Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A

• Main Author: Fraley, Mark E.
• Format: Thesis
• Language: English
• Published: California Institute of Technology 1995
• Subjects: Chemistry; chemistry; Carbonic acid
• Online Access: https://dx.doi.org/10.7907/7a9e-t435; https://resolver.caltech.edu/CaltechETD:etd-10022007-135120

A highly convergent synthetic route to the potent natural antitumor agent (+)-dynemicin A (1) is described. Key features of the synthesis include: (1) the condensation of the potassium enolate of menthyl acetoacetate with trans-ethyl crotonate, providing the optically pure trans-disubstituted 1,3-cyclohexanedione 38; (2) the palladium-catalyzed coupling of the enol triflate 37 with t-butyl 2-borono-4-methoxycarbanilate to furnish 35, followed by the thermolysis of the latter to afford the quinolone 34; (3) the stereoselective acetylide addition of the (Z)-enediyne bridge to an acylquinolinium intermediate derived from quinoline 60, affording the addition product 61; (4) the acetylide-mediated closure of the (Z)-enediyne bridge of ketone 65 to produce 66; (5) the carboxylation and subsequent methylation of ketone 69, providing the vinylogous carbonic acid 70; (6) the oxidation of the phenol 73 to furnish the enone 74, as well as the reductive deprotection of 75 to afford the quinone imine 77; and (7) the Diels-Alder cycloaddition reaction of the quinone imine 77 with 1,4,7-tris(trimethylsiloxy)isobenzofuran, followed by the desilylation and oxidation of the resultant adduct to complete the synthesis of 1. The preparation of structurally diverse analogs of 1 by late-stage modification of the synthetic route is detailed. The absolute configuration of natural 1 is determined to be 2S, 3S, 4S, 7R, 8R, by the comparison of circular dichroism spectra of synthetic and authentic 1.