Total Synthesis of -Sordaricin

Carbohydrate derivatives of sordaricin 3 are clinically-effective antifungal agents, but development efforts were halted when a suffficient supply of 3 could not be established. Koichi Narasaka of the University of Tokyo recently reported Chem. Lett. 2004,33,942) a total synthesis of 3, based on the elegant Pd-mediated cyclization of 1 to 2. 

The B-keto ester was protected as the enol acetate, then the ketone 12 was homologated to the 

To complete the synthesis, the ketone of 2 was homologated to the alkene 12. Selective oxidative cleavage of the two vinyl groups followed by reduction provided the diol, the less encumbered alcohol of which was protected to deliver the fully-differentiated ester 13. Oxidation followed by ester cleavage then gave 3. 

This strategy has already been found useful in natural product synthesis. In the course of a synthesis of V-ATPase inhibitor oximidine III, John Porco of Boston University has described (Angew. Chem. Int. Ed. 2004, 43, 3601) the cyclization of 7 to 8. In the absence of the penlenlyl director, the initial complexation of the Ru catalyst was with the 1,3-diene, leading to allylidene complex and so effectively killing the catalyst. In this case, the Hoveyda catalyst 8 provided a cleaner product than G2 did. 

Many macrocyclic lactams have potent physiological activity. Daesung Lee of the University of Wisconsin has taken advantage Organic Lett. 2004. 6, 4351) of the conformational preference of diacyl hydrazides such as 8 to prepare, by Grubbs cyclization of 8 and then again of 10, the 8-8 system 11. Exposure of 11 to Na in liquid ammonia reduced the N-N bond and opened the epoxide, to deliver macrocyclic lactam 12. 

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Recently, Mander and coworkers [122] reported the total synthesis of sordaricin (4-347), the aglycone of the potent antifungal diterpene sordarin which was first isolated in 1971 from the ascomycete Sordaria araneosa. Two approaches were explored the first method utilized a possible biogenetic Diels-Alder reaction the second was based on a domino retro-Diels-Alder/intramolecular Diels-Alder process. Thus, heating of 4-348 led, with extrusion of cyclopentadiene, to a 1,3-butadiene as intermediate which underwent an intramolecular Diels-Alder reaction to give the desired 4-349 as the main product, together with a small amount of 4-350 (Scheme 4.77). 

Mander and Thomson reported the total synthesis of sordaricin (120), a diterpene isolated from the ascomycete Sordaria araneosa Cain (Scheme 8.19) [51]. Inspired by its biogenesis, they devised a synthetic plan involving a domino retro Diels-Alder/IMDA reaction of a mask cyclopentene 121. Upon liberation of cyclopentene, intermediate 122 underwent an IMDA reaction to give the desired sordaricin analog 123 along with a minor cycloaddnct regioadduct 124. 

Narasaka and co-workers reported a successful p-selective glycosylation, which is one of the key steps in the total synthesis of (—)-sordarin, by employing the remote participation of the 0-3 axial p-methoxybenzoyl group of glycosyl donor 134 the glycosylation of sordaricin ethyl ester 135 with 134 provided glycoside 136 (p/a = 6.5 1) with an excess of the P-anomer (Scheme 22) [75]. 

Sordaricin 2 is the aglycone of sordarin 3, the parent of a family of clinically-effective antifungal agents. Lewis N. Manderof the Australian National University has published (./. Org. Chern. 2005, 70, 1654) a full account of their enantioconvergent (see below) synthesis of 2, based on the intramolecular Diels-Alder cyclization of the triene 1. For a complementary total synthesis by Narasaka of sordaricin 2, see Org. Chem. Highlights 2005, April 4. 

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