Xerulinic acid

C18H14O2, Mr 262.31, orange-yellow cryst., mp. 143-153 °C. Highly conjugated eneyne-furanone from cultures of the toadstool Xerula melanotricha (Basidiomycetes). X. co-occurs with the 16,17-dihy-drocompound (C,gH,j02, Mr 264.32) and xerulinic acid (C,8H,204, Mr 292.29, orange-yellow cryst., mp. 250 °C - decomp.). All three compounds inhibit cholesterol biosynthesis. 

Synthetic applications of the alkenyl-alkenyl Negishi cross-coupling are intimately related to the preparation method of the alkenylzinc nucleophile. Reagents obtained by Zn(0) insertion from the corresponding halide, or by a halogen-hthium or a tin-lithium exchange/transmetallation sequence, are weU suited, as illustrated with the preparation of compounds 202 [170] and 205 (Scheme 4.46) [46]. Further evidence for the applicability of this method is its use in recent total syntheses of natural products, such as xerulinic acid [171], 6,7-dehydrostipiamide [172], epolactaene [173], and the side chains of mycolactones A and B [174]. 

At that time, we strived for the first total synthesis of a polyunsaturated natural product named xerulinic acid (22 Scheme 4). We envisaged using the hexatriene-l,6-distannane trans,trans,trans-lS (Fig. 5) as a Cg linchpin for joining the Z-configured y-(hromomethylidene)butenolide 20 and the polyunsaturated bromoalkyne 23 by sequential Stille couplings. 

SCHEME 4 The first total synthesis of the fungal dye xerulinic acid (22) was highly convergent. Its Ci8 backbone stemmed from the symmetric hexatriene-l,6-distannane trans,trans,trans-18/ a Negishi coupling with the bromobutenolide 20, and an ensuing Stille coupling with the... 

Xerulinic acid (151) inhibited the biosynthesis of cholesterol in HeLa S3 cells by blocking HMG-CoA synthase. Bisstannane 147 was transmetallated to the zincate intermediate and was Negishi cross-coupled with butenolide 148 to give the all tra 5-polyene 149. The Stille reaction of 149 with enediyne 150 followed by deprotection of the silyl group with tetrabutylammonium fluoride afforded xerulinic acid (151). 

Fiandanese and coworkers [103] described a new approach for the synthesis of the butenolides xerulin (6/1-207) and dihydroxerulin (6/1-208), which are of interest as potent noncytotoxic inhibitors of the biosynthesis of cholesterol (Scheme 6/1.53). The key transformation is a Pd°-catalyzed Sonogashira/addition process of 6/1-204 or 6/1-206 with (Z)-3-iodo-2-propenoic acid 6/1-205, which is followed by the formation of a lactone to give 6/1-207 and 6/1-208, respectively. 

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