selective synthesis from an enynecarboxylic acid system 1
has not been available.5 Furthermore, Baldwin’s rule predicts
that both 5-exo-dig and 6-endo-dig cyclizations are favorable,
making selective synthesis difficult in practice.6,7 Herein, we
describe a novel, selective cyclization from an enynecar-
boxylic acid system, based on asymmetrical activation of
the carbon-carbon triple bond by either acid or base catalyst
and its application to the synthesis of thunberginol A (4).
In order to achieve regioselective activations of the
carbon-carbon triple bonds of 2-(2-phenylethynyl)benzoic
acids (1a), we systematically examined the relationship
between regioselectivity and solvent acidity or basicity (Table
1). As the simple heating of 1a at reflux in toluene (neutral
amine, induced the opposite regioselectivity, giving (Z)-3-
(1-benzylidene)phthalide (3a) selectively,9 together with a
small amount of 2a. More strongly basic catalysts, such as
sodium ethoxide and sodium hydride, proved ineffective
(entries 8-10). Thus, the selective syntheses of isocoumarin
and phthalide skeletons from 2-(2-phenylethynyl)benzoic
acid (1a) were achieved through the use of simple acid and
base catalysts, respectively.
We next focused our attention on the role of the catalyst
in promoting the different cyclization modes of 1. It appears
that protonation or deprotonation of the carboxylic acid (1)
is critical in determining the resulting regioselectivity.
Plausible mechanisms for alternative intramolecular cycliza-
tions of 1, leading to either phthalide (5-exo) or isocoumarin
(6-endo) skeletons are depicted in Figure 2. In the presence
Table 1. Phthalide (5-exo) vs Isocoumarin (6-endo)
Cyclization
solvent) did not effect thermal cyclization, we next examined
the reactions of 1a in the presence of a variety of acid
catalysts. Cyclization was not observed at all in acids as weak
as acetic acid, while stronger acids such as CF3COOH, 97%
H2SO4, and CF3SO3H (TFSA) catalyzed the 6-endo cycliza-
tion selectively to give 3-phenylisocoumarin (2a)8 in good
to excellent yields. In sulfuric acid, the yield of 2a was
relatively low, presumably due to sulfonylation. In TFSA,
the yield of 2a was almost quantitative. In contrast, nitrogen-
containing, basic catalysts, such as pyridine and triethyl-
Figure 2. Possible mechanisms for phthalide (5-exo) vs iso-
coumarin (6-endo) cyclization.
of strong acid catalysts, the carbonyl group of 1 is protonated,
as would be expected from the basicity of the acid carbonyl
oxygen atoms (cf. pKBH+ value of benzoic acid ) -7.18 to
-7.38).10 Thus, the electronic bias on both carbons of the
triple bond favors Michael-type (6-endo) cyclization. In the
presence of basic catalysts, the carboxylate anion can be
generated via deprotonation of the carboxylic acid, providing
the initial intermediate for cyclization. These intuitions are
in good agreement with the DFT-calculated value (Figures
2 and 3).
(2) (a) Letsinger, R. L.; Oftedahl, E. N.; Nazy, J. R. J. Am. Chem. Soc.
1965, 87, 742-749. (b) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka,
H. Chem. Pharm. Bull. 1986, 34, 2754-2759. (c) Sashida, H.; Kawamukai,
A. Synthesis 1999, 1145-1148. (d) Villemin, D.; Goussu, D. Heterocycles
1989, 29, 1255-1261. (e) Anastasia, L.; Xu, C.; Negishi, E.-i. Tetrahedron
Lett. 2002, 43, 5673-5676.
(3) 3-Substituted isocoumarin skeleton: (a) Barry, R. D. Chem. ReV.
1964, 64, 229-260. (b) Turner, W. B. Fungal Metabolites; Academic
Press: London, 1971; Chapter 5. (c) Hill, R. A. In Progress in the Chemistry
of Organic Natural Products; Wien-Springer-Verlag: New York, 1986;
Vol. 49. (d) Bovicelli, P.; Lupattelli, P.; Crescenzi, B.; Sanetti, A.; Bernini,
R. Tetrahedron 1999, 55, 14719-14728. (e) Bellina, F.; Ciucci, D.;
Vergamini, P.; Rossi, R. Tetrahedron 2000, 56, 2533-2545. (f) Yao, T.;
Larock, R. C. J. Org. Chem. 2003, 68, 5936-5942. (g) Cherry, K.; Parrain,
J. L.; Thibonnet, J.; Duchene, A.; Abarbri, M. J. Org. Chem. 2005, 70,
6669-6675. (h) Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J.
Org. Chem. 2005, 70, 4778-4783. (i) Woon, E. C. Y.; Dhami, A.; Mahon,
M. F.; Threadgill, M. D. Tetrahedron 2006, 62, 4829-4837 and references
cited therein.
Because of the protonation-deprotonation equilibria, the
acid or base catalysts should be regenerated at the final step.
(6) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
(b) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476-482.
(7) We have reported some cyclization reactions which cannot be
explained in terms of Baldwin’s rule; see: (a) Uchiyama, M.; Koike, M.;
Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996, 118, 8733-
8734. (b) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike,
M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934-4946.
(8) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60, 3711-3716.
(9) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin Trans. 1
1998, 60, 561-568.
(4) 3-Alkylidenephtalide skeleton: Rossi, R.; Bellina, F.; Biagetti, M.;
Catanese, A.; Mannina, L. Tetrahedron Lett. 2000, 41, 5281-5286 and
references cited therein.
(5) Only one successful example of the silver salt-catalyzed cyclization
of 2-(1-pentynyl)benzoic acid has been reported: Ogawa, Y.; Maruno, M.;
Wakamatsu, T. Heterocycles 1995, 41, 2587-2599.
(10) Arnett, E. M. Prog. Phys. Org. Chem. 1963, 1, 223-403 and
references cited therein.
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