合成路线1

The Western fragment (VI) of SC-53228 was derived from methyl 2,4-dihydroxybenzoate (I). Allylation of this material under standard conditions (allyl bromide, potassium carbonate, DMF) afforded the 4-allyl ether as the predominant product along with a smaller quantity (approx. 5%) of the 2-allyl ether. This mixture was subjected to thermally induced Claisen rearrangement (neat, 190 C) to access the requisite tetrasubstituted aromatic nucleus (II). The yield for these two steps was approx. 55%. Cyclopropanation of the allyl group was best effected by the Denmark modification of Simmons Smith reaction (Et2Zn, Cl(CH2)2Cl, ClCH2l). This process proved to be somewhat capricious in that, as a general rule, some starting material was always recovered from the reaction mixture regardless of the stoichiometry of the reagents used. This unreacted olefin could be removed by treating the crude reaction mixture with palladium (II) salts (palladium trifluoroacetate, tetrabutylammonium chloride in acetone/water). Yields of the cyclopropane product (III) resulting from this 2-step sequence ranged between 50 and 90%. This diol ester was converted, uneventfully, to the monomethyl amide (IV) (CH3NH2, NH4Cl, 77%) and the linker attached under standard conditions (Cl(CH2)3Br, DMF, K2CO3) (V). This reaction proved to be nonselective and low yielding (approx. 45% yield). Methylation (dimethyl sufate, KOH, THF) followed by Finkelstein reaction (NaI, MEK) provided the key Western fragment (VI) in approximately 10% overall yield from methyl 2,4-dihydroxybenzoate.