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 2016-02-10

Varinder K. Aggarwal Education: 1980-1983 BA, University of Cambridge 1983-1986 PhD in Organic Chemistry with Dr. Stuart Warren, University of Cambridge (Stereocontrolled Synthesis with Phenylthio Migration) 1986-1988 Postdoctoral position with Prof. Gilbert Stork, Columbia University. Academic Positions: 1988-1991 Lecturer in Chemistry, Bath University 1991-1995 Lecturer in Chemistry, Sheffield University 1995-1997 Reader in Chemistry, Sheffield University 1997-2000 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

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

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.

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

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

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

Commonly Used Fluorinating Agents  

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.

Synthesis of Fluorine-Bearing Stereocenters Distal to Functional Groups  

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

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, 16794.

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, 16794.

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

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

Scope Of the Reaction  

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

Proposed Mechanism  

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

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