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Research 1..10 -.:. Michael Pittelkow Article pubs.acs.org/joc Thiosemicarbazone Dynamic Combinatorial Chemistry: Equilibrator- Induced Dynamic State, Formation of Complex Libraries, and a Supramolecular On/Off Switch Dennis Larsen,† Anne Jeppesen,‡ Claudia Kleinlein,§ and Michael Pittelkow* Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark *S Supporting Information ABSTRACT: Dynamic combinatorial libraries that equilibrate under thermodynamic control and can be trapped kinetically when desired are key to creating complex systems that can mimic dynamic biological systems, such as the biochemical system of life. A much-sought-after feature is the ability to turn off the dynamic exchange of the system, in order to investigate a transient state away from thermodynamic equilibrium, and then turn on the dynamic exchange again. We describe here the first use of thiosemicarbazone exchange to form dynamic combinatorial libraries. The libraries were found to require a nucleophilic catalyst, or equilibrator, in order to reach thermodynamic equilibrium. This equilibrator approach adds a supramolecular level of control over the dynamic system and allows the dynamic exchange to be turned off by addition of 18-crown-6, which binds the equilibrator in a nonnucleophilic complex. The dynamic exchange can be restarted by addition of potassium ions that competitively bind 18-crown-6, thus liberating the equilibrator. The highly complex thiosemicarbazone-based macrocyclic libraries contain both [2]catenanes and sequence isomers, which can be distinguished by HPLC-MS/MS. 1. INTRODUCTION off the equilibrating reaction, and that the molecules produced Abiogenesis,1 one theory on the origin of life,2 describes how in the DCL experiment are stable enough to be isolated and life on Earth could have developed from inanimate matter studied under the conditions of the equilibrating mixture. For example, the use of acylhydrazones as the reversible reaction in through a wealth of interconnected equilibria by building up fi 4a,7 more and more complex dynamic systems, which eventually DCLs has received signi cant attention. The reaction resulted in the formation of living cells.3 In recent decades, the between an aldehyde and a hydrazide produces acylhydrazones fi mediated by acidic conditions, typically the addition of 2−5% elds of dynamic combinatorial chemistry and systems fl chemistry have investigated how interconnected equilibria can tri uoroacetic acid (TFA). This generally gives DCLs that equilibrate under thermodynamic control: the template- lead to highly complex dynamic systems from mixtures of fi simple molecular building blocks,4,5 thus providing a bottom-up ampli ed species from the DCL can be isolated, and the interactions of the DCLs with the template can be studied. approach toward understanding how complex systems, such as fi life itself, could have evolved from relatively simple small However, the ampli cation process occurs in the presence of molecules.6 TFA, and the molecular recognition event cannot be studied Dynamic combinatorial chemistry provides an appealing (e.g., by NMR spectroscopy) under the same conditions as the entry point to study systems chemistry.5 In dynamic DCL, as it would cause the DCL to start equilibrating again. combinatorial chemistry, reversible chemical reactions mediate Here we establish thiosemicarbazone exchange by the the formation of dynamic combinatorial libraries (DCLs) that reaction between an aldehyde and a thiosemicarbazide as a equilibrate under thermodynamic control.4a The addition of new reversible reaction for dynamic combinatorial chemistry templates to a DCL enables the selection of strong receptors (Figure 1). We also demonstrate the use of a nucleophilic for added templates from the DCLs.4b hydrazide catalyst, termed an equilibrator, to make the system “Ideal” reversible chemical reactions must live up to a reach a thermodynamic equilibrium. By exploiting the require- ment for an equilibrator, we show how the dynamic system can number of requirements to create functioning DCLs; these ff requirements may differ depending on the individual be turned on and o via a supramolecular capture/release mechanism. It was found that the thermodynamic equilibration application of the DCL. Universally, it is essential that the ff reversible chemical reaction proceeds to the thermodynamic can be turned o by capturing the equilibrator as its ammonium equilibrium, and it is necessary to confirm this each time a new DCL is studied. Other requirements, which are often more Received: June 2, 2017 difficult to achieve experimentally, are the ability to turn on and © XXXX American Chemical Society A DOI: 10.1021/acs.joc.7b01161 J. Org. Chem. XXXX, XXX, XXX−XXX The Journal of Organic Chemistry Article scaffold in which one amino group was converted into a thiosemicarbazide, while an amide coupling strategy was used to append an aromatic aldehyde-containing moiety onto the other amino group (Chart 1). Use of the C2-symmetric 1R,2R- diaminocyclohexane as a central scaffold ensures that only one stereoisomer can result from this type of modular synthesis. Chart 1. Catalyst Structures Building block C is based on a simple benzene scaffold with a Figure 1. Principle of thiosemicarbazone-based dynamic systems thiosemicarbazone and a protected aldehyde in a 1,3- presented in this study. Use of a nucleophilic catalyst, or equilibrator, ff substitution pattern. While conventional aldehyde protection allows for turning on or o the dynamic state of the system. (Inset) ffi Structure of thiosemicarbazone motif, with thiourea and imine schemes proved su ciently stable for building blocks A and C moieties highlighted. (acetals of methanol and ethylene glycol, respectively), successful isolation of building block B was achieved only after forming the kinetically stabilized acetal of 2,2-dimethyl- ion complex with 18-crown-6, and by exploiting 18-crown-6’s propane-1,3-diol in a practical example of applying the stronger affinity for potassium over ammonium ions, it was also Thorpe−Ingold effect.11 possible to revert the static mixture to its dynamic state. We 2.2. Reaching Thermodynamic Equilibrium: The Need describe two different types of equilibrators: one that interferes for an Equilibrator. With building block A in hand, we with the DCL (addition of excess thiosemicarbazide) and one initiated experiments to determine whether thiosemicarbazone that mediates the equilibration but does not incorporate into exchange can be used to form dynamic systems. Initially, we the DCL (addition of excess hydrazide). dissolved A (1.0 mM) in chloroform with TFA (5 vol %), thereby exposing the acetal-protected aldehyde function and 2. RESULTS AND DISCUSSION starting thiosemicarbazone formation (Figure 2). These initial Thiosemicarbazones were traditionally used to precipitate conditions were similar to those used to achieve equilibration of aldehydes from solution, and more recently they have been acylhydrazone DCLs. By use of high-performance liquid applied in anion recognition.8 Furthermore, the last couple of chromatography (HPLC) with UV detection coupled with decades has seen a vastly expanded use of thiourea-based mass spectrometry (MS), we were able to identify several of the 9 receptors, for example, for organocatalysis, and the inherent expected macrocyclic oligomers, An, ranging from dimer A2 to thiourea moiety of thiosemicarbazones is a desirable recog- heptamer A7 in a distribution pattern systematically favoring nition motif to incorporate into DCLs. the smallest macrocyclic species (black trace in Figure 2). In comparison to acylhydrazones, thiosemicarbazones are Macrocycle formation was fast, as evidenced by the fact that expected to be more resilient to hydrolysis (and thus exchange) macrocycles were present in the library in high concentrations because of attenuation of the electron-withdrawing effect from immediately after preparation. the thiocarbamoyl in thiosemicarbazones in comparison to the To verify whether this distribution was a true dynamic acyl in hydrazones. Therefore, use of an equilibrator is expected system at thermodynamic equilibrium, we isolated the ffi to be required for e cient thiosemicarbazone exchange, as has macrocyclic dimer A2 by preparative chromatography and set also been found necessary for some electron-deficient up a library under identical conditions to the library started acylhydrazone-based DCLs.10 This makes thiosemicarbazone from monomer building block A. In a truly thermodynamic exchange ideal for the formation of DCLs whose exchange system, the library should equilibrate to give the same reaction can be stopped by supramolecular means. distribution, but as is evident from Figure 2, the library started 2.1. Building Block Design. Three building blocks, from A2 showed only minor signs of formation of larger comprising a central scaffold onto which was placed a macrocycles after 28 days (compare black and red traces in thiosemicarbazide and a protected aldehyde, were synthesized Figure 2). Thus, the thiosemicarbazone exchange reaction is (see Supporting Information). Building blocks A and B were significantly more resistant to equilibration than acylhydrazone both designed around a central 1R,2R-diaminocyclohexane exchange. B DOI: 10.1021/acs.joc.7b01161 J. Org. Chem. XXXX, XXX, XXX−XXX The Journal of Organic Chemistry Article amine. Therefore, we turned our attention to hydrazide and thiosemicarbazide-based equilibrators 3 and 4. Both aniline 1 and hydrazide 3 have been employed in previous studies to afford faster exchange in
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