Zirconocene-mediated route to enantiopure 9-oxabicyclononanes functionalized on both carbon bridges

Article abstract of DOI:10.1021/ol027336t

(Matrix presented) A zirconocene-mediated ring contraction of 4-vinylfuranosides generated either from D-arabinose or D-glucose is followed by sequential oxidation to the ketone and alkynyl Grignard addition. The resulting cis-cyclobutanediols are subjected in turn to thermal rearrangement and intramolecular oxymercuration-demercuration. The regiochemistry of the final ring closure is controlled by the nature of R.

Full text of DOI:10.1021/ol027336t

ORGANIC
LETTERS
2003
Vol. 5, No. 2
221-223
Zirconocene-Mediated Route to
Enantiopure 9-Oxabicyclononanes
Functionalized on Both Carbon Bridges
Leo A. Paquette,* In Ho Kim, and Nicolas Cunie`re
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received November 22, 2002
ABSTRACT
A zirconocene-mediated ring contraction of 4-vinylfuranosides generated either from D-arabinose or D-glucose is followed by sequential oxidation
to the ketone and alkynyl Grignard addition. The resulting cis-cyclobutanediols are subjected in turn to thermal rearrangement and intramolecular
oxymercuration-demercuration. The regiochemistry of the final ring closure is controlled by the nature of R.
The unique structural features of oxa-bridged cyclooctanes
have caused them to serve as favored building blocks for
many types of applications. During the past 35 years, the
most commonly applied synthetic route to 1 and 2 has been
via electrophilic addition to (Z,Z)-1,5-cyclooctadiene.1 If
water is present or an oxygenated nucleophile is involved,
the incorporation of an oxa bridge results. The process
leading to 1 is customarily favored kinetically2 and somewhat
takings that involve enantioenriched 9-oxabicyclononanes
advantaged over that which delivers the bicyclo[3.3.1]nonane
have been very few in number.9 The present contribution
alternative 2. Equilibration between these isomers is pos-
constitutes an attempt to offset this void to some degree.
sible.3 4-Cycloocten-1-ol,4 its 5-isomer,1e 9-oxabicyclo[6.1.0]-
Our entirely new route to compounds of type 1 and 2 is
nonenes,5 5-alkoxycyclooct-1-enes,1e,3c and cyclooctanol
founded on carbohydrates as starting materials. Specifically,
itself6 have also proven to be suitable precursors.
advantage is taken of the highly diastereoselective ring
Although newer and more elegant routes to this class of
contraction that operates upon exposure of 4-vinylfuranosides
heterocycles have been reported recently,7,8 synthetic under-
to zirconocene10,11 in tandem with a notably facile oxy-Cope
(1) (a) Cope, A. C.; McKervey, M. A.; Weinshenker, N. M. J. Org. Chem.
1969, 34, 2229. (b) Ganter, C.; Wicker, K.; Zwahlen, W.; Schaffner-Sabba,
K. HelV. Chim. Acta 1970, 53, 1618. (c) Franz, H.; Hoebold, W.; Hoehn,
R.; Mueller-Hagen, G.; Mueller, R.; Pritzkow, W.; Schmidt, H. J. Prakt.
Chem. 1970, 312, 622. (d) Duthaler, R. O.; Wicker, K.; Ackermann, P.;
Ganter, G. HelV. Chim. Acta 1972, 55, 1809. (e) Labows, J. N., Jr.; Swern,
D. J. Org. Chem. 1972, 37, 3004. (f) Haufe, G.; Kleinpeter, E.; Muehlstaedt,
M.; Graefe, J. Monatsh. Chem. 1978, 109, 575. (g) Haufe, G. Tetrahedron
Lett. 1984, 25, 4365. (i) Eaton, P. E.; Millikan, R. Synthesis 1990, 483. (h)
Toshimitzu, A.; Aoai, T.; Owada, H.; Uemura, S.; Okano, M. Tetrahedron
1985, 41, 5301.
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Perkin Trans. 1 1986, 1277. (b) Mayer, W.; Meier, H. Chem. Ber. 1989,
122, 509. (c) Alvarez, E. Diaz, M. T.; Rodriguez, M. L.; Martin, J. D.
Tetrahedron Lett. 1990, 31, 1629.
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I. IzV. Akad. Nauk SSSR, Ser. Khim. 1988, 2327. (b) Kapustina, N. I.;
Popkov, A. Yu.; Nikishin, G. I. IzV. Akad. Nauk SSSR, Ser. Khim. 1988,
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(2) Hegemann, K.; Wibbeling, B.; Haufe, G. J. Prakt. Chem./Chem.-
Ztg. 1998, 340, 455.
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Bloodworth, A. J.; Eggelte, H. J. J. Chem. Soc., Perkin Trans. 1 1984,
1009.
(4) (a) Ganter, C.; Duthaler, R. O.; Zwahlen, W. HelV. Chim. Acta 1971,
54, 578. (b) Schlecht, M. F.; Kim, H. J. Org. Chem. 1989, 54, 583.
(8) Delgado, A.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2002, 4, 3091.
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W. G. Chem. Commun. 1999, 749. (b) Takahashi, A.; Aso, M.; Tanaka,
M.; Suemune, H. Tetrahedron 2000, 56, 1999. (c) van Hooft, P. A. V.; van
der Marel, G. A.; van Boeckel, A. A.; van Boom, J. H. Tetrahedron Lett.
2001, 42, 1769. (d) van Hooft, P. A.; Litgens, R. E. J. N.; van der Marel,
G. A.; van Boeckel, C. A.; van Boom, J. H. Org. Lett. 2001, 3, 731.
10.1021/ol027336t CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002

rearrangement and transannular oxymercuration. Most im-
portantly, the absolute stereochemistry resident in the sugar
is transformed efficiently and specifically into the hetero-
cyclic product.
Scheme 1
The highly reactive complex generated in situ by treating
solutions of Cp2ZrCl2 with n-BuLi in toluene or THF12 is
often referred to as “zirconocene” and depicted simply as
“Cp2Zr”.13 One of the key properties of this reagent is its
ability to enter into ligand exchange with unsaturated
compounds. If the substrate is an allylic ether, the high
oxophilicity of the zirconium atom subsequently manifests
itself via â-elimination of the alkoxy group.14 Reaction of
Cp2Zr with vinyl sugars in the presence of boron trifluoride
etherate results in extrusion of the oxygen atom and
formation of a highly functionalized carbocyclic ring, often
with high levels of diastereodifferentiation.10,11 For the
present purposes, the goal was to generate 2,3,4-trisubstituted
cyclobutanones such as 7 in advance of the stereocontrolled
1,2-addition of an acetylide anion, thermal activation of 6
so produced to deliver 5, and ultimate conversion to 3 and/
or 4 via intramolecular Hg(II)-promoted cyclization15 (Scheme
1). Indeed, highly functionalized oxabicyclics of type 3 and
4 are attainable from D-arabinose and D-glucose via this
protocol.
The tert-butylsiloxy substituent in 11 must be R-oriented
in the vinyl group. An assessment of this requirement
demands that carbinol 8, which is readily available from
D-arabinose,11,16 be initially subjected to sequential Dess-
Martin oxidation17 and NaBH4 reduction.18 The ketone
intermediate is attacked exclusively syn to the vinyl group,
such that 9a is obtained in 88% overall yield (Scheme 2).
After hydroxyl protection, pursuit of the deoxygenative ring
contraction of 9b by Cp2Zr was examined and found to
proceed too slowly to be preparatively useful. Consequently,
anomer 10 was prepared and integrated into the synthetic
pathway. In an alternative route to 10 developed simulta-
neously, D-glucose diacetonide was converted to 12a via the
Horton protocol,19 protected as the p-methoxybenzyl ether,
and selectively hydrolyzed to give the exocyclic vicinal diol.
Advancement to 13 took advantage of the reliability associ-
ated with the capability of zinc dust and NaI in hot DMF to
induce reductive elimination of the ditosylate.20-22
Exposure of 10 to Cp2Zr and BF3‚OEt2 in toluene resulted
in forward progress to deliver 11 as the only characterizable
product in 65% yield. The success of this transformation is
consistent with adoption of transition state A. The manner
in which all four cyclobutane substituents are set in a well-
defined absolute configurational sense introduces a minimum
of nonbonded steric interactions along this reaction trajectory.
Oxidation of 11 with the Dess-Martin reagent17 resulted
in formation of the cyclobutanone without loss of stereo-
chemical integrity. As hoped for,23-25 the double bond does
not migrate into conjugation with the carbonyl provided that
the use of silica gel chromatography is skirted. The appropri-
ate tactic was to add the acetylenic Grignard directly, in
which case 1,2-addition to produce 14a occurred with
complete diastereocontrol (Scheme 3).
This intermediate was, in turn transformed into diol 14b
via mild acid hydrolysis. The platform established in 14b
was responsive to ring strain effects,26,27 heating in benzene
leading smoothly to 15 in quantitative yield. The oxygen
(10) (a) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem.
Soc. 1993, 115, 8835. (b) Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995,
299.
(11) Paquette, L. A.; Cunie`re, N. Org. Lett. 2002, 4, 1927.
(12) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829.
(13) (a) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (b)
Negishi, E.; Takahashi, T. Synthesis 1988, 1. (c) Buchwald, S. L.; Nielsen,
R. B. Chem. ReV. 1988, 88, 1047.
(14) (a) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33,
1295. (b) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33,
7873. (c) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y. Tetrahedron
Lett. 1992, 33, 3769. (d) Ito, H.; Taguchi, T.; Hanzawa, Y. J. Org. Chem.
1993, 58, 774.
(15) Paquette, L. A.; Bolin, D. G.; Stepanian, M.; Branan, B. M.;
Mallavadhani, U. V.; Tae, J.; Eisenberg, S. W. E.; Rogers, R. D. J. Am.
Chem. Soc. 1998, 120, 11603.
(16) Dahlman, O.; Garegg, P. J.; Mayer, H.; Schramek, S. Acta Chem.
Scand. B 1986, 40, 15.
(17) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277,
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(18) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc. 1982,
104, 2027.
(20) Tipson, R. S.; Cohen, A. Carbohydr. Res. 1965, 1, 338.
(21) Yamazaki, T.; Matsuda, K.; Sugiyama, H.; Seto, S.; Yamaoka, N.
J. Chem. Soc., Perkin Trans. 1 1977, 1981.
(22) Paquette, L. A.; Arbit, R. M.; Funel, J. A.; Bolshakov, S. Synthesis
2002, 2105.
(23) Harris, N. J.; Gajewski, J. J. J. Am. Chem. Soc. 1994, 116, 6121.
(24) Ollivier, J.; Salaun, J. Tetrahedron Lett. 1984, 25, 1269.
(25) Miller, S. A.; Gadwood, R. C. Org. Synth. 1989, 67, 210.
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24, 192.
222
Org. Lett., Vol. 5, No. 2, 2003

Scheme 2
Scheme 3
thermal rearrangement,30 the operative pathway adopted by
their 1-alkenyl-2-alkynyl congeners is entirely dependent on
the cis or trans relationship of the two unsaturated side chains.
For 14, the discharge of strain operates exclusively by oxy-
Cope rearrangement.31 When the groups are disposed trans
as in 19, ring opening occurs by way of a retro-ene process
leading to 20 rather than a ring-expanded product (Scheme
4).
Scheme 4
bridge was next installed by subjecting 15 (R ) SiMe3) to
the action of mercuric trifluoroacetate,28 with subsequent
reductive cleavage of the organomercurial so formed with
1,3-propanedithiol.29 This two-step sequence gave rise with
reasonable efficiency to the [4.2.1] bicyclic ketone 16 (78%).
In the case of the protio analogue 15 (R ) H), only 17a was
produced in 91% yield, a result of preferred neighboring
group participation by the OPMB oxygen center. Analogous
treatment of 15 (R ) CH3, C6H5) gave rise to readily
separable two-component product mixtures in which the
bicyclo[3.3.1]nonane isomers 17 were more prevalent.
In line with the response of 1,2-dialkenylcyclobutanols to
Acknowledgment. The authors thank the Yamanouchi
USA Foundation and Dr. Robert Gold, Dean of the College
of Mathematical and Physical Sciences, for financial support.
Supporting Information Available: Full spectral char-
acterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Gadwood, R. C.; Lett, R. M.; Wissinger, J. E. J. Am. Chem. Soc.
1984, 106, 3869; 1986, 108, 6353.
(27) Ohnuma, T.; Hata, N.; Miyachi, N.; Wakamatsu, T.; Ban, Y.
Tetrahedron Lett. 1986, 27, 219.
OL027336T
(28) Kocovsky, P. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; p 3267.
(29) Gauzoules, F. H.; Whitney, R. A. J. Org. Chem. 1986, 51, 2024.
(30) Barnier, J. P.; Ollivier, J.; Salaun, J. Tetrahedron Lett. 1989, 30,
2525.
(31) Paquette, L. A. Tetrahedron 1997, 53, 13971.
Org. Lett., Vol. 5, No. 2, 2003
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