Several research groups have recently reported syntheses
of resveratrol-derived compounds. In 2006, Li et al. em-
ployed the biomimetic dimerization of a resveratrol derivative
for the total synthesis of quadrangularin A (2a, Figure 1).7a
In the same year, She, Pan, and co-workers reported the total
synthesis of pauciflorol F by employing a Pd-catalyzed
5-endo Heck cyclization strategy.7b Snyder et al. subse-
quently reported the syntheses of several polyphenolic natural
products, including 2a, 3, and 5.7c,d
We envisioned that compounds such as pauciflorol F (5,
Scheme 2) could arise from a 2,3-disubstituted indenone
Scheme 2. Retrosynthetic Analysis of 5
As a part of a program to develop concise synthetic routes
to resveratrol-derived compounds, we recently reported a
domino Heck cyclization/pentannulation process, which
provided the scaffold of a subset of dimeric resveratrol-
derived compounds (Scheme 1).8 The single-pot preparation
precursor (e.g., 10a) using a related carbocyclization strategy.
Encouraged by the wide substrate scope of Larock’s Pd-
catalyzed annulation of alkynes to form 2,3-disubstituted
1-indenones,9 we imagined obtaining 10a from o-bromoben-
zaldehyde 1110 and tolane 7.8
Scheme 1. Heck Pentannulation Cascade
When a mixture of 11 and 7 was subjected to Larock’s
original annulation conditions,9 a 1:1 mixture of indenone
regioisomers 10a and 10b was obtained, which could be
separated by column chromatography (Scheme 3).
Scheme 3. Synthesis of Indenones 10a and 10b
of the dimeric resveratrol framework (see 8) employed the
Pd-catalyzed reaction of bromostilbene derivative 6 and
tolane 7. Oxidative cyclization of 8 using iron(III) chloride
provided pentalene 9, which is the core for pallidol (3) and
related fused [3.3.0] bicyclic molecules.
(6) (a) Ohyama, M.; Tanaka, T.; Iinuma, M. Phytochemistry 1995, 38,
733–740. (b) Ohyama, M.; Tanaka, T.; Iinuma, M. Chem. Pharm. Bull.
1994, 42, 2117–2120. (c) Adesanya, S. A.; Nia, R.; Martin, T. M.;
Boukamcha, N.; Montagnac, A.; Pais, M. J. Nat. Prod. 1999, 62, 1694–
1695. (d) Luo, H.-F.; Zhang, L.-P.; Hu, C.-Q. Tetrahedron 2001, 57, 4849–
4854. (e) Li, W. W.; Ding, L. S.; Li, B. G.; Chien, Y. Z. Phytochemistry
1996, 42, 1163–1165. (f) Tanaka, T.; Ito, T.; Nakaya, K.; Iinuma, M.;
Riswan, S. Phytochemistry 2000, 54, 63–69. (g) Coggon, P.; Janes, N. F.;
King, T. J.; Wallwork, S. C. J. Chem. Soc. 1965, 406–408. (h) Ito, T.;
Tanaka, T.; Iinuma, M.; Iliya, I.; Nakaya, K.; Ali, Z.; Takahashi, Y.; Sawa,
R.; Shirataki, Y.; Murata, J.; Darnaedi, D. Tetrahedron 2003, 59, 5347–
5363. (i) Supudompol, B.; Likhitwitayawuid, K.; Houghton, P. J. Phy-
tochemistry 2004, 65, 2589–2594. (j) Sahadin, E. H.; Hakim, L. D.;
Juliawaty, Y. M.; Syah, L. B. D.; Ghisalberti, E. L.; Latip, J.; Said, I. M.;
Achmad, S. A. Z. Naturforsch., C: Biosci. 2005, 60, 723–727. (k) Ito, T.;
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Darnaedi, D. J. Nat. Prod. 2004, 67, 932–937.
Regiocontrol in the Larock pentannulation to form inde-
nones remains a challenge,11 as confirmed by our observa-
tions in the reaction of 7 and 11. However, either regioisomer
(i.e., 10a or 10b) provides access to a resveratrol-derived
compound (i.e., pauciflorol F, 5, or its regioisomer isopauci-
florol F7d).
Our initial studies examined the conversion of 10a
(Scheme 4) to the resveratrol-derived natural product pauci-
florol F. Reduction of the indenone double bond was
accomplished using heterogeneous catalytic hydrogenation
conditions (Pd/C, H2), which yielded cis indanone 12.
Epimerization of the C(2) stereocenter of 12 was attempted
(7) For selected synthetic investigations of resveratrol-derived natural
products, see: (a) Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem., Int. Ed.
2006, 45, 7609–7611. (b) Bo, C.; Lu, J.-P.; Xie, X.-G.; She, X.-G.; Pan,
X.-F. Chin. J. Org. Chem. 2006, 26, 1300–1302. (c) Snyder, S. A.; Zografos,
A. L.; Lin, Y. Angew. Chem., Int. Ed. 2007, 46, 8186–8191. (d) Snyder,
S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J. Am. Chem.
Soc. 2009, 131, 1753–1765.
(8) Jeffrey, J. L.; Sarpong, R. Tetrahedron Lett. 2009, 50, 1969–1972.
(9) (a) Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58, 4579–4583.
For previous examples of palladium-catalyzed syntheses of indenones, see
also: (b) Tao, W.; Silverberg, L. J.; Rheingold, A. L.; Heck, R. F.
Organometallics 1989, 8, 2550–2559. (c) Vicente, J.; Abad, J.-A.; Gil-
Rubio, J. J. Organomet. Chem. 1992, 436, C9-C12. (d) Liebeskind, L. S.;
South, M. S. J. Org. Chem. 1980, 45, 5426–5429.
(10) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508–
4509.
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