The discovery and development of new chemical reactions is a major focus of research activity in organic chemistry. The classes of reactions which have found the broadest applicability in organic chemistry are those that address the issues of regio-, stereo- and enantiocontrol. Reactions which form multiple bonds, rings, and stereocenters are particularly important tools for the efficient assembly of complex molecular structures. The objective of our research program is to develop new methodologies in organic synthesis to construct complex organic molecules with high regio-, stereo- and enantiocontrol. Investigation on novel synthetic methodologies for the construction of different ring systems, including: nitrogen-containing heterocyclic compounds, spirocyclic compounds, attached-ring compounds and polycyclic compounds, is of particular interest. These ring systems are present in many biologically important natural products, which have found use in anti-HIV, anticancer, antiviral and antiretroviral researches.

The Tam Research Group is interested in several areas of Synthetic Organic Chemistry, including:

  • The Use of Transition Metal Catalysts in Organic Synthesis
  • Novel Cycloaddition Reactions
  • The Chemistry of Bicyclic Alkenes
  • Ring-forming and ring-opening reactions
  • Synthesis of Novel Chiral Ligands & their Applications in Asymmetric Synthesis
  • Studies on Remote Substituent Effects and Long-Range Stereoelectronic Effects
  • Synthesis of Novel Organic Polymers
  • Natural Product Synthesis

Intramolecular Cycloadditions of Substituted Norbornadienes

Since 1998, we have developed a program on the study of various types of intramolecular cycloadditions of substituted norbornadienes. Our long-term goal on this project is to develop an efficient route for the construction of anguarly fused tricyclic and spirocyclic complex natural products with biological activity. We have reported the first examples of intramolecular cycloadditions of norbornadiene-tethered nitrile oxides (Org. Lett. 1999, 1, 791–794; J. Org. Chem. 2001, 66, 276–286), and nitrones (Chem. Commun. 2000, 863–864; J. Org. Chem. 2001, 66, 5113–5123). These cycloadditions were found to be highly regio- and stereoselective and single regio- and stereoisomers were produced in most cases. We have studied the cleavage reactions of these cycloadducts (Org. Lett. 2002, 4, 4101–4104) for the synthesis of spirocyclic frameworks which are present in many biologically active natural products.

Intramolecular Cycloadditions of Substituted Norbornadienes image

Synthesis of Substituted Norbornadienes

Substituted norbornadienes are important compounds, which have found a place as key intermediates in the synthesis of many natural products, such as prostaglandins PGH2 and PGG2, cis-Trikentrin B, and b-santalol. Photochemical valence isomerization between norbornadiene and quadricyclane is of interest as a solar energy conversion and storage system. The traditional synthesis of the 2,3-disubstituted norbornadienes relies mainly on the Diels-Alder reaction between cyclopentadiene and the corresponding alkyne. Since unactivated alkynes are poor dienophiles in Diels-Alder cycloadditions, the variety of 2,3-disubstituted norbornadienes that could be synthesized using the Diels-Alder method is rather limited. We have developed a new method via a double lithium-halide exchange of 2,3-dibromonorbornadiene for the synthesis of a variety of 2,3-disubstituted norbornadienes (Can. J. Chem. 2000, 78, 527). We have also studied the Pd-catalyzed Sonogashira couplings and Suzuki couplings of 2,3-dibromonorbornadienes for the synthesis of symmetrical and unsymmetric norbornadiene-2,3-diynes (Synthesis 2002,1675) and 2,3-diarylsubstituted norbornadienes (Eur. J. Org. Chem. 2005, 1044). These studies significantly increased the variety of 2,3-disubstituted norbornadienes beyond those that can be prepared by the Diels-Alder methodology.

Transition Metal-Catalyzed [2+2] Cycloadditions

Studies on transition metal-catalyzed [2+2] cycloadditions between alkenes and alkynes are one of the major foci of our research program. We have recently studied various aspects of Ru-catalyzed [2+2] cycloadditions, including: asymmetric cycloadditions (Angew. Chem. Int. Ed. 2004, 43, 610), reactivity studies (J. Org. Chem. 2004, 69, 8467; J. Org. Chem. 2006, 71, 5830), remote substituent effects (Org. Lett. 2000, 2, 3031), studies of alkynyl halides (Org. Lett. 2004, 6, 4543) and ynamides (Org. Lett. 2005, 7, 3681) as the alkyne component in the cycloaddition, theoretical studies (J. Org. Chem. 2006, 71, 3793; Tetrahedron 2007, 63, 7659) and others. In 2004, we reported the first examples of asymmetric induction studies in ruthenium-catalyzed [2+2] cycloadditions between alkenes and alkynes (Angew. Chem. Int. Ed. 2004, 43, 610). The cycloadditions were found to be highly stereo- and regioselective, and excellent levels of asymmetric induction (up to 99% ee) in the cycloadditions were achieved. This chemistry is currently being expanded and applied to the asymmetric synthesis of 5-membered and 7-membered rings.

Intramolecular Cycloadditions of Substituted Norbornadienes image

Novel Metal-Catalyzed Organic Reactions

The design and development of new transition metal-catalyzed reactions that are normally forbidden or difficult to achieve under ordinary conditions are crucial in organic synthesis. During the last two years, we have initiated several new programs on novel transition metal-catalyzed reactions, including: Ru-catalyzed Isomerization of Oxa/azabicyclic Alkenes for the Synthesis of 1,2-Naphthalene Oxides and Imines (J. Am. Chem. Soc. 2006, 128, 3514), Ru-catalyzed cyclopropanation reactions (Organometallics 2006, 25, 843), Rh-catalyzed Diels-Alder reactions of Alkynyl Halides (Org. Lett. 2005, 7, 5853), Palladium-catalyzed Suzuki Couplings (Eur. J. Org. Chem. 2005, 1044), Fe-catalyzed couplings, Ring-Opening Metathesis-Cross Metathesis reactions, and others.

Intramolecular Cycloadditions of Substituted Norbornadienes image