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Curmmt Cammsmts@ EUGENE GARFIELD INSTITUTE FOR SCIENTIFIC lNFOHMATION@ 3S01 MARKET ST., PHILADELPHIA, PA 19104 Work on That Mimic ~~obgical Processes Leads to 1987 in for Jean-Marie Lehn, Charles J. Pedersen, and Donald J. Cram

Number 15 April 11, 1988

The 1987Nobel Prize in chemistry was awarded to Charles J, Pedersen, Donatd J. Cram, and Jean- Marie L.ehnfor their work in the field of of molecules that mimic blologicat pro- cesses. These have previously appeared in lS1° studies of most-cited papers in the physicat and chemicat and the most-cited papers from 1961-1982. The history of the discoveries that led to the 1987 award is reviewed. as well as a Ciration Cla.rsic@commentary. bv. Pedersen on hk seminal work involving crown ethers.

For over 30 years, one of the goals of syn- formation) interrupted at regular intervals thetic chemistry has been to faithfully imi- by oxygen ; in the absence of metaf tate biological activity. The 1987 chemistry , the crown ether ring is “floppy.” prize was awarded to three reaearchers— However, upon introducing a metal two American and one French—for their (where the binding takes place at the center work in elucidating mechanisms of molec- of the crown ether’s circle), the ion makes ular recognition, which are fundamental to the crown assume a more organized, plate- errzymic , regulation, and transport. like shape.q In the words of the Nobel cmnrrrittee, “The Pedersen’s serninrd paper, “Cyclic poly- laureates’ research has been of great impor- ethers and their complexes with metal tance for developments within coordination Salts,”z has been explicitly referenced in chemistry, organic synthesis, analytical nearly 1,400 publications since its appear- chemistry, and bioorganic and bioinorganic ance in 1967. According to Pederaen, he be- chemistry, and has thus laid the foundation gan his work on crown ethers rather late in for the active interdisciplinary area of re- his career, in 1%1 at the age of 57. In a search within chemistry that has now come 1985 Cirution (Xz.rsic” commentary on the to be termed host-guest chemistry or supra- work, he observed molecular chemistry. ” 1 the crown ethers might have been stiJl- bom in another environment. They were Crown Ethers A History discovered in the Elas~omer Chemicats Department of E.I. du Font de Nemours In 1967 Charles J. Pederaen, formerly of and Company, but what had they to do E.I. du Pent de Nemoura and Company, with elastomers? Moreover, the small Wihnington, Delaware, published two pa- amount of the byprwhwt might have been pers that described the binding of alkah met- tossed out or disregarded as something Other than the desiredproduct.... I WOlkd al ions (lithium, sodium, potassium, rubid- independently with these compounds for ium, and cesium) by compounds he called nearly eight years.f “crown ethers” (cyclic Polyethers),z.s These compounds are made up of a large Pederaen’s discovery was the begiming circle of carbon atoms (the “crown” con- of a new direction in chemistry research,

111 Table 1: Charles I. Pedersen’s most-cited papers. A=nurnber of citations.. B=bibiiogrsphic citation. The SCF research fronts to which the paper is core are included in parentheses.

A B

1,368 Pedersen C J. Cyclic pcdyethers and their complexeswithIMtst~ts. J. ~CK Chem. .$oc. 89:7017-36, 1%7. (86-4022, 85-4065, 84-1038, 83-1019, 81-1304, 78-0920, 77-2325, 76-0762, 75-0644, 74-0609, 73-0063) 652 Pedersm C J & Frerrsdorff H K. Macmcyclic polyethers and ttseir complexes.~ngerv.C&m M. Ed. 11:16-251972. (85-4065, 84-0420, 81-1304, 78-0920, 77-2325, 76U762, 75-0644, 74-0609, 730063) 306 Pedersen C J. CrystaWresnltcomplexesof macrocyclicpolyerhers.J. Arnsr. chart Sot. 92:38691, 1970. (86-4022, 854065, 83-1019, 81-1304, 79-t376, 77-2326, 76-0762, 75-0644, 74-0609, 734063) 306 Pedersen C J. Letrer to editor. (Cyclic polyethers and @ek complexes with metal sak..) J. Amer. Chem. Sot. 89:2495-6, 1%7. (86-4022, 854065, 84-1038, 83-1019, 81-1304, 78-2143, 77-2326) 237 Pedersen C J. New macmtyclic polyethers. J. Amer. Chem. SK 92:391-4, 1970. (854065, 83-1019, 78-2143, 77-2326, 75-0644, 744509, 73-@363) with an emphasis on ionic bonding. Accord- functions. g Then Lehn read about ing to Franqois Diederich, Department of Pedersen’s work the following year, and re- , University of Califor- calls that nia, Los Angeles (UCLA), “ in the century before Pedersen’s work concen- trated on the covalent bond. From now for- for me the crown ether results were an isn- ward, there will be increased focus on the portant indication about the category of chernicat functions &at may bind alkali noncovalent bond-on very weak interac- cations. However, tie start was really my tions in biological and abiotic systems.’ ‘b interest for .,.ionophoretic Nobel laureate Linus Pauhng (chemistry, ...[and] about the structure and 1954; , 1%2) initiated work on weak synthesisof these substances.... I wish to interactions in the 1940s, especially focusing stress these points because the natural an- on the partial ionic character of chemical tibiotics acting as ionophores have been bonds, using the concept of negativity.T neglectd inpresentation of the field, and, Table 1 lists Pedersen’s most-cited papers. for me at least, they gave the first clues In 1969, via the paper ‘‘Diaza-polyoxa- that afkafi ion transport and binding was achievablewithmacrocyclicchemicatsub macrocyclic and macrobicyclic com- stancesof suitablestructure, This then led pounds,”s Jean-Marie Lehn and coauthors to the cryptates [complexes in which the B. Dietrich and J.P. Sauvage, Institute of eation is contained inside the molecular Chemistry, Strasbourg, , took cavi~-the crypt], whichincorporatedthe Pedersen’s principle into three dimen- demonstrationby Pedersmrthate?hertimc- sions—by adding more bridges of these tions were suitable binding sites. 10 crowns, creating polycyclic compounds that L-A-mcalled “.” These three-di- mensional molecules contain molecular Lehn termed the complexes of bridged clefts, or crypts. The effect of the additional crown ethers suprarnolectdar chernistry— bridges was to make the structure less flop- “chemistry beyond the ’ ‘%Y3- py and to expand the range of substrates that cause of the speeific but weaker intermolec- could be made to fit. ular interaction between the two entities (the This achievement had its roots back in molecule and the substrate), instead of the 1966, when L.ehn’scuriosity about the pro- formation of strong, intramolecular covalent cesses Occurnng in the human nervous sys- bonds (which is the basis of molecular chem- tem led him to wonder how a might istry). Table 2 lists Lehn’s most-cited pa- contribute to the study of these biological pers.

112 Tabte Z Jean-MsrieLeho’smost-citedpapers,A =number of citations. B =bibliographk citation.TtESCF research frontsto whichthe psper is coreare includedin parentheses.

A B

569 Lehn J-M. Design of orgsnic completing agents. Strategies towarck properties, Struct. Bond. 16:1-69, 1973. (86-4436, 85-4065, 844861, 83-1OI9, 82-2755, 81-1304, 78-0920, 76-0759, 75-0721, 74-06C9) 350 L&r J-M. Cryptates: the chemismy of rrracropolycyclic inclusion complexes. Account, Chem. Res. 11:49-57, 1978. (S6-4436, 85-0920, 84-0420, 83-1019, 81-1304, 80-1084) 298 Lebrr J-M. Nbrogen inversion. Experiment andthemy. Fortschr. Chem. Forsch. 15:311-77, 1970. (84-8029, 83-S092, 82-2723, 77-2043, 7.$1519, 75-1263, 74-1230) 271 Dfetrkh B, Lehn J-M & Smrvage J P. Disza-pdyoxa-macrncycles et nracrobicycles (Dia.ra-pnlyoxs- macrocyclic snd nracrnhicyclic compounds). Tetrahedron La. 34:2885-8, 1%9, 259 LAO J-M & &mvage J P. (2)-crypcwcs: stabifity and selectivity of dkati snd FdkdiIIe-earth macroblcyclic complexes. J. Amer. Char. Sot. 97:6700-7, 1975. (86-4436. 85-4065, 844861. 83-1019, -81-1304, ”77-2066)

In 1978 Donald J. Cram, Department of organic chemistry in their attempts to build Chemistry, UCLA, coauthored a paper with compounds containing cavities shaped to ac- his wife, Jane M. Cram (also of UCLA), commodate a desired substrate. entitled’ ‘Design of complexes between syn- The historiograph in Figure 1 shows the thetic hosts and organic guests, ” 11which growth of the specialized area of chemistry was inspired by Pedersen’s original work. that deals with crown ethers and the subse- But Cram’s efforts were towards creating quent advances in supramolemdar and host- cyclic compounds that would remain rigid— guest chemistxy from 1978 to 1986. whether or not they were binding a sub- strate. This principle of’ ‘preorganization” has been designed into the more than 500 Citation Analysis of the Laureates binding molecules, or cavitands, synthesized so far by Cram and colleagues. Cram calls this phenomenon “host-guest” chemistry, It is hardly surprising that the three chem- with the “host” containing binding sites that istry laureates have turned up in several converge and’ ‘guests” binding sites that di- “most-cited” studies that have appeared in verge to meet one another. 12Cram’s most- Current Contentsm since 1980. Lehn, who cited works are listed in Table 3. first appeared in a study in November Although Lehn and Cram employed dif- 1980,13 has appeared in a total of five ferent approaches, they both used synthetic studies. 13-17Cram and Pedersen have each

Table3 Donstd J. Cmm’smost-cited papers. A =number of citations. B=bibliographic citation. The SCF research fronts to which the paper is core are included in parentheses.

A B

571 Cram D J & Ebfez. F A A. Studies in sterecchernistry. X. The rule of “steric control of asymmetric induction” in the synthesis of acyclic systems. J. Amer. Chem. SW. 74:5828-35, 1952. (86-0989, 85067, 84-1969, 83-4315, 82-1702, 734657) 351 Cram D J & Kopecky K R. Studies in . XXX. Models for steric cmrtrol of asymmetric induction. J. Amer. C&n. Sot. 81:2748-55, 1959. (85-0967, 84-1969, 82.1702, 73-0657) 219 Cram D J, Aninger N L & Steinberg H. Macrorings.VII. The spectrslconsequencesof bringing two benzeneringsfaceto face.J. Amer. Chem. Sot. 76:613241, 1954. (83-1 156) 214 Gokel G W, Cram D J, Liotta C L, Harris H P & Conk F L. Preparation and purification of 1S-crown-& J. Org. Chem. 39:2445-6, 1974. (82-1904) 212 Cram D J & Cram J M. Design of complexes lxtween synthetic hosts snd orgsnic guests. Account. Chem. Res. 11:8-14, 1978, (86-4022, 85-0920, 83-1019, 81-1304, 80-1084) 212 Cram D J. Studies in stereochemistry. I. The stereospccitic Wagner-Meerwein rearrangement of the isomers of 3-phenyl-2-butanol, J. Amer. Chern. Sot. 71 :3S63-70, 1949.

113 F&rare1: SYNTHESESOF MOLECULESTHAT MIMIC BIOLOGICAL PROCESSES. Historiosrasrh-. show- ing developmentsin this research. Numbers of cnrelciting papers are indicated at the twttom of each box. Aster- isks (*) indicate research fronts in which C.J. Pcderaenis a core author; da~ers (t) indicate researchfrmrrs in which J.-M. Leho is a core author; and number signs (#) iodicatc research fronts in which D.J. Cmm is a core author.

t7941327 t#80-10B4 Light inducedelectron Syrrtfseaisand transfer reactionsin characterizationn “t78-0920 nonnatural systems of crown athers ●#t61.1304 t82.2755 Macrocyclic 15/12~ 2/67 IMacrocyclic Eomplaxationand catalysis complexes E complexes ly mr3crocycliccrown and ions athersand cryptands ❑12/141 2/61 = F6’2’2- lE3_!w

appeared in one—Cram in March 198214 ing crown ethers.zo “We have a very long and Pedersen in October 1984.18 way to go before we can match natural sys- A multidimensional scaling map for tems, but we are on the road, ” asserted C2-level research front #86-0466 on host- Cram during a interviewed guest chemistry and molecular recognition is depicted in Figure 2. The map shows the interrelatedness of cryptands, organic syn- thesis, and crown ethers research. Biographical Sketches The laureates’ work has implications for of the Laureatea the better understanding of how biological mechanisms function, especially those of the Charles J. Pedersen was born in 1904 in human body. Their work provides insights Pusan, Korea, of Norwegian and Japanese into how recognize substrates and parents. He earned his BS degree in chemi- the way hormones communicate with cells. cal engineering at the University of Dayton, The results of the prizewinning research also Ohio, and an MS degree in organic chem- illuminate how neurotransmitters propagate istry at the Massachusetts Institute of Tech- signals, how CXAIsread genetic code, as well nology, Cambridge. It is indeed unusual for as how antibodies and immune cells a non-PhD to be awarded the Nobel Prize recognize antigens.b This research may also in chemistry. have applications in the design of extreme- In 1927 he began to work at du Pent, ly sensitive chemicals for use in removing where he remained for 42 years, retiring in poisonous substanm from contaminated soil 1969. While at du Pent he was the author or water, 19and already experiments have of 65 patents. In 1%8 he reeeived the Del- shown that rats have been partially detoxi- aware Section Award of the American fied of lead and radioactive strontium by us- Chernicrd Society (ACS).Z1

114 L.--w?4

Donald J. Cram was born in 1919 in 1970 he has been a professor of chemistry Chester, Vermont. He received his BS de- at Louis Pasteur University, Strasbourg, and gree in chemistry from Rollins College, since 1979, also a professor at the College Winter Park, Florida, and his MS degree in of France, . L.ehn has been called the the same field from the University of Ne- foremost chemist in France,zl and the Na- braska, Lincoln. He then worked at Merck tional Center for Scientific Research and Company for three years. Cram gradu- (CNRS) has conferred upon him their ated from Harvard University, Cambridge, bronze, silver, and medals for his work in 1947 with a PhD in chemistry; in that in chemistry. He was also the recipient of same year he became a professor at the a gold medal from the Pontifical Academy UCLA Department of chemistry, where he of Sciences in Rome in 1981 and the 1982 has remained. (3am has had much irdluence Paracelsus Prize of the Swiss Chemical throughout the international chemistry com- Society. Lehn is a foreign associate member mUnity.21He was ekxted to the US Nation- Of the NAS.23 al Academy of Sciences (NAS) in 1961, at the age of 42; in 1965 he rweived the ACS Crowning Conclusion Award for Creative Work in Synthetic Or- ganic Chemistry, as well as fhrt.her ACS According to the ., the awards-in 1974, the Arthur C, Cope work of these three chemists is part of the Award, and in 1985, both the Roger Adams Award and the WWard Gibbs Medrd.2z goal...toproducesynthetichostmolecules that recognize blologicatly active - Jean-Marie Mm was born in 1939 in cules.... The explosivedevelopmentof the Rosheim, France. He received his BS, MS, art of organic synthesishas enabledCram and PhD (1963) in the field of chemistry and Lehn to produce hosts which to some from the University of Strasbourg. Since extent mimic enzymes such as proteases,

115 Figure 2: HOSTGUESTCHEMISTRYAND MOLECULAR RECOGNITION, Multidimensional scaling map forC2-leve}researchfront#S6-04&.Tbesizeoftbecirclesisdeterminedby the total numbmof citesreceived bytbecorepapersintheresearchfront.Numbers of core/citing papers in each Cl front are indicated atler the research-front name.

ATP-sses and transacylases. Supercom- Ck.rsic commentary,s Pedersen includes plexes which bind organic substrates and his poem, reprinted below, on crown ethers. metal ions have reeentty been produced by Lehn. It will thus be possible to pro- duce supermolecufes which do not suffer THE CROWNING from the present limitations on substrate stmcture and reaetion tyw in, for examp- The afksline earth cations le, enzymes. Through their work, Cram, And the alkafi too, tihn and Pcdersen have shown the way.1 Used to aet lie freeborn lions, %oming some things to do. Organic Iigands they disdained Outside of the laboratory, ptry is a fa- Till crown ethers were found, Now with these compounds scierree ordained vorite means of self-expression for some They can bc meekfy crowned. scientists. There are a number of eminent scientists, including chemists, who have ***** published their poetry; we have discussed the works of and Nobel My thanks to C.J. Fiscus and Peter laureate Roald HoffinsuuI.24 Some, like Pesavento for their help in the preparation Pederaen, draw upon their research activities ~f this essay. as a source of inspiration. In his Citation G,7381s1

116 REFERENCES

1. Royof Swetfiak Academy of Seierm?s. Awarded for syntheses of molecules that mimic implant biological processes. 14 Cktober 1987.4 p. (Press release, ) 2. Pedersen C J. CycJiC polyetkrs and their complexes with metal salts. J. Arncr. C7rem.Sot. 89:7017-36, 1%7. 3. —--—-. Letter tn editor. (Cyclic @yethers and their complexes with metal Saks,) J. Amer. Chem. Sot. 89:2495-6, 1%7. 4, Lewin R. Chemistry in the image of biology, Science 238(4827):611-2, 30 October 1987, 5, Pedereen C J. Citation Classic. Commentary on J, ,irrrer, Chem. Sot. 89:7017-36, 1967, Currenr Cbntents/Engirreering, Technology & Applied Sciences lq32): 18, 12 August 1985 and Currenr Contents/Physical, Chemicof & Earth Scienres 25(32): 18, 12 August 1985, 6, Nobel Prizes: U. S., French chemists ahsre award. C7tem. Eng. News 65(42):4-5, 19 October 1987. 7, Pmdkrg L. Jhe nature of the rrnd the structure of molecules and : an inmoduction to modem . Ithaca, NY: ComeU University Press, 1960, 644 p, 8. Dietrkh B, Mm J-M & Sauvage J P. Diam-pnlyoxe-macrncycles et rnacrobicycka (Diaza-pnlyoxa- macmcyclic and macrobicycJic compounds). Tetrahedron Lett. 34:2885-8, 1%9. 9. Lehn J-M. suprarnolecolar chemistry-acops and perspectives. Molecules, supermolmdes, and rrmkular devices (Nobel lecture). Angew. Chem. ht. EM 271(1):89-112, January 1988. 10, ——. Persoualeommunicmion.17 February1988. 11, Cram D J & Cram J M. Design of complexes between synthetic hosts and organic guests. Account. Chem. I& 11:8-14, 1978. 12. Cram D J. Personal conmtuoication, 12 February 1988, i 3. Gctrffeld E. 1978 articles most cited in 1978 and 1979, 1. Physical sciences. Essays of an infer-marion , Phtidelplk 1S1 Press, 1981. Vol. 4. p. 674-85, (Reprinted from: Current Contents (46):5-16, 17 November 1980.) 14. ——. The 1,000 most-cited contemporary authors. Part 2A. Details on authors in the physical and chemcal sciences and anme cmrrrnentsabnut Nnbals aml academy memberships. Ibid., 1983. Vol. 5. p. 428-36. (Reprinted from Current Contents (9):5-13, 1 March 1982.) 15. —--—. The 1,OfJOcontemporary scientists nmat+itcd 1965-1978. Part 1. The basic list md irrtrcduction. ibid. p. 269-78, 16. —. The 1979 articles moat cited frnm 1979 to 1981.2. Physical sciences. Jbid. p. 634-42. 17. —------The 1980 chemistry articles most cited in 1980-1982. ibid., 1984. Vol. 6. p. 276-86. 18. ---—-. ‘The articles most cited in 1%1-1982. 5. Annther 100 Citation Cfassics and a summary of the 500 papers identified to date, J6id., 1985. Vol, 7. p. 326-35. (Reprinted from: Current Contents (42):3-12, 15 Ctctober 1984.) 19. Scfrmesk H M. Chemistry end Nolrels haiJ discoveries on life and sufxxcnnductors. New York Jlmes 15 fktnber 1987. p. A14. 20. Lernonfck MD. Feats of inspiration and originahty. 7ime 26 fktober 1987. p. 134. 21. Winners of Nobels in chemistry and physics. New J’ork Jimes 15 October 1987. p. A14. 22. Prestigious awards to four noted professors. Chem. Eng. News 63(22):59-60; 70, 3 June 1985. 23. lahn, Jean-Marie Pierre. Internotiorral who’s who 19S687 Fif?ieth edition. London: Europa, 1986. p, 928, 24. Garffeld E. Further reflections on the poetry-science connection. Curreru Contents (7):3-9, 17 February 1986,

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