Document Detail


A thermal decarbonylation of penam beta-lactams.
MedLine Citation:
PMID:  18348573     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Penam acids 6-8 [i.e., (2S,5R,6R)-, (2S,5S,6R)-, and (2S,5R,6S)-isomers of 6-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid] were prepared by deesterification of the corresponding methyl esters 2-4. The same methodology applied to ester 1 did not lead to the (2S,5S,6S)-isomer 5 but rather a 72% yield of the thiazoline derivative 9. High-resolution mass spectrometry analysis of the reaction headspace gases indicated that a stoichiometric amount of carbon monoxide is produced during the deesterification of 1. A mechanism for this decarbonylation reaction is proposed. This appears to represent a new type of fragmentation reaction for a penam carboxylic acid. The free energies of various reaction species along viable decarbonylation reaction coordinates for acids 5 and 7 were computed by using the density functional theory method IEFPCM/M06/6-31+G(d). Anionic and zwitterionic (neutral) variants of the proposed mechanism were considered, but each produced computed activation free energies deemed to be too high (>45 kcal/mol) to be experimentally relevant. The computed activation free energies for the protonated (cationic) variant of the mechanism were 17.3 kcal/mol for 7 vs 8.8 kcal/mol for 5. The value of this difference in energies of activation (DeltaDeltaG++) is quite consistent with experimental observations and supports the proposed mechanism. For a portion of the computed reaction coordinate that involves ring opening of the lactam ring by an internal carboxylic acid group to form a cyclic anhydride, the expected tetrahedral intermediate was circumvented by a direct (concerted) and facile N- to O-acyl migration event. Additional thermal gas-phase reaction products produced during gas chromatographic analysis of the penams 1-8 were characterized with high-resolution mass spectrometry, and possible mechanisms for their formation are presented.
Authors:
Keith W Wiitala; Zhixin Tian; Christopher J Cramer; Thomas R Hoye
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-03-19
Journal Detail:
Title:  The Journal of organic chemistry     Volume:  73     ISSN:  0022-3263     ISO Abbreviation:  J. Org. Chem.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-14     Completed Date:  2008-06-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985193R     Medline TA:  J Org Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3024-31     Citation Subset:  IM    
Affiliation:
Department of Chemistry and Supercomputer Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455-0431, USA.
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MeSH Terms
Descriptor/Qualifier:
Carboxylic Acids / chemistry*
Computer Simulation
Mass Spectrometry
Models, Molecular
Molecular Structure
Stereoisomerism
Temperature*
beta-Lactams / chemical synthesis,  chemistry*
Grant Support
ID/Acronym/Agency:
CA-76497/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carboxylic Acids; 0/beta-Lactams

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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