A photochemical route to vinylglycine and a vinylglycine dipeptide

Abstract

Enantiomerically pure vinylglycine (4b) can be prepared (S)-homoserine (two-step synthesis). The photoelimination from natural ("chiral pool") amino acids by photoelimination (of HOSMe from 3b and of HX from 3d, e) proceeds quantitaof y-functionalized N-phthaloyl amino acid esters. Two routes tively and leads to N,C-protected vinylglycine 4a in high have been developed: (a) a three-step synthesis of substrate yields. This strategy could also be applied to peptide-bound 3b [PhtN-Met(SO)OMe] from (S)-methionine and subse-substrates as was shown for the protected Met-Gly (5b) quent photolysis, (b) the use of N-phthaloyl activated methyl which was transformed into the N-protected vinylglycine-2-amino-4-chloro-or -4-bromobutanoates 3d, e which are glycine dipeptide 6 in three steps. available from (S)-methionine (four-step synthesis) or fromThe synthesis of P,y-unsaturated amino acids has been a focus of synthetic organic chemistry for several decades [']. These compounds serve as flexible and versatile substrates for the synthesis of enantiomerically pure amino acid derivatives because they offer the a-stereogenic center as well as further options for modification due to the extra C-C double bond [']. Amongst all p, y-unsaturated amino acids it is vinylglycine which has found considerable interest due to several retrosynthetic pathways leading to pharmaceutical active compounds from this starting materialC3I. Vinylglycine, a natural amino acidr41 acts as an inhibitor of pyridoxal dependent aspartate aminotransferase~ [~] and is also considered as an important intermediate in several biogenetic pathways [6]. A number of (thermal) processes leading to vinylglycine have been developed using other amino acids (methi~nine [',~], glutamic acidl91, homoserine[lOl) as substrates. The most successful synthetic route to enantiomerically pure vinylglycine up to now is the thermolysis of n! Cprotected methionine sulfoxide developed [7] and optimized" ' 1 by Rapoport and coworkers.We investigated during the last few years photochemical pathways to P,y-unsaturated amino acids using the Nphthaloyl(chromophore)-activated and C-protected amino acids valine and isoleucine[121. Irradiation of both substrates gave the respective P,y-dehydro isomers by a sequence of yand &hydrogen migrations. This approach, however, was unsuccessful in the case of 2-amino-butyric acid, the logical precursor of the photoisomerization to vinylglycine[121. Assuming, that an increase in the migratory ability or in the leaving group ability of the second fragment after primary hydrogen abstraction should favor vinylglycine formation, we investigated a series of possible substrates. In view of recent results by Giese and coworkers on radical cation and hydroxyl anion formation from P-hydroxy radicals in DNAcleavage processes ['3], the use of appropriate OH-substituted amino acids was investigated. In principle, threonine and homoserine appeared to be suitable substrates by assuming that p-hydroxy radicals were formed via hydrogen abstraction in the primary r...

Synthesis of α,ω-polyfluorinated α-amino acid derivatives and δ,δ-difluoronorvaline

“…Having the protected δ,δ-difluorinated amino acid ester 27 in hand, we adapted a method by Griesbeck and Hirt 45 to obtain the free racemic amino acid in the form of the hydrochloride salt 28 in 89% yield after solid phase extraction (SPE). While the pK a value of the amino function was determined to be 9.01, similar to that of δ-fluoronorvaline ( pK a (NH 2 ) = 8.…”

Synthesis and Modifications of Amino Acids and Peptides via Diradicals

“…Thus, compounds 48, prepared from L-methionine or L-homoserine and bearing a leaving group in the y-position provided the unsaturated product 49 in good yield. Deprotection of 49 affords vinylglycine 50, a amino acid which is of considerable interest for the synthesis of pharmaceutically active compounds [27].…”

Synthetic Applications of Photoinduced Electron Transfer Decarboxylation Reactions

“…In the last years we discovered a series of photochemical transformations involving homolytic CHactivation at specific positions of amino acids and thus de-veloped routes to b,g-unsaturated a-amino acids (A), benzoazepines (B) and benzopyrrolizidines (C). 13…”