Éric Godin Literature Meeting October 12th 2016

Steven Victor Ley Academic Background: B. Sc. Loughborough University (Diploma in Industrial Studies) Ph. D. (1972) Loughborough University (Pr Harry Heaney) PDF Ohio State University (Pr Leo Paquette) PDF Imperial College London (Pr Derek Barton) Lecturer (1975) Imperial College London Professor (1983) Imperial College London Head of Dept. (1989) Imperial College London BP Pr of Org. Chem. (1992) University of Cambridge er

Steven Victor Ley Research Interests: Publications: Total Synthesis (­>140 complex molecules) Catalysis/Methodology (Ley-Griffith Oxidation (1994)) Flow Chemistry (Conception & Application) Publications: Since 2013, published 82 papers in 32 different journals (837 in total) 1 Nat. Chem. 6 ACIE 3 Chem. Sci. 7 Org. Lett. 6 Chem. Eur. J. er

Cross-Coupling Reactions Homo Cross Cadiot-Chodkiewicz 1957 Kumada + Heck 1972 Sonogashira 1975 Negishi 1977 Suzuki 1979 Buchwald-Hartwig 1994 Wurtz 1855 Gomberg-Bachmann 1924 Nobel Prize (2010): "for palladium-catalyzed cross couplings in organic synthesis" Richard Heck Akira Suzuki Ei-ichi Negishi Homo : Glaser, Ullmann Cross: Castro-Stephens, Gilman, Stille, Hiyama,

Suzuki-Miyaura Cross-Coupling er

Iterative Suzuki-Miyaura Cross-Coupling using MIDA boronates Gillis, E. P.; Burke, M. B. J. Am. Chem. Soc. 2007, 129, 6716.

Iterative Suzuki-Miyaura Cross-Coupling using MIDA boronates Gillis, E. P.; Burke, M. B. J. Am. Chem. Soc. 2007, 129, 6716.

Metal-Free Suzuki-like Cross-Coupling Functional-Group Tolerance: Aldehydes Ketones Esters Nitriles Halogens Unprotected Amines Heterocycles er Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat. Chem. 2009, 1, 494.

Metal-Free Suzuki-like Cross-Coupling er Bamford-Stevens Reaction Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat. Chem. 2009, 1, 494.

Diazo Generation via MnO2 Oxidation of Hydrazone Tran, D. N.; Battilocchio, C.; Lou, S.-B.; Hawkinsb, J. M.; Ley, S. V. Chem. Sci. 2015, 6, 1120.

This Work Remaining Challenges/Disadvantages of Previous Methods: Use of expensive transition-metal catalysts/ligands (Suzuki Coupling; Burke) Poor atom economy (Burke (MIDA) & Barluenga (Tosyl)) Scope extension (Allylic & Benzylic boronic acid partners) Strategies: Controlled in situ generation of highly reactive/unstable intermediates Use of continuous flow apparatus for safer generation of diazo compounds Milder conditions (reaction occurs at room temperature) er Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Nat. Chem. 2016, 8, 360.

Iterative Coupling – First Order 0.41 mL min-1 FlowIR : 2050-2100 N≡N Storage tank (-20°C)

Iterative Coupling – First Order 0.41 mL min-1 EDG er EWG

Iterative Coupling – First Order 0.41 mL min-1 Heterocycles er Allylic

Iterative Coupling – Second Order

Iterative Coupling – Second Order

Iterative Coupling – Second Order

Iterative Coupling – Third Order

Iterative Coupling – Allylation Synthesis of (±)-Bakuchiol Precursor Shortest Previous Total Synthesis: 3 Steps from Geraniol (25 % overall yield) Chin. J. Chem. 2014, 32, 715. Geraniol –[Pd]+B2Pin2-> boronic acid ---pOTBShomobenzaldehyde- alcool ----MsCl-----KOtBU/DMSO--- bakuchiol 60 % yield

Burgess Reagent Synthesis of Burgess Reagent Dehydratation Mechanism The reagent is prepared from chlorosulfonylisocyanate by reaction with subsequent treatment with methanol and triethylamine in benzene alcohol dehydration takes place with syn elimination through an intramolecular elimination reaction

Iterative Coupling – Allylation

Conclusion New approach for iterative C-C bond formation Flow chemistry allowed safe use of reactive/unstable intermediates Diversity-oriented synthesis (Protodeboronation; Allylation or Boronic ester) ‘One-pot’ synthesis of complex molecules from readily accessible starting material

Conclusion Is it worth a Nature Chem?