Polyepoxide cyclization

As an alternative to polyepoxide cyclization, cascade cyclization of cyclic sulfates... 

Polyepoxide Cyclization Cascade Based on the proposed biosynthesis of polyether toxins, Holton and coworkers used an electrophile-initiated epoxy alcohol cyclization cascade as a key step for the total synthesis of hemibrevetoxin B (37) (Scheme 4.7) [14], Treatment of 33 with N-phenylselenophthalimide (A -PSP) led to sequential cyclization to give 36 in 83% yield as a single stereoisomer. The cascade... 

Lindo-rv.ff oselecli ve oxacydization of polyepoxides is less common the first ster-eospedfic tandem endo-regioselective biomimetic oxacydization of polyepoxides to fused THP rings has only recently been reported [38a], The cyclization of the hydroxy-methoxymethyl-substituted triepoxide 75 (a 1,4,7-triepoxide), promoted and directed by La(OTf)3 through an intramolecular chelation and based on a procedure originally described for a monoepoxide system [38b], afforded the tri-... 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

McDonald and coworkers studied a series of tandem endo-selective and stereospecific oxacyclization of polyepoxides by reaction with Lewis acid [92-95]. Polyepoxides, such as 50, can be obtained from the epoxidation of triene 49 with ketone 26 (Scheme 8). This cascade cyclization of polyepoxides provides an efficient method to synthesize substituted polycyclic ether structures, which are present in a number of biologically active marine natural products. 

The Shi epoxidation has found several applications in total synthesis [15]. Particularly attractive are examples in which it has been used to establish the stereochemistry of polyepoxides which can undergo cascade cyclizations to polyether products, mimicking possible biosynthetic pathways. An example is the construction of the tetahydrofuran rings of the natural product glabrescol via highly stereoselective formation of the tetraepoxide 10 from the polyene 9 (Scheme 12.6) [22]. 

The question of oxidative cyclization versus a polyepoxide cascade in the biosynthesis of polyether natural products has been reviewed <1995AGE298>. Enzymatic domino reactions involving epoxide intermediates have been reviewed <2001CSR332>. The DNA-damaging activity of epoxides and other oxidized species has been examined using chemical models <1995ACR289>. 

Recent advances in the synthesis of trans-iused polycyclic ethers by hydroxy epoxide cyclization reactions via monocyclic epoxonium ion intermediates and ether ring expansion reactions via bicyclic epoxonium ion intermediates are described in a review by Fujiwara and Murai. Natural trans-iu eA polycyclic ethers (e.g., brevetoxin A and ciguatoxin), produced by marine sources such as dinoflagellates, are hypothesized to be constructed from the corresponding polyepoxide precursors by a cascade of ring-closure reactions, which has prompted much work in the development of new methods for the construction of cyclic ethers from epoxides <2004BCJ2129>. 

Independently, Prasad and Shimizu (24) as well as Lee et al. (25) proposed that brevetoxin A is biosynthesized from the cyclization of a polyepoxide precursor in a series of Sn2 R,R)-trans epoxide openings (Fig. 4c). Galfimore and Spencer (3) argue that the nine disfavored endo-tet closures required for this mechanism makes it mechanistically unlikely and point out that an alternative cascade of Sn2 epoxide openings in the opposite direction from all (S,S)-trans epoxides yields the same structure. 

A group of polycyclic polyether natural products are of special interest owing to their fascinating structure and biological activities. One of the proposed biosynthetic origins of these molecules features an epoxide-opening cascade pathway. Shi asymmetric epoxidation of un-activated alkenes has been frequently employed in the preparation of polyepoxide intermediates. McDonald and co-workers studied a series of tandem e 7o-selective and stereospecific oxacyclization of polyepoxides mediated by Lewis acid. Polyepoxides, such as 64, can be obtained from the epoxidation of triene 63 with ketone 2. Furthermore, a cascade cyclization, initiated by a Lewis acid-promoted epoxide opening of 64, furnished the desired polyether 65. 

More recently, Jamison and coworkers reported that water can act as the optimal reaction medium. Polyepoxide 121 selectively cyclized to form the fused tetrahydropyran rings when the epoxide-opening reactions were carried out in water (Scheme 3.39) [77, 78]. 

Many naturally occurring polyethers such as brevitoxin B (123) have been proposed to biosynthetically derive from the polyepoxidation of polyenes and subsequent cyclization of the resulting polyepoxides (Scheme 3.40) [79, 80]. Such a biomimetic polyene-polyepoxide-polycyclization approach would provide a potentially powerfid and versatile strategy for the synthesis of polyethers, with quick assembly of stereochemically complex molecules from relatively simple achiral polyalkene precursors. The epoxidation with ketone 42 should provide a valuable method to investigate this biosynthetic hypothesis and possible application of the proposed pathway in the synthesis of polyethers. 

Acid-catalyzed cyclization of polyepoxides such as 28 strongly favors five-membered ring formation. In that cyclization, the central reaction in the synthesis of (+)-omaezakianol 29 reported (Angew. Chem. Int. Ed. 2009, 48, 2538) by Yoshiki Morimoto of Osaka City University, three of the four tetrahydrofuian rings of 29 are formed in a single step, each with high steieocontrol. 

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