anniversary of the tröger’s base molecule: synthesis and...

MICROREVIEW

DOI: 10.1002/ejoc.201201249

The 125th Anniversary of the Tröger’s Base Molecule: Synthesis andApplications of Tröger’s Base Analogues

Ögmundur Vidar Rúnarsson,[a] Josep Artacho,[a] and Kenneth Wärnmark*[a]

Dedicated to the memory of Julius Tröger on the 150th anniverary of his birth and to Craig S. Wilcox forreopening the field of Tröger’s base chemistry

Keywords: Tröger’s base / Supramolecular chemistry / Synthetic methods / Materials science / Nitrogen heterocycles

In 2012 we celebrate the 125th anniversary of the unique mo-lecule Tröger’s base (TB), first synthesized by Julius Trögerin 1887. Being a V-shaped C2-symmetric chiral molecule, itpossesses many interesting features. The TB field was re-opened in 1985, when Craig S. Wilcox published the firstcrystallographic study of TB and described the synthesis andpotential applications of TB analogues in supramolecularchemistry and in ligand design. This led to increasing inter-est in the development of synthetic methodology for TB ana-logues, initially for applications in the field of molecular re-cognition. In this review we give a short historical overviewof TB and its chemical properties. In addition, we cover thefast progress in the development of synthetic methodologiesto synthesize TB analogues that has taken place during re-cent decades. The functionalization of TB at almost any posi-

Introduction

The history of Tröger’s base (TB) began in 1887 whenCarl Julius Ludwig Tröger published a paper on condensa-tions between aromatic amines and methylal [CH2-(OCH3)2].[1] From the reaction between p-toluidine andmethylal in aqueous HCl he isolated an unexpected productthat he described as “base C17H18N”. Nearly half a centurylater, in 1935, the correct chemical structure was determinedwhen Spielman assigned TB as racemic 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine [(�)-1,Figure 1] after carefully studying the reactivity of the sub-stance.[2] In the same year, Wagner reported a proposedmechanism for the condensation by which TB (1) is formed(vide infra).[3]

TB consists of a bicyclic aliphatic unit fused with twoaromatic rings. The central methanodiazocine unit projects

[a] Center of Analysis and Synthesis, Department of Chemistry,Lund University,P. O. Box 124, 22100 Lund, SwedenFax: +46-462224119E-mail: [email protected]: http://www.chem.lu.se/People/Warnmarkgroup/

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tion in its skeleton is now possible and we discuss in detailrecent developments in the functionalization of TB in the aro-matic rings and in the methano bridge. The reopening of thefunctionalization of the diazocine ring itself is also discussed.In addition, progress in the synthesis of heterocyclic TB ana-logues and recent developments in the field of fused TB ana-logues are covered. The improvements in synthetic ap-proaches have resulted in TB analogues with interestingproperties that have inspired investigation of TB analoguesin new fields of applications, among others as receptors, asmolecular torsion balances, as ligands in asymmetric cataly-sis, as drug candidates, and as new materials for photo- andoptical applications. The most recent developments in thosefields are also discussed.

Figure 1. TB [ (�)-1] and the MMFFs-optimized structures of itstwo enantiomers.

the aromatic rings in nearly perpendicular fashion, makingTB a rather rigid V-shaped molecule possessing a hydro-phobic cavity (Figure 1). In addition, TB is C2-symmetricand thus a chiral molecule. The methylene bridge precludespyramidal inversion of the two nitrogen atoms, makingthem configurationally stable stereogenic centers; TB wasone of the first molecules containing such N atoms to beisolated. Because the stereogenic N atoms are bridgeheadatoms, only the enantiomers of either the R,R or S,S config-uration are possible (Figure 1), with the diastereomeric(R,S)-TB being geometrically unfeasible.

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWIn 1944, Prelog and Wieland resolved the two enantio-

mers of TB by chromatographic separation with (+)-α-lac-tose hydrate,[4] making TB one of the first molecules to beresolved on an enantiopure stationary phase. In 1986 thestructure proposed fifty years earlier by Spielman was un-ambiguously confirmed by single-crystal X-ray diffractionanalysis by Wilcox.[5] The matter of the disputed absoluteconfiguration of TB was settled in 1991, when XRD analy-sis of a diastereomeric salt of monoprotonated TB contain-ing a chiral counterion of known configuration concludedthat (+)-TB had the S,S configuration.[6]

Despite the widespread use of liquid chromatography forthe resolution of (�)-1, efficient enantiomeric separationsof functionalized TB analogues were unknown for a longtime. However, the use of commercial HPLC stationaryphases for this purpose has recently been reported.[7] Theseparation of enantiomers of TB and its analogues on semi-preparative scales and in routine manner is now possible.

Prelog was the first to report that TB slowly racemizesin a dilute acidic medium. He postulated that the inversionof configuration occurs through the reversible formation ofthe methylene-iminium ion 2 (Scheme 1) as a key intermedi-ate,[4] despite the fact than no spectroscopic evidence forsuch an intermediate had been observed.[8] Nevertheless, itwas suggested that the iminium species exists only tran-siently and in too low a concentration to be detected. Thismechanism of racemization is indirectly supported by thefact that ethano-bridged TB analogues, which are unable toform such stabilized iminium intermediates, are configura-tionally stable to acidic conditions.[9] In concentrated acids,in which both nitrogen atoms are protonated,[8] it is not

Ögmundur Vidar Rúnarsson obtained his B.Sc. in 2002 and M.Sc. in pharmaceutical sciences in 2004 from the Universityof Iceland. He is currently a postdoc fellow in the K.W. group, where he is synthesizing new TB analogues and investigatingtheir drug–receptor interactions. He received his Ph.D. in medicinal chemistry in January 2009 from the University ofIceland, where he worked on synthesis and structure–activity relationship investigations of novel analogues of chito-saccharides (polymers, oligomers, and monomers) against various Gram-negative and Gram-positive bacteria.

Josep Artacho graduated from Universitat de Girona (Spain) in 2004. He joined the K.W. group as an exchange studentthe following year and then later did his Ph.D. project in the group. The purpose of his PhD work was to fuse a numberof Tröger’s base molecules together linearly and in a controlled manner. Special attention was given to the functionalizationof the TB core, leading to interesting molecules such as twisted amides and crown ethers. Dr. Artacho obtained his Ph.D.in October 2011. He is currently a postdoc fellow at the University of Copenhagen.

Kenneth Wärnmark obtained his Ph.D. at the Royal Institute of Technology, Stockholm, under the supervision of Prof.Christina Moberg, working with macrocyclic ligands. He then continued with postdoc studies at l’Université de Strasbourg(1994–1996) with Prof. Jean-Marie Lehn, working on ruthenium-N-heterocyclic complexes. He started his independentcareer at Lund University as assistant professor in 1996 and he was promoted to senior lecturer in 2000. He becameassociate professor in 2003 and since December 2010 he has been full professor of organic chemistry at Lund University.His research interests, apart from Tröger’s base chemistry, include supramolecular catalysis, self-assembly, moleculartubes, and molecular receptors.

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possible to form the iminium intermediate, probably be-cause there is no free electron pair available for the openingof the bridge, and so racemization does not occur.

Scheme 1. Mechanism of racemization of TB in acidic media.

A different racemization mechanism was proposed byTrapp and Schurig.[10] They suggested that in the (inert) gasphase at ambient temperature the TB racemization pathwayinvolves a retro-hetero-Diels–Alder ring opening followedby hetero-Diels–Alder ring closure, via intermediate 3 (Fig-ure 2). However, recent work by Schröder and co-workersstudying the epimerization of fused bis-TB analogues byion-mobility MS demonstrated that inversion of the config-uration only occurred for the protonated species. The ab-sence of this process in the cationic sodiated species sug-gested that the sequence via iminium ion 2 is the moreprobable mechanism.[11]

The pKa of the monoprotonated salt of TB in 50% aque-ous alcohol was determined by Wepster to be 3.2.[12] TheV-shaped structure of TB forces the free electron pairs of

Tröger’s Base’s 125th Anniversary: Synthesis and Applications of Analogues

Figure 2. Proposed intermediate for the retro-hetero-Diels–Alder/hetero-Diels–Alder mechanism for the racemization of TB.[10]

the bridgehead nitrogen atoms out of conjugation with re-spect to the aromatic planes, which hinders full conjugationwith the aromatic system. This restriction would be ex-pected to result in the pKa of monoprotonated TB havinga value between those of the anilinium ion (ca. 5) and thealkylammonium ion (ca. 10). Wepster explained the appar-ently abnormal pKa of protonated TB by the fact that thebenzylamine and the methylenediamine groups present inTB should lower the basicity and estimated this to be bytwo pKa units.[12–13] We propose that the low pKa is in ad-dition a consequence of stabilization through an anomericeffect. The electron lone pair of one nitrogen atom thusoverlaps with the antibonding orbital of the bond betweenthe carbon at the methylene bridge and the second nitrogen(Figure 3), making the N lone pair even less available forproton binding. This effect can be geometrically observedin the bond lengths of unsymmetrical TB derivatives suchas protonated TB. Thus, the bond length between the pro-tonated N and the bridging CH2 has hence increased rela-tive to that in TB itself, whereas that between the other Nand the bridging CH2 has decreased (Figure 3) as expectedfor an anomeric effect,[14] according to DFT calculations.[15]

Figure 3. Overlap of the lone pair of one nitrogen atom with theantibonding orbital of the bond of the carbon and the other nitro-gen atom (left). Selected bond lengths in TB (middle) and in pro-tonated TB (right), supporting the presence of hypoconjugation(see text for details).

Until the 1980s, TB was used mainly as a model sub-stance for the evaluation of new chiral chromatographictechniques, due to its easy separation into its enantiomers(vide supra). In the second half of the 1980s, however, inter-est in analogues of TB emerged. In a pioneering work in1985, Wilcox reported the XRD structure of the TB frame-work with the synthesis of several simple yet unprecedentedTB analogues.[16] This triggered further developments in thesynthesis of TB analogues, which have found applicationsas building blocks in various fields of chemistry. Over 530

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articles dealing with TB chemistry are currently to be foundin the literature, and approximately 60 % of these have beenpublished in the last decade. Review articles and book chap-ters thoroughly covering TB chemistry have been publishedregularly in the past years.[17] This review focuses on thesynthetic aspects of functionalized TB analogues and theirbroad spectrum of applications in various fields of chemis-try.

Synthesis of Tröger’s Base and Analogues

The Tröger’s Base Condensation

The first TB synthesis involved the condensation betweenp-toluidine and methylal in aqueous HCl.[1] The variousmethodologies used for the synthesis of TB analogues areindeed variations of the original conditions. A syntheticequivalent of methylene – namely formaldehyde or a pre-cursor, such as paraformaldehyde or hexamethylenetetra-mine – is treated with a suitably substituted aniline deriva-tive under acidic conditions, usually aqueous or alcoholicHCl solutions, acetic acid, trifluoroacetic acid (TFA), ormethanesulfonic acid (Scheme 2).[16,18] Nonetheless, the se-arch for improved synthetic protocols is still ongoing, as isillustrated by recent reports[19] on the rediscovery ofDMSO, first used by Becker in 1993,[20] as a methylene syn-thetic equivalent. Furthermore, improvements in Lewis-acid-catalyzed TB synthesis[21] and in the use either of un-usual condensation media such as ionic liquids[22] or digly-colic acid/polyphosphoric acid[23] or of super-acidic condi-tions have been reported.[24]

Scheme 2. The TB condensation.

Condensations based on this general approach have dem-onstrated high sensitivity both towards the electronic prop-erties of the substituents and towards the substitution pat-terns of the aniline components. It was long believed thatthe substituents on the aromatic ring should have electron-donating natures, to avoid the low-yielding, sluggish reac-tions observed with electron-withdrawing groups.[25] In ad-dition, it was also believed that a substituent in the para-position might be needed to avoid polymerization.

A synthetic breakthrough occurred, however, with thedevelopment of a condensation protocol for the synthesisof halogenated TB analogues, introduced by our group in2001.[26] The use of paraformaldehyde and TFA overcamethe longstanding limitation of electron-withdrawing substi-tutes mentioned above and gave access to TB analoguessubstituted with halogen atoms in virtually any position inthe aromatic rings.[27] This protocol has become the mostregularly used method of all the known variations. Accord-ingly, this methodology does not only allow multi-gram

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWsyntheses of halogenated TB analogues,[28] but also enablesthe introduction of a wide range of both electron-donatingand -withdrawing substituents, such as alkyl chains, MeOand MeS, COOR, CF3, and even the strong electron-ac-ceptor NO2.[7d,29] Importantly, this method has also provedvalid for the condensation of aniline itself, giving the di-demethylated TB analogue in a remarkable 78 % yield,[30]

so para-substitution to avoid polymerization is no longerneeded.

Wagner was the first to attempt to explain the acid-in-duced reaction sequences between formaldehyde and p-to-luidine by which TB (1) is formed.[3] Both Farrar[31] andWagner[18a,32] reexamined this work, which led to the pro-posed mechanism for the formation of the methano[1,5]di-azocine skeleton. The formation involves a series of electro-philic aromatic substitutions as key steps and assumes thepresence of four important intermediates (4–7, Scheme 3).

The first step of the mechanism (for R = Me, Scheme 3)involves an acid-catalyzed condensation between p-tolu-idine and formaldehyde to form iminium ion 4, which inturn reacts with a second equivalent of the aniline to giveintermediate 5. Two sequential methylene additions ac-companied by cyclizations yield TB through intermediates6 and 7. The rate-limiting step of the reaction sequence isthe conversion of tetrahydroquinazoline derivative 6 intothe reactive intermediate 7 and the subsequent electrophilicaromatic substitution.

The presence of electron-withdrawing groups in the an-iline component reduces the nucleophilicity of the second-ary amine in 6, resulting in a further decrease in the rate ofthe intramolecular electrophilic substitution, and gives riseto the formation of the dihydroquinazoline A as a side reac-tion (Scheme 3). Our group suggested that the use of para-formaldehyde in TFA increases the concentration of pro-tonated formaldehyde relative to formalin/HCl in ethanol

Scheme 3. The proposed mechanism for the formation of TBs proposed by Wagner and Farrar.


and therefore increases the reaction rate for the formationof 7.[26] In addition, TFA allows for the reduction of dihy-droquinazoline A to tetrahydroquinazoline 6 after proton-ation by the relatively strong acid TFA, resulting in B, andsubsequent hydride transfer from paraformaldehyde.Sergeyev, on the other hand, argued that iminium ion 4 isinvolved in the rate-determining formation of 7(Scheme 3).[7d] He reasoned that the iminium cation 4 isabundant in the early stages of the reaction, resulting in therapid formation of 7. Later on, however, the concentrationof 4 becomes low due to the slow reverse reactions from 5and 6. The formation of 7 is therefore sluggish and sidereactions occur instead. However, he did not discuss whythe reactions occur successfully with electron-deficient an-iline derivatives in TFA whereas with formalin/HCl they donot.

In a recent work, Eberlin and Coelho monitored the con-densations between p-toluidine and formaldehyde or hexa-methylenetetramine in situ in TFA by electrospray ioniza-tion mass and tandem mass spectrometry [ESI-MS/MS].[33]

This technique permitted the detection and characterizationof – along with iminium ion 4 (Scheme 3) – the oxidizedforms of two of the intermediates suggested by Wagner ([6–H] and [10–H], Figure 4). The natures of the cationic spe-cies observed were argued to be due to oxidation of 6 and7 by the ESI source.

The “Wagner mechanism” that was supported by theESI-MS investigation above was also supported by Wanand co-workers when they isolated compounds 11 and 12(Figure 4) during the synthesis of TB in an ionic liquid (1-butylpyridinium tetrafluoroborate) in the presence of 1-methyl-3-[2-(sulfoxy)ethyl]-1H-imidazol-3-ium chloride ascatalyst.[34] Upon subjection of the isolated intermediates tothe reactions conditions and heating to 150 °C, the expectedTB (1) was formed.


Figure 4. Structures of intermediates and byproducts in the TBcondensations.

Alternative Syntheses of Tröger’s Base Analogues

Elegant one-step condensations of simple aniline deriva-tives to form TB analogues are not always applicable. Be-cause of the relatively harsh reaction conditions, the rangeof analogues is to some extent limited. At the same time,direct condensations between aniline derivatives and form-aldehyde only give access to symmetric analogues of TB.To circumvent these limitations, other methods have beeninvestigated.

Stepwise methods have been employed for the synthesisof unsymmetrical analogues of TB. Webb and Wilcox sug-gested the rational synthesis of such analogues through thetethering of two differently substituted aniline derivativesthrough a methylene unit followed by cyclization with form-aldehyde (Scheme 4).[30,35] It is noteworthy that this methodalso provided the option to prepare TB analogues bearingelectron-withdrawing groups for the first time, although theexamples were limited to such substitution only in one ofthe aniline rings.

Scheme 4. Stepwise preparation of unsymmetrical TB analogues.

In another stepwise approach, Becker synthesized ahighly functionalized TB analogue by treatment of the anil-ine derivative with ethyl oxalyl chloride,[20] followed by

Scheme 5. Stepwise synthesis of a highly functionalized TB analogue.


heating of the resulting ethyl oxalate derivative at 185 °C inDMSO, with the oxalate moiety functioning as a formalde-hyde equivalent (Scheme 5). This approach was developedfurther in recent years by Li and co-workers (vide supra).[19]

TB analogues have also been synthesized by directly in-serting the 5,11-methylene bridge into the tetrahydrodi-benzo[b,f][1,5]diazocine framework. This is carried out invery good yields with formaldehyde, which yields TB (1, R= R� = H, Scheme 6).[36] Alternatively, aldehydes andketones can be used instead of formaldehyde, giving accessto analogues with substituents on their methylene bridges(Scheme 6, R � R� = H and R = R� � H).[37]

Scheme 6. Synthesis of TB analogues by insertion of the bridgingmethylene component into the tetrahydrodibenzo[b,f][1,5]diazocineframework.

Maitra and co-workers reported the asymmetric synthe-sis of a TB derivative in approximately 40 % ee by means ofchiral induction with a 7-deoxycholic acid template, al-though this would nowadays be referred to as a diastereo-selective synthesis, thus giving dr = 7:3 (Scheme 7).[38] Thealteration of the spacer lengths, linking the aniline compo-nent to the chiral template, was found to influence the selec-tivity to some extent.[39]

Scheme 7. Asymmetric synthesis with a chiral template.

Functionalization of Tröger’s Base

TB analogues can today be formed by different methodsallowing for functionalization in almost any position in theTB core (see Figure 5). All the different functionalizationpatterns shown in Figure 5 are discussed below.

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEW

Figure 5. TB (1) and functionalization of TB discussed in this re-view (HCA = heterocyclic amine).

Functionalization of the Aromatic Rings

Halogenation and Cross-Coupling Reactions

Regrettably, in the prominent history of TB there hasbeen a lack of general methodologies to functionalize theTB core, resulting in restricted access to its analogues. Ofthe chemistry devoted to the derivatization of TB, most at-tention has centered on the aromatic rings, due to the easyaccess to halogenated analogues of TB as previously men-tioned.[7d,27–28,29b,30,40] In our 2001 paper introducing theprotocol for the synthesis of halogenated analogues ofTB,[26] it was demonstrated that such analogues can provideaccess to many other functional groups through the intro-duction of ethynyl groups by Corriu–Kumada cross-cou-

Scheme 8. Selected examples of transition-metal-catalyzed transformations with halogenated analogues of TB. Reaction conditions: a) eth-ynylmagnesium bromide, Pd(PPh3)4; b) Pd(PhCN)2Cl2, P(tBu)3, CuI, alkyne-R substrate; c) Pd[P(tBu)3]2, CsF, substituted phenylboronicacid; d) for example, nBuLi, THF, –78 °C, B(OCH3)3, then Pd[P(tBu)3]2, CsF, substituted halobenzene; e) Zn(CN)2, Zn, Pd(Ph3)4, dppf.

Scheme 9. Selected examples of transition-metal-catalyzed carbon–heteroatom bond formation with diiodo-TB analogues. Reaction condi-tions: a) NaOCH3, CuCl, MeOH/DMF; b) 1) Pd2(dba)3, BINAP, NaOtBu, benzophenone imine, toluene. 2) HClaq, THF.


pling (Scheme 8, Route a). Indeed, several research groupsincluding ours have applied a series of transition-metal-cat-alyzed C–C cross-coupling reactions with halogenated TBanalogues as substrates. We introduced substituted alkynylgroups by Sonogashira coupling (Scheme 8,Route b).[28c,40b,41] Lützen introduced arylations by Suzuki–Miyaura coupling with arylboronic acids as coupling part-ners to halogenated TB analogues (Scheme 8,Route c).[41–42] A study published by our group, comparingdifferent palladium-catalyzed cross-coupling methods forthe introduction of aryl and heteroaryl groups via met-alated TB analogues (Scheme 8, Route d), demonstratedSuzuki coupling to be the best method, giving excellentyields, whereas Stille and Negishi coupling both gave mod-erate to good yields.[42b] In addition to classical cross-cou-pling reactions, C–C bond formation has also beenachieved by palladium-catalyzed cyanations (Scheme 8,Route e).[42a,43]

Carbon-heteroatom bond formation through transition-metal-catalyzed reactions starting from dihalogenated ana-logues of TB has also been reported. Ullmann conditionshave been employed for C–O bond formation (Scheme 9,Route a).[7c,41] Our group has formed C–N bonds from ha-logenated TB analogues by halogen/lithium exchange fol-lowed by quenching with TSN3 and subsequent reductionof the corresponding azide (vide infra).[44] This can also becarried out by Buchwald–Hartwig protocols such as Cu-catalyzed amidation[42a] and Pd-catalyzed amination(Scheme 9, Route b).[42a,43,45] This latter example is thor-oughly discussed in the section on functionalization of TBsby amination reactions.


Our group has also developed a different approach tosynthesize valuable analogues of TB.[46] Symmetrical disub-stituted TB analogues were obtained by double halogen/lithium exchange with 2.4 equiv. nBuLi followed by electro-philic quenching. (Scheme 10, Route A). Alternatively, sub-jection of the 2,8-dibromo-substituted TB analogue to thesame conditions, but now with only 1.1 equiv. of nBuLi,resulted instead in the asymmetrically monosubstituted an-alogue of TB (Scheme 10, Route B). The selectivity for thesingle bromine/lithium exchange was attributed to a solventeffect. It was suggested that the dilithiated species was bet-ter solvated in THF than in Et2O. This difference in sol-vation results in a larger difference in energy between themono- and the dilithiated species in the THF/Et2O solventmixture than in THF. Through a second bromine/lithiumexchange of the singly substituted TB analogue and subse-quent electrophilic quenching, asymmetric disubstituted TBanalogues were obtained. We have used the desymmetri-zation protocol as the key step in the synthetic developmentof fused tris-TB analogues (vide infra). Our developeddouble halogen/lithium exchange protocol was later used byDiederich and Sergeyev[47] and by Saigo and co-workers asa key step in the regio- and diastereoselective tether-di-rected remote functionalization of C60 with analogues ofTB.[48]

Scheme 10. Halogen/lithium exchange protocol to provide symmet-ric and asymmetric analogues of TB.

Scheme 12. Synthesis of monoamino-substituted TB analogue 15a and diamino-substituted TB analogue 15b by single and doublebromine/lithium exchange protocols.


Recently, different studies on the direct halogenation ofthe aromatic rings of TB analogues have been reported. Di-dier and Sergeyev synthesized the 8-bromo-2-iodo-substi-tuted TB analogue shown in Scheme 11 from the di-de-methylated analogue of TB by sequential iodination andbromination.[49] In addition, Try and co-workers studied themono- and dichlorination and -bromination of di-demethyl-ated TB and also of differently substituted analogues of TB,resulting in moderate overall yields of halogenated TB ana-logues.[50]

Scheme 11. Sequential halogenation of di-demethylated TB.

Amination

The synthesis of 2-amino-8-bromo-substituted analoguesof TB by our desymmetrization protocol discussed above(Scheme 12, Route A) plays a key role in the synthesis offused analogues of tris-TB.[40b,44] In contrast, by the doublehalogen/lithium protocol we were able to synthesize the 2,8-diamino-substituted TB shown in Scheme 12 (Route B)from a dihalogenated TB analogue.[44]

In our 2006 paper we attempted to optimize the condi-tions further and in particular to increase the scale of thedouble lithiation approach.[44] It was observed during thisinvestigation that the use of large amounts of nBuLi re-sulted in more complex mixtures, making the protocol un-suitable for the preparation of diamino-substituted TB ana-logues on a large scale. An alternative approach using thepalladium-catalyzed aminations of aromatic halides devel-oped by Hartwig and Buchwald was then envisaged.[51] Thisalternative approach gave the best results when the reactionwas performed on a 0.5 mmol scale of 13 (Scheme 13) intoluene at 80 °C in the presence of Pd2(dba)3 (0.5 mol-%),BINAP (1.5 mol-%), benzophenone imine (2.4 equiv.), andNaOtBu (2.8 equiv.), followed by acidic hydrolysis to give15b in an excellent yield of 89%. Scaling up to 4 mmol ofstarting material 13 with 0.7 mol-% precatalyst and 2.1 mol-% BINAP lowered the yield somewhat to 76 %.


Scheme 13. Palladium-catalyzed synthesis of a diamino-substitutedTB.

Some years earlier, Didier and Sergeyev had reported thesynthesis of 2,8- and 4,10-diamino-substituted TB ana-logues from the corresponding 2,8-diiodo- and 4,10-di-bromo-substituted substrates in 86 and 69% yields, respec-tively, also with use of the benzophenone imine/BINAP/Na-OtBu/Pd2(dba)3 catalytic system on a 1 mmol scale, butwith 25 mol-% precatalyst.[43] Although the yields werecomparable to those obtained by us, the amount of precata-lyst used was significantly higher. This contrast motivateda more extensive study of the application of the methodol-ogy,[45] with the 2,8-dibromo-, 2,8-dibromo-4,10-dimethyl-,2,8-diiodo-, and 2,8-diiodo-4,10-dimethyl-subsituted com-pounds as starting materials. These compounds representdifferent reactivities (bromo and iodo), and solubilities(methyl and non-methyl), which are important issues forcontrollability of the amination reaction on a larger scale(4 mmol). The investigation revealed that the catalyst waspoisoned by the released iodide formed in the reaction.Repetition of the reaction in the presence of NaI supportedthis, and as expected the yield decreased when NaI wasadded, explaining the need for higher catalytic loadingwhen iodoaniline derivatives were employed in the TB con-densation.

Pd-catalyzed monoamination of 2,8-dihalo analogues ofTB was attempted, but resulted only in moderate yields ofisolated pure monoamino analogues of TB, although satis-factory ratios between the monoamino- and diamino-sub-stituted TB products were observed in the crude reactionmixture. The best yield of monoamino-substituted TB ana-logue (51%) was achieved after a reaction time of only 2 h.The desymmetrization protocol with selective monolithi-

Scheme 14. Alkylation, benzylation, and acylation of TB itself.

Scheme 15. Stepwise synthesis of analogues of TB with substituted methano bridges.


ation of dibromo-substituted TB analogues followed byTSN3 addition and finally reduction, discussed above, gaveyields of the monoamino-substituted TB product compar-able to those of the Pd-catalyzed reactions (illustrated inScheme 12).[44]

In another approach to amino-substituted TB analogues,Lützen and co-workers obtained a 59% overall yield (twosteps) of the 2,8-diamino-substituted TB analogue by re-duction of the 2,8-dinitro-substituted TB analogue,[29c] thelatter synthesized by a TB condensation with the corre-sponding nitroaniline.

Functionalization of the Methanodiazocine Ring

Functionalizing the Nitrogen Atoms in theMethanodiazocine Ring

The nitrogen atoms of the methanodiazocine ring areclear targets for functionalization. Monoquaternary salts ofTB are easily prepared by treatment with the appropriatealkyl or benzyl bromide (Scheme 14, Path A).[18b,52] Quat-ernization of both nitrogen atoms has been argued to beunfeasible due to the strong negative inductive effect fromthe first formed quaternary nitrogen atom, which might beexpected to eliminate the nucleophilicity of the other terti-ary nitrogen atom. However, Lenev and co-workers haverecently reported the synthesis of the dimethylated TB ana-logue on treatment with dimethyl sulfate.[9b] Acetylationand benzoylation were performed in the original elucidationof the structure of TB (1) by Spielman,[2] who obtained thediacylated derivative with the loss of methylene bridge car-bon atom as formaldehyde (Scheme 14, Path B).

Nitrosation of TB (1) with the loss of the methylenebridge was also reported by Spielman.[2] Cooper and Par-tridge converted the resulting di-N-nitroso analogue into di-amine 16 (Scheme 15) by treatment with CuCl/HCl.[37a]

Compound 16 was then condensed with various aldehydesand ketones to afford analogues of TB containing function-alized methylene bridges. This stepwise methodology waslater used as a general methodology for the synthesis ofdifferent analogues of TB with mono- or disubstitutedmethylene bridges.[8,37b]


Recent progress in the functionalization of the methano-diazo ring has made it possible to avoid the removal of themethano bridge before functionalization. In 2012 Perias-amy and co-workers reported exchange reactions of themethano bridge of TB (1) with aromatic carbonyl com-pounds in the presence of TiCl4 or POCl3 (Scheme 16,Path A).[53] The proposed mechanism for the TiCl4-inducedreaction involved cleavage of the methano bridge in situ(Scheme 16, Path B). In addition, Periasamy and co-workers demonstrated that in the presence of POCl3 it waspossible to use DMF as the carbonyl partner, to obtain thecorresponding TB analogue, under Vilsmeier–Haack condi-tions. In the same year Reddy and co-workers also reportedthe regioselective synthesis of dialkylamino-substituted TBanalogues under Vilsmeier–Haack conditions.[54] This wasachieved by treatment of DMF with various aromaticallyfunctionalized methano-TB analogues in the presence ofPOCl3, yielding arylalkylamino-substituted TB analoguessubstituted on their respective methano bridges in yieldsranging between 53–83%. Use of POBr3 instead gave sim-ilar results for the insertion of N,N-disubstituted amines.[55]

Scheme 16. One-pot syntheses of analogues of TB containing sub-stituted methano bridges.

A different approach for the modification of the methanobridge involving its cleavage was reported by Hamada andMukai.[9a] They synthesized the ethano-TB analogue bytreatment with 1,2-dibromoethane (Scheme 17). It was sug-gested that the “bridge-replacement” took place throughammonium ion and dibromide intermediates before forma-tion of the ethano-TB analogue along with dibromometh-ane.

The introduction of spiro[4.5]lactone straps onto the TBscaffold was developed by Try and co-workers.[56] It was

Scheme 17. Synthesis of an ethano-TB analogue.


achieved by treatment of TB with phthaloyl dichloride andEt3N to yield analogue 17 (Figure 6). No mechanistic as-pects were discussed, but the same product was obtainedwith diazocine 16 (Scheme 15) as a starting material, sug-gesting a probable cleavage of the methylene bridge of TBas part of the reaction mechanism.

Figure 6. Different methylene-bridge-substituted TB analogues.

Other examples of modifications of the methylene bridgeof TB without involvement of its prior cleavage have re-cently been reported. In 2006, Kim and co-workers re-ported the synthesis of what they believed to be the unusual[3.3.3]bicyclic analogue 18 (Figure 6) formed by treatmentof TB (1) with methyl propiolate in the presence of ZnBr2

in CH3CN.[57] A year later, however, Lenev and co-workersdemonstrated by XRD analysis that the actual structure ofthe product of this reaction was in fact that of the TB ana-logue 19 (Figure 6).[58]

Lacour and co-workers have recently developed two dif-ferent approaches to the stereoselective synthesis of the con-figurationally stable ethano-TB analogues.[9c,59] One in-volved the formation of the quaternary salts 20 of TB(Scheme 18) by treatment with alkyl halides, followed by[1,2]-Stevens rearrangements promoted by basic alumina[9c]

to give the ethano-TB analogues 21 with diastereomeric ra-tios (drs) of �98:2. The other approach involved one-steprhodium(II)-catalyzed reactions proceeding through theformation of electrophilic metal carbenoids formed by reac-tions between the catalyst and diazo esters.[59] The metalcarbenoids attached to the N-lone pair of the TB to givenitrogen ylides that finally rearranged to generate the con-figurationally stable ethano-bridged TB analogues 22(Scheme 18). High diastereoselectivities of up to 49:1 wereobserved, as well as enantioselectivities of up to 99% ee inthe retention of configuration at the 5- and 11-positionswhen enantiopure TB was used as starting material. In2012, Lacour and co-workers extended the scope of theirchemistry by showing that CuTC [copper(I) thiophene-2-carboxylate] catalyzes the same reactions with good dia-stereo- and enantiocontrol (drs and ees of up to 12:1 and95 %, respectively) (Figure 18).[60]


Scheme 18. Synthesis of substituted ethano-TB analogues.

Scheme 19. Mono- and disubstitution at the exo positions of the benzylic methylenes of TB.

Synthesis of 6-exo- and 6,12-exo,exo-Substituted Analoguesof Tröger’s Base

Harmata and co-workers were the first to conductderivatization of the benzylic methylene components inTB,[61] although TB analogues substituted in these positionshad been synthesized previously, but not from TB itself.[62]

Harmata’s methodology from 1996 involved the metalationof the benzylic methylene groups by treatment of TB (1)with BF3·OEt2 followed by nBuLi and then quenching withan electrophile to give the exo-monosubstituted species. ex-o,exo-Disubstitution could also be achieved by sequentialmonometalation and electrophilic quenching(Scheme 19).[63]

The downside of Harmata’s procedure is that disubsti-tuted analogues have to be synthesized in a sequential man-ner, resulting in decreased overall yields.[63] It was demon-strated that exo-6-substituted TB analogues (R =–CH2OH, –CPh2OH, –CH2CPh2OH, or –CH2OCH2CPh2-OH) were reasonably good asymmetric inductors in ad-ditions of Et2Zn to aromatic aldehydes.[61b]

Oxidation of the Benzylic Methylenes of Tröger’s Base

The oxidized TB species 24 (Scheme 20), a lactam ana-logue of TB, was originally obtained serendipitously byelectrophilic quenching by DMF after treatment of 1 with1 equiv. sBuLi/TMEAD and accidental air oxidation.[64]

This led to a joint investigation between the Snieckus, Har-mata, and Wärnmark groups to find a robust preparativemethod for the oxidation.

Scheme 20. Formylation of TB (1) and subsequent oxidation toform the monolactam TB analogue 24.

A variety of oxidizing agents such as different manganeseand chromium salts, ruthenium catalysts, and hypervalentiodine were screened. The best results, however, were ob-tained when 1 was treated with 3 equiv. of KMnO4 and


benzyltriethylammonium chloride (BTEAC) in anhydrousCH2Cl2 at reflux for 9 h, affording monolactam 24 in 25%yield together with 30% reclamation of unreacted startingmaterial. The reaction conditions were then optimized toperform a double benzylic oxidation. This was achievedthrough the use of 9 equiv. of the reagents and a 4 h reac-tion time, to afford the bis-lactam 25 (Scheme 21) in 28%yield, as well as 15 % and 5% yields of the quinazoline sideproducts 26 and 27, respectively.

Scheme 21. Synthesis of the bis-lactam TB analogue 25 by directoxidation.

Interestingly, the solid-state structure revealed the bis-lactam TB analogue 25 to be an example of a twisted amide(Figure 7). The monooxidized analogue 24 was also iden-tified as a twisted amide on the basis of the similar spectro-scopic data for 24 and 25. The XRD analysis revealed thatthe twist angle τ,[65] describing the deviation from co-plan-arity between the carbon π orbital and the nitrogen lone-pair, is –43.7° for TB analogue 25, rather than the valuesclose to 0° and 180° commonly found in unconstrainedcisoid and transoid amides, respectively. Furthermore, theoverall distortion parameter θ,[66] an additive term that pro-vides a quantitative description of the combined defor-mation or pyramidality of the nitrogen and carbonyl car-bon together with the twist angle, was determined to be106.1°, whereas that of a simple planar amide is 0°. As a


Scheme 22. A suggested mechanism for the acid-catalyzed hydrolysis of 25 that is consistent with the experimental data.

result of the presence of two such amide functionalities inthe molecule, compound 25 is classified as a twisted bis-amide, and is, to the best of our knowledge, the first exam-ple of such a compound reported to date.

Figure 7. ORTEP representation of the solid-state structure oftwisted bis-amide 25.

The reactivity of the amide functionality in TB analogue25 was investigated in kinetic studies of its acid-catalyzedhydrolysis in which the twisted bis-amide 25 was subjectedto different concentrations of DCl (0.058 to 0.87 m) in aCD3CN/D2O mixture (5:1) and the hydrolysis was followedin situ by 1H NMR spectroscopy. Pseudo-first-order kinet-ics were observed at the acid concentrations employed,measured at ambient temperature. Under these conditions,the product of the amide hydrolysis – compound 30(Scheme 22) – being a normal amide, did not undergo fur-ther hydrolysis. Amide 30 was characterized directly in thereaction mixture by NMR and ESI MS spectroscopy.

Hydrolysis experiments were also performed with 18O-labeled water in order to investigate the reversibility in theformation of the tetrahedral intermediates. The detection of18O-labeled 25 can only be explained by the involvement ofthe reversible formation of tetrahedral intermediates 28 and29.

Synthesis of 6-endo- and 6,12-endo,endo-SubstitutedAnalogues of Tröger’s Base via its Twisted Amides

The unconventional amide reactivity that is manifestedin twisted amides[67] was also observed for monoamide 24and bis-amide 25.[68] Wittig reactions are not possible withnormal amides. However, in a collaboration between theWärnmark, Snieckus, and Harmata groups, a Wittig proto-col approach with the bis-amide 25 and Ph3P=CHCO2Etwas successfully employed to give the olefinated bis-en-amino-substituted TB analogue 31 (Scheme 23) in 77%yield as a mixture of the three possible diastereomers (Z,Z,


E,Z, and E,E) in approximately 69:33:2 ratio, according to1H NMR and GC–MS analysis.

Scheme 23. The synthetic route to endo,endo-substituted analoguesof TB.

Compound 31 was hydrogenated over Pd/C, resulting incompound 32. NOESY experiment showed through-spacecoupling of the H-6 and H-12 protons with the protons onthe methylene bridge. This correlation is only possible ifthe ethoxycarbonylmethyl chains are in endo configurations,leaving the hydrogen atoms at the 6- and 12-positions of 32oriented towards the methylene bridge. The stereoselectivityof the hydrogenation is due to the fact that the convex sideof 31 is more accessible to the heterogeneous catalyst thanits more hindered concave aromatic cavity. By the samemethodology monolactam 24 could be converted into the6-endo-ethoxycarbonylmethylene-substituted TB, the firstreported endo-substituted TB analogue.

Although one endo,endo-TB analogue had previouslybeen synthesized in low yield from a 2,5-disubstituteddiazocine,[62a] the synthetic sequence described aboveis, to date, the first rational synthesis of the highly desirable

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWendo,endo-substituted TB analogues, introducingfunctional groups oriented towards the aromatic cavity ofTB. To demonstrate the utility of endo,endo-substituted TBanalogues, diester 32 was reduced to diol 33 (Scheme 23)and further alkylated with diethylene glycol ditosylate,which surprisingly resulted in a dimerization to give the bis-TB crown ether analogue 34 in 30% yield as a mixture ofthe meso isomer (RR,SS; meso-34) and the racemate(RR,RR and SS,SS; rac-34), as revealed by 1H NMR andMS-ESI analysis. The structure of meso-34 was unambigu-ously assigned by XRD analysis (Figure 8), which corrobo-rated the endo,endo configurations of compounds 31–34previously established by NOESY experiments. Interest-ingly, the crystal structure of meso-34 revealed that themethano bridges of each of the two TB frameworks weredirected towards one another. This configuration was alsoestablished in solution by NOESY experiments.

Figure 8. ORTEP representation of the solid-state structure of thebis-TB crown ether analogue meso-34. Hydrogen atoms have beenomitted for clarity.

Fused Tröger’s Base Analogues

Recognition processes of relatively unfunctionalized mo-lecules often take place on concave surfaces and involve

Scheme 24. Stepwise (A) and simultaneous (B) route for the preparation of fused bis-TB analogues.


mainly non-directional solvophobic effects and van derWaals interactions.[69] Additional interactions such as aro-matic stacking and cation–π interactions are feasible if thesurface is aromatic. Synthetic molecules with extended con-cave aromatic surfaces are generally referred to as molecu-lar cleft compounds. TB analogues, with their relatively ri-gid chiral concave aromatic surfaces, are inherently goodstructural motifs for the construction of synthetic receptors.In this context, attention has been drawn to the synthesisof fused analogues of TB. A fused TB analogue is a TBthat contains more than one methanodiazocine unit andhas an aromatic ring fused to two such units (Figure 9).“Bis-”, “tris-”, and “oligo-”fused TB analogues thus referto molecules containing two, three, or more methanodiazo-cine units, respectively. Dolenský and co-workers have re-cently reviewed the progress in fused TB chemistry.[70]

Figure 9. Representative structural unit of a fused TB analogue.

The first molecule containing two methanodiazocineunits fused to the same aromatic ring was synthesized byPardo in 2001,[71] by an approach similar to the Wilcox pro-cedure for the synthesis of unsymmetrical TB analogues(see Scheme 4). In this line of research, mono-TB analogue35 (Scheme 24) was extended stepwise to the fused bis-TBanalogue 36 (Pathway A) in the forms of the syn (36a) andanti (36b) diastereoisomers. The total yield of TB analogue36 was 14% after nine steps from commercially availablestarting materials. Both symmetrical (R = R�) and unsym-metrical (R � R�) analogues could be synthesized. Ashorter route to fused bis-TB analogues starting from 1,2-,1,3-, and 1,4-diaminobenzenes was later reported (Path-way B, Scheme 24).[72]

This “simultaneous” formation strategy, originally em-ployed in the synthesis of symmetric TB analogues (36 with


R = R�, 38 and 39, Figure 10), was later applied in thesynthesis of unsymmetrical fused bis-TB analogues (36 withR � R�),[72a] although it gave lower overall yields than thestepwise approach.

Figure 10. Two examples of the “simultaneous formation” of fusedbis-TB analogues. Each diaminobenzene results in specifically oneregio- and one diastereoisomer.

Both cyclizations, by the stepwise (A) and the “simulta-neous” (B) routes, in the formation of fused bis-TB ana-logues 36 are regio- and stereoselective. Of the two possibleregioisomers, only the one with the 1,2,3,4-substituted cen-tral aromatic ring (the angular isomer) was obtained.[71–72]

The synthesis of fused bis-TB 36 (R = NO2, R� = CH3) bythe two different routes (Scheme 24) gave different relativeproportions of the syn and anti diastereoisomers. Whereasthe stepwise approach resulted in a 4:1 mixture of isomers36a and 36b,[71] the “simultaneous” strategy gave a 1:1 mix-ture.[72b] It is noteworthy that the latter method gave onlythe anti isomer 36b when the temperature was reduced from90 °C to 50 °C, albeit in 10% yield. The relative influenceof kinetic and thermodynamic control in Methods A and Bwas briefly investigated in isomerization studies, in whichisomerization experiments were performed on fused bis-TBanalogue 36. Subjecting the chemically pure syn isomer 36a(R = NO2, R� = CH3) to the cyclization reaction conditions(formalin/HCl in EtOH, 90 °C, 24 h), for instance, resultedin a mixture with a 4:1 ratio of the syn and the anti iso-mers.[71] On the other hand, subjecting the anti-bis-TB ana-logue 36b (R = R� = CH3 or NO2) to similar conditionsreturned a 1:1 mixture of the two isomers.[72b,72c] This isprobably due to the syn isomer being thermodynamicallymore stable than the anti isomer as a result either of π-stacking interaction between the parallel aromatic rings ofthe syn isomer or of differences in solvation energies be-tween the two isomers.

Scheme 25. Synthesis of tris-TB 40.


The first fused tris-TB analogue was synthesized in 2002by Dolenský and Král,[72a] who built a system in which allthree methanodiazocine units share a common centralbenzene ring (Scheme 25). By the “simultaneous” ap-proach, fused tris-TB analogue 40 was synthesized from1,3,5-triaminobenzene. Of the two possible diastereoiso-mers, only the fused tris-TB analogue 40a (R = CH3) wasisolated.

In a later work from the same group, the synthesis ofdifferently substituted 40a by the same strategy was re-ported.[73] The one-pot synthesis of fused tris-TB analogue40 was also achieved by the condensation of 1,3,5-triamino-benzene and p-toluidine in 2 % yield, meaning over 80%yield “per bond formed”.

Remarkably, rapid epimerization of fused tris-TB ana-logue 40 occurred in TFA at room temperature, which al-lowed the isolation of fused tris-TB analogue 40b. Thestructures of both diastereomers were unambiguously as-signed by single-crystal XRD analysis. The solid-state struc-tures revealed fused tris-TB analogue 40a to have a “throne”configuration, whereas 40b displayed a “calix” shaped cav-ity (Figure 11).

Figure 11. ORTEP representations of the throne tris-TB 40a (left)and the calix tris-TB 40b (right). Hydrogen atoms are omitted forclarity.

Naphthalene and anthracene derivatives of throne andcalix tris-TB analogues were also prepared by Dolenskýand Král.[74] The sizes of the cavities were estimated by mo-lecular modeling. The volume of the cavity of calix tris-TB-A (a benzene tris-TB analogue) was 30% of the volumeof the cavity of α-cyclodextrin (α-CD; CDs were used as

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWreferences). The volumes of the cavities of calix-tris-TB-B(a naphthalene tris-TB analogue) and -C (an anthracenetris-TB analogue) were calculated to be 65 % and 124%,respectively, of the volume of the cavity of α-CD (Fig-ure 12).

Figure 12. Optimized geometries of calix tris-TB derivatives (fromthe left: calix-A, calix-B and calix-C). A purple cone indicates thecalculated cavity volume.

Fused tris-TB analogues not sharing common benzenoidrings can variously form linear symmetric, non-symmetric,or non-linear symmetric regioisomers (Figure 13).[75]

Pardo and co-workers were the first to introduce linearlyfused tris-TB analogues.[76] By a stepwise methodologystarting from fused bis-TB analogues 36a and 36b(Scheme 24), they obtained three of the four possible dia-stereomers of the “non-linear symmetric” fused tris-TB an-alogue (41–44, R = CH3 and R� = NO2; Figure 14). Thesyn-syn-TB analogue 41 was envisaged to have interestinghost–guest applications due to its cage-like structure butthis was never investigated. It was also revealed that fusedtris-TB analogue 42 epimerized in 0.8 m HCl solution inEtOH at 80 °C to a 1:2:2:2 isomeric mixture of 41/42/43/44,analogously with fused bis-TB analogues.

Our group contributed with another strategy to buildfused tris-TB analogues.[75] Both the syn-anti and the anti-anti non-linear symmetric fused tris-TB analogues 43 and44 (R = R� = Br; Figure 14) were synthesized from thestarting 2,8-dibromo-substituted TB analogue, and isolatedby the desymmetrization route. The anti-anti diastereomer44 is the first example of an isolated fused tris-TB analogueof this configuration.

Figure 14. The four possible diastereomers of the “nonlinear symmetric” tris-TB, and tetracyanobenzene (TCB). Pardo and co-workers:R = CH3, R� = NO2.[76] Our work: R = R� = Br.[75]


Figure 13. Regioisomers of fused tris-TB analogues not sharingcommon benzenoid rings: “linear symmetric”, “non-symmetric”,and “non-linear symmetric”.

Compounds 43 and 44 were subjected to an epimeri-zation study: stirring of 43 in TFA for several days at roomtemp. gave a mixture of 43 and 44 in an approximately 4:1ratio, whereas subjection of 44 to the same conditions re-turned only 44. It was argued that this occurred because ofthe higher thermodynamic stability of anti-anti 44, probablydue to better solvation.

Kessler and co-workers recently presented cases in whicha guest molecule [tetracyanobenzene (TCB), Figure 14] wascaptured for the first time in the cavities of fused-TB ana-logues.[77] Five synthesized TB tweezers were modeled andsynthesized for this purpose (Figure 15). These pincers ortweezers were designed to hold and release the guest mole-cule. Association constants were obtained by 1H NMR ti-trations and compared with calculated binding energiesfrom computational chemistry modeling.

Interestingly, all the synthetic methodologies describedabove gave exclusively the non-linear symmetric regioiso-mers of fused tris-TB analogues, with none of the other


Figure 15. The lowest-energy structures of the tweezer/TCB complexes and definition of the ligand–tweezer distances (d1) and the tipdimension (d2, displayed for D only).

plausible regioisomers – the linear symmetric and non-sym-metric (Figure 13) – being observed. This can be explained,as in the case of fused bis-TB analogues, in terms of thepreference to form 1,2,3,4-substituted aromatic rings, socalled angular isomers, during the cyclization.[44] To im-plement linearity in fused-tris-TB analogues, Král and co-workers used 2,5-dimethylbenzene-1,4-diamine in a one-potoligomerization reaction,[78] which gave a mixture of fusedmono-TB, bis-TB, and tris-TB analogues in 5%, 10 % and1% yields, respectively. The methyl group was used to blockother reactive positions. The presence of higher generationsof fused TB analogues could be detected by MS analyses,but none of these isomers were ever isolated.

To us, the linear symmetric regioisomers of fused tris-TBanalogues are the most interesting, due to their cavity-shaped binding sites, especially the syn-syn diastereoiso-mers, which would result in nearly circular geometries ofthe molecules. At that time, however, such regioisomers hadonly been obtained in low yields and were synthesized inan uncontrolled manner (vide supra).[78] Our group devel-oped a synthetic strategy for the rational construction oflinear symmetrically fused tris-TB analogues by a stepwiseapproach in which the unwanted reactive positions of theaniline were blocked (Scheme 26).

In our 2006 paper we thus reported a condensation be-tween aniline 47 (Scheme 26) and paraformaldehyde in TFAto afford the C2-symmetric dibromo-substituted TB ana-logue 48,[44] and this was then desymmetrized by applica-tion of our previously published conditions.[46,75] TB ana-logue 48 was thus subjected to a single bromine/lithium ex-change (1.1 equiv. of nBuLi), followed by electrophilic


quenching with tosyl azide, yielding the asymmetric 2-azido-8-bromo-substituted TB analogue 49. Reduction withNaBH4 gave the amino-substituted TB analogue 50 in anexcellent yield. Compound 50 was in turn treated with para-formaldehyde in TFA to afford the linear symmetricallyfused tris-TB analogue 51 as the only regioisomer. 1HNMR analysis of the crude product of the reaction mixturerevealed a diastereomeric ratio of 53:34:13 of syn-anti (51a),anti-anti (51b), and syn-syn (51c) isomers when the TFAused in the reaction was added at –10 °C. All the isomers –51a–c – could be isolated by preparative TLC. Isomers 51aand 51c was assigned by single-crystal XRD analysis (Fig-ure 16) and the remaining third isomer was then assignedas 51b, supported among other things by its symmetricalNMR spectra. The ratio of diastereomers was affected onlyto a minor extent by allowing the temperature during theaddition of TFA to increase to 0 and 10 °C. This led tolower yields, however, which is in agreement with our pre-vious investigations when we studied how the reaction tem-perature during the addition of the TFA influenced theyield in the TB condensation.[28a]

Interestingly, conducting the reaction at –10 °C in thepresence of 10 equiv. of NH4Cl led to an increase in theproportions of the diastereomers containing clefts – 51aand 51c – relative to the cavity compound 51b, with nodecrease in total yield, suggesting a templating effect of theammonium ion through cation–π interactions with the aro-matic rings during the reaction to form the fused tris-TBanalogues. Recent results from Král and Dolenský,[70] how-ever, might point towards anion–π interactions being re-sponsible for this effect.


Scheme 26. Synthetic route to the racemic linear tris-TB analogues 51a–c and schematic view of the three possible diastereomers.

Figure 16. A) ORTEP representation of the crystal structure of 51c.Hydrogen atoms have been omitted for clarity. There was residualelectron density in the cavity formed by the molecules, probablydue to the presence of disordered solvent molecules. B) ORTEPrepresentation of the crystal structure of diastereomer 51a. Hydro-gen atoms have been omitted for clarity. The data unambiguouslyshow the molecular structure of 51c to be that of the syn-syn dia-stereomer and 51a to be the syn-anti diastereomer. C) View alongthe b axis of the packing of isomer 51c.

All three diastereomers 51a–c were separately subjectedto isomerization studies under different acidic conditionsand temperatures: each compound was dissolved in neat


TFA or CHCl3/EtOH (2:1), the latter containing variousamounts of HCl in dioxane (4 m) so that the resulting solu-tions were 3, 0.8, and 0.01 m in HCl. The solutions werestirred at 25, 60, and 95 °C for different periods of time. Asa general trend, all three diastereomers 51a–c were reluctantto isomerize under the conditions investigated. From theseresults, we concluded that the syn-anti 51a is slightly morestable than the anti-anti 51b, which is in turn slightly morestable than syn-syn 51c. Caution must be exercised, how-ever, due to the very low degrees of isomerization observed.We believe that fused tris-TB analogues 51a–c display reluc-tance to invert at their stereogenic nitrogen atoms undervarious sets of acidic conditions and temperatures becauseof the presence of the blocking groups at the ortho-positions(4,10-positions) in their aromatic rings, hampering the in-version of configuration. Such an explanation has also beenput forward by Lenev for the slow racemization of opticallypure 4,10-dimethyl-substituted TB analogues.[79] This sta-bility towards inversion of configuration makes the aboveTB analogues attractive building blocks for use in diluteacids and they should be compared to the ethano-TB ana-logues, which are also configurationally stable.

Heterocyclic Analogues of Tröger’s Base

Formation of Tröger�s Base Aromatic Heterocycles in One-Step Condensation Reactions

The unique structural architecture of TB in combinationwith the acceptor and donor properties of aromatic hetero-


cycles yield interesting structures that could be bene-ficial in many fields of application, such as medicinal chem-istry.

It was not until 1991 that the first aromatic heterocyclicanalogue of TB was synthesized, by Yashima and co-workers.[80] They condensed 5-amino-1,10-phenanthroline(52, Figure 17) with formaldehyde (aq. HCl in EtOH) toafford a TB analogue in 22% yield. The next milestone inthe production of heterocyclic TB analogues came in 1993,when Pardo and co-workers,[25a] and Johnson and co-workers reported azolyl-based (compounds 54–56, Fig-ure 17) and 3-picoline-based (compound 64, Figure 17) TBanalogues,[37b] respectively, providing early rare examples ofdirect syntheses of TB analogues bearing σ-electron-with-drawing groups. Later, in 1997, Cudero and co-workers syn-thesized the first TB analogue in which a heterocyclic aro-matic framework was fused directly to the methanodiazonicring (57, Figure 17).[25b] In that paper they compared thereactivities of π-excessive (azoles) and π-deficient (azines)heterocycles, with the use of either HCl and formaldehydeor of TFA and hexamethylenetetramine as acid and methyl-ene source, respectively (compounds 53, 57–63, Figure 17).Interestingly, when TFA was used as the acid and 57 as

Figure 17. Examples of aromatic heterocyclic aniline derivatives that have been condensed to afford TB analogues. The arrows show thesites of reaction with formaldehyde equivalents.[83a,83b]


starting material, no reaction occurred. As expected, all theazines were recovered from the reaction mixtures un-changed, due to the low reactivities of π-deficient heterocy-cles towards electrophilic attack at carbon atoms.

Abonia and co-workers later investigated the direct fu-sion of heterocyclic amines to the methanodiazocine ring,using starting materials 71 and 72 together with acetic acidand formaldehyde.[81] They suggested that the low yieldswere probably due to the formation of stable side productsthat did not react further. Some seven years later, Wu andco-workers introduced new members of the class of five-membered-ring heterocyclic-ring-fused TB analogues by asimilar synthetic approach (from compounds 72, 85–87,Figure 17).[82] Since then, numerous heterocyclic TB ana-logues, summarized in Figure 17, have been produced inone-step condensations.[18e,25,71,81–83] Some of them weresynthesized by use of biologically active materials contain-ing free aromatic amine groups (from compounds 68, 73–79;[84] 81–83,[83c] Figure 17) as starting materials in conden-sations to afford the TB analogues. In addition to the het-erocycles mentioned, Valik and co-workers have producedseries of pyrrole TB analogues utilizing the structural fea-tures of known antibiotics (vide supra).[85]


Scheme 27. A) Formation of an aromatic heterocyclic analogue through functionalization of the aromatic group of the TB intermediate.B) One-step condensation to form the same analogue.

The syntheses of heterocyclic derivatives through a one-step condensation reactions in which the aromatic heterocy-clic molecule is directly fused into the methanodiazonic ringstill need more study to provide an appropriate general syn-thetic methodology. The TFA method that we developed,for instance, cannot be generally applied in the synthesis ofheterocyclic TB analogues. The synthetic approach for eachanalogue thus has to be developed individually to producehigh yields. The scope for improvements in the synthesis ofheterocyclic TB analogues is illustrated in a recent publica-tion by Dolenský and co-workers in which they fused theheterocyclic [2-aminotetraarylporphyrinato(2–)]nickel sys-tem directly to the methanodiazonic ring.[86] They manipu-lated the condensation by varying the formaldehyde sourceand, particularly, the solvent, which made it possible todrive the reaction selectively towards the desired product, a[tetraarylporphyrinato(2–)]nickel TB analogue.

Formation of Heterocyclic Tröger’s Base Analogues afterTB Condensation

As discussed above, the π-deficient properties of manyheterocycles hamper the production of heterocyclic TB ana-logues by one-step condensation protocols. A solution canbe found, however, by attaching the heterocyclic functionalgroup to a formed TB analogue. Goswani and Ghosh syn-thesized aminopyridine analogues by both approaches –Routes A and B in Scheme 27 – to form the hydrogen-bondreceptor TB analogue 88.[87] Approaches similar to Route A(Scheme 27) have been developed for production of hetero-cyclic TB analogues (e.g., bis-pyridinium analogues).[88] Inaddition, benzodiazolium TB analogues have been synthe-sized by an approach in which the heterocyclic functionalgroup is introduced after the TB condensation has takenplace.[89]

Applications of Tröger’s Base Analogues

The remarkable structural features of TB were underex-ploited until the 1980s, before which it was used solely as astandard for the evaluation of new chiral chromatographic


techniques. However, the groundbreaking report by Wilcoxin 1985,[16] introducing new TB analogues as a potentialunit for chiral hosts and metal ion ligands, represented theresurrection of TB as a hot research topic. Since then, TBanalogues have found applications as building blocks in thefields of, among others, supramolecular chemistry, molecu-lar recognition, catalysis, enzyme inhibitors, and new mate-rials.

Hydrogen-Bonding Tröger’s Base Analogues as Receptors

In 1989, Wilcox and Adrian described the synthesis ofcarboxylic-acid-substituted TB derivatives (compounds 89,Figure 18) designed to form four hydrogen bonds simulta-neously with cyclic urea derivatives and adenine base moie-ties.[90] The binding process was studied by NMR and UV/fluorescence spectroscopy techniques in solvents with dif-ferent polarities and hydrogen bonding capabilities. Thesame system was used for determining the effect of wateron the binding abilities of similar hosts.[18d]

Figure 18. Diacid- and aminopyridene-derived TBs as hydrogen-bonding receptors.

The design and the synthesis of the TB amidopyridineanalogues 88 and 90 were reported by Goswami and Ghosh


(Figure 18).[83d,87] Complexation studies of the recognitionof dicarboxylic acids of different lengths showed the TBanalogue 88 to be a selective host for suberic acid in thepresence of other α,ω-diacids. The more flexible TB recep-tor 90 exhibited weaker binding towards the same dicar-boxylic acid and the loss of binding selectivity.

Our group investigated the use of the C2-symmetricbis(crown ether) TB analogue 91 (Figure 19) for recognitionstudies of achiral and chiral primary bisammonium salts.[91]

Experiments conducted on the dihydrochloride salts of α,ω-diaminoalkanes showed very similar binding affinities forbisammonium salts n = 6–8. Enantiomeric discriminationby receptor 91 was explored with the dihydrochloride saltsof the methyl esters of l-cystine and l-lysine. The diastereo-selectivity of the complexation for l-cystine was estimatedfrom the 1H NMR spectra to be 62:38, whereas no enantio-meric discrimination was observed for l-lysine.

Figure 19. A TB-bis(crown ether) receptor for bisammonium salts.

Macrocyclic Tröger’s Base Analogues as Receptors

The use of macrocyclic frameworks to construct recep-tors is especially suitable for relatively unfunctionalized TBanalogues, with the cavity of the receptor providing scopefor solvophobic effects and van der Waals interactions. Theuse of a TB scaffold in the synthesis of cyclophanes wasdemonstrated by Inazu and Fukae in 1984.[92] The dimericTB analogue 92 (Figure 20) was prepared in 45% yield andthe meso and rac forms were isolated by fractionalrecrystallization. However, the limited size of the cavityhampered any inclusion phenomena. The same researchgroup was the first to incorporate crown ethers into TBanalogues (compounds 93, n = 3–5; Figure 20).[93] Despitethe differences in length of the polyethylene chains, bindingstudies revealed similar binding affinities for all cationsstudied, with the high degree of flexibility impeding anyselectivity.

Figure 20. The first macrocyclic and crown-ether-derived TB ana-logues, respectively.

Wilcox and co-workers developed a series of water-solu-ble cyclophanes based on the TB scaffold as chiral receptorsfor small and neutral organic molecules.[94] The first macro-


cycle of this series contained a diphenylmethane unit linkedto a TB with an alkyl tether containing secondary ammo-nium groups (compound 94; Figure 21). The association ofTB macrocycle 94 with several benzenoid substrates wasanalyzed in acidic aqueous media and showed a preferencefor aromatic molecules with electron-withdrawinggroups.[94a,94b]

Figure 21. TB-based cyclophanes.

The optically pure macrocyclic TB bis-sulfone 95 demon-strated binding of isomeric menthols with reasonable selec-tivity (Figure 21).[94c,94d] In a more recent contribution, acyclophane consisting of two TB moieties and bearing amercaptoimidazole group on the alkyl linker was designedto bind biologically relevant substrates. 1H NMR studiesshowed that TB analogue 96 preferably bound 4-ni-trophenyl phosphate over its non-phosphate analogue (Fig-ure 21).[94e]

Porphyrin-Derived TB Analogues as Receptors

The coordination abilities of metal-containing por-phyrins have also been exploited when fused to a TB scaf-fold. Crossley and co-workers synthesized different TB ana-logues in which the methanodiazocine ring is fused to twotetraarylporphyrins, forming a well-defined chiral cleft mo-lecule.[95] These series of bisporphyrino-TB analogues withinserted metal ions exhibited strong affinities with differentselectivities towards diamine guests such as α,ω-diaminoal-kanes of different lengths,[95a] as well as towards histidineand lysine esters.[95b] TB analogue 97 (Figure 22), in ad-dition to binding simple diaminoalkanes, encapsulated atetramine dendrimer, forming a spherical cage.[95c] Specifi-cally, in a recent report based on similar structures, theCrossley group demonstrated ditopic binding of an α,ω-di-carboxylic acid in the cavity when Sn(OH)2 was coordi-nated to the porphyrin rings.[96]


Figure 22. A porphyrin-containing TB analogue.

Tröger’s Base Analogues as a Molecular Torsion Balances

Arguably the most elegant application of TB analoguesis in the molecular torsion balances designed by Wilcox andco-workers. Use of structures such as TB analogues 98 (Fig-ure 23), allowed for the quantification of weak forces (e.g.,aromatic edge-to-face interactions,[97] or CH–π interac-tions[98]) believed to play an important role in protein fold-ing. Later improvements resulted in water-soluble struc-tures, thus avoiding the need for corrections for the changein the direction of the dipoles between folded and unfoldedconformers.[99] Further developments by Diederich and co-workers provided molecular balances for study of the inter-actions between “organic” fluorine atoms and an amidegroup.[100] This work was followed by a new generation ofmolecular torsion balances based on an indole fragment,which provided evidence of the existence of a favorable or-thogonal dipolar interaction between the C–F bond and anamide carbonyl group.[101]

Tröger’s Base Analogues in Selective Catalysis

The rigid chiral structure of TB and the presence of atransition-metal binding sites (the nitrogen atoms) make TBand its analogues good candidates as ligands in asymmetriccatalysis. Applications in this field, however, have to datebarely been investigated.

The first use of TB as a ligand for catalytic applicationswas demonstrated in the hydrosilylation of terminal al-kynes.[102] The complex TB·2 RhCl3 (99, M = Rh, Fig-ure 24) showed catalytic activity, giving rise to the thermo-dynamically less stable cis products with selectivity up to95%. Enantiopure (+)-1 was employed as an additive in thePt/Al2O3 hydrogenation of ethyl pyruvate, resulting in ethyllactate with 65 % ee.[103] The same enantiomer gave ees of

Figure 23. TB molecular torsion balances for the quantification of aromatic edge-to-face interactions.[97,98,101]


up to 67 % in the amine-promoted aziridation of chalc-ones,[104] whereas (–)-1 gave rise to a 57% ee when used asan additive in the 1,4-addition of alkyllithium species toα,β-unsaturated tert-butyl esters.[105]

Figure 24. Examples of TB analogues used as ligands in catalysis.

Different TB analogues have been screened as inductorsof asymmetry in catalytic processes. Harmata studied theeffect of different TB chiral ligands in the additions ofEt2Zn to aromatic aldehydes.[61b] Although enantiopureparent TB (1) gave poor enantioselectivity in the resultingalcohol, 6-exo-substituted TB analogue 100 (Figure 24) af-forded up to 86 % ee in the alcohol product. In addition,substituted pyrazole analogues of TB (compounds 101; Fig-ure 24) were used as organocatalysts in one-pot Mannichreactions between aromatic aldehydes, aniline derivatives,and cyclohexanone in aqueous media, resulting in verygood yields and remarkable anti/syn stereoselectivities inthe products.[82] The dimeric dipalladium complex 102,based on the same pyrazole TB architecture, was used as acatalyst in the Mizoroki–Heck C–C coupling reaction, dis-playing high catalytic activity and considerable selectivitytowards the formation of trans-stilbenes with 89–93% con-version (Figure 24).[106] TB analogues containing thioureachains linked to the aromatic rings showed activity as cata-lysts in Michael additions of malonate derivatives to ni-troolefins, but no enantioselectivity was observed.[107]


In recent years TB-embedded materials have been em-ployed in different heterogeneous catalytic processes withencouraging results. A nanoporous polymer containingcovalently bonded TB analogues, for instance, showed rea-sonable catalytic activity in the addition of diethylzinc to 4-chlorobenzaldehyde, affording 1-(4-chlorophenyl)propan-1-ol in 60–56% yield.[108] The catalytic efficiency was main-tained after at least three catalytic cycles. Investigationsconducted with mesoporous organosilicas containing TB(1) revealed their activities in promoting reactions such asthe Knoevenagel reaction, S-arylation of aryl iodides, andazide–alkyne cycloaddition.[109]

Medicinal Properties of Heterocyclic Tröger’s BaseAnalogues

TB analogues containing aromatic heterocyclic ringshave shown great ability to interact with DNA. Yashimaand co-workers introduced the first TB analogue of thisfamily (compound 103; Figure 25), a phenanthroline ana-logue that exhibited higher affinity towards DNA than theparent 1,10-phenanthroline.[80] Demeunynck and Lhommehave widely explored this field.[18e,83f,84a,110] The proflavineTB analogue 104 (Figure 25) is a representative example.Compound (–)-104 binds in a sequence-selective fashion tocalf thymus B-DNA.[83f,84a] Sequences with motifs such as5�-GTT·AAC or 5�-ATGA·TCAT bound preferably tocompound (–)-104. In another example, a DNA interactionassay involving the non-symmetric proflavine-phenan-throline TB 105[110c] (Figure 25) revealed that the acridinering intercalates between the DNA pairs whereas the phen-anthroline moiety resides in one groove of the DNA.

Figure 25. Phenanthroline and proflavine analogues of TB.

The well-known B-DNA is a double helix and is twistedin a right-hand direction. However, studies have shown thepresence of another conformation, Z-DNA, in which thehelix is twisted in the left-hand direction (Figure 26). Theexistence and biological function of this conformer in vivois still unclear, however, and requires further studies.[111]

Historically, only chiral metal complexes have been investi-gated for “enantioselective”[112] recognition of DNA con-formations. However, when coupled to acridine, the geome-try of TB 106 (Figure 26) gives rise to a helical shape of themolecule, which can be either similar or opposite to that ofDNA, thus resulting in “enantioselective” binding (Fig-ures 27 and 28).[113]


Figure 26. The chirality of acridine TB analogue 106 in relation todifferent DNA conformers.[114]

Figure 27. Molecular modeling of binding of acridine TB analogue106 to DNA. One of the acridine rings intercalates between neigh-boring base pairs whereas the other acridine ring is positioned inthe minor or major groove.[114]

Figure 28. Molecular modeling of binding of acridine TB analogue106 to DNA. Both acridine rings are positioned in one of thegrooves.[114]

Tatibuet and co-workers reported that the (2)-(7R,17R)enantiomer of an acridine analogue of TB[113] – compound(–)-106 – showed preferential binding to calf-thymus B-

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWDNA (i.e., the conformer in which the double helix istwisted in a right-hand direction) and hence the potentialto serve as an “enantioselective” molecular DNA probe.Molecular modeling predicted selective binding of acridineTB analogues to DNA. This can occur by different mecha-nisms, as illustrated in Figures 27 and 28.[115]

In a recent work, Veale and Gunnlaugsson reported thesynthesis of a small library of fluorescent 1,8-naphthal-amide analogues of TB (compounds 107; Figure 29).[83h] Itwas predicted that at physiological pH the cationic aminotermini of TB analogues 107 would strongly bind to thephosphate backbone of DNA, and all three compounds in-deed showed high affinities. Fluorescence imaging studiesdemonstrated the rapid uptake of TB analogues 107 by can-cer cells and that the compounds become localized withinthe nuclei.

Figure 29. Fluorescent analogues of TB.

TB analogues containing two 3-picolyl groups (com-pounds 108, Figure 30) showed inhibition activity towardsthe enzyme thromboxane A2 synthase (TxA2).[37b] The em-ployment of the picoline functional group on the TB struc-ture was based on the same structural characteristics as theknown TxA2 inhibitor sodium furegrelate (Figure 30),which also bears a 3-picoline functional group. An attemptto increase the activity by adding substituents in the di-azocine methylene bridge in fact significantly decreased theactivity. Dolenský and co-workers described the synthesis

Figure 30. Biologically active sodium furegrelate, together with the pyridyl- and acronycine-, N-methylpyrroline-, and benzimidazole-based TB analogues.


of the N-methylpyrrole TB analogues 109 (Figure 30),which mimic the building blocks of natural antibiotics suchas distamycin and netopsin.[85b] The fusion of the N-methyl-pyrrole rings with the methanodiazocine ring resulted incompounds with binding ability to DNA, although to thebest of our knowledge no biological activity studies forthose compounds have been reported. Recently, TB ana-logues bearing the cytotoxic acronycine motif, such as com-pound 110 (Figure 30), have been reported to be cytotoxicagainst L-1210 leukemia and KB-3–1 solid tumor celllines.[116]

In 2012, Ananya and co-workers published an investiga-tion about the use of benzimidazole-derived TB analogues111 (Figure 30) as cancer treatment candidates, based ontheir inhibition of teleomerase activity.[117] Inhibition of te-lomerase activity leads to cell death. In cancer cells the te-lomerase is over-expressed whereas in normal somatic cellsit is has undetectable activity, and this is the basis for cancertreatment based on telomerases. The TB analogues 110 in-hibited human telomerase activity by acting as G-quadru-plex ligands that fold guanidine-rich DNA into G4DNA(G-quadruplex DNA) and hence inhibit telomerase activity.

Other Applications of Tröger’s Base

The rigid V-shaped geometry of Tröger’s base has beenexploited in the construction of elaborated metallomacro-cycles. In the first example of these structurally beautifulcomplexes, reported by Mirkin, a phosphane/thioether li-gand containing the TB motif formed a dimeric metallocy-cle when coordinated to CuI, whereas with RhI a mixtureof trimer and tetramer was obtained (Figure 31).[118]

TB analogues have been studied in supramolecular self-assembly, a broad field ranging from the DNA helix to in-clusion compounds. It is generally regarded as the process


Figure 31. Left) TB ligand, and right) solid-state structure of its RhI-complexed tetramer. Hydrogen atoms are omitted for clarity.

Figure 32. Left) TB ligand, and right) the solid-state structure of the PtII-coordinated cage. Hydrogen atoms are omitted for clarity.

through which individual molecules form defined aggre-gates, which can then self-organize to form higher-orderstructures. Lützen has made two very important observa-tions in the field of self-assembled TB metallohelicates. Thefirst relates to the presence or absence of diastereoselectivityin the self-assembly process. He showed that several TB li-gands bearing 2,2�-bipyridine or 2-pyridylmethaniminemoieties self-assembled into dinuclear double-stranded hel-icates upon coordination to AgI and CuI.[29c] The complex-

Figure 33. TB analogues used in optical and optoelectronic applications.


ation of the metal ion by the racemic ligand is diastereospe-cific in a self-recognition manner, giving rise to dia-stereomerically pure complexes.[29c,119] In contrast, coordi-nation to FeIII and ZnII results in triple-stranded helicates.Whereas FeIII resulted in diastereomerically pure com-plexes, ZnII displayed no diastereoselectivity.[29c] In a similarapproach, Lützen and our own group built a metallomacro-cycle from a racemic bis(4-pyridyl-alkyne)-derived TB ana-logue (Figure 32) and (dpp)Pt(OTf)2 in a diastereoselective

Ö. V. Rúnarsson, J. Artacho, K. WärnmarkMICROREVIEWself-discrimination process, which formed exclusively theheterochiral R,R,S,S isomer.[88] Our group showed that theresulting cage (Figure 32, right) displayed greatly enhancedfluorescence relative to the TB ligand alone. The fluores-cence was quenched upon addition of C60. The quenchingmight be due to the interaction of π-accepting C60 and thelone pair of the TB nitrogen atoms, because no evidence ofC60 inclusion was found.

Lützen’s second observation, this time together with Pig-uet, was in an experimental and theoretical analysis ofmetal–metal interactions in solution. They point to two ef-fects that oppose each other: Coulombic interactions pro-duce large intermetallic repulsion at short distances, andsolvation effects result in large intermetallic attractions forsmall pseudo-spherical ions with short intermetallic separa-tions.[120]

Incipient applications of TB analogues as optical and op-toelectronic materials have been reported in recent yearsand were recently reviewed by Yuan and co-workers.[121]

The bis-pyridinium-derived TB analogue 112 (Figure 33)exhibits aggregation-induced light emission in the solidstate but is virtually non-emissive in solution, a feature notobserved in a planar counterpart.[122] Photophysical andelectroluminescent properties have been examined in fluor-ene-derived TB analogues.[123] Compounds such as TB ana-logue 113 (Figure 33) exhibit strong fluorescence emissionin dilute solutions and in aggregated states. Organic light-emitting diodes (OLEDs) fabricated with these TB ana-logues show high brightness, high efficiency, and low turn-on voltage. Benzothiazolium- and para-nitrophenyl-derivedTB analogues 114 and 115, respectively (Figure 33), showsecond-order nonlinear optic properties, the former beingthe more active.[89,124]

Conclusions

Since the beginning of the 21st century synthetic TBchemistry has developed rapidly, allowing for the position-ing of functional groups in virtually any position of the TBcore and for the formation of TB analogues fused withphenylene rings. In addition, resolution of TB analoguesinto their antipodes by chiral HPLC on a semipreparativescales has become almost routine. The essential propertiesof TB – the chiral, rigid, and aromatic cavity, together withthe synthetic entries available to the scientific community –are bound to inspire new applications of TB analogues. Onecould argue that no real groundbreaking application of mo-lecules containing the TB skeleton has yet arrived, but withthe molecular torsion balance being a possible exception.However, the reason for this shortage of applications mightbe that the synthetic tools needed to make new buildingblocks for applications are quite recent. We argue that theproperties of the TB skeleton discussed above are especiallysuited for applications in the fields of asymmetric catalysisand of sensors for biomolecules with diagnostic applica-tions. Hopefully, the very recently introduced methodolo-gies for the insertion of endo-substituted groups reaching


the chiral cavity of TB, the variety of methods to modifythe bridging methano bridge of TB now available, and fi-nally the introduction of configurationally stable ethano-bridged or 4,10-disubstituted TB analogue might inspirenew entries into the applied fields.

Acknowledgments

K. W. thanks the Swedish Research Council, The Royal Physio-graphic Society in Lund, the Crafoord Foundation, and the Swed-ish Foundation for Strategic Research for financial support.Ö. V. R. thanks the Olle Engkvist Byggmästare foundation for apostdoc fellowship. We would like to acknowledge Martine Demeu-nynck (Figures 26, 27, and 28),[114] the Taylor & Francis publica-tion (Figure 12),[74] and Wiley publications (Figure 15) for per-mission to use these illustrations. Furthermore, we thank Per OlaNorrby, University of Gothenburg, and Anders Sundin, Lund Uni-versity, for discussions and calculations, respectively, relating to theanomeric effect in TB.

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Received: September 20, 2012Published Online: November 20, 2012

anniversary of the tröger’s base molecule: synthesis and...

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