Few medicinal chemists know that the palladium-catalyzed cross-coupling of organoboron compounds was observed in 1978 by Ei-Ichi Negishi.
While a postdoctoral associate to the 1979 Nobel Laureate H.C. Brown at Purdue University.(1) At the conclusion of Dr. Negishi’s post-doctoral work, he accepted a position at Purdue. In what may be interpreted as a weakness in the American system, Dr. Negishi was encouraged to study something largely unrelated to his work as a post-doctoral researcher.
Another postdoctoral associate to H.C. Brown, Akira Suzuki returned to Japan upon completing his time at Purdue. Not under the same pressure to research different chemistries in Japan, and seeing the potential synthetic value of such a reaction, he began to explore the reaction with his associate N. Miyaura and first published in 1979. (2) Research in the Suzuki group continued with organoborons, but it was not until 1981 that Miyaura and Suzuki made their first preparation of biaryls via cross-coupling. (3) Their methodology has become known as the Suzuki-Miyaura reaction.
Many natural products with medicinal value contain a difficult sp2-sp2 carbon-carbon bond which is synthetically difficult to form. Drug discovery teams and medicinal chemists were limited in scope and utility when trying to make these kinds of chemical bonds. But, with the advent of this new reaction, drug discovery became armed with a powerful new tool which has only gained notoriety, utility and application. Since the original Suzuki-Miyaura publication, each year has seen an increase in the number of publications and researchers working with this reaction. Many researchers have expanded the original methodology to include more active catalysts, other aryl halides, and the scope of the reaction to include sp2-sp3 carbon-carbon bond formation. Others have successfully expanded the cross-coupling reaction to be able to form carbon-sulfur, carbon-oxygen, carbon-nitrogen and other carbon-heteroatoms.(4) As illustrated in the diagram below, publications focused on boronic acids are increasing nearly exponentially. As a result, boronic acids have been elevated from their humble beginnings in 1860 when Frankland first isolated a boronic acid, to that of a prized class of organic compounds. (5) Experts in the field expect their use to increase. (6)
In its natural state, boron exists mainly as boron oxides, boric acid being the most commonly known form. Although a long useful and known state of boron, boric acid is not very useful to the synthetic chemist. It is not until a researcher can successfully attach at least one carbon moiety that the boron containing molecule becomes widely applicable to organic synthesis. The limited number of methods for the preparation of boronic acid derivatives and commercial availability has long impeded their use as synthetic reagents.
Frontier Scientific, a leader in boronic acid synthesis, continues to expand the commercial offering of boronic acids. Medicinal chemists regularly search the Frontier Scientific webpage (www.frontiersci.com) for new and useful products. Many times the bench chemist is delighted to find just the right kind of boronic acid that allows them to selectively modify their candidate to optimize efficacy and potency.
In addition to Frontier Scientific’s constant expansion of commercially available boronic acids, boron compounds are finding new and powerful applications. These applications are not isolated to starting materials but are being used as final products as well.
For example, the first boron containing FDA approved agent has found its way into the market. Bortezomib (Velcade), a potent ubiquitin proteasome (26S) inhibitor was launched as a treatment for multiple myeloma, a bone marrow cancer that affects two to three people per 100,000. (7) Required for proteolytic degradation of the majority of cellular proteins, 26S, is found in all cells. It is essential for the control of inflammatory processes, cell cycle regulation and gene expression. These qualities make 26S a novel target in cancer treatment. Bortezomib is an N-acyl-pseudo-dipetidyl boronic acid and formulated as a mannitol ester.
One of the key features of Velcade is based on the fact that many aldehyde containing peptides are proteasome inhibitors, but lack chiral stability and selectivity against other proteases including cysteine proteases. Using a boronic acid instead of an aldehyde circumvents these shortcomings and provides a measure of selective proteasome inhibition relative to many other serine proteases. The synthesis of this new cancer treatment is unique in that it starts with a boronic acid, yet it carries the boronic through to the final product; truly a first for the industry.
Another application of boron is based on the boron’s ability to be a biomimic for carbon. Boron is an element that is similar but different from carbon, allowing for novelty in biomimicy design. In medicinal chemistry, boron used as a carbon analog in the binding process, but not in terms of reactions, allows for enzyme inhibitors to be tailored and synthesized. Using organoboron compounds opens large fields of unexplored intellectual property.
Other researchers are exploiting the well known strong and reversible complexation between boronic acids and diol (1,2 or 1,3)-containing compounds. By forming transient esters with these kinds of alcohols, boronic acids can act as catalysts or templates for directed reactions. For example, Yamamoto and co-workers discovered that several electron poor arylboronic acids, in particular 3,4,5-trifluorobenzeneboronic acid, catalyzes amidation reactions between carboxylic acids and amines. (8) Aryl boronic acids also catalyze the alkaline conversion of D-glucos to D-fructose. (9)
Nagasaka and co-workers demonstrated that simple phenylboronic acid can be used to hold the diene and dienophile in such a way that the normal regiocontrol of a Diels-Alder reaction can be inverted. (10) This templating strategy was elegantly exploited in the synthesis of a key intermediate in the total synthesis of Taxol (a powerful anti-cancer agent) by K.C. Nicaolaou and co-workers. (11)
Optically active alcohols and amines are important compounds used extensively as starting materials, intermediates, and chiral auxiliaries for preparing biologically active substances, including natural products. One of the simplest and most useful methods for the preparation of such compounds is the asymmetric reduction of prochiral ketones and ketimines. Boron based reagents have been used to enantioselctively reduce such ketones in a stoichometric and catalytic manner. Both Isuno’s (12) and Corey’s (13) groups discovered oxazaborolidine (OAB)-catalyzed reductions. This reduction furnishes high enantioselectivety with predictable configurations even in the presence of 2 mole% of OAB. More recent work has allowed for these types of reactions to be accomplished using polymer or nickel boride-bound procedures. Having a heterogeneous type catalyst makes this procedure attractive industrially because of the easy of catalyst recovery and separation of products from the reaction mixture. (14-17)
More than a century ago, phenylboronic acid was noted to be toxic to microorganisms and relatively harmless to higher animals. (18) Further work was conducted in the 1930’s into boronic acids’ antimicrobial properties. (19) For example, the diazaborine family exemplified by the thienodiazoborine (below) has long been known to have potent activity against a wide range of gram-negative bacteria. (20)
Originally, this biological effect was said to be the result of inhibition of lipopolysaccharide synthesis. (21) More recent evidence points to a different molecular target, the NAD(P)H-dependent enoyl acyl carrier protein reductase. (22) This enzyme is involved in the last reductive step of fatty acid synthase in bacteria, and the structure of the inhibitory complex with diazaborines in the presence of the nucleotide cofactor. This was clearly demonstrated by X-ray crystallography. (23) Interestingly, in the X-ray structure is found a covalent bond between boron, in a tetracoordinated geometry, and the 2’hydroxyl of the nicotinamide ribose. (6)
In drug discovery, boronic acid based enzyme inhibitors target specificity
within a wide family. This is crucial to avoid side effects. The development
of the ?-aminoalkylboronic acid analogues of ?-amino acids was key in the recent
development of potent peptidylboronic acid analogues with improved specificity.
The usual mechanism of inhibition is the formation of a tetracoordinate boronate
complex by coordination of the side chain hydroxyl nucleophile of the active
serine residue. This complex mimics the tetrahedral intermediate for amidolysis.
(24) Other modes of inhibition have been indentified. For example, as mentioned
above, the formation of covalent adducts with the serine or histidine residues
of the active site.(25-26)
Carbohydrates on cell surfaces structures, as part of glycosylated proteins and lipids, form characteristic signatures of different cell types.(27-28) For example, sialyl Lewis X (slex) (below), silyl lewis a, Lewis Y and Lewis X are associated with the development and progression of many types of cancers.(29-32)
The over expression of sLex containing mucins signals the development of gastrointestinal, pancreatic and breast cancer. Therefore, the development of sensors that recognize sLex could help the diagnosis and early detection of cancers. (33) This tetrasaccaride (sLex) contains multiple 1,2 and 1,3 diols making it an ideal binding partner for boron containing sensors. These sensors mimic the action of lectins and have been called boronolectins. (34) Wang et. al. have developed several boronic acids that show a fluorescence intensity increase upon the boronic acid binding with the cell surface saccharide. (35-36)
Forward thinking researchers are increasingly looking to boron containing molecules. This short paper has discussed several applications and uses of boronic acids. All indications point to continued growth in the use of boronic acids. Even as this article is being written more reports are emerging. From its humble beginnings in 1865, to the meteoric rise resulting from Suzuki and Miyaura’s reaction, organoboron compounds are fast becoming compounds used for everything from starting materials to approved drugs. Frontier Scientific stands ready to help researchers create novel chemistries. Give the people at Frontier a call today; the future awaits.
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