Sulfinyl-directed diastereoselective [5 + 2] pyrone-alkene cycloadditions: A practical route to enantiopure 8-oxabicyclo[3.2.1]octane derivatives

Article abstract of DOI:10.1021/ol005724u

(figure presented) Introduction of a homochiral p-tolylsulfinyl group at an appropriate position in the alkene accelerates the thermal [5C + 2C] intramolecular cycloaddition to β-silyloxy-γ-pyrones and, most importantly, leads to excellent levels of diast

Full text of DOI:10.1021/ol005724u

ORGANIC
LETTERS
2000
Vol. 2, No. 7
1005-1007
Sulfinyl-Directed Diastereoselective
[5 + 2] Pyrone−Alkene Cycloadditions:
A Practical Route to Enantiopure
8-Oxabicyclo[3.2.1]octane Derivatives
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, 15706 Santiago de Compostela, Spain
qojoselm@usc.es
Received February 25, 2000
ABSTRACT
Introduction of a homochiral p-tolylsulfinyl group at an appropriate position in the alkene accelerates the thermal [5C + 2C] intramolecular
cycloaddition to â-silyloxy-γ-pyrones and, most importantly, leads to excellent levels of diastereodifferentiation. The resulting adducts can be
easily desulfinylated to give optically active 8-oxabicyclic[3.2.1]octane intermediates which by virtue of their rich functionalization might be
susceptible to elaboration into enantiomerically pure natural products containing seven-membered carbocycles and tetrahydrofurans.
The great utility of 8-oxabicyclo[3.2.1]octane frameworks
as versatile, stereochemically biased building blocks in
organic synthesis1 is currently encouraging the development
of methods to prepare these bicycles as single enantiomers.
Of the few approaches hitherto described, the most effective
are based on the desymmetrization of meso derivatives2 and
on asymmetric versions of allyl cation-furan [4 + 3]
cycloadditions.3 Very recently an asymmetric [5C + 2C]
cycloaddition of a carbonyl ylide to dimethylacetylenedi-
carboxylate4 and an elegant [5 + 2] cycloaddition of
pyranylmolybdenum π-complexes to electron-deficient al-
kenes5 have also been reported. Whereas these efforts
represent a significant contribution in the area, the develop-
ment of a truly practical and general alternative for the
assembly of enantiopure oxabicyclo[3.2.1]octane structures
remains an important synthetic objective.
Our work in recent years has shown that the intramolecular
thermal [5C + 2C] cycloaddition of â-alkoxy-γ-pyrones to
alkenes is a remarkably practical method to assemble
relatively complex 8-oxabicyclo[3.2.1]octane skeletons from
simple, readily available precursors.6 The particularly rich
functionalization of the resulting adducts offers unique
possibilities for gaining rapid access to a variety of valuable
(3) (a) Lautens, M.; Aspiotis, R.; Colucci, J. J. Am. Chem. Soc. 1996,
118, 10930. (b) Kende, A. S.; Huang, H. Tetrahedron Lett. 1997, 38, 3353.
(c) Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem., Int.
Ed. 1998, 37, 1266. (d) Harmata, M.; Jones, D. E.; Kahraman, M.; Sharma,
U.; Barnes, C. L. Tetrahedron Lett. 1999, 40, 1831. (e) Cho, S. Y.; Lee, J.
C.; Cha, J. K. J. Org. Chem. 1999, 64, 3394. (f) Ou, L.; Hu, Y.; Song, G.;
Bai, D. Tetrahedron 1999, 55, 13999. See also ref 1g.
(4) (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.;
Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417. See
also: (b) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett.
1997, 38, 6471. (c) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem.
Commun. 1999, 2185.
(1) (a) Vogel, P. Bull. Soc. Chim. Belg. 1990, 99, 395. (b) Lautens, M.
Pure Appl. Chem. 1992, 64, 1873. (c) Lautens, M. Synlett 1993, 177. (d)
Arjona, O.; De Dios, A.; Ferna´ndez de la Pradilla, R.; Plumet, J.; Viso, A.
J. Org. Chem. 1994, 59, 3906. (e) Molander, G. A.; Swallow, S. J. Org.
Chem. 1994, 59, 7148. (f) Lampe, T. F. J.; Hoffman, H. M. R. J. Chem.
Soc., Chem. Commun. 1996, 1931. (g) Davies, H. M. L.; Ahmed, G.;
Churchill, M. R. J. Am. Chem. Soc. 1996, 118, 10774 and references therein.
See also: (h) Chiu, P.; Lautens, M. In Topics in Current Chemistry; Metz,
P., Ed.; Springer-Verlag: Berlin, 1997; Vol. 190, pp 1-85.
(2) (a) Cox, P. J.; Simpkims, N. S. Synlett 1991, 321. (b) Williard, P.
G.; Liu, Q. X. J. Am. Chem. Soc. 1993, 115, 3380. (c) Lautens, M.; Ma, S.
Tetrahedron Lett. 1996, 37, 1727.
(5) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 5811.
10.1021/ol005724u CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

cyclic systems.7 Therefore, the implementation of an asym-
metric version of this cycloaddition showed itself as a
meaningful, challenging goal.
Table 1. Intramolecular [5 + 2] Thermal cycloaddition
We have already shown that incorporating a sulfoxide in
the tether connecting the pyrone and the alkene leads to
modest levels of diastereofacial selectivity (X ) SO, Y )
H, Scheme 1).8
entry pyrone
X
yield, %a
4:5b
time, h
Scheme 1
1
2
3
2a
2bc
2cd
C(CN)2
C(CO2Et)2
S
98
99
95
4a :5a (91:9)
4b:5b (97:3)
4c:5c (93:7)
10
3.5
46
a Combined isolated yield after chromatography. b Ratio determined by
1H NMR of the crude reaction mixture. c The cycloaddition of its alkene-
unsubstituted analogue requires heating for 12 h at 110 °C. d The cycload-
dition of its alkene-unsubstituted analogue requires heating for 40 h at 160
°C.
Since this strategy is intrinsically limited by the presumable
difficulty in preparing enantiorich precursors, we envisaged
an alternative approach based on the introduction of a
homochiral sulfoxide unit at the trans terminal position of
the alkene (Y ) SOAr).9 Despite our concern about a
potentially deleterious steric effect of this substituent on the
cycloaddition rate, it was reasoned that the obligatory endo
approach of the sulfoxide group to the pyrone might give
rise to satisfactory levels of dissimilar facial interference.
Herein we show that the approach is indeed successful,
representing the first efficient application of a sulfur-based
chiral auxiliary in an intramolecular homo Diels-Alder type
of reaction.10
considerably milder than those needed to induce the reaction
of its alkene-unsubstituted analogue (12 h at 160 °C or more
than 60 h at 110 °C).7c This result indicates that the presence
of the sulfinyl substituent does not hamper the reaction but
actually accelerates it, probably by exerting a moderate
electron-withdrawing effect which activates the alkene
toward the cycloaddition. Most importantly, the diastereo-
selectivity of the reaction was notable (4a/5a 91:9, see Table
1), more than fulfilling our expectations in terms of the
anticipated facial differentiating effect of the endo-placed
arylsulfinyl group.
This high diastereoselectivity was also obtained with
substrates bearing other type of pyrone-alkene linkers, such
as dicarboxylate 2b or sulfide 2c, with their cycloaddition
being again faster than that of their unsubstituted alkene
analogues (Table 1).
The feasibility of the strategy was tested on dinitrile 2a,
which was readily prepared in good yield from the known
bromopyrone 17b by displacement with malononitrile and
subsequent coupling with the enantiopure mesylate 3 (Scheme
2). This compound was prepared by mesylation of the
(6) (a) Rumbo, A.; Castedo, L.; Mourin˜o, A.; Mascaren˜as, J. L. J. Org.
Chem. 1993, 58, 5585. (b) Mascaren˜as, J. L.; Pe´rez, I.; Rumbo, A.; Castedo,
L. Synlett 1997, 81. For a recent review, see: Mascaren˜as, J. L. In AdVances
in Cycloaddition; Harmata, M., Ed.; Jai Press: Stamford, 1999; Vol 6, pp
1-54.
Scheme 2
(7) (a) Mascaren˜as, J. L.; Rumbo, A.; Castedo, L. J. Org. Chem. 1997,
62, 8620. (b) Rodr´ıguez, J. R.; Rumbo, A.; Castedo, L.; Mascaren˜as, J. L
J. Org. Chem. 1999, 64, 966. (c) Rodr´ıguez, J. R.; Rumbo, A.; Castedo,
L.; Mascaren˜as, J. L. J. Org. Chem. 1999, 64, 4560.
(8) Rumbo, A.; Castedo, L.; Mascaren˜as, J. L. Tetrahedron Lett. 1997,
38, 5885.
(9) Vinyl sulfoxides have been used as chiral two-carbon components
in other cycloadditions such as intermolecular [3 + 2] and [4 + 2] reactions,
although to be useful as dienophiles in Diels-Alder reactions, the presence
of an additional electron-activating group at the double bond is required.
For [3 + 2] reactions, see: (a) Chaigne, F.; Gotteland, J.-P.; Malacria, M.
Tetrahedron Lett. 1989, 30, 1807. For Diels-Alder applications, see: (b)
Garcia Ruano, J. L.; Carretero, J. C.; Carren˜o, M. C.; Martin Cabrejas, L.
M.; Urbano, A. Pure Appl. Chem. 1996, 68, 925.
(10) p-Tolyl vinyl sulfoxide has been used as chiral dipolarophile in
intermolecular [5 + 2] cycloadditions to 3-oxodipyridinium betaines,
although the reaction produces mixtures of regio- and stereoisomers: (a)
Takahash, 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.
(11) This alcohol was synthesized from (+)-methyl p-tolyl sulfoxide in
three steps and 43% overall yield by following the procedure described in
Mart´ın, L. M. Ph.D. Dissertation, Universidad Autonoma de Madrid, 1996.
The product can be alternatively prepared from 2-propyn-1-ol in five steps
and 33% overall yield according to the procedure described in Posner, T.
Tetrahedron Lett. 1984, 25, 2627.
corresponding alcohol ([R]20 ) +234, c 1, CHCl3, [R]20
D
D
lit ) +233, c 1, CHCl3), itself obtained by following a known
procedure.11 Remarkably, the cycloaddition of 2a could be
efficiently carried out by simple heating in toluene under
reflux for 10 h (Table 1). These thermal conditions are
1006
Org. Lett., Vol. 2, No. 7, 2000

Diastereoisomeric products 4 and 5 were easily separated
by flash chromatography, and their structures were estab-
lished by 1H NMR on the basis of the shielding (anisotropic
effect of the aryl group) and deshielding (syn-axial effect of
the sulfinylic oxygen) effects observed in the major and the
minor diastereoisomers with respect to their sulfide homo-
logues.12 The hydrogens more affected are bold in the Figure
1.
complex reaction mixtures, probably because of concomitant
reactions of the reducing agents with the nitriles. However,
treatment of diester 4b with excess of Raney nickel in
refluxing THF did afford the expected enantiomerically pure
tricycle 6 (ee > 96%),14 a class of building block with evident
potential for obtaining synthetically appealing bicyclo[5.3.0]
ring systems (Scheme 3).15 On the other hand, similar
Scheme 3
Figure 1.
treatment of sulfoxide 4c under an atmosphere of hydrogen
gave optically active oxabicycle 7 (ee > 96%).14
The stereochemical outcome of the above reactions could
be rationalized by assuming that the alkenyl sulfoxide unit
adopts an S-trans conformation in order to avoid repulsive
dipole-dipole interactions with the pyrone, disfavoring the
approach from the face of the sulfoxide displaying the p-tolyl
group (Figure 2).13
We have already shown for the racemic case that this type
of oxabicyclic R-silyloxyketone is particularly useful for
obtaining stereochemically rich tetrahydrofurans.7a,b
In summary, attaching a p-tolylsulfinyl group at an
appropriate position in the alkene leads to acceleration of
its thermal [5C + 2C] intramolecular cycloaddition to
â-silyloxy-γ-pyrones and, most importantly, leads to excel-
lent levels of diastereodifferentiation. The ready availability
and low cost of a variety of homochiral sulfinyl-containing
cycloaddition precursors coupled with the polyfunctional
nature of the oxabicyclic products augurs well for the
application of the strategy to the enantioselective synthesis
of natural products containing seven-membered carbocycles
and tetrahydrofurans.
Acknowledgment. Support of this research by the Span-
ish Ministry of Education and Culture under Grant PB97-
0524 is gratefully acknowledged. F.L. thanks the Spanish
Ministry of Education and Culture for a predoctoral research
grant. We also thank Prof. J. C. Carretero for helpful
discussions.
Figure 2.
Supporting Information Available: Characterization
data and experimental procedures for the preparation of 2a,
2b, 2c, 3, 4a, 4b, 4c, 5a, 5b, 5c, 6, and 7, as well as the
sulfide derivatives of 4 and 5. 1H NMR spectra relevant for
deducing diastereo- and enantioselectivities. This material
is available free of charge via the Internet at http://pubs.acs.org.
It was now pertinent to demonstrate that the above
cycloaddition occurred without racemization at the sulfur and
hence that the cycloadducts could be desulfinylated to
synthetically valuable enantiopure derivatives. Several at-
tempts to remove the sulfoxide from dinitrile 4a gave
OL005724U
(12) See the Supporting Information for detailed NMR data of 4, 5, and
their sulfide analogues. For a discussion on the NMR effects of the aryl
sulfoxide group, see: (a) Carren˜o, M. C.; Garcia Ruano, J. L.; Martin, A.
M.; Pedregal, C.; Rodr´ıguez, J. H.; Rubio, A.; Sa´nchez, J.; Solladie, G. J.
Org. Chem. 1990, 55, 2120. (b) Lett, R.; Marquet, A. Tetrahedron 1974,
30, 3379.
(13) For conformational preferences of vinyl sulfoxides, see: (a) Arai,
I.; Takayama, H.; Koizumi, T. Tetrahedron Lett. 1987, 28, 3689. (b)
Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
1
(14) Enantiomeric excess was determined by H NMR in the presence
of Eu(hfc)3 using racemic mixtures as reference. Writing ee > 96% means
that the other enantiomer was not detected at the NMR scale.
(15) We have recently discovered a practical method for opening the
oxa bridge of these types of systems: Rodr´ıguez, J. R.; Castedo, L.;
Mascaren˜as, J. L. Synthesis (Special issue), in press. For a discussion on
the relevance of the bicyclo[5.3.0] ring systems, see: Lautens, M.;
Kumanovic, S. J. Am. Chem. Soc. 1995, 117, 1954.
Org. Lett., Vol. 2, No. 7, 2000
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