Glenn Micalizio, an associate professor in the chemistry department at the Scripps Research Institute in Florida, gave a presentation last Tuesday titled, “Metallacycle-Mediated Cross-Coupling: Reaction Development and Application in Stereoselective Synthesis,” which summarized his recent research which substantially expands of the scope and applications of a developing class of synthetic reactions aimed at selective carbon—carbon bond formation.

While there are a great number of chemical reactions under the domain of organic chemistry, of particular significance are reactions that form C—C bonds, as these reactions create the backbone of a target molecule. Because there is a limited number of well-developed C—C bonds forming reactions (e.g. Grignard, cycloaddition, Aldol, Wittig), Micalizio’s goal of developing a new class of these reactions is of great interest to synthetic chemists who must synthesize stereospecific, complex, and biologically-active molecules in as few steps as possible.

Micalizio highlighted notable compounds that are best synthesized using this cross-coupling reaction. The synthesis of Lehualide B, a marine natural product that displays potent anticancer activity, now requires only eight steps and no protecting groups. Hsp90 inhibitors, which also display cytotoxicity in clinical trials, have been synthesized in Micalizio’s lab using these techniques. Also synthesized was the compound Conolidine, a painkiller similar to morphine in effectiveness yet is not an opiate.

These reactions can couple the pi systems of two molecules by first converting one reactant into a reactive metallacycle intermediate, then allowing the second molecule to add to the intermediate as shown below.


The term “metallacycle” refers to atoms bonded in a ring, with one of the atoms being a metal. Titanium alkoxides were chosen for this research because titanium is relatively inexpensive and safe to work with, and its alkoxides are easily separated from product and undergo fast and reversible ligand exchange. Additionally, the byproducts formed are i-PrOH and TiO2, neither of which is prohibitively unsafe.

There are a number of common problems associated with this kind of coupling reaction. There are different geometries that can be produced when the two fragments are coupled, posing regiochemical and stereochemical challenges. The reaction needs to favor one molecule being coupled to the other, rather than coupling with the same molecule. Additionally, when there are groups substituted onto alkenes or alkynes, their bulkiness can often hinder reactivity and prevent a successful coupling reaction.

Micalizio’s research determined reaction conditions and substrates that could overcome the problems of reactivity and selectivity for the coupling of many kinds of pi systems. Viable substrates with good yield and a single product were expanded to internal and external alkynes, imines, allylic alcohols, substituted olefins, and others.

In addition to steric effects of the two substrates and strain in the chair-like intermediate, the selectivity of the reaction is strongly influenced by hydroxyl groups in the vicinity of the pi system, which are deprotonated and then coordinate with the titanium atom of the metallacycle.

While significant limitations remain in regards to the types of substrates that can be used and products that can be formed, Micalizio’s presentation demonstrated that this area of research can prove to be a useful tactic in syntheses today and has the potential to become a staple tool in the future synthetic chemist’s repertoire.

Micalizio is the recipient of many prestigious awards, including: University of Michigan Department of Chemistry Kasimir Fajans Award, 2007; Boehringer Ingelheim New Investigator Award, 2007; Yale University Junior Faculty Fellowship in the Natural Sciences, 2006; Lilly Grantee Award, 2006; American Cancer Society Research Scholar Award, 2006; and the Beckman Young Investigator Award, 2005.

Further Reading

Stephen N. Greszler, Holly A. Reichard, and Glenn C. Micalizio. Asymmetric Synthesis of Dihydroindanes by Convergent Alkoxide- Directed Metallacycle-Mediated Bond Formation. J. Am. Chem.Soc. 2012, 134, 2766−2774.

Takahashi, M.; McLaughlin, M.; and Micalizio, G.C. Complex allylation by the direct cross-coupling of imines with unactivated allylic alcohols. Angew Chem Int Ed Engl. 2009;48(20):3648-52.