Synthesis and Manipulation of Orthogonally Protected Dendrimers: Building Blocks for Library Synthesis

Steffensen, Mackay B.; Simanek, Eric E.

doi:10.1002/anie.200460031

Cited by 93 publications

(65 citation statements)

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“…1,2 Our early targets commonly incorporated p-aminobenzylamine because of the significant differences in the reactivity of the amines of this group. That is, during a convergent synthesis, protecting group manipulations and functional group interconversions could be avoided because the benzylic amine would react preferentially (essentially exclusively) with the monochlorotriazine dendron being elaborated.…”

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confidence: 99%

“…1 From these studies, aminomethylpiperidine emerged as a diamine linker of choice and was used extensively. 1,2,7,9,[15][16][17]19,20 Using competition experiments, the relative reactivity difference measured for the cyclic secondary amine and primary amine of aminomethylpiperidine is ~ 20 times. Theoretically, 5% of the product formed might derive from reaction of the monochlorotriazine dendron with the primary amine instead of the desired secondary amine.…”

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confidence: 99%

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Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Moreno

Simanek

2008

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Diamine linkers for the synthesis of dendrimers based on melamine were identified using competition reactions. The relative reactivity of the cyclic monoamines surveyed vary in relative reactivity by 40 times, expanding the previously identified series to an overall relative reactivity range of 320 times. Azetidine is 40 times more reactive than the cyclic, nine-membered ring (C 8 H 17 N), and 320 times more reactive than benzylamine. Reactivity differences are attributed to pKa values and sterics. Incorporating these groups into diamines provides linkers that can be employed in dendrimer synthesis. Specifically, the nucleophilicity of the individual amine groups comprising 3-aminoazetidine, 3-aminopyrrolidine, and 4-aminopiperidine vary by 100 times, 70 times, and 20 times, respectively. These linkers are incorporated into a generation three dendrimer.Our group has invested significant energies in the synthesis of dendrimers based on triazines, also referred to as dendrimers based on melamine deriving from our use of diamine linkers. 1, 2 Our early targets commonly incorporated p-aminobenzylamine because of the significant differences in the reactivity of the amines of this group. That is, during a convergent synthesis, protecting group manipulations and functional group interconversions could be avoided because the benzylic amine would react preferentially (essentially exclusively) with the monochlorotriazine dendron being elaborated. 1,[3][4][5][6][7] The low stability of these aniline derivatives required reasonable, but additional, care on handling. While the use of distilled solvents and inert atmospheres are not uncommon, nor is the requirement for refrigerated storage of intermediates, we recognized that these precautions could impact the broader acceptance of these materials.The low cost and high reactivity of piperazine soon made it a linking diamine of choice for our investigations. However, when using piperazine, dimerization of monochlorotriazines was observed under non-ideal reaction conditions that were usually attributed to concentration, rate of addition, ineffective stirring or lack thereof, temperature of addition and the magnitude of stoichiometric excess. 4,[8][9][10][11][12][13][14][15][16][17][18] Reactions with either p-aminobenzylamine or piperazine could be readily followed by NMR. The shift of the benzylic protons on reaction with the monochlorotriazine dendron or the desymmetrization of methylene groups of the piperazine group were diagnostic. The use of piperazine led to the undesirable formation of dimers, unfortunately. Detecting these dimers by NMR proves difficult due to signal degeneracy between the desired asymmetric monoamine and the symmetric dimer.

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Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Moreno

Simanek

2008

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“…These disulfide groups readily underwent exchange with biotin, captopril, a small peptide sequence, or even a DNA oligonucleotide (67 and 68, Chart 16), although the characterization and purification of the latter were challenging, and no general protocols emerged. 37,84,85 Qualitative observations resulting from these experiments indicated that steric factors arising from the size of the substrate or the dendrimer influenced the degree of exchange that occurred. A related kinetic study of disulfide exchange on the periphery of other melaminederived dendrimers confirmed that the rate of exchange increases as the size of the dendrimer decreases (69-73, Chart 17).…”

Section: Biologically Relevant Moleculesmentioning

confidence: 97%

“…37 The inference to the potential utility of this dendrimer for drug delivery and related biological applications was based on the demonstration that the functional groups could be manipulated after the synthesis of the dendrimer with little formation of byproducts. The power of triazine chemistry is best exemplified in these targets.…”

Section: Nucleophilic Aromatic Substitutionmentioning

confidence: 99%

Dendrimers based on [1,3,5]‐triazines

Steffensen

Hollink

Kuschel

et al. 2006

J. Polym. Sci. A Polym. Chem.

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ABSTRACT:A comprehensive and chronological account of dendrimers based on [1,3,5]-triazines is provided. Synthetic strategies to install the triazine through cycloaddition, cyclotrimerization, and nucleophilic aromatic substitution of cyanuric chloride are discussed.Motivations and applications of these architectures are surveyed, including the preparation of supramolecular assemblies in the solution and solid states and their use in medicines, advanced materials, and separations when anchored to solid supports. V

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“…This limitation was offset by carrying latent functionality (in the form of orthogonal protecting groups) through the synthesis that could be manipulated. 10,11 Of greater issue, the repetitious coupling of smaller fragments into larger ones required that most of the mass be carried through the entire synthesis. Regardless, reasonable quantities of materials of high purity up to generation three could be obtained for evaluation.…”

Section: Introductionmentioning

confidence: 99%

A divergent route towards single-chemical entity triazine dendrimers with opportunities for structural diversity

et al. 2007

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This manuscript describes the successful synthesis and characterization of five generations of dendrimers based on melamine. Early generations of these materials appear to be single chemical entities: upon purification, no detectable impurities are observed using NMR spectroscopy, mass spectrometry, and HPLC and GPC analysis. The analysis of larger generation materials precludes an unambiguous statement of purity. The synthetic route to these targets is divergent, relying on dichlorotriazine monomers that react with a polyamine dendrimer core of generation n to produce a poly(monochlorotriazine) dendrimer of generation n + 1. Subsequently, the poly (monochlorotriazine) is derivatized through nucleophilic aromatic substitution before additional nucleophilic amines are unmasked and the process iterated.

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Synthesis and Manipulation of Orthogonally Protected Dendrimers: Building Blocks for Library Synthesis

Abstract: The synthesis of dendrimers containing up to six different functional groups by multistep one-pot reactions involving a selective manipulation and deprotection strategy is described by E. E. Simanek and M. B. Steffensen in their Communication on the following pages.

Cited by 93 publications

References 34 publications

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Dendrimers based on [1,3,5]‐triazines

A divergent route towards single-chemical entity triazine dendrimers with opportunities for structural diversity

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