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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

NOVEL METHANOPYRROLIDINE β– AMINO ACIDS

Lin, Guoliang January 2010 (has links)
Methanopyrrolidine-5-carboxylic acids (MetPyr-5-acids), or 5-syn-carboxy-2- azabicyclo[2.1.1]hexanes are building blocks for β-peptides that cannot form backbone hydrogen bonds. To introduce functionality to this ring system, 6-syn-benzyloxymethyl and 6-syn-phenyl substituted derivatives have been prepared by an efficient synthetic procedure. Addition of appropriately substituted allyl amines to 3-butynone, amide protection, and irradiation afford mainly 5-acetyl-2-azabicyclo[2.1.1]hexanes. Haloform oxidation leads to the desired 6-substituted MetPyr-5-acids. A 1-ethoxycarbonyl-MetPyr-5-acid also was prepared in high yield. Condensation of ally amine with ethyl 2,4-dioxopentanoate afforded ethyl 2-(allylamino)-4-oxopent-2- enoate, and this was protected to give ethyl 2-[allyl(tert-butoxycarbonyl)amino]-4- oxopent-2-enoate. Irradiation afforded 5-syn-acetyl-1-ethoxycarbonyl-2- azabicyclo[2.1.1]hexane with high stereoselectivity and oxidation of the acetyl group afforded the desired 1-ethoxycarbonyl-MetPyr-5-acid. Resolutions of (±)-6-syn-benzyloxymethyl-MetPyr-5-acid and (±)-1- ethoxycarbonyl-MetPyr-5-acid were carried out (> 98% ee) by a classical resolution method using (S)-(-)-α-methylbenzylamine. The absolute configurations of (1S,4R,5R,6S)-(-)-6-benzyloxymethyl-MetPyr-5-acid and (1R,4S,5S)-(+)- 1- ethoxycarbonyl-MetPyr-5-acid were determined by X-ray analysis of their 5-(S)-(-)-α- methylbenzylamide. A prior X-ray analysis of N-Boc-(MetPyr)4-CO2Me indicated all amides to be trans oriented with all 5-syn-carbonyl groups directed toward Carbon-4 of the methanopyrrolidine. These structures were assigned as T4T4T4T4 or [T4]n (n = 4). The solution structure was not determined. Homooligomers of (1S,4R,5R)-5-syn-carboxy-2- azabicyclo[2.1.1]hexane (MPCA) terminally protected as N-Boc methylesters were constructed by EDC/HOBt coupling of terminal ester N-deprotected free amine units and N-Boc free acid units. To facilitate NMR analysis of the secondary structures of homooligomers, N-Boc was replaced by N-isobutyryl. NMR experiments indicated that N-isobutyryl-(MetPyr)n-CO2Me, (n = 2, 3, 4) have major favored [T4]n-1T where the orientation of the terminal ester carbonyl could not be determined. / Chemistry

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