Interplay of Cascade Oxidative Cyclization and Hydride Shifts in the Synthesis of the ABC Spiroketal Ring System of Pectenotoxin‐4

Abstract

The pectenotoxins (PTXs) are a family of cyclic polyether macrolide toxins first isolated in 1985 by Yasumoto and coworkers from the digestive glands of scallops (Patinopecten yessoensis). [1] It has since been discovered that the producers of pectenotoxins are toxic plankton (Dinophysis dinoflagellate) found in many coastal areas around the world. To date, more than 20 members have been isolated and characterized, with structural variations commonly involving the configuration of the AB spiroketal (C7) as well as the oxidation state at C43. Recent studies have demonstrated that the pectenotoxins exhibit potent biological activity, including selective cytotoxicity against p53 mutant and p53-deficient tumors. [2] The exquisite architectural complexity of these 26-membered macrolactones, which consist of either 19 or 20 stereogenic centers embedded within three tetrahydrofuran rings, plus one spiroketal and one bicyclic ketal, poses a synthetic challenge that has attracted considerable attention from many research groups. While significant synthetic endeavors have been directed toward the pectenotoxins, [3] to date only one total synthesis of PTX-4 and PTX-8 has been reported. [4] In particular we were drawn to the C1-16 fragment of the pectenotoxins, because it contains a pair of THF rings terminating with a spiroketal unit that could be derived from a linear precursor; a synthesis would allow us to develop two concepts that should find general use in organic synthesis. Our first idea was to prepare a triol-containing linear diene, such as 1 (Scheme 1), and carry out an oxidative cyclization [5] in a cascade mode, catalyzed by osmium(VI). In the first instance, we might expect the vicinal diol unit in 1 to chelate to the osmium catalyst and facilitate an oxidative cyclization onto the trisubstituted alkene, thus forming a THF ring (2). The stereospecific (syn) addition of the two oxygen atoms across the alkene will ensure the correct configuration in the product. We then hoped that the metal chelate formed after cyclization would translocate onto the hydroxy group at C10 and thus enable a second oxidative cyclization onto the pendent C-6,7 alkene, forming 3 in the process. If successful, this method would expand the limits of the catalytic oxidative cyclization and form both THF rings of the target in one pot.Our second point of interest was the notion of using the exocyclic hydroxy group at C6 to initiate a hydride shift and form an oxo-carbenium ion in situ (see 4!5). [6] If this reaction were successful, we wanted to explore the role of a pendent (protected?) hydroxy group in trapping the cation and forming a spiroketal (6). [7] This sequence, which we called hydride-shift-initiated spiroketalization, would be another potentially general piece of methodology for organic synthesis.Initial results strongly suggested that the success of the hydride shift depended on the relative configuration between the exocyclic hydroxy group (activated as a leaving group) and the ring junction. [8] Moreover, previous experi...

CH Bond Functionalization through Intramolecular Hydride Transfer

“…In a further application of their general concept, Donohoe et al. reported the successful synthesis of the spirocyclic acetal 334 from linear precursor 333 as a key step in their synthesis of the ABC spiroketal ring system of pectenotoxin‐4 101b…”

Control of Molecular Weight and End-Functional Groups of Polyester from A2 + B2 Polycondensation via Cross-Metathesis of Cyclic Unsaturated Polyester with Difunctional Olefin

“…Polycondensation of cis-or trans-4-Octene-1,8-diol (2, 3) and Sebacoyl Dichloride (4). We next conducted polycondensation of cis-4-octene-1,8-diol (2) 10,11 or the trans counterpart (3) 12 with 4 because we considered that the backbone of the polyester derived from 1 and 4 might not be flexible enough to cyclize. The geometry of the carbon−carbon double bond might influence cyclization of the polyester and the desired cross-metathesis of cyclic polyester with ExR.…”

Spiroacetal Formation through Telescoped Cycloaddition and Carbon–Hydrogen Bond Functionalization: Total Synthesis of Bistramide A

“…[6,7] However the electron-rich alkene and cation-stabilizing oxygen atom make the dihydropyran an ideal substrate for in situ oxidative carbon-hydrogen bond cleavage by 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in accord with our studies on related transformations. [8] The resulting dihydropyrone can undergo intramolecular nucleophilic addition [9] to yield the target product in which two rings and three bonds are created from readily available precursors.…”