• C-H Bond Activation
• Heterocycles via Tandem Catalysis
• Enantioselective Desymmetrization
• Total Synthesis

The Lautens group is focused on the investigation and development of novel transition-metal-mediated organic transformations. Some projects include catalyst-controlled asymmetric transformations while others focus on controlled tandem or domino processes.

Of particular interest are reactions which can efficiently construct frameworks of pharmaceutical compounds or fragments of biologically-active natural products.

C-H Activation

Palladium-Catalyzed Domino Reactions with C-H Bonds: Synthesis of Substituted Carbocycles and Heterocycles using Strained Alkene Shuttles

Domino reactions are efficient and cost-effective as they allow for more than one transformation in a single synthetic sequence. In 2000, we reported a palladium-catalyzed, norbornene-mediated domino reaction based on the work of Catellani¹ to allow a novel synthesis of functionalized carbocycles.² Norbornene is necessary for the reaction as it allows for the assembly of the product scaffold without being incorporated into the final product (Scheme 1). Over the years, we have modified this domino approach to include variations in the ortho C-H functionalization and the terminal functionalization steps (Scheme 2). The result is a highly general and versatile approach to functionalized carbocycles, heterocycles, and fused compounds. Current work in the area explores the synthetic diversity of the ortho-functionalization steps and the application of the methodology to new synthetic targets.

Seminal Publications

Domino C-H Activation - Heck Reaction

Domino C-H Activation - C-H Functionalisation

Domino C-H Activation - Reduction

Domino C-H Activation - With Secondary Alkyl Halides

Domino C-H Activation - Cyanation

Domino C-H Activation - Buchwald-Hartwig Coupling

Domino C-H Activation - Formation of Fused Aromatics

Heterocycles via Tandem Catalysis

We had envisioned the synthesis of annulated heterocycles via a tandem catalytic process in which a carbon-heteroatom bond and a carbon-carbon bond could be formed in a single operation. Indoles are a particularly attractive target of this methodology, since molecules containing this moiety are of great utility in a variety of areas. We have developed a cheap, scalable route to the necessary starting materials, where an ortho-nitro aldehyde is converted to the dibromide olefin followed by selective hydrogenation to the arylamine over a vanadium-doped platinum catalyst.¹

The tandem process displays high versatility: Suzuki,^2,3 Heck,⁴ and Sonogashira⁵ couplings, as well as direct arylation⁶ can be used orthogonally to carbon-nitrogen bond formation under palladium-catalyzed conditions to create a diverse set of 2-substituted indoles, and a wide range of functionality is tolerated at all positions of the benzenoid ring. Azaindoles (including 4-, 5-, and 6- isomers) and thienopyrroles, difficult targets by traditional methodologies, can also be obtained.⁷ Copper catalysis is effective, as demonstrated by the synthesis of a biologically important series of imidazoindolones by tandem intramolecular amidation.⁸ We have demonstrated the applicability of this chemistry in the synthesis of Merck’s KDR Kinase inhibitor.⁹

More recent work has focused on replacement of the arylamine moiety with other heteroatoms as well as carbon-based coupling partners,^10,11 as well as the facile synthesis of 2-brominated heterocycles in the absence of a coupling partner.¹²

References

Rhodium-Catalyzed Enantioselective Desymmetrization

Part of our research program focuses on the development of catalytic enantioselective addition reactions to activated alkenes and alkynes. More specifically, we use rhodium catalysts to perform highly selective transformations creating new C-C bond that are not easily furnished by traditional methods. We also apply the concept of enantioselective desymmetrization for the advantage it possesses over kinetic resolution reactions in that the totality of the substrate can be converted into the desired chiral products.

A wide range of functionalized chiral alcohol building blocks can be prepared from simple starting materials bearing symmetrical allylic leaving groups. Recently, we have successfully extended the reaction to less activated linear alkenes bearing leaving groups. Prior to our work, the substitution patterns of the cyclopentenols were not accessible using existing methods. Addressing selectivity is a key element of this methodology.

While many reactions exist for the desymmetrization of oxygenated compounds, nitrogen-containing molecules have received much less attention. Adapting our methodology for the ring-opening of diazabicycles with organometallic nucleophiles, cyclopentyl hydrazines could be prepared in high enantioselectivity. The reaction was not only successful, but also led to the unanticipated discovery of a new mechanism yielding hydroarylated products. Investigating this process in details showed that modification of the chiral ligand could favor an uncommon 1,4-Rh migration onto the aromatic ring and creating potential for further functionalization.

The strategy could be extended to a novel acylative displacement reaction. We discovered that acyl anions can be generated with a rhodium catalyst from simple boronic acids in the presence of CO. This finding makes obsolete the need for sensitive organometallic species to obtain densely functionalized carbonylated products. The unusually mild reaction condititons for this reaction (r.t., 1 atm CO) circumvents the typical need for specialized high-pressure equipment.

Total Synthesis

Completed syntheses:

Current Targets:

The phorbol esters are a class of molecules marked by their high bioactivity, and represent some of the most potent tumor promoters known to humankind.¹ They have seen widespread use in biological assays, and are known to produce potent inflammatory reactions in living organisms. Their mode of action is through activation of protein kinase C as a diacyglycerol mimic.² Phorbol was first isolated in 1934 from the oil of Croton tiglium,³ and later its structure was determined in 1967.⁴

References

Other syntheses: