Sulfoxide-directed intramolecular [4 + 2] cycloadditions between 2-sulfinyl butadienes and unactivated alkynes

Article abstract of DOI:10.1021/jo9024489

Chemical Equation Presented Sulfinyl dienynes undergo thermal and catalyzed IMDA cycloadditions, often at room temperature, to produce cyclohexa-1,4-dienes with good yields and high selectivities. Additionally, the products preserve a synthetically useful vinyl sulfoxide functionality. The selective manipulation of the double bonds in the cycloadducts has also been examined in this work.

Full text of DOI:10.1021/jo9024489

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Sulfoxide-Directed Intramolecular [4 þ 2] Cycloadditions between
2-Sulfinyl Butadienes and Unactivated Alkynes
ꢀ
Roberto Fernandez de la Pradilla,* Mariola Tortosa,* Esther Castellanos, Alma Viso, and
Raquel Baile
´
ꢀ
Instituto de Quımica Organica General, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
iqofp19@iqog.csic.es; mtortosa@iqog.csic.es
Received November 16, 2009
Sulfinyl dienynes undergo thermal and catalyzed IMDA cycloadditions, often at room temperature,
to produce cyclohexa-1,4-dienes with good yields and high selectivities. Additionally, the products
preserve a synthetically useful vinyl sulfoxide functionality. The selective manipulation of the double
bonds in the cycloadducts has also been examined in this work.
Introduction
sulfoxide is generated upon a highly selective Diels-Alder
cycloaddition.4
The Diels-Alder reaction is one of the most powerful
methods for stereospecific carbon-carbon bond formation.1
The asymmetric version is a fundamental process in modern
synthetic chemistry, since compounds with up to four enantio-
and diastereomerically pure stereogenic centers are created in a
single step.2 In this context, the use of chiral dienophiles has
been extensively studied, and more recently the use of chiral
Lewis acids and catalysts has resulted in good levels of asym-
metric induction. However, the use of enantiopure dienes has
received less attention. In most cases,3 the nature of the chiral
auxiliary (chiral tetrahydropyrans,3d chiral amines and oxazo-
lidinones,3e or homochiral anthracenes3m among others) does
not allow for subsequent chirality transfer operations. Simple
2-sulfinyl dienes are therefore attractive because a vinyl
In recent years, we have been involved in the development
of different strategies for the synthesis of enantiopure hydro-
xy sulfinyl dienes,5 and we have carried out a general study of
their intermolecular Diels-Alder reactivity.6 To extend this
study, we decided to test the intramolecular Diels-Alder7
(IMDA) variant using 2-sulfinyl dienes A, and we focused
our attention on the cycloadditions of dienynes B (Figure 1)
to produce cyclohexa-1,4-dienes C,8 which preserve a synthe-
tically useful vinyl sulfoxide.9,10 In the absence of a sulfinyl
moiety, IMDA cycloadditions of this class of dienynes
generally requires harsh thermal conditions that limit their
(3) For reviews on chiral dienes, see: (a) Winterfeldt, E. Chem. Rev. 1993, 93,
827–843. (b) Fringelli, F.; Tatichi, A. Dienes in the Diels-Alder Reaction; Wiley:
ꢀ
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New York, 1990. (c) Barluenga, J.; Suarez-Sobrino, A.; Lopez, L. A. Aldrichimica
Acta 1999, 32, 4–15. For recent references on asymmetric Diels-Alder with
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Chem. Commun. 2000, 1579–1580. (e) Janey, J. M.; Iwama, T.; Kozmin, S. A.;
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Suzuki, D.; Sato, F. Tetrahedron Lett. 2002, 43, 285–289. (g) Jarosz, S.;
Szewczyk, K.; Stanislaw, S.; Ciunik, Z.; Pietrzak, A. Tetrahedron: Asymmetry
2002, 13, 2223–2228. (h) Huang, H.-L; Liu, R.-S. J. Org. Chem. 2003, 68, 805–
810. (i) Kuethe, J. T.; Brooks, C. A.; Comins, D. L. Org. Lett. 2003, 5, 321–323.
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Chem. Soc. 2004, 126, 9522–9523. (m) Burgess, K. L.; Lajkiewicz, N. J.; Sanyal,
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Smolko, K. I. Org. Lett. 2005, 7, 251–253. (o) Monbaliu, J.-C.; Robiette, R.;
Peeters, D.; Marchand-Brynaert, J. Tetrahedron Lett. 2009, 50, 1314–1317.
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DOI: 10.1021/jo9024489
r
Published on Web 01/29/2010
J. Org. Chem. 2010, 75, 1517–1533 1517
2010 American Chemical Society

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Fernandez de la Pradilla et al.
JOCArticle
and vinyl stannanes.5a,b,13 Dienols 1a-g were selected to
evaluate the effect of different substituents on the diene and
different Ar groups on sulfur. Additionally, dienes 1h,i were
prepared in order to study the influence of the sulfoxide on
different positions of the diene.
Diels-Alder Cycloaddition with Sulfinyl Dienynes. For
our initial study, we selected dienyne 2a and triene 2a0
(Scheme 2), which were readily available by standard pro-
pargylation and allylation of dienol 1a. Dienyne 2a gave a
67:33 mixture of cycloadducts 3a and 4a under exceptionally
mild conditions (rt, CDCl3, 10 days, Table 1, entry 1) in con-
trast with the high temperature needed for the IMDA cyclo-
addition of related dienynes lacking the sulfinyl group.11a,14
Next, we studied the effect of Lewis acid catalysis (Table 1,
entries 2-4), observing an enhancement of rate and selectiv-
ity with ZnBr2. Unfortunately, the IMDA reaction of 2a0 was
not successful under any of the conditions described above.
Finally, we were also interested in testing the influence of
FIGURE 1. Intramolecular Diels-Alder cycloaddition with sulfi-
nyl dienynes.
application in synthesis. The use of transition metal catalysts
provides a useful alternative affording cyclohexa-1,4-dienes
by a different mechanism.11 Metals such as Ni, Rh, Pd, Au,
and Cu have been successfully used with this aim, but a
general enantioselective variant of the process remains elu-
sive.12 In this report, we describe in full our results on the
diastereoselective IMDA cycloadditions of dienynes B to
afford cyclohexa-1,4-dienes C that take place under remark-
ably mild conditions, with good selectivities and with pre-
servation of the synthetically useful vinyl sulfoxide.
€
copper salts in the reaction. Recently, Furstner et al. have
suggested the intervention of copper acetylide species for the
Results and Discussion
(10) For selected synthetic applications of alkenyl sulfoxides, see the follow-
Synthesis of Starting Substrates. To carry out our study,
we synthesized several sulfinyl dienes (Scheme 1) by using a
Stille coupling from the corresponding iodo vinyl sulfoxides
ꢀ
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(13) All new products were fully characterized by standard techniques.
For more details see Supporting Information. For convenience racemic
dienes were used in several examples.
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SCHEME 1. Hydroxy Sulfinyl Dienes
SCHEME 3. Change of the Diene Geometry
substituents on the diene, with various 3-atom tethers and
with a p-toluenesulfinyl auxiliary (Table 2). Dienynes 2b-f
and 2l were prepared by standard propargylation (Method
A) following the procedure described above for 2a.13 Com-
pound 2k was synthesized from 2a by treatment with N-
bromosuccinimide and AgNO3 (Method B). Standard ester-
ification (Method C) of 1a afforded ester 2m, and dienynes 2n
and 2o were prepared from 1b using Mitsunobu conditions
(Methods D and E).15
Substitution of the n-butyl chain with a phenyl or a
cyclohexenyl group (2b and 2c) produced an enhancement
of the rate and diastereoselectivity of the cycloaddition even
in the absence of CuI (Table 2, entries 1 and 3). The use of
CuI with 2b further increased the reaction rate but had no
effect on the final diastereomeric ratio (Table 2, entry 2).
Dienyne 2e, with a cyclohexenyl moiety as part of the diene,
afforded tricyclic compound 3e as a single diastereomer. In
this case, the cycloaddition needed 10 days at 23 °C for
completion (Table 2, entry 4), but moderate heating gave 3e
in just 38 h without affecting the diastereoselectivity of the
process. In contrast, tetrasubstituted dienyne 2f gave a 66:34
mixture of 3f and 4f. The reduced diastereoselectivity ob-
served may be due to conformational changes around the
carbon-sulfur bond in order to minimize A1,2 allylic strain
on the diene moiety.16 As alkynyl bromides are known to be
effective substrates in thermal cycloadditions of similar
dienynes not bearing the sulfinyl moiety,11h we decided to
study the IMDA of dienyne 2k. Internal dienyne 2k required
heating to give the desired cycloadducts with high yield but
modest selectivity (Table 2, entry 7). In the case of a methyl-
substituted alkyne (2l), we first attempted ZnBr2 conditions
but observed primarily the undesired aromatized product
(Table 2, entry 8). Instead, thermal conditions were applied
(Table 2, entry 9), affording cycloadducts 3l and 4l with high
yield and good diastereoselectivity.
SCHEME 2. IMDA of Dienyne 2a
TABLE 1. Optimization of IMDA Cycloaddition for Dienyne 2a
entry
conditions
yield [%] 3aa 4aa
1
2
3
4
5
CDCl3, rt, 10 days
95
67
67
67
73
80
33
33
33
27
20
b,c
4 equiv Et2AlCl, CH2Cl2, rt, 6 days
4 equiv ZnI2, CH2Cl2, rt, 2 days
4 equiv ZnBr2, CH2Cl2, rt, 3 days
0.1 equiv CuI, Et3N, CH2Cl2, rt, 18 h
We next introduced modifications on the 3-atom tether.
Propiolate 2m required heating at 80 °C for 8 h to give
bicyclic lactones 3m and 4m in excellent yield and high
diastereoselectivity. Gratifyingly, replacement of the oxygen
for a tosylamido nitrogen (2n) or by a bis-phenylsulfonyl-
methane carbon tether (2o) resulted in spontaneous cycload-
dition and higher selectivity. The cycloaddition has been run
79
79
81
aRatios determined by 1H NMR spectra of the crude product. bYield
was not determined. cIsolated 15% of aromatized cycloadduct.
copper-catalyzed intramolecular Diels-Alder reactions of
unactivated alkynes.11k To our delight, we found not only a
reduction of the reaction time but also an enhancement in the
selectivity of the process (Table 1, entry 5).
The influence of the geometry of the vinyl sulfoxide on the
diene was next addressed with dienyne 2j (Scheme 3). Un-
fortunately, we found a total absence of reactivity, even at
higher temperatures or in the presence of a Lewis acid.
Encouraged by the results obtained with 2a, we examined
the reaction scope on several substrates bearing different
(15) (a) Mitsunobu, O. Synthesis 1981, 1–28. For reviews, see: (b)
Hughes, D. L. Org. React. 1992, 42, 335–669. (c) Hughes, D. L. Org. Prep.
Proc. Int. 1996, 28, 127–164. (d) For an amino-Mitsunobu reaction with
N-(prop-2-ynyl)-p-tolylsulfonamide, see: Xiong, Y.; Moore, H. W. J. Org.
Chem. 1996, 61, 9168–9177. (e) For Mitsunobu reactions with bis-sulfonyl
methanes, see: Yu, J.; Cho, H.; Falck, J. R. J. Org. Chem. 1993, 58, 5892–
5894.
(16) This rationalization is in agreement with the results observed by
Aversa et. al for the intermolecular Diels-Alder cycloaddition of related 2-
sulfinyl dienes substituted at C-3: Aversa, M. C.; Barattuci, A.; Bonaccorsi,
P.; Giannetto, P. Arkivoc 2002, xi, 79–98.
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TABLE 2. IMDA of Dienynes with a 3-Atom Tether
aMethod A: propargyl bromide (3 equiv), triton B (0.2-0.5 equiv), NaOH/CH2Cl2. Method B: NBS (1.1 equiv), AgNO3 (0.9 equiv), acetone. Method
C: propiolic acid (1.5 equiv), DCC (1.5 equiv), DMAP (0.4 equiv), CH2Cl2. Method D: Ph3P (2 equiv), N-(prop-2-ynyl)-p-tolylsulfonamide, DIAD (1.5
equiv), THF. Method E: Ph3P (1.5 equiv), DIAD (1.5 equiv), 4,4-bis-benzenesulfonylbut-1-yne (1.1 equiv), C6H6. bYield of isolated dienyne.
1
d
cDiastereomeric ratios are shown in parentheses. Ratios determined by H NMR spectra of the crude product. Combined yields of pure products
after chromatography. eNot determined because of spontaneous cycloaddition. fYield was not determined. gYield calculated over two steps. hIsolated
30% of aromatized compound and 50% of isomerized dienyne (7E,9E). Isolated 2% of isomerized dienyne and aromatized compound after
chromatography.
i
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SCHEME 4. Copper-Promoted Tandem Cyclization
SCHEME 5. Synthesis of Dienynes 2p, 2q, and 2r
double bond in the 1H NMR spectra, to give an 85:15
mixture of 3q and 4q in good yield (75%). Finally, dienyne
2r, with a bis-phenylsulfonylmethane moiety, afforded a 91:9
mixture of cycloadducts 3r and 4r.
To test the influence of the aryl substituent on sulfur,
dienyne 2g, bearing a readily available 2-methoxy-1-naphthyl
moiety, was synthesized from diene 1g employing standard
propargylation conditions (Scheme 6). Dienyne 2g underwent
smooth Diels-Alder cycloaddition affording 3g and 4g with
higher selectivity than the p-tolyl analogue (Scheme 2). In the
presence of ZnBr2, the cycloaddition was complete in just 12 h
at 23 °C. Additionally, preliminary studies with a tert-butyl-
sulfinyl moiety showed results similar to those using the p-tolyl
analogue and therefore it was not pursued any further.
The IMDA reaction with the regioisomeric dienyne 2h
occurred more rapidly (1 day) to produce 3h and 4h with
excellent yield and selectivity (Scheme 7). Again, the use of
the 2-methoxy-1-naphthyl derivative 2i improved the dia-
stereoselectivity of the cycloaddition (3i:4i, 89:11). In these
examples, the spontaneous cycloaddition prevented us from
isolating pure samples of dienynes 2h and 2i.
in a variety of solvents without observing any noticeable
differences.
€
Recently, Furstner et al. have reported a copper-mediated
[4 þ 2] cycloaddition-alkylation cascade to obtain tricyclic
compounds.11k They found that stoichiometric mesitylcopper
(instead of catalytic CuI, Et3N) was necessary in order to avoid
protonation of the vinyl copper intermediate formed after
cycloaddition. In order to try this copper-mediated cycloaddi-
tion-alkylation cascade, we synthesized dienyne 2d with a pen-
€
dant alkyl iodide (Scheme 4). As in Furstner’s case, treatment of
dienyne with catalytic copper iodide and Et3N gave cycload-
ducts 3d and 4d with good diastereoselectivity but without
subsequent cyclization to the alkyl iodide. Using a slight excess
of mesityl copper instead, the cycloaddition-alkylation cascade
took place but with nearly complete loss of diastereoselectivity
(54:46 mixture of 3d0 and 4d0). Oxidation of a mixture of 3d0 and
4d0 afforded nearly racemic sulfone 5d along with some aroma-
We believe the IMDA reaction of sulfinyl dienynes, at least
for nonactivated alkynes, is consistent with an inverse elec-
tron demand Diels-Alder primarily controlled by stereo-
electronic effects.17,18 To probe this, we thought it would be
1
(17) For recent selected examples of inverse electron demand
Diels-Alder reactions, see: (a) Li, P.; Yamamoto, H. J. Am. Chem. Soc.
2009, 131, 16628–16629. (b) Jung, M. E.; Chu, H. V. Org. Lett. 2008, 10,
3647–3649. (c) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc.
2008, 130, 8604–8605. (d) Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell,
G. J. Org. Lett. 2008, 10, 233–236. (e) Juhl, M.; Nielsen, T. E.; Le Quement,
S.; Tanner, D. J. Org. Chem. 2006, 71, 265–280. A significant number of the
reported inverse electron demand Diels-Alder reactions can be classified as
hetero-Diels-Alder reactions. For a review, see: Boger, D. L. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 5, pp 451-512.
(18) For examples of inverse electron demand Diels-Alder reactions with
sulfoxide-substituted dienes and heterodienes, see the following. Sulfinyl
pyrones: (a) Posner, G. H. Acc. Chem. Res. 1987, 20, 72–78. β-Sulfinyl R,β-
unsaturated compounds: (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P.; Policicchio, M. J. Org. Chem. 2001, 66, 4845–4851. Sulfinyl
tetrazines: (c) Hamasaki, A.; Ducray, R.; Boger, D. L. J. Org. Chem. 2006,
tized product 6d. The H NMR spectra of the crude product
showed a single compound (5d), proving that 3d0 and 4d0 had
the opposite absolute stereochemistry in the two new stereo-
centers generated during the cycloaddition.
The use of a 4-atom tether was then addressed with
dienynes 2p, 2q, and 2r, prepared from 1b using Mitsunobu
conditions (Scheme 5).15 In all cases, heating at 80 °C was
necessary to promote the IMDA reaction (Table 3). Heating
a toluene solution of 2p at 80 °C for 5 days provided tricyclic
compounds 3p and 4p with moderate yield (57%) but high
diastereomeric ratio (87:13, Table 3, entry 1). Next, we tested
the use of an allene as a dienophile with compound 2q. Only
the external double bond of the allene participated in the
IMDA reaction, as revealed by the absence of an exocyclic
€
71, 185–193. (d) Seitz, G.; Dietrich, S.; Gorge, L.; Richter, J. Tetrahedron
Lett. 1986, 27, 2747–2750.
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TABLE 3. IMDA Reaction of Dienynes and Allenyl Dienes with a 4-Atom Tether
aDiastereomeric ratios are shown in parentheses. Ratios determined by 1H NMR spectra of the crude product. bCombined yields of pure products
after chromatography.
SCHEME 6. Sulfur Substitution in the Sulfoxide Group
SCHEME 7. Diels-Alder Cycloaddition with Regioisomeric
Dienynes
interesting to compare the reactivity of sulfinyl dienynes with
their analogous sulfones and sulfoximines (Scheme 8). Oxi-
dation of 2a with m-CPBA at low temperature afforded
racemic sulfone 5a along with a small amount of aromatized
product 6a (83:17 mixture, 70%). The cycloaddition pro-
ceeded smoothly, and no sulfonyl dienyne 2s was isolated.
Additionally, sulfoximine 2t was synthesized from sulfoxide
2a using a copper-catalyzed imination reaction with moder-
ate yield.19 The rate of cycloaddition was similarly increased
but unfortunately with lower diastereoselectivity (10:11, 60:40).
Cycloadduct 3a was treated under the same imination condi-
tions to give a 25:75 mixture of 10 and aromatized sulfoximine
100. Despite the low yield, this experiment showed that 10 and
3a had the same absolute stereochemistry in the two new
stereogenic centers generated during the cycloaddition.
the sulfinyl group, we carried out several chemoselective trans-
formations on the more electron-rich double bond (Scheme 9).
Hydrogenation and electrophilic epoxidation of 3a and 3b
proceeded smoothly to give 12a,b and 13a,b with good yields.
Additionally, we were able to find conditions that allowed us to
obtain diols 14a,b and 15 without oxidizing the sulfoxide to
sulfone. In all cases a single diastereomer was observed.
Finally, functionalization of the vinyl sulfoxide handle
was addressed (Scheme 10). Oxidation followed by nucleo-
philic epoxidation of diol 14b gave epoxy sulfone 17 as a
single diastereomer. Next, epoxide opening with MgBr2
afforded a mixture of bromides 19 and dehalogenated com-
pound 18.20 Further treatment of 19 with aluminum amal-
gam produced the highly functionalized bicyclic ketone 18.
Additionally, we tested the lactonization conditions de-
scribed by Marino.21 For the sulfoxide configuration of
Reactivity of Sulfinyl Cyclohexane-1,4-dienes. The metho-
dology described above allows for the preparation of cyclo-
hexane-1,4-dienes with two stereoelectronically differen-
tiated double bonds ready for selective functionalization.
Taking advantage of the electron-withdrawing character of
(20) Reinach-Hirtzbach, F.; Durst, T. Tetrahedron Lett. 1976, 17, 3677–
3680.
(21) (a) Marino, J. P.; Neisser, M. J. Am. Chem. Soc. 1981, 103, 7687–
ꢀ
7689. (b) Marino, J. P.; Perez, A. D. J. Am. Chem. Soc. 1984, 106, 7643–7644.
For a recent application, see: (c) Marino, J. P.; Gao, G. Tetrahedron Lett.
^
(19) Leca, D.; Song, L.; Amatore, M.; Fensterbank, L.; Lacote, E.;
Malacria, M. Chem.;Eur. J. 2004, 10, 906–916.
ꢀ
2006, 47, 7711–7713. For a recent review, see: Fernandez de la Pradilla, R.;
Tortosa, M.; Viso, A. Top. Curr. Chem. 2007, 275, 103–129.
1522 J. Org. Chem. Vol. 75, No. 5, 2010

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Fernandez de la Pradilla et al.
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SCHEME 8. Diels-Alder Cycloaddition of Dienyl Sulfones and
Sulfoximines
SCHEME 10. Vinyl Sulfoxide Reactivity
SCHEME 9. Double Bond Functionalization
Treatment of cycloadduct 3b with trichloroacetyl chloride
and Zn-Cu gave a 65:35 mixture of chlorides 20a and 20b.
To our delight, both R-chlorolactones 20a,b afforded the
same dehalogenated product 21 upon treatment with Zn
in AcOH. This result proves that the lactonization occurs
with complete diastereoselectivity on the convex face of the
bicycle.13 Additionally, the coupling constant (J = 13.2 Hz)
between H-8a and H-8b in 21 and the absence of NOE effect
between H-8b and H-8a or H-4 is consistent with the
proposed structure.
Relative Stereochemistry. To ensure the relative stereo-
chemistry of 3 and 4, mixtures of these sulfoxides were
oxidized with magnesium monoperoxyphthalate (MMPP,
Table 4). The 1H NMR of the crude product showed a
single cyclohexadienyl sulfone 5 in each case, demonstrat-
ing that 3 and 4 had opposite absolute stereochemistry in
the two new stereogenic centers generated during the
cycloaddition.
The relative cis-trans stereochemistry between the sub-
stituents at C3a and C6 was derived from the characteristic
homoallylic coupling of 1,4-cyclohexadienes. The coupling
constants JH3a-H6 of cycloadducts 3m and 4m (Figure 2) are
in good agreement with previous data that reported values of
9.1 and 5.3 Hz, respectively, for related cis and trans com-
pounds.11d For all 3 and 4 cycloadducts the assignment was
made by assuming a similar stereochemical course for the
IMDA and by comparison of their spectral features with
those of compounds 3m and 4m.
The relative stereochemistry of diols 14a and 15 was
based on the coupling constants of the diols and nuclear
cycloadduct 3b, lactonization was expected to occur on the
convex face of the bicycle, which is also the less hindered face.
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TABLE 4. Sulfoxide Oxidation to the Corresponding Sulfones
SCHEME 11. Absolute Stereochemistry Assignment
entry
X
R1
R2
3
4
yield [%]a
1
2
3
4
5
O
O
O
NTs
n-Bu
Ph
Ph
H
H
3a (67) 4a (33)
3b (75) 4b (25)
4l (35)
3n (58) 4n (42)
3r (74) 4r (26)
95
80
73
79
75
Me 3l (65)
H
H
Ph
CH2C(SO2Ph)2 Ph
aYield of pure product (5) after chromatography.
FIGURE 2. Structural assignment for cycloadducts 3 and 4.
moiety. The stereochemical assignment of diol 15 was made
similarly.
Absolute Stereochemistry. The absolute stereochemistry of
cycloadducts 3 and 4 was also derived from their dihydroxy-
lated derivatives. To determine the absolute stereochemistry
of diol 14a, we synthesized the (R)- and (S)-methoxy pheny-
lacetates 22 and 23 by selective esterification of the secondary
alcohol (Scheme 11). Previous studies have shown that in the
L2L1CH-CO-CHPh-OMe fragment the preferred conformer
is that where the CR-OMe bond, the CdO, and the C4-H4
bond are nearly eclipsed.23 For the C-S bond we suggest
that the main conformer in each case is the one that places
the bulky p-tolyl group away from the bicyclo concave face.
As shown in Scheme 11, H7a (2.75 ppm), H1β (4.10 ppm),
and HR (4.48 ppm) are further upfield in the (R)-isomer 22
compared to 23 (H7a 3.03 ppm, H1β 4.24 ppm, and HR 4.70
FIGURE 3. Relative stereochemistry assignment.
Overhauser (NOE) experiments. The absence of NOE effect
between H4 and H7a in compound 14a (Figure 3) is in
agreement with a cis fusion on the bicycle and the coupling
constant JH7-H7a (4.6 Hz) is in agreement with previously
reported data for cis (J = 3-4 Hz) and trans (J = 1-1.5 Hz)
related compounds.22 These arguments support approach by
osmium to the less hindered face of the 1,4-cyclohexadiene
ꢀ
(22) (a) Areces, P.; Jimenez, J. L.; Pozo, M. C.; Roman, E.; Serrano, J. A.
~ ꢀ
(23) (a) Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem.
~ ꢀ
1996, 61, 8569–8577. For a review, see: Seco, J. M.; Quinoa, E.; Riguera, R.
Chem. Rev. 2004, 104, 17–117.
J. Chem. Soc., Perkin Trans. 1 2001, 754–762. (b) Becher, J.; Nielsen, H. C.;
Jacobsen, J. P.; Simonsen, O.; Clausen, H. J. Org. Chem. 1988, 53, 1862–
1871.
1524 J. Org. Chem. Vol. 75, No. 5, 2010

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Fernandez de la Pradilla et al.
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metal to the sulfoxide. We believe that this coordination
could be changing the conformational preferences around
the C-S bond and consequently modifying the diastereos-
electivity of the process.
Conclusions
Sulfinyl dienynes undergo thermal and catalyzed IMDA
cycloadditions under remarkable mild conditions. The strat-
egy described herein allows for the construction of a broad
number of carbo- and heterocycles, with a bicyclic or tricyclic
structure, in generally good yields and high diastereo-
selectivities. Importantly, the methodology provides cyclo-
adducts with two electronically differentiated double
bonds, one of them bearing a synthetically useful vinyl
sulfoxide. The selective manipulation of the alkenes allows
for the preparation of highly functionalized compounds with
broad structural diversity. We are currently exploring the
application of this methodology to the synthesis of natural
products.
FIGURE 4. Favored transition states for sulfoxide-directed
IMDA.
ppm) due to the shielding effect of the phenyl group (on H7a
and H1β) and the p-tolyl group (on HR) in (R)-isomer 22. In
contrast, in the (S)-isomer 23, the phenyl group is shielding
the methyl group of the n-butyl chain (0.79 ppm for 23 and
0.85 ppm for 22). The absolute stereochemical assignment
of diol 15a was made similarly. We synthesized the (R) and
(S)-methoxy phenylacetates 24 and 25 from diol 15a. As
shown in Scheme 11, H7a (2.49 ppm), H1R (4.01 ppm) and
HR (4.31 ppm) are further upfield in 25 compared to 24 (H7a
2.88 ppm, H1R 4.17 ppm and HR 4.66 ppm) due to the shielding
effect of the phenyl group (on H7a and H1R) and the p-tolyl
group (on HR) in (S)-isomer 25. In contrast, in the (R)-isomer
24, the phenyl group is shielding the methyl group of the n-butyl
chain (0.73 ppm for 24 and 0.82 ppm for 25).
Stereochemical Pathway. These results may be tentatively
rationalized in terms of diastereomeric transition states D
and E for which S-cis CdC/SdO and S-cis CdC/S-: con-
formations around the C-S bond are proposed, respectively
(Figure 4).24 We believe the IMDA reaction of sulfinyl
dienynes, at least for nonactivated alkynes, is consistent with
an inverse electron demand Diels-Alder cycloaddition pri-
marily controlled by stereoelectronic effects. The electron-
rich alkyne moiety would approach the moderately electron-
deficient diene anti to the highest electron density to avoid
electron-electron interactions (β face for E, and R face for
D). Delocalization of the sulfur lone pair in transition state D
(this delocalization is not possible in transition state E) could
explain the preferred formation of diastereomer 3 in most
cases. This model is also consistent with data observed upon
addition of resonance stabilization to the diene (e.g., R1 =
Ph or cyclohexenyl, Table 2, entries 1 and 3) which signifi-
cantly improves the diastereoselectivity by increasing the
delocalization of the sulfur lone pair in transition state D.
The low diastereoselectivity observed for dienyne 2f (Table 2,
entry 6) could be explained by destabilization of transition
state D due to increased A1,2 allylic strain on the diene
moiety. Aditionally, the unexpected loss of diastereoselec-
tivity observed for dienyne 2d in the presence of mesityl
copper (Scheme 4) could be explained by coordination of the
Experimental Section
General Procedure for the Synthesis of Dienyne Ethers. To a
solution of the corresponding dienyl sulfoxide in CH2Cl2 (10
mL/mmol of sulfoxide) were added 3 equiv of propargyl bro-
mide (80 wt %), 0.2-0.5 equiv of Triton B (40 wt %) and
60% aqueous sodium hydroxide (10 mL/mmol of sulfoxide).
The mixture was vigorously stirred at room temperature and
monitored by TLC until starting material disappearance. Then
the reaction mixture was filtered through Celite, a saturated
solution of NaCl (5 mL/mmol of sulfoxide) was added and
the layers were separated. The aqueous layer was extracted
twice with CH2Cl2 and the combined organic extracts were
dried over anhydrous MgSO4 and filtered to give, after evapora-
tion of the solvents, a crude product that was purified by
chromatography on silica gel using the appropriate mixture of
solvents.
General Procedure for Mitsunobu-Type Reaction of Hydroxy
4-sulfinyl Butadienes. To a solution of dienyl sulfoxide in THF
or benzene (5 mL/mmol sulfoxide), under an argon atmosphere,
were added 1.5 equiv of Ph3P (recrystallized), 1.1 equiv of a pro-
pargylic derivative in anhydrous THF or benzene (10 mL/mmol
of sulfoxide) and 1.5 equiv of diisopropyl azodicarboxylate. The
reaction was monitored by TLC until starting material disap-
pearance. Then the solvent was removed and the crude product
was purified by chromatography on silica gel using the appro-
priate mixture of solvents.
General Procedure for the Thermal Diels-Alder Reaction of
Sulfinyl Dienynes. A kimble vial equipped with a stirring bar was
charged with a solution of the corresponding dienyne and 0.2
equiv of 2,6-di-tert-butyl-4-methylphenol (BHT) in anhydrous
toluene (10 mL/mmol of dienyne). Argon was bubbled through
the solution for 15 min using a needle, and the vial was quickly
stoppered. The vial was then immersed in a preheated oil bath
(80-90 °C) if appropriate and the reaction was monitored by
TLC until starting material disappearance. The solvent was
removed and the crude product was purified by chromatogra-
phy using the appropriate mixture of solvents.
General Procedure for the Diels-Alder Reaction of Sulfinyl
Dienynes in the Presence of ZnBr2. To a solution of sulfinyl
dienyne in anhydrous CH2Cl2 (10 mL/mmol), under an argon
atmosphere, was added ZnBr2 (4.0 equiv). The reaction mixture
was stirred until starting material disappearance (TLC). The
reaction was quenched with a 5% solution of NaHCO3, phases
were separated and the aqueous layer was extracted with
(24) The energy difference between the more stable conformers for a
simple Z-propenyl sulfoxide (s-cis, CdC/SdO and s-cis, CdC/S-:) has been
evaluated as just -0.4 kcal mol-1. See: Tietze, L. F.; Schuffenhauer, A.;
Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 7952–7958.
J. Org. Chem. Vol. 75, No. 5, 2010 1525

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Fernandez de la Pradilla et al.
JOCArticle
CH2Cl2 (twice). The organic phase was washed with brine, dried
over anhydrous MgSO4, filtered and concentrated under re-
duced pressure. The resulting crude was purified by chromatog-
raphy using the appropriate mixture of solvents.
(m, 2 H, CH2-n-Bu), 2.39 (s, 3 H, Me-p-Tol), 2.58 (m, 1 H, H-6),
3.32-3.34 (m, 2 H, H-3a, 1 H-3), 4.25-4.41 (m, 3 H, 1 H-3, 2 H-
1), 5.36 (br s, 1 H, H-7), 6.86 (t, J = 2.2 Hz, 1 H, H-4), 7.23 (d,
J = 8.1 Hz, 2 H, p-Tol), 7.53 (d, J = 8.1 Hz, 2 H, p-Tol); 13
C
General Procedure for the CuI-Catalyzed Diels-Alder Reac-
tion of Sulfinyl Dienynes. To a solution of sulfinyl dienyne in
CH2Cl2 (4 mL/mmol) were added 0.1 equiv of CuI and 1.0 equiv
of Et3N at room temperature. The mixture was stirred until
starting material disappearance (TLC). Then the solvent was
removed under reduced pressure and the resulting crude product
was purified by chromatography using the appropriate mixture
of solvents.
NMR (50 MHz) δ 13.9 (Me-n-Bu), 21.5 (Me-p-Tol), 22.8, 26.4,
31.7, 36.0, 41.0, 69.0, 71.4, 119.1, 123.0, 126.4 (2 C), 130.2 (2 C),
137.9, 139.4, 142.6, 146.6; IR (KBr) 2952, 2930, 2859, 1631,
1593, 1493, 1455, 1378, 1306, 1182, 1082, 1044, 1012, 896, 872,
819 cm-1; MS (ES) m/z (%) 633 [2M þ H]þ, 317 (100) [M þ H]þ.
Anal. Calcd for C19H24O2S: C 72.11, H 7.64, S 10.13. Found: C
72.30, H 7.93, S 10.41.
Data for 4a: Rf = 0.27 (50% EtOAc/hexane); [R]20D = -11.4
(c 1.19); 1H NMR (300 MHz) δ 0.80 (t, J = 7.0 Hz, 3 H, Me-n-
Bu), 1.11-1.25 (m, 4 H, 2 CH2-n-Bu), 1.62-1.75 (m, 2 H, CH2-
n-Bu), 2.39 (s, 3 H, Me-p-Tol), 3.05 (m, 1 H, H-6), 3.28 (m, 1 H,
H-3a), 3.33 (dd, J = 10.9, 6.6 Hz, 1 H, H-3), 4.21-4.27 (m, 2 H,
H-3, H-1), 4.35 (dm, J = 12.0 Hz, 1 H, H-1), 5.37 (m, 1 H, H-7),
6.63 (t, J = 2.4 Hz, 1 H, H-4), 7.29 (d, J = 7.9 Hz, 2 H, p-Tol),
7.48 (d, J = 8.3 Hz, 2 H, p-Tol); 13C NMR (50 MHz) δ 13.9 (Me-
n-Bu), 21.3 (Me-p-Tol), 22.6, 27.6, 31.9, 36.6, 41.2, 69.0, 70.8,
120.2, 125.3 (2 C), 129.8 (2 C), 131.5, 136.1, 138.7, 141.2, 148.3;
IR (film) 2956, 2926, 2857, 1651, 1456, 1260, 1084, 1048, 898,
809 cm-1; MS (ES) m/z (%) 633 (100) [2M þ H]þ, 317 [M þ H]þ.
Anal. Calcd for C19H24O2S: C 72.11, H 7.64, S 10.13. Found: C
72.20, H 7.78, S 10.27.
Synthesis of (-)-(S)-4-Oxa-8-(p-tolylsulfinyl)-6-(E)-8-(Z)-tri-
decadien-1-yne, 2a, (þ)-(3aR,6R,SS)-6-n-Butyl-5-(p-tolylsulfinyl)-
1,3,3a,6-tetrahydroisobenzofuran, 3a, and (-)-(3aS,6S,SS)-6-n-
Butyl-5-(p-tolylsulfinyl)-1,3,3a,6-tetrahydroisobenzofuran, 4a.
From sulfinyl diene 1a (835 mg, 3.00 mmol), propargyl bromide
(1.29 mL, 1.78 g, 12.00 mmol), Triton B (0.30 mL, 275 mg, 0.60
mmol) and 60% aqueous sodium hydroxide (15 mL) following
the general procedure (5 h), compound 2a was obtained. Pur-
ification by chromatography (20-50% EtOAc/hexane) af-
forded 2a (518 mg, 1.86 mmol, 62%) as a yellow oil, 92 mg
(0.33 mmol, 11%) of a 67:33 mixture of 3a and 4a and 84 mg
(0.30 mmol, 10%) of starting material.
Data for 2a: Rf = 0.22 (30% EtOAc/hexane); [R]20
=
D
1
Synthesis of (S)-4-Oxa-9-phenyl-8-(p-tolylsulfinyl)-6-(E)-
8-(Z)-nonadien-1-yne, 2b, (þ)-(3aR,6S,SS)-6-Phenyl-5-(p-tolylsul-
finyl)-1,3,3a,6-tetrahydroisobenzofuran, 3b, and (þ)-(3aS,6R,
SS)-6-Phenyl-5-(p-tolylsulfinyl)-1,3,3a,6-tetrahydroisobenzofur-
an, 4b. From sulfinyl diene 1b (298 mg, 1 mmol), propargyl
bromide (0.32 mL, 446 mg, 3 mmol), Triton B (0.10 mL, 91 mg,
0.2 mmol) and 60% aqueous sodium hydroxide (10 mL) follow-
ing the general procedure (2 h) compound 2b was obtained. The
1H NMR spectra of the crude product run after the workup
procedure showed a 30:65:5 mixture of 2b, 3b and 4b. After 2
days at room temperature the cycloaddition was complete and a
92:8 mixture of 3b and 4b was obtained. Purification by chro-
matography (20-80% EtOAc/hexane) afforded 14 mg of a 1:1
mixture of isomerized 8-(E)-dienyne SI-34 (2%) and the aro-
matized cycloaduct SI-35 (2%), 218 mg (0.65 mmol, 65%) of 3b
as a white solid that was recrystallized from EtOAc/hexane, 19
mg (0.05 mmol, 5%) of 4b and 7 mg (0.02 mmol, 2%) of starting
material 1b.
-161.1 (c 1.11); H NMR (300 MHz) δ 0.93 (t, J = 7.0 Hz, 3
H, Me-n-Bu), 1.33-1.54 (m, 4 H, 2 CH2-n-Bu), 2.35-2.37 (m, 4
H, Me-p-Tol, H-1), 2.49 (m, 1 H, H-10), 2.71 (m, 1 H, H-10), 3.90
(dd, J = 2.4, 1.4 Hz, 2 H, 2 H-3), 3.98 (m, 2 H, 2 H-5), 5.98 (dt,
J = 15.9, 5.9 Hz, 1 H, H-6), 6.12 (d, J = 15.7 Hz, 1 H, H-7), 6.24
(dd, J = 8.3, 7.4 Hz, 1 H, H-9), 7.25 (d, J = 8.1 Hz, 2 H, p-Tol),
7.39 (d, J = 8.3 Hz, 2 H, p-Tol); 13C NMR (50 MHz) δ 13.8 (Me-
n-Bu), 21.3 (Me-p-Tol), 22.3, 28.6, 31.5, 56.7, 69.6, 74.4, 79.5,
124.2 (2 C), 124.4, 128.3, 129.5, 129.8 (2 C), 139.0, 140.6, 142.1;
IR (film) 3036, 2955, 2929, 2859, 1595, 1492, 1465, 1399, 1379,
1303, 1178, 1147, 1083, 1049, 1014, 899, 844, 810, 705 cm-1; MS
(ES) m/z (%) 633 [2M þ H]þ, 317 (100) [M þ H]þ. Anal. Calcd
for C19H24O2S: C 72.11, H 7.64, S 10.13. Found: C 71.97, H
7.35, S 10.36.
From 2a (492 mg, 1.55 mmol) and ZnBr2 (1400 mg, 6.20
mmol) following the general procedure (3 days), a 73:27 mixture
of 3a and 4a with traces of 2j was obtained. Purification by
chromatography (10-50% EtOAc/hexane) afforded 5 mg of 2j
as a colorless oil, 47 mg (0.15 mmol, 10%) of 4a as a colorless oil,
168 mg (0.53 mmol, 34%) of a mixture of 4a and 3a and 172 mg
(0.54 mmol, 35%) of 3a as a white solid that was recrystallized
from Et2O-hexane.
In a related experiment a solution of 2a in CDCl3 was kept at
room temperature and monitored by 1H NMR until cycloaddi-
tion was complete (10 days), affording a 67:33 mixture of 3a
and 4a.
From 2a (96 mg, 0.30 mmol), CuI (6 mg, 0.03 mmol) and Et3N
(40 μL, 0.30 mmol) following the general procedure (18 h), an
80:20 mixture of 3a and 4a was obtained. Purification by
chromatography (10-50% EtOAc/hexane) afforded 48 mg
(0.015 mmol, 50%) of an 83:17 mixture of 3a and 4a and 28
mg (0.093 mmol, 31%) of pure 3a.
From sulfinyl dienyne 2b (165 mg, 0.49 mmol), CuI (9 mg,
0.04 mmol) and Et3N (68 μL, 0.49 mmol) following the general
procedure (18 h), a 92:8 mixture of 3b and 4b was obtained.
Purification bychromatography afforded3b (124 mg, 0.34mmol,
75%) as a white solid that was recrystallized from EtOAc/
hexane, and 17 mg (0.05 mmol, 10%) of a mixture of 3b and 4b.
Data for 2b: Rf = 0.37 (50% EtOAc/hexane); 1H NMR (300
MHz) δ 2.36 (s, 3 H, Me-p-Tol), 2.37 (m, 1 H, H-1 overlapped),
3.94 (m, 2 H, 2 H-3), 4.04 (m, 2 H, 2 H-5), 6.17 (dt, J = 15.7, 5.6
Hz, 1 H, H-6), 6.31 (dd, J = 15.7, 1.0 Hz, 1 H, H-7), 7.23-7.29
(m, 4 H), 7.35-7.42 (m, 4 H), 7.48-7.51 (m, 2 H).
1
Data for SI-34: Rf = 0.37 (50% EtOAc/hexane); H NMR
(300 MHz) δ 2.36 (s, 3 H, Me-p-Tol), 2.89 (t, J = 2.4 Hz, 1 H, H-
1), 3.87 (d, J = 2.4 Hz, 2 H, 2 H-3), 3.96 (d, J = 6.0 Hz, 2 H, 2 H-
5), 6.07 (dt, J = 16.3, 5.8 Hz, 1 H, H-6), 6.43 (d, J = 16.5 Hz, 1
H, H-7), 7.31-7.47 (m, 8 H), 7.55 (d, J = 8.2 Hz, 2 H).
Data for 3b: Rf = 0.11 (50% EtOAc/hexane); mp 164 °C;
Data for 2j: Rf = 0.27 (30% EtOAc/hexane); 1H NMR (300
MHz) δ 0.89 (t, J = 7.1 Hz, 3 H, Me-n-Bu), 1.22-1.55 (m, 4 H, 2
CH2-n-Bu), 2.25-2.39 (m, 3 H), 2.35 (s, 3 H, Me-p-Tol), 3.94 (d,
J = 2.4 Hz, 2 H, 2 H-3), 4.00 (d, J = 5.6 Hz, 2 H, 2 H-5), 5.89 (dt,
J = 16.3, 5.6 Hz, 1 H, H-6), 6.20 (d, J = 16.3 Hz, 1 H, H-7), 6.50
(t, J = 7.6 Hz, 1 H, H-9), 7.22 (d, J = 8.1 Hz, 2 H, p-Tol), 7.46 (d,
J = 8.2 Hz, 2 H, p-Tol). Anal. Calcd for C19H24O2S: C 72.11 H
7.64, S 10.13. Found: C 72.34 H 7.35, S 10.41.
[R]20 = þ243.3 (c 0.55); 1H NMR (300 MHz) δ 2.39 (s, 3 H,
D
Me-p-Tol), 3.41 (m, 1 H, H-3a), 3.47 (ddd, J = 11.0, 7.0, 0.7 Hz,
1 H, H-3), 3.56 (m, 1 H, H-6), 4.26 (dm, J = 11.7 Hz, 1 H, H-1),
4.37-4.43 (m, 2 H, H-3, H-1), 5.34 (t, J = 2.0 Hz, 1 H, H-7),
6.92-6.96 (m, 2 H), 6.99 (t, J = 2.2 Hz, 1 H, H-4), 7.22-7.33 (m,
7 H); 13C NMR (75 MHz) δ 21.5 (Me-p-Tol), 40.8, 43.4, 68.9,
71.5, 119.6, 122.9, 126.9 (2 C), 127.6, 128.8 (2 C), 129.1 (2 C),
130.0 (2 C), 136.6, 138.9, 140.5, 142.6, 147.4; IR (KBr) 3026,
Data for 3a: Rf = 0.22 (50% EtOAc/hexane); mp 83-85 °C;
[R]20D = þ179.2 (c 1.00); 1H NMR (300 MHz) δ 0.87 (t, J = 7.0
Hz, 3 H, Me-n-Bu), 1.08-1.38 (m, 4 H, 2 CH2-n-Bu), 1.57-1.67
1526 J. Org. Chem. Vol. 75, No. 5, 2010

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Fernandez de la Pradilla et al.
JOCArticle
2922, 2859, 1629, 1595, 1493, 1452, 1328, 1306, 1182, 1082, 1047,
1014, 959, 896, 851, 813, 763, 700 cm-1; MS (ES) m/z (%) 695
(100) [2M þ Na]þ, 673 [2M þ H]þ, 659 [M þ Na]þ, 337 [M þ
H]þ. Anal. Calcd for C21H20O2S: C 74.97, H 5.99, S 9.53.
Found: C 74.68, H 6.10, S 9.42.
Data for 4b: Rf = 0.20 (50% EtOAc/hexane); mp 175-177
°C; [R]20D = þ3.5 (c 0.35); 1H NMR (300 MHz) δ 2.31 (s, 3 H,
Me-p-Tol), 3.40-3.48 (m, 2 H, H-3a, 1 H-3), 4.26-4.35 (m, 2 H,
1 H-1, 1 H-6), 4.39-4.47 (m, 2 H, 1 H-1, 1 H-3), 5.46 (br s, 1 H,
H-7), 6.70 (t, J = 2.3 Hz, 1 H, H-4), 6.90-6.94 (m, 2 H),
6.97-7.15 (m, 7 H); 13C NMR (75 MHz) δ 21.3 (Me-p-Tol),
40.8, 43.9, 69.0, 71.3, 119.5, 125.6 (2 C), 125.9, 127.3, 128.4 (2 C),
129.4 (2 C), 129.5 (2 C), 136.9, 139.6, 139.9, 141.2, 148.6; IR
(KBr) 3026, 2922, 2859, 1595, 1493, 1452, 1306, 1082, 1047,
1014, 959, 896, 813, 763, 700 cm-1; MS (ES) m/z (%) 659 [M þ
Na]þ, 337 (100) [M þ H]þ. Anal. Calcd for C21H20O2S: C 74.97,
H 5.99, S 9.53. Found: C 74.80, H 6.04, S 9.42.
Synthesis of (1R,SS)-(Z)-(2-[(3-Prop-2-ynyloxy)cyclohex-1-
enyl]-2-(p-tolylsulfinyl)vinyl)benzene, 2e, and (-)-(2aS,4S,8aR,
SS)-4-Phenyl-5-(p-tolylsulfinyl)-2a,4,6,7,8,8a-hexahydro-2H-
naphtho[1,8-bc]furan, 3e. From diene 1e (40 mg, 0.12 mmol, 1.0
equiv), propargyl bromide (0.20 mL, 1.77 mmol, 15.0 equiv) and
Triton B (27 μL, 0.059 mmol, 0.5 equiv) following the general
procedure (6 h), dienyne 2e was obtained. Purification by flash
chromatography afforded dienyne 2e (7 mg, 0.019 mmol, 16%,
44% based on recovered starting material) as a yellow oil, and 24
mg (0.017 mmol, 60%) of 1e.
5.9 Hz, 2 H, H-1), 6.25 (dt, J = 15.9, 6.0 Hz, 1 H, H-2), 6.38 (dm,
J = 15.6 Hz, 1 H, H-3), 7.25-7.28 (m, 3 H), 7.38-7.44 (m, 5 H),
7.51-7.54 (m, 2 H); 13C NMR (50 MHz) δ 21.3 (Me-p-Tol), 65.9
(C-1), 74.3, 75.1, 124.4 (2 C), 126.6, 127.2, 128.6 (2 C), 129.3,
129.9 (2 C), 130.0 (2 C), 133.7, 136.6, 139.3, 141.0, 142.2, 152.2
(CO). Anal. Calcd for C21H18O3S: C 71.98, H 5.18, S 9.15.
Found: C 72.19, H 5.30, S 8.96.
From dienyne 2m (62 mg, 0.17 mmol) following the general
procedure for the thermal cycloaddition (80 °C, 8 h) an 84:16
mixture of 3m and 4m was obtained. Purification by chroma-
tography (5-20% EtOAc-CH2Cl2) afforded 3m (45 mg, 0.12
mmol, 72%) as a white solid that was recrystallized from
EtOAc/hexane and 4m (9 mg, 0.025, 14%) as a white solid that
was recrystallized from Et2O.
Data for 3m: Rf = 0.26 (80% EtOAc/hexane); mp 208-
210 °C; 1H NMR (300 MHz) δ 2.41 (s, 3 H, Me-p-Tol), 3.71 (dt,
J = 11.7, 2.2 Hz, 1 H, H-6), 3.84 (m, 1 H, H-3a), 4.06 (dd, J =
10.1, 8.2 Hz, 1 H, 1 H-3), 4.84 (t, J = 8.4 Hz, 1 H, 1 H-3), 6.55 (t,
J = 2.4 Hz, 1 H, H-7), 6.91-6.94 (m, 2 H), 7.03 (t, J = 2.3 Hz, 1
H, H-4), 7.27 (m, 4 H), 7.32-7.35 (m, 3 H); 13C NMR (50 MHz)
δ 21.6 (Me-p-Tol), 38.4, 43.9, 70.1 (C-3), 122.2, 126.2, 126.8 (2
C), 128.4, 129.1 (2 C), 129.2 (2 C), 130.2 (2 C), 135.7, 137.9,
138.0, 143.1, 148.3, 168.3 (CO); IR (KBr) 3027, 2912, 1760,
1693, 1627, 1492, 1454, 1333, 1205, 1182, 1085, 1048, 1021, 974,
897, 809, 757, 739, 701 cm-1; MS (ES) m/z (%) 373 [M þ Na]þ,
351 (100) [M þ H]þ. Anal. Calcd for C21H18O3S: C 71.98, H
5.18, S 9.15. Found: C 72.12, H 5.35, S 9.32.
Data for 4m: Rf = 0.21 (80% EtOAc/hexane); mp 202-
204 °C; 1H NMR (300 MHz) δ 2.31 (s, 3 H, Me-p-Tol), 3.86 (m, 1
H, H-3a), 3.99 (dd, J = 10.3, 8.7 Hz, 1 H, 1 H-3), 4.59 (dt, J =
12.1, 2.3 Hz, 1 H, H-6), 4.79 (t, J = 8.7 Hz, 1 H, 1 H-3), 6.70 (m, 1
H, H-7), 6.77 (t, J = 2.6 Hz, 1 H, H-4), 6.85-6.87 (m, 2 H),
6.93-7.19 (m, 7 H); 13C NMR (50 MHz) δ 21.4 (Me-p-Tol),
38.3, 44.5, 69.9 (C-3), 124.9, 125.6 (2 C), 127.0, 128.0, 128.7 (2
C), 129.4 (2 C), 129.7 (2 C), 135.8, 137.3, 139.2, 141.8, 149.3,
168.1 (CO); IR (KBr) 3038, 2917, 1753, 1626, 1454, 1178, 1080,
1045, 981, 807, 759, 702 cm-1; MS (ES) m/z (%) 373 [M þ Na]þ,
351 (100) [M þ H]þ. Anal. Calcd for C21H18O3S: C 71.98, H
5.18, S 9.15. Found: C 72.18, H 5.26, S 9.32.
Synthesis of (()-N-[5-Phenyl-4-(p-tolylsulfinyl)penta-2-(E)-
4-(Z)-dienyl]-N-prop-2-ynyl-p-tolylsulfonamide, 2n, (()-(3aR,
6S,SS)-6-Phenyl-5-(p-tolylsulfinyl)-2-(p-tolylsulfonyl)-2,3,3a,6-
tetrahydroisoindole, 3n, and (()-(3aS,6R,SS)-6-Phenyl-5-(p-
tolylsulfinyl)-2-(p-tolylsulfonyl)-2,3,3a,6-tetrahydroisoindole, 4n.
From dienol 1b (60 mg, 0.2 mmol), Ph3P (79 mg, 0.3 mmol),
N-(prop-2-ynyl)-p-tolylsulfonamide (63 mg, 0.3 mmol) and
diisopropyl azodicarboxylate (60 μL, 61 mg, 0.3 mmol), fol-
lowing the general procedure for Mitsunobu transformations,
(THF, 0 °C, 1 h 30 min) compound 2n was obtained. Purifica-
tion by chromatography (20-50% EtOAc/hexane) afforded a
72:28 mixture of 2n and 3n with traces of 4n (95 mg, 0.19 mmol,
95%).
A solution of 2e in CDCl3 was kept at room temperature and
monitored by H NMR until cycloaddition was complete (10
days) affording 3e as a single diastereomer.
1
In a related experiment, a solution of 2e in C6D6 was heated at
70 °C for 38 h affording 3e as a single diastereomer. Purification
by chromatography (10-50% EtOAc/hexane) gave 3e (11 mg,
0.029 mmol, 73%) as a colorless oil.
1
Data for 2e: Rf = 0.33 (30% EtOAc/hexane); H NMR (300
MHz) δ 1.36-1.72 (m, 4 H), 1.83-1.92 (m, 1 H), 2.16-2.27 (m, 1
H), 2.37 (s, 3 H, Me-p-Tol), 2.38 (brs, 1 H, H-alkyne), 3.94-3.98
(m, 1 H), 4.05 (d, J = 2.4 Hz, 2 H), 5.79-5.80 (m, 1 H), 7.15 (s, 1
H), 7.23 (d, J = 7.9 Hz, 2 H), 7.35-7.40 (m, 5 H), 7.52-7.55 (m, 2
H); MS (ES) m/z (%) 399 (100) [M þ Na]þ. Anal. Calcd for
C24H24O2S: C 76.56, H 6.42, S 8.52. Found: C 76.41, H 6.37, S 8.75.
Data for 3e: Rf = 0.20 (50% EtOAc/hexane); [R]20D = -62.3
(c 0.19); 1H NMR (300 MHz) δ 1.29-1.40 (m, 1 H), 1.75-1.89
(m, 2 H), 1.95-2.04 (m, 1 H), 2.20-2.33 (m, 1 H), 2.27 (s, 3 H,
Me-p-Tol), 3.29 (m, 1 H), 3.26-3.40 (m, 1 H), 4.27 (m, 2 H),
4.31-4.41 (m, 2 H), 5.50 (dd, J = 3.0, 1.5 Hz, 1 H), 6.78-6.81
(m, 3 H), 6.90-6.93 (m, 6 H); 13C NMR (75 MHz) δ 19.3, 21.1,
26.0, 28.2, 43.9, 45.2, 68.8, 77.5, 123.1 (3 C), 123.2, 126.4, 127.4,
129.2 (2 C), 130.1, 132.1, 134.7, 138.3, 138.7, 140.2 (2 C), 146.4;
IR (film) 3027, 2925, 2856, 1598, 1492, 1454, 1376, 1081, 1042,
863, 806, 768, 734, 699, 619, cm-1; HRMS calcd for C24H25O2S
[M þ H]þ 377.1575, found 377.1569.
Synthesis of (()-2-(E)-4-(Z)-5-Phenyl-4-(p-tolylsulfinyl)penta-
2,4-dienyl propiolate, 2m, (()-(3aR,6S,SS)-6-Phenyl-5-(p-tolyl-
sulfinyl)-3a,6-dihydro-3H-isobenzofuran-1-one, 3m, (()-(3aS,6R,
SS)-6-Phenyl-5-(p-tolylsulfinyl)-3a,6-dihydro-3H-isobenzofuran-
1-one, 4m. To solution of (()-1b (120 mg, 0.40 mmol), and
propiolic acid (37 μL, 42 mg, 0.60 mmol) in 4 mL of CH2Cl2, at
0 °C, dicyclohexylcarbodiimide (124 mg, 0.6 mmol) and di-
methylaminopyridine (20 mg, 0.16 mmol) were added. The
mixture was allowed to warm to room temperature and mon-
itored by TLC until starting material disappearance (1 h). The
reaction mixture was filtered to remove dicyclohexylurea and
the ester was purified by column chromatography (20% EtOAc/
hexane) affording 2m (83 mg, 0.28 mmol, 70%) as a colorless oil
that cyclized slowly upon standing in solution.
A solution of this mixture in CDCl3 was cooled at 5 °C
and monitored by H NMR until cycloaddition was complete
1
(3 days), affording a 94:6 mixture of 3n and 4n. Purification by
chromatography (20-50% EtOAc/hexane) afforded 3n (89 mg,
0.18 mmol, 90%) as white solid that was recrystallized from
EtOAc/hexane and 4n (5 mg, 0.01 mmol, 5%) as a white solid
that was recrystallized from EtOAc/hexane.
When the amino-Mitsunobu reaction was carried out at room
temperature 2n was not detected and a mixture of 3n and 4n was
obtained after chromatography in an identical diastereomeric
ratio to that described above.
Partial data for 2n: Rf = 0.12 (30% EtOAc/hexane); 1H
NMR (300 MHz) δ 2.35 (s, 3 H, Me-p-Tol), 2.37 (m, 1 H, H-1
overlapped), 2.38 (s, 3 H, Me-p-Tol), 3.50-3.90 (m, 4 H, 2 H-3, 2
H-5), 5.97 (dt, J = 15.6, 6.8 Hz, 1 H, H-6), 6.30 (dd, J = 15.7, 0.9
Hz, 1 H, H-7).
Data for 2m: Rf = 0.41 (50% EtOAc/hexane); 1H NMR (300
MHz) δ 2.38 (s, 3 H, Me-p-Tol), 2.87 (s, 1 H, H-30), 4.66 (d, J =
J. Org. Chem. Vol. 75, No. 5, 2010 1527

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JOCArticle
Data for 3n: Rf = 0.19 (50% EtOAc/hexane); mp 97-98 °C;
1H NMR (300 MHz-COSY) δ 2.37 (s, 3 H, Me-p-Tol), 2.43 (s, 3
H, Me-p-Tol), 2.89 (dd, J = 11.2, 9.3 Hz, 1 H, H-3), 3.23 (m, 1 H,
H-3a), 3.44 (m, 1 H, H-6), 3.76 (dd, J = 13.4, 1.2 Hz, 1 H, H-1),
4.00 (m, 1 H, H-1), 4.04 (dd, J = 9.0, 8.3 Hz, 1 H, H-3), 5.29 (t,
J = 1.8 Hz, 1 H, H-7), 6.76-6.82 (m, 2 H), 6.87 (t, J = 2.4 Hz,
1 H, H-4), 7.20-7.27 (m, 7 H), 7.32 (m, 2 H), 7.71 (d, J = 8.3 Hz,
2 H); 13C NMR (50 MHz) δ 21.5 (2 C, 2 Me-p-Tol), 39.2 (C-3a),
42.8 (C-6), 50.3 (C-1), 52.2 (C-3), 121.7, 122.5, 126.7 (2 C), 127.5
(2 C), 127.7, 128.7 (2 C), 128.9 (2 C), 129.8 (2 C), 130.0 (2 C),
132.9, 133.7, 138.5, 139.8, 142.7, 143.7, 147.2; IR (KBr) 2923,
153.1; IR (KBr) 3060, 2924, 2851, 1631, 1492, 1447, 1331, 1312,
1146, 1078, 1042, 809, 757, 730 cm-1; MS (ES) m/z (%) 615 (100)
[M þ H]þ. Anal. Calcd for C34H30O5S3: C 66.42, H 4.92, S 15.65.
Found: C 66.29, H 5.15, S 15.57.
Synthesis of (()-5,5-Bis-benzenesulfonyl-10-phenyl-9-(p-tolyl-
sulfinyl)-7-(E)-9-(Z)-decadien-1-yne, 2r, (()-(4aR,7S,SS)-3,3-
Bis-benzenesulfonyl-7-phenyl-6-(p-tolylsulfinyl)-1,2,3,4,4a,7-hexa-
hydronaphthalene, 3r, and (()-(4aS,7R,SS)-3,3-Bis-benzenesul-
fonyl-7-phenyl-6-(p-tolylsulfinyl)-1,2,3,4,4a,7-hexahydronaph-
thalene, 4r. From 3-butyn-1-ol (76 μL, 1.0 mmol), PPh3 (525 mg,
2.0 mmol), 4,4-bis-benzenesulfonylmethane (385 mg, 1.3 mmol)
and diisopropyl azodicarboxylate (0.39 mL, 2.0 mmol), follow-
ing the general procedure for Mitsunobu transformations
(C6H6, 2 h), compound 9 was obtained. Purification by chro-
matography (60-100% CH2Cl2-hexane) afforded 9 (174 mg,
0.5 mmol, 50%) as a white solid.
From dienol 1b (39 mg, 0.13 mmol), PPh3 (52 mg, 0.20 mmol,
1.5 equiv), 5,5-bis-benzenesulfonyl-pent-1-yne 9 (50 mg, 0.14
mmol) and diisopropyl azodicarboxylate (40 μL, 40 mg, 0.20
mmol, 1.5 equiv) following the general procedure (C6H6, rt, 1 h)
compound 2r was obtained. Purification by chromatography
(10-50% EtOAc/hexane) afforded 70 mg of impure 2r. A
second chromatography (5-50% EtOAc-CH2Cl2) afforded
pure 2r (30 mg, 0.05 mmol, 38%).
2862, 1630, 1492, 1453, 1346, 1163, 1095, 1051, 811, 703 cm-1
;
MS (ES) m/z (%) 979 [2M þ H]þ, 490 (100) [M þ H]þ. Anal.
Calcd for C28H27NO3S2: C 68.68, H 5.56, N 2.86, S 13.10.
Found: C 68.57, H 5.35, N 2.82, S 13.42.
Data for 4n: Rf = 0.14 (50% EtOAc/hexane); mp 140-142
°C; 1H NMR (300 MHz) δ 2.29 (s, 3 H, Me-p-Tol), 2.42 (s, 3 H,
Me-p-Tol), 2.86 (dd, J = 11.2, 9.3 Hz, 1 H, H-3), 3.15 (m, 1 H,
H-3a), 3.83 (dd, J = 14.2, 1.0 Hz, 1 H, H-1), 3.95 (ap t, J = 8.5
Hz, 1 H, H-3), 3.97 (m, 1 H, H-1), 4.29 (m, 1 H, H-6), 5.40 (br s, 1
H, H-7), 6.53 (t, J = 2.6 Hz, 1 H, H-4), 6.73-6.80 (m, 2 H),
6.93-7.12 (m, 7 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.70 (d, J = 8.1
Hz, 2 H); 13C NMR (75 MHz) δ 21.4 (Me-p-Tol), 21.6 (Me-p-
Tol), 39.1 (C-3a), 43.4 (C-6), 50.4 (C-1), 52.1 (C-3), 121.7, 125.5
(2 C), 125.6, 127.4, 127.5 (2 C), 128.4 (2 C), 129.2 (2 C), 129.5 (2
C), 129.9 (2 C), 133.1, 134.0, 139.3, 141.4, 143.8 (2 C), 148.6; IR
(KBr) 2922, 2851, 1631, 1493, 1453, 1344, 1155, 1091, 1038, 805,
756, 701, 667 cm-1; MS (ES) m/z (%) 490 [M þ H]þ. Anal. Calcd
for C28H27NO3S2: C 68.68, H 5.56, N 2.86, S 13.10. Found: C
68.71, H 5.43, N 2.91, S 13.12.
Synthesis of (()-(3aR,6S,SS)-2,2-Bis-benzenesulfonyl-6-phen-
yl-5-(p-tolylsulfinyl)-2,3,3a,6-tetrahydro-1H-indene, 3o, and
(()-(3aS,6R,SS)-2,2-Bis-benzenesulfonyl-6-phenyl-5-(p-tolylsul-
finyl)-2,3,3a,6-tetrahydro-1H-indene, 4o. From dienol 1b (49
mg, 0.16 mmol), Ph3P (63 mg, 0.24 mmol), 4,4-bis-benzenesul-
fonylbut-1-yne (60 mg, 0.18 mmol) and diisopropyl azodicar-
boxylate (50 μL, 49 mg, 0.24 mmol), following the general pro-
cedure for Mitsunobu transformations (C6H6, rt, 1 h 30 min), a
98:2 mixture of 3o and 4o was obtained. Dienyne 2o was not
detected in the 1H NMR spectra of the crude product. Purifica-
tion by chromatography (20-50% EtOAc/hexane) afforded 3o
(90 mg, 0.146 mmol, 90%) as a white solid that was recrystal-
lized from EtOAc/hexane and 4o (2 mg, 0.003 mmol, 2%) as a
white solid.
Data for 2r: Rf = 0.18 (60% Et2O-hexane); mp 84-85 °C; 1H
NMR (300 MHz) δ 1.97 (t, J = 2.3 Hz, 1 H, H-1), 2.24-2.48 (m, 4
H, 2 H-3, 2 H-4), 2.38 (s, 3 H, Me-p-Tol), 2.93 (d, J = 6.6 Hz, 2 H,
2 H-6), 6.17 (d, J = 16.1 Hz, 1 H, H-8), 6.39 (dt, J = 15.7, 6.6 Hz, 1
H, H-7), 7.21-7.75 (m, 15 H), 7.95-7.99 (m, 4 H); 13C NMR (75
MHz) δ 13.5, 21.4 (Me-p-Tol), 28.8, 33.0, 69.5, 82.3, 89.5, 124.5 (2
C), 126.7, 127.1, 128.6 (2 C), 128.8 (4 C), 130.0 (2 C), 130.1 (2 C),
131.1 (5 C), 133.8, 134.7, 136.1, 136.3, 139.6, 140.9, 142.5; IR
(KBr) 3060, 2917, 1631, 1447, 1310, 1144, 1079, 724 cm-1; MS
(ES) m/z (%) 629 (100) [M þ H]þ. Anal. Calcd for C35H32O5S3: C
66.85, H 5.13, S 15.30. Found: C 66.73, H 5.34, S 15.47.
From dienyne 2r (30 mg, 0.05 mmol) following the general
procedure for thermal cycloadditions (80 °C, 14 h) a 91:9 mixture
of 3r and 4r was obtained. Purification by chromatography
(2-5% EtOAc-CH2Cl2) afforded pure 3r (18 mg, 0.029 mmol,
58%) as a white solid that was recrystallized from EtOAc/hexane
and a mixture of 3r and 4r (10 mg, 0.016 mmol, 32%).
Data for 3r: Rf = 0.23 (10% EtOAc-CH2Cl2); mp 223-225
°C; 1H NMR (300 MHz) δ 2.00-2.27 (m, 3 H), 2.40 (s, 3 H, Me-
p-Tol), 2.58 (m, 1 H), 2.88-3.00 (m, 2 H), 3.45 (m, 1 H, H-7),
3.88 (m, 1 H, H-4a), 5.30 (t, J = 1.7 Hz, 1 H, H-8), 6.71 (dd, J =
3.4, 1.2 Hz, 1 H, H-5), 6.82-6.88 (m, 2 H), 7.20-7.29 (m, 5 H),
7.41 (d, J = 8.3 Hz, 2 H), 7.58-7.68 (m, 4 H), 7.71-7.79 (m, 2
H), 7.96 (d, J = 8.3 Hz, 2 H), 8.14 (d, J = 8.1 Hz, 2 H); 13C
NMR (50 MHz) δ 21.5 (Me-p-Tol), 27.9, 29.7, 33.9, 34.6, 42.3,
87.5 (C-3), 122.7, 126.5, 126.6 (2 C), 127.4, 128.4 (2 C), 128.8 (4
C), 128.9 (2 C), 130.1 (2 C), 131.1 (2 C), 131.5 (2 C), 132.1, 134.6,
134.8, 135.7, 136.6, 138.8, 140.5, 142.7, 144.6; IR (KBr) 3060,
2921, 2851, 1633, 1491, 1447, 1376, 1325, 1310, 1146, 1080, 1049,
810, 756, 724, 704, 687 cm-1; MS (ES) m/z (%) 629 (100) [M þ
H]þ. Anal. Calcd for C35H32O5S3: C 66.85, H 5.13, S 15.30.
Found: C 67.02, H 5.40, S 15.14.
Data for 3o: Rf = 0.45 (80% EtOAc/hexane); mp 229-230
1
°C; H NMR (300 MHz) δ 2.37-2.42 (m, 1 H), 2.40 (s, 3 H,
Me-p-Tol), 3.08 (t, J = 7.3 Hz, 1 H), 3.16 (d, J = 18.6 Hz, 1 H),
3.37 (m, 1 H), 3.41-3.54 (m, 2 H), 5.23 (br s, 1 H, H-7),
6.78-6.82 (m, 2 H), 6.93 (br s, 1 H, H-4), 7.24-7.35 (m, 6 H),
7.54-7.78 (m, 7 H), 7.99 (m, 2 H), 8.13 (m, 2 H); 13C NMR (50
MHz) δ 21.5 (Me-p-Tol), 35.7, 37.3, 39.7, 42.9, 89.9, 121.7,
124.2, 126.9 (2 C), 127.6, 128.7 (2 C), 128.8 (2 C), 128.9 (2 C),
129.0 (2 C), 130.0 (2 C), 131.3 (2 C), 131.5 (2 C), 134.1, 134.7,
134.9, 135.8, 135.9, 138.6, 140.0, 142.7, 145.6; IR (KBr) 3060,
3021, 2917, 2840, 1631, 1491, 1448, 1323, 1312, 1143, 1077, 1051,
757, 733, 703 cm-1; MS (ES) m/z (%) 615 (100) [M þ H]þ. Anal.
Calcd for C34H30O5S3: C 66.42, H 4.92, S 15.65. Found: C 66.33,
H 5.08, S 15.43.
Partial data for 4r (from the mixture): Rf = 0.21 (10%
1
EtOAc-CH2Cl2); H NMR (300 MHz) δ 2.33 (s, 3 H, Me-p-
Tol), 3.85 (m, 1 H, H-4a), 4.19 (m, 1 H, H-7), 5.37 (m, 1 H, H-8),
6.46 (d, J = 3.8 Hz, 1 H, H-5).
Data for 4o: Rf = 0.41 (80% EtOAc/hexane); mp 114-115 °C;
1H NMR (300 MHz) δ 2.32 (s, 3 H, Me-p-Tol), 2.36 (m, 1 H), 2.98
(dd, J = 14.4, 8.1 Hz, 1 H), 3.14 (d, J = 9.4 Hz, 1 H), 3.23-3.47
(m, 2 H), 4.28 (m, 1 H), 5.35 (br s, 1 H, H-7), 6.59 (t, J = 2.6 Hz, 1
H, H-4), 6.83 (dd, J = 8.1, 1.7 Hz, 1 H), 6.98-7.11 (m, 7 H),
7.50-7.77 (m, 6 H), 8.00 (dd, J = 8.5, 1.2 Hz, 2 H), 8.09 (dd, J =
8.5, 1.2 Hz, 2 H); 13C NMR (50 MHz) δ 21.4 (Me-p-Tol), 36.2,
36.8, 39.4, 43.6, 90.0(C-2), 122.0, 125.5 (2 C), 127.3, 127.8, 128.4(2
C), 128.9 (2 C), 129.0 (2 C), 129.4 (2 C), 129.5 (2 C), 131.3 (2 C),
131.4 (2 C), 134.2, 134.7, 135.0, 136.1, 139.5, 139.6, 141.3, 147.2,
Synthesis of (()-(3aS,6R,RS)-6-n-Butyl-4-(2-methoxynaph-
thalene-1-ylsulfinyl)-1,3,3a,6-tetrahydroisobenzofuran, 3i, and
(()-(3aR,6S,RS)-6-n-Butyl-4-(2-methoxynaphthalene-1-ylsulfi-
nyl)-1,3,3a,6-tetrahydroisobenzofuran, 4i. From diene 1i (25 mg,
0.072 mmol), propargyl bromide (39 μL, 54 mg, 0.36 mmol),
Triton B (8 μL, 7 mg, 0.04 mmol) and 60% aqueous sodium
hydroxide (0.7 mL) following the general procedure (3 h)
compound 2i was obtained. The 1H NMR of the crude product,
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recorded immediately after workup showed a 64:32:4 mixture of
2i, 3i and 4i. After 1 day at room temperature the cycloaddition
was complete and an 89:11 mixture of 3i and 4i was obtained.
Purification by chromatography (20-40% EtOAc/hexane) af-
forded 3i (18 mg, 0.047 mmol, 65%) as a white solid that was
recrystallized in EtOAc/hexane and 4i (3 mg, 0.008 mmol, 11%)
as a white solid.
Data for 3i: Rf = 0.46 (80% EtOAc/hexane); mp 155-156 °C;
1H NMR (300 MHz) δ 0.92 (t, J = 7.0 Hz, 3 H, Me-n-Bu),
1.29-1.44 (m, 4 H, CH2-n-Bu), 1.61-1.68 (m, 2 H, CH2-n-Bu),
2.51 (m, 1 H, H-3a), 3.05 (m, 1 H, H-6), 3.39 (dd, J = 10.9, 7.7 Hz,
1 H, H-3), 3.97 (t, J = 7.8 Hz, 1 H, H-3), 4.00 (s, 3 H, OMe), 4.17
(br s, 2 H, H-1), 5.47 (br s, 1 H, H-7), 6.78 (m, 1 H, H-5), 7.25 (d,
J = 9.1 Hz, 1 H, H-30), 7.37 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H, H-60),
7.49 (ddd, J = 8.4, 7.0, 1.5 Hz, 1 H, H-70), 7.78 (d, J = 8.1 Hz, 1 H,
H-50), 7.96 (d, J = 9.2 Hz, 1 H, H-40), 8.66 (d, J = 8.5 Hz, 1 H, H-
80); 13C NMR (50 MHz) δ 14.0 (Me-n-Bu), 22.9, 28.6, 34.9, 38.1,
39.3, 56.9, 68.5, 70.7, 112.8, 118.8, 120.0, 122.6, 124.6, 128.2, 128.8,
129.5, 132.2, 132.5, 135.3, 137.7, 138.1, 158.0; IR (KBr) 2958,
2932, 2856, 1620, 1592, 1505, 1458, 1432, 1336, 1273, 1250, 1150,
1047, 1027, 904, 879, 829, 777, 753 cm-1; MS (ES) m/z (%) 383
(100) [M þ H]þ. Anal. Calcd for C23H26O3S: C 72.22, H 6.85, S
8.38. Found: C 72.68, H 6.72, S 8.45.
Data for 4i: Rf = 0.43 (80% EtOAc/hexane); mp 114-116 °C;
1H NMR (300 MHz) δ 0.91 (t, J = 6.8 Hz, 3 H, Me-n-Bu),
1.27-1.39 (m, 4 H, CH2-n-Bu), 1.57-1.66 (m, 2 H, CH2-n-Bu),
2.33 (dd, J = 10.7, 7.6 Hz, 1 H, H-3), 3.15 (m, 1 H, H-6), 3.36 (m,
1 H, H-3a), 3.49 (t, J = 7.5 Hz, 1 H, H-3), 4.00 (s, 3 H, OMe),
4.03 (m, 1 H, H-1), 4.22 (dm, J = 12.0 Hz, 1 H, H-1), 5.43 (br s, 1
H, H-7), 6.75 (m, 1 H, H-5), 7.23 (d, J = 9.3 Hz, 1 H, H-30), 7.36
(ddd, J = 8.1, 6.8, 1.2 Hz, 1 H, H-60), 7.47 (ddd, J = 8.3, 6.8, 1.5
Hz, 1 H, H-70), 7.76 (dd, J = 6.6, 0.7 Hz, 1 H, H-50), 7.95 (d, J =
9.0 Hz, 1 H, H-40), 8.69 (dd, J = 8.5, 1.0 Hz, 1 H, H-80); 13C
NMR (50 MHz) δ 14.1 (Me-n-Bu), 22.9, 28.5, 35.0, 38.0, 38.9,
56.8, 68.3, 70.0, 112.8, 119.8, 123.1, 124.6, 128.0, 128.3, 128.8,
129.4, 132.5, 133.7, 135.2, 137.4, 138.6, 157.9; IR (KBr) 2927,
2856, 1621, 1593, 1506, 1465, 1431, 1335, 1272, 1250, 1151, 1034,
908, 813, 747 cm-1; MS (ES) m/z (%) 421, 419 (100), 383 [M þ
H]þ . Anal. Calcd for C23H26O3S: C 72.22, H 6.85, S 8.38.
Found: C 72.37, H 6.59, S 8.52.
General Procedure for the Catalytic Hydrogenation of Cy-
cloadducts. To a solution of the corresponding cycloadduct in
EtOH (10 mL/mmol) under an argon atmosphere, a 10% mol of
Pd on charcoal was added. A hydrogen atmosphere was
achieved using a balloon charged with H2, and the reaction
was stirred until the complete disappearance of the starting
material (TLC). The reaction mixture was filtered through a pad
of Celite and concentrated under reduced pressure. The crude
product was purified by chromatography using the appropriate
mixture of solvents.
318 [M]þ, 301 (100). Anal. Calcd for C19H26O2S: C 71.66, H 8.23,
S 10.07. Found: C 71.42, H 8.15, S 10.13.
Synthesis of (þ)-(3aS,5S,7aS,SS)-5-Phenyl-6-(p-tolylsulfinyl)-
1,3,3a,4,5,7a-hexahydroisobenzofuran, 12b. From 3b (60 mg,
0.18 mmol) and Pd (C) (20 mg, 0.018 mmol), following the
general procedure (20 h), compound 12b was obtained. Purifi-
cation by chromatography (20-70% EtOAc/hexane) afforded
12b (43 mg, 0.13 mmol, 71%) as a white solid.
Data for 12b: Rf = 0.28 (70% EtOAc/hexane); mp 145-147
°C; [R]20D = þ14.8 (c 1.22); 1H NMR (400 MHz-COSY) δ 1.65
(ap q, J = 13.0 Hz, 1 H, H-4), 1.82 (dt, J = 13.3, 4.8 Hz, 1 H, H-
4), 2.30 (s, 3 H, Me-p-Tol), 2.25-2.35 (m, 1 H, H-3a), 2.85
(dquint, J = 11.1, 2.5 Hz, 1 H, H-5), 2.95-3.03 (m, 1 H, H-7a),
3.51 (dd, J = 8.8, 1.8 Hz, 1 H, H-3), 3.56 (t, J = 8.4 Hz, 1 H, H-
1), 3.88 (dd, J = 8.8, 5.9 Hz, 1 H, H-3), 4.12 (t, J = 8.4 Hz, 1 H,
H-1), 6.86-6.88 (m, 3 H), 7.06 (d, J = 8.3 Hz, 2 H), 7.10 (d, J =
8.1 Hz, 2 H), 7.17-7.21 (m, 3 H); 13C NMR (75 MHz) δ 21.5,
36.9, 37.2, 39.8, 42.2, 71.8, 73.8, 126.7 (2 C), 127.0, 127.3, 128.5
(2 C), 128.9 (2 C), 129.8 (2 C), 139.2, 140.5, 142.3, 146.8.
NOESY-2D (400 MHz): a correlation peak between H-3a and
H-7a was observed; IR (KBr) 2924, 2849, 1631, 1595, 1493,
1455, 1084, 1043, 1014, 816, 759, 700, 516 cm-1; MS (ES) m/z
(%) 361 [M þ Na]þ, 339 [M þ H]þ. Anal. Calcd for C21H22O2S:
C 74.52, H 6.55, S 9.47. Found: C 74.67, H 6.46, S 9.51.
General Procedure for the Oxidation-Epoxidation of Cy-
cloadducts. To a cold (0 °C) solution of the corresponding
cycloadduct (1.0 equiv) in CH2Cl2 (10 mL/mmol), m-CPBA
(3.0 equiv) was added. The mixture was allowed to reach room
temperature and was stirred until starting material disappear-
ance (TLC). Then the reaction mixture was quenched with a 1 M
solution of Na2S2O4 (2 mL/mmol peracid) and a saturated
solution of NaHCO3 (2 mL/mmol peracid) and diluted with
CH2Cl2. The phases were separated and the aqueous phase was
extracted with CH2Cl2 (twice), the organic extract was dried
over anhydrous MgSO4, filtered and concentrated under re-
duced pressure. The crude product was purified by column
chromatography using the appropriate mixture of solvents.
Synthesis of (þ)-(3aR,4R,5R,7aS)-5-n-Butyl-3a,4-epoxy-6-
tosyl-1,3,3a,4,5,7a-hexahydroisobenzofuran, 13a. From 3a (28
mg, 0.09 mmol) and m-CPBA (67 mg, 0.27 mmol) following the
general procedure (3 days), compound 13a was obtained. Pur-
ification by chromatography (50% CH2Cl2/hexane/10%
EtOAc/CH2Cl2) afforded 13a (27 mg, 0.072 mmol, 80%) as a
white solid that was recrystallized from Et2O/hexanes.
Data for 13a: Rf = 0.40 (50% EtOAc/hexane); mp 138-140
°C; [R]20D = þ61.8 (c = 1.07); 1H NMR (400 MHz-COSY) δ
0.81 (t, J = 7.1 Hz, 3 H, Me-n-Bu), 1.09-1.26 (m, 4 H),
1.72-1.90 (m, 2 H), 2.41 (s, 3 H, Me-p-Tol), 2.92 (ap quint,
J = 3.1 Hz, 1 H, H-5) 3.09 (s, 1 H, H-4), 3.22-3.29 (m, 1 H, H-
7a), 3.55 (dd, J = 11.2, 8.4 Hz, 1 H, H-1), 3.80 (d, J = 9.9 Hz,
1 H, H-3), 3.94 (d, J = 9.9 Hz, 1 H, H-3), 4.34 (t, J = 8.3 Hz, 1 H,
H-1), 6.84 (dd, J= 5.1, 0.9 Hz, 1 H, H-7), 7.31 (d, J=7.9Hz, 2H),
7.69 (d, J = 8.3 Hz, 2 H); 13C NMR (75 MHz) δ 12.3, 21.6, 22.6,
27.9, 30.6, 35.1, 39.8, 62.1, 64.1, 67.3, 70.6, 128.1 (2 C), 129.8 (2 C),
132.1, 136.1, 142.1, 144.6; IR (KBr) 2955, 2927, 2872, 1642, 1596,
1465, 1303, 1143, 1092, 1083, 1044, 1008, 902, 686, 544 cm-1; MS
(ES) m/z(%) 371[M þ Na]þ. Anal. Calcd for C19H24O3S: C 68.64,
H 7.28, S 9.64. Found: C 68.36, H 7.09, S 9.55.
Synthesis of (þ)-(3aR,4R,5R,7aS)-3a,4-Epoxy-5-phenyl-6-to-
syl-1,3,3a,4,5,7a-hexahydroisobenzofuran, 13b. From 3b (82 mg,
0.24 mmol) and m-CPBA (124 mg, 0.72 mmol), following the
general procedure (3 days), compound 13b was obtained along
with aromatized sulfone 6b. Purification by chromatography
(10-50% EtOAc/hexane) afforded 13b (53 mg, 0.14 mmol,
60%) and 6b (4 mg, 0.012 mmol, 5%) both as white solids that
were recrystallized from Et2O/hexane.
Synthesis of (þ)-(3aS,5R,7aS,SS)-5-n-Butyl-6-(p-tolylsul-
finyl)-1,3,3a,4,5,7a-hexahydroisobenzofuran, 12a. From 3a (10
mg, 0.03 mmol) and Pd (C) (3 mg, 0.003 mmol) following the
general procedure (2 days), compound 12a was obtained. Pur-
ification by chromatography (10-70% EtOAc/hexane) af-
forded 12a (5 mg, 0.015 mmol, 52%) as a colorless oil.
Data for 12a: Rf = 0.13 (50% EtOAc/hexane); [R]20D = þ26.7
(c 0.46); 1H NMR (400 MHz) δ 0.83 (t, J = 7.1 Hz, 3 H, Me-n-
Bu), 1.05-1.44 (m, 6 H), 1.55-1.63 (m, 1 H), 1.74 (dt, J = 13.1,
4.8 Hz, 1 H, H-4), 1.84-1.90 (m, 1 H, H-3a), 2.18-2.30 (m, 1 H,
H-5), 2.39 (s, 3 H, Me-p-Tol), 2.92-3.00 (m, 1 H, H-7a), 3.48 (dd,
J = 9.2, 8.2 Hz, 1 H, H-3), 3.64 (dd, J = 8.7, 1.9 Hz, 1 H, H-1),
3.95 (dd, J = 8.7, 5.9 Hz, 1 H, H-1), 4.10 (t, J = 8.4 Hz, 1 H, H-3),
6.76 (dd, J = 4.8, 2.1 Hz, 1 H, H-7), 7.27 (d, J = 7.9 Hz, 2 H), 7.52
(d, J = 8.1 Hz, 2 H); 13C NMR (100 MHz) δ 13.9, 21.5, 22.6, 27.7,
31.2, 31.9, 34.6, 36.5, 39.9, 71.7, 74.1, 126.1, 126.6 (2 C), 130.1 (2
C), 139.8, 142.3, 147.0; IR (film) 2927, 2857, 1732, 1596, 1492,
1456, 1378, 1261, 1082, 1050, 1015, 809 cm-1; MS (EI) m/z (%)
Data for 13b: Rf = 0.48 (50% EtOAc/hexane); mp 179-182
°C; [R]20D = þ59.8 (c 0.93); 1H NMR (400 MHz-COSY) δ 2.23
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(s, 3 H, Me-p-Tol), 3.09 (s, 1 H, H-4), 3.38 (m, 1 H, H-7a), 3.64
(d, J = 8.7 Hz, 1 H), 3.67 (d, J = 8.4 Hz, 1 H), 3.88 (d, J = 10.0
Hz, 1 H, H-3), 4.23 (d, J = 3.4 Hz, 1 H, H-5), 4.43 (ap t, J = 8.3
Hz, 1 H, H-1), 6.86 (m, 2 H), 6.91 (d, J = 8.3 Hz, 2 H), 7.00-7.09
(m, 4 H), 7.18 (d, J = 8.3 Hz, 2 H); 13C NMR (100 MHz) δ 21.4,
40.0, 42.5, 61.9, 64.0, 67.5, 71.1, 127.6, 127.8 (2 C), 128.6 (2 C),
128.9 (2 C), 129.3 (2 C), 132.3, 136.6, 136.7, 142.3, 143.7; IR
(KBr) 3027, 2923, 1644, 1598, 1492, 1457, 1305, 1147, 1089,
1040, 702, 684, 538 cm-1; MS (ES) m/z (%) 391 [M þ Na]þ, 369
[M þ H]þ. Anal. Calcd for C21H20O3S: C 71.56, H 5.72, S 9.10.
Found: C 71.67, H 5.68, S 9.23.
Data for 6b: Rf = 0.60 (70% EtOAc/hexane); mp 161-165
°C; 1H NMR (400 MHz) δ 2.31 (s, 3 H, Me-p-Tol), 5.12 (s, 2 H),
5.22 (s, 2 H), 6.92-6.97 (m, 4 H), 7.04-7.07 (m, 3 H), 7.15-7.19
(m, 2 H), 7.26-7.30 (m, 1 H), 8.29 (s, 1 H); 13C NMR (100 MHz)
δ 21.5, 73.2, 73.3, 121.4, 125.2, 127.2 (2 C), 127.6, 127.7 (2 C),
128.9 (2 C), 130.1 (2 C), 137.8, 138.0, 138.9, 139.5, 141.8, 143.4,
144.4; IR (KBr) 2921, 1631, 1460, 1306, 1162, 1138, 1088, 710,
555 cm-1; MS (ES) m/z (%) 373 [M þ Na]þ, 351 [M þ H]þ.
Anal. Calcd for C21H18O3S: C 71.98, H 5.18, S 9.15. Found: C
72.14, H 5.34, S 9.28.
General Procedure for Osmium-Catalyzed Dihydroxylation.
To a solution of the sulfoxide in a 9:1 mixture of acetone and
H2O (0.1 M), at rt, were added 2.5 equiv of Me3NO and 0.05
equiv of OsO4. The solution was stirred until starting material
disappearance and then quenched with a solution of aqueous
Na2S2O4 (1 M, 5 mL/mmol). The solvent was evaporated and
the crude product was filtered through a short pad of silica gel.
Synthesis of (þ)-(3aS,4R,5R,7aS,SS)-5-n-Butyl-6-(p-tolyl-
sulfinyl)-1,3,3a,4,5,7a-hexahydroisobenzofuran-3a,4-diol, 14a.
From sulfoxide 3a (32 mg, 0.100 mmol), Me3NO (28 mg,
0.250 mmol) and OsO4 (65 μL, 52 mg (2.5 wt %), 0.005 mmol)
following the general procedure (15 min), a 96:4 mixture of
sulfoxide 14a and sulfone SI-39 was obtained. Purification by
chromatography (20-50% EtOAc/hexane) afforded 1 mg
(0.003 mmol, 3%) of sulfone SI-39 as a colorless oil and
sulfoxide 14a (25 mg, 0.072 mmol, 72%) as a white solid that
was recrystallized from EtOAc/hexane.
Data for 14a: Rf = 0.27 (100% EtOAc); mp 148-150 °C;
[R]20D = þ108.2 (c 0.65); 1H NMR (300 MHz) δ 0.88 (t, J = 7.0
Hz, 3 H, Me-n-Bu), 1.31-1.38 (m, 4 H, 2 CH2-n-Bu), 1.42 (m, 1
H, n-Bu), 1.62 (m, 1 H, n-Bu), 2.13 (m, 1 H, H-5), 2.38 (s, 3 H,
Me-p-Tol), 2.39 (m, 1 H, OH), 2.79 (s, 1 H, OH), 3.03 (m, 1 H, H-
7a), 3.60 (d, J = 9.3 Hz, 1 H, H-3), 3.61 (dd, J = 8.8, 7.0 Hz, 1 H,
H-1), 3.78 (ap t, J = 6.9 Hz, 1 H, H-4), 3.99 (d, J = 9.3 Hz, 1 H,
H-3), 4.25 (t, J = 8.7 Hz, 1 H, H-1), 6.65 (dd, J = 4.6, 1.7 Hz,
1 H, H-7), 7.28 (d, J = 7.8 Hz, 2 H, p-Tol), 7.53 (d, J = 8.3 Hz, 2
H, p-Tol); DNOE between H-5/OH-4: 1.9%; between H-5/OH-
3: 1.6%; between H-5/H-4: 2.1%; between H-5/H-p-Tol: 1.8%;
between H-7a/H-1 (3.61 ppm): 4.6%; between H-7a/H-1 (4.25
ppm): 1.8%; between H-7a/H-7: 4.4%; between H-4/Me-n-Bu:
3.1%; between H-4/CH2-n-Bu: 6.8%; between H-4/H-5: 3.9%;
between H-4/CH3-p-Tol: 4.5%; between H-3 (3.99 ppm)/H-3
(3.60 ppm): 19.0%; between H-1 (4.25 ppm)/H-7a: 5.7%; be-
tween H-1 (4.25 ppm)/H-7a: 5.7%; between H-1 (4.25 ppm)/H-1
(3.61 ppm): 20.7%; 13C NMR (50 MHz) δ 13.9 (Me-n-Bu), 21.5
(Me-p-Tol), 22.9, 27.1, 27.9, 38.9 (C-5), 47.0 (C-7a), 70.4 (C-4),
72.2 (C-1), 75.4 (C-3), 79.1 (C-3a), 126.4 (C-7), 126.8 (2 C), 130.3
(2 C), 139.0, 142.9, 143.3; IR (KBr) 3436, 2959, 2873, 1637, 1454,
1350, 1277, 1082, 1033, 917, 808 cm-1; MS (ES) m/z (%) 351
(100) [M þ H]þ. Anal. Calcd for C19H26O4S: C 65.11, H 7.48, S
9.15. Found: C 64.78, H 7.36, S 9.40.
3.91 (d, J = 10 Hz, 1 H, H-3), 3.98 (dd, J = 4.9, 3.4 Hz, 1 H, H-4),
4.15 (dd, J = 8.8, 7.3 Hz, 1 H, H-1), 6.93 (d, J = 4.6 Hz, 1 H, H-7),
7.31 (d, J = 8.5 Hz, 2 H, p-Tol), 7.72 (d, J = 8.5 Hz, 2 H, p-Tol);
DNOE between H-5/H-4: 2.0%; between H-7a/H-1 (4.15 ppm):
4.2%; between H-7a/H-7: 3.4%; between H-3 (3.63 ppm)/H-3
(3.91 ppm): 13.9%; between H-1(3.76 ppm)/H-1(4.15 ppm): 17.4;
between H-1 (3.76 ppm)/H-7: 2.2%; between H-3 (3.91 ppm)/H-3
(3.63 ppm): 73.2%; between H-4/H-3 (3.91 ppm): 5.5%; between
H-1 (4.15 ppm)/H-7a: 3.2%; H-1 (4.15 ppm)/H-1 (3.76 ppm):
12.4%; 13C NMR (50 MHz) δ 13.8 (Me-n-Bu), 21.6 (Me-p-Tol),
22.4, 29.2, 30.3, 42.5 (C-5), 47.5 (C-7a), 69.7 (C-4), 71.6 (C-1), 76.1
(C-3), 80.0 (C-3a), 128.0 (2 C), 129.9 (2 C), 136.4, 138.3, 141.3,
144.5; IR (film) 3435, 2962, 2925, 2862, 1642, 1597, 1261, 1147,
1088, 1020, 803, 671 cm-1; MS (ES) m/z (%) 349 (100) [(M - 18)
þ1]þ. Anal. Calcd for C19H26O5S: C 62.27, H 7.15, S 8.75. Found:
C 62.53, H 7.29, S 8.54.
Synthesis of (-)-(3aR,4S,5S,7aR,SS)-5-n-Butyl-6-(p-tolyl-
sulfinyl)-1,3,3a,4,5,7a-hexahydroisobenzofuran-3a,4-diol, 15. From
sulfoxide 4a (23 mg, 0.073 mmol), Me3NO (20 mg, 0.180 mmol)
and OsO4 (51 μL, 41 mg (2.5 wt %), 0.004 mmol) following the
general procedure (15 min), an 83:17 mixture of sulfoxide 15 and
sulfone SI-40 was obtained. Purification by chromatography
(20-50% EtOAc/hexane) afforded sulfone SI-40 (4 mg, 0.011
mmol, 15%) and sulfoxide 15 (16 mg, 0.046 mmol, 63%) as a white
solid that was recrystallized from EtOAc/hexane.
Data for 15: Rf = 0.21 (100% EtOAc); mp 137-138 °C;
[R]20D = -19.1 (c 0.71); 1H NMR (300 MHz-COSY) δ 0.83 (t,
J = 7.0 Hz, 3 H, Me-n-Bu), 1.18-1.32 (m, 4 H, 2 CH2-n-Bu),
1.48-1.61 (m, 1 H, n-Bu), 1.73-1.83 (m, 1 H, n-Bu), 2.15 (br s, 1
H, OH), 2.39 (s, 3 H, Me-p-Tol), 2.52 (ap quint, J = 4.4 Hz, 1 H,
H-5), 2.86 (m, 1 H, H-7a), 3.17 (br s, 1 H, OH), 3.62 (d, J = 9.8
Hz, 1 H, H-3), 3.70 (dd, J = 8.8, 4.4 Hz, 1 H, H-1), 3.84 (t, J =
4.9 Hz, 1 H, H-4), 3.98 (d, J = 9.8 Hz, 1 H, H-3), 4.17 (dd, J =
8.8, 7.8 Hz, 1 H, H-1), 6.37 (dd, J = 4.6, 1.0 Hz, 1 H, H-7), 7.30
(d, J = 8.5 Hz, 2 H, p-Tol), 7.46 (d, J = 8.3 Hz, 2 H, p-Tol); 13
C
NMR (50 MHz-HMQC) δ 13.9 (Me-n-Bu), 21.4 (Me-p-Tol),
22.6, 28.9, 30.2, 41.0 (C-5), 47.6 (C-7a), 70.0 (C-4), 71.9 (C-1),
75.8 (C-3), 79.7 (C-3a), 125.2 (2 C), 130.0 (2 C), 133.8 (C-7),
138.7, 141.6, 145.6; IR (KBr) 3466, 2955, 2870, 1630, 1413, 1309,
1082, 1022, 1004, 928, 819, 705 cm-1; MS (ES) m/z (%) 701 (100)
[2M þ H]þ, 351 [M þ H]þ. Anal. Calcd for C19H26O4S: C 65.11,
H 7.48, S 9.15. Found: C 64.88, H 7.19, S 8.98.
Data for SI-40 is identical to that described above for SI-39
except for optical rotation: [R]20D = -56.4 (c 0.54).
Synthesis of (þ)-(3aR,4R,5R,7aS,SS)-5-Phenyl-6-(p-tolylsulfinyl)-
1,3,3a,4,5,7a-hexahydroisobenzofuran-3a,4-diol, 14b. From 3b
(45 mg, 0.13 mmol, 1.0 equiv), Me3NO (37 mg, 0.33 mmol,
2.5 equiv) and OsO4 (2.5% in t-butanol, 88 μL, 0.007 mmol,
0.05 equiv), following the general procedure (20 h), com-
pound 14b was obtained. Purification by chromatography
(0-80% EtOAc/hexane) afforded diol 14b (31 mg, 0.083 mmol,
64%) as a white solid that was recrystallized from EtOAc/
hexane.
Data for 14b: Rf = 0.15 (EtOAc); mp 191-194 °C; [R]20
=
D
þ5.8 (c 1.01); 1H NMR (400 MHz-COSY) δ 2.07 (d, J = 3.8 Hz,
1 H, OH), 2.36 (s, 3 H, Me-p-Tol), 2.75 (s, 1 H, OH), 3.06 (dt,
J = 9.1, 2.2 Hz, 1 H, H-5), 3.17-3.23 (m, 1 H, H-7a), 3.61 (d,
J = 9.1 Hz, 1 H, H-3), 3.66 (t, J = 8.6 Hz, 1 H, H-1), 3.84 (dd,
J = 9.1, 3.8 Hz, 1 H, H-4), 3.96 (d, J = 9.1 Hz, 1 H, H-3), 4.34 (t,
J = 9.1 Hz, 1 H, H-1), 6.78 (dd, J = 4.2, 2.4 Hz, 1 H, H-7),
6.94-6.96 (m, 2 H), 7.06-7.09 (m, 2 H), 7.15 (d, J = 8.4 Hz, 2
H), 7.28-7.31 (m, 3 H); 13C NMR (100 MHz) δ 21.5, 46.0, 46.8,
72.2, 75.7, 75.8, 78.5, 126.2, 127.1 (2 C), 128.2, 128.8 (2 C), 129.9
(2 C), 130.1 (2 C), 136.2, 138.3, 142.7, 142.9; IR (KBr) 3412,
2922, 1638, 1493, 1452, 1320, 1082, 1041, 913, 811, 749, 702, 646,
515 cm-1; MS (ES) m/z (%) 393 [M þ Na]þ, 371 [M þ H]þ.
Anal. Calcd for C21H22O4S: C 68.08, H 5.99, S 8.66. Found: C
68.13, H 6.09, S 8.93.
Data for SI-39: Rf = 0.18 (50% EtOAc/hexane); [R]20
=
D
þ43.4 (c 0.58); 1H NMR (300 MHz) δ 0.83 (t, J = 7.1 Hz, 3 H,
Me-n-Bu), 1.17-1.45 (m, 5 H, n-Bu), 1.78 (m, 1 H, n-Bu), 1.90
(d, J = 5.1 Hz, 1 H, OH), 2.42 (s, 3 H, Me-p-Tol), 2.62 (dt, J =
10.3, 3.4 Hz, 1 H, H-5), 2.88 (m, 1 H, H-7a), 3.01 (s, 1 H, OH), 3.63
(d, J = 10.2 Hz, 1 H, H-3), 3.76 (dd, J = 9.0, 2.9 Hz, 1 H, H-1),
1530 J. Org. Chem. Vol. 75, No. 5, 2010

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Synthesis of (-)-(3aR,4R,5R,6R,7R,7aR)-6,7-Epoxy-5-phen-
yl-6-tosyl-1,3,3a,4,5,6,7,7a-octahydroisobenzofuran-3a,4-diol, 17.
In a two-necked round-bottomed flask, using polyethylene stop-
pers, anhydrous THF (10mL/mmol) was chargedand cooled to 0
°C. Thenn-BuLi (1.6 M inhexane, 0.31 mL, 0.50 mmol, 6.0 equiv)
and HOO-t-Bu (80 wt % in t-BuOO-t-Bu, 54 μL, 0.54 mmol, 6.5
equiv) were added. The mixture was stirred for 30 min and cooled
to -60 °C. Then a solutionof16 (32mg, 0.083mmol, 1.0 equiv) in
THF (10 mL/mmol) was slowly added. The mixture was allowed
to reach room temperature and stirred until starting material
disappearance (TLC, 2 days). Then the reaction mixture was
quenched with a 1 M solution of Na2S2O4, extracted with EtOAc
(3 times), dried overanhydrousMgSO4, filtered andconcentrated
under reduced pressure. Purification by chromatography
(20-100% EtOAc/CH2Cl2) afforded 17 (18 mg, 0.045 mmol,
55%) as a white solid that was recrystallized from Et2O/hexane.
10.7 Hz, 1 H, H-4), 2.75 (d, J = 10.7 Hz, 1 H, H-4), 2.72-2.80
(m, 1 H, H-3a), 3.56 (dd, J = 9.2, 6.6 Hz, 1 H, H-3), 3.77 (d, J =
9.1 Hz, 1 H, H-1), 3.82 (d, J = 11.6 Hz, 1 H, H-6), 4.06 (d, J =
9.1 Hz, 1 H, H-1), 4.19 (d, J = 11.6 Hz, 1 H, H-7), 4.21 (dd, J =
9.1, 7.7 Hz, 1 H, H-3), 7.14-7.18 (m, 2 H), 7.30-7.42 (m, 3 H);
13C NMR (100 MHz) δ 40.0, 42.7, 58.5, 72.6, 73.6, 77.6, 78.9,
128.2, 129.2 (2 C), 129.5 (2 C), 134.7, 207.0 (CdO); IR (KBr)
3440, 2924, 2851, 1713, 1630, 1071, 1029 cm-1; MS (ES) m/z (%)
271 [M þ Na]þ. Anal. Calcd for C14H16O4: C 67.73, H 6.50.
Found: C 67.92, H 6.76.
Sulfoxide-Directed Lactonization of Cycloadducts. To a solu-
tion of 3b (28 mg, 0.083 mmol, 1.0 equiv) in anhydrous THF (20
mL/mmol) was added Zn-Cu (84 mg, 1.3 mmol, 20 equiv), and
the mixture was cooled to -60 °C. Then, a solution of freshly
distilled trichloroacetyl chloride (36 μL, 0.325 mmol, 5.0 equiv)
in anhydrous THF (30 mL/mmol) was added dropwise. The
reaction mixture was stirred and allowed to warm up slowly.
After 2 h (-30 °C), the reaction mixture was filtered through a
pad of Celite and poured into a saturated solution of NaHCO3.
The biphasic mixture was stirred for 30 min and then extracted
with Et2O (3 times), washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
product was purified by chromatography (10-30% EtOAc/
hexane) to afford a 65:35 mixture of two diastereomeric mono-
chlorolactones (22 mg, 0.053 mmol, 64%) and 10 mg (0.029
mmol, 35%) of starting material. A second chromatography
(10-30% EtOAc/hexane) afforded 14 mg (0.047 mmol) of 20a
and 7 mg (0.024 mmol) of 20b.
Data for 17: Rf = 0.22 (40% EtOAc/hexane); mp 227-
D
1
229 °C; [R]20 = -46.4 (c 0.11); H NMR (400 MHz-COSY)
δ 2.40 (s, 3 H, Me-p-Tol), 2.62 (d, J = 8.6 Hz, 1 H, OH), 2.91 (qd,
J = 4.6, 1.2 Hz, 1 H, H-7a), 3.16 (s, 1 H, OH), 3.41 (d, J = 9.8
Hz, 1 H, H-3), 3.50 (d, J = 9.8 Hz, 1 H, H-3), 3.60 (d, J = 6.0 Hz,
1 H, H-5), 3.85 (dd, J = 8.4, 5.8 Hz, 1 H, H-4), 4.06 (s, 1 H, H-7),
4.08 (dd, J = 9.5, 4.6 Hz, 1 H, H-1), 4.24 (dd, J = 9.5, 7.9 Hz,
1 H, H-1), 7.17 (d, J = 8.5 Hz, 2 H), 7.18-7.31 (m, 5 H), 7.32 (d,
J = 8.3 Hz, 2 H); 13C NMR (75 MHz) δ 21.7, 45.8, 47.1, 59.0,
69.9, 74.1, 74.6, 76.7, 78.1, 128.1 (2 C), 128.2 (2 C), 129.0 (2 C),
129.6 (2 C), 130.6, 132.9, 133.2, 145.4; IR (KBr) 3435, 2923,
2851, 1631, 1321, 1148, 1085, 934, 809, 702, 536 cm-1; MS (ES)
m/z (%) 425 [M þ Na]þ. Anal. Calcd for C21H22O6S: C 62.67, H
5.51, S 7.97. Found: C 62.89, H 5.89, S 8.05.
Data for major lactone 20a: Rf = 0.42 (30% EtOAc/hexane);
[R]20D = þ11.1 (c 0.52); 1H NMR (400 MHz) δ 2.30 (s, 3 H, Me-
pTol), 2.56 (dd, J = 9.6, 5.3 Hz, 1 H, H-8b), 2.83-2.90 (m, 1 H,
H-8a), 3.47 (dd, J = 9.6, 8.3 Hz, 1 H, H-8), 3.85 (m, 1 H, H-4),
4.27 (t, J = 8.2 Hz, 1 H, H-8), 4.35 (d, J = 9.6 Hz, 1 H, H-1),
4.46-4.57 (m, 2 H, H-6), 6.03-6.05 (m, 1 H, H-5), 7.12 (d,
J = 7.9 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.35-7.42 (m, 5 H);
13C NMR (100 MHz) δ 21.2, 44.7, 48.6, 50.9, 57.5, 69.4,
72.5, 99.5, 117.5, 124.4, 128.1, 128.2 (2 C), 130.2 (2 C), 130.4
(2 C), 136.2, 137.0 (2 C), 140.6, 142.1, 169.0 (CdO); IR (film) 3033,
2925, 2856, 1791, 1688, 1597, 1492, 1454, 1265, 1188, 1105, 1038,
944, 813, 758, 737, 701, 612, 500 cm-1; HRMS (ES) calcd for
C23H22ClO3SNa [M þ Na]þ 435.0794, found 435.0793 [M þ H]þ.
Data for minor lactone 20b: Rf = 0.33 (30% EtOAc/hexane);
[R]20D = -281.1 (c 0.91); 1H NMR (300 MHz, C6D6) δ 1.98 (s,
3 H, Me-pTol), 2.43 (t, J = 11.2 Hz, 1 H, H-8b), 2.73-2.83 (m,
1 H, H-8a), 3.33 (dd, J = 10.2, 8.3 Hz, 1 H, H-8), 4.06-4.10 (m,
2 H, H-4 and H-6), 4.19 (t, J = 7.9 Hz, 1 H, H-8), 4.28 (d, J =
11.8 Hz, 1 H, H-1), 4.34-4.38 (m, 1 H, H-6), 5.14-5.15 (m, 1 H,
H-5), 6.85-6.89 (m, 4 H), 6.92-6.99 (m, 3 H), 7.53 (d, J = 7.9
Hz, 2 H); 13C NMR (75 MHz, C6D6) δ 21.0, 41.9, 49.0, 51.1,
55.0, 68.9, 71.5, 94.8, 117.6, 124.9, 127.8, 128.1 (2 C), 130.0 (2 C),
130.4 (2 C), 135.9, 137.4 (2 C), 140.5, 143.5, 169.6 (CdO); IR
(film) 3027, 2925, 2856, 1809, 1596, 1492, 1452, 1400, 1364,
1302, 1264, 1236, 1211, 1172, 1129, 1048, 938, 871, 812, 733, 700,
594 cm-1; HRMS (ES) calcd for C23H22ClO3S [M þ H]þ
413.0978, found 413.0976 [M þ H]þ.
Synthesis of (-)-(3aS,6R,7R,7aR)-7,7a-Dihydroxy-6-phenyl-
hexahydroisobenzofuran-5-(1H)-one, 18. A two-necked round-
bottomed flask equipped with a reflux condenser was char-
ged with Mg(0) (39 mg, 1.6 mmol, 1.0 equiv) and Et2O (5 mL/
mmol). Then 1,2-dibromoethane (0.16 mL, 1.9 mmol, 1.2 equiv)
was added dropwise. The mixture was stirred at room tempera-
ture until consumption of Mg(0), affording a MgBr2 solution
that was used immediately.
To a cold solution (0 °C) of 17 (10 mg, 0.025 mmol) in a 50:50
mixture of Et2O/CH2Cl2 (0.5 mL) and under an argon atmo-
sphere was slowly added 0.63 mL of a freshly prepared MgBr2
solution (0.2 M, 0.125 mmol, 5.0 equiv). The mixture was
allowed to reach room temperature and stirred until starting
material disappearance (TLC, 20 h). The reaction was quenched
with a 5% solution of NaHCO3 (1 mL) and a 1 M solution of
Na2S2O4 (1 mL). The phases were separated, and the aqueous
layer was extracted with EtOAc (3 times), dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure.
Purification by chromatography (30-100% EtOAc/hexane)
afforded 19 (5 mg, 0.017 mmol, 69%) as a colorless oil and 18
(2 mg, 0.008 mmol, 30%) as a white solid.
Partial data for 19 (from a mixture of epimers in C-4): Rf1
=
0.44; Rf2 = 0.38 (EtOAc); 1H NMR (300 MHz) δ 4.96 (d, J =
6.4 Hz, 1 H, H-4), 5.04 (d, J = 5.1 Hz, 1 H, H-4), 7.17-7.44 (m);
MS (ES) m/z (%) 351 [M(Br81) þ Na]þ, 349 [M(Br79) þ Na]þ.
To a solution of 19 (10 mg, 0.031 mmol, 1.0 equiv) in a 9:1
mixture of THF/H2O (30 mL/mmol) was added amalgamated
Al (5 mg, 0.186 mmol, 6.0 equiv) (Al was introduced for a few
seconds in a 10% solution of HgCl2, then in EtOH and finally in
Et2O). The reaction was stirred at room temperature until
starting material disappearance (TLC, 20 h). Then the solution
was filtered through a pad of Celite and the solvent was removed
under reduced pressure. The crude product was purified by
chromatography (0-100% EtOAc/CH2Cl2) to afford 18 (4 mg,
0.016 mmol, 53%) as a white solid that was recrystallized from
EtOAc/hexane.
Dechlorination of r-Chlorolactones 20. To a solution of the
major lactone 20a (15 mg, 0.036 mmol, 1.0 equiv) in AcOH (10
mL/mmol) was added Zn powder (23 mg, 0.36 mmol, 10 equiv).
The reaction mixture was stirred at ambient temperature until
starting material disappearance (8 h) (TLC). Then it was filtered
by Celite, treated with saturated solution of NaHCO3 and
extracted with EtOAC (3 times). The combined organic layers
were dried over MgSO4, filtered and concentrated under re-
duced pressure. The resulting crude was then purified by flash
chromatography (20-50% EtOAc/hexane) to afford 21 (10 mg,
0.026 mmol, 73%) as a colorless oil.
Data for 18: Rf = 0.38 (EtOAc); mp 138-142 °C; [R]20
=
D
-59.3 (c 0.26); 1H NMR (400 MHz-COSY) δ 2.40 (dd, J = 17.4,
When the minor lactone 20b (14 mg, 0.034 mmol, 1 equiv) was
treated with Zn/AcOH under the same reaction conditions, it
J. Org. Chem. Vol. 75, No. 5, 2010 1531

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Fernandez de la Pradilla et al.
JOCArticle
was necessary to heat the reaction at 80 °C. After 8 h lactone 21
was obtained (3 mg, 0.0079 mmol, 23%) along with recovered
starting material 5 mg (0.012 mmol, 35%).
cm-1; MS (ES) m/z (%) 331 (100) [(M - 2) þ 1]þ. Anal. Calcd for
C19H24O3S: C 68.64, H 7.28, S 9.64. Found: C 68.76, H 7.34, S 9.87.
Synthesis of (3aR*,6S*)-6-Phenyl-5-(p-tolylsulfonyl)-1,3,3a,
6-tetrahydroisobenzofuran, 5b. From a 75:25 mixture of 3b and
4b (19 mg, 0.056 mmol) and MMPP (52 mg (80%), 0.084 mmol)
following the general procedure (4 h), scalemic sulfone 5b was
obtained. Purification by chromatography (10-30% EtOAc/
hexane) afforded 5b (16 mg, 0.045 mmol, 80%) as a white solid
that was recrystallized from EtOAc/hexane.
Data for 5b: Rf = 0.41 (50% EtOAc/hexane); mp 145-147 °C;
1H NMR (300 MHz) δ 2.28 (s, 3 H, Me-p-Tol), 3.41-3.57 (m, 2 H,
H-3a, 1 H-3), 4.24 (d, J = 11.5 Hz, 1 H, 1 H-1), 4.36-4.43 (m, 2 H,
1 H-3, 1 H-1), 4.50 (m, 1 H, H-6), 5.38 (t, J = 1.9 Hz, 1 H, H-7),
6.83-7.14 (m, 9 H), 7.34 (t, J = 2.4 Hz, 1 H, H-4); 13C NMR
(75 MHz) δ 21.4 (Me-p-Tol), 41.2, 43.3, 68.8, 70.8, 120.1, 126.9,
127.3 (2 C), 128.1 (2 C), 129.0 (2 C), 129.5 (2 C), 134.2, 134.6, 137.6,
139.9, 142.9, 144.6; IR (KBr) 3060, 3027, 2857, 1626, 1492, 1453,
1310, 1153, 1076, 1043, 1016, 812, 766, 700 cm-1; MS (ES) m/z (%)
370 (100) [M þ NH4]þ, 353 [M þ H]þ. Anal. Calcd for C21H20O3S:
C 71.56, H 5.72, S 9.10. Found: C 71.32, H 5.34, S 9.07.
Synthesis of (3aR*,6S*)-6-Phenyl-2,5-bis(p-tolylsulfonyl)-2,3,
3a,6-tetrahydroisoindole, 5n. From a 58:42 mixture of 3n and 4n
(10 mg, 0.020 mmol) and MMPP (18 mg (80%), 0.03 mmol)
following the general procedure scalemic sulfone 5n was ob-
tained. Purification by chromatography (20-30% EtOAc/
hexane) afforded 5n (8 mg, 0.016 mmol, 79%) as a white solid
that was recrystallized from EtOAc/hexane.
Data for 5n: Rf = 0.43 (50% EtOAc/hexane); mp 183-185
°C; 1H NMR (300 MHz) δ 2.28 (s, 3 H, Me-p-Tol), 2.42 (s, 3 H,
Me-p-Tol), 2.25 (dd, J = 11.2, 9.3 Hz, 1 H, H-3), 3.23 (m, 1 H,
H-3a), 3.80 (dd, J = 13.2, 1.2 Hz, 1 H, H-1), 3.95 (m, 1 H, H-1),
4.00 (dd, J = 9.0, 8.1 Hz, 1 H, H-3), 4.39 (dm, J = 13.2 Hz, 1 H,
H-6), 5.35 (t, J = 1.7 Hz, 1 H, H-7), 6.69 (m, 2 H), 6.88-6.94 (m,
4 H), 6.98-7.06 (m, 3 H), 7.21 (dd, J = 3.3, 1.8 Hz, 1 H, H-4),
7.32 (m, 2 H), 7.71 (d, J = 8.1 Hz, 2 H); 13C NMR (50 MHz) δ
21.4 (Me-p-Tol), 21.6 (Me-p-Tol), 39.5 (C-3a), 42.8 (C-6), 50.2
(C-1), 51.8 (C-3), 122.2, 127.0, 127.3 (2 C), 127.4 (2 C), 128.2 (2
C), 129.1 (2 C), 129.3 (2 C), 129.9 (2 C), 130.7, 134.1 (2 C), 137.2,
139.2, 143.2, 143.9, 144.6; IR (KBr) 3054, 2923, 2862, 1629,
1599, 1492, 1454, 1349, 1303, 1157, 1092, 1042, 984, 809, 763,
702, 683, 667 cm-1; MS (ES) m/z (%) 506 (100) [M þ H]þ. Anal.
Calcd for C28H27NO4S2: C 66.51, H 5.38, N 2.77, S 12.68.
Found: C 66.80, H 5.35, N 2.39, S 12.57.
General Procedure for the Synthesis of 2-Methoxy-2-phenyl
Acetates. To a solution of the corresponding alcohol in CH2Cl2
(10 mL/mmol of sulfoxide), at 0 °C, were added 1 equiv of 2-
methoxy-2-phenylacetic acid, 1.2 equiv of dicyclohexylcarbodii-
mide and 0.4 equiv of dimethylaminopyridine. The mixture was
allowed to warm to room temperature and monitored by TLC
until starting material disappearance (1 h). The reaction mixture
was filtered to remove dicyclohexylurea and the ester was purified
by chromatography using the appropriate mixture of solvents.
Synthesis of (þ)-(3aS,4R,5R,7aS,SS)-5-n-Butyl-3a-hydroxy-
6-(p-tolylsulfinyl)-1,3,3a,4,5,7a-hexahydroisobenzofuran-4-yl-(S)-
2-methoxy-2-phenyl Acetate, 23, and (3aS,4R,5R,7aS,SS)-5-n-
Butyl-3a-hydroxy-6-(p-tolylsulfinyl)-1,3,3a,4,5,7a-hexahydroiso-
benzofuran-4-yl-(R)-2-methoxy-2-phenyl Acetate, 22. From diol
14a (10 mg, 0.028 mmol), (()-2-methoxy-2-phenylacetic acid
(4 mg, 0.028 mmol), DCC (7 mg, 0.034 mmol) and DMAP
(1 crystal), following the general procedure, a 50:50 mixture of
22 and 23 was obtained. Purification by chromatography affor-
ded 12 mg (0.023 mmol, 83%) of 22 and 23.
Data for 21: Rf = 0.29 (50% EtOAc/hexane); [R]20
=
D
1
-110.5 (c 0.62); H NMR (500 MHz-COSY) δ 1.46 (dd, 1 H,
J = 18.3, 10.6 Hz, 1 H, H-1), 1.94 (dd, J = 18.3, 2.9 Hz, 1 H, H-
1), 2.30 (s, 3 H, Me-pTol), 2.46, (ddd, J = 13.2, 10.2, 2.9 Hz, 1 H,
H-8b), 2.55-2.61 (m, 1 H, H-8a), 3.51 (dd, 1 H, J = 8.9, 6.3 Hz,
H-8), 3.86-3.88 (m, 1 H, H-4), 4.16 (dd, 1 H, J = 8.8, 7.5 Hz, H-
8), 4.42-4.53 (m, 2 H, H-6), 6.06-6.08 (m, 1 H, H-5), 7.16 (d, 2
H, J = 7.8 Hz), 7.28 (d, 2 H, J = 8.0 Hz), 7.34-7.42 (m, 3 H),
7.49-7.51 (m, 2 H); 13C NMR (125 MHz) δ 21.2, 29.7, 34.8,
45.8, 46.2, 52.9, 70.0, 72.5, 102.1, 117.3, 125.6, 127.8, 128.2 (2 C),
130.1 (2 C), 130.3 (2 C), 137.1 (2 C), 140.2, 144.4, 175.1 (CdO);
IR (film) 2920, 2850, 1786, 1597, 1493, 1413, 1189, 1094, 1032,
933, 814, 736, 700, 606 cm-1; HRMS (ES) calcd for C23H23O3S
[M þ H]þ 379.1360, found 379.1359 [M þ H]þ.
General Procedure for Oxidation of Sulfoxides with MMPP.
To a cold (0 °C) solution of the sulfoxide in MeOH (10 mL/
mmol) was added 1.5 equiv of magnesium monoperoxyphtha-
late hexahydrate (MMPP). The mixture was allowed to warm to
rt, monitored by TLC until completion and then quenched with
a saturated solution of NaHCO3 (4 mL/mmol). After removal of
MeOH under reduced pressure, the mixture was diluted with
EtOAc (5 mL/mmol), the layers were separated and the aqueous
phase was extracted with EtOAc (3 times, 4 mL/mmol). The
combined organic layers were washed with a saturated solution
of NaCl (1 mL/mmol), dried over MgSO4, filtered and concen-
trated under reduced pressure to give a crude product that was
purified by chromatography on silica gel using the appropriate
mixture of solvents.
Synthesis of (þ)-(3aR,4R,5R,7aS)-5-Phenyl-6-tosyl-1,3,3a,4,
5,7a-hexahydroisobenzofuran-3a,4-diol, 16. From 14b (31 mg,
0.082 mmol) and MMPP (61 mg, 0.123 mmol) following the
general procedure (20 h), compound 16 was obtained. Purifica-
tion by chromatography (30-100% EtOAc/hexane) afforded
sulfone 16 (24 mg, 0.062 mmol, 76%) as a white solid that was
recrystallized from EtOAc/hexane.
Data for 16: Rf = 0.40 (EtOAc); mp 200-207 °C; [R]20
=
D
þ35.7 (c 0.30); 1H NMR (300 MHz, CD3OD-COSY) δ 2.35 (s, 3
H, Me-p-Tol), 3.13 (m, 1 H, H-7a), 3.39 (d, J = 9.3 Hz, 1 H, H-
3), 3.68 (d, J = 9.3 Hz, 1 H, H-3), 3.79 (dd, J = 8.8, 6.3 Hz, 1 H,
H-1), 3.86 (d, J = 6.6 Hz, 1 H, H-5), 3.99 (dm, J = 6.6 Hz, 1 H,
H-4), 4.26 (t, J = 8.5 Hz, 1 H, H-1), 6.92-7.12 (m, 7 H),
7.22-7.29 (m, 3 H); 13C NMR (75 MHz, CD3OD) δ 21.4, 48.8,
49.2, 72.4, 75.6, 76.1, 79.8, 127.8, 128.8 (2 C), 128.9 (2 C), 130.5
(2 C), 130.8 (2 C), 138.7, 139.1, 140.5, 142.4, 145.1; IR (KBr)
3448, 2920, 2868, 1632, 1452, 1298, 1146, 1059, 918, 810, 700,
678, 557 cm-1; MS (ES) m/z (%) 795 [2M þ Na]þ, 409 [M þ
Na]þ, 387 [M þ H]þ. Anal. Calcd for C21H22O5S: C 65.27, H
5.74, S 8.30. Found: C 65.36, H 5.99, S 8.21.
Synthesis of (3aR*,6R*)-6-n-Butyl-5-(p-tolylsulfonyl)-1,3,3a,
6-tetrahydroisobenzofuran, 5a. From a 67:33 mixture of 3a and
4a (13 mg, 0.041 mmol) and MMPP (38 mg (80%), 0.061 mmol)
following the general procedure (3 h), a scalemic sulfone 5a was
obtained. Purification by chromatography (10-30% EtOAc/
hexane) gave 5a (13 mg, 0.039 mmol, 95%) as a colorless oil.
Data for 5a: Rf = 0.20 (30% EtOAc/hexane); 1H NMR (300
MHz) δ 0.72 (t, J = 7.0 Hz, 3 H, Me-n-Bu), 0.80-1.18 (m, 4 H, 2
CH2-n- Bu), 1.49-1.79 (m, 2 H, CH2-n-Bu), 2.42 (s, 3 H, Me-p-
Tol), 3.27 (m, 1 H, H-6), 3.32-3.40 (m, 2 H, H-3a, 1 H-3),
4.22-4.27 (m, 2 H, 1 H-3, 1 H-1), 4.35 (m, 1 H, H-1), 5.38 (br s, 1
H, H-7), 7.09 (t, J = 2.2 Hz, 1 H, H-4), 7.31 (d, J = 7.8 Hz, 2 H,
p-Tol), 7.73 (d, J = 8.3 Hz, 2 H, p-Tol); 13C NMR (50 MHz) δ
13.9 (Me-n-Bu), 21.5 (Me-p-Tol), 22.6, 27.0, 32.2, 36.2, 41.3,
68.8, 70.1, 120.1, 128.0 (2 C), 129.7 (2 C), 129.9, 135.1, 135.6,
137.3, 144.3; IR (film) 2956, 2928, 2870, 1766, 1597, 1494, 1464,
1402, 1380, 1302, 1151, 1086, 1047, 1017, 902, 845, 814, 709
In an identical experiment with (þ)-2-methoxy-2-phenylace-
tic acid, 23 (14 mg, 0.027 mmol, 96%) was obtained as a white
solid that was recrystallized from EtOAc/hexane. The 1H NMR
of the crude product did not show any signal of compound 22
and thus the optical purity of 14a was established.
1532 J. Org. Chem. Vol. 75, No. 5, 2010

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Fernandez de la Pradilla et al.
JOCArticle
Data for 23: Rf = 0.33 (100% EtOAc); mp 60-61 °C; [R]20
=
Data for 25: Rf = 0.30 (100% EtOAc); mp 57 °C; [R]20
=
D
D
þ51.0 (c1.23); 1HNMR(300MHz) δ0.79 (t, J= 7.3 Hz, 3 H, Me-
n-Bu), 0.99-1.27 (m, 6 H, n-Bu), 2.21 (m, 2 H, H-5, OH), 2.39 (s, 3
H, Me-p-Tol), 3.03 (m, 1 H, H-7a), 3.32 (s, 3 H, OMe), 3.48 (d, J =
9.3 Hz, 1 H, H-3), 3.62 (d, J = 9.5 Hz, 1 H, H-3), 3.64 (t, J = 8.1
Hz, 1 H, H-1), 4.24 (t, J = 8.7 Hz, 1 H, H-1), 4.70 (s, 1 H, HR), 5.21
(d, J = 7.8 Hz, 1 H, H-4), 6.66 (dd, J = 4.4, 1.9 Hz, 1 H, H-7), 7.26
(d, J = 8.1 Hz, 2 H, p-Tol), 7.34 (m, 5 H, Ph), 7.48 (d, J = 8.1 Hz, 2
H, p-Tol); 13CNMR (50MHz) δ13.7 (Me-n-Bu), 21.5 (Me-p-Tol),
22.6, 26.5, 27.1, 37.0 (C-5), 47.7 (C-7a), 57.4 (OMe), 71.9 (C-4),
73.4 (C-1), 75.2 (C-3), 78.8 (C-3a), 82.8 (CR), 125.8, 126.7 (2 C),
126.8 (2 C), 128.8 (2 C), 129.1, 130.3 (2 C), 135.8, 139.3, 142.8,
143.2, 170.0; IR (KBr) 3436, 2956, 2930, 2868, 1750, 1638, 1456,
1174, 1108, 1039, 811, 733, 698 cm-1; MS (ES) m/z (%) 499 (100)
[M þ H]þ. Anal. Calcd for C28H34O6S: C 67.44, H 6.87, S 6.43.
Found: C 67.57, H 7.02, S 6.70.
þ49.2 (c 0.65); 1H NMR (300 MHz) δ 0.82 (t, J = 7.2 Hz, 3 H,
Me-n-Bu), 1.14-1.47 (m, 5 H, n-Bu), 1.74 (m, 1 H), 2.41 (s, 3 H,
Me-p-Tol), 2.49-2.57 (m, 2 H, H-5, H-7a), 3.29 (s, 3 H, OMe),
3.43 (d, J = 10.2 Hz, 1 H, H-3), 3.76 (dd, J = 8.8, 2.7 Hz, 1 H, H-
1), 3.78 (d, J = 10.7 Hz, 1 H, H-3), 4.01 (dd, J = 8.7, 6.7 Hz, 1 H,
H-1), 4.31 (s, 1 H, HR), 5.11 (d, J = 3.2 Hz, 1 H, H-4), 6.44 (d,
J = 4.1 Hz, 1 H, H-7), 7.27-7.39 (m, 7 H), 7.47 (d, J = 8.3 Hz, 2
H, p-Tol); 13C NMR (75 MHz) δ 13.8 (Me-n-Bu), 21.4 (Me-p-
Tol), 22.2, 28.8, 31.1, 39.1 (C-5), 48.3 (C-7a), 57.2 (OMe), 71.8
(C-4), 73.0 (C-1), 76.0 (C-3), 79.3 (C-3a), 81.7 (CR), 125.0 (2 C),
126.9 (2 C), 129.1 (2 C), 129.4, 129.9 (2 C), 133.2, 136.3, 139.5,
141.4, 145.5, 169.1 (CO); IR (KBr) 3434, 2959, 2926, 2870, 1749,
1631, 1493, 1455, 1261, 1172, 1102, 1082, 1029, 808, 729, 697
cm-1; MS (ES) m/z (%) 499 (100) [M þ H]þ. Anal. Calcd for
C28H34O6S: C 67.44, H 6.87, S 6.43. Found: C 67.76, H 6.96, S
6.62.
Data for 22 (from a mixture of 22 and 23): Rf = 0.27 (100%
EtOAc); 1H NMR (300 MHz) δ 0.85 (t, J = 7.3 Hz, 3 H, Me-n-
Bu), 2.10-2.24 (m, 2 H, H-5, OH), 2.40 (s, 3 H, Me-p-Tol), 2.75
(m, 1 H, H-7a), 3.30 (s, 3 H, OMe), 3.52 (d, J = 9.8 Hz, 1 H, H-3),
3.62 (m, 2 H, 1 H-1, H-3), 4.10 (dd, J = 8.7, 7.7 Hz, 1 H, H-1), 4.48
(s, 1 H, HR), 5.11 (d, J = 5.6 Hz, 1 H, H-4), 6.62 (dd, J = 4.4, 1.5
Hz, 1 H, H-7), 7.30-7.36 (m, 7 H), 7.52 (d, J = 8.1 Hz, 2 H).
Synthesis of (þ)-(3aR,4S,5S,7aR,SS)-5-n-Butyl-3a-hydroxy-
6-(p-tolylsulfinyl)-1,3,3a,4,5,7a-hexahydroisobenzofuran-4-yl-
(S)-2-methoxy-2-phenyl Acetate, 25, and (3aR,4S,5S,7aR,SS)-5-
n-Butyl-3a-hydroxy-6-(p-tolylsulfinyl)-1,3,3a,4,5,7a-hexahydro-
isobenzofuran-4-yl-(R)-2-methoxy-2-phenyl Acetate, 24. From
diol 15 (8 mg, 0.023 mmol), (()-2-methoxy-2-phenylacetic acid
(4 mg, 0.023 mmol), DCC (7 mg, 0.034 mmol) and DMAP
(1 crystal), following the general procedure, a 50:50 mixture of
24 and 25 was obtained. Purification by chromatography af-
forded 25 (5 mg, 0.020 mmol, 45%) and 24 (5 mg, 0.020 mmol,
45%) as white solids.
Data for 24: Rf = 0.25 (100% EtOAc); 1H NMR (300 MHz) δ
0.73 (t, J = 7.1 Hz, 3 H, Me-n-Bu), 1.00-1.36 (m, 6 H), 2.24 (br
s, 1 H, OH), 2.40 (s, 3 H, Me-p-Tol), 2.50 (m, 1 H, H-5), 2.88
(dtd, J = 7.3, 4.1, 1.5 Hz, 1 H, H-7a), 3.34 (s, 3 H, OMe), 3.57 (d,
J = 9.8 Hz, 1 H, H-3), 3.76 (dd, J = 8.8, 4.4 Hz, 1 H, H-1), 3.82
(d, J = 9.8 Hz, 1 H, H-3), 4.17 (dd, J = 8.6, 7.4 Hz, 1 H, H-1),
4.66 (s, 1 H, HR), 5.17 (d, J = 4.4 Hz, 1 H, H-4), 6.43 (dd, J =
4.1, 1.2 Hz, 1 H, H-7), 7.27 (d, J = 8.1 Hz, 2 H, p-Tol), 7.34 (m, 5
H), 7.42 (d, J = 8.3 Hz, 2 H, p-Tol). Anal. Calcd for C28H34O6S:
C 67.44, H 6.87, S 6.43. Found: C 67.17, H 6.95, S 6.28.
Acknowledgment. This research was supported by DGI
(CTQ2006-04522/BQU) and CM (S-SAL-0249-2006). We
thank MCI for doctoral fellowships to M.T. and E.C. and for
a Juan de la Cierva contract to M.T.
In an identical experiment with (þ)-2-methoxy-2-phenylace-
tic acid 25 was obtained (10 mg, 0.020 mmol, 90%) as a white
solid that was recrystallized from EtOAc/hexane. The 1H NMR
of the crude product showed 25 as a single diastereomer.
Supporting Information Available: Experimental details and
spectral data (1H NMR and 13C NMR) for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1533