1. Éric Godin Literature Meeting October 12th 2016

2. 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

3. 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

4. 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,

5. Suzuki-Miyaura Cross-Couplinger

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

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

8. 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.

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

10. 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.

11. 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.

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

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

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

15. Iterative Coupling – Second Order

16. Iterative Coupling – Second Order

17. Iterative Coupling – Second Order

18. Iterative Coupling – Third Order

19. 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

20. 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

21. Iterative Coupling – Allylation

22. 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

23. Conclusion
Is it worth a Nature Chem?