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.

The Eastern fragment (XIV) was derived from 2',4'-dihydroxy-3'-propylacetophenone (VII). This material could be converted into (X) using identical procedures to those developed in house for the synthesis of SC-41930. (X) was resolved into its two homochiral components using enzymatic methods (Amano lipase AK, pH 7.4 buffer followed by selective methylation [CH3l, KHCO3, DMSO] and recrystallization. The overall yield for this process was 33% [based on a resolution yield of 40%]) and afforded the desired (-)-isomer (XII) in > 99% e.e. This material was silylated (TBDMS chloride, DMF, imidazole) and reduced to the primary carbinol with DIBAL-H. Conversion to the Eastern fragment (XIV) was accomplished by an efficient 3-step process involving triflation (Tf2O, CH2Cl2), homologation with lithium tert-butyl acetate and protective group removal/transesterification with ethanolic hydrogen chloride (92% for the three steps). The overall yield of Eastern fragment (> 99% e.e.) was 17% based on 2',4'-dihydroxy-3'-propylacetophenone (VII) as starting material.

The synthesis of SC-53228 was finally consummated (Scheme 3) through the coupling of Eastern (XIV) and Western (VI) fragments in a 2-step process involving intermolecular alkylation (K2CO3, DMF) followed by lithium hydroxide-mediated ester hydrolysis.

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.

The Eastern fragment (XIV) was derived from 2',4'-dihydroxy-3'-propylacetophenone (VII). This material could be converted into (X) using identical procedures to those developed in house for the synthesis of SC-41930. (X) was resolved into its two homochiral components using enzymatic methods (Amano lipase AK, pH 7.4 buffer followed by selective methylation [CH3l, KHCO3, DMSO] and recrystallization. The overall yield for this process was 33% [based on a resolution yield of 40%]) and afforded the desired (-)-isomer (XII) in > 99% e.e. This material was silylated (TBDMS chloride, DMF, imidazole) and reduced to the primary carbinol with DIBAL-H. Conversion to the Eastern fragment (XIV) was accomplished by an efficient 3-step process involving triflation (Tf2O, CH2Cl2), homologation with lithium tert-butyl acetate and protective group removal/transesterification with ethanolic hydrogen chloride (92% for the three steps). The overall yield of Eastern fragment (> 99% e.e.) was 17% based on 2',4'-dihydroxy-3'-propylacetophenone (VII) as starting material.

The synthesis of SC-53228 was finally consummated (Scheme 3) through the coupling of Eastern (XIV) and Western (VI) fragments in a 2-step process involving intermolecular alkylation (K2CO3, DMF) followed by lithium hydroxide-mediated ester hydrolysis.