Krow, Grant; Davis, Franklin A.; Schafmeister, Christian; Cannon, Kevin C. (Temple University. Libraries, 2010)
      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.