A formal total synthesis of ipalbidine

Abstract
The synthesis of 1,2,3,5,8,9-hexahydro-6-(4-methoxyphenyl)indolizin-7(6H)-one (5), a key intermediate in the synthesis of (±)-ipalbidine (3), is described. The 1;3-dipolar cycloaddition of the nitrone (9) to p-methoxy(allyl)benzene (8) proceeded highly regio- and stereo-selectively to give the trans-hexahydropyrroloisoxazole (10). Reduction of compound (10) with zinc–aqueous acetic acid yielded the aminoalcohol (14) which was then converted into the amino ketone (16)via amino protection (carbamate), Collins oxidation, and deprotection. The direct cyclization of compound (16) to the indolizinone (5) by a Mannich reaction failed; however, treatment of the ketoformate (20), prepared fromcompound (14)via N-formylation followed by Collins oxidation, with aluminium t-butoxide resulted in cyclization to furnish the bicyclic ketone (5). This constitutes a formal total synthesis of (±)-ipalbidine.

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