Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

The incorporation of fluorine into APIs continues to be a key approach to improving important properties of candidate drug substances. While there are numerous methods for introducing trifluoromethyl groups, effective routes for selectively incorporating a single fluorine atom at a chiral center remain limited. Expensive, specialized fluorinating reagents and/or precious metal catalysts are often required to achieve the latter transformations. Researchers at GlaxoSmithKline (GSK) reported a simpler, cost-effective method for the preparation of fluorolactams via copper-catalyzed selective, direct fluorination using fluorine (F2) gas. This article summarizes the GSK research efforts (1).

	Although incorporation of fluorine atoms into APIs is known to increase their lipophilicity and impart other beneficial pharmacokinetic properties, there remain few commercial drugs with single fluorine atoms introduced at chiral quaternary carbons due to the difficulty in achieving this chemistry at scale. Numerous methods have been introduced in recent years for the enantioselective synthesis of these types of compounds, but most suffer from high cost.

	Specialized reagents based on Selectfluor (chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), transition-metal catalyzed reactions, and routes mediated by organocatalysts have all been reported. Unfortunately, all of these methods rely on reagents and/or ligands that often require multiple steps to synthesize and are typically too expensive to allow their use at commercial scale. In addition, most of these processes result in the production of large volumes of waste, which further reduces their practicality for large-scale manufacturing.

	As part of its environmental strategy, GSK aims to make its operations carbon neutral by 2050 (2). The company uses methods based on both qualitative and quantitative criteria to evaluate the atom economy and level of waste generation for proposed synthetic strategies. The obtained process mass intensity (PMI) values for different routes are compared to identify the most effective synthetic strategy.

	Scaling up a chiral fluorolactam building block

	Recently GSK researchers needed to scale up a process for the synthesis of chiral fluorolactam building blocks (enantiopure 2-fluoro-1,3-amidoesters) for the preparation of a series of spleen tyrosine kinase inhibitors as pre-clinical candidates. Three possible existing methods were considered: enantioselective fluorination of malonate esters using N-fluorobenzenesulfonimide (NFSI) and a Zn(OAc)

/DBFOX-Ph (4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline)) catalyst followed by formation of the amide, chiral alkylation of fluoromalonate derivatives followed by formation of the amide, or palladium-catalyzed fluorination using NFSI.

	Initially, the palladium-catalyzed route was selected for production of 100 g of the first chiral fluorolactam. The researchers found, however, that preparation of the catalyst involved a complex, multistep synthesis with low selectivity at large scale, leading to the need for extensive purification. A green metric analysis of the route identified issues with the enantioselective fluorination step due to the fact that NFSI is prepared using fluorine gas and the loss of material resulting from the low selectivity during catalyst preparation.

	As a second attempt, the GSK researchers considered the use of a fluoromalonate derivative. In this approach, a fluoromalonate ester would be converted to the desired fluorolactams via simple chemical transformations, which would then be subjected to enzyme-catalyzed resolution.

	The desired fluoromalonate was prepared via direct fluorination of the corresponding dimethyl malonate ester using fluorine gas. The reaction was catalyzed by copper nitrate and performed in acetonitrile, affording the desired product in high yield, even at the 50-g scale. Notably, the mass intensity was quite low.

	This fluoromalonate was then converted to the racemic fluorolactam derivative in three steps: Michael addition of acrylonitrile to form the nitrile, hydrogenation of the nitrile over palladium, and base-catalyzed ring closure. Hydrolase-catalyzed resolution of the nitrile, salt, and fluorolactam was then attempted.

	Ultimately after screening numerous enzymes, the GSK researchers found an effective method for the hydrolase-promoted amidation of the reduced salt to the fluorolactam in phosphate buffer with high enantioselectivity. The inexpensive enzyme CAL-B 10 000, a recombinant Candida Antartica Lipase B that is commercially available in multi-kilogram and tonne quantities, was selected. The enzyme was shown to be quantitatively recoverable and reusable three times without loss of activity.

	The researchers then further optimized each step in the conversion of the fluoromalonate ester to the reduced salt. The resulting three-step synthesis of the fluorolactam was found to have a PMI of 201, which was more than four times lower than that of the initial route based on palladium-catalyzed fluorination using NFSI (925).

	The optimized alternative route based on direct fluorination using fluorine gas was found to be highly competitive from a PMI perspective compared to the approach based on methods previously reported in the literature. A large percentage of the PMI value for the optimized synthesis is due to the final resolution step, which leads to loss of 50% of the product (as is the case in all resolutions).

	Despite this loss, the cost of the fluorination-amidase process was also found to be significantly lower than that for syntheses based on specialized (and expensive) electrophilic fluorinating agents prepared from fluorine gas and palladium catalysis. The researchers attributed this result to the facile recycling of the enzyme catalyst and solvents and the use of an inexpensive copper catalyst for the fluorination step. They also noted that the low cost and straightforward synthesis make this strategy suitable for scale up.

. 18, 1313-1318 (2016).
	2. GSK, Green Chemistry, www.gsk.com/en-gb/behind-the-science/how-we-do-business/green-chemistry/ accessed Aug. 12, 2016.

Articles

A simpler, cost-effective method for the preparation of fluorolactams may be suitable for scale-up.

Researchers Identify a Greener Fluorination Reaction

A small-molecule APIs become increasingly complex, designing concise, practical, and economical synthetic routes for their commercial production becomes increasingly challenging. There is, consequently, growing demand for cost-effective, highly efficient catalysts that mediate atom-economical, environmentally friendly transformations that can replace traditional, non-catalytic processes that require multiple steps. A summary of selected new catalysts that show promise for pharmaceutical intermediate and API synthesis is presented in the following.

	Silicon-containing compounds are of interest as potential drug candidates because silicon can impart greater stability and lead to compounds with improved solubilities and pharmacokinetic properties. There are two common routes to heteroarylsilanes: stoichiometric reaction of a silicon electrophile with a heteroaromatic organometallic intermediate (prepared via a Grignard reaction) or rhodium- or iridium-catalyzed C-H silylation in the presence of an excess of a hydrogen acceptor. Neither approach is practical on an industrial scale, and both suffer from limited functional group tolerance.

	Researchers in the Grubbs and Stoltz groups at the California Institute of Technology fortuitously discovered an attractive alternative method based on the inexpensive base potassium tert-butoxide (KOtBu) (1). When investigating a reaction to convert biomass to chemicals via the breakage of C-O bonds using an iron catalyst, KOtBu, and a hydrosilane as a hydride equivalent, they observed that silylated heteroaromatics were formed in minor quantities in a control reaction using only KOtBu and the hydrosilane. In addition, they noted that the yield of silylated products increased as the reaction temperature decreased.

	The cross-dehydrogenative heteroaromatic C-H silylation reaction with hydrosilanes was found to proceed best using a catalytic amount of KOtBu (1-20 mol%) in the absence of an acceptor, with only hydrogen gas as the byproduct. The fact that a common base catalyzes this important reaction was quite surprising, and thus the researchers went to great lengths to confirm that the KOtBu was indeed the catalyst and not some unknown impurity.

	The reaction is believed to proceed via a radical mechanism that is completely different from the mechanisms observed with transition-metal catalysts. Its scope is also very broad. Indoles with a variety of substituents on the nitrogen and various positions on the arene ring and many different electron-neutral and electron-rich N-, O-, and S-containing heterocyclic compounds are suitable substrates. Carbonyl groups are generally not tolerated except when protected as acetals. Some groups (bromide, iodide, cyano, and nitro substituents) do hinder the reaction. Interestingly, fluoride, chloride, trifluoromethyl, epoxide, N-alkyl aziridine, pyridine, and tertiary amine and phosphine groups do not.

	Notably, even simple arenes serve as good substrates. Substitution affects the regioselectivity; however, ortho-substitution occurs with anisole, while directing-group-free C(sp3)-H silylation leads to silylated benzyl derivatives with toluene and similar compounds. The researchers are also exploring the reaction of non-aromatic compounds (e.g., aliphatic compounds, alkenes, and alkynes).

	The scientists have also shown that the cross-dehydrogenative heteroaromatic C-H silylation reaction is scalable. When run neat using N-methyl indole and 1.5 equivalents of triethylsilane at 45 °C on a 100-gm scale, desired C2 silylated product was obtained in 76% yield with a greater than 20:1 regioselectivity after simple filtration and distillation.

	The researchers also demonstrated the utility of the reaction by silylating the antihistamine thenalidine and the antiplatelet drug ticlopidine in 58-68% yield with high chemo- and regioselectivity, indicating the applicability of the transformation for late-stage modification of pharmaceutically relevant compounds.

	Sites of unsaturation (alkenes in particular) are widely present in pharmaceutical compounds and their introduction can be achieved using a variety of methods, such as the elimination of alcohols, halides or other leaving groups, the reduction of acetylenes, and Wittig and Diels-Alder reactions. Dehydrogenation of alkanes is highly attractive because it allows for the flexible placement of alkenes. In addition, when performed under acceptor-less or terminal oxidant-free conditions, only hydrogen is generated as the byproduct. It is, however, a highly endothermic reaction traditionally mediated by expensive noble-metal catalysts at high temperature. Enzyme-based systems do proceed at room temperature, but require the use of a full equivalent of a terminal oxidant, and thus hydrogen recovery is not possible.

	Scientists at Princeton University have overcome these issues with the development of a reaction that is noble-metal-free, does not require the use of a terminal oxidant (and thus generates hydrogen), and proceeds at mild temperatures (2). Their approach is based on key aspects of the iron-based desaturase system, which catalyzes dehydrogenation reactions via step-wise hydrogen atom removal. The first hydrogen atom transfer (HAT) occurs from the alkane substrate to a high-valent oxo species, which is much more difficult than the second, which can occur via HAT or electron transfer followed by proton transfer.

	In their new approach, the researchers use cooperative catalysis with a dual-catalyst system to achieve the two steps. The polyoxometalate tetra-n-butylammonium decatungstate (TBADT) is easy to synthesize and has been shown to mediate HAT reactions of unactivated alkanes under near-UV light irradiation. For the second catalyst, the researchers were interested in cobaloximes because they are known to catalyze radical reactions including the reversible formation of alkenes and cobalt hydrides and have been shown to mediate water reduction under photo-irradiation conditions. Cobaloxime pyridine chloride (COPC) was selected because it is also readily synthesized.

	When used together (1.5 mol% TBADT and 0.75 mol% COPC) under irradiation at 323 nm, which is the absorbance maximum of TBADT, cyclooctane was converted to cyclooctene in 23% yield. The researchers also showed that cyclopentane was converted to cyclopentene and cyclopentadiene, while cyclohexane was dehydrogenated to cyclohexane rather than benzene, which commonly occurs under noble-metal catalysis.

	The reactivity of ethyl isovalerate was also interesting. Rather than produce the thermodynamically most stable product, which is generally the case with noble-metal catalysts, the dehydrogenation proceeded to form the skipped-enone product. The researchers are also exploring the tolerance for functional groups other than esters.

	While the initial results of the cooperative catalysis approach with simple alkanes are not as efficient as reactions with noble-metal catalysts, the researchers believe there is potential to improve the reaction. In fact, when secondary alcohols are used as substrates, the yields increase (i.e., 83% for 1-phenylethanol).

	Researchers at the Scripps Research Institute (TSRI) developed a catalyst that mediates C-H activation in the synthesis of heterocycles (3). Using an N-methoxy amide group as both a directing group and an anionic ligand, the PdX2 (X = ArCONOMe) catalyst is generated in situ from a Pd(0) source using air as the oxidant. With the PdX2 species localized near the target C-H bond, the natural preference of the metal to coordinate to the heteroatom is avoided. The catalyst has been used to synthesize a number of different compound types, including furans, benzofurans, benzothiophenes, indoles, pyrroles, thiazoles, pyrazoles, imidazoles, pyridines, quinolines, pyrazines, pyrimidines, pyrazoles, and thiazoles.

	Catalysts that mediate other types of C-H activation reactions have also been developed by TSRI researchers. In one case, sequential diarylation is achieved to afford non-natural β -Ar-β-Ar’-β-α-amino acids with diastereomeric ratios of greater than 20:1 (4). These compounds are building blocks for peptide drugs with structural diversity that may make them resistant to enzyme degradation. In the second reaction, palladium-catalyzed enantioselective C-H iodination is used to achieve the kinetic resolution of chiral amines (5). Notably, the reaction proceeds at room temperature and involves only inexpensive and commercially available reagents.

	Coupling of heteroatom-substituted olefins

	Carbon-carbon coupling reactions have become, in recent years, fundamental transformations for the commercial production of small-molecule APIs. Researchers at TSRI recently developed a new coupling reaction for the preparation of highly substituted, uniquely functionalized compounds catalyzed by an inexpensive iron complex (6). The reaction is also attractive because it is performed open to the air at room temperature.

	While typically run in ethanol, the researchers showed that reactions run in vodka, gin, whiskey, tequila, beer, and wine also afforded the desired coupling products. In addition, they demonstrated the broad scope of the reaction by synthesizing more than 60 different compounds, most of which were new chemical entities not previously reported.

, 518, 80-84 (2015).
	2. J. G. West, D. Huang, and E.J. Sorensen, 

, 515, 389-393 (2014).
	4. J-Q Yu, et al., 

, 343 (6176), 1216-1220 (2014).
	5. J-Q. Yu, et al., 

, 346 (6208), 451-455 (2014).
	6. P.S. Baran, et al., 

	When referring to this article, please cite it as C. Challener, "The Search for Practical and Economical Catalysts,” 

Researchers develop catalysts that mediate complex transformations under conditions appropriate for commercial manufacture.

The Search for Practical and Economical Catalysts

Pressures on drug manufacturers to reduce development timelines and costs while also providing safer and more effective medications are driving the pharmaceutical industry to seek more effective, alternative manufacturing solutions. In addition to continuous processes, both branded drug companies and contract development and manufacturing organizations are seeking greener routes to the production of complex APIs--routes that consume fewer resources and produce less waste. Replacement of more traditional reactions mediated by transition-metal catalysts with those facilitated by enzymes, or biocatalysts, is one option receiving growing attention. Jim Lalonde, senior vice-president of R&D with enzyme engineering company Codexis, shares his perspective on the benefits of biocatalysis for API synthesis.

: Why is biocatalysis considered to be greener than chemo (transition metal) catalysis?

: Biocatalysis is considered to be greener than transition metal catalysis in some key regards. Using the comparison of Merck’s second-generation process for sitagliptin (Rh/Josiphos asymmetric hydrogenation) with its third-generation biocatalytic transaminase process is illustrative, as it meets the green chemistry principles of safety, atom economy, waste prevention, and energy efficiency. Firstly, we eliminated the use of rhodium, which is considered toxic and had to be removed with an absorbent (which also generated a solid waste). Secondly, we eliminated the need for high-pressure, high-temperature hydrogenation and replaced it with a process that runs at ambient pressure and near ambient temperature. This change makes the biocatalytic process inherently safer, less energy-consumptive, and less expensive. The hydrogenation had to be performed in an expensive, custom high-pressure reaction vessel, while the biocatalytic transformation is conducted in standard reactors. The use of the transaminase catalyst also eliminated several synthetic steps, gave a higher overall yield, reduced the solvent demand, and resulted in a high purity product. The latter is often a feature of biocatalytic processes with engineered enzymes, as we can ‘evolve’ the enzyme until we have one that meets or exceeds product purity requirements. This high degree of customization is not typically possible with transition metal catalysts.

: What are the key changes that have led to growing interest in the use of biocatalysis in the pharmaceutical industry?

: The key advancement that has led to a large increase in the application of biocatalysis in the pharmaceutical industry has been the availability of enzyme engineering technologies. Previously, enzyme development took too long to allow the wide application of biocatalysts in commercial manufacturing, except for later-generation processes.

	Advances in genetics (genomic databases and next-gen sequencing), high-throughput biochemistry and robotics, data analysis, and computational modeling have enabled the rapid development of novel, customized biocatalysts that are optimized for API manufacture with improved efficiencies and reduced costs.

: When in the drug development cycle have biocatalysts most likely been used and why? Is this changing? If so, what is driving the change?

: Biocatalysts are used throughout the drug development process, from discovery through clinical Phases I, II, and III, to commercialization and even for generic drugs. The biggest change, however, is that biocatalysis is now becoming a first approach, rather than one of last resort. GlaxoSmithKline and Merck, through licensing our technology, now have the ability to rapidly demonstrate proof of concept with custom biocatalysts during the development of first scale-up routes to produce kilogram quantities. This milestone typically occurs in Phase I or II. With the in-house capability to then optimize an enzyme in months, they can meet their clinical development demands with enzyme-based routes. The second major change, which is just beginning to take hold, is that enzymes can enable the rapid synthesis of complex drug molecules that are not easily made using traditional organic chemistry. Consequently, many more candidates can be synthesized early in discovery programs.

: What are the most recent enzymes introduced to the market for API synthesis on a large scale? What might be expected in the next several years?

: Examples of new enzymes recently made available for API manufacture include an acylase specific for simvastatin manufacture that can regiospecifically acylate monocolin J, eliminating the need for protection and deprotection steps; imine reductases that reductively couple ketones with amines for the convergent synthesis of secondary and tertiary chiral amine drug targets; large libraries of transaminases and ketone reductases capable of enantiospecific synthesis of primary amines and secondary alcohols; and oxidases for the manufacture of asymmetric sulfoxides like esomeprazole and armodafinil.

	Of these transformations, currently there are only conventional catalysts for asymmetric oxidation, reduction of ketones, and asymmetric reductive amination. The enzymes are superior to conventional catalysts in that an enzyme with the targeted enantioselectivity can be developed for almost any substrate and is tolerant for virtually all functionality in the molecule.

	In development, there are enzymes for direct hydroxylation of unactivated C-H bonds, enzymes for direct synthesis of amides (no need for protection, activation, or deprotection steps), enzymes for regiospecific glycosylation of hydroxyl groups, and enzymes for the site-specific conjugation of proteins. There are no conventional transition metal catalysts for any of these transformations.

: What are the key advances in protein engineering and related technologies that have had the greatest impact on biocatalyst development in recent years? What might be expected in the next several years?
	

: Current engineering advances are such that wild-type enzymes are no longer used, and virtually all biocatalysts are engineered. Computational advances, metagenomics, gene synthesis, and sequencing advances have had the largest impact. Computational advances include molecular modeling in which docking of a target substrate into enzyme models can be performed 

 with sufficient accuracy to dramatically accelerate development of suitable biocatalysts. Data mining and machine learning algorithms that can correlate the performance data for a biocatalyst with the structure of the enzyme also guide the design of more optimal enzymes.

	Genomic databases, which contain sequence information on a vast and growing number of organisms, provide access to diverse enzyme starting points for engineering programs. The cost to synthesize and sequence genes has dropped exponentially, so we now typically sequence thousands of variants per week per development program. This information is used in the data mining algorithms. The combined effect of all of these advances is such that an enzyme development program that took several man-years a decade ago now can happen in a few months.

	Current molecular models of enzymes are static and based on X-ray crystallography, which is only a snap shot of a dynamic structure. As computational models improve with increased computational speed, we can expect to develop predictive models for protein structure that do not require crystallographic structure determination and molecular dynamics that will better model the kinetics of catalysis. Using these predictive models, one should need to only make and test a small number of variants to come up with a commercial biocatalyst. We should also be able to expand the types of enzymes to ones that catalyze non-natural transformations that are desirable to organic chemists.

: What about whole cell production of pharmaceutical intermediates and APIs? What is the state of this technology?

: Whole cell production of pharmaceuticals has been established for decades for the manufacture of natural product drugs (e.g., antibiotics such as streptomycin and the immunosuppressant Tacrolimus). Semisynthetics, or drugs that are made from fermentation followed by chemical modification, often have enhanced efficacy, however. Recently, routes to natural and semisynthetic drugs that are rare in nature (e.g., artemisinin from the sweet wormwood plant and opiods from poppies) have been produced using synthetic biology; the complete biosynthetic pathway for these drugs has been installed in an easily fermentable yeast, vastly lowering the cost of production and simplifying the supply chain for these valuable drugs. In addition, we can now create enzymes that act on non-natural molecules and even ones that catalyze non-natural reactions, which will allow the direct fermentation of a much wider range of drug molecules.

: Is there anything else about biocatalysis as a green alternative that is worth noting?
	

: We continue to be surprised by the breadth of chemistries possible using biocatalysis. Pharma companies estimate that anywhere from 25-75% of their pipeline can benefit from biocatalytic methods. In the area of drug discovery, there is a trend toward molecules of higher complexity with higher specificity and thus both lower dosage requirements and fewer side effects. Enzymes that have been designed for selective transformations allow the rapid creation of libraries of these complex molecules.

Drug companies and CDMOs seeking greener routes to the production of complex APIs may look to biocatalysis.

The Enzymatic Catalysis Route to Going Green


	When referring to this article, please cite as C. Challener, “The Search for a Greener Fluorination Reaction," 

Researchers at GlaxoSmithKline report a greener and lower-cost route to chiral fluorolactams that is suitable for scale up.

The Search for a Greener Fluorination Reaction

The majority of small-molecule drugs in development today contain chiral centers, and according to Global Industry Analysts (GIA) nearly 95% of drugs will be chiral by 2020 (1). GIA estimates that the global chiral technology market, which is dominated by pharmaceutical applications (followed by agrochemicals and flavors and fragrances), will reach $5.1 billion by 2017.

	Because FDA requires manufacturers to investigate the properties (physicochemical, pharmacokinetic, etc.) of all enantiomers/diastereomers of chiral drugs to determine their individual safety and efficacy, the development of efficient chiral synthesis technologies remains a primary target for many academic and industrial researchers. Several transformations with significant potential for use in API manufacture have been published in the past year. A few of them are highlighted in the following.


	Researchers in the Doyle lab at Princeton University in New Jersey have developed a direct cross-coupling reaction to produce 1,2-dihydropyridines, versatile building blocks that are highly useful for API synthesis (2). The reaction involves the enantioselective Ni-catalyzed cross coupling of arylzinc reagents with pyridinium ions formed 

	The use of pyridine is of particular interest, according to Abigail Doyle, an associate professor of chemistry at Princeton and corresponding author of the article. “A highlight of the method is being able to use pyridine as a substrate because it’s inexpensive and abundant and has rarely been used in transition metal and asymmetric catalysis,” she said (3). Pyridine typically binds to nickel catalysts, inhibiting further catalytic activity. This issue was avoided by adding a slight excess of iso-butylchloroformate, an activating agent that reacts with pyridine to form an intermediate species that does not bind to the catalyst.

	The generated, enantioenriched 2-aryl-1,2-dihydropyridine products can be elaborated to numerous piperidine derivatives with little or no loss in enantiomeric excess. Nine different elaborations commonly used by medicinal chemists for drug development were performed to demonstrate their utility (3).

Radical strategy for enantioselective carbon-carbon bond formation


	Most enantioselective reactions proceed via polar reactivity, with few radical reactions providing high selectivities. Radical mechanisms are attractive for forming quaternary carbon centers, however, because radical intermediates are not significantly affected by steric factors, as is the case with cationic and anionic intermediates. Researchers at the Institute of Chemical Research of Catalonia (ICIQ) in Spain have recently reported a method that harnesses the potential of radicals for enantioselective synthesis of quaternary carbon stereocenters (4). Paolo Melchiorre and his group at ICIQ used a combination of photoredox and asymmetric organocatalysis to mediate enantioselective radical conjugate additions to β,β-disubstituted cyclic enones.

	A chiral organocatalyst containing a redox-active carbazole moiety was designed to generate iminium ions that are then stereoselectively trapped via an electron-relay mechanism by photochemically generated carbon-centered radicals. The reaction proceeds under mild reaction conditions with high enantioselectivity and without the need for transition-metal catalysts, making it a sustainable process (5). “Combining the potential of metal-free enantioselective organocatalysis and visible light photocatalysis can significantly advance the development of a more responsible and sustainable stereoselective chemistry while strengthening the chemistry toolbox to better face the challenges of modern organic chemistry,” noted Melchiorre. He added that “This catalyst may provide further opportunities to stereoselectively generate quaternary stereocenters that cannot be forged by using traditional polar reactivity.”

-symmetrical, atropoisomeric functionalized biaryls


	Organocatalysis was also employed by scientists at Rice University in Texas to achieve the direct arylation of aromatic C(sp

)-H bonds in phenols and naphthols for the preparation of 1,1Ê¹-linked functionalized biaryls (6). Not only have the non-C

-symmetrical, atropoisomeric products not been previously synthesized, they are formed with complete regioselectivity, and the reaction is readily scalable and does not require an external oxidant. Results of density-functional theory calculations suggest that the reactions proceed via an asynchronous [3,3]-sigmatropic rearrangement of an 

	The biaryls are synthesized from readily available compounds, including quinone monoacetals and phenols/ naphthols. “Using these building blocks, we made 41 different chiral biaryl compounds in a relatively short time,” said corresponding author László Kürti (7). He added that the functionalized chiral biaryls are really versatile compounds. “You can use them outright as organocatalysts or complex them with transition metals to make new transition-metal catalysts. So the possibilities are unlimited. Moreover, these compounds can be used as building blocks en route to natural products with biaryl substructures in them.”


	Researchers at the University of Sydney in Australia have focused on the development of switchable phosphine ligands for transition metals whose chirality is modulated through an external trigger signal. These molecular motors make it possible to change the enantioselectivity in a catalytic process without the need to synthesize new catalysts. In the report, a photoswitchable chiral bisphosphine was prepared based on a unidirectional light-driven molecular motor that can be used to invert the stereoselectivity of a palladium-catalyzed desymmetrization reaction (8). As a result, each enantiomer can be formed using just one ligand.

	The bisphosphine ligand undergoes photochemical and thermal isomerization during unidirectional rotation around the motor central double bond, allowing for control of both the helicity of the ligand and the distance between the two phosphines. Notably, light-induced isomerizations in the ligand are endothermic, while heat-induced isomerizations are exothermic (9). The researchers report obtaining a nearly racemic mixture to very high enantiomeric ratios for each isomer (93:7 and 6:94) for the Pd-catalyzed desymmetrization reaction (8).

Understanding how chiral molecules behave


	Scientists at Newcastle University in England and the Swiss Federal Laboratories for Materials Science and Technology are learning about mechanisms of chirality through investigation of biomineralization, a process by which inorganic materials are formed with chiral structures following contact with proteins and polysaccharides, which act as modifiers during nucleation and crystal growth (10). The chirality of the biomolecules is transferred to the mineral structure; understanding how this process occurs can provide insights into the design of organic chiral transformations.

	In this report, Werner Hofer and his colleagues used scanning tunneling microscopy, photoelectron diffraction, and density functional theory to investigate how the chiral compound ‘buckybowl’ hemibuckminsterfullerene arranges copper surface atoms. “By understanding this process, we can now force materials to behave in a certain way, using biological plans to create the shapes and structures that we want. This has huge potential in the fields of materials design and drug synthesis,” Hofer said (11). In particular, the knowledge gained could facilitate the development of more efficient and effective enantioselective heterogeneous catalysts.
	Now that the proof of concept has been demonstrated, the challenge, according to the researchers, is to identify the right biomolecules that create the specific metal surface morphologies that are suitable for specific catalytic reactions (11).


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	6. H. Gao, et al., Angewandte Chemie International Edition, 55 (2), 566-571 (2016).
	7. Rice University, “Chemical Design Made Easier,” Press Release (Houston, TX, Nov. 24, 2015).
	8. D. Zhao et al., 

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	9. The University of Sydney, “Molecular Motors For Chiral Catalysis,” Press Release (Sydney, Australia, October 2015).
	10. W. Xiao et al., 

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	11. Newcastle University, “Nature’s Mirror-the Code for Chirality,” Press Release, (Newcastle upon Tyne, England, Feb. 8, 2016).

Recent research of efficient chiral synthesis technologies reveals potential uses in API manufacturing.

Chiral Advances Demonstrate Promise for API Synthesis


	When referring to this article, please cite as C. Challener, “Going Green with Biocatalysis," 

Enzymatic catalysis offers pharma manufacturers a way to implement the Principles of Green Chemistry.