Glabrescol epoxidation

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]. 

The structure of glabrescol was subsequently revised, and the new structure was synthesized enantioselectively through sequential hydroxy-directed anti-oxidative cyclization of acyclic y-alkenols with VO(acac)2/TBHP to construct the adjacent THF rings via epoxides under acid conditions [35b],... 

Polycyclic oxasqualenoid glabrescol was synthesized by Corey and coworkers in order to confirm its structure. Several pentaoxacyclic compounds were synthesized via epoxidation with ketone 26 followed by cyclizations [90]. Finally, compound 48 was synthesized to match the properties of the naturally occurring glabrescol, leading to the determination of the stereochemistry of glabrescol (Scheme 7) [91]. 

Scheme 14 Dimerization of vinyl epoxides in the preparation of glabrescol.

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]. 

Scheme 12.6 Shi epoxidation in the total synthesis of glabrescol (right).

In 2000, in an effort to verify the structure of a polycyclic oxasqualenoid, glabrescol 71, Corey and co-workers applied the Shi epoxidation in the conversion of tetraene 69 to tetra-epoxide 70, which was subsequently transformed to glabrescol 71 in three steps/ ... 

In their synthesis of the proposed glabrescol (90) (Scheme 3.30) [65], Kodama and coworkers reported that compound 88 was regio- and stereoselectively epoxidized at the central alkene with ketone 42 to give compound 89 after ring closure. The alkene inductively deactivated with the allylic acetate is less reactive. 

Corey and coworkers reported that (i )-2,3-dihydroxy-2,3-dihydrosqualene (104) was rapidly converted into proposed glabrescol 90 in 31% overall yield by enantio-selective pentaepoxidation with ketone 42 and subsequent cascade epoxide opening (Scheme 3.34) [69]. In their efforts to determine the correct stmcture of glabrescol, tetraene 106 was epoxidized with ketone 42. The resulting epoxide 107 was transformed into a chiral C2-symmetric pentacydic oxasqualenoid 109 (Scheme 3.35), which matches the reported isolated natural product glabrescol [70, 71]. 

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]. 

A recent application in the synthesis of (-)-glabrescol, by Corey, illustrates the scope of dioxirane-mediated asymmetric epoxidation (Scheme 1.20) [50],... 

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