Model studies on the synthesis of the tetracyclic ABCD ring system of lactonamycin (1) are described. The key step involved the double Michael addition reaction of alcohol 8 to propynoate esters to produce the BCD units 13 and 14 of the target 1. Alternatively, double Michael addition of alcohol 8 to di-tert-butyl acetylenedcarboxylate gave the corresponding BCD ring systems 36 and 37. Acid-mediated hydrolysis of the dihydroquinone monoketal units of 13 and 14 and 36 and 37 in the presence of air gave the corresponding quinones 7 and 39. These were converted into the tetracyclic ABCD units 6, 26a, 40, and 42 of lactonamycin (1) by either dihydroxylation or epoxidation and acid-catalyzed lactonization.
[reaction: see text] Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H-1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from d- or l-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using beta-cyclodextrins as a chiral selector.
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