Enantioselective Synthesis of (−)‐Exiguolide by Iterative Stereoselective Dioxinone‐Directed Prins Cyclizations

Abstract

Three become one: The title compound can be prepared in 26 steps by employing a unified Prins cyclization strategy to construct both tetrahydropyran rings (see scheme). The route combines two similar dioxinone fragments and one aldehyde component to generate the core structure. (−)‐Exiguolide selectively inhibits the growth of A549 cancer cells at low concentrations; the triene side chain and the Z‐enoate geometry are both necessary for this cytotoxicity.

A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

“…Several approaches toward this aldehyde were attempted, including reduction of the ethyl ester 33 and Weinreb amide 34,35 substrates with DIBAL-H, 36,37 cleavage of the allyl ether with OsO 4 /NaIO 4 , 38 and oxidation of the alcohol precursor with TPAP•NMO or Dess-Martin periodinane. 17 However, the desired product could not be obtained using any of these routes. Ultimately, we were able to obtain the desired material in 88% yield through the mildly acidic deprotection of dimethyl acetal 15 with Amberlyst-15 resin, 39,40 although the material had to be stored at −20 °C at all times to prevent decomposition.…”

Conformation–activity relationships of polyketide natural products

“…Recently, the Sasaki laboratory complemented existing SAR studies 37 by focusing on the relationship between exiguolide’s conformation and the molecule’s cytotoxicity. 38 Since previous studies established the importance of the triene side chain and C5- Z -enoate, Sasaki and co-workers investigated how functional groups on exiguolide’s macrocyclic backbone impacted cytotoxicity.…”

Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

“…Our previously developed Prins cyclization of β-hydroxy dioxinones enabled efficient assembly of a range of highly functionalized tetrahydropyranones. 17 Validated through several applications in the synthesis of complex polyketide natural products, 18 this method could afford a variety of 3-carbomethoxy-4-tetrahydropyranones 24 diversified at both the C(2) and the C(6) positions (Table 2). …”