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Synthesis of enantiomerically enriched, alpha-branched alpha-amino acids
Abstract
Alpha-branched amino acids are of mechanistic and therapeutic interest as inhibitors of pyridoxal phosphate dependent enzymes. They also have potential use in de novo peptide design. For both enzyme inhibition and peptide synthesis applications, enantiomerically enriched $\alpha$-branched amino acids are desirable. Enantioselective approaches to $\alpha$-branched amino acids will be described. A procedure for the synthesis of L-$\alpha$-vinylglycine from L-homoserine is described. Key features include the use of acid-labile protecting groups for the amino and carboxyl groups, and the use of the phenylselenolate equivalent derived from sodium borohydride and diphenyl diselenide for L-homoserine lactone cleavage. One approach to $\alpha$-branched amino acids makes use of chiral dianions, wherein a chiral auxiliary is appended via the ester functionality. A chiral alanine-derived dianion reacts diastereoselectively ($\sim$90:10-96:4) with a variety of primary alkyl halides to provide ultimately, L-$\alpha$-methyl amino acids. Similarly, alkylation of a chiral $\alpha$-vinylglycine-derived dianion with a number of electrophiles gives L-$\alpha$-vinyl amino acids with excellent stereoselectively ($\sim$90:10-98:2 dr $\Rightarrow$ er). In both cases the chiral auxiliary can easily be recovered. A self-regeneration of chirality approach to enantiomerically enriched $\alpha$-vinyl amino acids is developed. Beginning from L-vinylglycine, the stereochemical information is transmitted from the original $\alpha$-stereogenic center to a new $\beta$-stereogenic center via a PhSe-X-mediated 5-exo-trig cyclization. Enantiomerically enriched cis- and trans-oxazolines result. These diastereomers are readily separated and carry stereochemical information at the $\beta$-center, leading ultimately to the formation of higher, L- and D-$\alpha$-vinyl amino acids, following an alkylation/double bond-unmasking sequence. A fundamentally new transformation, the direct conversion of vinyl selenides to vinyl stannanes under the agency of trialkyltin hydride is described. A preliminary investigation of the scope, limitations, and mechanism of this reaction has been carried out. This conversion allows for the straightforward synthesis of vinyl stannanes from aldehydes, ketones, and $\omega$-vinyl amides and acids.
Subject Area
Organic chemistry
Recommended Citation
Sloss, Marianne Kay, "Synthesis of enantiomerically enriched, alpha-branched alpha-amino acids" (1998). ETD collection for University of Nebraska-Lincoln. AAI9839148.
https://digitalcommons.unl.edu/dissertations/AAI9839148