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. 2021 Nov 5;86(21):15139-15152.
doi: 10.1021/acs.joc.1c01798. Epub 2021 Oct 12.

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

Manshu Li  1 , Koushik Banerjee  1 , Gregory K Friestad  1
Affiliations

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

Manshu Li et al. J Org Chem. .

Abstract

Radical addition to chiral N-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-O-benzyltubulysin V benzyl ester.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Methodology for Mn-mediated radical generation and stereocontrolled addition to C=N bonds using chiral N-acylhydrazones. (b) Key bond constructions (blue highlights) in synthetic applications to various chiral amines.
Figure 2
Figure 2
Structures of selected tubulysins, highlighting the unusual amino acids tubuvaline (green) and tubuphenylalanine (blue).
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Figure 3
Figure 3
Structures of selected tubulysin analogues.
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Figure 4
Figure 4
Examples of 1,3-diastereocontrol in additions to β-alkoxyimines. (a) Chelation-controlled antiselective Grignard addition with matched and mismatched α-phenethyl imines. (b) Pinacol-type radical addition to a β-alkoxysulfinimine.
Scheme 5
Scheme 5
Scheme 6
Scheme 6
Scheme 7
Scheme 7
Scheme 8
Scheme 8
Scheme 9
Scheme 9
See this image and copyright information in PMC

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