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β,γ-unsaturated amino acids: Asymmetric synthesis and installation of the (1-fluoro)vinyl trigger
Abstract
A generalizable synthesis of higher L-α-vinyl amino acids has been developed. This strategy involves highly diastereoselective alkylations (91:9 ≥ 98:2 dr's) of a chiral, vinylglycine derived dianion dienolate, bearing the (−)-8-(β-naphthyl)menthyl (d'Angelo) auxiliary. A model [semiempirical optimized geometries (PM3)] is suggested that postulates a favored “exo-extended” conformation for this dienolate, leading to Cα-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate geometry and soft-soft interactions between the polarizable β-naphthyl ring of the auxiliary and the extended π-system of the dienolate to shield the re face. The auxiliary may be recovered in high yield using a modification of Gassman's “anhydrous hydroxide” conditions. This represents the first asymmetric synthesis of L-α-vinyl analogues of m-tyrosine, ornithine and lysine, known time-dependent inhibitors for amino acid decarboxylases. Monomeric and peptidyl analogs containing the diaminopimelate template may be potential inhibitors or unnatural substrates for ATP-dependent ligases, which function in the biosynthesis of the peptidoglycan of the bacterial cell wall. Stereoselective synthesis of both (2S,6S) and (2R,6S)-2-Vinyl-2,6-diaminopimelate was achieved using our self-regeneration of chirality approach. The synthesis is convergent, with the DAP side chain entering as an L-glutamate derived-electrophile. Following alkylation of our masked vinylglycine enolates, the vinyl group is unveiled in a sequence that involves basic (alkoxide), reductive (HSnBu 3) and oxidative (PDC) conditions. The synthesis of a new fluorovinyl cation equivalent, β,β-difluorovinyl phenyl sulfone has been achieved. This fluorinated electrophile readily undergoes addition to the α-carbon of N-benzylidene AA esters with subsequent elimination of fluoride yielding α-[(Z)-(1-fluoro-2-phenylsulfonyl)]vinyl amino acids. McCarthy conditions (SnBu3H, AIBN, Δ) cleanly convert the β-fluorinated vinyl sulfones to their corresponding β-fluorinated vinyl stannanes. Acidic deprotection yields higher α-(1-fluoro)vinyl amino acids for the first time. Synthesis of unnatural amino acids in which the 1-fluoro-trigger is incorporated within the side chain of α-methyl amino acids including those of m-tyrosine, glutamate, and lysine is presented. These β,γ-unsaturated amino acids are accessed using palladium catalyzed cross-coupling reactions between the α-[(Z)-(1-)-fluoro-2-tributystannyl]vinylalanine and vinyl, aryl, and allylic halides.
Subject Area
Organic chemistry|Biochemistry
Recommended Citation
McFadden, Jill Marie, "β,γ-unsaturated amino acids: Asymmetric synthesis and installation of the (1-fluoro)vinyl trigger" (2000). ETD collection for University of Nebraska-Lincoln. AAI9967390.
https://digitalcommons.unl.edu/dissertations/AAI9967390