Enantioselective synthesis of 2,2,5-triand 2,2,5,5-tetrasubstituted tetrahydrofurans via [4 + 2] cycloaddition and ring-opening cross-metathesis

Article abstract of DOI:10.1021/ol102798f

A chiral vinyl sulfoxide has been developed that undergoes highly diastereoselective Diels-Alder cycloadditions with various substituted furans in excellent yield. The cycloadducts can be stereoselectively transformed into 2,2,5-tri-and 2,2,5,5-tetrasubstituted tetrahydrofurans, which are structural subunits of many natural products, via regioselective ring-opening metathesis/cross-metathesis or oxidative cleavage/refunctionalization.

Full text of DOI:10.1021/ol102798f

ORGANIC
LETTERS
2011
Vol. 13, No. 3
450-453
Enantioselective Synthesis of 2,2,5-Tri-
and 2,2,5,5-Tetrasubstituted
Tetrahydrofurans via [4 + 2]
Cycloaddition and Ring-Opening
Cross-Metathesis
Noah M. Benjamin and Stephen F. Martin*
Department of Chemistry & Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712, United States
sfmartin@mail.utexas.edu
Received November 17, 2010
ABSTRACT
A chiral vinyl sulfoxide has been developed that undergoes highly diastereoselective Diels-Alder cycloadditions with various substituted
furans in excellent yield. The cycloadducts can be stereoselectively transformed into 2,2,5-tri- and 2,2,5,5-tetrasubstituted tetrahydrofurans,
which are structural subunits of many natural products, via regioselective ring-opening metathesis/cross-metathesis or oxidative
cleavage/refunctionalization.
The 2,2,5-tri- and 2,2,5,5-tetrasubstituted tetrahydrofuran
substructure 1 is a common motif found in a number of
biologically active natural products such as cortistatin A,1
(+)-davanone,2 and caruifolin A3 (Figure 1). In the context
of several ongoing projects, we were confronted with the
challenge of the enantioselective synthesis of substructures
related to 1 (Z ) H). A survey of the literature4 revealed
that available methodology for such constructions is limited
largely to cyclizations of unsaturated or epoxy alcohols, and
more general entries to these important substructures are
lacking.
(1) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.;
Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148–3149.
(2) Sipma, G.; Van der Wal, B. Recl. TraV. Chim. Pays-Bas. 1968, 87,
715–720.
(3) Ma, C.; Nakamura, N.; Hattori, M.; Zhu, S.; Komatsu, K. J. Nat.
Prod. 2000, 63, 1626–1629.
(4) (a) Figadere, B.; Harmange, J. Tetrahedron: Asymmetry 1993, 4,
1711–1754. (b) Hay, M. B.; Wolfe, J. P. Tetrahedron 2007, 63, 261–290.
(c) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,
130, 16864–16866. (d) Morimoto, Y.; Okita, T.; Kambara, H. Angew.
Chem., Int. Ed. 2009, 48, 2538–2541. (e) Ward, A. F.; Wolfe, J. P. Org.
Lett. 2010, 12, 1268–1271. (f) Marshall, J. A.; Griot, C. A.; Chobanian,
H. R.; Myers, W. H. Org. Lett. 2010, 12, 4328–4331.
Figure 1. Natural products related to 1.
10.1021/ol102798f  2011 American Chemical Society
Published on Web 01/06/2011

Various enantioselective [4 + 3]5 and [4 + 2]6,7 cycload-
ditions involving furan itself to give bridged bicyclic adducts
are known, but the application of such tactics for elaboration
to 2- and 2,5-substituted furans is not well established.
Moreover, tactics for elaborating the products of these
cycloadditions into monocyclic, substituted tetrahydrofurans
are not well developed.8,9 In view of the current state of the
art, we recognized the significant opportunity to develop an
efficacious entry to highly substituted tetrahydrofurans related
to 1, and we now report the results of some of our findings.
Based upon a survey of the literature, we reasoned that
processing enantiomerically pure oxabicycloheptenes 3 Via
regioselective ring-opening cross-metathesis (ROCM) or oxida-
tive cleavage would lead to tetrahydrofurans 2;8,9 removal or
refunctionalization of the electron-withdrawing group (EWG)
in 2 would then deliver the desired tetrahydrofurans 1
(Scheme 1). Access to enantiomerically pure 3 would require
be more readily removed and/or refunctionalized than
carboxylic acid derivatives.10 p-Tolyl vinyl sulfoxide (6a)
was known to undergo [4 + 2] cycloaddition with furan,
but not substituted furans, in the presence of a Lewis acid
promoter in good yield and de,7 so we initiated our studies
by examining the reaction of 6a with 2,5-dimethylfuran (7c).
After screening a series of Lewis acids, we found TBSOTf
to be the optimal promoter for this cycloaddition giving
oxabicycle 8a in 68% yield (Table 1). In an effort to improve
Table 1. Development of Dienophile 6c
Scheme 1. Retrosynthetic Analysis of 1
a All cycloadditions proceeded with greater than >20:1 endo/exo selectivity.
the yield in this reaction, we explored other aryl vinyl
sulfoxides as dienophiles and discovered that cycloadditions
of 7c with phenyl vinyl sulfoxide (6b) and p-chlorophenyl
vinyl sulfoxide (6c) proceeded to give 8b and 8c in 81%
and 94% yields, respectively.
Having established that 6c was the preferred dienophile,
it was necessary to develop an efficient means to prepare
both enantiomers in pure form. Fortunately, we were able
to adapt a procedure that had been developed by Maignan
for the preparation of both enantiomers of 6a11 (Scheme 2).
the development of a highly enantioselective or diastereo-
selective Diels-Alder reaction of substituted furans 5 with
a dienophile 4 wherein the EWG could be easily transformed
into a hydrogen atom or an oxygen function. Namely, we
required that 4 serve as an ethylene, vinyl alcohol, or ketene
equivalent. We were thus attracted to the use of sulfoxides
as the preferred activating groups because this moiety can
Scheme 2. Enantioselective Synthesis of (+)-6c and (-)-6c
(5) (a) Kende, A. S.; Huang, H. Tetrahedron Lett. 1997, 38, 3353–3356.
(b) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem. Soc.
2003, 125, 12694–1295. (c) Harmata, M.; Ghosh, S. K.; Hong, X.;
Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058–
2059. (d) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50–51. (e)
Harmata, M.; Brackley, J. A.; Barnes, C. L. Tetrahedron Lett. 2006, 47,
8151–8155. (f) Olson, J. P.; Davies, H. M. L. Org. Lett. 2008, 10, 573–
576. (g) Xu, J.; Caro-Diaz, E. J. E.; Theodorakis, E. A. Org. Lett. 2010,
12, 3708–3711.
(6) (a) Fraile, J. M.; Garcia, J. I.; Gracia, D.; Mayoral, J. A.; Pires, E.
J. Org. Chem. 1996, 61, 9479–9482. (b) Hayashi, Y.; Nakamura, M.; Nakao,
S.; Inoue, T.; Shoji, M. Angew. Chem., Int. Ed. 2002, 41, 4079–4082. (c)
Ryu, D. H.; Kim, K. H.; Sim, J. Y.; Corey, E. J. Tetrahedron Lett. 2007,
48, 5735–5737
.
(7) Ronan, B.; Kagan, H. B. Tetrahedron: Asymmetry 1991, 2, 75–90
.
(8) For examples, see: (a) Ager, D. J.; East, M. B. J. Chem. Res. Synop.
1986, 4622–463. (b) Klein, L. L.; Shanklin, M. S. J. Org. Chem. 1988, 53,
5202–5209
.
(9) (a) Arjona, O.; Csa´ky¨, A. G.; Murcia, M. C.; Plumet, J. J. Org. Chem.
1999, 64, 9739–9741. (b) Usher, L. C.; Estrella-Jimenez, M.; Ghiviriga, I.;
Wright, D. L. Angew. Chem., Int. Ed. 2002, 41, 4560–4562. (c) Arjona,
O.; Csa´ky¨, A. G.; Plumet, J. Eur. J. Org. Chem. 2003, 611–622. (d) Rainier,
J. D.; Liu, Z. Org. Lett. 2005, 7, 131–133. (e) Ikoma, M.; Oikawa, M.;
Gill, M. B.; Swanson, G. T.; Sakai, R.; Shimamoto, K.; Sasaki, M. Eur. J.
Org. Chem. 2008, 5215–5220
.
Org. Lett., Vol. 13, No. 3, 2011
451

In the event, racemic 6c underwent base-induced, conjugate
addition of (-)-menthol (9) giving the easily separable
diastereomers 10 and 11; the structure of 10 was determined
by X-ray crystallographic analysis. Elimination of mentholate
ion was then promoted using LiHMDS, giving both (-)-6c
and (+)-6c in >99% ee and good yield. Unlike a previous
report of a similar reaction,11 our procedure does not rely
upon methylation of the intermediate alkoxide, thereby
allowing facile recovery of menthol in about 90% yield.
We then examined the diastereoselectivities of the cy-
cloadditions of enantiopure (+)-6c with furans 7a-c in the
presence of TBSOTf, and the results of the optimized
reactions are collected in Table 2. Two workup procedures
then necessary to identify ring-opening transformations that
would provide 2,2,5-tri- and 2,2,5,5-tetrasubstituted tetrahy-
drofurans related to 1. Toward this end, we were attracted
to the possibility that regioselective, ring-opening/cross-
metathesis (ROCM) of the oxabicyclic systems 13a-c might
lead to 2,2,5-tri- and 2,2,5,5-tetrasubstituted tetrahydrofurans
of the general form 1. This premise was founded on the
knowledge that regioselective ROCM reactions had been
applied to unsymmetrically substituted norbornene deriva-
tives bearing electron-withdrawing groups.9,12 Consistent
with our expectations, reaction of enantiomerically pure 13c
withexcessallyltrimethylsilaneinthepresenceofHoveyda-Grubbs
second generation catalyst13 led to a completely regioselec-
tive ROCM reaction to furnish 14a as the only observable
product in 94% yield (Table 3). In order to expand the scope
Table 2. Diels-Alder Cycloaddition with Substituted Furans
Table 3. Ring-Opening/Cross-Metathesis of 13c
a 6-10 equiv of olefin. b Reaction performed with enantiomerically pure
13c for entry a and racemic 13c for entries b-f. c Reaction only proceeds
under an atmosphere of ethylene.
a Determined by NMR. b Determined by chiral HPLC. c Cycloaddition
proceeded with complete regioselectivity and with the methyl substituent
proximal to the sulfoxide/sulfone.
of this ROCM, a number of monosubstituted alkenes were
allowed to react with racemic 13c to give racemic 14b-f as
the only observed products in yields ranging from 55% to
93%. The structure of 14a was determined by X-ray analysis,
whereas those of 14b-f were assigned by a characteristic
NOE signal between the vinylic protons and the proximal
methyl substituents. Although several of these ROCM
reactions proceeded with identical regioselectivity using the
sulfoxide 8c, >10% catalyst loadings were required, and the
yields were generally ∼30% lower.
were developed that enabled the direct and facile synthesis
of either sulfinyl substituted cycloadducts 12a-c or sulfonyl
substituted adducts 13a-c.
The ability to access both cycloadducts with equal ease
enhances the versatility of the method. It is noteworthy that
the yield and diastereoselectivity observed for the reaction
of (+)-6c with furan (7a) compare favorably with the report
of Kagan for the reaction of 7a with (-)-tolyl vinyl sulfoxide.
The stereoselectivity of the cycloaddition improves signifi-
cantly when the substituted furans 7b,c are employed as
dienes. The structures of 12a, 12b, and 13c were established
by X-ray crystallography.
We then queried whether regioselective ROCM reactions
could be applied to 13b. Reaction of enantiomerically pure
13bwithallyltrimethylsilaneinthepresenceofHoveyda-Grubbs
second generation catalyst at 70 °C proceeded regioselec-
tively to give a mixture (12:1) of 15a and 16a in 76% yield
(Table 4). Interestingly, when the reaction was performed
Having developed the highly stereoselective cycloadditions
of various furans with the chiral vinyl sulfoxide 6c, it was
(10) (a) Magnus, P. D. Tetrahedron 1977, 33, 2019–2045. (b) Brown,
A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749–1750. (c) Becker, S.;
Fort, Y.; Caubere, P. J. Org. Chem. 1990, 55, 6194–6198. (d) Najera, C.;
Yus, M. Tetrahedron 1999, 55, 10547–10658. (e) Clayden, J.; Kenworthy,
M. N.; Helliwell, M. Org. Lett. 2003, 5, 831–834.
(12) (a) Carreras, J.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. J. Org.
Chem. 2009, 74, 1736–1739. (b) Weeresakare, G. M.; Liu, Z.; Rainier, J. D.
Org. Lett. 2004, 6, 1625–1627
.
(11) Alexandre, C.; Guillot, C.; Hayes, P.; Maignan, C. Tetrahedron
Lett. 1998, 39, 5769–5770.
(13) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799.
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Table 4. Ring-Opening/Cross-Metathesis of 13b
Scheme 3. Oxidative Cleavage Methods
without concomitant carbon-oxygen bond cleavage by the
action of Na-Hg amalgam in aqueous methanol to deliver
19 in 79% yield (Scheme 4).
a 6-10 equiv olefin. b Reaction performed with enantiomerically pure
13c for entry a and racemic 13c for entries b-d. c Reaction was run in neat
methyl acylate in a sealed tube.
Scheme 4. Desulfurization of 14a
at room temperature, the selectivity eroded, and a mixture
(3:1) of 15a and 16a was isolated. Several other olefins also
engaged in efficient ROCM with 13b, but the reaction with
methyl acrylate proceeded in the opposite regiochemical
sense. The origin of this difference is not clear, but the
reversal of regiochemical preference in ROCM reactions
based on the electronics of the metathesis cross-partner has
been observed previously.12 When 13a was used as a
substrate in these ROCM reactions, only mixtures were
obtained.
Oxidative cleavage was then explored as a tactic to convert
oxabicyclo[2.2.1]heptenes into substituted tetrahydrofurans.
For example, we found that ozonolysis of 13c in the presence
of lutidine at -78 °C in acetone/H2O (9:1),14,15 followed
by reduction of the crude product with excess sodium
borohydride, furnished the diol 17 in 84% yield (Scheme
3). Alternatively, reaction of the intermediate obtained from
ozonolysis with the Ohira-Bestmann reagent gave the diyne
18 in 53% yield as a mixture (4:1) of epimeric sulfones.16
In order to access substituted tetrahydrofurans of the
general type 1, it remained to establish a suitable protocol
for removing the sulfonyl group. Although there are methods
for converting sulfones into ketones by oxidative desulfo-
nylation to give tetrahydrofurans related to 1 (Z ) O, OH),10d
we were primarily interested in targeting substituted tetrahy-
drofurans of the general type 1 (Z ) H).
In summary, we have developed the chiral vinyl sulfoxide
6c, both enantiomers of which are readily available, that
undergoes highly diastereoselective [4 + 2] cycloadditions
with several substituted furans. These represent the first
examples of the use of substituted furans in enantioselective
[4 + 2] cycloadditions with vinyl sulfoxides. The cycload-
ducts obtained from the reaction of 6c with furans may be
further processed Via several different refunctionalization
manifolds to give facile access to 2,2,5-tri- and 2,2,5,5-
tetrasubstituted tetrahydrofurans that comprise structural
subunits in a broad array of biologically active natural
products. We are also exploring other applications of 6c as
a chiral dienophile in other Diels-Alder reactions.
Acknowledgment. We thank the National Institutes of
Health (GM 31077) and the Robert A. Welch Foundation
(F-652) for their generous support of this research. We are
also grateful to Dr. Richard Pederson (Materia, Inc.) for
catalyst support and to Anna J. Smith (The University of
Texas) for helpful discussions.
Accordingly, we found after extensive experimentation that
the sulfonyl group in 14a could be selectively removed
(14) The presence of tertiary amines is known to improve the yield of
certain ozonolysis reactions. See: Smith, A. B.; Kingery-Wood, J.; Leenay,
T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438–
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of 1H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1449
(15) Ozonolysis in the presence of water leads directly to aldehydes.
See: Schiaffo, C. E.; Dussault, P. H. J. Org. Chem. 2008, 73, 4688–4690
.
.
(16) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis
2004, 59–62.
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