Advances in Small-Molecule Synthesis - Pharmaceutical Technology

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Advances in Small-Molecule Synthesis
Approaches in cyclization, palladium-catalyzed cross couplings, fluorination, and natural product synthesis help to optimize routes for select drugs.


Pharmaceutical Technology
Volume 34, Issue 12, pp. 40-42

Coupling reactions

Palladium-catalyzed coupling. Palladium-catalyzed cross-coupling, in which the metal is used to catalyze the formation of carbon–carbon bonds, is an important reaction in organic synthesis, particularly for complex molecules such as pharmaceutical compounds. The importance of these reactions was underscored by the awarding of the 2010 Nobel Prize for Chemistry to Richard F. Heck, Professor Emeritus at the University of Delaware in Newark, Ei-ichi Negishi, the Herbert C. Brown Distinguished Professor of Chemistry at Purdue University in West Lafayette, Indiana, and Akira Suzuki, Distinguished Professor Emeritus at Hokkaido University in Sapporo, Japan, for the development of palladium-catalyzed cross coupling.

The Heck reaction is a palladium-catalyzed cross coupling of organyl halides with olefins. The Negishi reaction is a palladium-catalyzed cross coupling of organozinc compounds with organohalides. Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides (2). The legacy of any advance is reflected in how it is applied, and these reactions play an important role in organic synthesis and the development of medicinal compounds.

Christopher W. Jones, a professor of chemical and biomolecular engineering at the Georgia Institute of Technology in Atlanta, was awarded the Ipatieff Prize from Northwest University earlier this year for advancing understanding of the interface between homogeneous and heterogeneous catalysis (3). His work involved elucidating the reaction pathways for palladium-catalyzed carbon–carbon coupling reactions, including Heck and Suzuki coupling reactions, using several Pd(II) pincer complex catalysts. His research showed that these reactions proceed by a Pd(0)–Pd(II) catalytic cycle as opposed to a Pd(II)–Pd(IV) catalytic cycle, which many thought was the case using the purportedly stable Pd(II) pincer complexes. He synthesized Pd(II) pincer complexes supported on solids and used testing based on kinetics, spectroscopy, and catalyst poisoning to show that the reactions proceed via a Pd(0)-Pd(II) catalytic cycle. His research also showed the reactions are mediated by palladium species that are leached from the immobilized (heterogeneous) phase to the solution (homogeneous) phase. From this work, he developed so-called palladium "scavengers" to examine the different roles played by homogeneous and heterogeneous species in these reactions (3–6).

Jones also is part of the Georgia Institute of Technology's Center for Drug Design and Delivery's Pharmaceutical Pipeline Project, which addresses challenges in drug development and manufacturing. The project consists of the three entities within the university: the Drug Design Consortium, the Drug Development Consortium, and the Drug Delivery Consortium. The Drug Development Consortium is involved with improving drug manufacturing. The consortium's work includes using supercritical fluids as a solvent-replacement strategy, crystallization-control methods applied to Crixivan (indinavir), an AIDS drug manufactured by Merck & Co. (Whitehouse Station, NJ), and applying membrane technology for drug isolation. The Drug Design Consortium focuses on the delivery of novel chemical entities and the optimization of existing chemical entities to generate promising therapies. Some projects include the design of histone deacetylase inhibitors, the biosynthetic engineering of natural products to explore structure–function relationships, and natural product research using marine organisms.

Georgia Tech also is the lead institution in the Center for Pharmaceutical Development, a newly established National Science Foundation Industry/ University Cooperative Research Center. The Georgia Tech site in the center focuses on the development of novel and improved biocatalysis for more selective and environmentally benign manufacturing. It also developed an accelerated assay to detect aggregation in therapeutic proteins.

Although useful, palladium-catalyzed coupling can be costly both because of the palladium and the ligand used with the transition metal in the catalyst. Researchers at the Leibniz Institute for Catalysis at the University of Rostock in Germany have addressed that problem by developing a new family of phosphane ligands, which are recyclable, and therefore could help to bring down the cost of certain palladium-catalyzed coupling reactions. Specifically, the researchers developed recyclable imidazolium phosphanes that work effectively in palladium-catalyzed carbon–oxygen, carbon–nitrogen, and carbon–carbon bond-forming reactions. The homogeneous palladium catalyst can be recycled directly from the reaction without any heterogenization (7).

Palladium-catalyzed cross-coupling of aryl halides and amines, known as Buchwald–Hartwig amination, is a key tool for constructing arylamines in organic synthesis. Researchers at Dalhousie University in Halifax, Nova Scotia, recently reported on a new phosphine ligand, which, when combined with palladium, selectively reacts ammonia or hydrazine with a broad range of aryl halides and tosylates, including reactions at room temperature in the case of ammonia (8, 9). The ligand employed in the chemistry, Mor-DalPhos, consists of an adamantyl-substituted phosphorus and a morpholino fragment bridged by a phenylene unit. The reactivity and selectivity of Mor-DalPhos/Pd with ammonia and hydrazine makes it an attractive choice in carbon–nitrogen couplings in which primary anilines and aryl hydrazines are the desired target compounds. Notably, aryl hydrazines are key intermediates in the preparation of nitrogen-containing heterocycles such as indoles, indazoles, and pyrazoles. Before this work by the Stradiotto group, however, the synthesis of aryl hydrazines directly from hydrazine sources had not been reported (8, 9). Strem Chemicals (Newburyport, MA) is marketing the ligand.


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