ChemInform Abstract: Synthesis of the Unique All-cis Cyclopentanetetraol Moiety in Funiculosin

A total synthesis of the all-cis cyclopentanetetraol moiety 2,3,4,5-tetrahydroxycyclopentane-1-acetonitrile, present in the antiviral substance funiculosin produced by Penicillium funiculosum, is described. Conversion of the known cyclopent-4-ene-1,2,3-triol into the 1-[1-(t-butyldimethylsiloxy)vinyl] 2,3-methylene trisether, followed by Claisen–lreland rearrangement in xylene at 190 °C, first provided the key intermediate all-cis-4,5-(methylenedioxy)cyclopent-2-ene-1-acetic acid. Iodolactonisation of this acid then led to the iodo lactone 4β-iodohexahydrofuro[2′,3′:4,3]cyclopenta [d][1,3]dioxolan-6-one, which on direct nucleophilic displacement using potassium superoxide in the presence of 18-crown-6 produced the corresponding 4β-hydroxy lactone by an SN1 mechanism probably via the C-4 radical intermediate. The structure and stereochemistry of the hydroxy lactone were determined by X-ray analysis of its t-butyldimethylsilyl ether.The above iodo lactone was converted into the iodohydrin-acetonitrile 2α-hydroxy-3β-iodo-4α,5α-(methylenedioxy)cyclopentane-1α-acetonitrile in three steps, which was then treated with methyl (chloroformyl)acetate to give the corresponding mixed malonate diester. Treatment of this diester with sodium hydride resulted in smooth, intramolecular oxygen nucleophile displacement leading to the all-cis ketene acetal methyl [7-(cyanomethyl)-3b,6a,7,7a-tetrahydro-3aH-cyclopenta [1,2-d;3,4-d′]-di [1,3]dioxol-2-ylidene]acetate in 92% yield, hydrolysis of which produced a mixture of positional isomers of all-cis-2-(cyanomethyl)-5-hydroxy-3,4-(methylenedioxy)cyclopentyl methyl malonate, which was then saponified to give the all-cis cyclopentane-substituted 2,3-dihydroxy-4,5-(methylenedioxy) cyclopentane-1-acetonitrile. The full structure and stereochemistry of this acetonitrile followed from X-ray analysis. The synthesis of (±)-all-cis-2,3,4,5-tetrahydroxycyclopentane-1-acetonitrile was then completed following treatment of the 4,5-methylenedioxy compound with ozone, leading to the 4-formate (and its 5-isomer), and saponification.