Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O -Benzyltubulysin V Benzyl Ester

Manshu Li; Koushik Banerjee; Gregory K Friestad

doi:10.1021/acs.joc.1c01798

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Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O -Benzyltubulysin V Benzyl Ester

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Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O -Benzyltubulysin V Benzyl Ester

Manshu Li, Koushik Banerjee and Gregory K Friestad

Journal of organic chemistry, Vol.86(21), pp.15139-15152

11/05/2021

DOI: 10.1021/acs.joc.1c01798

PMCID: PMC8576829

PMID: 34636574

Appears in UI Libraries Support Open Access

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Abstract

Radical addition to chiral -acylhydrazones has generated unusual amino acids tubuphenylalanine (Tup) and tubuvaline (Tuv) that are structural components of the tubulysin family of picomolar antimitotic agents and previously led to a tubulysin tetrapeptide analog with a C-terminal alcohol. To improve efficiency in this synthetic route to tubulysins, and to address difficulties in oxidation of the C-terminal alcohol, here we present two alternative routes to Tuv that (a) improve step economy, (b) provide modified conditions for Mn-mediated radical addition in the presence of aromatic heterocycles, and (c) expose an example of double diastereocontrol in radical addition to a β-benzyloxyhydrazone with broader implications for asymmetric amine synthesis via radical addition. An efficient coupling sequence affords 11- -benzyltubulysin V benzyl ester.

Esters

Hydrazones

Oligopeptides

Valine - analogs & derivatives

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Title: Subtitle: Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O -Benzyltubulysin V Benzyl Ester
Creators: Manshu Li - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
Koushik Banerjee - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
Gregory K Friestad - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
Resource Type: Journal article
Publication Details: Journal of organic chemistry, Vol.86(21), pp.15139-15152
DOI: 10.1021/acs.joc.1c01798
PMID: 34636574
PMCID: PMC8576829
NLM abbreviation: J Org Chem
ISSN: 0022-3263
eISSN: 1520-6904
Publisher: American Chemical Society
Grant note: DOI: 10.13039/100000165, name: Division of Chemistry, award: CHE-1362111; DOI: 10.13039/100008893, name: University of Iowa
Language: English
Date published: 11/05/2021
Academic Unit: Chemistry
Record Identifier: 9984216565502771

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