Total Synthesis of Zaragozic Acid C

<p>Zaragozic acid C (1), which was structurally determined by researchers at Merck in 1992, has a picomolar inhibitory activity toward mammalian squalene synthases. Therefore, 1 has been expected as a promising lead compound for development of cholesterol-lowering drugs. The structure of 1 consists of the dioxabicyclo[3.2.1]octane tricarboxylic acid core possessing the six contiguous stereocenters and the two side chains at C1 and C6 positions. The combination of the densely oxygenated core and hydrophobic side chains in 1poses a synthetically formidable challenge. Herein we report the total synthesis of 1.</p><p>From a synthetic point of view, efficient construction of contiguous C4- and C5-tetrasubstituted carbon centers of 1 would be the most important issue. To realize this task, we planned to employ chemo- and stereoselective C(sp³)–H acylation via Norrish-Yang photocyclization. </p><p>Our synthesis began from gluconolactone derivative (4). Addition of alkyl lithium 9 to 4 introduced the C1-side chain unit. Then, the following eight-step transformation, including stereoselective introduction of three-carbon unit at C5 position, afforded 1,2-diketone 5. The key Norrish-Yang photocyclization of 5 proceeded chemo- and stereoselectively by using 405 nm LED to give 6 with the contiguous C4- and C5-tetrasubstituted carbon centers of 1. Subsequent oxidative cleavage of four-membered ring of 6 provided ketoester 18. Reduction of the C3-ketone (18→20), functionalization at the C8 and C9 positions (20→23), exchange of the protecting group at the C4’ position (23→7), and transacetalization at the C1 position of 7 completed the construction of the zaragozic acid core 28. </p><p>The total synthesis of zaragozic acid C (1) has been accomplished from 28. Hydrolysis of the benzoyl group and three methyl esters of 28, followed by t-butyl peresterification, provided triol 8. Removal of the benzyl group of 8 and acetylation of 29 gave triacetate 30. The last four-step transformation, including introduction of the C6-side chain, delivered 1. </p><p>In conclusion, the key chemo- and stereoselective C(sp³)–H acylation via Norrish-Yang photocyclization enabled the efficient assembly of the densely oxygenated intermediate, and simplified the synthetic route toward zaragozic acid C (1) (total 26 steps from 4).</p>