| N-Methylwelwitindolinone C isothiocyanate 1 was first isolated from a blue-green algae. It has been shown to be an antagonist to P-170 glycoprotein and can serve as an MDR reversal reagent. A convergent approach was designed to synthesize this molecule.; The cyclohexanone fragment 18 was prepared stereoselectively by two conjugate additions to α,β-unsaturated ketoesters with a ketal chiral auxiliary. The couplings of 18 with a variety of indole substrates by Mukaiyama-type reaction or Pd(0)-catalyzed reaction were not successful. Although a quaternary center can be generated by iodonium salts, this approach was not practical and was abandoned.; The formation of quaternary center C11 through the reaction of indole lead(IV) tricarboxylates with β-ketoesters was investigated in detail. 3-Vinyl or acetyl 4-stannyl indole cannot undergo tin-lead exchange. With 3-H or 3-alkyl substituents, tin-lead exchange can take place in high yields. High diastereoselectivity was achieved with bulky substituents at the 5-position of β-ketoesters. The coupling was not successful with β-ketoester 18 because the steric interaction with adjacent quaternary center at the C12 position. The increase of the size of the aryl lead triacetate reagent will increase the selectivity as well. After the formation of the C11 quaternary center for the synthesis, the coupled product 89b and 89e were then transformed to the corresponding oxindole compounds by deprotection, methylation and oxidation. Attempts to cyclize the 7-membered ring in those systems failed.; The 3-CH2CH2OTBS indole lead triacetate 124 was prepared and coupled to β-ketoester 20 to generate compound 125 which was, in turn, transformed to 3-vinyl compound 127. The cyclization of the 7-membered ring to form the core structure 129 is currently being pursued. |
