Natural products are the major source of drugs for various diseases including cancer in clinical use today. Lignans constitute a big group of bioactive natural products with anti-viral, anti-bacterial, anti-inflammatory, anti-parasitic and anti-cancer activities. Aryltetraline lignans such as deoxypodophyllotoxin (DPT) are potent anti-viral and anticancer compounds. Efficacy of these lignans and their derivatives is attributed to the unique stereochemistry around the polycyclic core that is synthetically challenging. Majority of the total syntheses for DPT involve over 10 steps and they give low yields with poor stereoselectivity. The number of steps in the synthesis of DPT are significantly reduced by intramolecular styryl Diels Alder (ISDA) reaction. Novel chiral ISDA substrates featuring activated dienophiles tethered to styryl moiety by ester or amide groups have been synthesized from readily available simple starting materials. Unoptimized cyclization of the substrates presenting alkynyl dienophile forms the polycyclic core of arylteraline lignans in a yield of 32%. Conversely, activated alkenyl dienophiles form furo[3,4-c] pyranone ring structure in 30-70% yields and 7:1 stereoselectivity in absence of Lewis acid. These results demonstrate the potential of asymmetric ISDA reaction in total synthesis of bioactive natural products.

Development of asymmetric intramolecular styryl\hetero Diels-Alder protocol for the total synthesis of lignans and furopyranone containing natural products

ACS Spring 2022

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