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James Leighton

MC 3117

work:+1 212-854-4262

leighton@chem.columbia.edu

Leighton Research Group
Selected Publications

Research Summary

 

Our research interests lie in the development of diastereoselective and enantioselective catalytic reactions and the total synthesis of biologically and structurally interesting natural products. Often, these programs are interrelated as reaction methodology developed in the group is brought to bear on target-oriented synthetic problems.

In one active area of investigation, we are developing methods for the efficient synthesis of macrolide antibiotics. This is a large class of medicinally relevant natural products that often contain long polyol segments. We are challenging the supremacy of the aldol reaction in this context and finding that transition metal catalyzed alkene carbonylation reactions offer a unique approach with some advantages. In this approach, the protecting groups are installed as an integral part of the bond-forming and stereochemistry-determining events, and, in stark contrast to aldol chemistry, the products are aldehydes. In this fashion, separate protection and oxidation state adjustment reactions have been obviated, leading to previously unseen levels of efficiency in some cases. In addition, the direct production of aldehydes has led to the discovery of tandem reactions that can establish up to four new stereocenters in a single process. We are continuing to investigate the full scope of these reactions, as well as to pursue new directions that are suggested along the way.

In work related to this program, we are applying the methods we are developing to the efficient synthesis of selected natural products. Target selection is driven by several factors, including biological activity, scarcity, and structural and stereochemical complexity. Recent successes in this regard include the formal synthesis of mycoticin A and the first synthesis of the marine macrolide leucascandrolide A. As the methodology continues to develop, so too will the choice of targets.

In another area, we are actively engaged in the target-oriented synthesis of architecturally complex polycyclic natural products such as CP-263,114 and Phomactin A. We are principally interested in the development of efficient strategies for the synthesis of challenging ring systems. In the process, new reactions are often discovered out of necessity, and, where appropriate, may develop into methodological studies in their own right.

We have also recently initiated a program devoted to the delineation of new principles for the design of asymmetric catalytic reactions. We are investigating chiral Lewis acid catalysts with a second binding element, as well as new methods for the control of regio- and enantio-selectivity in catalytic alkene carbonylation reactions.


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Publications

"Toward More "Ideal" Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester" Harrison, T. J.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 7308-7311.

"A More Comprehensive and Highly Practical Solution to Enantioselective Aldehyde Crotylation" Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517-6520.  

 

"Highly Enantioselective Mannich Reactions with α-Aryl Silyl Ketene Acetals and Imines" Notte, G. T.; Baxter Vu, J. M.; Leighton, J. L. Org. Lett 2011, 13, 816-818.

 

"Enantioselective (Formal) Aza-Diels−Alder Reactions with Non-Danishefsky-Type Dienes" Tambar, U. K.; Lee, S. K.; Leighton, J. L. J. Am. Chem. Soc. 2010, 132, 10248–10250.

 

"Highly enantioselective formal aza-Diels–Alder reactions with acylhydrazones and Danishefsky's diene promoted by a silicon Lewis acid" Lee, S. K.; Tambar, U. K.; Perl, N. R.; Leighton, J. L. Tetrahedron 2010, 66, 4769-4774.

 

"Asymmetric Allylation, Crotylation, and Cinnamylation of N-Heteroaryl Hydrazones" Feske, M. I.; Buitrago Santanilla, A.; Leighton, J. L. Org. Lett. 2010, 12, 688-6919.

 

"Highly Enantioselective Pictet-Spengler Reactions with α-Ketoamide-Derived Ketimines: Access to an Unusual Class of Quaternary α-Amino Amides"  Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem. Int. Ed., Accepted (2009)

 

"Tandem Silylformylation-Crotylsilylation/Tamao Oxidation of Internal Alkynes: A Remarkable Example of Generating Complexity from Simplicity"  Spletstoser, J. T.; Zacuto, M. J.; Leighton, J. L. Org. Lett. 10, 5593–5596 (2008)

 

"An Efficient Asymmetric Synthesis of Manzacidin C"  Tran, K.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 10, 3165-3167 (2008)

 

"A New Silicon Lewis Acid for Highly Enantioselective Mannich Reactions of Aliphatic Ketone-Derived Hydrazones" Notte, G. T.; Leighton, J. L. J. Am. Chem. Soc 130, 6676-6677 (2008)

 

"Allylsilane Vinylarene Cross-Metathesis Enables a Powerful New Approach to Enantioselective Imine Allylation"  Huber, J. D.; Perl, N. R.; Leighton, J. L. Angew. Chem. Int. Ed. 47, Early View (2008)

 

"Highly Enantioselective Imine Cinnamylation with a Remarkable Diastereochemical Switch" Huber, J. D.; Leighton, J. L. J. Am. Chem. Soc. 129(47), 14552-14553 (2007)

 

"Enantioselective Imidazole-Directed Allylation of Aldimines and Ketimines"  Perl N. R.; Leighton, J. L. Org. Lett. 9, 3699-3701 (2007)

 

"A Modified Approach to the Phomoidrides: Synthesis of a Late-Stage Intermediate Containing a Key Carbon Quaternary Center" Castagner, B.; Leighton, J. L. Tetrahedron  63, 5895-5902 (2007)

 

"Phenol-Directed Enantioselective Allylation of Aldimines and Ketimines"  Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 7, 6119-6121 (2006)

 

"A Simple, Efficient, and Highly Enantioselective Synthesis of MS-153 Employing a Chiral Silane Lewis Acid-Promoted Acylhydrazone-Enol Ether [3+2] Cycloaddition"  Tran, K.; Leighton, J. L. Adv. Synth. Catal. 348 2431 (2006)

 


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