WO2014127171A1 - Macrocycles de poly-cyanostilbène - Google Patents

Macrocycles de poly-cyanostilbène Download PDF

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WO2014127171A1
WO2014127171A1 PCT/US2014/016332 US2014016332W WO2014127171A1 WO 2014127171 A1 WO2014127171 A1 WO 2014127171A1 US 2014016332 W US2014016332 W US 2014016332W WO 2014127171 A1 WO2014127171 A1 WO 2014127171A1
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alkyl
macrocycle
cyanostilbene
poly
formula
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PCT/US2014/016332
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Amar H. Flood
Semin Lee
Chun-Hsing Chen
Kevin Mcdonald
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Indiana University Research And Technology Corporation
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Priority to US14/767,570 priority Critical patent/US9701621B2/en
Publication of WO2014127171A1 publication Critical patent/WO2014127171A1/fr
Priority to US15/645,721 priority patent/US10077233B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/47—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of rings being part of condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention pertains to the synthesis and use of poly-cyanostilbene macrocycles for selective anion binding.
  • macrocycles have proven to be fundamental to the foundation of molecular recognition and have seeded potential applications across chemistry and biology, such as phase transfer catalysis and drug delivery. Building on their propensity for self-assembly, macrocycles also serve as precursors to interlocked molecules where host- guest complexes are captured covalently as rotaxanes and catenanes using mechanical bonding. While this diversity of usage marks macrocycles as singularly attractive synthetic and functional targets, their plentiful numbers and varieties demands that any new
  • Pentameric phenylene ethynylenes have been examined for surface self-assembly at the liquid-solid interface.
  • Zeng's aryl-amide pentamers can be optimized for one-pot preparations, and can be tailored for selective cation binding, dense crystal packing, and gelation.
  • MacLachlan's aryl-imine campestarene which can be prepared in high yields in one pot, shows keto-enol tautomerism within the H-bonded imines.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), -C0 2 R 9 , -C(O)-N(R 10 R n ), wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen.
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), -C0 2 R 9 , -C(O)-N(R 10 R n ), wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen, and L comprising an alkyl moiety ranging from Ci_3o, said alkyl moiety comprising a saturated or unsaturated alkyl mo
  • a complex that includes (a) an anion and (b) a poly- cyanostilbene macrocycle of Formula (I) is disclosed:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), -C0 2 R 9 , -C(O)-N(R 10 R n ), wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen.
  • a complex that includes (a) an anion and (b) a poly- cyanostilbene macrocycle of Formula (IV) is disclosed:
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), -C0 2 R 9 , -C(O)-N(R 10 R n ), wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen, and L comprising an alkyl moiety ranging from Ci_3o, said alkyl moiety comprising a saturated or unsaturated alky
  • a method of removing an anion from a solution containing the anion includes three steps.
  • the first step includes contacting the solution with a poly-cyanostilbene macrocycle.
  • the second step includes forming a complex, said complex comprising the anion and the poly-cyanostilbene macrocycle.
  • the third step includes removing the complex from the solution.
  • FIG. 1A illustrates an exemplary synthesis of "Cyanostar” (CS), a poly- cyanostilbene macrocycle with five-fold symmetry, using Knoevenagel condensation and the calculated (B3LYP/6-31G*) dipole moment and electrostatic potential.
  • CS Cyanostar
  • B3LYP/6-31G* calculated dipole moment and electrostatic potential
  • FIG. IB illustrates an example one -pot synthesis of cyanostar.
  • FIG. 1C illustrates a crystal structure of cyanostar. The major set of CS ( ) and the minor set (P) exist in the same space. Disordered methyl groups are omitted for clarity.
  • FIG. ID illustrates a sandwich of two CSs resulting in mixture of stereoisomers.
  • FIG. 2 A illustrates and a plot of binding constants between CS and select anions for log Kn (squares), log (circles) and log 3 ⁇ 4 (triangles). Data obtained from equilibrium- restricted factor analysis implemented with Siwu (40% MeOH/CIH C ⁇ ) at RT.
  • FIG. 2B illustrates the cavity size of CS and anion binding selectivity.
  • FIG. 3 A illustrates an NMR spectroscopic characterization of anion complexes and the [3]rotaxane, wherein an NMR Titration of CS with TBAC10 4 (40% CD 3 OD in CD 2 CI 2 , 500 MHz, 298 K) is shown.
  • FIG. 3B illustrates variable temperature NMR 1H spectroscopy of the 2: 1 complex CS 2 'C10 4 ⁇ + .
  • FIG. 4A illustrates synthesis of phosphate templated [3]rotaxanes, wherein an exemplary synthetic scheme for formation of 2 ⁇ + and 3 ⁇ + is shown.
  • FIG. 4B illustrates the X-ray crystal structure of 3 ⁇ ⁇ +, (solvent molecules, TBA , t-Bu groups and protons are removed for clarity). The M-P isomer is shown.
  • FIG. 4C illustrates CH » "0 hydrogen bonds (d ⁇ 3 A) between CS inner cavity protons and phosphate oxygen atoms.
  • FIG. 5A illustrates partial 1H NMR titration of a dodecylene-bridged bis- cyanostar (1 mM, CD 2 CI 2 ) with increasing equivalents of added TBAPF 6 .
  • the portions of the NMR spectra showing spectral changes in the dodecylene-bridged bis-cyanostar upon addition of TBAPF 6 are depicted by the symbols (black and blue squares, blue triangles, and red circles).
  • FIG. 5B illustrates the dodecylene-bridged bis-cyanostar structure, wherein the proton sites demonstrating titration-like changes in FIG. 5A are illustrated by the symbols (empty black squares and solid blue squares, blue triangles, and red circles).
  • FIG. 5C depicts molecular modeling (MMFF) of a self-complex bismacrocycle having formula (IV-CS-12D) (dodecylene-bridged bis-cyanostar) with PF 6 " supporting a m/z signal of 2164.09 Daltons by ESI-MS.
  • IV-CS-12D formula (IV-CS-12D) (dodecylene-bridged bis-cyanostar) with PF 6 " supporting a m/z signal of 2164.09 Daltons by ESI-MS.
  • the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements.
  • the terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
  • the term “or” means any one member of a particular list and also includes any combination of members of that list, unless otherwise specified.
  • the compounds herein described may exhibit chirality and may be isolated in optically active or racemic forms.
  • Methods for preparing optically active forms include, for instance, resolution of racemic forms or synthesis from optically active starting materials.
  • the compounds herein described may exist as salts.
  • the term "salt,” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid.
  • the resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt.
  • Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate,
  • benzenesulfonate bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like.
  • amino groups of the compounds may also be quatemized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
  • Basic addition salts may be prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Oxo substituents are not present on aromatic moieties.
  • a ring system e.g., carbocyclic or heterocyclic
  • the carbonyl group or double bond be part (i.e., within) of the ring.
  • sulfonyl refers to a -S(0) 2 - group.
  • carbonyl refers to a -C(O)- group.
  • carboxy refers to a -C(0)-OH group.
  • halo or “halogen,” as used herein, refers to -CI, -Br, -I or -F.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbons and containing at least one carbon- carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, trisdecyloxy, tetradecyloxy, and pentadecyloxy.
  • alkyl refers to a straight or branched chain
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkyl-NH refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • alkyl-NH-alkyl refers to an alkyl-NH group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • aryl as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system, as defined herein and fused to a monocyclic cycloalkyl group, as defined herein, a phenyl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahy dronaphthy 1.
  • cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Bicyclic fused ring systems are exemplified by a cycloalkyl group appended to the parent molecular moiety, which is fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system fused to an additional cycloalkyl group, as defined herein, a phenyl group, a heteroaryl, as defined herein, or a heterocycle as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane,
  • Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane and tricyclo [3.3.1.13 ,7] decane (adamantane).
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S.
  • the five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and
  • heterocycle refers to a non-aromatic monocyclic ring or a non-aromatic bicyclic ring.
  • the non-aromatic monocyclic ring is a three, four, five, six, seven, or eight membered ring containing at least one heteroatom, independently selected from the group consisting of N, O and S.
  • monocyclic ring systems include, but are not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxido
  • bicyclic heterocycles are exemplified by a monocyclic heterocycle appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent atoms of the monocyclic ring are linked by a bridge of between one and three atoms selected from the group consisting of carbon, nitrogen and oxygen.
  • bicyclic ring systems include but are not limited to, for example, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, 1,5- diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane, octahydro- pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[b]azepine, 2,3,4,5-tetrahydro-lH-benzo[d]azepine,
  • the present disclosure is based on the discovery of a new type of Cs-symmetric macrocycle based on cyanostilbene, as exemplified in FIG. 1.
  • the discovery of a high yielding, multi-gram scale and one-pot synthesis for the macrocycles both stimulated and enabled a rapid evaluation of its properties.
  • the poly-cyanostilbene macrocycles offer properties that are complementary to those of traditional macrocycles and that are believed to stem from their cyanostilbene repeating unit.
  • electropositive cyanostilbene -based CH groups are believed to form H-bonds with anions inside the macrocycle cavities.
  • the receptor's size shows a bias towards large and traditionally weakly-coordinating anions and its shallow-bowl shape and electron-deficient cyanostilbene constituents help create a ⁇ -surface that favors 2: 1 sandwich complexes in mixed apolar-protic solvents.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), -C0 2 R 9 , -C(0)- N(R 10 R n ), wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen.
  • moieties R 1 , R 2 , R 3 , R 4 and R 5 are all the same R group, as illustrated below in Formula (IR):
  • R is selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH- alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, hydrogen, iodo, -OR 6 , -N(R 7 R 8 ), - C0 2 R 9 , -C(O)-N(R 10 R n ), and R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of alkenyl, alkyl, alkoxy, alkyl-NH-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocycle, haloalkyl, and hydrogen [0054] Substituent R may be chosen according to the properties one wishes to impart to the macrocycle.
  • a group having a more pronounced hydrophilic or hydrophobic nature may be chosen in order to increase a macrocycle 's solubility in a given solvent or solvent mixture. Substituent characterized by different electronegativities may also be relied upon for the purpose of optimizing the complexation of a given anion. Similarly, the geometry and rigidity of the macrocycle and of its internal cavity, may be tweaked by choosing substituents characterized by differing degrees of steric hindrance. In
  • R may be an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and hexyl.
  • group R is a tert-butyl moiety:
  • moiety R is an alkoxy group having 1 to 15 carbon atoms, such as methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, trisdecyloxy, tetradecyloxy, and pentadecyloxy.
  • moiety R of macrocycles of Formula (I) and (IR) can be selected based upon the availability of known reagents from which the macrocycles are synthesized, as further explained in the synthetic schemes presented herein. For example, different R group substituents are presented in macrocycles 1-1 through 1-8:
  • moiety R 1 of Formula (I) can be a mono-iodo substituent, as depicted below for Formula (I-Iodo), wherein the remaining moieties R 2 , R 3 , R 4 and R 5 can include the substituents selected from the same group as for Formula (I):
  • a highly preferred embodiment of compounds having Formula (IR-Iodo) include Formula (CS-I), wherein the R groups are a t-butyl group, as illustrated below:
  • Compounds having the structure of Formulas (I-Iodo), (IR-Iodo) and (CS-I) provide a synthetic path for further mono-substituted derivatives, owing to nucleophilic aromatic substitution ( ⁇ ) of the iodide anion by a suitable nucleophile containing the desire substituent.
  • ⁇ nucleophilic aromatic substitution
  • CS-Cii-methacrylate can be readily prepared from compounds having Formula (CS-I), or by using synthetic reagents leading to compounds having Formula (CS-I):
  • the compounds having Formula (I-Iodo) also provide for novel, robust synthesis of bismacrocycles having Formula (IV) through reaction of two compounds having Formula (I-Iodo) with a suitable bifunctional crosslinking reagent that provides for an intermacrocyclic linker L, as depicted below:
  • the bifunctional crosslinking reagent leading to bismacrocycle compounds includes a linker L having alkyl chain lengths ranging from Ci_3o, and more preferably from C 2-18 .
  • the linkers can include saturated or unsaturated alkyl moieties, as well as substituents within the alkyl moieties.
  • One particularly useful substituent includes a third functional group (for example, amines, thiols, alcohols, activated carbonyls and carboxylates, polyhistidine moieties, among others) that permits crosslinking with another reactive group, such as those found on select activated resins or other substrate matrix supports, such as epoxides, hydrazydes, N-hydroxy-succinimide esters, metal chelate agents (such as polyhistidine (e.g., hexahistidine)), 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (ED AC) carbodiimide coupling reagent, among others).
  • the reactive groups that displace the iodo-substituent contribute to the overall structure and length of linker L following crosslinking to form the bismacrocyclic structure of Formula (IV).
  • the compound having Formula (CS-I) can provide for novel, robust synthesis of bismacrocycles through reaction of two compounds having Formula (CS-I) with a suitable bifunctional crosslinking reagent (for example, using a diazide dodecyl linker under click chemistry conditions).
  • a suitable bifunctional crosslinking reagent for example, using a diazide dodecyl linker under click chemistry conditions.
  • An example of one such bismacrocycle is illustrated by the compound having formula (IV-CS-12D):
  • Compounds of formula (IV) provide structurally unique anion binding activity as clam-shell anion chelates.
  • An example of one such binding geometry is depicted in FIG. 5 for the compound of formula (IV-CS-12D).
  • Such unimolecular bivalent, anion coordination geometries make possible anion coordination and clearance using lower concentrations of bismacrocycle reagents as compared to unimacrocycle reagents, owing to the entropic advantages afforded by having two anion-coordinating macrocycle groups linked together.
  • Typical unimolecular macrocycles can only bind anion targets efficiently under conditions where the concentration of the unimolecular macrocyles are above the dissociation constant for formation of the trimeric complex containing two unimolecular macrocycles in complex association with the target anion.
  • bismacrocycles are expected to display little concentration dependence as a function of bismacrocyccle concentration for binding an anion.
  • the polycyanostilbene macrocycles can be easily prepared in a synthesis where a benzylic nitrile and benzaldehyde functional groups are reacted with each other, as illustrated in reaction Scheme A (in reactions Schemes A and B, R has the same meaning as described above). Both such groups are featured in a meta substituted difunctional non-symmeteric arene precursor of Formula (II): Scheme A
  • Such bases include carbonate salts, such Li 2 C0 3 , Na 2 C0 3 , K2CO3, Rb 2 C0 3 , Cs 2 C0 3 , MgC0 3 , CaC0 3 , SrC0 3 , BaC0 3 , and mildly basic amines, such as pyridine or piperidine.
  • carbonate salts such Li 2 C0 3 , Na 2 C0 3 , K2CO3, Rb 2 C0 3 , Cs 2 C0 3 , MgC0 3 , CaC0 3 , SrC0 3 , BaC0 3
  • mildly basic amines such as pyridine or piperidine.
  • Arene precursors of Formula (II) can be prepared, for instance, by oxidizing a hydroxymethyl-substituted 2-pheynlacetonitrile molecule of Formula (III), as described in reaction Scheme B:
  • Compounds having Formula (CS-I) can be prepared by reacting one part of the mono-iodo substituted building block reagent (3) with 15 parts of the tert-butyl building block reagent (4), according to Scheme C.
  • Compounds having Formula (CS-Py) can be prepared by reacting one part of the mono-pyridyl substituted building block reagent (6) with 15 parts of the tert-butyl building block reagent (4), according to Scheme D. Each reaction is run under statistical conditions and the single-substituted product is separated by
  • Compound having Formula (IV-CS-12D) can be prepared from (CS-I), for example, according to Scheme E that employs (CS-TMS) and (CS-Ac) as intermediates.
  • Compounds having Formula (IV) can be prepared in a similar manner described for (IV-CS- 12D), for example, according to Scheme E that employs reagents having the desired substituents as intermediates.
  • anion X may be a tetrafluoroborate (BF 4 ), perchlorate (C10 4 ), and hexafluorophosphate (PF 6 ).
  • BF 4 tetrafluoroborate
  • C10 4 perchlorate
  • PF 6 hexafluorophosphate
  • Other example anions include
  • n may be 1 or 2, depending on factors such as the relative amounts of the macrocycle and anion when the complex is formed.
  • R 1 , R 2 , R 3 , R 4 , and R 5 have the same meaning as defined above, and may all be the same group, for instance a tert-butyl group as in molecule CS.
  • the complexes may be prepared by adding a salt of anion X to a solution of a poly-cyanostilbene macrocycle of Formula (I), as illustrated in Scheme F:
  • a salt MX including anion X and positive counterion M may be added to a solution of (I).
  • X is a monoanion, such as tetrafluoroborate (BF 4 ), perchlorate (C10 4 ), or hexafluorophosphate (PF 6 ⁇ )
  • the counterion may be chosen from among monocations, for example, those of alkali metals or ammonium, or dications such as those of alkaline earth metals.
  • the complex may be isolated alongside a desired counterion(s) by methods known in the art, for example, precipitation and/or anion exchange chromatography.
  • Example 1 Studies based upon computer-guided design.
  • Example 2 One-pot, multigram-scale, macrocycle synthesis.
  • PCC (920 mg, 4.26 mmol) and silica gel (5 g) were mixed well using a mortar and pestle and suspended in CH 2 C1 2 (50 mL).
  • the reaction mixture was stirred at room temperature overnight and filtered through a short silica gel column and washed with CH 2 C1 2 to give a white solid product (1.08 g, 2.50 mmol, 88% yield).
  • TIPS-aldehyde-CN (100 mg, 0.31 mmol) was dissolved in THF (2 mL) and added to a solution of CS 2 CO 3 (20 mg) dissolved in ethanol (30 mL) and THF (30 mL). The reaction was kept in the dark and stirred at room temperature for 12 hours. The resulting yellow suspension was concentrated, washed with H 2 0, brine, and dried over MgS0 4 . After removal of the solvent, the crude material was chromatographed over S1O 2 (5-30% acetone/hexanes) to yield TIPS-CS (42 mg, 45%) as an off-white solid.
  • OTBDMS-aldehyde-CN 75 mg, 0.22 mmol was dissolved in THF (20 mL) and ethanol (20 mL). Cs 2 C0 3 (14 mg) was then added as a solution in THF/EtOH (1 : 1, 10 mL). The resulting solution was kept in the dark and stirred at room temperature for 12 hours. After removal of the solvent, the crude product was chromatographed over Si0 2 (CHC1 3 ) to yield OTBDMS-CS as a white solid (42 mg, 60% yield).
  • CS 2 CO 3 (1.19 g) was suspended in EtOH (2 L), poured into a 4 L amber bottle, and stirred for 30 minutes to promote dissolution. Once dissolved, THF was added (2 L) followed by 2-(3-(fert-butyl)-5-formylphenyl)acetonitrile (4) (6.90 g, 34.3 mmol) and 2-(3- formyl-5-iodophenyl)acetonitrile (3) (620 mg, 2.3 mmol) as solutions in THF (60 mL). The solution was kept in the dark and stirred for 24 hours at room temperature. The resulting light yellow suspension was concentrated to dryness and separated over Si0 2 (2: 1
  • TMS-CS (630 mg, 0.66 mmol) was dissolved in THF (25 niL), sat. K 2 C0 3 /MeOH (3 mL) and stirred for 20 minutes. After removal of the solvents, the crude material was separated over Si0 2 (dichloromethane). The product was further purified via slow diffusion of Et 2 0 into a concentrated CHC1 3 solution to yield CS-Ac (500 mg, 85% yield) as an off- white solid.
  • CS-Cn-methacrylate [00138] CS-Ac (30 mg, 0.03 mmol) and 11-azidoundecyl methacrylate (14 mg, 0.03 mmol) was dissolved in THF (2 mL), t-BuOH (500 ⁇ ), H 2 0 (250 ⁇ ), and degassed with argon. TBTA (5 mg), CuS0 4 »5H 2 0 (1.7 mg in 170 ⁇ , H 2 0), and sodium ascorbate (2 mg in 200 H 2 0) was then added and the solution was stirred at room temperature for 24 hours. The resulting suspension was diluted with dichloromethane, washed with brine, and dried over MgS0 4 .
  • CS-Ac 100 mg, 0.11 mmol
  • 1,12-bisazidododecane 13.5 mg, 0.11 mmol
  • THF 5 mL
  • t-BuOH 1 mL
  • H 2 0 500 L
  • degassed with argon To the solution was then added tris[(l-benzyl-lH-l,2,3-triazol-4-yl)methyl]amine (12 mg), CuS0 4 »5H 2 0 (5.6 mg dissolved in 200 ⁇ H 2 0), and sodium ascorbate (7 mg dissolved in 200 ⁇ H 2 0).
  • the solution was warmed to 60 °C and stirred under argon for 18 hours.
  • CS 2 CO 3 (65 mg, 0.2 mmol) was suspended in EtOH (250 mL) and stirred for 30 minutes. Once dissolved, THF was added (200 mL) followed by 2-(3-(tert-butyl)-5- formylphenyl)acetonitrile (4) (820 mg, 4.1 mmol) and 2-(3-formyl-5-(pyridin-4-yl)phenyl) acetonitrile (6) (50 mg, 0.23 mmol) as solutions in THF (50 mL). The solution was kept in the dark and stirred for 24 hours at room temperature.
  • Example 15 Solid-state structure of the cyanostar macrocycle (CS).
  • cyanostars are shaped like shallow bowls akin to chiral sumanenes and corannulenes where the CS dimers meet at the seams created by their inner rims rather than being nested together.
  • the two macrocycles are rotationally offset from each other, which is attributed to a combination of electrostatic complementarity between the electron deficient ⁇ surfaces of the two cycles and steric effects involving tert-butyl groups.
  • the diastereomeric P-M and M-P dimers are also present. These dimers are also enantiomers of each other but only in the solid state because of their translational and rotational degrees of freedom are frozen. If present in solution, this pair of dimers would exist as the meso compound.
  • Example 16 Size-selective recognition of large weakly coordinating anions.
  • CS displays size-selective binding of large anions in a mixed solution of 40% methanol (MeOH) in dichloromethane (CH 2 CI 2 ), selected to dissociate ion pairs.
  • the macrocycle has a pseudo-spherical shape and a diameter of ⁇ 4.5 A with the dimer's cavity slightly larger at ⁇ 5.2 A. Titrations were conducted to quantify the binding affinity of variously sized anions (see Supplementary Information) having ionic diameters ranging from CI " ( ion ⁇ 3.4 A) to FeCl 4 ⁇ (d ion ⁇ 6.3 A).
  • a plot of log and log 3 ⁇ 4 versus the anion size shows high binding affinities and a peak preference for bigger anions that match the large central cavity.
  • the breadth of the peak is consistent with a certain degree of flexibility in the receptor.
  • the binding affinities observed for BF 4 ⁇ , C10 4 and PF 6 ⁇ , log K u > 5 and log 3 ⁇ 4 > 11, are unusually large for such "weakly coordinating" anions.
  • anion stabilization may be attributed to the electropositive cavity defined by the olefmic and phenylene H-bonding environment as well as the benefits gained from the Hofmeister bias.
  • tetrabutylammonium (TBA + ) salt of C10 4 showed monotonic shifts in position that locked into place upon addition of 0.5 eq, while only modest movements occurred during the addition of extra salt, up to 10 equivalents. Similar behavior was observed for PF 6 ⁇ .
  • the 1H NMR spectrum of [3]rotaxane 3 ⁇ + shows a major and minor component with a ⁇ 7:2 integration ratio similar to the C10 4 sandwich complex, ⁇ 8:2.
  • the major and minor peaks from the t-butyl peaks (H e and H e ), the dumbbell (H and H ) and the CS macrocycles (H c and H c ).
  • the isomers are configurationally stable based on heating 3 ⁇ + to 393 K. Further confirmation that the signals for the two diastereomers originate from different spin systems are provided from unique cross peaks in the through-bond COSY and TOCSY spectra (see Supplementary Information).
  • the crystal structure of the meso compound (M-P) shows H b located deeper within the phenylene ring current of the neighboring p-stacked macrocycle than for the chiral compound (M-M and P-P).
  • H b (meso) is located (see
  • Example 18 NMR titration data and ESI-MS evidence of 1: 1 stoichiometry for bismacrocycle (IV-CS-12D)-anion complexes.

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Abstract

L'invention concerne des caractéristiques de synthèse et de liaison d'anions de macrocycles de polycyanostilbène (représentés structurellement).
PCT/US2014/016332 2013-02-13 2014-02-13 Macrocycles de poly-cyanostilbène WO2014127171A1 (fr)

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