1. Guillaume Benoit – Charette Group
Synthesis of Enantioenriched Alkylfluorides by the Fluorination of Boronate Complexes
Sandford, C.; Rasappan, R.; Aggarwal, V. K. J. Am. Chem. Soc. 2015, 137, 10100
Guillaume Benoit – Charette Group
Literature Meeting

2. Varinder K. Aggarwal Education: 1980-1983 BA, University of Cambridge
PhD in Organic Chemistry with Dr. Stuart Warren, University of Cambridge (Stereocontrolled Synthesis with Phenylthio Migration)
Postdoctoral position with Prof. Gilbert Stork, Columbia University.
Academic Positions:
Lecturer in Chemistry, Bath University
Lecturer in Chemistry, Sheffield University
Reader in Chemistry, Sheffield University
Professor in Chemistry, Sheffield University
Professor in Synthetic Chemistry, Bristol University (current position)
Awards:
1997 Royal Society of Chemistry (RSC) Hickinbottom Fellowship; 1999 RSC Corday Morgan Prize and Medal; Novartis Lectureship; Liebig Lectureship, Gesellschaft Deutscher Chemiker (GDCh; German Chemical Society); 2007 RSC/GDCh Alexander Todd/Hans Krebs Lectureship; RSC Tilden Lectureship; 2009 RSC Stereochemistry Award; SCI Award for Process Research (GSK-AZ-Pfizer); 2012 elected Fellow of the Royal Society; 2013 RSC Perkin Award

3. Aggarwal’s Group : Research Interests
Epoxidation and aziridination using new chiral sulfur ylides
Annulation reactions
Transition metal catalyzed processes
Total synthesis of natural products

4. Aggarwal’s Group : Research Interests
Synthesis of enantioenriched secondary boronate and applications in synthesis
D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2007, 46, 7491.

5. Aggarwal’s Group : Research Interests
Synthesis and functionalization of secondary and tertiary boronates
Arylation
Nat. Chem. 2014, 6, 584
Protodeboronation
JACS 2010, 132, 17096
Quaternary center formation
ACIE 2011, 50, 3760
Amination
ACIE 2011, 50, 1080
D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174

6. Aggarwal’s Group : Research Interests
Iterative homologations: formation of contiguous stereocenters
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183.
D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174

7. Why Organofluorine Are Important ?
In Medicinal Chemistry, 20-25% of pharmaceuticals on the market contain fluorine :
-increasing lipophilicity and bioavailability, hence binding efficacy
18F are also used as markers in PET scans
Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.Chem. Rev. 2014, 114, 2432

8. Commonly Used Fluorinating Agents

9. Electrophilic Fluorination of Activated Positions : State of the Art
For Reviews:
Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708.
Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826.

10. Synthesis of Fluorine-Bearing Stereocenters Distal to Functional Groups

11. The Paper Main Goal: Enantioenriched Boronate as starting material
Enantioenriched Boronate as starting material
Activation of the boronate as a boron ate complex via addition of an Ar-Li
Enantiospecific fluorination in presence of a F+ source

12. Enantiospecificity (es) : ee product / ee SM
Previous Work
Boronate activation via an ate complex  
Enantiospecificity (es) : ee product / ee SM
Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc. 2011, 133,

13. Boron Ate-Complexes : Previous Work
Proposed mechanism to explain the loss of enantiospecificity 
Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc. 2011, 133,

14. The Paper Same idea but utilisation of a « F+ » as electrophile
Enantioenriched Boronate as starting material
Activation of the boronate as a boron ate complex via addition of an Ar-Li
Enantiospecific fluorination in presence of a F+ source

15. Optimization of the Reaction
Entry
Ar-Li
Selectfluor
Additive
Yield (%)
es (%) 1
S. I
None 78 37 2 61 47 3 59 4
Styrene 81 89 5
4-MeO-styrene
>99 74 6
4-CF3-styrene 87 7
4-tBu-catechol 67 24 8
1-octene 9
Toluene 72 46 10
n-octane 33 11 12
S. II 94 13 83
100 14 80

16. Scope Of the Reaction

17. Mechanism Investigations : Radical Clock Experiment
Entry
T °C / time
Additive
Yield (%)
Ratio A:B
es (%) 1
25 / 1h
None 62
95:5 52 2
Styrene 69
>99:1 56 3
-30 / 16h
97:3 4 74 64

18. Proposed Mechanism

19. Proof of an Amine Radical Cation Formation
Amine radical Cation is capable of abstracting an H from adamantane and this new radical can react with Selectfluor.
Addition of styrene inhibits the radical propagation cycle

20. Summary
First enantiospecific method to convert chiral secondary boronic esters into alkylfluorides.
SE2 inv. mechanism
Addition of styrene as radical trap can prevent the radical pathway
Wide substrates scope, tolerant to other chemical functions but not specific for tertiary boronate