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

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.

Highlights

IntroductionRadical additions to imino compounds offer a useful carbon−carbon bond construction approach to chiral amine synthesis.[1] Seminal efforts to generalize this reaction for intermolecular coupling led to stereocontrolled alkylborane-, zinc-, and tin-mediated additions by Naito,[2] Bertrand,[3] and our group.[4] A significant early limitation on this chemistry restricted the scope of radicals to simple 2° and 3° alkyls, usually from reagents in large excess, due to unfavorable halogen atom transfer or competitive reduction of the radicals
Stereocontrolled Mn-Mediated Radical Additions to Chiral Hydrazones
Preliminary studies in that venture revealed an incompatibility of the Mn-mediated radical addition with the basic nitrogen of a quinoline aromatic N-heterocycle present in the N-acylhydrazone radical acceptor

Summary

Introduction

Radical additions to imino compounds offer a useful carbon−carbon bond construction approach to chiral amine synthesis.[1] Seminal efforts to generalize this reaction for intermolecular coupling led to stereocontrolled alkylborane-, zinc-, and tin-mediated additions by Naito,[2] Bertrand,[3] and our group.[4] A significant early limitation on this chemistry restricted the scope of radicals to simple 2° and 3° alkyls, usually from reagents in large excess, due to unfavorable halogen atom transfer or competitive reduction of the radicals. The portfolio of radical generation conditions continues to widen[6] and includes a variety of photoredox catalysis methods[7] as well as very recent approaches to Mn-mediated radical chemistry that render the processes catalytic in Mn.[8]

Methods

Results

Conclusion