SCIENCE/TECHNOLOGY
Fluorine Chemistry Branches Out From Its Traditional Focus Thrasher, an associate professor of rinated compounds for biological studchemistry at the University of Ala- ies can be difficult. Nevertheless, he bama, Tuscaloosa, and cochairman of believes that over the next few years the conference. "A lot of people at the more and more results will be anconference will tell you that they are an nounced showing the usefulness of fluoorganic chemist, an inorganic chemist, rinated compounds in various biologia physical chemist, or a polymer chem- cal applications. ist. However, all chemists who use fluoHis views are echoed by many rerine chemistry in their research are de searchers in organic and biological Stephen K. Ritter, C&EN Washington facto fluorine chemists." chemistry. "Fluorine is an excellent tool The Fluorine Chemistry Division is in biological chemistry," notes C. Dale ew materials, fuels, and other unique, adds Thrasher, because it is the Poulter, professor of chemistry at the items for military and space- only ACS division dedicated to a single University of Utah, Salt Lake City. At flight applications have always element. Thrasher notes that this dis- the conference, Poulter reported on the played an important role in fluorine tinction actually helps to broaden the use offluorineas a probe to study the chemistry. Much of this work has been composition of the division's member- mechanism of enzyme-catalyzed reaccarried out at national laboratories and ship. He says the conference draws a tions in biosynthesis. through contract research to universi- good balance of researchers from aca"Fluorine is a good replacement for ties and industry. Other high-priority demia, industry, and government hydrogen in a lot of cases where you interests, such asfluoropolymersand agencies whose specific interests com- want to stabilize molecules toward oxichlorofluorocarbons, have helped in- prise a broad spectrum of topics, from dation reactions or in cases where you dustry to develop many commercial basic research to applied research to really want to change reactivity," Poulproducts over the years. commercial products. ter says. "There are many molecules in Recently, however, researchers have Research in the biological area is not which you can replace hydrogen with been branching out from these tradi- strictly new, says conference cochairman fluorine, alter the chemical reactivity, tional fields to explore, among other John T. Welch, an associate professor of and still have the molecules serve as areas, fluorine-containing compounds chemistry at the State University of New substrates for enzymatic reactions to get with biological activity or potential York, Albany. "Simply replacing hydro- information about the mechanism of the for use in medical diagnostics. Some gen or hydroxyl groups with fluorine is reaction." of these newer directions in fluorine now well established. There are new inPoulter described the synthesis of research were featured at the 12th teresting approaches to the study of fluorinated analogs of farnesyl diphosWinter Fluorine Conference, held late binding interactions where you can take phate—a substituted C15 triene that is a last month in St. Petersburg Beach, advantage of subtle discrimination that key enzyme in isoprenoid biosynthesis Fla. The biennial conference is hosted occurs on fluorination. I think that is the (C&EN, Sept. 26,1994, page 27). Isopreby the ACS Division of Fluorine next generation." noids are biologically essential comChemistry. Welch admits that synthesis of fluo- pounds that include cholesterol, steroid This year's conference included 19 plenary lectures, 63 additional lectures, and 90 presentations in two poster sesTwo-step reaction leads to titanium(IV) amino add complexes sions. Fluorine chemistry is an inherently interdisciplinary field of research AsF6becausefluorineimparts unique physi/NH3 cal properties to a wide range of inorcoa V C C H ganic and organic compounds. Thus, H3N—C — H < ^ 7 " \ r u C| n / 3 topics ranged from fluorination meth'Ul | I.CH3OH/H2O ^ ^ \ ^O CK \ CI odologies, fluoropolymers, and chlo^ ,CH; rofluorocarbon alternatives to catalysis, \ nC—CH.. Titanocene fluoroanions,fluoroaromatics,and fluo// NH3 dichloride rine-containing ligands. + "The fact of the matter is that no one AsF6 R = H or F works on just fluorine/' says Joseph S.
• Conferencefeatures research onfluorinated compounds that show biological activity and have uses in medical diagnostics
N
FEBRUARY 27,1995 C&EN 39
SCIENCE/TECHNOLOGY
Difluoromethyl ketones are prepared from a lifhiated difluoroenol carbamate OLi
(DCONEto
RCOR'
F . JL
OH
,R OCONEt2
Product OH
RCOR = Propanal OH
O
O
Acrolein F
OH
F OCONEt2
F
O
OH
7
^
F OCONEt2 O
Crotonaldehyde F
F
F OCONEt2
OH Benzaldehyde
Product
R'CHO
Methacrolein
Acrolein
F 'F OCONEt2 7
RCOR' = Pentan-3-one R'CHO
O
> R R''^S< S< '
R-CHO^
O
/
\-\ Q
OH Benzaldehyde
F
F OCONEt2
OH
F OCONEt2 O
H5C6 F
F OCONEto
O
Crotonaldehyde F
F
OCONEto
Et = CH2CH3
hormones, and carotenoid compounds such as ^-carotene. Poulter and postdoctoral fellow Julia M. Dolence created the analogs by adding a fluorinated farnesyl group to a cysteine residue to form a thioether linkage between the C15 isoprenoid and proteins. Kinetic data showed that the reaction proceeds by an electrophilic mechanism. "The insight gained about the mechanism of the farnesylation reaction will be helpful in designing new inhibitors of the enzyme," Poulter says. In another study presented at the conference, research associate Inis C. Tornieporth-Oetting from the Technical University of Berlin discussed research involving a fluorinated analog of an essential amino acid. Tornieporth-Oetting and coworkers in Berlin, along with professor of chemistry Peter S. White at the University of North Carolina, Chapel Hill, have prepared what they claim is the first bioinorganic titanocene(IV) complex, [Cp2Ti(aa)2][Cl]2 (Cp = T] -C5H5, aa = amino acid), that contains an essential amino acid—D,Lphenylalanine (D,L-Phe). The chemists also prepared a com40
FEBRUARY 27,1995 C&EN
plex that contains a fluorinated analog of D,L-Phe: D,L-p-fluorophenylalanine (D,L-FPhe). They found that the fluorinated complex and fluorinated complexes containing AsF6" in place of Cl~ show much higher biological activity than the nonfluorinated complexes. Titanium and other early-transition metallocene complexes exhibit antitumor activity against a number of experimental tumors as well as some human tumors heterotransplanted into mice. Titanocene dichloride is one of the most effective antitumor agents of this metallocene class. However, because of its limited stability in aqueous solution, the use of titanocene dichloride to prepare model complexes containing biologically important ligands under physiological conditions has proven difficult. Tornieporth-Oetting determined that an aqueous methanol "waterlike" system and the use of naturally occurring compounds such as amino acids as ligands could facilitate synthesis of the complexes. Thus in earlier work, her group prepared [Cp2Ti(aa)2][Cl]2 by reaction of titanocene dichloride with the ot-amino acids glycine, L-alanine, and
2-methylalanine in aqueous methanol [Organometallics, 13, 3628 (1994)]. These results led to the synthesis of the new complexes containing D,L-Phe and D,L-FPhe described in Horida. Fluorinated analogs of amino acids act as antiviral, antitumor, and antifungal agents in many new drugs, Tornieporth-Oetting notes. She selected D,L-FPhe because other researchers have previously shown that peptides that use phenylalanine in normal biosynthesis also can use D,L-FPhe and that there is some suppression of protein synthesis by the fluorinated analog. This finding led to the research group's interest in investigating the biological effects of the complexes on Escherichia coli. Elongation of E. coli cells by bactericides is generally interpreted as evidence that cell division and DNA replication are being disrupted. Inorganic platinum complexes—such as cisplatin—as well as organobismuth compounds and D,L-FPhe, all cause elongation of E. coli. These observations led to the discovery that the compounds have pronounced antitumor activity. Tornieporth-Oetting reported that titanocene dichloride alone failed to show any biological activity against E. coli. D,L-Phe and [Cp2Ti(D,L-Phe)2] inhibited bacterial growth modestly but only when high concentrations were used. By contrast, D,L-FPhe and [Cp2Ti(D,LFPhe)2][Cl]2 showed strong biological activity at modest concentrations. Further reaction of [Cp2Ti(D,LPhe)2][Cl]2 and [Cp2Ti(D,L-FPhe)2][Cl]2 with AgAsF6 yielded complexes in which Cl~ was replaced with AsF6~. The activity of the AsF6" complexes against £. coli was significantly greater than that of the complexes containing
cr. The researchers determined from X-ray diffraction studies that, in chloride complexes, strong cation-anion interactions exist between CI" and the NH3+ group of the amino acid ligands. In AsF6" complexes, TornieporthOetting says, the extremely low basicity of the AsF6" group prevents such cation-anion interactions. She thinks the higher activity of AsF6" complexes may be directly related to this effect.
An example of work in organic chemistry with applications in the pharmaceutical industry was reviewed by lecturer Jonathan M. Percy, graduate student Judith A. Howarth, and coworkers from the School of Chemistry at the University of Birmingham, England, and by W. Martin Owton from the Department of Medicinal Chemistry at Eli Lilly's research center in Windlesham, England. The Birmingham group's work is based on the hypothesis that the important reactions from mainstream synthetic organic chemistry—such as sigmatropic rearrangements, cycloadditions, and acyl anion equivalent and aldol reactions—should be adaptable to the presence of one or two fluorine atoms. "The chemistry should be entered through inexpensive and easy-tohandle starting materials that already contain the fluorine atoms," Percy says. Many natural product analogs with difluoromethyl groups are biologically active. Some of these include difluoro threonine, an antileukemic; Gemciti-
bine, an antitumor nucleoside analog; tion failed to yield aldol products, preand difluorotobramycin, an antibiotic. sumably because of the relatively low At the conference, the researchers re- nucleophilicity of the enolate. But new work reported by Howarth ported progress in the use of retaliated enol acetals and carbamates to place at the conference reveals that addition CF2 groups at the termini of, or to em- of a second nonenolizable aldehyde in bed them within, complex acyclic mol- the course of the reaction allows the ecules that are synthesized in short re- lithium enolate to be trapped, leading to formation of aldol products in good action sequences. Earlier, the team prepared difluo- yields. "This is a particularly exciting romethyl ketones in good yields by area," says Percy, "because it allows adding a metallated difluoroenol car- us to use a simple carbamate of trifluobamate, CF2=C(Li)C02N(CH2CH3)2, to roethanol and trade one of the fluocarbonyl electrophiles [Synlett., 1992, rine atoms for new carbon-carbon 483]. The enol carbamate was synthe- bonds to both carbon atoms of the sized from trifluoroethanol, an inex- starting material in a simple one-pot pensive and readily available starting reaction." Percy notes that the carbamate material. The key feature of the chemistry is a chemistry is already being used by at transacylation reaction in which the least one drug company in the U.K. carbamoyl group relocates after the ad- The Birmingham researchers are now dition reaction, releasing difluoroenol- refining the enolate chemistry and are ate and potentially allowing the fluo- beginning to look at cascade applicarine-bearing carbon to be used in C-C tions on their way to what they hope to bond formation. Percy notes that addi- be one-pot syntheses of highly function of a second enolizable aldehyde, tionalized fluorinated carbocycles and such as propanal, to the enolate solu- carbohydrate analogs.
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SCIENCE/TECHNOLOGY Another example of work with fluorinated analogs in biological chemistry Fluorinated flrreo-dihydroxyphenylserines are was presented at the meeting by Kenpotential precursors to active (Jtyfluoronorepinephrines neth L. Kirk of the National Institute of Diabetes & Digestive & Kidney DiseasF H OH F H OH es, National Institutes of Health, BeAromatic amino acid H 0 C H thesda, Md. Kirk reported on the syndecarboxylase ^ ^ N S ^ ° 2 thesis of 2-fluoro- and 6-fluoro-f/ireo-diJ H NH2 hydroxyphenylserine (2-FDOPS and 6-FDOPS). 2-(/7)-Fluoronorepinephrine 2-Fluoro-f/?reo-dihydroxyphenylserine The threo isomer of dihydroxyphenylserine (DOPS) has been studied as a bioH OH H OH logical precursor of norepinephrine. Aromatic amino acid decarboxylase Norepinephrine (along with dopamine and epinephrine) is one of the naturally HO v F occurring catecholamines that functions 6-(fl)-Fluoronorepinephrine 6-Fluoro-f/7reo-dihydroxyphenylserine as a neurotransmitter in the central nervous system and, as such, controls a host of important biological processes. The action of norepinephrine (and other ad- is its poor ability to permeate the blood- the most widely used anticancer drugs renergic agonists) is mediated through brain barrier. He holds out promise that (C&EN, June 6,1994, page 25). He carits interaction with transmembrane (3- the fluorinated analogs may have en- ries out his research with a standard and oc-adrenergic receptors. clinical MRI instrument that has been hanced permeability. 2-FDOPS and 6-FDOPS are precurOne possible application, which Kirk tuned to measure 19F. The 19F NMR sors to 2- and 6-fluoronorepinephrine admits is at a very early stage of devel- spectroscopic technique differs from (2-FNE and 6-FNE). Kirk and his co- opment, is use of FDOPS as an imaging standard MRI in that the fluorinated workers have discovered that 2-FNE is agent. "In our research, we are always drugs are being monitored through a selective (3-adrenergic agonist and mindful of potentially useful com- spectroscopy—because they are not that 6-FNE is a selective cc-adrenergic pounds for PET [positron emission to- present in sufficient quantities to allow agonist. The research team is investi- mography] imaging agents," he says. imaging. gating the possibility that subsequent The goal of 19F NMR spectroscopy PET imaging and the development selective actions at p- and a-adrenergic of PET imaging agents are areas of as a diagnostic tool is to study the dyreceptors may lead to beneficial thera- growing interest in chemistry. PET re- namics of a drug once it has been peutic results. quires a positron-emitting nuclide, administered—something that cannot Kirk's group prepared a racemic mix- such as 18F, that must be generated in a be done with anatomical or physioture of the threo-FDOPS compounds by acyclotron. Another imaging technique logical imaging techniques. AnatomiZnCl2-catalyzed reaction of a protected that already is in wide practice is mag- cal imaging "captures only static imglycine trimethylsilylketene acetal with netic resonance imaging (MRI). MRI es- ages," says Wolf, "and physiological benzyl-protected 2- and 6-fluoroproto- sentially involves obtaining a *H nucle- imaging does not reveal what hapcatechualdehyde. The preparation and ar magnetic resonance spectrum of wa- pens to a specific chemical entity inisolation of the threo (2S,3R) isomer is ter. At the conference, Walter Wolf, a side the body." He emphasizes that PET imaging critical, explains Kirk, because only it can professor of pharmaceutical sciences at lead to (R)-norepinephrine. Only (R)- the University of Southern California, techniques and NMR spectroscopic norepinephrine is an active adrenergic Los Angeles, reported on develop- techniques are intended to be compleagonist. ments of a newer medical diagnostic mentary. For example, either NMR DOPS already has shown value in technique—19F nuclear magnetic reso- spectroscopy or PET imaging can be used to locate where a particular drug clinical trials for treating some symp- nance (NMR) spectroscopy. toms of Parkinson's disease. Kirk notes, Wolf's work involves the study of in might concentrate in the body. Howevhowever, that one problem with DOPS vivo 19F NMR of 5-fluorouracil, one of er, once the site is located, only NMR
Fluorination of phenylacetate precursor leads to potential imaging agent
c=o I
Diethyl ether
HO-t-C02CH2CH3 (CH2)5CI
CO2CH2CH3
1. Nal acetone 2. AgOS02C6H5CH3/acetonitrile 3. [CH3(CH2)3]4NF/tetrahydrofuran
FQNPe = 1-azabicyclo[2.2.2]oct-3-yl (/-hydroxy- a-(1-fluoropentan-5-yl)-(x-phenylacetate
42
NaO
Series of steps
CI(CH2)5MgBr
FEBRUARY 27,1995 C&EN
HO-|-C02CH2CH3 (CH2)4CH2F
t) x° .in HO-^C—O—Uv^J (CH2)4CH2F FQNPe
spectroscopy can provide information about how the drug is metabolized. Furthermore, pharmacokinetic methods can be used to estimate the temporal relation between the drug and its active metabolites. Each of the techniques has its own particular advantages and disadvantages, Wolf tells C&EN. Radionuclide imaging has excellent sensitivity, whereas NMR has poor sensitivity. But NMR has excellent chemical resolution, whereas radionuclide imaging has no chemical resolution. In short, Wolf says, "You can see very small amounts of materials with PET but you don't know exactly what they are; with NMR, you can measure exactly what chemicals are present in vivo provided they are there in a sufficiently large amount." An example of a potential ligand for PET imaging is a fluorinated analog of the muscarinic-cholinergic receptor IQNP, l-azabicyclo[2.2.2]oct-3-yl ct-hydroxy-oc-(l-iodo-l-propen-3-yl)-aphenylacetate. Synthesis of the new compound, called FQNPe—1-azabicyclo[2.2.2]oct-3-yla-hydroxy-a-(l-fluoropentan-5-yl)-a-phenylacetate—was described at the conference by postdoctoral fellow Huimin Luo, who carried out the work with nuclear medicine group leader Russ Knapp and staff scientist Dan W. McPherson from the Health Sciences Research Division at Oak Ridge National Laboratory (ORNL) in Tennessee. The synthesis involved a Grignard reaction of ethyl benzoyl formate with l-bromo-5-chloropentane in diethyl ether leading to a chlorinated phenylacetate. This chlorinated derivative was subsequently converted to the fluorinated analog by a series of steps. The product, FQNPe, was generated from the fluorinated phenylacetate by transesterification with racemic quinuclidinol. The purpose of the ORNL group's research is to develop radiolabeled ligands such as FQNPe for use in further studies in nuclear medicine. The project described at the conference is based on McPherson's design and development of IQNP. The researchers began by preparing isomers of IQNP, which show rapid and significant localization in muscarinic-receptor-rich areas of the brain. IQNP isomers allow the researchers to observe changes in muscarinic re-
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FEBRUARY 27,1995 C&EN 43
SCIENCE/TECHNOLOGY
ceptors that are thought to occur with brain and heart disease. The major area of focus is dementias, in particular Alzheimer's disease. Postmortem autopsy studies have shown that the number of one subtype of the receptor is less in brains from patients with established Alzheimer's disease. 123 I-Labeled IQNP is an attractive candidate to evaluate the receptors in humans by single photon emission computerized tomography (SPECT). However, compared with SPECT, PET imaging has the advantage of higher resolution and shorter acquisition times, the researchers say. Thus, they have turned to preparation of IQNP analogs that can be used for PET. Knapp's group carried out an initial in vivo evaluation of the brominated IQNP analog, BrQNP, to develop a specific and selective muscarinic ligand for labeling with 76Br for PET. The researchers determined that BrQNP blocks the uptake of IQNP in the brain and heart of rats, demonstrating the affinity of BrQNP for muscarinic recep-
tors. An initial in vivo experiment shows that FQNPe also blocks the cardiac and cerebral uptake of IQNP by greater than 70%. The ORNL team has carried out in vitro binding assays with FQNPe in conjunction with Barry Zeeberg, Virender Sood, and Richard McRee of the Division of Nuclear Medicine at George Washington University Medical Center, Washington, D.C., and Dick Reba, chief of nuclear medicine at the University of Chicago Hospital. The results confirm that FQNPe has a high affinity for the muscarinic receptors. The researchers are currently working on methods for 18F labeling of FQNPe for use as a PET agent. Given the growing importance of fluorinated amino acids and their derivatives in biological and medical applications, the ACS Divisions of Fluorine Chemistry and Medicinal Chemistry are planning a joint symposium on fluorinated amino acids at the 210th ACS national meeting in Chicago in
August.
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George Olah reflects on chemical research George A. Olah won the 1994 Nobel Prize in Chemistry for his lifelong work on carbocations. C&EN's assistant managing editor for science and technology, Rudy M. Baum, attended Olah's Nobel Lecture in Stockholm. Recently, Baum talked with Olah about his work and his views on-the role of chemistry in modern society.
George A. Olah is an optimistic chemist. "I'm a great believer that chemistry has a major role to play in our lives and the lives of future generations," Olah says. "Not only in exciting fields like the biological and health sciences, where chemistry contributes a great deal to our understanding at the molecular level, but as a core science in its own right. Chemistry is often maligned—we are the guys who are fouling up the atmosphere, we have the stinky plants, and so on. But we are also the guys who can produce essential materials and compounds that are touching all of our lives. "However, we have to do this," he continues, "in a way that protects the environment to the maximum possible extent. I believe you can do both. In other words, you can fulfill mankind's needs, produce what is needed for the high standard of living we are all used to. Few want to give that up. But at the same time, do it in new ways that are more compatible with a safe and an environmentally benign coexistence between technology and nature." Olah is also a very practical chemist. "I spent most of my life in basic research, which I find very challenging and rewarding," he observes. "But if you keep your eyes open and you observe new phenomena, sometimes you can apply them to very practical uses. I am no believer in a dichotomy between basic science and applied science. The two can very much complement each other. "I spent eight years in industry, at Dow Chemical, and I had a very good time. I also think I was quite productive for my employer. I've always felt that practical challenges are also intellectually challenging. I think too many people disregard the practical applications of basic research. To me, it was always a pleasure to do both." Optimism and practicality, idealism
