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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ftcaltechdiss:oai:thesis.library.caltech.edu:3870 2023-09-05T13:18:48+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 application/pdf https://thesis.library.caltech.edu/3870/ https://thesis.library.caltech.edu/3870/1/Fraley_me_1995.pdf https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 en eng https://thesis.library.caltech.edu/3870/1/Fraley_me_1995.pdf Fraley, Mark E. (1995) Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/7a9e-t435. https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 <https://resolver.caltech.edu/CaltechETD:etd-10022007-135120> other Thesis NonPeerReviewed 1995 ftcaltechdiss https://doi.org/10.7907/7a9e-t435 2023-08-14T17:27:00Z 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 CaltechTHESIS (California Institute of Technology |
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CaltechTHESIS (California Institute of Technology |
op_collection_id |
ftcaltechdiss |
language |
English |
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. |
spellingShingle |
Fraley, Mark E. Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A |
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 |
publishDate |
1995 |
url |
https://thesis.library.caltech.edu/3870/ https://thesis.library.caltech.edu/3870/1/Fraley_me_1995.pdf https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_relation |
https://thesis.library.caltech.edu/3870/1/Fraley_me_1995.pdf Fraley, Mark E. (1995) Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/7a9e-t435. https://resolver.caltech.edu/CaltechETD:etd-10022007-135120 <https://resolver.caltech.edu/CaltechETD:etd-10022007-135120> |
op_rights |
other |
op_doi |
https://doi.org/10.7907/7a9e-t435 |
_version_ |
1776199671013703680 |