Scheme 1. Enantioselective Assembly of the Tricyclic Core
Figure 1. Retrosynthetic analysis of bromoallenes 1 and ent-2.
alkynylation,8 followed by sulfonylation and center-to-axis
chirality transfer by anti-SN2′ displacement with bromide.9
The desired C4-stereochemistry would be installed by taking
advantage of the steric bias provided by oxonium ion 4 for
cyanation from the less hindered convex face. Stereo-
controlled assemblage of the tricyclic core would rely on
Pd(II)-mediated intramolecular alkoxycarbonylation-lacton-
ization10-12 of alcohol 5. In light of the anticipated acid
sensitivity of 5, lack of examples involving phenols, and
well-documented problems with even less labile substrates,12
we viewed this tandem process as a central issue to be
explored en route to panacene.
Our synthesis began with lateral lithiation-methylation13
of commercially available 2-methoxy-6-methylbenzoic acid
(6) to provide the ethyl homologue 7 in excellent yield
(Scheme 1). Conversion of 7 to aldehyde 8, followed by
asymmetric alkynylation with Pu’s protocol,14 afforded
propargyl alcohol 9 (96% ee) whose R configuration was
firmly established by X-ray analysis of the 4-bromobenzoate
ester of its antipode. Reduction of 9 with Lindlar catalyst
over hydrogen and subsequent demethylation with lithium
diphenylphosphide15 furnished phenol 5 in 82% yield over
two steps.
With ready access to 5, the stage was set to investigate
the crucial Pd(II)-mediated alkoxycarbonylation-lactoniza-
tion. After initial attempts to carry out this reaction under
classical catalytic conditions,11,12a which led exclusively to
side products,12 the desired tandem cyclization was achieved
by using 2 equiv of Pd(OAc)2 in dichloromethane to afford
lactone 10 in 55% yield (Scheme 1). Moreover, running the
reaction in the presence of an excess of N-methylmorpholine
improved the yield to 81%. To our dismay, however, the ee
of 10 obtained from these experiments was 71% and 60%,
respectively,16 suggesting that inadvertent racemization had
occurred. To the best of our knowledge, this finding is
unprecedented. While the precise mechanism is unclear, it
would appear that racemization of alcohol 5 occurs before
alkoxycarbonylation, possibly by a competing Pd-mediated
hydrogen transfer process.17,18 Gratifyingly, further experi-
mentation revealed that the use of THF as a solvent
completely suppresses racemization, delivering 10 in repro-
ducibly high ee (96%)16 and a yield of 58%.
Reductive acylation19 of 10 provided the separable â and
R anomers of 11 (2:1 ratio) in quantitative yield (Scheme
2); the stereochemistry at the anomeric center is inconse-
quential at this stage since both acetates would provide the
same oxonium ion (4, Figure 1). Despite the apparent steric
bias for cyanide attack from the convex face, attaining the
required exo-selectivity proved to be a more difficult task
than initially anticipated.20 After exploring several methods,21
we were pleased to find that the reaction of 11 with
(7) (a) Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251. (b) Yamada, K.;
Kigoshi, H. Bull. Chem. Soc. Jpn. 1997, 70, 1479. (c) Krause, N.; Hoffmann-
Ro¨der, A. Tetrahedron 2004, 60, 11671.
(8) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41,
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(9) (a) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem.
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(10) Recent reviews: (a) Schmalz, H.-G.; Geis, O. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley: New York, 2002; Vol. 2, pp 2377-2397. (b) Muzart, J. Tetrahedron
2005, 61, 5955.
(11) Boukouvalas, J.; Fortier, G.; Radu, I.-I. J. Org. Chem. 1998, 63,
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(12) (a) Semmelhack, M. F.; Bodurow, C.; Baum, M. Tetrahedron Lett.
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1
(16) The ee of 10 was determined by H NMR analysis of the Mosher
ester of the diol obtained by reduction with LiAlH4; see the Supporting
Information for details.
(17) Pa`mies, O.; Ba¨ckvall, J.-E. Chem. ReV. 2003, 103, 3247.
(18) Alternatively, racemization of 5 may occur via π-allylpalladium
complex formation: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
121, 3543. (b) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I. T.; Jung, J. Y.;
Kim, M.-J. J. Org. Chem. 1999, 64, 8423 and references therein. See also:
(c) Braun, M.; Meier, T. Synlett 2006, 661.
(19) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(20) (a) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc.
2003, 125, 14149. (b) Smith, D. M.; Woerpel, K. A. Org. Lett. 2004, 6,
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K. A. J. Am. Chem. Soc. 2005, 127, 10879.
(13) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Clark, R. D.;
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(14) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855.
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