Total Synthesis of (−)-Spinosyn A via Carbonylative Macrolactonization

• Published in: Journal of the American Chemical Society Vol. 138; no. 34; pp. 10838 - 10841
• Main Authors: Bai, Yu, Shen, Xingyu, Li, Yong, Dai, Mingji
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 31.08.2016; Amer Chemical Soc
• Subjects: Amines - chemistry; Catalysis; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Multidisciplinary; Lactones - chemistry; Macrolides - chemical synthesis; Macrolides - chemistry; Physical Sciences; Science & Technology; Stereoisomerism; GOLD CATALYSIS; MECHANISM; NATURAL-PRODUCTS; PALLADIUM-CATALYZED CYCLIZATION; CROSS-RESISTANCE; PROTOCOL; GLYCOSYLATION; SPINOSYN; INSECTICIDES; MACROLIDES
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b07585

Spinosyn A (1), a complex natural product featuring a unique 5,6,5,12-fused tetracyclic core structure, is the major component of spinosad, an organic insecticide and an FDA-approved agent used worldwide. Herein, we report an efficient total synthesis of (−)-spinosyn A with 15 steps in the longest linear sequence and 23 steps total from readily available compounds 14 and 23. The synthetic approach features several important catalytic transformations including a chiral amine-catalyzed intramolecular Diels–Alder reaction to afford 22 in excellent diastereoselectivity, a one-step gold-catalyzed propargylic acetate rearrangement to convert 28 to α-iodoenone 31, an unprecedented palladium-catalyzed carbonylative Heck macrolactonization to form the 5,12-fused macrolactone in one step, and a gold-catalyzed Yu glycosylation to install the challenging β-forosamine. This total synthesis is highly convergent and modular, thus offering opportunities to synthesize spinosyn analogues in order to address the emerging cross-resistance problems.