The total synthesis of (±)- and (+)-biocyclomycin
| dc.contributor.author | Armstrong, Robert W., author | |
| dc.contributor.author | Williams, Robert M., advisor | |
| dc.date.accessioned | 2022-11-28T17:44:43Z | |
| dc.date.available | 2022-11-28T17:44:43Z | |
| dc.date.issued | 1984 | |
| dc.description.abstract | The completely regio- and stereocontrolled total synthesis of bicyclomycin (1) is described in 12 chemical steps. A new carbon-carbon bond-forming reaction of 1,4-dibenzyl- and 1,4-di-p-methoxybenzyl-3,6'-bis-(2'-thiopyridyl)-2,5-piperazinediones (234 and 275) has been discovered involving complexation of 234 or 275 with silver(I)triflate followed by addition of the trimethylsilyl ketene acetal of γ-butyrolactone to afford 1,4-dibenzyl- and l,4-di-p-methoxybenzyl-3-(2'-thiopyridyl)-6-(2"- γ-butyrolactonyl)-2,5-piperazinediones (236, 237, and 276-279) in good yield. The reaction proceeds in THF at 25°C with predominant syn-stereospecificity. LiA1H4 reduction of lactones 276-279 provides the corresponding diols 280-282 which are cyclized to the bicyclo[4.2.2]nucleus 284 in the presence of silver(I)triflate in THF at 25°C. Dehydration of 284 in three steps affords the key olefinic intermediate 8,10-di-p-methoxybenzyl-8,10-diaza-5-(methylene)-2-oxabicyclo[4.2.2]decane-7,9-dione (294) which is regio- and stereoselectively elaborated at the bridgehead positions via: 1) C-6-bridgehead carbanion formation followed by quenching with O2; and 2) C-1-bridgehead carbanion formation followed by aldol condensation with 2,2,4-trimethyl-l,3-dioxolane-4-carboxyaldehyde to afford a single diastereomer (279a) possessing the correct relative configuration at C-1', C-2'. Protection of the secondary hydroxyl at C-1' as the trifluoroacetate followed by oxidative removal of all the protecting groups with ceric ammonium nitrate in MeCN/H2O affords directly, totally synthetic bicyclomycin. Condensation of the racemic bicyclic nucleus 296 with optically active S-2,2,4-trirnethyl-1,3-dioxolane-4-carboxaldehyde (83% ee) provides after protection and deprotection, (+)-bicyclornycin in 78% ee. Preliminary results establishing a structure-activity correlation requiring an obligate partnership of the C-6 hydroxyl and the C-4, C-5 exomethylene are described. | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier.uri | https://hdl.handle.net/10217/235824 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation | Catalog record number (MMS ID): p91006709539703361 | |
| dc.relation | QD262.A75 1984 | |
| dc.relation.ispartof | 1980-1999 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | Organic compounds -- Synthesis | |
| dc.subject | Antibiotics | |
| dc.title | The total synthesis of (±)- and (+)-biocyclomycin | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Chemistry | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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