The Napyradiomycins, a class of halogenated natural products with more than 50 family members isolated from strains of <i>Streptomyces</i> bacteria, show promising anticancer, antiangiogenic, and gram-positive antibacterial activities. Our group, with a decade of experience in asymmetric halofunctionalization chemistry, envisioned this important family can be accessed via asymmetric chloroetherification to construct the core chlorinated lapachone derivative with cinchona alkaloid catalysts. With structural modification of the mentioned catalysts, we were able to achieve the key chiral halogenated lapachone in 81% yield and 86% <i>ee</i> in 6 steps from commercially available starting materials via chloroetherifiction of the prenylated phenol intermediate. The 1,4-addition approach to install the geranyl moiety to the subsequent quinone intermediate has been challenging. An alternate approach, allylboration/1,3-sigmatropic rearrangement for indirect access to geranylated intermediate is under study.

Total synthesis of (+)-napyradiomycin A1 via catalytic asymmetric halofunctionalization

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