Chemical Science Blog

The utility of palladium-catalyzed coupling has grown extensively as it has become one of the most powerful tools available to synthetic chemists.  By playing a strategic role in the formation of carbon-carbon and carbon-heteroatom bonds, this synthetic technology has provided numerous opportunities to access diverse molecular architectures. 

In this recently published Chemical Science Edge Article, Professor Uttam K. Tambar and colleague from the University of Texas Southwestern Medical Center at Dallas set out to determine whether the Mizoroki–Heck reaction could be extended to generate dicarbonyl species while circumventing the usual alkene products.  They envisioned that under the modified reaction conditions the initial coupling of substituted allylic alcohols and organohalides would be followed by the key 1,2-migration step, instead of the conventional β-hydride elimination.

After screening various reaction conditions, the Tambar group found that the desired aryl dicarbonyls were furnished in good yield when a catalytic amount of  bis(benzonitrile)dichloropalladium(II) was combined with a silver salt in the presence of 1,1-diphenylallyl alcohol and ethyl bromoacetate. 

An investigation of the scope revealed that the aryl groups substituted with electron-rich and electron-deficient groups, as well as geminal-disubstituted allylic alcohols provided the desired coupling products.  Based on the preliminary mechanistic studies, they proposed that the reactions proceeded through the acyclic free radical pathway.

Furthermore, Prof. Tambar and his coworker also tested the possibility of producing additional acyclic 1,5-dicarbonyl compounds containing multiple stereogenic centers.  For instance, when they utilized the piperidine-substituted methyl bromoamide as the reaction partner with 1,1-diphenylallyl alcohol, the researchers found that the coupling reaction yielded the diketone product with diastereomeric ratio of 5:1.

Because acyclic stereocontrol remains a challenging research area in stereoselective free radical reactions, the 5:1 ratio is notably the highest reported level of 1,3-stereoinduction in 1,2-aryl migrations. 

This exciting article was just published in Chemical Science as an Edge Article. Read “Palladium-catalyzed cross-coupling of α-bromocarbonyls and allylic alcohols for the synthesis of α-aryl dicarbonyl compounds” (DOI: 10.1039/C5SC00505A) by Professor Uttam K. Tambar and Yang Yu to learn more about their chemistry. The article is free to access until 20th May 2015*.

*Access is free through a registered RSC account

Dr. Tezcan Guney is a web writer for Chemical Society Reviews, Chemical Science and Chemical Communications. Dr. Guney received his Ph.D. from the Department of Chemistry at Iowa State University with Prof. George Kraus, where he focused on the synthesis of biologically active polycyclic natural products and multifunctional imaging probes. Currently, he is a postdoctoral research scholar at the Memorial Sloan-Kettering Cancer Center in New York with Prof. Derek Tan, contributing to the efforts to access biologically active small molecules using the diversity-oriented synthetic approach.

Although substantial advancements have been made in the functionalization of C–H bonds of diazo compounds, accessing β-lactams via intramolecular pathways remains a challenge.  Researchers must address the chemo-, regio-, and stereoselectivity of diazoacetamide derivatives based on their electronic, steric, and conformational impacts on β-lactam synthesis

In this recent Chemical Science Edge Article, Professor Michael P. Doyle and his coworkers report a very selective asymmetric intramolecular C–H functionalization reaction of enoldiazoacetamides catalyzed by a chiral dirhodium carboxylate to achieve cis-β-lactam scaffolds.

The broad-spectrum biological activities of β-lactam motifs in treatment have proven valuable since the discovery and development of penicillin antibiotics. The magnitude of the joint scientific achievement of Sir Alexander Fleming, Ernst B. Chain and Sir Howard W. Florey in penicillin research were recognized by their receipt of the Nobel Prize in Physiology or Medicine in 1945.

The Doyle group prepared a number of donor–acceptor enoldiazoacetamides to extend beyond the less selective acceptor–acceptor diazoamides.  By capitalizing on a sterically hindered dirhodium carboxylate catalyst, donor-acceptor cyclopropene intermediates led to the key intramolecular C–H insertion.  Exclusive formation of cis-β-lactams resulted in high yields (80-92%) and notably high enantioselectivities (83-99% ee).

I recommend reading “Enantioselective cis-β-lactam synthesis by intramolecular C–H functionalization from enoldiazoacetamides and derivative donor–acceptor cyclopropenes” by Professor Michael P. Doyle and his colleagues to learn more about their asymmetric approach to β-lactams*.

Enantioselective cis-β-lactam synthesis by intramolecular C–H functionalization from enoldiazoacetamides and derivative donor–acceptor cyclopropenes
Xinfang Xu, Yongming Deng, David N. Yim, Peter Y. Zavalij and Michael P. Doyle �
Chem. Sci., 2015, Advance Article
DOI: 10.1039/C4SC03991B, Edge Article

*Access is free through a registered RSC account

Dr. Tezcan Guney is a guest web writer for Chemical Science. Dr. Guney received his Ph.D. from the Department of Chemistry at Iowa State University with Prof. George Kraus, where he focused on the synthesis of biologically active polycyclic natural products and multifunctional imaging probes. Currently, he is a postdoctoral research scholar at the Memorial Sloan-Kettering Cancer Center in New York with Prof. Derek Tan, contributing to the efforts to access biologically active small molecules using the diversity-oriented synthetic approach.