Polyepoxide cascade

In the synthesis of the squalenoid glabrescol (72 originally attributed structure), containing five adjacent (all cis) THF rings, the necessary precursor of the polyepoxide cascade, the pentaepoxide 71, was achieved by epoxidation of each of the trisubstituted double bonds of the known (R)-2,3-dihydroxy-2,3-dihydrosqualene (70) by the Shi epoxidation approach (Scheme 8.18) [34]. Treatment of 71 with CSA at 0 °C and subsequent purification by column chromatography provided the pure polycyclic ether 72 by a cascade process reasonably initiated by the free secondary alcohol functionality [35a]. 

Scheme 8.18 Corey s synthesis of glabrescol (72 originally attributed structure) by a polyepoxide cascade.

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]. 

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>. 

Oxidative Polycyclization Versus the Polyepoxide cascade" New Pathways in Polyether 231... 

Scheme I. The Cane-Celmer-Westley hypothesis for the biosynthesis of monensin A (3) (a) stereoselective epoxidation (b) polyepoxide cascade it is assumed that the OH group at C(26) is also introduced during the epoxidation step.

The bis(tetrahydrofuranyl) Annonaceous acetogenin ( + )-(15,16,19,20,23,24)-hexepiuva-ricin (74), has been synthesized utilizing a polyepoxide cascade reaction. The diiodide 70 is transformed into the bis-allylic alcohol 72, which is subsequently converted to a C2-sym-metric diepoxide utilizing the Sharpless asymmetric epoxidation reaction. Selective mono-tosylation of the primary hydroxyl groups served to desymmetrize the system. An acid-catalyzed deketalization followed by simultaneous epoxide opening affords the erythro trans threo trans erythro-conf gmdXion present in the tosylate 73. Transformation of 73 to the desired 74 completes the synthesis [32] (Scheme 17). 

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

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]. 

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. 

In 1983, Cane et al. postulated that polyether biosynthesis takes place as a two step process. The first of these steps was proposed to be the enzymatically polyepoxidation of an acyclic hydroxypolyene precursor, and the second comprised a cascade of intramolecular epoxide ring openings with formation of the polyether frame work. [1] For monensin A... 

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. 

McDonald and coworkers reported a series of studies on biomimetic syntheses of fused polycyclic ethers [73, 74). For example, polyepoxide IIS, resulting from the epoxidation of triene 114 with ketone 42, was transformed into fused polycyclic ether 116 via the BF3-Et20-promoted cascade endo-oxacychzation (Scheme 3.37) [73d]. 

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... 

Jamison and coworkers developed a bromonium-initiated polyepoxide-opening cascade in their total synthesis of mt-dioxepandehydrothyrsiferol ( /if-40) (Scheme 4.8) [16]. Treatment of trisepoxide 38 with A -bromosuccinimide (NBS) in HFIP resulted in the formation of a 7,7,6-trans-anti-trans-fused tricyclic subunit 39a and 39b in 72% yield as a mixture of two diastereomers (dr = 1 1). All the quaternary stereocenters in 38 (C6, CIO, and C15) underwent clean inversion to afford the desired trans-anti-trans geometry of ring junctions in 39a and 39b. 

Scheme 4.8 Bromonium-initiated polyepoxide-opening cascade in the total synthesis of ent-dioxepandehydrothyrsiferol.

The Shi epoxidation has been used in several total syntheses [14], Of particular note is its use in establishing the stereochemistry of polyepoxides, which can undergo cascade cycUzation to polyether products [22, 23], mimicking possible biosynthetic pathways. Corey has put this strategy to use in several natural product syntheses such as the total synthesis of glabrescol [24, 25] and more recently in the total synthesis of (+)-omaezakinol 12 (Scheme 19.4) [26]. 

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