Amines and alcohols are functional groups that are found in a great number of biologically active molecules;in many instances, these structural units contain N- or O- substituted tertiary or quaternary carbon stereogenic centers. Design and development of transformations that are promoted by a readily accessible and reliable set of catalysts and which afford amines and alcohols in high enantiomeric purity is thus a compelling objective of research in modern chemistry. Other important attributes of such reactions is that the chiral catalysts do not require precious and/or expensive elements, reagents are robust, readily accessible and do not contain toxic metals (such as Cr or Sn). It is equally important that reactions proceed at ambient temperature and are complete within a few hours (ideally, in less than eight hours). Research in this program is focused on the design, synthesis and development of a range of easily accessible chiral catalysts that allow for the efficient and enantioselective addition of a variety of readily available and robust unsaturated organoboron reagents to aldimines, aldehydes, ketones and ketoimines. One class of catalysts require the inexpensive and abundant salts of copper and chiral ligands that can be prepared in no more than five steps. Another catalyst class, more recently discovered in our laboratories, is boron-based, is generated in situ and the requisite chiral ligand can be prepared in four simple steps in high yield from cheap and commercially available materials;it can be purified without silica gel chromatography or distillation. We plan to utilize the above catalysts, which were designed in-house, in the development of highly efficient, diastereo- and enantioselective additions of allenyl, homoallenyl, dienyl, and halo- or alkoxy-substituted allyl(pinacolato)boron reagents to an assortment of readily accessible aldimines, ketones, aldehydes and ketoimines. The resulting products can be functionalized in a wide range of manners, thus allowing access to a great number of valuable amines and alcohols in high yield and enantiomeric purity. In nearly all cases, alternative catalytic methods for enantioselective synthesis of the resulting products are unavailable;in many cases, there are also no stoichiometric approaches known either. Selected conceptually innovative aspects of our investigations are: use of a single proton and H-bond to achieve high activity and selectivity;design of catalysts that allow high efficiency and stereoselectivity through a single point of contact, use of F atoms as H-bond acceptors to achieve high efficiency and enantioselectivity, and the use of unprotected ketoimines in various catalytic transformations. The utility of catalysts and methods developed will be demonstrated by application to the concise synthesis of a number of biologically active natural products, which include anti-tumor agent cyclooroidin, anti-inflammatory agent bisavenanthramide B-3, anti-malarial bielschowskysin, anti-inflammatory setileuton, and members of a recently discovered family of aspartyl protease inhibitors.

Public Health Relevance

Our ability to prepare various medicinally active agents in a cost-effective, reliable, efficient and selective manner is most critical to advances in human health care. The proposed research will afford unique, inexpensive and highly potent catalysts that promote efficient formation of some of the most commonly occurring units found in a large number of biologically significant molecules, but which cannot be accessed easily by other methods.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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Boston College
Schools of Arts and Sciences
Chestnut Hill
United States
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Mszar, Nicholas W; Haeffner, Fredrik; Hoveyda, Amir H (2014) NHC-Cu-catalyzed addition of propargylboron reagents to phosphinoylimines. Enantioselective synthesis of trimethylsilyl-substituted homoallenylamides and application to the synthesis of S-(-)-cyclooroidin. J Am Chem Soc 136:3362-5
Meng, Fanke; Haeffner, Fredrik; Hoveyda, Amir H (2014) Diastereo- and enantioselective reactions of bis(pinacolato)diboron, 1,3-enynes, and aldehydes catalyzed by an easily accessible bisphosphine-Cu complex. J Am Chem Soc 136:11304-7
Radomkit, Suttipol; Hoveyda, Amir H (2014) Enantioselective synthesis of boron-substituted quaternary carbon stereogenic centers through NHC-catalyzed conjugate additions of (pinacolato)boron units to enones. Angew Chem Int Ed Engl 53:3387-91
Meng, Fanke; McGrath, Kevin P; Hoveyda, Amir H (2014) Multifunctional organoboron compounds for scalable natural product synthesis. Nature 513:367-74
Wu, Hao; Haeffner, Fredrik; Hoveyda, Amir H (2014) An efficient, practical, and enantioselective method for synthesis of homoallenylamides catalyzed by an aminoalcohol-derived, boron-based catalyst. J Am Chem Soc 136:3780-3
Manville, Nathan; Alite, Hekla; Haeffner, Fredrik et al. (2013) Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. Nat Chem 5:768-74
Meng, Fanke; Jang, Hwanjong; Jung, Byunghyuck et al. (2013) Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their in situ site-, diastereo-, and enantioselective additions to aldehydes and ketones. Angew Chem Int Ed Engl 52:5046-51
Silverio, Daniel L; Torker, Sebastian; Pilyugina, Tatiana et al. (2013) Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols. Nature 494:216-21
Rodrigo, Jason M; Zhao, Yu; Hoveyda, Amir H et al. (2011) Regiodivergent reactions through catalytic enantioselective silylation of chiral diols. Synthesis of sapinofuranone A. Org Lett 13:3778-81
O'Brien, Jeannette M; Hoveyda, Amir H (2011) Metal-free catalytic C-Si bond formation in an aqueous medium. Enantioselective NHC-catalyzed silyl conjugate additions to cyclic and acyclic ?,?-unsaturated carbonyls. J Am Chem Soc 133:7712-5

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