C O M M U N I C A T I O N S
githorone A (Scheme 2). An intermolecular Diels-Alder reaction
between 16 and 21 was performed by treating 21 with 1.35
equivalents of 16 and Me2AlCl at -20 °C affording 22 and a
diastereomer in 70% yield as a 1:1.4 ratio disfavoring 22. Exposure
of 16 and 21 to other Lewis acids such as TiCl4, BF3‚OEt2, SnCl4,
and Yb(OTf)3 led to either no reaction, diminished selectivity for
References
(1) (a) Fu, X.; Hossain, M. B.; Schmitz, F. J.; van der Helm, D. J. Org. Chem.
1997, 62, 3810-3819. (b) Fu, X.; Hossain, M. B.; van der Helm, D.;
Schmitz, F. J.. J. Am. Chem. Soc. 1994, 116, 12125-12126.
(2) For a discussion of atropisomerism, see: (a) Stereochemistry of Organic
Compounds; Eliel, E. L.; Wilen S. H.; Mander, L. N.; Wiley-Inter-
science: New York 1994. (b) Moss, G. P. Pure Appl. Chem. 1996, 68,
2193-2222.
(3) For a recent review of the transannular Diels-Alder reaction, see:
Marsault, E.; Toro, A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001,
57, 4243-4260.
(4) For a synthesis of longithorone B in racemic form, see: Kato, T.; Nagae,
K.; Hoshikawa, M. Tetrahedron Lett. 1999, 40, 1941-1944.
(5) For examples of olefin metathesis macrocyclization applied to the syntheses
of [7.7]-paracyclophanes, see: Smith, A. B., III.; Adams, C. M.; Kozmin,
S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925-5937 and
references therein.
1
22, or decomposition. H NMR analysis indicated that the cyclo-
addition was completely endo selective with the diastereomers
resulting from a lack of facial selectivity. Lewis acid catalysis of
the intermolecular Diels-Alder reaction is required22 which
indicates that if the biosynthesis of 1 involves a similar cycload-
dition, a Diels-Alderase may be involved at this step.23 The lack
of substrate-based diastereoselectivity in the cycloaddition may also
implicate a Diels-Alderase. Removal of both TBS groups from
22 with TBAF delivered 23 which was directly oxidized with
iodosylbenzene to afford bisquinone 24. The bisquinone, which was
observed by NMR and TLC underwent a transannular Diels-Alder
cycloaddition at room temperature over the course of 40 h to
generate the A, C, and D rings of 1 and directly afford longithorone
A in 90% yield from 22. A synthetic sample of 1 was judged to be
(6) (a) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654-664. (b) Mori,
M.; Kitamura, T.; Sakakibara, N.; Sata, Y. Org. Lett. 2000, 2, 543-545.
(c) Kinoshita, A.; Mori, M. Synlett 1994, 1020-1022.
(7) (a) Stragies, R.; Voigtmann, U.; Blechert, S. Tetrahedron Lett. 2000, 41,
5465-5468. (b) Stragies, R.; Schuster, M. Blechert, S. Angew. Chem.
Int. Ed. Engl. 1997, 36, 2518-2520.
(8) Hoffman, R. W. Chem ReV. 1989, 89, 1841-1860.
(9) For an example of the use of a benzylic substituent to control atropisom-
erism via A(1,3) strain, see: Evans, D. A.; Dinsmore, C. J.; Watson, P.
S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew.
Chem., Int. Ed. 1998, 37, 2704-2708.
(10) Dibromide 8 was synthesized in three steps (nBuLi/DMF, NaBH4, PBr3)
from 1,4-dibromo-2,5-dimethoxybenzene. Vinyl iodide 9 was synthesized
in three steps (TIPSCl, Dess-Martin periodinane, Ph3PdC(I)Me) from
4-pentyn-1-ol. See the Supporting Information for details.
(11) Negishi, E.; Matsuhita, H. Tetrahedron Lett. 1981, 22, 2715-2718.
(12) For formation of benzylic zinc reagents from benzylic halides, see: Jubert,
C.; Knochel, P. J. Org. Chem. 1992, 57, 5425-5431.
1
identical to a sample of the natural product by H and 13C NMR,
IR, HRMS, and TLC analyses. The optical rotation of synthetic 1
was [R]D -47.6° (c ) 0.00077, CH2Cl2) while natural 1 was [R]D
-47.4° (c ) 0.00108, CH2Cl2), thereby confirming that the absolute
configuration of synthetic 1 matches natural 1.
(13) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777-
5780. For a recent review on enantioselective organozinc additions to
carbonyl compounds, see: (b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101,
757-824.
(14) A 1:1 ratio of the vinyl bromozinc reagent to chiral ligand was crucial
for the high ee of this reaction.
(15) The assignments of absolute configuration in the asymmetric vinyl zinc
additions were made by analogy to other similar additions, the X-ray
structure of compound 15a (see Supporting Information), and by
comparison of the optical rotation of natural 1 to synthetic 1.
(16) The ee was determined at this stage since the enantiomers of this compound
were separable by chiral HPLC.
In summary, an enantioselective biomimetic synthesis of lon-
githorone A has been accomplished that demonstrates the feasibility
of the reactions proposed for the biosynthesissalbeit using non-
enzymatic conditions. The syntheses of two [12]-paracyclophanes
were realized by using the first examples of ene-yne metathesis
macrocyclization. In both cases, 1,3-disubstituted dienes were
generated, demonstrating a different mode of reactivity from all
other reported examples of intramolecular ene-yne metathesis. A
mechanistic basis for this result and the synthetic utility of ene-
yne metathesis macrocyclization are under investigation. In addition,
this synthesis presents a unique example of chirality transfer in
complex molecule synthesis involving the use of stereogenic centers
to control atropisomerism, removal of the stereogenic centers, and
transfer of the atropisomerism back to stereogenic centers in the
natural product.
(17) (a) Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (b)
Fu¨rstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012-3043. (c) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(18) The byproduct of this metathesis reaction is:
which was confirmed by X-ray analysis. For loss of propene during a
metathesis macrocyclization, see: Joe, D. and Overman, L. E. Tetrahedron
Lett. 1997, 38, 8635-8638.
Acknowledgment. We gratefully acknowledge financial support
from the following sources: Bristol-Myers Squibb, Astra-Zeneca,
Novartis, Pharmacia, Eli Lilly, the Camille and Henry Dreyfus
Foundation, the Alfred P. Sloan Foundation, and SmithKline
Beecham. M.E.L. and C.A.M. acknowledge the NSF for predoctoral
fellowships. We also thank Professor F. J. Schmitz for a sample of
1 and Mr. J. Freed for his important contributions.
(19) The relative stereochemistry of atropdiastereomers were determined by
1H NMR nOe analysis. See the Supporting Information for details.
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(21) Heating 16 and 21 to 100 °C for 1 h did not result in any loss of ee.
(22) None of the intermolecular Diels-Alder adduct 22 was formed upon
exposure of 16 to 21 for 15 h at 23 °C or 1 h at 80 °C.
(23) For reports of apparent Diels-Alderases, see: (a) Auclair, K.; Sutherland,
A.; Kennedy, J.; Witter, D. J.; Van den Heever, J. P.; Hutchinson, C. R.;
Vederas, J. C. J. Am. Chem. Soc. 2000, 122, 11519-11520. (b) Oikawa,
H.; Kobayashi, T.; Katayama, K.; Suzuki, Y.; Ichihara, A. J. Org. Chem.
1998, 63, 8748-8756.
Supporting Information Available: Details of experimental
procedures and analytical data are included (PDF). This material is
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