Formal Ring-Opening/Cross-Coupling Reactions of 2-Pyrones: Iron-Catalysed Entry into Stereodefined Dienyl Carboxylates Dr. Chan-Liang Sun Pr. Alois FürstnerIron Litterature Meeting Maxime Dauphinais November 13th, 2013

Pr. Alois Fürstner Managing Director of the Max-Planck-Institut für Kohlenforschung Director at the MPIfK and professor at the Technical University of Dortmund 1993 – 1998Group leader MPIfK and lecturer at the University of Dortmund 1992Habilitation in organic chemistry at the Technical University of Graz, Austria 1990 – 1991Post-doctoral fellow at the University of Geneva, Switzerland (Oppolzer) 1987 – 1990PhD at the Technical University of Graz, Austria (Weidmann) 1962Birth in Austria

Pr. Alois Fürstner 24 major awards Arthur C. Cope Scholar Award Mukaiyama Award Prelog Medal Member of boards of 15 journals Angewandte Chemie Organic Syntheses Journal of Organic Chemistry Author of over 300 publications

« Organometallic Chemistry » Alkyne Metathesis Alkene Metathesis π-Acid Catalysis Fürstner Group commercial Novel Concepts for Catalysis Total Synthesis Iron catalysis

2-Pyrones Reactivity with Nucleophiles 1,2 – addition : Hard organometallics Dreux, Tet. Lett. 1984, Christl, Eur. JOC 2006, ,2 – addition : L.A. Hydrides

2-Pyrones Reactivity with Nucleophiles 1,4 – addition : Organocuprates Feringa, Org. Lett. 2013, 286.

2-Pyrones Reactivity with Nucleophiles 1,6 – addition : Cyanide and other heteroatom nucleophiles 1,6 – addition : Grignards with Fe cat 1,6 – addition : Non-L.A. Hydrides Vogel, Chemistry & Industry 1962, Vogel, Chemistry & Industry 1962, 268.

Initial Foray in Fe-Catalysed Couplings Kharasch, JACS 1942, “Although (Table I) no one of the metallic halides (2 to 5 mole per cent.) has any effect on the ratio of the 1,2 and 1,4 addition of methylmagnesium bromide to chalcone, yet they profoundly influence the nature of the products formed in the reaction.”

Urabe’s Work on Acyclic Substrates Urabe, Tet. Lett. 2004, 603.

Previous Fe Work with 2-Pyrones Initial « Discovery » Maulide, JOC 2010, 7962.

Optimisation Exclusive cis isomer requires complete absence of THF

Accessing the Trans Isomer and Scope Most cis isomers > 20 : 1 (-30 o C) Trans isomers 8-10 :1 (r.t.) Compatible with primary alkyl iodides esters α-cyclopropanes Complete conversion in min Methyl only?

Limitations No example of secondary R-MgX Only E isomer accessible (>10:1) Works best with 3 equiv. of R-MgX For cis isomer, no THF solution

Mechanism – Acyclic System Urabe, Tet. Lett. 2004, 603. expected 1,6-addition product with trans alkene no reaction with cis alkene 2-pyrone forces cis alkene

Mechanism – pyrones Fürstner, ACIE 2006, 440. DePuy, JACS 1977, Standard redox cycle unlikely Substrates that could not be engaged

Sequential Couplings : Back to the Beginning Synthesis of Fragment of Pateamine A

Total Synthesis of Granulatamide B Cytotoxic tryptamine derivative from Eunicella granulate 4-step synthesis from cheap commercial materials 57% overall yield

Conclusion 1,6-addition of Grignards to 2-pyrones complements 1,2 and 1,4-addition precedents Cis and trans isomers can be obtained almost exclusively by tweaking conditions Possible to alkylate sequentially two different positions of 2-pyrone with Grignard reagents One partial synthesis and one total synthesis accomplished using this methodology

Questions?