2170
J . Org. Chem. 1999, 64, 2170-2171
Sch em e 2
Syn th esis of An gu la r ly-F u sed
Ben zocyclobu ten ed ion e Mon ok eta ls: Usefu l
Syn th etic In ter m ed ia tes to An gu cyclin es
Ralf Tiedemann, Matthew J . Heileman, and
Harold W. Moore*
Department of Chemistry, University of California,
Irvine, California 92697-2025
Ernst Schaumann
Institut fu¨r Organische Chemie, Technische
Universita¨t Clausthal, Leibnizstrasse 6,
D-38678 Clausthal-Zellerfeld, Germany
Received December 10, 1998
Recently, we reported a dual annulation method that is
applicable for the synthesis of polycyclic angularly fused
quinones. This involves the well-known ring expansions of
Sch em e 1
mixture was directly subjected to thermolysis (refluxing
benzene) to give the annulated benzocyclobutenedione
monoketal 9 in 83% overall yield from 5. The second
annulation step was accomplished upon treatment of 9 with
phenyllithium followed by hydrolysis of the ketal leading to
the benzocyclobutenone 10. This was not isolated but directly
heated in refluxing p-xylene followed by oxidation of the
initially formed hydroquinone to give quinone 11 in 81%
overall yield.
Initial attempts to prepare the regioisomeric benzo-
cyclobutenedione monoketal 19 by an analogous sequence
of reaction failed. Specifically, treatment of dimethyl squarate
(12) with 1-lithio-2,2-diphenylethene and then trifluoroacetic
anhydride (TFAA) and methanol gave 13 in 98% yield
(Scheme 3).6 This was converted to 14 upon treatment with
1-lithio-2-ethenylcyclohexene7 in THF at -78 °C. Immediate
thermolysis of 14 in refluxing diethyl ether gave 15 (64%
overall from 13), which unlike its regioisomer 8, was stable
in refluxing benzene. Apparently, the diradical intermediate
appropriately substituted cyclobutenones and a new me-
tathesis sequence leading to aromatic rings arising from a
photofragmentation of cyclobutyl-substituted quinones as
the ultimate step.1,2 For example, thermolysis of 2-(2-
ethenylphenyl)-4,4-dimethoxy-3-(2-methyl-1-propenyl)cy-
clobutenone 1 (refluxing benzene) induced an 8π electrocyclic
ring closure to a cyclooctatriene intermediate followed by a
6π electrocyclic ring closure to give the corresponding
bicyclo[4.2.0]octadiene derivative (90%).3 This was easily
converted to 2 which gave the quinone 3 (>90%) upon mild
thermolysis followed by oxidation of the resulting hydro-
quinone. Photolysis of 3 using visible light then gave the
angularly fused quinone 4 in 87% yield (Scheme 1). We now
report a modification of this method that allows the facile
synthesis of the angularly fused regioisomeric benzocy-
clobutenedione monoketals 9 and 19, compounds envisaged
to be useful synthetic precursor to angucycline antibiotics.4
The salient points of this new dual annulation procedure
are outlined in Scheme 2. Treatment of 5 with 1-lithio-2,2-
diphenylethene5 gave an 84% yield of a mixture of 6, 7, and
8 in a respective ratio of 1:1.15:1.25 (1H NMR analysis). This
(4) For a recent review on these compounds, see: Rohr, J .; Thiericke, R.
Natural Prod. Rep. 1992, 103. Also see: (a) Krohn, K.; Ballwanz, F.; Baltus,
W. Liebigs Ann. Chem. 1993, 911. (b) Larsen, D. S.; O’Shea, M. D.
Tetrahedron Lett. 1993, 34 1373. (c) Krohn, K.; Khanbabaee, K. Angew.
Chem., Int. Ed. Engl. 1994, 33, 99. (d) Larsen, D. S.; O’Shea, M. D. J . Chem.
Soc., Perkin Trans. 1 1995, 1019. (e) Kim, K.; Sulikowski, G. A. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2397. (f) Matsuo, G.; Miki, Y.; Nakata, M.;
Matsumura, S.; Toshima, K. Chem. Commun. 1996, 225. (g) Carreno, M.
C.; Urbano, A.; Fischer, J . Angew. Chem., Int. Ed. 1997, 36, 1621. (h) Larsen,
D. S.; O’Shea, M. D.; Brooker, S. Chem. Commun. 1996, 203.
(5) Ko¨brich, G.; Sto¨ber, I. Chem. Ber. 1970, 103, 2744.
(6) For examples of analogous synthetic methodology, see: (a) Gayo, L.;
Moore, H. W. J . Org. Chem. 1992, 57, 6896. (b) Santora, V. J .; Moore, H.
W. J . Am. Chem. Soc. 1995, 117, 8486.
(7) Denmark, S. E.; Hite, G. A. Helv. Chim. Acta 1988, 71, 195. A better
yield of 1-bromo-2-ethenylcyclohexene can be obtained by doing a Peterson
(1) Heileman, M. J .; Tiedemann, R.; Moore, H. W. J . Am. Chem. Soc.
1998, 120, 3801.
(2) For a recent review on the ring expansion of cyclobutenones, see:
Moore, H. W.; Yerxa B. R. Adv. Strain Org. Chem. 1995, 4, 81-162.
(3) For an elegant application of this electrocyclic cascade in natural
products synthesis, see: Nicolaou, K. C.; Petasis, N. A.; Zipin, R. E.; Uenishi,
J . J . Am. Chem. Soc. 1982, 104, 5555.
instead of
a Wittig olefination. Specifically, treatment of 2-bromo-1-
cyclohexene-1-carbaldehyde with trimethylsilylmethyllithium followed by
acidic workup (concentrated HCl) furnished the bromodiene in 80% yield.
10.1021/jo982422l CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/09/1999