Highly diastereoselective Diels-Alder reactions with enantiopure sulfinyl-substituted 1-hydroxymethyldienes

Article abstract of DOI:10.1002/chem.200500191

Enantiopure hydroxy-2- and -3-sulfinyldienes undergo highly selective Diels-Alder cycloadditions with various dienophiles controlled by the chiral sulfur atom. The related hydroxy-2-sulfonyldienes display complementary π-facial selectivity.

Full text of DOI:10.1002/chem.200500191

Highly Diastereoselective Diels–Alder Reactions with Enantiopure Sulfinyl-
Substituted 1-Hydroxymethyldienes
Roberto Fernµndez de la Pradilla,* Carlos Montero, Mariola Tortosa, and Alma Viso[a]
Abstract: Enantiopure hydroxy-2- and -3-sulfinyldienes undergo highly selective
Diels–Alder cycloadditions with various dienophiles controlled by the chiral sulfur
atom. The related hydroxy-2-sulfonyldienes display complementary p-facial selec-
tivity.
Keywords: asymmetric synthesis ·
cycloaddition
·
Diels–Alder
·
sulfones · sulfoxides
Introduction
The asymmetric Diels–Alder reaction is a fundamental pro-
cess in modern synthetic chemistry, since up to four enantio-
and diastereomerically pure stereogenic centers are created
in a single step.[1] Within this field the use of chiral dieno-
philes has been extensively studied and more recently the
use of chiral Lewis acids as catalysts has achieved good
levels of asymmetric induction.[2] In contrast, the use of
enantiopure dienes has received far less attention, perhaps,
due to the difficulty often associated with the preparation of
these substrates.[3] Simple 2-sulfinyldienes[4,5] are especially
Scheme 1. Diastereoselective Diels–Alder cycloadditions with sulfinyl-
substituted 1-hydroxymethyldienes.
appealing, since, after a highly selective Diels–Alder cyclo-
addition, a vinyl sulfoxide is generated allowing for subse-
quent chirality-transfer operations.[6]
In recent years, we have been involved in the develop-
ment of different strategies for the synthesis of the enantio-
the sulfinyl Ar group in the cycloaddition process. Herein
we describe in detail our efforts in this field.
pure hydroxy-3- and -2-sulfinyldienes
C
and
D
(Scheme 1).[7,8] Since these routes gave access to substrates
with different substitution patterns, we thought it would be
interesting to carry out a general study of their Diels–Alder
reactivity.[9] Moreover, the synthesis of enantiopure dienes
D would provide a unique opportunity to assess the relative
p-facial stereodirecting abilities of two powerful elements of
stereocontrol in a Diels–Alder process.[5,10,11] In addition, in
some cases we have explored the influence of the nature of
Results
Preparation of starting materials: To begin our study we
synthesized several enantiopure dienols (Shown here). Hy-
droxy-3-sulfinyldienes 1 and 2 were prepared by Stille cou-
pling from the corresponding iodo vinyl sulfoxides.[8] Dien-
ols 1a–c were selected to evaluate the effect of representa-
tive R groups and different Ar substituents on sulfur. Com-
pound 2 was selected to test the influence of the E/Z geom-
etry of the dienol.
Hydroxy-2-sulfinyldienes 3 and 5 were synthesized from
enantiopure epoxy vinyl sulfoxides following our own meth-
odology.[7] We selected (Z,E)-dienes 3a–c and (E,E)-dienes
5a–c with different R2 and Ar groups to modulate 1,3-allylic
strain[13] and substrates 3d and 5d to explore the behavior
[a] Dr. R. Fernµndez de la Pradilla, Dr. C. Montero, Dr. M. Tortosa,
Dr. A. Viso
Instituto de Química Orgµnica
CSIC, Juan de la Cierva, 3
28006 Madrid (Spain)
Fax : (+34)91-564-4853
E-mail: iqofp19@iqog.csic.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200500191
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FULL PAPER
Treatment of a solution of these cycloadducts with silica
gel resulted in regioselective lactonization affording mix-
tures of lactones 8 and 9. The structure of these compounds
1
was derived from their H and 13C NMR spectra as well as
differential NOE data (Figure 1). At this stage, the structure
Figure 1. Spectral data for imide 7a and amide 9a.
assigned for minor isomer 9 made us readdress our previous
results on Diels–Alder cycloadditions with hydroxy-2-sulfi-
nyldienes and led us to revise our initial assignment (see
below).[9]
We then set out to explore the reactivity of diene 1a, as a
model substrate, with different dienophiles. The use of
maleic anhydride (MA) afforded lactone 10 practically as a
single isomer (Table 1, entry 4). Additionally, the reaction
with phenyltriazolinedione (PTAD) and p-benzoquinone
(Table 1, entries 5 and 6) took place with complete p-facial
selectivity to produce adducts 11 and 12 respectively. Com-
pound 12 was isolated by recrystallization from the crude
mixture, as purification by chromatography on silica gel led
to the formation of the aromatic derivative 13.
In contrast, the use of dimethyl acetylenedicarboxylate
(DMAD, Table 1, entry 7) required heating at 508C for
seven days, and produced a nonselective mixture of the dia-
stereoisomers 14a and 15a. Encouraged by the remarkable
rate enhancement observed for 1c with NPM, we explored
the reactivity of this diene with DMAD (Table 1, entry 8).
To our delight, the introduction of a 2-MeO-1-naphthylsul-
finyl substituent resulted in higher reactivity and p-facial se-
lectivity affording an 80:20 mixture of adducts 14c and 15c.
Finally, to investigate the influence of the geometry of the
diene in the Diels–Alder process, the behavior of dienol 2
with NPM was examined with disappointing results. Treat-
ment of 2 with NPM in CH2Cl2 for two days afforded cyclo-
adduct 7b and isomeric diene 1b. We believe dienol 2 iso-
merized to diene 1b, which reacted with NPM as described
above. In contrast, the more reactive PTAD gave a smooth
reaction with dienol 2 and cycloadduct 16 was obtained in
good yield and with high selectivity (Table 1, entry 9).
of a tetrasubstituted diene. Moreover, we prepared sulfonyl-
dienols 4a–d and 6a,c,d, by oxidation of the corresponding
sulfoxides, to clarify the role of the sulfinyl moiety on the
Diels–Alder process.
Diels–Alder cycloadditions with hydroxy-3-sulfinyldienes:
For our initial studies, we selected enantiopure dienes 1a–c
and the dienophile N-phenylmaleimide (NPM) (Table 1).
Treatment of 1a with NPM at room temperature afforded
cycloadduct 7a as a single isomer (Table 1, entry 1). The
process was also compatible with the presence of a conjugat-
ed phenyl group (Table 1, entry 2), affording cycloadduct 7b
in good yield and with high selectivity. The influence of the
Ar substituent on sulfur was then addressed by using the
readily available 2-MeO-1-naphthyl moiety;[13] we found a
striking enhancement of the rate with respect to the p-tolyl
analogue. Diene 1c underwent smooth Diels–Alder cycload-
dition affording 7c in just 2 h at 08C with excellent yield
and selectivity (Table 1, entry 3).
Diels–Alder cycloadditions of hydroxy-2-sulfinyldienes: Ini-
tially, we selected dienes 3a–c and NPM for our studies
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R. Fernµndez de la Pradilla et al.
Table 1. Diels–Alder cycloadditions of hydroxy-3-sulfinyldienes.
Entry Substrate Conditions[a]
Products[b]
Yield [%][c] Conditions[d] Products[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1a
1a
1a
1c
2
NPM, 2 d
NPM, 3 d
NPM, 08C, 2 h
MA, 1 d
7a
7b
7c
10
11
12
85
100
93
94
86
83
40
50
82
2 d
20 d
20 d
7a (8), 8a (78), 9a (14) 71
7b (3), 8b (97)
7c (6), 8c (72), 9c (22)
89
75
PTAD, CH2Cl2, À788C to RT, 2 h
p-benzoquinone, 1 d
13
70[e]
3.0 equiv, DMAD, 10 d; then 508C, 7 d 14a (50), 15a (50)
3.0 equivDMAD, 11 d
PTAD, CH2Cl2, À78 to 08C, 1 h
14c (80), 15c (20)
16
[a] Unless otherwise noted, the reactions were carried out with 1.5 equivof dienophile in toluene at RT. [b] Diastereomeric ratios are shown in parent he-
ses. [c] Combined yields of pure products after column chromatography. [d] Unless otherwise noted, the reactions were carried out with silica gel in
CH2Cl2 at RT. [e] Obtained after silica gel chromatography of 12.
(Table 2). Diene 3a afforded cycloadduct 18a as a single
isomer (shown by 300 MHz H NMR spectroscopic analysis
of the carboxamide bearing center (Figure 2). However, a
detailed 1H NMR spectroscopic study, the NOE enhance-
ments observed, and the assignment made for amides 9 re-
vealed that the correct structure of 20a was a regioisomeric
lactone.
1
of the crude reaction mixture), which was isolated in good
yield by recrystallization (Table 2, entry 1). To assess the in-
fluence of intramolecular hydrogen bonding on the stereo-
chemical outcome of this process, the cycloaddition between
diene 3a and NPM was carried out in MeOH and adduct
18a was easily obtained (Table 2, entry 2). However, treat-
ment of a solution of 18a with silica gel resulted in sponta-
neous lactonization and produced a 25:75 mixture of amides
19a and 20a. The structure of these compounds was also es-
tablished from their 1H and 13C NMR spectroscopic data.
Moreover, amides 19a and 20a displayed significant NOE
enhancements between Ha and Hb (11.5% and 10.4% re-
spectively). Considering the behavior observed for the lacto-
nization of related compounds,[14] we initially assigned
amide 20a as lactone E, derived from 19a by epimerization
Figure 2. Structural assignment for amide 20a.
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Diels–Alder Reactions
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Table 2. Diels–Alder cycloadditions of hydroxy-2-sulfinyl- and -sulfonyldienes with NPM.
Entry
Substrate
Conditions[a]
Products[b]
Yield [%][c]
71
Conditions[e]
5 d
Products[b]
Yield [%][d]
81
1
2
3
4
5
6
7
8
3a
3a
3b
3c[f]
3d
4a
4b
4d
5 d
18a
18a
19a (25), 20a (75)
MeOH, 5 d
1.1 equivNPM, 3 d
1.0 equivNPM, 18 d
1008C, 3 d
17b (5), 18b (95)
17c (8), 18c (92)
21 (90), 22 (7), 23 (3)
24a
25b
26
74
50
1 d
1 d
20b
20c
100
65 (2 steps)
5 d
25a
66
81
50
2.3 equivNPM, 3 d
1008C, 3 d
[a] Unless otherwise noted, the reactions were carried out with 1.5 equivof NPM in toluene at RT. [b] Diastereomeric ratios are shown in parentheses.
[c] Combined yield after recrystallization. [d] Combined yields of pure products after column chromatography. [e] Unless otherwise noted, the reactions
were carried out with silica gel in CH2Cl2 at RT. [f] 90% conversion.
Diene 3b (R2 =CH2Ph) afforded a 95:5 mixture of cyclo-
adduct 18b and amide 17b, respectively, as shown by the
1H NMR spectrum of the crude reaction mixture (Table 2,
entry 3). Treatment of 18b, isolated by recrystallization,
with silica gel resulted in a smooth cyclization affording
amide 20b and trace amounts of 19b. Diene 3c (R2 =iPr)
produced a 92:8 mixture of 18c and 17c after a longer reac-
tion time of 18 days (Table 2, entry 4). Treatment of cycload-
duct 18c with silica gel produced lactone 20c exclusively.
We then studied the cycloaddition of the tetrasubstituted
diene 3d with NPM (Table 2, entry 5), which required heat-
ing at 1008C for three days to afford a 90:7:3 mixture of 21,
22, and 23. The coupling constants and NOE enhancements
observed for Hb-Hc (JHc-Hb =8.8 Hz, NOE (Hb-Hc)=11.8%,
NOE (Hc-Hb)=10.4%) and Ha-Hb (JHa-Hb <1 Hz, NOE
(Ha-Hb)=2.8%) revealed that the major isomer 21 was de-
rived from opposite diastereofacial selectivity relative to the
examples above.
thesized enantiopure hydroxysulfonyldienes 4 from sulfox-
ides 3 by oxidation with MMPP (MMPP=magnesium bis-
(monoperoxyphthalate) hexahydrate).[15] Dienes 4a (Table 2,
entry 6) and 4b (Table 2, entry 7), with different steric re-
quirements, underwent cycloaddition with NPM affording
the very unstable cycloadduct 24, which lactonized sponta-
neously in the reaction media to give 25. Tetrasubstituted
diene 4d (Table 2, entry 8) was also an appropriate substrate
although it was found to be less reactive. These results show
that the allylic hydroxyl group is a powerful element of ster-
eocontrol in these compounds.
We believe that after treatment with silica gel, cycload-
ducts 18 afford amides 20 as major isomers as a conse-
quence of the location of the R2 group in the sterically de-
manding concave region of the molecule in lactones 19,
while for amides 21 and 25, R2 is placed on the convex face.
This fact would also explain the higher regioselectivity
found upon the lactonization of 18b and 18c.
To extend the scope of our methodology and seeking ad-
ditional support for the stereochemical assignments, we syn-
Our results for the cycloaddition between hydroxy-2-sulfi-
nyl and -2-sulfonyldienes and PTAD are presented in
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R. Fernµndez de la Pradilla et al.
Table 3. The cycloaddition of (Z,E)-dienes 3 (Table 3, en-
tries 1 and 2) and 4 (Table 3, entries 3 and 4) took place
with complete p-facial selectivity, essentially controlled by
the oxidation state at sulfur, and in high yield to produce ad-
ducts 27 and 28, respectively.
Next, we explored the reactivity of (E,E)-hydroxy-2-sulfi-
nyldienes. Treatment of diene 5a with NPM, under a variety
of conditions, resulted in the recovery of the starting materi-
al. In contrast, the use of PTAD afforded cycloadducts 29a
and 30a in high yield and with moderate p-facial selectivity
(Table 3, entry 5). We tried to diminish the extent of allylic
control by changing the polarity of the solvent; however,
this only led to a modest increase in the amount of 30a pro-
duced (Table 3, entries 6–9).[11] To our surprise, the diene
with the bulkier R2 substituent, 5b, produced a practically
nonselective mixture (Table 3, entry 10). To increase control
by the sulfinyl group we carried out the reaction of 5c with
a 2-MeO-1-naphthyl moiety in CH3CN affording, surprising-
ly, 29c as a single isomer in very good yield (Table 3,
entry 11). These somewhat unexpected results suggest that
for these dienes there is a reinforcing relationship[16] be-
tween the two elements of stereocontrol involving a confor-
mational change (see below). Diene 5d, with a tetrasubstitu-
tion pattern afforded practically a single isomer with PTAD
(Table 3, entry 12).
Table 3. Diels–Alder cycloadditions of hydroxy-2-sulfinyl- and -sulfonyldienes with PTAD.
Entry
Substrate
Conditions[a]
Products[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3c
4a
4c
5a
5a
5a
5a
5a
5b
5c
5d
6a
6c
6d
À78 to 08C, 1 h 15 min
27a
27c
28a
28c
87
90
78
90
83
–
–
–
–
90
92
82
74
63
100
2.0 equivPTAD, À788C to RT, 15 h
À78 to 08C, 1 h 15 min
2.0 equivPTAD, À788C to RT, 15 h
À78 to 08C, 1 h 30 min
29a (83), 30a (17)
29a (76), 30a (14)
29a (58), 30a (42)
29a (48), 30a (52)
29a (48), 30a (52)
29b (60), 30b (40)
29c
31d (99), 32d (1)
33a
33c
1% THF/CH2Cl2, À78 to 08C, 1 h 30 min
CH3CN, À78 to 08C, 1 h 30 min
acetone, À78 to 08C, 1 h 30 min
DMF, À78 to 08C, 1 h 30 min
2.0 equivPTAD, À78 to 08C, 1 h 30 min
CH3CN, À40 to 08C, 1 h
toluene, À788C to RT, 4 h
À78 to 08C, 1 h 30 min
À78 to 08C, 1 h
À788C to RT, 12 h
34d
[a] Unless otherwise noted, the reactions were carried out with 1.5 equivof PTAD in CH 2Cl2. [b] Diastereomeric ratios are shown in parentheses.
[c] Combined yields of pure products after column chromatography.
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Diels–Alder Reactions
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Finally, sulfonyldienes 6a,c,d produced cycloadducts 33a,c
and 34, respectively, as single products (Table 3, entries 13,
14, and 15) in good yield and with high selectivity, demon-
strating once again the powerful stereocontrol of the allylic
stereocenter.
(Z,E)-hydroxy-2-sulfinyldienes and from the mixture of 14c/
15c derived from the 3-sulfinyldienol. Thus, imide 18a was
oxidized to sulfone 36a, which upon treatment with silica
gel afforded a 25:75 mixture of amides 37a and 38a. Addi-
tionally, the oxidation of 18b, which contained the bulkier
R2 group, produced the unstable sulfone 36b. This com-
pound cyclized spontaneously to afford sulfone 38b, which
was also obtained by oxidation of lactone 20b. The diaster-
eomeric relationship found between amides 25 and 37/38,
along with the NOE enhancement observed between Ha-Hb
in amides 19 and 20, establishes that the p-facial selectivity
of the cycloaddition between dienes 3a–c and NPM is exclu-
sively controlled by the chiral sulfur atom. However, the ox-
idation of 21 afforded tricyclic sulfonyl amide 26, identical
to the product obtained from the cycloaddition of the sulfo-
nyl dienol 4d with NPM.
Chemical characterizations: To support the stereochemical
assignments discussed previously, we carried out several
sulfoxide oxidations using either MMPP or m-CPBA (meta-
chloroperbenzoic acid) (Schemes 2 and 3). Scheme 2 shows
both the oxidations of the cycloadducts obtained from the
For further verification of the stereochemical assignments,
the minor isomer 17b was oxidized with m-CPBA affording
amide 25b, which was also previously prepared from sulfo-
nyl diene 4b. This result confirmed that 17b was derived
from the approach of the dienophile to the chiral sulfinyl-
diene with opposite diastereofacial selectivity. Finally, the
oxidation of a mixture of 14c and 15c resulted in the obser-
1
vation of just a single sulfone in the H NMR spectrum of
the crude product, corroborating their diastereomeric rela-
tionship.
Scheme 3 shows the results found for cycloadducts synthe-
sized from hydroxy-2-sulfinyldienes and PTAD. Standard
oxidation of 27a,c afforded 39a,c, the spectral features of
which indicated a diastereomeric relationship to 28a,c. In
analogy with the Diels–Alder reaction with NPM, these ob-
servations established a sulfur-directed p-facial selectivity
for hydroxy sulfoxides 3 with PTAD and an allylic control
for hydroxydienyl sulfones 4. The stereochemical assignment
for 29a and 30a was made by oxidation of these compounds
and comparison of their spectral features to those of cyclo-
adduct 33a, previously prepared from sulfonyl diene 6a. Fi-
nally, oxidation of 31 and 29c revealed a similar stereochem-
ical outcome for the reaction of sulfoxides 5c,d and their
corresponding sulfones 6c,d with PTAD. Surprisingly, in the
oxidation of 29c with m-CPBA epoxy sulfone 41 was detect-
ed.[17] This compound was obtained as a single product by
using an excess of the oxidizing agent and longer reaction
time.
Discussion
We believe that this process is primarily controlled by ster-
eoelectronic effects. An early transition state is proposed in
each case with the most stable conformation also being the
most reactive. The stereochemical outcome of the Diels–
Alder cycloaddition for hydroxy-3-sulfinyl dienes may be ra-
tionalized by an exclusive endo approach of the dienophile
from the least hindered, highest electron density face of the
À
diene (a-face), for which an S-cis C=C/S : arrangement is
Scheme 2. Chemical characterizations by oxidation and lactonization.
proposed (Scheme 4).[18]
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R. Fernµndez de la Pradilla et al.
Scheme 5. Stereochemical rationalization for (Z,E)-sulfinyl- and -sulfo-
nyldienes.
the allylic stereocenter directs the approach of the dieno-
phile from the a-face, anti to R2, presumably with the aid of
attractive interactions between the hydroxyl group and the
dienophile.[11] However, for (Z,E)-sulfinyldienes the two ele-
ments of stereocontrol are in a nonreinforcing relationship
and the dienophile approaches the diene from the b-face,
anti to the Ar group on sulfur. The opposite p-facial selec-
tivity observed for diene 3d may be rationalized by assum-
À
ing that the conformation around the C S bond changes in
order to minimize steric interactions between the cyclohex-
enyl group and the Ar substituent (Scheme 5). Now the al-
lylic stereocenter and the sulfinyl group are in a reinforcing
relationship. This rationalization is in agreement with the re-
sults observed by Aversa et al. for related 2-sulfinyldienes
substituted at C3.[4b]
Scheme 3. Chemical characterizations of PTAD-derived cycloadducts by
oxidation.
In the case of hydroxy (E,E)-2-sulfonyldienes (Scheme 6)
an a-approach of the dienophile, anti to R2, is observed. Fi-
nally, the results found for (E,E)-2-sulfinyldienols
(Scheme 6) are likely to be a reflection of the conformation-
al equilibrium about the carbon–sulfur bond. Nevertheless,
for this dienophile both nonconcerted and stepwise mecha-
nisms have been proposed that could explain the low selec-
tivity found.[20] For diene 5d we also assumed that a confor-
À
mational change around the C S bond similar to that pro-
À
posed for 3d was occurring. This meant that the C S bond
Scheme 4. Stereochemical rationalization for 3-sulfinyldienes.
was more constrained due to C3 substitution, which justified
the selectivity enhancement observed with respect to 5a.
The preferred conformation for hydroxy-2-sulfonyl- and
-sulfinyldienes is likely to be dictated by 1,3-allylic strain be-
tween the hydroxyl-bearing stereocenter and the cis sub-
stituent. For (Z,E)-dienes the coupling constant between al-
lylic and vinylic protons (J=8–9 Hz) defined a dihedral
angle of 1808, which is in agreement with the proposed con-
formations E and F (Scheme 5).[19] For (Z,E)-sulfonyldienes
Conclusion
Hydroxy-2- and -3-sulfinyldienes display highly p-face selec-
tive Diels–Alder cycloadditions with various dienophiles
generating densely functionalized cycloadducts. Additional-
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Diels–Alder Reactions
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1
(determined by TLC analysis or H NMR spectroscopic analysis); the sol-
vent was then removed under reduced pressure and the crude product
was purified by recrystallization or by column chromatography on silica
gel by using the appropriate mixture of solvents.
General procedure for the cycloadditions between hydroxy sulfinyl/sulfo-
nyldienes and N-phenyltriazolinedione (PTAD): A pre-cooled solution
of N-phenyltriazolinedione (PTAD) (1.5–2.2 equiv) in CH2Cl2
(10 mLmmolÀ1 of PTAD) was added by syringe to a solution of hydroxy
diene (1.0 equiv) in CH2Cl2 (10 mLmmolÀ1) at À788C. The mixture was
then rapidly warmed to 08C whilst stirring. Once all of the starting mate-
rial had disappeared from the reaction mixture (determined by TLC
analysis) the solvent was removed under reduced pressure and the crude
product was purified by recrystallization or by column chromatography
on silica gel using the appropriate mixture of solvents.
(+)-(5S,8S,SS)-5-Butyl-8-hydroxymethyl-2-phenyl-6-(p-tolylsulfinyl)-2H-
[1,2,4]triazolo[1,2-a]pyridazine-1,3(5H,8H)-dione (11): Following the
general procedure cycloadduct 11 was obtained after 2 h from diene 1a[8]
(10 mg, 0.036 mmol, 1.0 equiv) and PTAD (10 mg, 0.054 mmol, 1.5 equiv)
in CH2Cl2 (0.4 mL). Purification by chromatography (30–80% EtOAc/
hexane) afforded 11 (14 mg, 0.031 mmol, 86%) as a white solid that was
recrystallized from EtOAc/hexane. Rf =0.31 (80% EtOAc/hexane); m.p.
90–928C; [a]2D0 =+104.3 (c=0.54 in acetone); 1H NMR (300 MHz,
CDCl3): d=0.85 (t, J=7.1 Hz, 3H), 1.17–1.38 (m, 4H), 1.71 (m, 1H),
1.95 (m, 1H), 2.41 (s, 3H), 3.97 (ddd, J=12.0, 6.3, 2.7 Hz, 1H), 4.14 (ddd,
J=12.0, 10.0, 2.7 Hz, 1H), 4.24 (dd, J=10.0, 2.6 Hz, 1H), 4.26 (td, J=5.1,
1.9 Hz, 1H), 4.65 (m, 1H), 6.73 (dd, J=2.8, 0.8 Hz, 1H), 7.32–7.48 (m,
7H), 7.53 ppm (d, J=8.3 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=13.7,
21.6, 22.4, 27.0, 32.8, 52.0, 60.9, 64.8, 122.9, 125.4 (2C), 125.9 (2C), 128.6,
129.2 (2C), 130.6, 130.8 (2C), 137.9, 143.7, 145.2, 149.7, 154.1 ppm; IR
(KBr): n˜ =3421, 3043, 2957, 2927, 2862, 1769, 1711, 1503, 1421, 1298,
1136, 1052, 811, 766 cmÀ1; MS (ES): m/z (%): 929 [2M+Na]+, 907
[2M+H]+, 476 [M+Na]+, 454 [M+H]+ (100); elemental analysis calcd
(%) for C24H27N3O4S (453.5): C 63.56, H 6.00, N 9.26, S 7.07; found: C
63.62, H 6.14, N 9.18, S 7.16.
Scheme 6. Stereochemical rationalization for (Z,E)-sulfinyl and -sulfonyl-
dienes.
ly, for 2-sulfinyldienes a reversal of p-facial selectivity is
found, relative to related sulfonyldienes, demonstrating that
the sulfinyl group is an extremely powerful element of ste-
reocontrol for intermolecular Diels–Alder cycloadditions.
We are currently addressing the application of these densely
functionalized cycloadducts in synthesis, particularly focus-
ing on subsequent regio- or stereocontrolled sulfur-directed
transformations,[6,21] and taking advantage of the remarkable
control of the p-facial selectivity of the cycloaddition by the
oxidation state at sulfur.
(À)-(3aR,4S,7S,7aR,SS)-4-[(1S)-Hydroxypentyl]-7-propyl-2-phenyl-5-(p-
tolylsulfinyl)-1,3,3a,4,7,7a-tetrahydro-2H-isoindole-1,3-dione (18a): Fol-
lowing the general procedure cycloadduct 18a was obtained after five
days from diene 3a[7] (38 mg, 0.12 mmol, 1.0 equiv) and NPM (63 mg,
0.36 mmol, 1.5 equiv) in toluene (1.5 mL). The product was obtained as a
white solid (42 mg, 0.085 mmol, 71%) after recrystallization (EtOAc/
hexane). In a related experiment cycloadduct 18a was obtained as a
single isomer from diene 3a (10 mg, 0.031 mmol) and NPM (8 mg,
0.046 mmol, 1.5 equiv) in MeOH (1 mL). The yield was not determined.
Rf =0.20 (30% EtOAc/hexane); m.p. 180–1828C; [a]2D0 =À92.0 (c=0.65
in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.88 (t, J=7.2 Hz, 3H), 1.02
(t, J=7.0 Hz, 3H), 1.21–1.61 (m, 7H), 1.73 (m, 1H), 1.91 (m, 1H), 2.07
(m, 1H), 2.13 (s, 3H), 2.53 (m, 1H), 2.77 (m, 1H), 3.28 (dd, J=9.0,
7.6 Hz, 1H), 3.43 (dd, J=9.1, 5.2 Hz, 1H), 4.38 (m, 1H), 5.25 (dd, J=3.3,
1.3 Hz, 1H), 6.75 (d, J=7.9 Hz, 2H), 6.87 (dd, J=3.7, 2.4 Hz, 1H), 7.21
(m, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.38 (m, 1H), 7.45 ppm (t, J=7.3 Hz,
2H); 13C NMR (50 MHz, CDCl3): d=13.9, 14.1, 21.2, 21.4, 22.7, 27.2,
32.7, 34.1, 38.3, 42.9, 43.3, 49.4, 67.1, 124.5 (2C), 125.8 (2C), 128.1, 128.7
(2C), 130.0 (2C), 138.0, 141.4, 143.6 (2C), 147.6, 174.4, 175.0 ppm; IR
(KBr): n˜ =3480, 3320, 2960, 2940, 2860, 1710, 1600, 1500, 1455, 1370,
Experimental Section
General: Reagents and solvents were handled by using standard syringe
techniques. All reactions were carried out under an argon atmosphere.
Hexane, toluene, and CH2Cl2 were distilled from CaH2; THF and Et2O
from sodium. Crude products were purified by flash chromatography on
230–400 mesh silica gel with distilled solvents. Analytical TLC was car-
ried out on silica gel plates with detection by UV light, iodine, acidic va-
nillin solution, and/or 10% phosphomolybdic acid solution in ethanol.
All reagents were commercial products. Throughout this section, the
1
volume of solvents is reported in mLmmolÀ1 of starting material. H and
13C NMR spectra were recorded at 200, 300, 400, or 500 MHz (1H) in
CDCl3 and with the residual solvent signal as an internal reference
(CDCl3, d=7.24 and 77.0 ppm). The following abbreviations are used to
describe peak patterns when appropriate: s (singlet), d (doublet), t (trip-
let), q (quartet), m (multiplet), and br (broad). Melting points are uncor-
rected. Optical rotations were measured at 208C using a sodium lamp
and in CHCl3. Low-resolution mass spectra were recorded using the elec-
tronic impact technique (EI) with an ionization energy of 70 eV or using
the atmospheric pressure chemical ionization (APCI) or electrospray
(ES) chemical ionization techniques in its positive or negative modes.
1330, 1180, 1140, 1120, 1080, 1030, 1015, 960, 940, 810, 750, 690, 625 cmÀ1
;
MS (EI): m/z (%): 494 [M+H]+, 476, 392, 348, 268, 217, 174, 139, 123, 91
(100), 77, 55, 41; elemental analysis calcd (%) for C29H35NO4S (493.7): C
70.56, H 7.15, N 2.84, S 6.50; found: C 70.65, H 7.06, N 2.93, S 6.58.
(À)-(1S,3aR,4R,5S,7aS,SS)-1-Butyl-3-oxo-5-propyl-7-(p-tolylsulfinyl)-
1,3,3a,4,5,7a-hexahydroisobenzofuran-4-N-phenylcarboxamide (19a) and
(À)-(1S,4S,5S,8S,9R,SS)-4-butyl-3-oxa-8-propyl-6-(p-tolylsulfinyl)bicyclo-
[3.3.1]non-6-en-2-one-9-N-phenylcarboxamide (20a): Following the gen-
eral procedure regioisomeric lactones 19a and 20a were obtained after
five days from diene 3a[7] (38 mg, 0.12 mmol, 1.0 equiv) and NPM
(63 mg, 0.36 mmol, 1.5 equiv) in toluene (1.5 mL). Purification was ach-
ieved by slow chromatography (5–50% EtOAc/hexane) and recrystalliza-
tion (MeOH) producing a 37:63 mixture of the regioisomeric lactones
19a (18 mg, 0.036 mmol) and 20a (30 mg, 0.061 mmol) as white solids
General procedure for the cycloadditions between hydroxy sulfinyl/sulfo-
nyldienes and dienophiles excluding N-phenyltriazolinedione (PTAD):
The dienophile (1–2.3 equiv) was added to a solution of hydroxydiene
(1.0 equiv) in toluene (10–15 mLmmolÀ1) at RT. Subsequently, the mix-
ture was stirred at RT until all of the starting material had disappeared
Chem. Eur. J. 2005, 11, 5136 – 5145
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5143

R. Fernµndez de la Pradilla et al.
(81% combined yield). In a related experiment, lactone 19a (10 mg,
0.020 mmol) was dissolved in CH2Cl2 (2 mL, 100 mLmmolÀ1), and silica
gel (430 mg, 2 gmmolÀ1) was added. The reaction mixture was stirred at
RT and monitored by TLC (5 days). After this time, the silica gel was re-
moved by filtration with EtOAc to yield a 25:75 mixture (determined by
1H NMR spectroscopic analysis) of 19a and 20a (90%). A similar mix-
ture of lactones was obtained from the treatment of cycloadduct 18a
with silica gel.
(%) for C29H35NO5S (509.7): C 68.34, H 6.92, N 2.75, S 6.29; found: C
68.48, H 6.84, N 2.67, S 6.17.
General procedure for oxidation with m-CPBA: m-CPBA (55 or 70% by
weight, 1.5–1.8 equiv) was added to a solution of sulfoxide (1.0 equiv) in
CH2Cl2 (15 mLmmolÀ1) at À788C. The reaction mixture was stirred and
gradually warmed to RT. Once the starting material had disappeared (de-
termined by TLC analysis) the mixture was quenched with a saturated
solution of Na2S2O4 (4 mLmmolÀ1) and diluted with EtOAc, and the
layers were separated. The organic phase was washed three times with
NaHCO3 solution (5%, 50 mLmmolÀ1), once with a saturated solution of
NaCl (10 mLmmolÀ1), dried over anhydrous MgSO4, and concentrated to
give the crude product, which was then purified by column chromatogra-
phy or by recrystallization.
Data for 19a: Rf =0.25 (50% EtOAc/hexane); m.p. 182–1838C; [a]D20
=
À12.0 (c=0.52 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.90 (t, J=
7.1 Hz, 3H), 0.91 (t, J=7.0 Hz, 3H), 1.31–1.72 (m, 9H), 1.87 (m, 1H),
2.40 (s, 3H), 2.80 (m, 1H), 2.85 (t, J=4.9 Hz, 1H), 2.95 (m, 1H), 3.40
(dd, J=8.9, 4.5 Hz, 1H), 4.44 (m, 1H), 7.09 (t, J=7.4 Hz, 1H), 7.28–7.33
(m, 4H), 7.36 (d, J=5.1 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.55 (d, J=
7.5 Hz, 2H), 10.15 ppm (brs, 1H); NOE between H-1/H-7a: 11.5%, be-
tween H-3a/H-7a: 11.0%, between H-3a/H-4: 11.0%; 13C NMR
(50 MHz, CDCl3): d=13.8, 14.0, 21.3, 21.5, 22.3, 29.0, 33.4, 33.5, 38.4,
40.6, 42.0, 47.6, 82.5, 120.1 (2C), 124.5, 126.1 (2C), 128.9 (2C), 130.6
(2C), 136.4, 138.0, 139.4, 139.7, 143.3, 168.9, 178.9 ppm; IR (CCl4): n˜ =
3300, 3150, 2970, 2940, 2880, 1750, 1680, 1600, 1550, 1500, 1490, 1450,
1200, 1080, 1050, 1020 cmÀ1; MS (EI): m/z (%): 493 [M]+, 476, 444, 391,
354, 285, 243, 217, 174, 139, 123, 93, 91 (100), 77, 41; elemental analysis
calcd (%) for C29H35NO4S (493.7): C 70.56, H 7.15, N 2.84, S 6.50; found:
C 70.49, H 7.07, N 2.95, S 6.40.
(À)-(3aR,4S,7S,7aR)-4-[(1S)-Hydroxypentyl]-5-(p-tolylsulfonyl)-7-
propyl-2-phenyl-1,3,3a,4,7,7a-tetrahydro-2H-isoindole-1,3-dione
(36a):
Following the general procedure sulfonyl cycloadduct 36a was obtained
after 2 h 30 min from cycloadduct 18a (27 mg, 0.054 mmol, 1.0 equiv) and
m-CPBA (25 mg, 0.081 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL). Recrystalli-
zation (EtOAc) produced the sulfonyl cycloadduct 36a as a white solid
(18 mg, 0.035 mmol, 65%). This compound was unstable in CDCl3 and
evolved into a 50:50 mixture of the corresponding lactones after three
days. Rf =0.18 (30% EtOAc/hexane); m.p. 152–1608C; [a]2D0 =À65.6 (c=
0.67 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.91 (t, J=7.3 Hz, 3H),
0.97 (t, J=7.2 Hz, 3H), 1.21–1.60 (m, 6H), 1.78–1.89 (m, 1H), 1.96–2.06
(m, 3H), 2.23 (s, 3H), 2.45 (m, 1H), 2.73 (m, 1H), 3.28 (dd, J=8.9,
7.3 Hz, 1H), 3.49 (dd, J=9.0, 5.0 Hz, 1H), 4.37 (brs, 1H), 4.55 (m, 1H),
6.90 (dd, J=4.4, 2.2 Hz, 1H), 6.96 (d, J=7.9 Hz, 2H), 7.14 (dt, J=7.0,
1.6 Hz, 2H), 7.44–7.46 (m, 3H), 7.57 ppm (d, J=8.3 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d=13.9, 14.1, 21.3, 21.6, 22.7, 27.3, 32.5, 34.3, 35.3,
38.1, 43.1, 48.0, 67.4, 125.9 (2C), 128.2 (2C), 128.3, 128.8 (2C), 129.9,
130.2, 131.6, 144.5, 144.9, 146.3, 161.2 ppm (2C); MS (ES): m/z (%): 1041
[2M+Na]+, 1019 [2M+H], 532 [M+Na]+, 510 [M+H]+ (100).
Data for 20a: Rf =0.17 (50% EtOAc/hexane); m.p. 183–1858C; [a]D20
=
À66.8 (c=1.84 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.85 (t, J=
6.9 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H), 1.20–1.69 (m, 10H), 2.33 (brs, 1H),
2.44 (s, 3H), 2.56 (brs, 1H), 2.68 (m, 1H), 3.12 (d, J=6.0 Hz, 1H), 4.37
(tt, J=8.5, 3.1 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 7.10 (t, J=7.3 Hz, 1H),
7.16 (brs, 1H), 7.28–7.39 (m, 6H), 7.55 ppm (d, J=8.1 Hz, 2H); NOE be-
tween H-1/H-9: 4.4%, between H-1/H-8: 8.9%, between H-4/H-5:
10.4%, between H-5/H-9: 3.0%, between H-5/H-4: 13.7%; 13C NMR
(50 MHz, CDCl3): d=13.9, 20.4, 21.6, 22.4, 27.9, 29.7, 34.0, 34.1, 35.0,
41.2, 41.4, 47.9, 79.0, 119.8 (2C), 125.1, 126.4 (2C), 129.1 (2C), 130.4
(2C), 133.9, 136.9, 139.3, 140.7, 143.1, 168.8 ppm (2C); IR (CCl4): n˜ =
3340, 3320, 2960, 2940, 2880, 1740, 1680, 1610, 1550, 1500, 1450, 1385,
1320, 1260, 1210, 1180, 1080, 1040, 810, 760, 690 cmÀ1; MS (EI): m/z (%):
494 [M+H]+, 477, 476 (100), 392, 348, 268, 217, 174, 123, 93, 91, 77, 65,
57, 41; elemental analysis calcd (%) for C29H35NO4S (493.7): C 70.56, H
7.15, N 2.84, S 6.50; found: C 70.45, H 7.05, N 2.75, S 6.59.
Acknowledgements
This research was supported by DGICYT (BQU2003–02921) and CAM
(GR/SAL/0823/2004). We thank JANSSEN-CILAG for generous addi-
tional support. We thank CAM and MEC for the doctoral fellowships
granted to C.M. and M.T.
(+)-(1S,3aS,4S,5R,7aR)-1-Butyl-3-oxo-5-propyl-7-(p-tolylsulfonyl)-
1,3,3a,4,5,7a-hexahydroisobenzofuran-4-N-phenylcarboxamide (25a): Fol-
lowing the general procedure amide 25a was obtained after five days
from diene 4a[7] (12 mg, 0.035 mmol, 1.0 equiv) and NPM (9 mg,
0.053 mmol, 1.5 equiv) in toluene (0.5 mL). Recrystallization of the crude
(EtOAc) produced amide 25a as a white solid (12 mg, 0.023 mmol,
66%). This product was subjected to chromatography on silica gel (5–
50% EtOAc/hexane) uneventfully. In a separate experiment the reaction
described above was monitored by 1H NMR spectroscopy, and after 24 h
was found to show a 60:40 mixture of 24a and 25a with 47% conversion.
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Partial data for 24a (from the crude reaction mixture after 24 h):
1H NMR (300 MHz, CDCl3): d=2.41 (s, 3H), 3.31 (dd, J=9.0, 6.8 Hz,
1H), 3.64 (d, J=4.1 Hz, 1H), 3.80 (dd, J=8.9, 6.0 Hz, 1H), 4.54 (m, 1H),
6.96 (dd, J=4.7, 2.1 Hz, 1H).
Data for 25a: Rf =0.38 (50% EtOAc/hexane); m.p. 190–1928C; [a]D20
=
101.5 (c=0.98 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.89 (t, J=
6.9 Hz, 6H), 1.19–1.78 (m, 9H), 1.80 (m, 1H), 2.44 (s, 3H), 2.87–2.88 (m,
2H), 3.10 (brd, J=9.3 Hz, 1H), 3.44 (dd, J=9.3, 4.7 Hz, 1H), 4.86 (m,
1H), 7.10 (t, J=7.3 Hz, 1H), 7.27–7.36 (m, 5H), 7.52 (d, J=8.3 Hz, 2H),
7.77 (d, J=8.3 Hz, 2H), 9.97 ppm (brs, 1H); NOE between H-1/H-7a:
1.5%, between H-3a/H-7a: 7.4%, between H-3a/H-4: 6.6%; 13C NMR
(50 MHz, CDCl3): d=13.9, 21.1, 21.6, 22.2, 27.3, 33.3, 35.4 (2C), 38.2,
39.6, 40.9, 46.5, 83.5, 120.3 (2C), 124.7, 127.7 (2C), 129.0 (2C), 130.1
(2C), 136.1, 136.6, 137.8, 144.9, 145.7, 168.7, 178.5 ppm; IR (KBr): n˜ =
3440, 3380, 2960, 2860, 1760, 1680, 1600, 1530, 1500, 1440, 1310, 1260,
1140, 1090, 1030, 800, 760, 690, 670 cmÀ1; MS (EI): m/z (%): 510 [M+1]+,
354, 233, 155, 139, 117, 91 (100), 93, 77, 55, 41; elemental analysis calcd
5144
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 5136 – 5145

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Received: February 21, 2005
Published online: July 6, 2005
Chem. Eur. J. 2005, 11, 5136 – 5145
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