Efficient and stereoselective synthesis of chiral organic molecules is critical to the availability of therapeutic agents. Development of catalysts that promote important bond forming reactions, and which are readily accessible, inexpensive, and air stable is a compelling goal of modern chemistry. In this context, chiral catalysts, required for enantioselective formation of small organic molecules, are of particularly high value. Among the most ubiquitous building blocks needed for preparation of a large assortment of biologically active and medicinally relevant molecules are enantiomerically pure amines and alcohols. Although enantioselective syntheses of these two important classes of molecules have benefited from recent advances, a significant number of shortcomings remain unresolved. We will address such issues through innovations in catalyst design and by advances in chemical reactivity. In the first segment of our program, we will design and develop amino acid-based catalysts for enantioselective silyl protection of alcohols. This unique class of catalysts delivers a range of otherwise difficult-to-access enantiomerically enriched alcohols;our goal is to discover catalysts that promote alcohol silylations with exceptional efficiency (i.e., <2 mol % catalyst). The availability of highly efficient catalysts would render this important class of transformations truly practical, as this class of reactions is performed under air, with reagent grade (or no) solvents. Moreover, we will use the same class of catalysts for enantioselective activation of alcohols through the corresponding alcohol tosylations. The resulting enantiomerically enriched tosylates can be readily converted to other useful organic molecules. In the second part of our program, we will develop new catalysts for another important and underdeveloped class of processes: enantioselective allylations of aldimines. The enantiomerically enriched allylic amines obtained through serve as precursors that various other useful nitrogen-containing molecules. The third objective of our program involves innovations in catalytic C-B bond formation. Carbon-boron bonds are among the most useful entities in organic chemistry, and a number of metal-catalyzed method for their enantioselective formation of have been developed. We have discovered the first set of metal-free set protocols for formation of C-B bonds;these reactions proceed by an entirely different mechanism versus the metal-catalyzed variants. We will develop methods for metal-free enantioselective C-B bond formation where readily available small organic molecule serve as catalysts. The entities used as catalysts will also be utilized as ligands in the corresponding Cu-catalyzed reactions.

Public Health Relevance

Efficient, practical and stereoselective preparation of chiral organic molecules is critical to the availability of therapeutic agents;development of catalytic enantioselective methods is a compelling objective in modern chemistry and medicine. Among the most useful intermediates in organic synthesis are enantiomerically pure amines and alcohols. The investigations outlined in this proposal aim to design and introduce new catalysts and protocols for efficient, practical and enantioselective synthesis of a wide range of amines and alcohols, which are difficult to prepare by any other method.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057212-15
Application #
8324690
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1998-05-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
15
Fiscal Year
2012
Total Cost
$325,364
Indirect Cost
$117,464
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
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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