Sordaricin synthesis

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). 

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. 

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. 

Bp3-Et20 resulted in a shift of stereoselectivity towards 3-glycoside formation in the synthesis of sordaricin [345]. 

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]. 

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. 

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