HETEROCYCLES

Communication | Special issue | Vol. 84, No. 1, 2012, pp. 323-326
Received, 10th June, 2011, Accepted, 1st August, 2011, Published online, 10th August, 2011.
DOI: 10.3987/COM-11-S(P)34

■ Highly Regioselective Intramolecular Biaryl Coupling Reaction of a Phenyl Benzoate Derivative for the Synthesis of Graphislactone G

Hitoshi Abe,* Takuya Matsukihira, Tomoko Fukumoto, Yoshikazu Horino, Yasuo Takeuchi,* and Takashi Harayama

Department of Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

The 6H-dibenzo[b,d]pyran-6-one type natural product graphislactone G was synthesized using a palladium-mediated aryl-aryl coupling reaction of the phenyl benzoate derivative. The regioselectivity in the coupling step was also investigated.

A palladium-catalyzed intramolecular aryl-aryl coupling reaction is a useful technique for preparing heterocyclic compounds.1 For example, phenyl benzoates are good precursors for constructing a 6H-dibenzo[b,d]pyran-6-one ring system (Scheme 1).2 Using this strategy, we synthesized several natural products possessing a 6H-dibenzo[b,d]pyran-6-one skeleton,3 such as graphislactones A-D4 and H,5 and alternariol.6, 7

Recently, the total synthesis of graphislactone G (1), which is a phenolic constituent isolated from Cepharosporium acremonium IFB-E007 in 2005,8 was reported by Cudaj and Podlech.9 Structually, compound 1 possesses a highly functionalized 6H-dibenzo[b,d]pyran-6-one ring system and has a chlorine atom at the 2-position. Biologically, 1 is cytotoxic to the SW1116 cell line.8

In the Podlech’s synthesis, they employed the Suzuki-Miyaura coupling reaction as the key step.9
In this study, we planned the synthesis of 1, using the intramolecular aryl-aryl coupling reaction of a phenyl benzoate derivative. Initially, we prepared the ester (2) by simple condensation between the corresponding phenol and benzoic acid derivative as a precursor for the intramolecular biaryl coupling reaction. Several reaction conditions were examined for the palladium-mediated biaryl coupling of 2 in order to construct the 6H-dibenzo[b,d]pyran-6-one skeleton (Table 1).

In each case, the coupling reaction proceeded smoothly, producing the lactone compounds 3 and 4 in moderate to good yield. The product ratio of 3 and 4 changed dramatically with the reaction conditions. When P(o-tolyl)3­ was used as the ligand, extremely high regioselectivity was observed (run 1), generating the product 3, which was reacted at the position ortho to the methyl group. By contrast, the DPPP-nBu3P combination system10 was not effective for regioselectivity (run 4).
These results are very different from our previous report on the synthesis of alternariol, in which the similar coupling reaction of 5 proceeded with the regioselectivity of 0.6:1 to 1.5:1 ratio (Scheme 2).6 This difference of selectivity indicates that the chlorine atom on the phenoxy group exhibits a powerful directing property in the coupling reaction. The mechanistic aspect of this selectivity is being studied intensively in our laboratory.
Using the major cyclized product 3, selective demethylation was achieved with Node’s protocol (AlCl3-NaI/MeCN-CH2Cl2, 0 oC to rt, 84%),11 to complete the synthesis of graphislactone G (1). The 1H- and 13C-NMR data of the product were identical to those reported by Podlech et al.9

ACKNOWLEDGEMENTS
A part of this research was financially supported by the Japan Society for the Promotion of Science to H. A. (22590003). The authors thank the SC-NMR Laboratory of Okayama University for the NMR experiments.

References

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