Important therapeutic agents are prepared by chemists through the use of chemical reactions. The available reaction methods represent invaluable tools that allow us to synthesize agents critical to human health care selectively and efficiently. Selectivity - particularly enantioselectivity - is crucial, because various studies underline the need for the preparation of drugs in the non-racemic form. This proposal will outline experiments that will lead to the development of new enantioselective catalytic processes for C-C bond formation through addition of Grignard reagents to alkenes. These studies should result in the emergence of effective modern methods that can be utilized in the preparation of important organic molecules in the optically pure form. Many of the transformations described herein are unique - they do not have an existing catalytic or non-catalytic counterpart. (1) We will develop new catalysts and protocols for more efficient and less costly asymmetric catalytic reactions. The (EBTHI) Zr system has been shown to be an impressive construct capable of effecting highly enantioselective C-C bond forming and kinetic resolution processes. However, it suffers from several drawbacks. We will search for a more efficient and less costly route to non-racemic chiral zirconocenes. (2) We will develop a general asymmetric addition of alkylmagnesium halides to alkenes. We will extend the utility of enantioselective carbomagnesation reaction to reactions where a large variety of alkyl units can be selectively and efficiently added to unactivated C-C double bonds. (3) We will develop the Zr-catalyzed enantioselective carboalumination of unsaturated heterocycles. This reaction technology will lead to an efficient and highly asymmetric method for the synthesis of a range cyclic and bicyclic compounds in the enantiomerically pure form. The utility of this method will be demonstrated through short and enantioselective total syntheses of highly potent antibacterial agents. (4) We will demonstrate that Zr-catalyzed kinetic resolution provides a variety of functionalized carbo-and heterocycles efficiently and with outstanding enantioselectivity. This research will lead to a concise and asymmetric total synthesis of (+)- Pumiliotoxin C and the potent antihypertensive agent (S.R.R.R.)-Nebivolol.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047480-08
Application #
2910102
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1992-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Lee, Jaehee; Radomkit, Suttipol; Torker, Sebastian et al. (2018) Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre. Nat Chem 10:99-108
Huang, Youming; Del Pozo, Juan; Torker, Sebastian et al. (2018) Enantioselective Synthesis of Trisubstituted Allenyl-B(pin) Compounds by Phosphine-Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates. J Am Chem Soc 140:2643-2655
Radomkit, Suttipol; Liu, Zhenxing; Closs, Anna et al. (2017) Practical, efficient, and broadly applicable synthesis of readily differentiable vicinal diboronate compounds by catalytic three-component reactions. Tetrahedron 73:5011-5017
Lee, Jaehee; Torker, Sebastian; Hoveyda, Amir H (2017) Versatile Homoallylic Boronates by Chemo-, SN 2'-, Diastereo- and Enantioselective Catalytic Sequence of Cu-H Addition to Vinyl-B(pin)/Allylic Substitution. Angew Chem Int Ed Engl 56:821-826
Li, Xiben; Meng, Fanke; Torker, Sebastian et al. (2016) Catalytic Enantioselective Conjugate Additions of (pin)B-Substituted Allylcopper Compounds Generated in situ from Butadiene or Isoprene. Angew Chem Int Ed Engl 55:9997-10002
Shi, Ying; Hoveyda, Amir H (2016) Catalytic SN2'- and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis. Angew Chem Int Ed Engl 55:3455-8
Meng, Fanke; Li, Xiben; Torker, Sebastian et al. (2016) Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups. Nature 537:387-393
Shi, Ying; Jung, Byunghyuck; Torker, Sebastian et al. (2015) N-Heterocyclic Carbene-Copper-Catalyzed Group-, Site-, and Enantioselective Allylic Substitution with a Readily Accessible Propargyl(pinacolato)boron Reagent: Utility in Stereoselective Synthesis and Mechanistic Attributes. J Am Chem Soc 137:8948-64
McGrath, Kevin P; Hoveyda, Amir H (2014) A multicomponent Ni-, Zr-, and Cu-catalyzed strategy for enantioselective synthesis of alkenyl-substituted quaternary carbons. Angew Chem Int Ed Engl 53:1910-4
Jang, Hwanjong; Jung, Byunghyuck; Hoveyda, Amir H (2014) Catalytic enantioselective protoboration of disubstituted allenes. Access to alkenylboron compounds in high enantiomeric purity. Org Lett 16:4658-61

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