Marine meroterpenoids, (+)-frondosin A (1) and (+)-liphagal (2) are structurally related natural products that present important biological activities. They act as inhibitors of interleukin-8 (IL-8) cognate receptors CXCR 1-2 (IC50 = 3.2-3.4 µM) and phosphatidylinositol-3-kinase enzyme (PI-3K) inhibitors (IC50 = 100 nM) respectively. Both IL-8 receptors and PI3K play a key role in central mechanisms in several cancer progression (notably in breast and prostate cancers). The biosynthetic pathway to liphagal from siphonodictyal B via a transient epoxide was first proposed by Andersen which inspired us to study the key synthetic transformation: the House-Meinwald rearrangement (HMR). HMR is a regioselective ring opening reaction of epoxides followed by subsequent migration that has been shown to be catalyzed by Lewis and bronsted acids to produce aldehydes or ketones. HMR of mono- and di-substituted epoxides were widely studied. Herein, we will report our results for the challenging HMR of tri-substituted spiro-epoxides to achieve ring-enlargement catalyzed by Lewis acids (Paths A and B). Both pathways would lead to α-arylated chiral ketone 5, a key common intermediate for both natural products 1 and 2. Path A will examine the tactic of enantioselective epoxidation to 4 followed by a Lewis acid-catalyzed stereospecific ring enlargement reaction, while Path B will examine the asymmetric rearrangement of racemic epoxide (±)-4 to achieve an enantioselective HMR. The role of different substituents on the aromatic ring and Lewis acid catalysts in directing the reactions’ regioselectivity will be discussed as well.

Study of regioselective House-Meinwald rearrangement (HMR) of spiro-epoxides

255th National Meeting (2018)

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