SCIENCE & TECHNOLOGY
100% ORGANIC
C–H ACTIVATION
At the 2015 NATIONAL ORGANIC SYMPOSIUM, chemists discussed the latest in synthesizing and characterizing molecules STU BORMAN, C&EN WASHINGTON
vened at the University of Maryland, College Park, for the National Organic Chemistry Symposium (NOS) to discuss the art and science of synthesizing and characterizing organic molecules. Held every two years, the meeting, sponsored by the American Chemical Society’s Division of Organic Chemistry, started in 1925, when it was held in Rochester, N.Y. It played a key role in the conception and start-up of the Journal of Organic Chemistry, noted Marisa C. Kozlowski of the University of Pennsylvania, primary organizer of the 2015 NOS. This year, “we had 560 attendees from 27 countries, six continents, 46 companies, seven government labs, and over 100 universities,” she said. The University of California, Davis, will host the 2017 NOS. Highlights of this year’s conference included talks about photoredox catalysis, C–H activation, synthesis of quaternary carbon stereocenters, and work on a potential new drug for two autoimmune diseases. PHOTOREDOX CATALYSIS
The first use of visible-light photoredox catalysis was in the late 1970s, but the field has taken off only recently, experiencing an explosive growth in popularity in the past five years. For example, Merck & Co., in Rahway, N.J., recently built a photoredox catalysis reactor that is equipped with light-emitting diodes and can produce at least 25 kg per day of products. When activated by light, photoredox cat-
alysts such as tris(bipyridyl)ruthenium(II) can catalyze both oxidation and reduction, sometimes in the same reaction sequence. “This makes it possible to invent new transformations that were not previously possible,” said David W. C. MacMillan of Princeton University in his talk at NOS. MacMillan, his Princeton colleague Abigail G. Doyle, and coworkers recently developed a technique in which they used a photoredox catalyst and an organometallic catalyst to carry out difficult sp3-sp2 cross-coupling reactions. Such crosscouplings have typically been much more challenging to perform than connections between two unsaturated (sp2) carbon reactants. But in the new technique, called “synergistic catalysis,” two catalytic reaction sequences work together to form the tricky sp3-sp2 bonds. The chemists used an iridium(III) photoredox catalyst to transform a carboxylic acid into an α-amino radical intermediate. By catalyzing oxidation and reduction in a single reaction cycle to create this hardto-make intermediate, the photoredox catalyst allowed a nickel organometallic catalyst to then form the sp3-sp2 linkage between the radical and an aromatic halide, yielding a benzylic amine (Science 2014, DOI: 10.1126/science.1255525). The researchers believe synergistic catalysis will be useful for other types of sp3-sp2 couplings as well, and MacMillan noted that the technique is already being adopted in the pharmaceutical industry.
SYNERGISTIC This reaction combines photoredox and organometallic catalysis to form a hard-to-make sp3-sp2 link between a carboxylic acid and an aromatic halide. Boc = tert-butyloxycarbonyl protecting group. I OH +
N Boc
Concurrent photoredox and transition-metal catalysis
N
O
Carboxylic acid
COURTESY OF MERCK & CO.
EARLIER THIS MONTH, chemists con-
Boc Aromatic halide
Benzylic amine
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Amines are important components of many drugs and natural products, but chemists have few tools to add functionality to amines in their syntheses. For example, there are only a limited number of ways to convert simple aliphatic amines into more complex ones, said Matthew J. Gaunt of the University of Cambridge, in England, during his NOS talk. Gaunt and coworkers have developed a new method to functionalize aliphatic carbon atoms in these amines using C–H bond activation. This general class of transformations takes an aliphatic C–H bond—such as one in a simple amine— and replaces it, in a single step, with an alternative linkage such as C–C, C–O, or C–N. Amines make this process tricky, in part because the amine group is sufficiently nucleophilic to deactivate catalysts. So existing methods for the C–H activation of aliphatic amines “require bespoke protecting groups or directing auxiliaries attached to the amine to attenuate its nucleophilicity,” Gaunt said. These extra steps lengthen syntheses and lower their yields. “There are very few examples of unprotected amines used in C–H activation,” Gaunt said. The new method gets around the nucleophilicity problem with a more direct approach: The nitrogen atom of the amine functions as what Gaunt’s team calls a “native directing group” to position a metal catalyst in close proximity to the desired C–H
INDUSTRIAL SCALE Merck process chemist
Daniel DiRocco (left) and chemical engineer Jonathan McMullen (center) discuss a reaction they will run in a custom-built photoredox reactor (right).
HO HO
ers have focused on a transformation boost the responsiveness of the human chemists have long sought: forming a immune system. Blocking BTK’s activity in bond in the compound. They then carry out quaternary stereocenter by synthesizing immune system B cells and myeloid cells a cyclometallation reaction, which activates a single bond between sp3-hybridized carreduces those immune responses. the C–H bond and forms a bond between bons in each of two highly functionalized CH3O Studies in rodents have suggested the carbon atom and a metal. Other molorganic fragments. In recent years, Overthat BTK inhibitors might be effececules can then react with the carbon-metal man and coworkers developed a way to tive treatments for RA and lupus. N bond to generate new products. forge such bonds by coupling nucleophilic A number of BTK inhibitors Gaunt’s team has recently developed a carbon radicals with electron-deficient are currently in clinical triN number of such reactions, including one in alkenes. They have demonstrated this apals. But Young noted N which amino alcohols undergo C–H arylaproach by using it to make the diterpene NH that most of tion. They demonstrated how the method aplyviolene —typically produced by a OH O N allowed them to make pharmaceutically marine sponge. And in a study published relevant molecules by synthesizing the apearlier this year, they used it to make N N proved multiple sclerosis drug fingolimod plant-based trans-clerodane diterpenoids H3 C O N (Gilenya), which is also in clinical trials for such as solidagolactone (J. Am. Chem. Soc. a number of other conditions. 2015, DOI: 10.1021/ja512527s). G-309 The chemists hope eventually to develop Besides discussing quaternary stereothis approach into a general strategy for the centers, Overman also lamented a trouthe disclosed ones are covalent inhibitors C–H activation of aliphatic amines. “Amines bling trend in organic synthesis. “Unforthat also hit other kinases besides BTK, have often been a graduate student’s entunately, we’re currently in a period where potentially causing undesired side effects. emy,” Gaunt said. “There used to be a saying there is a lack of respect and funding for Genentech wants to avoid such off-target that went, ‘For every nitrogen in a molecule, people who tackle complex structures, in effects by developing a noncovalent inhibiyou should add a year to your tor that is highly selective for BTK. Ph.D.’” A family of molecules the company is inPRESTO, STEREOCENTER Overman vestigating interacts with an inducible bindand coworkers constructed the diterpenoid QUATERNARY CARBON ing site on BTK. It’s called inducible because O solidagolactone by linking two cyclic STEREOCENTERS a tyrosine motif that plays a key role in the O fragments to create a quaternary At each NOS, the rebinding interaction moves into the site from carbon stereocenter (yellow). cipient of the Roger Adams another location in the protein only when Award in Organic Chemisthe compounds are present. Young said that O H try delivers a lecture. This going after this site could make inhibitors O H • year, Larry E. Overman of selective for BTK since, “to the best of our + the University of California, knowledge, no structurally related kinases Irvine, received the honor undergo this structural change.” for the “design and syntheThe Genentech team started with a lead Nucleophilic Electronsis of complex natural prodcompound that bound to the inducible site carbon radical deficient alkene Solidagolactone ucts of plant and marine and showed good selectivity for BTK but origin.” lacked other important druglike properDuring the lecture, Overman discussed spite of the many opportunities for meanties. They improved its potency by adding his group’s efforts to construct quateringful discovery this area of chemical rea gem-dimethyl group that enhanced bindnary carbon stereocenters. These transsearch currently provides,” Overman said. ing affinity, but the resulting product also formations, he said, remain a continuing He believes that this is misguided—in part inhibited cytochrome P450, an undesirable challenge in the field of organic synthesis. because the chemical insights gained in property that can cause unsafe interacIn the past decade or so, chemists have such studies are often much more importions with other drugs. They blocked cytomade considerable progress in developing tant than being able to access the natural chrome P450 inhibition by adding an alkyl methods to synthesize these centers, with products themselves. substituent to a pyrimidine group, but that, much of that headway having been made in turn, lowered potency. The team then in Overman’s own lab. BTK INHIBITOR restored high potency by replacing the Nevertheless, synthesizing these stereoChemists at Genentech, in South San pyrimidine entirely with a five-membered centers is still not exactly a walk in the park. Francisco, have been hard at work looking heterocyclic ring. Overman noted that nearly all commercial for a new drug to treat two autoimmune With further optimizations, the team drugs that have quaternary carbon stereoconditions, rheumatoid arthritis (RA) arrived at a pyrazolopiperazine desigcenters, such as Advair and OxyContin, and lupus. At NOS, Wendy B. Young, vice nated G-309, which Genentech has adare currently made by semisynthesis from president of small-molecule discovery vanced into preclinical development for natural product precursors that already chemistry, discussed their efforts at tarpotential treatment of RA and lupus. “The have the stereocenters in place, thus avoidgeting an enzyme called Bruton’s tyrosine program has had its ups and downs along ing the difficult process of forming them. kinase (BTK). the way, with many lessons learned, and To make these centers more synthetiBTK helps transmit cell signals that start I am very proud of the work the team has cally accessible, Overman and his coworkat cell surface receptors and then go on to accomplished,” Young said. ◾ NH2
Fingolimod
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