In pursuit of pestalotiopsin A via zirconocene-mediated ring contraction

Article abstract of DOI:10.1021/ol060827j

An asymmetric route from the epimeric β-hydroxy esters 4 and 5 to the densely functionalized (+)-10 and (-)-10, respectively, is described. Either cyclobutanol can be made available as the predominant product. The levorotatory antipode has been transforme

Full text of DOI:10.1021/ol060827j

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2429-2431
In Pursuit of Pestalotiopsin A via
Zirconocene-Mediated Ring Contraction
Shuzhi Dong, Gregory D. Parker, Takahiro Tei, and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 5, 2006
ABSTRACT
An asymmetric route from the epimeric
â
-hydroxy esters 4 and 5 to the densely functionalized (
+
)-10 and (−)-10, respectively, is described.
Either cyclobutanol can be made available as the predominant product. The levorotatory antipode has been transformed into the advanced
intermediate 21 bearing side chains destined to become incorporated into the cyclononene ring of the title compound (1).
The highly successful introduction of taxol1 into cancer
chemotherapy2 has caused its natural habitat, the Pacific yew
Taxus breVifolia, to be thoroughly examined for secondary
metabolites. Associated microorganisms have likewise come
under intense scrutiny. This surge of activity has been
rewarded with the discovery and isolation of two endophytic
fungi having novel properties. The first microorganism to
be recognized was Taxomyces andreanae, a species capable
of producing taxol in pure cultures.3 The second was
identified as a Pestalotiopsis species, the interest in which
stems from its ability to generate the caryophyllene-type
sesquiterpenes defined as pestalotiopsins A (1) and B (2).4
Together these natural products constitute a unique pair of
compounds, in that 1 shows very respectable immunosup-
singled out as the sector likely responsible for its pharma-
cological profile,5 which also includes cytotoxicity at roughly
the same applicable level of effectiveness. Whereas the
architectural features associated with 1 rigidify the structural
framework, 2 exists as two slowly equilibrating atropisomers
in chloroform solution at room temperature.
pressive activity in the mixed lymphocyte reaction (IC50
3-4 µg/mL), whereas 2 exhibits little interesting biology.
The oxatricyclic architecture resident in 1 has therefore been
)
In light of these findings, 1 has become an attractive
synthetic target. The Procter group has examined a stereo-
controlled approach to a functionalized 2-oxabicyclic inter-
mediate that takes advantage of the ability of samarium
diiodide to effect a key 4-exo-trig cyclization.5,6 More
recently, Tadano has explored an asymmetric route that
features a Lewis acid catalyzed [2 + 2] cycloaddition as the
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J. Am. Chem. Soc. 1971, 93, 2325.
(2) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665.
(3) Stierle, A.; Strobel, G.; Stierle, D. Science 1993, 260, 214.
(4) (a) Pulici, M.; Sugawara, F.; Koshino, H.; Okada, G.; Esumi, Y.;
Uzawa, J.; Yoshida, S. Phytochemistry 1997, 46, 313. (b) Pulici, M.;
Sugawara, F.; Koshino, H.; Uzawa, J.; Yoshida, S.; Lobkovsky, E.; Clardy,
J. J. Org. Chem. 1996, 61, 2122.
(5) Johnston, D.; Couche´, E.; Edmonds, D. J.; Muir, K. W.; Procter, D.
J.Org. Biomol. Chem. 2003, 328.
10.1021/ol060827j CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/04/2006

means to craft an enantioenriched cyclobutane precursor to
a related lactone.7
Scheme 1. Synthesis of Cyclobutanols (+)-10 and (-)-10
We have recently demonstrated that the deoxygenative ring
contraction of vinylated furanosides can be applied success-
fully to the elaboration of enantiopure polysubstituted
cyclobutanes that feature several stereogenic centers of
defined absolute configuration.8 With this success as a
backdrop, we have presently focused our attention on the
enantioselective construction of the core of 1. The pathway
originated with D-glyceraldehyde acetonide, a building block
readily available from D-mannitol.9
Kita and co-workers have demonstrated that Lewis acid
catalyzed aldol reactions of such aldehydes with ketene silyl
acetals proceed diastereoselectively to give the corresponding
â-siloxy ester exemplified by 3 (Scheme 1).10 In this instance,
the hydroxyl group could be unmasked quantitatively with
potassium carbonate in methanol, thereby allowing for the
convenient, large-scale separation of 4 from 5 (9:1). Because
the direct generation of 5 as the major product through an
uncatalyzed aldol reaction is not practical,11 inversion of the
epimeric ratio to 1:8 was realized by perruthenate oxidation12
of the original 4/5 mixture followed by low-temperature
(-100 to -40 °C) reduction of the resulting ketone with
zinc borohydride in ether.13 In turn, both hydroxy esters were
O-benzylated in a highly efficient manner provided that the
addition of benzyl bromide was conducted at a very slow
rate. The independent reduction of these products with
LiAlH4 generated the primary carbinols, making it possible
to effect sequential oxidation to the aldehyde level under
Swern conditions and cyclization to the methyl furanosides
6 and 7 with p-toluenesulfonic acid in methanol. Advantage
was next taken of the ability of IBX in refluxing acetonitrile14
to bring about conversion to the sensitive aldehydes, which
were submitted directly to Wittig olefination without column
chromatography. The extent of competing â-elimination was
more extensive when producing 8 relative to 9, presumably
as the direct result of a more sterically crowded trans E2
elimination option available to the former. Alternatively, this
phenomenon may reflect the increased accessibility of the
enolizable proton in the aldehyde leading to 8 with respect
to that leading to 9.
tactic well suited to accessing the enantiomerically pure gem-
dimethyl substituted cyclobutanols (+)-10 and (-)-10. The
desirability of crafting both antipodes of 10 originated from
our recognition of the fact that reductive removal of the
benzyloxy substituent in (+)-10 or the hydroxyl group in
(-)-10 permits targeting of the same enantiomer of pesta-
lotiopsin A. Furthermore, since the absolute configuration
of 1 is presently unknown, deoxygenation of (+)-10 or (-)-
10 in the reverse fashion would allow acquisition of the other
enantiomer of the target. Different chemical challenges were
anticipated. As matters have worked out, (-)-10 lends itself
well to efficient conversion to 17 (Scheme 2). Deoxygenation
studies performed at the vinylcyclobutanol stage proved to
be uniformly unsuccessful. To skirt this problem, the next
steps involved protection as the TBS ether and anti-
Markovnikov hydration. To ensure a high yield of 12, the
hydroboration reaction was performed with a low loading
Significantly, all four vinylated furanosides proved to be
responsive to the zirconocene ring contraction conditions,15
thus providing experimental verification of this route as a
(6) (a) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem. 2003,
68, 3190. (b) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J.
Org. Lett. 2001, 3, 2001.
(7) Takao, K.; Saegusa, H.; Tsujita, T.; Washizawa, T.; Tadano, K.
Tetrahedron Lett. 2005, 46, 5815.
(8) Paquette, L. A.; Kang, H.-J. Tetrahedron 2004, 60, 1353.
(9) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
(10) (a) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino, H.; Ke, Y.
Y.; Tamura, Y. J. Org. Chem. 1988, 53, 554. (b) Kita, Y.; Yasuda, H.;
Tamura, O.; Itoh, F.; Ke, Y. Y.; Tamura, Y. Tetrahedron Lett. 1985, 26,
5777.
(11) Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am.
Chem. Soc. 1994, 116, 7026.
(12) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.
(13) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org.
Chem. 1998, 63, 7505.
(14) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(b) Yang, J.; Long, Y. O.; Paquette, L. A. J. Am. Chem. Soc. 2003, 125,
1567.
(15) Paquette, L. A.; Cunie`re, N. Org. Lett. 2002, 4, 1927.
Org. Lett., Vol. 8, No. 11, 2006
2430

Although the pathway embodied in Scheme 2 demonstrates
the feasibility of a key deoxygenative step, we viewed
removal of the OTBS group in 13 to be somewhat premature.
As part of an alternative strategy, reliance could be placed
on its â-orientation to relegate installation of the upper chain
to the opposite face of the cyclobutane ring. Computational
studies involving cyclobutanone 19 revealed the preferred
trajectory of an incoming nucleophile likely to involve an
angle of 107° from below plane18 in order to avoid the steric
blockade brought on by the bulky silyl moiety. To take
advantage of these options, 13 was hydrogenolized at 600
psi to give 18 as a prelude to perruthenate oxidation (Scheme
3). Cyclobutanone 19 prepared in this manner was treated
Scheme 2. Adjusting Functionality on the Four-Membered
Ring
Scheme 3. Attachment of Functionalized Side Chain
with CeCl3 followed by vinyl bromide (S)-20, which had
previously been lithiated with tert-butyllithium in THF at
-78 °C. The single carbinol that was thereby produced
(80%) was identified as 21 on the basis of COSY and
NOESY correlations between H3 and H4 in addition to a
NOESY interaction involving H4 and a vinyl proton.
In summary, an asymmetric synthesis of the multiply
functionalized cyclobutane 21 has been devised. The strategy
is based on the complementary deoxygenative ring contrac-
tion of 8 and 9 and features matching of the readily available
13 with a stereocontrolled 1,2-carbonyl addition to arrive at
the advanced intermediate. We hope to report on associated
transformations and on the successful acquisition of 1 soon.
of borane as well as alkaline hydrogen peroxide, but not
sodium perborate. The road to 17 was subsequently paved
by coupling 12 to MOMCl in advance of desilylation and
functionalization of the hydroxyl group with O-p-tolyl
chlorothionoformate.16 The latter step proceeded slowly but
led in quantitative fashion to the isomeric products 15 and
16 (2.5:1).17 The major constituent was deemed to be the
O,O-thiocarbonate on the strength of the downfield shift of
H-1 (5.32 ppm) relative to that exhibited by the O,S-
thiocarbonate 16 (4.75 ppm). The intense IR band displayed
by 16 at 1761 cm-1 provided added confirmation. Further-
more, the stereochemical assignments to 15 and 16 are based
on the application of NOESY methods that reveal strong
correlation of the 1,3-related cyclobutane protons with
different components of the gem-dimethyl group. As antici-
pated, 15 underwent efficient reduction to 17 (85%) when
heated with tributyltin hydride and AIBN in benzene.
Acknowledgment. This work was supported in part by
the Astellas USA Foundation for which we are appreciative.
S.D. thanks The Ohio State University for the award of a
Presidential Fellowship.
Supporting Information Available: Experimental details
1
and H NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060827J
(16) (a) Gerlach, H.; Houng, T. T.; Mu¨ller, W. Chem. Commun. 1972,
1215. (b) Gerlach, H.; Mu¨ller, W. HelV. Chim. Acta 1972, 55, 2277.
(17) Drescher, M.; O¨ hler, E.; Zbiral, E. Synthesis 1991, 362.
(18) Burgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,
95, 5065.
Org. Lett., Vol. 8, No. 11, 2006
2431