Application of radical conjugate addition reactions in Total Synthesis

1
Application of radical conjugate addition
reactions in Total Synthesis
2
Radical Chemistry in organic chemistry

• Radical dimerisation Pinacol reaction, Acyloin
  condensation, McMurry reaction
• Radical chain reactions Hydrohalogenation
  (Hydrobromation) of Alkenes-gt anti Markovnikov,
  Halogenation (Chlorination) of Alkanes, radical
  substitution with Bu3SnH,

3
Understanding the reactivity

• Carbon-carbon bond formation using radicals
  radical conjugate addition
• Stability of C-Sn-bond and Reactivity of
  alkylhalide (Br, I)

4
Understanding the reactivity

• Frontier orbital effects
• Reactive radical trap -gt major limitation of
  intermolekular radical carbon-carbon bond
  formation (only double bonds with electron
  withdrawning group will do)

5
Understanding the reactivity

• Low-energy SOMO
• Orbital diagramm will be showed on the board!
• NOT topic today Electrophilic radicals

6
Understanding reactivity

• Comparing radicals with polar reagent
• Radical are soft reagents
• Umpolung

7
Radical formation

• Homolysis of a realtivly weak bond (photolytic or
  thermic conditions)
• Dissoziation Energy R-I lt R-SePh lt R-Br R-SPh
  lt R-Cl
• Formation via a redox process (SET)
• Reduction
• Transition metals as Fe2, Ti3, Cu, Cr2
• Samarium(II)-iodide
• Alkali-metals (i.E. Acyloin Condensation,
  Bouveault-Blanc-reaction, Rühlmann protokoll)

8
Radical formation

• Oxidation
• Kolbe electrolysis

9
Stereoselective radical reaction

• Diastereoselective reactions of acyclic radicals
• Konformational more flexible than ionic compounds
• Many examples of 1,3 allyl strain or Felkin-Anh
  transition state

10
Stereoselective radical reactions

• There are although examples for polar effects and
  chelation

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Radical conjugate additions

• Radicals react as soft Nucleophiles
• Diastereoselectivity is often a result of steric
  hindrance
• Examples in total synthesis are mostly from
  intramolecular conjugate radical addition

12
Radical conjugate additions

• Substrate controlled diastereoselctive reactions
• Auxiliary controlled diastereoselective reactions
• Enantioselective reaction
• Chiral Lewis acids (Zn2/ Mg2/ Sm2/ Cu2 ions
  and chiral ligands)

13
Examples in Total synthesis

• JACS 1994, 116, 6943.
• JACS 1997, 119, 6226.

14
Examples in Total synthesis

• Can. J. Chem. 2004, 82, 314.

15
Examples in Total Synthesis

• Tetrahedron 1997, 53, 7127.

16
Examples in Total Synthesis

• Org. Lett. 2002, 4, 3959.

17
Examples in Total Synthesis

• Tetrahedron Lett. 1996, 37, 4191.
• J. Chem. Soc. Perk I 1998, 863.

18
Conclusion

• Radicals can be used for stereoselective
  reactions, inter- and intramolecular.
• Reaction usually occur under mild conditions,
  thus radical reactions tolerate many functional
  groups.
• Even in hindered positions quarternary carbon
  centers can be formed.
• There are many examples in Total Synthesis
• Today radicals can be formed with tin-free
  reagents, thus reactions can in principal be used
  in pharmaceutical research

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Literature

• Review G.S.C. Srikanth, S. L. Castle,
  Tetrahedron 2005, 61, 10377-10441.
• Book T. Linker, M. Schmittel, Radikale und
  Radikalanionen in der Organischen Synthese,
  Wiley-VCH 1998.
• Lecture Book Clayden, Greeves, Warren and
  Wothers, Organic Chemistry, Oxford Press 2001, p
  1019-1052.
• Cited Literature on the folies.