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Total Synthesis of Denbinobin Hsueh-Yun Lee,# Sunil Kumar,# Tzu-Cheng Lin, and Jing-Ping Liou* School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan S Supporting Information *
ABSTRACT: A total synthesis of denbinobin (1) in seven steps with an overall yield of 10% is reported. This synthesis used an FeCl3assisted cyclization of stilbene to form a phenanthrene. The poor yields of the decarboxylation and methoxylation steps were improved upon to become essentially quantitative. This scalable methodology was carried out using ordinary laboratory reagents.
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was also observed in the work of Thangaraj and associates on the cyclization of stilbene using hv/I2, PhI(OCOCF3)2/BF3· OEt2, or VOF3.14 In order to provide sufficient denbinobin for additional biological examination, a scalable methodology is necessary, and this has resulted in a continued focus on a synthetic approach to compound 1. The formation of the phenanthrene scaffold is crucial for phenanthrene quinone products such as denbinobin (1). Wang et al. reported the cyclization of stilbene using FeCl3 in the presence of m-CPBA to form phenanthrene,15 and this triggered the present efforts to develop a more efficient route to compound 1. Figure 1 outlines a retro-synthetic methodology aimed at the desired structure. Compound 1 may be prepared from compound II via demethylation using TMSI and regioselective substitution. Compound II is derived from the stilbene III through cyclization, decarboxylation, and oxidation. The disconnection of compound III through Perkin condensation leads to a phenylacetic acid (IV) and a benzaldehyde (V). On the basis of the retro-synthetic analysis, the synthesis of denbinobin (1) began with a reaction between 3,5-dimethoxyphenylacetic acid (2) and 2,5-dimethoxybenzaldehyde (3) under Perkin conditions followed by esterification, furnishing the corresponding stilbene (4) without any para-OCH3 groups on the benzene rings. Treatment of 4 with FeCl3 yielded successfully a phenanthrene (5) in 70% yield. The ester group of 5 was hydrolyzed to provide the corresponding acid (6) in 90% yield. The subsequent decarboxylation of compound 6 was carried out under conventional conditions using copper in the presence of refluxing quinoline, yielding compound 7 in very poor yield (
