Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A
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-cy...
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ftdatacite:10.7907/7a9e-t435 2023-05-15T15:52:51+02:00 Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A Fraley, Mark E. 1995 PDF https://dx.doi.org/10.7907/7a9e-t435 https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 en eng California Institute of Technology No commercial reproduction, distribution, display or performance rights in this work are provided. Chemistry chemistry Thesis Text Dissertation thesis 1995 ftdatacite https://doi.org/10.7907/7a9e-t435 2021-11-05T12:55:41Z 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. Thesis Carbonic acid DataCite Metadata Store (German National Library of Science and Technology) |
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English |
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Chemistry chemistry |
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Chemistry chemistry Fraley, Mark E. Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
topic_facet |
Chemistry chemistry |
description |
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. |
format |
Thesis |
author |
Fraley, Mark E. |
author_facet |
Fraley, Mark E. |
author_sort |
Fraley, Mark E. |
title |
Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
title_short |
Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
title_full |
Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
title_fullStr |
Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
title_full_unstemmed |
Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
title_sort |
synthesis of (+)-dynemicin a and analogs of wide structural variability. establishment of the absolute configuration of natural dynemicin a |
publisher |
California Institute of Technology |
publishDate |
1995 |
url |
https://dx.doi.org/10.7907/7a9e-t435 https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_rights |
No commercial reproduction, distribution, display or performance rights in this work are provided. |
op_doi |
https://doi.org/10.7907/7a9e-t435 |
_version_ |
1766387957813477376 |