A sulfinyl-directed asymmetric [5C + 2C] intramolecular acetoxypyranone-alkene cycloaddition

Article abstract of DOI:10.1021/ol026633v

(graph presented) Introduction of a homochiral p-tolylsulfinyl group at the trans terminal position of an alkene induces a total diastereodifferentiation in the intramolecular cycloaddition of the latter to 3-oxidopyrylium ylide precursors. The cycloadduc

Full text of DOI:10.1021/ol026633v

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3683-3685
A Sulfinyl-Directed Asymmetric
[5C + 2C] Intramolecular
Acetoxypyranone−Alkene Cycloaddition
Fernando Lo´pez, Luis Castedo, and Jose´ L. Mascaren˜as*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de
Santiago de Compostela, 15782 Santiago de Compostela, Spain
qojoselm@usc.es
Received July 30, 2002
ABSTRACT
Introduction of a homochiral p-tolylsulfinyl group at the trans terminal position of an alkene induces a total diastereodifferentiation in the
intramolecular cycloaddition of the latter to 3-oxidopyrylium ylide precursors. The cycloadducts can be readily desulfinylated to afford
enantiomerically pure oxa-bridged bicyclo[5.3.0]decane ring systems. Theoretical calculations confirm that diastereoselectivity stems from the
conformational preferences of the alkenylsulfoxide unit in the transition state of the reaction.
The 3-oxidopyrylium-alkene cycloaddition is a well-
established method for constructing relatively complex
8-oxabicyclo[3.2.1]octanes from readily available 6-acetoxy-
3-pyranone precursors (Scheme 1).1 The synthetic relevance
effectiveness of the sulfinyl group as chiral inducer in thermal
intramolecular pyrone-alkene annulations4 led us to find out
whether the same stereogenesis strategy could be used in
the above more classical oxidopyrylium-alkene cycloaddi-
tion.
Herein we demonstrate that, indeed, attaching a chiral
sulfoxide at the trans terminal position of an alkene allows
for its mild, fully diastereoselective intramolecular cyclo-
addition to 6-acetoxy-3-pyranones. We also report prelimi-
nary theoretical calculations that explain the observed
diasterereoselectivity.
Scheme 1
The synthesis of an appropriate cycloaddition precursor
was carried out as indicated in Scheme 2. The alkenylsulfinyl
derivative 3 could be readily prepared by alkylating the
of this reaction and, in particular, that of its intramolecular
version are demonstrated by its use as the key step in the
synthesis of natural products as complex as phorbol or
resiniferatoxin.2 It is evident that the reaction would be of
greater value if it could be carried out in an asymmetric
fashion so that the products could be obtained in an
enantiomerically enriched form.3 Our recent discovery of the
(2) (a) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc.
1997, 119, 7897. (b) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura,
N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976.
(3) Intermolecular 3-oxidopyridinium-vinylsulfoxide cycloadditions have
been previously reported, but they exhibit modest yields and relatively poor
stereoselectivities: (a) Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu,
H.; Koizumi, T. Chem. Lett. 1989, 597. (b) Araldi, G. L.; Prakash, K. R.
C.; George, C.; Kozikowski, A. P. Chem. Commun. 1997, 1875. (c) Prakash,
K. R. C.; Trzcinska, M.; Johnson, K. M.; Kozikowski, A. P. Bioorg. Med.
Chem. Lett. 2000, 10, 1443.
(1) (a) Katrizky, A. R.; Dennis, N. Chem. ReV. 1989, 89, 827. (b)
Sammes, P. G.; Street, L. J. Gazz. Chim. Ital. 1986, 116, 106. (c) Marshall,
K. A.; Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1996, 61, 9135.
(4) (a) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. Org. Lett. 2000, 2, 1005;
(b) 2001, 3, 623; (c) Chem. Eur. J. 2002, 8, 884.
10.1021/ol026633v CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002

diethyl ester of 2-(2,2-dimethoxyethyl)-malonic acid (1)5 with
the enantiopure iodosulfinyl derivative 2.4c However, cou-
pling of the aldehyde resulting from acidic treatment with
2-lithiofuran gave only a 32% yield of the desired alcohol
4a.
Table 1. Cycloaddition of 8a
Scheme 2a
entry
solvent
Ta (°C)
time (min)
9:10b
yieldc
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
DMF
CH2Cl2
toluene
toluene
Et2O
20
0
-30
0
-30
-30
0
5
5
90
85:15
85:15
88:12
85:15
100:0d
100:0
100:0
96:4
77%
75%
82%
72%
78%
86%
81%
80%
15
150
180
60
-30
180
a Reactions were carried out using 1.1 equiv of DBU and 1 mM
1
concentrations of 8. b This ratio was determined by H NMR of the crude
reaction residue. c For both acetylation and cycloaddition steps. d The ratio
100:0 means that the minor diastereoisomer was not detected.
completely stereoselective (entries 5-7, Table 1). The
solvent choice thus seems to be important for full realization
of the diastereoselectivity influence of the chiral sulfinyl
group, with less polar solvents giving better results.
The structure of the major diastereoisomer 9 was initially
a Reaction conditions: (a) NaH, THF, 0 °C, 2. (b) p-TsOH,
acetone-H2O. (c) n-BuLi, furan, THF, -78 °C, then 3. (d) n-BuLi,
furan, THF, -78 °C, then 5, and after 10 min Et3N and TMSCl.
(e) NaH, THF, 0 °C, 2. (f) TBAF, AcOH, THF, 0 °C. (g) NBS,
THF-H2O, 0 °C.
1
established by H NMR, on the basis of shielding and
deshielding effects observed in comparison with the sulfide
derivatives. Nonetheless, a definitive confirmation of the
stereochemistry was obtained by X-ray crystallography of
the alcohol produced by reduction of 9 with NaBH4/CeCl3
(Figure 1).
We therefore tried an alternative, more convergent ap-
proach to 4 that proved to be more efficient. Reaction of
2-lithiofuran with aldehyde 5, followed by in situ silylation
gave the expected trimethylsilyl ether 6 in 83% yield. This
diester derivative was alkylated with iodide 2 to give the
desired coupled product 4b in 93% yield. The transformation
of this furan derivative into the required pyranone 7 was
achieved by careful removal of the TMS group followed by
treatment of the resulting alcohol with NBS.
To carry out the cycloaddition reaction, the epimeric
alcohols 7 were transformed into the acetates 8, which upon
treatment with DBU in CH3CN, standard conditions for
inducing the formation of the required 3-oxidopyrylium ylide,
gave the expected [5 + 2] cycloadducts. The reaction was
quite fast (5 min at rt) and led to an 85:15 mixture of the
diastereoisomeric cycloadducts 9 and 10, which could not
be separated by standard chromatographic techniques.
As indicated in Table 1, the cycloaddition can be carried
out at lower temperatures (even -30 °C), albeit the propor-
tion of isomers is similar. Remarkably, with the use of CH2-
Cl2 or toluene as a solvent, the reaction is slower but
Figure 1.
(5) Rahman, A.; Beisler, J. A.; Harley-Mason, J. Tetrahedron 1980, 36,
1063.
3684
Org. Lett., Vol. 4, No. 21, 2002

Desulfinylation of the cycloadduct 9, which was easily
achieved by treatment with Raney Ni in refluxing THF, gave
the expected enantiopure oxa-bridged carbobicycle (+)-11
(ee > 97%).6 The synthesis of this cycloadduct in racemic
form was achieved from the furan derivative 12 (Scheme
3), itself prepared by coupling the anion of 6 with allyl
bromide (99%).
Scheme 3a
a Reaction conditions: (a) Raney Ni, THF, 60 °C. (b) TBAF,
AcOH, THF, 0 °C. (c) NBS, THF-H2O, 0 °C. (d) AcCl, Et3N,
DMAP, CH2Cl2, -78 °C. (e) DBU, toluene, -30 °C, 210 min.
Figure 2. Reaction coordinate diagram for the cycloaddition.
Models 10 and 9 do not include the diester present in 9 and 10.
∆E is given in kcal/mol.
To obtain precise information on the origin of the facial
stereoselectivity of the above cycloaddition reaction, we
performed a theoretical investigation of the reaction course
using DFT calculations. Previous studies by Domingo et al.
have shown the validity of the B3LYP hybrid functional for
obtaining accurate geometries and stationary point energies
for related oxidopyrylium-alkene cycloadditions.7 Energy
minima and transition-state structures were explored in a
model that lacked the diethylesters and with a phenyl instead
of a p-tolyl group on the sulfur. A search of the potential
energy surface8 revealed two energy minima oxidopyrylium
intermediates and four possible concerted and synchronical
transition states, the two with the lower activation barriers
being those represented in Figure 2.
transition states leading to the opposed selectivity. Therefore,
these theoretical results are in agreement with the observed
experimental stereoselectivities and support our initial hy-
pothesis4 that the diastereofacial selectivity is largely due to
the sulfinyl group preferring to adopt an s-trans conformation,
most probably to avoid repulsive dipolar interactions with
the oxidopyrylium. This is also consistent with the effect of
the solvent polarity in the diastereoselectivity.
In conclusion, we have demonstrated that attaching a
p-tolylsulfinyl group to the trans terminal position of an
alkene allows a mild, highly diastereoselective [5 + 2]
intramolecular cycloaddition of the alkene to 6-acetoxy-3-
pyranone derivatives. The approach provides a facile entry
to enantiopure oxa-bridged bicyclo[5.3.0]decanes, com-
pounds of palpable synthetic interest. We have also shown
that the observed diastereoselectivity is in agreement with
the results of theoretical calculations.
S-Cis and s-trans correspond to the more stable conforma-
tions of the alkenylsulfinyl functionality in the oxidopyrylium
ylide precursors.9 As can be deduced from the diagram,
transition state TS1, in which the alkenyl sulfoxide unit
adopts an s-trans type of conformation, is about 3 kcal/mol
more stable than TS2, which is the less energetic of the
Acknowledgment. This work was supported by the
Spanish MCyT (SAF2001-3120) and the ERDF. F.L. thanks
the MEC for a predoctoral fellowship. We also thank J.
Cereijo for early contributions and A. Navarro for his help
with the calculations.
(6) Enantiomeric excess was determined by 1H NMR in the presence of
Eu(hfc)3 using a racemic mixture as a reference.
(7) Domingo, L. C.; Zaragoza, R. J. J. Org. Chem. 2000, 65, 5480.
(8) Calculations were performed using the Gaussian 98 set of programs.
Geometries were preoptimized by the semiempirical PM3 method. Stationary
points were optimized at the B3LYP/6-31G* level of theory. Frisch, M. J.;
Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M.
C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci,
B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson,
B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, version A-7; Gaussian, Inc.: Pittsburgh,
PA, 1998.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and computational details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026633V
(9) Calculated CdC-S-O dihedral angle for s-cis: 9°. Calculated
CdC-S-O dihedral angle for s-trans: 127°. This last conformer is 0.81
kcal/mol less stable than s-cis. For previous conformational studies of R,â-
unsaturated sulfoxides, see: Tietze, L. F.; Schffenhauer, A.; Schreiner, P.
R. J. Am. Chem. Soc. 1998, 120, 7952.
Org. Lett., Vol. 4, No. 21, 2002
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