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
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/1740 |
| Date | January 2010 |
| Creators | Lin, Guoliang |
| Contributors | Krow, Grant, Davis, Franklin A., Schafmeister, Christian, Cannon, Kevin C. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 128 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/1722, Theses and Dissertations |
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