title: Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog.
abstract: Synthesis of tubuphenylalanine and tubuvaline (Tuv), α-substituted γ-amino acid building blocks for tubulysin family of antimitotic compounds, has been improved using a radical addition reaction in the presence of unprotected hydroxyl functionality. The key carbon-carbon bond construction entails stereoselective Mn-mediated photolytic additions of alkyl iodides to the C=N bond of chiral N-acylhydrazones, and generates the chiral amines in high yield with complete stereocontrol. Reductive N-N bond cleavage and alcohol oxidation converted these amino alcohols into the corresponding γ-amino acids. The route to Tuv proceeded via peptide coupling with serine methyl ester, followed by a high-yielding sequence to convert the serine amide to a thiazole. Finally, peptide bond construction established the tubulysin framework in the form of a C-terminal alcohol analog. Attempted oxidation to the C-terminal carboxylate was unsuccessful; control experiments with dipeptide 18 showed a cyclization interfered with the desired oxidation process.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Friestad
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Koushik
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Marié
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Umesh
authors.initials: U
authors.lastname: Mali
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D003500:Cyclization; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013237:Stereoisomerism; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D050256:Antimitotic Agents; D009842:Oligopeptides; C000614358:tubuphenylalanine; C000614359:tubuvaline; D010649:Phenylalanine; D014633:Valine