Total synthesis of cytochalasin D: total synthesis and full structural assignment of cytochalasin O

Abstract

A total synthesis of cytochalasin D 3 is reported in which the key step is an intramolecular Diels–Alder reaction used to close the 11-membered ring simultaneously introducing the required stereochemistry at four of the stereogenic centres, C(4), C(5), C(8) and C(9). The precursor 21 for the Diels–Alder reaction was prepared from the aldehyde 13 by condensation with the dienyl phosphonate 14 to give the triene 15 which, after conversion into the acyl imidazole 17, was used to acylate the pyrrolidinone 18. The unstable pyrrolinone 21 was then generated from the pyrrolidinone by phenylselenation–oxidative elimination and was cyclised by heating in toluene under high dilution conditions to give the macrocyclic triene 22 (25–30%). Selective functionalisation of the double-bonds in this triene was investigated with epoxidation being selective for the 17,18-double-bond and hydroxylation using osmium tetroxide taking place selectively at the 6,7-double-bond. For completion of the synthesis of cytochalasin D 3, the 6,7-diol 26 was converted into the exocyclic alkene 30 by protection and dehydration. Further hydroxylation using osmium tetroxide gave the diol 31 which was taken through to the enone 36 by protection followed by phenylselenation, N-debenzoylation and oxidative elimination. Reduction under Luche’s conditions gave the alcohol 37 which was converted into the acetate 41 by acetylation followed by protecting group exchange. Selective deprotection of the vicinal diol and mild oxidation then gave the ketone 43. Final deprotection gave cytochalasin D 3 so completing the first total synthesis of this natural product.

During the course of this work, the Diels–Alder adduct 22 was oxidised using an excess of osmium tetroxide to give the tetraol 28. After protection as its bis-acetonide 46, this was converted into the allylic acetate 51 using the chemistry developed during the synthesis of cytochalasin D 3. Selective hydrolysis of the 17,18-acetonide and oxidation under Swern conditions gave the hydroxyketone 53 which on deprotection gave cytochalasin O 54 so confirming the structure of this natural product.