Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

Gregory K Friestad; Koushik Banerjee; Jean-Charles Marié; Umesh Mali; Lei Yao

doi:10.1038/ja.2016.7

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Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

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Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

Gregory K Friestad, Koushik Banerjee, Jean-Charles Marié, Umesh Mali and Lei Yao

Journal of antibiotics, Vol.69(4), pp.294-298

04/2016

DOI: 10.1038/ja.2016.7

PMCID: PMC4924578

PMID: 26883395

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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.

Antimitotic Agents - chemical synthesis

Antimitotic Agents - chemistry

Cyclization

Oligopeptides - chemical synthesis

Oligopeptides - chemistry

Phenylalanine - analogs & derivatives

Phenylalanine - chemical synthesis

Stereoisomerism

Valine - analogs & derivatives

Valine - chemical synthesis

Details

Title: Subtitle: Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog
Creators: Gregory K Friestad - Department of Chemistry, University of Iowa, Iowa City, IA, USA
Koushik Banerjee - Department of Chemistry, University of Iowa, Iowa City, IA, USA
Jean-Charles Marié - Department of Chemistry, University of Iowa, Iowa City, IA, USA
Umesh Mali - Department of Chemistry, University of Iowa, Iowa City, IA, USA
Lei Yao - Department of Chemistry, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Journal of antibiotics, Vol.69(4), pp.294-298
DOI: 10.1038/ja.2016.7
PMID: 26883395
PMCID: PMC4924578
ISSN: 0021-8820
eISSN: 1881-1469
Grant note: R01 GM067187 / NIGMS NIH HHS CHE-0749850 / NSF CHE-1362111 / NSF
Language: English
Date published: 04/2016
Academic Unit: Chemistry
Record Identifier: 9984216614302771

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