Synthesis of complex delta-acetylenic amino acids as potential multisubstrate adduct inhibitors of methyltransferases.
The synthesis of two types of delta-acetylenic amino acids is described. Key intermediates were derived from terminal acetylenes via two different routes: (1) palladium-mediated, Heck-type arylation, and (2) Simmons-Smith homologation followed by reaction of the resulting propargylic organometallic with a benzoyltrimethylsilane. Further elaboration to the desired amino acids involved the coupling of carbanions derived from N-benzylidene glycine esters to complex alkyl halides. The synthesis of nonnucleoside delta-acetylenic amino acids was successfully effected using this chemistry. In the case of the nucleoside-containing amino acids, a potential multisubstrate adduct inhibitor of catechol O-methyltransferase was synthesized via this route. Unfortunately, the sensitivity to acid of 5'-deoxy, 5'-carbanucleosides prevented successful completion of the synthesis of a second nucleoside-containing delta-amino acid as a possible inhibitor of phenethanolamine N-methyltransferase.
Department of Chemistry, University of Michigan, Ann Arbor 48109, USA.
M R
MR
Burns
J K
JK
Coward
D000480:Alkynes; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D008780:Methyltransferases / Q000037:antagonists & inhibitors*
D000480:Alkynes; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C031203:2-hexadecynoic acid; D008780:Methyltransferases