790). By treatment of 13 with CH2N2
7^) methyl 77S,8R)-8-73,4,5-trimethoxyphenyl)-3,4,7,8-
tetrahydro-2H,6H-1,5-dithiocycloocta[2,3-g]benzothiophene-
7-carboxylate 714) was obtained. IR 7CHCl3): 1740, 1600
and 1510 cm21. MS m/z 7%): 478 7M1, 89). 1H-NMR
7CDCl3): 7.22 7d, Jˆ5.0 Hz, H4); 6.85 7d, Jˆ5.0 Hz, H5);
7d, Jˆ10.2 Hz, H7 ); 3.84 7s, OMe); 3.83 7s, 2£OMe); 3.26
0
7dd, J1ˆ13.5, J2ˆ10.2 Hz, H8 ); 3.01±2.98 7m, H8); 2.95±
1.80 7m, 6H); 2.27 7s, Me). 13C-NMR 7CDCl3): 13.9710);
24.57±CH2±); 27.77SCH2); 28.47SCH2); 42.1780); 44.478);
46.177); 51.1770); 56.2730,50OMe); 60.7740OMe); 66.879);
105.8720,60); 106.275); 120.276); 136.4710); 137.0740);
152.571); 153.0730,50); 154.274); 174.3790).
4.3.5. +^) +4R,4aS,7aS)-4-+4-benzyloxy-3,5-dimethoxy-
phenyl)-8,8-+propylen-1,3-dithio)-4,4a,5,7,7a,8-hexahydro-
thieno[2,3-f]isobenzofuran-5-one +5e) and +4R,4aS,7aS)-
4-+4-hydroxy-3,5-dimethoxyphenyl)-8,8-+propylen-1,3-
dithio)-4,4a,5,7,7a,8-hexahydro thieno[2,3-f]isobenzo-
furan-5-one +5e0). Following method A from 2.1 g of 3e,
quantities of 309 mg of 5e 715%) and 1.10 g of 5e0 762%)
were obtained. Following method B from 100 mg of 3e only
compound 5e0 760 mg, 74%) was obtained.
0
0
0
6.25 7s, H2 ,6 ); 4.69 7d, Jˆ4.4 Hz, H7 ); 4.40 7d, Jˆ13.2 Hz,
0
H9a); 3.87 7d, Jˆ4.4 Hz, H8 ); 3.80 7s, OMe); 3.75 7s,
2£OMe); 3.67 7s, COOMe); 3.30 7d, Jˆ13.1 Hz, H9b);
2.80±1.90 7m, 6H). 13C-NMR 7CDCl3): 28.47±CH2±);
34.37SCH2); 34.57SCH2); 37.079); 43.1780); 52.3
7COOMe); 53.0770); 56.3730,50OMe); 60.8740OMe); 105.6
720,60); 124.878); 125.275); 128.974); 135.077); 135.8710);
137.8740); 138.176); 140.271); 153.3730,50); 172.1790).
Synthesis of 5e from 5e0: K2CO3 7392 mg), KI 7479 mg) and
BnCl 70.17 mL) were added to a solution of 638 mg of 5e0 in
EtOH 760 mL) and re¯uxed for 12 h. After evaporation of
the solvent, the residue was extracted with EtOAc and the
organiclayer washed with brine and dried over Na 2SO4. By
¯ash chromatography 370 mg of 5e 750%) was isolated.
4.3.2. +^) +4R,4aS,7aS)-2-methyl-8,8-+propylen-1,3-
dithio)-4-+3,4,5-trimethoxyphenyl)-4,4a,5,7,7a,8-hexa-
hydrothieno[2,3-f]isobenzofuran-5-one +5b). Following
method B from 3.10 g of a mixture of 3b and 4b 73:1),
2.41 g of 5b 779%) was obtained. Mp 2568C. IR 7KBr):
1785, 1593, 1122 and 1010 cm21. MS m/z 7%): 478 7M1,
5e. IR 7CHCl3): 1780, 1630, 1520, 1220 and 940 cm21
.
42). 1H-NMR 7CDCl3): 6.46 7s, H2 ,6 ); 6.05 7s, H5); 4.68 7dd,
1H-NMR 7CDCl3): 7.50±7.25 7m, 5H, Ph); 7.15 7d, Jˆ
0
0
0
0
J1ˆ8.0, J2ˆ6.6 Hz, H9a); 4.51 7dd, J1ˆ10.6, J2ˆ8.0 Hz,
5.3 Hz, H4); 6.45 7s, H2 ,6 ); 6.36 7d, Jˆ5.3 Hz, H5); 4.98
0
H9b); 3.92 7d, Jˆ10.6 Hz, H7 ); 3.85 7s, OMe); 3.83 7s,
7s, CH2Ph); 4.65 7dd, J1ˆ8.3, J2ˆ6.8 Hz, H9a); 4.50
0
0
2£OMe); 3.43 7dd, J1ˆ14.0, J2ˆ10.6 Hz, H8 ); 3.30±3.10
7dd J1ˆ10.6, J2ˆ8.3 Hz, H9b); 4.00 7d, Jˆ10.5 Hz, H7 );
7m, H8); 2.97±2.00 7m, 6H); 2.34 7s, Me). 13C-NMR
3.76 7s, 2£OMe); 3.45 7dd, J1ˆ13.7, J2ˆ10.5 Hz, H8 );
0

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3971
3.30±3.10 7m, H8); 2.97±2.10 7m, 6H). 13C-NMR 7CDCl3):
23.37±CH2±) 29.17SCH2); 29.47SCH2); 44.2780); 45.178);
49.577); 55.6770); 56.2730,50OMe); 67.779); 74.87OCH2Ph);
106.5720,60); 125.775); 127.17OCH2Ph); 127.574); 127.9
7OCH2Ph); 127.97OCH2Ph); 128.17OCH2Ph); 136.5710);
137.4740); 139.776); 144.571); 153.4730,50); 174.1790).
of HgO and 0.1 mL of BF3´Et2O for 12 h, 83 mg of 6f0
765%) were isolated.
4.5. Epimerization of ketones 6 at C8
Method C. To a solution of trans-lactone 6 70.01 M in
EtOH) an excess of glacial acetic acid was added and
re¯uxed until disappearance of the starting material. Usual
work-up afforded after ¯ash chromatography cis-lactone 7.
5e0. Mp 2288C 7hexane±EtOAc). IR 7CHCl3): 3540, 1780,
1620, 1520 and 1210 cm21. MS m/z 7%): 450 7M1, 42). EA:
calc. for C21H22O5S3: C 56.0%; H 4.9%; found C 55.9%; H
1
4.7%. H-NMR 7CDCl3): 7.16 7d, Jˆ5.3 Hz, H4); 6.46 7s,
0
0
0
H2 ,6 ); 6.38 7d, Jˆ5.3 Hz, H5); 4.98 7d, Jˆ10.4 Hz, H7 );
4.68 7dd, J1ˆ8.3, J2ˆ6.7 Hz, H9a); 4.53 7dd J1ˆ10.6, J2ˆ
8.3 Hz, H9b); 3.84 7s, 2£OMe); 3.44 7dd, J1ˆ13.7, J2ˆ
By this method, 1.4 g of 6a were re¯uxed for 48 h to
produce 1.1 g of 7a 779%), and, 180 mg of 1:1 mixture
6e17e were re¯uxed for 48 h to produce 108 mg of 7e 759%).
0
10.3 Hz, H8 ); 3.30±3.10 7m, H8); 3.00±1.80 7m, 6H).
13C-NMR 7CDCl3): 23.77±CH2±) 29.47SCH2); 29.7
7SCH2); 44.5780); 45.678); 50.077); 55.9770); 56.7
730,50OMe); 68.079); 106.3720,60); 126.075); 127.574);
133.176); 133.1740); 134.1710); 140.471); 147.4730 50);
174.6790).
Method D. To a solution of trans-lactone 6 70.01 M in
CHCl3), TsOH 75 mol mol21) was added and re¯uxed
until disappareance of the starting material. Usual work-
up afforded after ¯ash chromatography cis-lactone 7.
By this method, 375 mg of 6c were treated with 597 mg of
TsOH for 3 h to produce 255 mg of 7c 768%), and 30 mg of
6d were treated with 80 mg of TsOH for 3 h to produce
14 mg of 7d 747%).
4.3.6. +^) +4R,4aS,7aS)-4-+4-hydroxy-3,5-dimethoxy-
phenyl)-8,8-+propylen-1,3-dithio)-4,4a,5,7,7a,8-hexahydro-
furo[3,4-f]benzofuran-5-one +5f0). Following method B
from 510 mg of 3f, 280 mg of 5f0 744%) was obtained. IR
7KBr): 3540, 1780 and 1620 cm21. MS m/z 7%): 434 7M1,
23). EA: calc for C21H22O6S2: C 58.0%; H 5.1%; found C
58.7%; H 5.4%. 1H-NMR 7CDCl3): 7.31 7d, Jˆ1.9 Hz, H4);
4.5.1. +^) +4R,4aS,7aS)-4-+3,4,5-trimethoxyphenyl)-
4,4a,5,7,7a,8-hexahydrothieno[2,3-f] isobenzofuran-5,8-
dione +6a). Mp 2108C 7CHCl3±hexane). IR 7KBr): 1780,
1
0
0
6.47 7s, H2 ,6 ); 5.94 7d, Jˆ1.9 Hz, H5); 4.58 7dd, J1ˆ8.9,
1687 and 1591 cm21. MS m/z 7%): 374 7M1, 100). H-
J2ˆ7.5 Hz, H9a); 4.51 7dd, J1ˆ10.4, J2ˆ8.9 Hz, H9b); 3.88
NMR 7CDCl3): 7.63 7d, Jˆ5.0 Hz, H4); 6.67 7d, Jˆ5.1 Hz,
0
0
0
7d, Jˆ10.3 Hz, H7 ); 3.85 7s, 2£OMe); 3.48±3.26 7m, H8);
H5); 6.45 7s, H2 ,6 ); 4.63 7dd, J1ˆ9.1, J2ˆ6.9 Hz, H9a); 4.38
0
0
3.27 7dd, J1ˆ13.3, J2ˆ10.3 Hz, H8 ); 3.00±2.00 7m, 6H).
7dd, J1ˆ10.2, J2ˆ9.1 Hz, H9b); 4.25 7d, Jˆ10.9 Hz, H7 );
13C-NMR 7CDCl3): 24.77±CH2±); 27.77SCH2); 28.8
7SCH2); 41.1780); 44.678); 46.077); 50.9770); 56.4
730,50OMe); 60.879); 105.5720,60); 110.275); 119.476);
131.771); 133.9710); 136.0740); 142.774); 146.9730,50);
174.3790).
3.85 7s, OMe); 3.83 7s, 2£OMe); 3.57 7ddd, J1ˆ15.8, J2ˆ
0
10.2, J1ˆ6.9 Hz, H8); 3.30 7dd, J1ˆ15.2, J2ˆ10.9 Hz, H8 ).
13C-NMR 7CDCl3): 45.9780); 49.178); 50.3770); 56.1
730,50OMe); 60.8740OMe); 65.979); 105.8720,60); 129.275);
134.776); 135.074); 136.7710); 137.4740); 153.4730,50);
155.271); 172.5790); 187.977).
4.4. Deprotection of dithianes 5
4.5.2. +^) +4R,4aS,7aR)-4-+3,4,5-trimethoxyphenyl)-4,4a,
5,7,7a,8-hexahydrothieno[2,3-f] isobenzofuran-5,8-dione
+7a). Mp 1848C 7CHCl3±hexane). IR 7KBr): 1770, 1660 and
1590 cm21. MS m/z 7%): 374 7M1, 100). EA: calc. for
C18H18O6S: C 60.9%; H 4.8%; found C 59.8%; H 4.6%.
1H-NMR 7CDCl3): 7.80 7d, Jˆ5.0 Hz, H4); 6.97 7d, Jˆ
To a solution of red HgO 72 mol mol21) and BF3´Et2O
72 mol mol21) in THF 7H2O 15%), the dithiane 5 70.05 M,
in THF±H2O 85:15) was slowly added and allowed to react
for 12 h. The mixture was diluted with CH2Cl2, ®ltered and
washed with saturated aq. NaHCO3 to yield 6.
0
0
5.0 Hz, H5); 6.27 7s, H2 ,6 ); 4.90 7d, Jˆ9.4 Hz, H9a); 4.88
0
7brs, H7 ); 4.36 7dd, J1ˆ9.4, J2ˆ4.5 Hz, H9b); 3.81 7s, OMe);
0
By this procedure the following results, after chromato-
graphicseparations, were obtained. 7a) By treatment of
1.9 g of 5a with 1.8 g of HgO and 1.0 mL of BF3´Et2O for
12 h, 1.3 g of 6a 784%) were isolated. 7b) By treatment of
32 mg of 5b with 30 mg of HgO and 16 mL of BF3´Et2O for
5 h, 26 mg of 6b 795%) were isolated; or by treatment of
2.4 g of 5b with 2.2 g of HgO and 1.2 mL of BF3´Et2O for
12 h, 818 mg of 7b 742%) and 510 mg of 15b were isolated.
7c) By treatment of 1.3 g of 5c with 1.2 g of HgO and
0.7 mL of BF3´Et2O for 12 h, 538 mg of 6c 754%) were
isolated. 7d) By treatment of 1.0 g of 5d with 940 mg of
HgO and 0.5 mL of BF3´Et2O for 12 h, 310 mg of 6d
739%) and 180 mg of 15d 723%) were isolated. 7e) By treat-
ment of 364 mg of 5e with 245 mg of HgO and 0.12 mL of
BF3´Et2O for 12 h, 180 mg of a 1:1 mixture of 6e17e 780%)
were isolated. 7f) By treatment of 161 mg of 5f0 with 161 mg
3.76 7s, 2£OMe); 3.40 7d, Jˆ4.5 Hz, H8); 3.39 7brs, H8 ).
13C-NMR 7CDCl3): 40.9780); 44.178); 48.2770); 56.1
730,50OMe); 60.8740OMe); 69.579); 104.4720,60); 129.475);
136.4710); 137.176); 137.1740); 137.474); 151.371);
153.7730,50); 175.5790); 187.977).
4.5.3. +^) +4R,4aS,7aS)-2-methyl-4-+3,4,5-trimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]isobenzo-
furan-5,8-dione +6b). IR 7KBr): 1782, 1682 and
1
1593 cm21. MS m/z 7%) 388 7M1, 88). H-NMR 7CDCl3):
0
0
6.66 7s, H5); 6.43 7s, H2 ,6 ); 4.65 7dd, J1ˆ9.5, J2ˆ3.9 Hz,
H9a); 4.39 7dd, J1ˆ10.6, J2ˆ9.5 Hz, H9b); 4.14 7d,
0
Jˆ11.0 Hz, H7 ); 3.86 7s, OMe); 3.83 7s, 2£OMe); 3.54±
0
3.42 7m, H8); 3.22 7dd, J1ˆ15.0, J2ˆ11.0 Hz, H8 ); 2.47 7s,
13
Me). C-NMR 7CDCl3): 16.4710); 40.8780); 43.878);
48.077 0); 56.173 0,5 0OMe); 60.774 0OMe); 69.579);

3972
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
13
104.4720,60); 128.075); 134.676); 137.0710); 137.2740);
152.074); 153.7730,50); 154.071); 175.6790); 187.077).
7s, Me). C-NMR 7CDCl3): 13.7710); 44.0780); 48.878);
50.4770); 56.3730,50OMe); 60.9740OMe); 66.179); 102.375);
105.9720,60); 124.576); 137.0710); 137.0740); 153.4730,50);
155.674); 164.871); 172.3790); 188.777).
4.5.4. +^) +4R,4aS,7aR)-2-methyl-4-+3,4,5-trimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]isobenzo-
furan-5,8-dione +7b). Mp 1788C 7hexane±EtOAc). IR
7KBr): 1770, 1651 and 1592 cm21. MS m/z 7%) 388 7M1,
99). EA: calc. for C20H20O6S: C 61.8%; H 5.2%; found C
4.5.9. 2-methyl-4-+3,4,5-trimethoxyphenyl)-5,7-dihydro-
furo[3,4-f]benzofurano-5-one +15d). Mp 2208C 7hexane±
EtOAc). IR 7KBr): 1757 and 1582 cm21. MS m/z 7%) 354
7M1, 100). H-NMR 7CDCl3): 7.70 7s, H7); 6.76 7s, H2 ,6 );
6.48 7s, H5); 5.34 7s, H9a, H9b); 3.94 7s, OMe); 3.88 7s,
2£OMe); 2.48 7s, Me). 13C-NMR 7CDCl3): 14.2 710); 56.2
730,50OMe); 60.9 740OMe); 68.0 79); 102.9 77); 103.0 75);
107.5 720,60); 116.1 76); 129.5 780); 130.9 78); 135.0 710);
138.1 740); 143.4 770); 152.7 730,50); 157.9 71); 158.1 74);
169.9 790).
1
1
0
0
61.0%; H 5.2%. H-NMR 7CDCl3): 6.66 7s, H5); 6.29 7s,
0
0
0
H2 ,6 ); 4.90 7d, Jˆ9.2 Hz, H9a); 4.77 7d, Jˆ1.1 Hz, H7 );
4.33 7dd, J1ˆ9.2, J2ˆ5.2 Hz, H9b); 3.81 7s, OMe); 3.78 7s,
0
2£OMe); 3.34 7d, Jˆ5.2 Hz, H8); 3.32 7d, Jˆ1.1 Hz, H8 );
13
2.52 7s, Me). C-NMR 7CDCl3): 16.5710); 46.0780);
49.178); 50.1770); 56.3730,50OMe); 60.9740OMe); 66.279);
105.8720,60); 127.875); 134.876); 137.5710); 137.7740);
152.874); 153.4730,50); 155.771); 172.6790); 186.677).
4.5.10. +^) +4R,4aS,7aR)-2-methyl-4-+3,4,5-trimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrofuro[3,4-f]benzofuran-
4.5.5. 2-methyl-4-+3,4,5-trimethoxyphenyl)-5,7-dihydro-
thieno[2,3-f]isobenzofuran-5-one +15b). Mp 2548C
5,8-dione +7d). IR 7KBr): 1780, 1694 and 1592 cm21. MS
1
m/z 7%) 372 7M1, 100). H-NMR 7CDCl3): 6.35 7s, H2 ,6 );
7hexane±EtOAc). IR 7KBr): 1758, 1581 and 1434 cm21
.
0
0
1
MS m/z 7%) 370 7M1, 100). H-NMR 7CDCl3): 7.79 7s,
0
6.32 7s, H5); 4.97 7d, Jˆ9.1 Hz, H9a); 4.71 7brs, H7 ); 4.31
7dd, J1ˆ9.1, J2ˆ5.8 Hz, H9b); 3.83 7s, OMe); 3.80 7s,
0
0
H7); 6.99 7s, H5); 6.68 7s, H2 ,6 ); 5.36 7s, H9a); 5.36 7s,
H9b); 3.95 7s, OMe); 3.86 7s, 2£OMe); 2.58 7s, Me). 13C-
NMR 7CDCl3): 16.4710); 56.2730,50OMe); 60.9740OMe);
67.879); 107.3720,60); 114.277); 121.575); 130.376); 130.3
780); 136.7710); 137.9740); 140.078); 141.3770); 142.674);
145.971); 152.7730,50); 169.8790).
2£OMe); 3.40 7dd, J1ˆ7.3, J2ˆ5.8 Hz, H8); 3.28 7d, Jˆ
7.6 Hz, H8 ); 2.42 7s, Me±C4). 13C-NMR 7CDCl3):
0
14.4710); 38.9780); 44.778); 48.3770); 55.3730,50OMe);
60.9740OMe); 69.079); 104.5720,60); 109.475); 123.476);
136.4710); 137.7740); 153.9730,50); 154.474); 162.271);
13
175.6790); 189.877). C-NMR 7CDCl3): 14.4710); 38.9780);
44.778); 48.3770); 55.3730,50OMe); 60.9740OMe); 69.079);
104.5720,60); 109.475); 123.476); 136.4710); 137.7740);
153.9730,50); 154.474); 162.271); 175.6790); 189.877).
4.5.6. +^) +4R,4aS,7aS)-4-+3,4,5-trimethoxyphenyl)-4,4a,
5,7,7a,8-hexahydrofuro[3,4-f] benzofuran-5,8-dione +6c).
Mp 2128C 7hexane±EtOAc). IR 7KBr): 1800, 1690, 1600
and 1510 cm21. MS m/z 7%) 358 7M1, 100). 1H-NMR
7CDCl3): 7.63 7d, Jˆ1.8 Hz, H4); 7.28 7d, Jˆ1.8 Hz, H5);
4.5.11. +^) +4R,4aS,7aR)-4-+4-benzyloxy-3,5-dimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]isobenzo-
furan-5,8-dione +7e). Mp 2088C. IR 7KBr): 1780, 1670 and
0
0
6.47 7s, H2 ,6 ); 4.64 7dd, J1ˆ9.6, J2ˆ7.0 Hz, H9a); 4.36 7t,
0
Jˆ9.6 Hz, H9b); 4.22 7d, Jˆ10.9 Hz, H7 ); 3.85 7s, OMe);
1600 cm21
.
1H-NMR 7CDCl3): 7.79 7d, Jˆ5.0 Hz, H4);
3.83 7s, 2£OMe); 3.55 7ddd, J1ˆ14.9, J2ˆ9.6, J3ˆ7.0 Hz,
H8); 3.25 7dd, J1ˆ14.9, J2ˆ10.9 Hz, H8 ). 13C-NMR
7.50±7.25 7m, 5H, Ph); 6.97 7d, Jˆ5.0 Hz, H5); 6.25 7s,
0
7CDCl3): 42.9770); 49.7780); 50.278); 56.1730,50OMe);
60.7740OMe); 65.779); 105.7720,60); 112.375); 133.676);
136.5710); 137.0740); 144.071); 148.974); 153.3730,50);
172.2790); 181.377).
0
0
H2 ,6 ); 4.96 7s, CH2Ph); 4.89 7d, Jˆ5.2 Hz, H9a); 4.88 7brs,
0
H7 ); 4.37 7dd, J1ˆ5.2, J2ˆ4.6 Hz, H9b); 3.74 7s, 2£OMe);
3.38 7d, Jˆ4.6 Hz, H8); 3.37 7brs, H8 ). 13C-NMR 7CDCl3):
0
41.4780); 44.378); 48.4770); 56.5730,50OMe); 69.579); 75.1
70CH2Ph); 105.2720,60); 127.87OCH2Ph); 127.97OCH2Ph);
128.37OCH2Ph); 128.37OCH2Ph); 129.575); 136.6710);
137.1 74); 137.276); 137.2740); 151.971); 154.3730,50);
175.4790); 187.977).
4.5.7. +^) +4R,4aS,7aR)-4-+3,4,5-trimethoxyphenyl)-4,4a,
5,7,7a,8-hexahydrofuro[3,4-f] benzofuran-5,8-dione +7c).
Mp 2488C 7CHCl3±ether). IR 7KBr): 1780, 1680, 1600 and
1470 cm21. MS m/z 7%) 358 7M1, 100). 1H-NMR 7CDCl3):
7.75 7d, Jˆ1.8 Hz, H4); 6.45 7d, Jˆ1.8 Hz, H5); 6.34 7s,
4.5.12. +^) +4R,4aS,7aS)-4-+4-hydroxy-3,5-dimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrofuro[3,4-f]benzofuran-
5,8-dione +6f0). IR 7KBr): 1760, 1680 and 1590 cm21. MS
0
0
0
H2 ,6 ); 4.95 7d, Jˆ9.2 Hz, H9a); 4.80 7d, Jˆ1.4 Hz, H7 );
4.33 7dd, J1ˆ9.2, J2ˆ5.6 Hz, H9b); 3.81 7s, OMe); 3.79 7s,
1
m/z 7%) 344 7M1, 79). H-NMR 7CDCl3): 7.62 7d, Jˆ
2£OMe); 3.47 7dd, J1ˆ7.6, J2ˆ5.6, J3ˆ7.0 Hz, H8); 3.30
13
7dd, J1ˆ7.6, J1ˆ1.4 Hz, H8 ). C-NMR 7CDCl3): 38.8780);
0
0
1.9 Hz, H4); 6.46 7s, H2 ,6 ); 6.18 7d, Jˆ1.9 Hz, H5); 4.65
0
45.078); 48.5770); 56.3730,50OMe); 60.9740OMe); 69.079);
104.5720,60); 112.575); 136.376); 136.3710); 137.6740);
140.371); 150.274); 153.9730,50); 175.4790); 181.377).
7dd, J1ˆ9.2, J2ˆ7.1 Hz, H9a); 4.35 7dd, J1ˆ11.5, J2ˆ
0
9.2 Hz, H9b); 4.20 7d, Jˆ10.7 Hz, H7 ); 3.86 7s, 2£OMe);
0
3.54±3.45 7m, H8); 3.20 7dd, J1ˆ14.8, J2ˆ10.7 Hz, H8 ).
13C-NMR 7CDCl3): 42.6780); 50.078); 50.2770); 56.3
730,50OMe); 65.679); 105.4720,60); 112.375); 128.976);
130.9740); 134.4710); 144.271); 147.3730,50); 148.874);
172.1790); 181.277).
4.5.8. +^) +4R,4aS,7aS)-2-methyl-4-+3,4,5-trimethoxy-
phenyl)-4,4a,5,7,7a,8-hexahydrofuro[3,4-f]benzofurano-
5,8-dione +6d). IR 7KBr): 1780, 1694 and 1592 cm21. MS
1
m/z 7%) 372 7M1, 100). H-NMR 7CDCl3): 6.42 7s, H2 ,6 );
0
0
6.31 7s, H5); 4.61 7dd, J1ˆ9.5, J2ˆ7.0 Hz, H9a); 4.42 7d,
4.6. Reduction of ketones 7
0
Jˆ10.6 Hz, H7 ); 4.36 7dd, J1ˆ10.6, J2ˆ9.5 Hz, H9b); 3.86
To a mixture of LiAlH 7tBuO)3 74 mol mol21) in THF
ketone 7 70.01 M in THF) was slowly added and allowed
7s, OMe); 3.84 7s, 2£OMe); 3.44 7ddd, J1ˆ15.0, J2ˆ10.6,
0
J3ˆ7.0 Hz, H8); 3.14 7dd, J1ˆ15.0, J2ˆ10.6 Hz, H8 ); 2.26

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3973
to react, at room temperature, for 4 h. The reaction was
quenched with a saturated NH4Cl solution and acidi®ed
with aqueous oxalicacid 7saturated solution). The aqueous
layer was extracted with EtOAc and after usual work-up
puri®ed by ¯ash chromatography.
OMe); 3.80 7s, 2£OMe); 3.13±3.05 7m, H8); 2.95 7dd,
42.778); 48.1770); 56.1730,50OMe); 60.8740OMe); 64.177);
71.179); 104.5720,60); 110.375); 119.476); 137.5710);
137.5740); 139.171); 143.674); 149.5730,50); 176.5790).
13
J1ˆ6.6, J2ˆ1.6 Hz, H8 ). C-NMR 7CDCl3): 37.9780);
0
4.6.5. +^) +4R,4aS,7aR,8R)-4-+4-benzyloxy-3,5-dimeth-
oxyphenyl)-8-hydroxy-4,4a,5,7,7a,8-hexahydrothieno-
[2,3-f]isobenzofuran-5-one +8e) and +^) +4R,4aS,7aR,8S)-
4-+4-benzyloxy-3,5-dimethoxyphenyl)-8-hydroxy-4,4a,5,
7,7a,8-hexahydrothieno[2,3-f] isobenzofuran-5-one +9e).
Data obtained from the NMR spectra of the mixture 8e19e.
By this procedure, 1.0 g of 7a, by treatment with 2.7 g of
LiAlH 7tBuO)3, yielded 610 mg 763%) of 8a19a 73:1).
300 mg of 7c, by treatment with 870 mg of LiAlH
7tBuO)3, yielded 175 mg 758%) of 8c19c 72:1). 117 mg of
7e, by treatment with 264 mg of LiAlH 7tBuO)3, yielded
45 mg 733%) of 8e19e 73:1). Characterization of
compounds 8, 9a and 9c was carried out with pure samples
isolated from the next protection and epimerization
processes.
1
8e. H-NMR 7CDCl3): 7.50±7.26 7m, 5H, Ph); 7.20 7d,
0
0
Jˆ5.0 Hz, H4); 6.60 7d, Jˆ5.0 Hz, H5); 6.38 7s, H2 ,6 );
4.97 7s, CH2Ph); 4.70 7d, Jˆ7.8 Hz, H7); 4.49 7d, Jˆ
0
9.2 Hz, H9a); 4.35 7brs, H7 ); 4.33 7dd, J1ˆ9.2, J2ˆ4.3 Hz,
4.6.1. +^) +4R,4aS,7aR,8R)-8-hydroxy-4-+3,4,5-trimeth-
oxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]isobenzo-
furan-5-one +8a). IR 7CHCl3): 3580, 1775, 1593 and
1130 cm21. MS m/z 7%) 376 7M1, 100). 1H-NMR
7CDCl3): 7.23 7d, Jˆ5.0 Hz, H4); 6.63 7d, Jˆ5.0 Hz, H5);
0
H9b); 3.76 7s, 2£OMe); 3.03 7dd, J1ˆ7.8, J2ˆ1.8 Hz, H8 );
2.73 7ddd, J1ˆ7.8, J2ˆ7.8, J3ˆ4.3 Hz, H8). 13C-NMR
7CDCl3): 40.7780); 43.178); 47.8770); 56.5730,50OMe);
66.977); 70.279); 75.170CH2Ph); 105.6720,60); 125.375);
127.87OCH2Ph);
127.87OCH2Ph);
128.174);
128.1
0
0
6.40 7s, H2 ,6 ); 4.77 7m, H7); 4.54 7d, Jˆ9.5 Hz, H9a);
7OCH2Ph); 128.37OCH2Ph); 136.6710); 138.1 740); 139.2
76); 140.671); 154.0730,50); 176.9790).
0
4.39 7d, Jˆ1.8 Hz, H7 ); 4.38 7dd, J1ˆ9.5, J2ˆ4.4 Hz,
H9b); 3.82 7s, OMe); 3.81 7s, 2£OMe); 3.04 7dd, J1ˆ7.7,
J2ˆ1.8 Hz, H8 ); 2.85±2.72 7m, H8). 13C-NMR 7CDCl3):
0
1
9e. H-NMR 7CDCl3): 7.50±7.26 7m, 5H, Ph); 7.21 7d,
40.4780); 42.978); 47.9770); 56.3730,50OMe); 60.9740OMe);
66.977); 70.379); 104.8720,60); 125.575); 128.274);
136.4710); 137.2740); 139.276); 140.671); 153.6730,50);
177.1790).
0
0
Jˆ5.2 Hz, H4); 6.66 7d, Jˆ5.2 Hz, H5); 6.35 7s, H2 ,6 );
5.09 7m, H7); 4.97 7s, CH2Ph); 4.61 7dd, J1ˆ9.0, J2ˆ
0
2.4 Hz, H9a); 4.35 7brs, H7 ); 4.47±4.35 7m, H9b); 3.76 7s,
0
13
2£OMe); 3.06 7m, H8, H8 ). C-NMR 7CDCl3): 40.1780);
45.6770); 45.678); 56.5730,50OMe); 64.077); 68.779);
4.6.2. +^) +4R,4aS,7aR,8S)-8-hydroxy-4-+3,4,5-trimeth-
oxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]isobenzo-
furan-5-one +9a). IR 7CHCl3): 3605, 1768, 1593 and
1130 cm21. MS m/z 7%) 376 7M1, 100). 1H-NMR
7CDCl3): 7.22 7d, Jˆ5.0 Hz, H4); 6.69 7d, Jˆ5.0 Hz, H5);
75.170CH2Ph); 105.6720,60); 125.175); 127.87OCH2Ph);
127.87OCH2Ph);
128.17OCH2Ph);
128.174);
128.3
7OCH2Ph); 136.6710); 137.7740); 138.176); 140.071);
153.7730,50); 177.3790).
0
0
6.36 7s, H2 ,6 ); 5.10 7d, Jˆ2.2 Hz, H7); 4.63 7d, Jˆ9.5 Hz,
0
H9a); 4.50 7brs, H7 ); 4.44 7dd J1ˆ9.5, J2ˆ6.5 Hz, H9b); 3.82
4.7. Protection of alcohols 819
7s, OMe); 3.79 7s, 2£OMe); 3.06 7m, H8, H8 ). 13C-NMR
0
7CDCl3): 39.0780); 40.978); 45.4770); 60.8740OMe); 63.877);
65.2730,50OMe); 68.979); 104.7720,60); 125.175); 128.174);
136.7710); 136.9740); 137.776); 140.371); 153.5730,50);
178.4790).
Method EÐas silyl derivates. To a solution of 8 and 9
70.05 M in CH2Cl2) and iPr2NEt 76 mol mol21), under
argon and cooled to 08C, TBDMSTf 74 mol mol21) was
added dropwise. After 4 h, a solution of oxalicacid was
added until acidic pH. The aqueous layer was extracted
with EtOAc. The crude product was puri®ed by ¯ash
chromatography.
4.6.3. +^) +4R,4aS,7aR,8R)-8-hydroxy-4-+3,4,5-trimeth-
oxyphenyl)-4,4a,5,7,7a,8-hexahydro furo[3,4-f]benzo-
furan-5-one +8c). IR 7KBr): 3380, 1760, 1660, 1580 and
1110 cm21. MS m/z 7%) 360 7M1, 100). 1H-NMR 7CDCl3):
Following this procedure, 390 mg of 10a 756%) and 180 mg
of starting 9a 735%) were obtained by treatment of 511 mg
of 8a19a 73:1) with 1.3 mL of TBDMSTf and 1.5 mL of
iPr2NEt. In the same way 95 mg of 10c 748%) and minor
amount of starting 9c 7,10%) were obtained by treatment
of 150 mg of 8c19c 72:1) with 0.3 mL of TBDMSTf and
0.4 mL of iPr2NEt.
0
0
7.41 7d, Jˆ1.8 Hz, H4); 6.37 7s, H2 ,6 ); 6.15 7d, Jˆ1.8 Hz,
H5); 5.02 7d, Jˆ6.6 Hz, H7); 4.78 7d, Jˆ9.5 Hz, H9a); 4.48
0
7d, Jˆ2.1 Hz, H7 ); 4.37 7dd J1ˆ9.5, J2ˆ5.8 Hz, H9b); 3.82
7s, OMe); 3.80 7s, 2£OMe); 3.13±3.05 7m, H8); 2.92 7dd,
13
J1ˆ8.0, J2ˆ2.1 Hz, H8 ). C-NMR 7CDCl3): 37.4780);
0
39.178); 46.0770); 56.1730,50OMe); 60.277); 60.8740OMe);
68.279); 104.3720,60); 110.475); 120.576); 137.5710); 137.5
740); 139.971); 143.674); 153.4730,50); 177.2790).
Method FÐas ethoxymethylether. A mixture of 120 mg of
a 3:1 mixture of 8a19a 70.02 M in CH2Cl2), 80 mL of
iPr2NEt 71.1 mol mol21), 33 mL of EOMCl 71.1 mol mol21
)
4.6.4. +^) +4R,4aS,7aR,8S)-8-hydroxy-4-+3,4,5-trimeth-
oxyphenyl)-4,4a,5,7,7a,8-hexahydrofuro[3,4-f]benzo-
furan-5-one +9c). IR 7KBr): 3380, 1760, 1660, 1580 and
1110 cm21. MS m/z 7%) 360 7M1, 100). 1H-NMR 7CDCl3):
7.39 7d, Jˆ2.0 Hz, H4); 6.15 7d, Jˆ2.0 Hz, H5); 6.45 7s,
and NaI 7catalytic) were re¯uxed for 12 h. The reaction was
quenched with a saturated NaHCO3 solution and after usual
work-up, the product was puri®ed by chromatography to
yield 98 mg of a 3:1 mixture of 16117 770%).
0
0
H2 ,6 ); 4.76 7m, H7); 4.46 7d, Jˆ9.1 Hz, H9a); 4.35 7d, Jˆ
0
1.6 Hz, H7 ); 4.33 7dd J1ˆ9.1, J2ˆ4.4 Hz, H9b); 3.82 7s,
By the same procedure 360 mg of 8a were converted into

3974
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
295 mg of 16 771%) by treatment with 0.25 mL of iPr2NEt
and 0.1 mL of EtOMCl, and 76 mg of 9a were converted
into 58 mg of 17 768%) by treatment with 54 mL of iPr2NEt
and 28 mL of EOMCl.
4.8. Epimerization of hydroxylactones 10 at C80
Method GÐwith LiHMDS. A solution of cis-lactone 10
70.05 M in THF) under argon, was cooled to 2788C and
LiHMDS 72 mol mol21) was added. The solution was main-
tained at this temperature for 10 min and then warmed to
08C and allowed to react for 40 min. Then it was cooled to
2788C and glacial acetic acid 74.3 M in THF) was added.
The usual work-up afforded after ¯ash chromatography the
reaction products.
4.7.1. +^) +4R,4aS,7aR,8R)-8-tert-butyldimethylsiloxy-4-
+3,4,5-trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno-
[2,3-f]isobenzofuran-5-one +10a). Mp 1848C 7CHCl3±
ether). IR 7KBr): 1782 and 1593 cm21. MS m/z 7%) 490
7M1, 57). EA: calc. for C25H34O6SSi: C 61.2%; H 7.0%;
1
found C 61.0%; H 7.1%. H-NMR 7CDCl3): 7.17 7d, Jˆ
0
0
5.1 Hz, H4); 6.58 7d, Jˆ5.1 Hz, H5); 6.43 7s, H2 ,6 ); 4.78
By this procedure only 10a or 10c were, respectively, recov-
ered in almost quantitative yield, from their treatment with
LiHMDS. When previous degasi®cation was not carried out
a mixture of 23 mg of 10a 746%) and 10 mg of 18 720%)
were produced from 50 mg of starting 10a.
7d, Jˆ7.4 Hz, H7); 4.48 7d, Jˆ9.1 Hz, H9a); 4.33 7dd J1ˆ
0
9.1, J2ˆ4.7 Hz, H9b); 4.32 7d, Jˆ2.2 Hz, H7 ); 3.83 7s,
OMe); 3.80 7s, 2£OMe); 3.06 7dd, J1ˆ7.5, J2ˆ1.8 Hz,
0
H8 ); 3.01 7m, H8); 0.98, 0.29, 0.22 7s, OTBDMS).
13C-NMR 7CDCl3): 24.177-OR); 24.177-OR) 18.077-OR);
25.777-OR); 40.4780); 43.778); 47.7770); 56.0730,50OMe);
60.6740OMe); 67.477); 69.779); 104.7720,60); 124.575);
127.674); 136.0710); 137.0740); 139.876); 140.471);
153.4730,50); 177.0790).
Method HÐLDA, tBuLi or NaNH2. A solution of cis-
lactone 10 70.05 M in THF) under argon, was cooled to
2788C and LDA, tBuLi or NaNH2 71.5 mol mol21) was
added, keeping the solution at this temperature for 15±
45 min. The reaction was quenched with glacial acetic
acid 74.3 M in THF) and the usual work-up afforded after
¯ash chromatography the reaction products.
4.7.2. +^) +4R,4aS,7aR,8R)-8-tert-butyldimethylsiloxy-4-
+3,4,5-trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrofuro-
[3,4-f]benzofuran-5-one +10c). 1H-NMR 7CDCl3): 7.34 7d,
0
0
Jˆ1.8 Hz, H4); 6.46 7s, H2 ,6 ); 6.14 7d, Jˆ1.8 Hz, H5); 4.74
4.9. Deprotection of the TBDMSO at C7
0
7d, Jˆ4.0 Hz, H7); 4.34 7m, H9a, H9b, H7 ); 3.83 7s, OMe);
0
3.81 7s, 2£OMe); 2.90 7m, H8, H8 ); 0.93, 0.29, 0.22 7s,
In some experiments, to a 0.02M solution of the crude
product from method H 710111) in CH3CN, 6 mol mol21
of TBAF was added and maintained at room temperature for
48 h. By evaporation of the solvent and chromatography
only non epimerized and deprotected 8 was isolated.
OTBDMS). 13C-NMR 7CDCl3): 24.37TBDMS); 24.8
7TBDMS); 18.17TBDMS); 25.77TBDMS); 38.1780);
44.878); 48.2770); 56.0730,50OMe); 60.7740OMe); 65.277);
71.179); 104.5720,60); 110.175); 119.476); 137.1710);
137.1740); 139.071); 143.174); 153.3730,50); 176.4790).
By this procedure, 70 mg of 10a were treated with LDA for
20 min to afford 65 mg of 5:1 mixture of 10a111a, which
was deprotected with 203 mg of TBAF, yielding 31 mg
763%) of 8a. After treatment of 100 mg of 10a with
12 mg of NaNH2 for 45 min, the starting material was
recovered unchanged. From the treatment of 75 mg of 10a
with 95 mL of tBuLi for 15 min, followed by deprotection
with 219 mg of TBAF, 30 mg 757%) of starting 10a and
11 mg of 19 718%) were obtained. The treatment of 42 mg
of 10c with LDA for 20 min, afforded 30 mg of a 5:1
mixture of 10c111c, which upon deprotection gave 20 mg
of 8c 763%).
4.7.3. +^) +4R,4aS,7aR,8R)-8-ethoxymethoxy-4-+3,4,5-
trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]-
isobenzofuran-5-one +16). IR 7KBr): 1775 and 1592 cm21
.
1
MS m/z 7%) 434 7M1, 83). H-NMR 7CDCl3): 7.23 7d, Jˆ
0
0
5.1 Hz, H4); 6.65 7d, Jˆ5.1 Hz, H5); 6.41 7s, H2 ,6 ); 4.95 7s,
0
OCH2O); 4.95 7c, Jˆ7.3 Hz, OEt); 4.83 7brs, H7 ); 4.76 7d,
Jˆ7.4 Hz, H7); 4.51 7dd, J1ˆ9.5, J2ˆ1.8 Hz, H9a); 3.81 7s,
OMe); 3.78 7s, 2£OMe); 3.36 7dd, J1ˆ9.5, J2ˆ4.7 Hz, H9b);
0
3.06 7dd, J1ˆ7.5, J2ˆ1.8 Hz, H8 ); 3.01 7m, H8); 1.26 7t,
Jˆ7.3 Hz, OEt). 13C-NMR 7CDCl3): 140.071); 127.874);
125.875); 136.376); 72.877); 41.278); 70.879); 136.9710);
104.7720,60); 153.4730,50); 137.0740); 47.6770); 40.7780);
177.0790); 56.1730,50OMe); 60.8740OMe); 95.277-OR);
64.177-OR); 15.177-OR).
4.9.1. +^) +4R,4aS,7aR,8R)-8,4a-dihydroxy-4-+3,4,5-tri-
methoxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]iso-
benzofuran-5-one +18). IR 7CHCl3): 3540, 1780, 1600,
1
1510 and 1110 cm21. MS m/z 7%) 392 7M1, 60). H-NMR
4.7.4. +^) +4R,4aS,7aR,8S)-8-ethoxymethoxy-4-+3,4,5-
trimethoxyphenyl)-4,4a,5,7,7a,8-hexahydrothieno[2,3-f]-
isobenzofuran-5-one +17). IR 7KBr): 1753, 1591 and
7CDCl3): 7.34 7d, Jˆ5.0 Hz, H4); 6.77 7d, Jˆ5.0 Hz, H5);
0
0
0
6.17 7s, H2 ,6 ); 4.88 7brs, H7); 4.42 7s, H7 ); 4.36 7d, Jˆ
9.0 Hz, H9a); 3.80 7s, OMe); 3.71 7s, 2£OMe); 3.40 7dd,
J1ˆ10.1, J2ˆ9.0 Hz, H9b); 3.30±3.10 7m, H8). 13C-NMR
7CDCl3): 51.078); 52.9770); 56.1730,50OMe); 60.9740OMe);
64.377); 67.979); 78.3780); 106.6720,60); 126.775); 128.174);
131.8710); 135.2740); 137.776); 138.071); 153.1730 50);
177.3790).
1
1028 cm21. MS m/z 7%) 474 7M1, 6). H-NMR 7CDCl3):
7.20 7d, Jˆ5.1 Hz, H4); 6.67 7d, Jˆ5.1 Hz, H5); 6.43 7s,
0
0
H2 ,6 ); 5.00 7d, Jˆ2.6 Hz, H7); 5.30 7s, OCH2O); 4.68 7c,
Jˆ7.3 Hz, OEt); 4.43 7dd, J1ˆ14.4, J2ˆ3.5 Hz, H9a); 3.84
7s, OMe); 3.80 7s, 2£OMe); 3.78±3.68 7m, H9b); 3.70 7d,
0
0
Jˆ7.1 Hz, H7 ); 3.56 7dd, J1ˆ9.5, J2ˆ7.1 Hz, H8 ); 3.12 7m,
H8); 1.23 7t, Jˆ7.3 Hz, OEt). 13C-NMR 7CDCl3): 15.177-
OR); 40.0780); 41.778); 45.5770); 56.2730,50OMe);
60.8740OMe); 64.077-OR); 68.577); 69.079); 93.077-OR);
104.9720,60); 124.675); 128.174); 133.8710); 136.8740);
138.976); 140.071); 153.5730,50); 178.4790).
4.9.2. +^) +4R,5S,6R,7R)-5-+2,2-dimethylpropanoyl)-7-
hydroxy-6-hydroxymethyl-4-+3,4,5-trimethoxyphenyl)-
4,5,6,7-tetrahydro benzothiophene +19). IR 7KBr): 3455,
1697, 1593 and 1127 cm21. MS m/z 7%) 434 7M1, 60).

A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
3975
13
1H-NMR 7CDCl3): 7.20 7d, Jˆ5.1 Hz, H4); 6.53 7d, Jˆ
3.66 7s, COOMe). C-NMR 7CDCl3): 45.9780); 52.4
7COOMe); 56.1730,50OMe); 56.7770); 60.8740OMe); 105.2
720 60); 125.079); 128.875); 135.774); 136.178); 137.0710);
137.3740); 139.276); 151.671); 153.4730,50); 171.7790);
179.877).
0
0
5.1 Hz, H5); 6.28 7s, H2 ,6 ); 5.06 7d, Jˆ2.6 Hz, H7); 4.20
7d, Jˆ10.6 Hz, H9a); 4.02 7dd, J1ˆ10.6, J2ˆ2.9 Hz, H9b);
0
3.93 7d, Jˆ11.3 Hz, H7 ); 3.80 7s, OMe); 3.76 7s, 2£
OMe); 2.50 7m, H8), 0.90 7s, tBu). 13C-NMR 7CDCl3):
26.97tBu); 29.87tBu); 43.3780); 46.878); 47.5770); 56.4
730,50OMe); 60.0740OMe); 60.579); 65.177); 106.5720,60);
125.375); 128.076); 135.9710); 137.2740); 138.774);
139.571); 153.2730,50); 218.2790).
4.10.3. +^) +4R,5S)-2-methyl-6-methylen-7-oxo-4-+3,4,5-
trimethoxyphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-
carboxylic acid +20b). IR 7KBr): 3480±2900, 1734, 1660,
1592 and 1127 cm21. MS m/z 7%) 388 7M1, 98). H-NMR
1
0
7CDCl3): 6.66 7s, H5); 6.50 7s, H9a); 6.31 7s, H2 ,6 ); 5.45 7s,
0
4.10. Synthesis of acids 20 and methyl esters 21
0
0
H9b); 4.63 7d, Jˆ4.4 Hz, H7 ); 3.93 7d, Jˆ4.4 Hz, H8 ); 3.82
7s, OMe); 3.76 7s, 2£OMe); 2.50 7s, Me±C4). 13C-NMR
7CDCl3): 16.6710); 45.7780); 56.2770); 56.3730,50OMe);
60.9740OMe); 105.2720,60); 125.379); 127.675); 136.276);
136.278); 137.4710); 137.4740); 138.874); 152.671); 153.5
730,50); 175.7790); 179.277).
Method IÐLactone ring opening. The trans-lactones 6 or
the cis-lactones 7 were treated with 1% KOH/MeOH at
room temperature for 30 min. After acidi®cation with 2N
HCl and usual work-up the acids 20 were isolated as pure
products.
4.10.4. +^) Methyl +4R,5S)-2-methyl-6-methylen-7-oxo-
4-+3,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydrobenzothio-
phene-5-carboxylate +21b). Mp 1308C 7hexane±EtAcO).
IR 7KBr): 1740, 1662, 1592 and 1266 cm21. MS m/z 7%)
Method JÐDiazomethane esteri®cation. Crude acids 20
from trans-lactones 6 or from cis-lactones 7 were treated
with an etheral CH2N2 solution for a few minutes. By
evaporation and chromatography the esters 21 were
isolated.
1
402 7M1, 37). H-NMR 7CDCl3): 6.50 7d, Jˆ1.1 Hz, H9a);
0
0
6.35 7s, H5); 6.32 7s, H2 ,6 ); 5.38 7d, Jˆ1.1 Hz, H9b); 4.64 7d,
0
0
Jˆ5.0 Hz, H7 ); 3.92 7d, Jˆ5.0 Hz, H8 ); 3.83 7s, OMe); 3.78
7s, 2£OMe); 2.51 7s, Me±C4). 13C-NMR 7CDCl3): 16.5710);
56.7770);
By these methodologies the following results were obtained.
7a) From 82 mg of 6a, by treatment with 10 mL of 1% KOH/
MeOH, 80 mg of 20a 798%) were produced and transformed
by method J into 75 mg of 21a 789%). From 67 mg of 7a by
method I 75 mL of 1% KOH/MeOH) followed by method J,
53 mg of 21a 776%) were isolated. 7b) From 24 mg of 6b, by
treatment with 5 mL of 1% KOH/MeOH, 21 mg of 20b
787%) were produced and transformed by method J into
15 mg of 21b 771%). From 50 mg of 7b by method I
73 mL of 1% KOH/MeOH) followed by method J, 35 mg
of 21b 767%) were isolated. 7c) From 225 mg of 6c, by
treatment with 10 mL of 1% KOH/MeOH, 192 mg of 20c
7not characterized) were produced and transformed by
method J into 120 mg of 21c 7overall 52%). 7d) From
82 mg of 6d, by treatment with 10 mL of 1% KOH/
MeOH, 80 mg of 20a 798%) were produced and transformed
by method J into 75 mg of 21a 789%). From 67 mg of 7a by
method I 75 mL of 1% KOH/MeOH) followed by method J,
53 mg of 21a 776%) were isolated.
45.9780);
52.67COOMe)
56.2730,50OMe);
60.9740OMe); 105.2720,60); 124.779); 127.675); 135.276);
136.278); 136.3710); 137.5740); 139.374); 152.471);
153.4730,50); 171.9790); 179.377).
4.10.5. +^) Methyl +4R,5S)-6-methylen-7-oxo-4-+3,4,5-
trimethoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-5-
carboxylate +21c). Mp 1248C 7hexane±EtAcO). IR 7KBr):
1740, 1680, 1600 and 1130 cm21. MS m/z 7%) 372 7M1,
1
52). H-NMR 7CDCl3): 7.69 7d, Jˆ1.8 Hz, H4); 6.38 7d,
0
0
Jˆ1.0 Hz, H9a); 6.36 7s, H2 ,6 ); 6.33 7d, Jˆ1.8 Hz, H5);
0
5.43 7d, Jˆ1.0 Hz, H9b); 4.63 7d, Jˆ5.1 Hz, H7 ); 3.89 7d,
0
Jˆ5.1 Hz, H8 ); 3.81 7s, OMe); 3.79 7s, 2£OMe); 3.68 7s,
13
COOMe). C-NMR 7CDCl3): 42.9780); 52.67COOMe);
56.1730,50OMe); 56.9770); 60.7740OMe); 105.0720,60);
111.975); 125.079); 135.3710); 135.3740); 139.976); 139.9
78); 148.371); 149.274); 153.3730,50); 171.5790); 173.977).
4.10.6. +^) +4R,5S)-2-methyl-6-methylen-7-oxo-4-+3,4,5-
trimethoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-5-
carboxylic acid +20d). IR 7KBr): 3497±3119, 1736, 1673,
1592 and 1100 cm21. 1H-NMR 7CDCl3): 6.38 7s, H9a); 6.31
4.10.1. +^) +4R,5S)-6-methylen-7-oxo-4-+3,4,5-trimethoxy-
phenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic
acid +20a). IR 7KBr): 3490±3080, 1730, 1592 and
1127 cm21. MS m/z 7%) 374 7M1, 100). 1H-NMR
7CDCl3): 7.69 7d, Jˆ5.0 Hz, H4); 6.82 7d, Jˆ5.0 Hz, H5);
0
0
0
7s, H5, H2 ,6 ); 5.48 7s, H9b); 4.71 7d, Jˆ4.4 Hz, H7 ); 3.88 7d,
0
Jˆ4.4 Hz, H8 ); 3.81 7s, OMe); 3.77 7s, 2£OMe); 2.29 7s,
0
0
6.38 7s, H9a); 6.29 7s, H2 ,6 ); 5.48 7s, H9b); 4.72 7d, Jˆ4.1 Hz,
13
Me±C4). C-NMR 7CDCl3): 13.6710); 43.4780); 55.6770);
0
0
H7 ); 3.98 7d, Jˆ4.1 Hz, H8 ); 3.81 7s, OMe); 3.74 7s,
56.2730,50OMe); 60.8740OMe); 102.775); 104.7720,60);
123.076); 125.979); 137.3710); 137.3740); 138.978); 153.5
730,50); 155.074); 163.771); 175.3790); 181.977).
13
2£OMe). C-NMR 7CDCl3): 45.6780); 56.1730,50OMe);
56.4770); 60.8740OMe); 105.1720,60); 125.879); 128.875);
136.174); 136.178); 136.9710); 137.2740); 138.776);
151.471); 153.4730,50); 175.7790); 179.977).
4.10.7. +^) Methyl +4R,5S)-2-methyl-6-methylen-7-oxo-
4-+3,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydrobenzo-
furan-5-carboxylate +21d). IR 7KBr): 1737, 1667, 1593
and 1130 cm21. MS m/z 7%) 386 7M1, 38). 1H-NMR
7CDCl3): 6.38 7d, Jˆ1.1 Hz, H9a); 6.36 7s, H5); 6.31 7s,
4.10.2. +^) Methyl +4R,5S)-6-methylen-7-oxo-4-+3,4,5-
trimethoxyphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-
carboxylate +21a). IR 7KBr): 1740, 1670,1600 and
1
1130 cm21. MS m/z 7%) 388 7M1, 68). H-NMR 7CDCl3):
0
0
0
H2 ,6 ); 5.43 7d, Jˆ1.1 Hz, H9b); 4.73 7d, Jˆ2.9 Hz, H7 );
7.68 7d, Jˆ4.8 Hz, H4); 6.82 7d, Jˆ4.8 Hz, H5); 6.37 7s,
0
0
0
0
3.89 7d, Jˆ2.9 Hz, H8 ); 3.82 7s, OMe); 3.78 7s, 2£OMe);
H9a); 6.31 7s, H2 ,6 ); 5.42 7s, H9b); 4.72 7d, Jˆ5.0 Hz, H7 );
0
3.70 7s, COOMe); 2.30 7s, Me±C4). 13C-NMR 7CDCl3):
3.98 7d, Jˆ5.0 Hz, H8 ); 3.82 7s, OMe); 3.77 7s, 2£OMe);

3976
A. C. Ramos et al. / Tetrahedron 57 ,2001) 3963±3977
13.6710); 43.7780); 52.97COOMe); 55.8770); 56.2
730,50OMe); 60.8740OMe); 102.775); 104.8720,60); 123.0
76); 125.479); 137.5710); 137.5740); 139.278); 153.5730,50);
154.974); 163.771); 171.8790); 181.877).
Financial support came from Spanish DGICYT 7Ref.:
SAF98-0103) and E. C. 7COST contract, Ref.: BIO4-
CT98-0451).
References
4.11. Synthesis of chloroderivatives
1. Jardine, I. In ªPodophyllotoxinsº in Anti-Cancer Agents
Based on Natural Products Models; Cassady, J. M.,
Douros, J. D., Eds.; Academic Press: New York, 1980; pp
319±351.
By treatment of 21 7in CH2Cl2) with a dry stream of HCl for
1.5 h followed by helium to eliminated the excess of
reagent, the chloro derivatives 22 were obtained in pure
form.
2. 7a) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984,
23, 1207±1220. 7b) MacRae, W. D.; Hudson, J. B.; Towers,
G. N. H. Planta Med. 1989, 55, 531±535.
Following this procedure, from 130 mg of 21a, 128 mg of
22a 797%), from 83 mg of 21c, 80 mg of 22c 790%) and
from 30 mg of 21d, 25 mg of 22d 789%), were produced.
3. 7a) Ward, R. S. Nat. Prod. Repts 1997, 14, 43±74. 7b) Ward,
R. S. Nat. Prod. Repts 1999, 16, 75±96. 7c) Massanet, G. M.;
Â
Pando, E.; Rodriguez-Luis, F.; ZubIa, E. Fitoterapia 1989, 60,
3±35.
4.11.1. +^) Methyl +4R,5S,6S)-6-chloromethyl-7-oxo-4-
+3,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydrobenzothio-
phene-5-carboxylate +22a). IR 7CHCl3): 1728, 1671, 1595
and 1120 cm21. 1H-NMR 7CDCl3): 7.63 7d, Jˆ4.8 Hz, H4);
4. 7a) Ward, R. S. Chem. Soc. Rev. 1982, 75±125. 7b) Ward, R. S.
Tetrahedron 1990, 46, 5029±5041. 7c) Ward, R. S. Synthesis
1992, 719±730.
0
0
6.61 7d, Jˆ4.8 Hz, H5); 6.40 7s, H2 ,6 ); 4.45 7dd, J1ˆ11.5,
5. Damayanthi, Y.; Lown, W. Current Med. Chem. 1998, 5,
205±252.
0
J2ˆ2.9 Hz, H9a); 4.38 7d, Jˆ11.0 Hz, H7 ); 3.86 7s, OMe);
0
3.82 7s, 2£OMe); 3.70 7t, Jˆ11.5 Hz, H8 ); 3.55 7dd, J1ˆ
6. 7a) Rao, C. B. S. Chemistry of Lignans; Andhra University
Press: Waltair, 1978. 7b) Ayres, D. C.; Loike, J. D. Lignans:
Chemical, Biological and Clinical Properties; Cambridge
University Press: Cambridge, 1990.
11.5, J2ˆ3.3 Hz, H9b); 3.54 7s, COOMe); 3.37 7dt, J1ˆ11.7,
13
J2ˆ2.9 Hz, H8). C-NMR 7CDCl3): 41.279); 47.3780);
50.878); 52.27COOMe); 53.4770); 56.3730,50OMe); 60.9
740OMe); 105.6720,60); 128.875); 135.374); 135.5710);
135.976); 137.7740); 152.971); 153.5730,50); 172.4790);
186.577).
È
7. Stahelin, H.; von Wartburg, A. ªFrom Podophylotoxin
Glucoside to Etoposideº. Prog. Drug Res. 1989, 33, 169±266.
 Â
8. Ramos, A. C.; Pelaez-Lamamie de Clairac, R.; Medarde, M.
Heterocycles 1999, 51, 1443±1470.
4.11.2. +^) Methyl +4R,5S,6S)-6-chloromethyl-7-oxo-4-
+3,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-
5-carboxylate +22c). IR 7KBr): 1737, 1693, 1593 and
9. 7a) Leteurtre, F.; Madalengoitia, J.; Orr, A.; Guzi, T.; Lehnert,
E.; MacDonald, T.; Pommier, Y. Cancer Res. 1992, 52, 4478±
4483. 7b) Tepe, J. J.; Madalengoitia, J. S.; Slunt, K. M.;
Werbovetz, K. W.; Spoors, P. G.; MacDonald, T. L. J. Med.
Chem. 1996, 39, 2188±2196. 7c) Madalengoitia, J. S.; Tepe,
J. J.; Werbovetz, K. W.; Lehnert, E. K.; MacDonald, T. L.
Bioorg. Med. Chem. 1997, 5, 1807±1815.
1134 cm21
.
1H-NMR 7CDCl3): 7.62 7d, Jˆ1.8 Hz, H4);
0
0
6.39 7s, H2 ,6 ); 6.17 7d, Jˆ1.8 Hz, H5); 4.45 7dd, J1ˆ11.7,
0
J2ˆ2.5 Hz, H9a); 4.38 7d, Jˆ11.0 Hz, H7 ); 3.86 7s, OMe);
0
3.83 7s, 2£OMe); 3.62 7t, Jˆ11.6 Hz, H8 ); 3.57 7s,
COOMe); 3.51 7dd, J1ˆ11.7, J2ˆ2.9 Hz, H9b); 3.33 7dt,
J1ˆ11.7, J2ˆ2.9 Hz, H8). 13C-NMR 7CDCl3): 41.079);
44.2780); 50.578); 52.27COOMe); 54.0770); 56.3
730,50OMe); 60.9740OMe); 105.3720,60); 111.975); 134.8
710); 134.8740); 141.076); 146.571); 148.874); 153.7730,50);
172.4790); 180.477).
Â
10. Medarde, M.; Ramos, A. C.; Caballero, E.; Lopez, J. L.;
Â
Pelaez, R.; San Feliciano, A. Tetrahedron Lett. 1996, 37,
2663±2666.
Â
Â
11. Medarde, M.; Ramos, A. C.; Pelaez-Lamamie de Clairac, R.;
Caballero, E.; San Feliciano, A. J. Chem. Soc. Perkin Trans.
1994, 1, 45±47.
4.11.3. +^) Methyl +4R,5S,6S)-6-chloromethyl-2-methyl-
7-oxo-4-+3,4,5-trimethoxyphenyl)-4,5,6,7-tetrahydro-
benzofuran-5-carboxylate +22d). IR 7KBr): 1736, 1682,
Â
12. Medarde, M.; Ramos, A. C.; Caballero, E.; Lopez, J. L.;
Â
Pelaez, R.; San Feliciano, A. Tetrahedron Lett. 1998, 39,
2001±2004.
13. 7a) San Feliciano, A.; Lopez, J. L.; Medarde, M.; Miguel del
Corral, J. M.; Pascual-Teresa, B.; Puebla, P. Tetrahedron
1593 and 1127 cm21
.
1H-NMR 7CDCl3): 6.35 7s, H5,
Â
0
0
0
H2 ,6 ); 4.47 7d, Jˆ11.3 Hz, H7 ); 4.40 7dd, J1ˆ11.7,
J2ˆ2.9 Hz, H9a); 3.87 7s, OMe); 3.83 7s, 2£OMe); 3.59 7s,
Â
1988, 44, 7255±7260. 7b) San Feliciano, A.; Lopez, J. L.;
0
COOMe); 3.58 7t, Jˆ11.5 Hz, H8 ); 3.50 7dd, J1ˆ11.7, J2ˆ
Medarde, M.; Miguel del Corral, J. M.; Pascual-Teresa, B.;
Puebla, P. Phytochemistry 1989, 28, 2863±2866.
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Van der Eycken, J.; Vandewalle, M. Tetrahedron 1991, 47,
4675±4682.
2.9 Hz, H9b); 3.26 7s, H10); 3.20 7dt, J1ˆ11.7, J2ˆ2.9 Hz,
13
H8). C-NMR 7CDCl3): 13.6710); 41.379); 45.3780); 50.4
78); 52.47COOMe); 52.9770); 56.3730,50OMe); 61.0
740OMe); 102.675); 105.5720,60); 122.676); 132.8710);
132.8740); 153.6730,50); 154.274); 163.571); 172.5790);
181.577).
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Acknowledgements
A. C. R. thanks the University of Salamanca for a predoc-
toral grant and R. P. the Spanish MEC for his contract.
16. Khun, M.; Von Wartburg, A. Helv.Chim. Acta 1967, 1546±
1565.

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Â
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Â
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