Tertiary stereogenic centers are a common motif in a variety of molecules with biological activities against targets associated with human disease. Cross coupling reactions of secondary alkyl electrophiles hold exciting promise for the synthesis of these scaffolds, but the couplings of these electrophiles to deliver enantioenriched products are underdeveloped. Those that have been reported often rely on reactive coupling partners and/or halide electrophiles. To solve these limitations, this research program will develop cross coupling reactions of amine- and alcohol-derived electrophiles with air-stable, functional group tolerant coupling partners. Amine and alcohol derivatives are ideal electrophiles due to their wide availability in both racemic and enantioenriched form. In the first aim, enantiospecific, nickel-catalyzed cross couplings of alkyl ammonium salts are proposed. Despite the fact that amines can be conveniently prepared in near perfect enantipurity, amine-derived electrophiles remain virtually unexplored in cross coupling chemistry. Based on preliminary results in the cross couplings of benzylic ammonium triflates, enantiospecific cross couplings of a range of alkyl ammonium salts with various coupling partners are proposed.
The second aim outlines the development of cross coupling reactions of alcohol-derived substrates to deliver enantioenriched products. Based on preliminary results with benzylic pivalate substrates, enantiospecific, nickel-catalyzed cross couplings of other enantioenriched alkyl pivalates will be developed. Enantioselective, nickel-catalyzed cross couplings of racemic alcohol-derived substrates will also be established. To date, couplings of alcohol derivatives have been largely limited to enantiospecific transformations. This research will circumvent the requirement for enantioenriched alcohol starting materials and demonstrate the potential of enantioselective cross couplings of readily available, racemic alcohol derivatives to deliver highly enantioenriched products. By exploiting the broad availability of amines and alcohols as starting materials and prioritizing the use of mild, air-stable coupling partners, this research will vastly improve the installation of tertiary stereocenters within an array of potentially bioactive target molecules. By expediting the synthesis of these targets in highly enantioenriched form, these methods will positively impact the discovery and development of new molecules with the potential to increase our understanding of and ability to treat human disease.
The proposed research is relevant to public health, because it will enable efficient synthesis of a range of highly enantioenriched molecules with known or promising biologically activity from widely available and inexpensive amine and alcohol derivatives. The ultimate goal of this research is to positively and significantly impact the discovery and development of new molecules with the potential to increase our understanding of and ability to treat human disease.
|Guan, Weiye; Liao, Jennie; Watson, Mary P (2018) Vinylation of Benzylic Amines via C-N Bond Functionalization of Benzylic Pyridinium Salts. Synthesis (Stuttg) 50:3231-3237|
|Pound, Sarah M; Watson, Mary P (2018) Asymmetric synthesis via stereospecific C-N and C-O bond activation of alkyl amine and alcohol derivatives. Chem Commun (Camb) 54:12286-12301|
|Liao, Jennie; Guan, Weiye; Boscoe, Brian P et al. (2018) Transforming Benzylic Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C-N Bond Activation. Org Lett 20:3030-3033|
|Basch, Corey H; Liao, Jennie; Xu, Jianyu et al. (2017) Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation. J Am Chem Soc 139:5313-5316|
|Cobb, Kelsey M; Rabb-Lynch, Javon M; Hoerrner, Megan E et al. (2017) Stereospecific, Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Allylic Pivalates To Deliver Quaternary Stereocenters. Org Lett 19:4355-4358|
|Zhou, Qi; Cobb, Kelsey M; Tan, Tianyu et al. (2016) Stereospecific Cross Couplings To Set Benzylic, All-Carbon Quaternary Stereocenters in High Enantiopurity. J Am Chem Soc 138:12057-60|
|Zhou, Qi; Srinivas, Harathi D; Zhang, Songnan et al. (2016) Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates. J Am Chem Soc 138:11989-11995|
|Basch, Corey H; Cobb, Kelsey M; Watson, Mary P (2016) Nickel-Catalyzed Borylation of Benzylic Ammonium Salts: Stereospecific Synthesis of Enantioenriched Benzylic Boronates. Org Lett 18:136-9|