Relative Reactivities of Activated Carboxylic Acids in Amide-Forming Reactions Employed for the Synthesis of Tetraphenylporphyrin Libraries

Dombi, Kendra L.; Richert, Clemens

doi:10.3390/51201265

Cited by 6 publications

(9 citation statements)

References 15 publications

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“…Scheme 1 shows the synthesis of the tetraphenylporphyrins that were employed in the reactivity tests. Starting from meso-tetrakis(p-aminophenyl)porphyrin (1), available from p-nitrobenzaldehyde and pyrrole in two steps, 17 NR-Boc-aspartic acid γ-benzyl ester or NR-Boc-alanine were coupled to produce protected acylamidoporphyrins, whose Boc-deprotection with TFA yielded 2a 16 and 2b, respectively. Exploratory coupling reactions with 2a and activated carboxylic acids of low reactivity showed side products presumably resulting from aspartimide formation.…”

Section: Resultsmentioning

confidence: 99%

“…Even if these drawbacks were not critical, it is important to remember that signal intensity in MALDI-TOF mass spectra does not necessarily correlate with concentration unless conditions for quantitative detection have been established. [12][13][14][15] In a recent preliminary research note published electronically, 16 we presented a method for measuring the relative reactivity of pairs of activated carboxylic acids used to synthesize tetraphenylporphyrin libraries. The method employs a tetrakis(aminoacylanilino)porphyrin as reaction partner and MALDI-TOF mass spectrometry as the analysis method for product analysis of competitive reactions.…”

Section: Introductionmentioning

confidence: 99%

“…However, the method presented 16 also had a number of drawbacks, such as being limited to adjusting the reactivity of pairs of building blocks, without yielding rate constants that could be employed for planning the syntheses of larger libraries. Further, the method had been tested on no more than seven building blocks and only porphyrins as the targets for library generation.…”

Section: Introductionmentioning

confidence: 99%

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Rapidly Measuring Reactivities of Carboxylic Acids to Generate Equireactive Building Block Mixtures: A Spectrometric Assay

2003

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The relative reactivity of building blocks is critical for a successful preparation of combinatorial libraries.Here, we present a method for measuring the reactivity of carboxylic acid building blocks in amide-forming reactions. The method involves competitive reactions between a reference and test acid and a tetraphenylporphyrin reaction partner with four reactive sites. Relative reactivities are calculated on the basis of the distribution of substituted porphyrins found in MALDI-TOF mass spectra. Reactivities thus determined were used to prepare reactivity-adjusted building block mixtures. These were reacted with amino-terminal oligonucleotide and peptide scaffolds on solid support, generating small libraries suitable for spectrometrically monitored selection experiments (SMOSE). The rate of building block "drop outs" that fail to couple as expected was not substantially lowered by acquiring spectra from two reactions, performed with different ratios of building blocks, where the effect of a given substituent on the desorption/ionization yield of the porphyrin can be eliminated. Instead, coupling building blocks of similar size together or employing N-hydroxysuccinimide esters rather than activating with a "uronium salt" were found to improve the quality of libraries generated via competitive reactions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapidly Measuring Reactivities of Carboxylic Acids to Generate Equireactive Building Block Mixtures: A Spectrometric Assay

2003

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“…MS/MS is expected to be useful for the chemical characterization of porphyrins because it allows a rapid identification of porphyrins in mixtures, especially those resulting from synthetic procedures. Further, the assembly of spectral databases will make widely available the valuable structural data from MS [17,18]. Nevertheless, mass spectral data of tetraphenylporphyrins substituted in ␤-pyrrolic positions comprise only two recent reports: One on ␤-bromotetraphenylporphyrins [19,20] and another on the fragmentation of ␤-nitrotetraphenylporphyrin [16], which is the precedent for this research.…”

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confidence: 99%

Unexpected fragmentation of β-substituted meso-tetraphenylporphyrins induced by high-energy collisional activation

Domingues

S.-Marques

Alonso

et al. 2002

J. Am. Soc. Mass Spectrom.

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The protonated molecules and radical cations of meso-tetraphenylporphyrins with ␤-pyrrolic substituents, when formed by fast atom bombardment (FAB) and subjected to high-energy collisions, give rise to unexpected fragment ions. The reaction involves hydrogen migration from the ortho position of the phenyl ring to the ␣ atom of the substituent, with formation of an intramolecular, six-membered ring. The process is analogous to condensed-phase cyclizations described for the same type of compounds. The fragmentation requires the presence of a double bond in the substituent group attached to the pyrrolic ring. A rearrangement process involving anchimeric assistance by the phenyl group (analogous to an ortho effect) is proposed for the formation of these ions. T he porphyrin macrocycle is present in a variety of systems found in nature and participates in numerous important biochemical functions. New porphyrins are being synthesized to mimic the natural systems. Research on porphyrins has accelerated recently because they are applicable in a variety of fields of chemistry, physics, medicine, and biology [1]. Most promising are applications as agents in photodynamic therapy in cancer treatment [2], receptor models in molecular recognition [3], and use in materials chemistry [4] owing to their optical properties and their ability to form microporous solids, conductive polymers, and sensors. The functionalization of the ␤-pyrrolic positions of meso-tetraphenylporphyrins is particularly of interest because the properties of the porphyrin macrocycle can be modified by small changes in the ␤-pyrrolic substituents [5]. The ability of these substituents to interact with the adjacent phenyl groups may lead to deviations of planarity of the porphyrin rings, affecting the chemical, spectroscopic, and other properties of the substituted porphyrins [6,7]. An example is the role of non-planar conformations of chlorophyll, vitamin B12, and cytochrome P450 in biological processes [8].Despite the increasing interest in this class of compounds, the mass spectrometric analysis of porphyrins is still relatively unexplored [9], particularly that of substituted meso-tetraphenylporphyrins [10 -16]. The few studies that describe the fragmentation of tetraphenylporphyrins in the MS/MS mode [12][13][14][15][16] show that this approach gives valuable structural information about the peripheral substituents. MS/MS is expected to be useful for the chemical characterization of porphyrins because it allows a rapid identification of porphyrins in mixtures, especially those resulting from synthetic procedures. Further, the assembly of spectral databases will make widely available the valuable structural data from MS [17,18]. Nevertheless, mass spectral data of tetraphenylporphyrins substituted in ␤-pyrrolic positions comprise only two recent reports: One on ␤-bromotetraphenylporphyrins [19,20] and another on the fragmentation of ␤-nitrotetraphenylporphyrin [16], which is the precedent for this research.In this report, we discuss the unexpected fragm...

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“…Since conventional methods of determining rate constants are time consuming we developed a rapid assay for determining relative reactivities, 6 building on earlier work on combinatorial libraries of porphyrins. 7 The assay involves competitive coupling reactions between test and reference acid with a porphyrin tetraamine under pseudo-first order conditions and product analysis via MALDI-TOF mass spectra. 6 One class of carboxylic acids, namely the N-methylpyrrole carboxylic acids, has not yet been explored by SMOSE.…”

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confidence: 99%

A Reactivity Test for HBTU-Activated Carboxylic Acids with Low Reactivity and Competitive Coupling ofN-Methylpyrrole Derivatives

Ernst¹,

Richert²

2005

Synlett

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N-Methylpyrrole carboxylic acids are building blocks for oligopyrroleamides that bind DNA duplexes via the minor groove. The reactivity of HBTU-based active esters of four methylpyrroles in amide-forming reactions was determined. When assayed against HBTU-activated N-acetylleucine, a 6-250-fold lower reactivity was found. When assayed against the NHS ester of Boc-valine, the reactivity was up to 4-fold lower. Despite large differences in reactivity, mixed couplings were successfully performed with all four pyrroles, generating small libraries of modified oligonucleotides suitable for spectrometrically monitored selection experiments. Microwave irradiation accelerated coupling of an Fmoc-protected pyrrole to an amine on solid support.Combinatorial searches for new structural motives that bind tightly to a given target can be performed in a number of different ways. 1 For modified oligonucleotides the synthesis of small combinatorial chemsets (libraries) that are then subjected to mass spectrometrically monitored selection experiments (SMOSEs) 2 has been one successful approach. 3 Other approaches involving combinatorial steps and spectrometric or spectroscopic techniques are known. 4,5 The small chemsets employed in SMOSE assays are usually prepared via mixed coupling of carboxylic acids and amine-terminated DNA on solid support. 3 After high yielding mixed couplings, crude libraries can be assayed directly, without purification or pooling steps, greatly enhancing the throughput. SMOSE assays require the unambiguous detection of all components of a given chemset. Since the reactivity of building blocks varies with structure, equireactive mixtures of the building blocks have to be generated for mixed couplings by adjusting the concentration of building blocks such that increased reactivity is compensated by a lower concentration and decreased reactivity by a higher concentration. This demands a knowledge of the relative reactivity of the active esters of the carboxylic acids. Since conventional methods of determining rate constants are time consuming we developed a rapid assay for determining relative reactivities, 6 building on earlier work on combinatorial libraries of porphyrins. 7 The assay involves competitive coupling reactions between test and reference acid with a porphyrin tetraamine under pseudo-first order conditions and product analysis via MALDI-TOF mass spectra. 6One class of carboxylic acids, namely the N-methylpyrrole carboxylic acids, has not yet been explored by SMOSE. Methylpyrroles are building blocks for oligopyrroleamides that bind sequence-specifically in the minor groove of DNA duplexes, 8,9 and conjugates of oligonucleotides and oligopyrroleamides show promising binding properties. 10 Our recent synthesis of stilbenelinked DNA-oligopyrroleamide hybrids required separate assembly of oligopyrroles in solution, 11 as coupling to amino-terminated DNA on controlled pore glass (cpg) was extremely low yielding. Attempts to terminate stilbene caps 12 in pyrrole amides using mixed coupling were also...

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Relative Reactivities of Activated Carboxylic Acids in Amide-Forming Reactions Employed for the Synthesis of Tetraphenylporphyrin Libraries

Cited by 6 publications

References 15 publications

Rapidly Measuring Reactivities of Carboxylic Acids to Generate Equireactive Building Block Mixtures: A Spectrometric Assay

Rapidly Measuring Reactivities of Carboxylic Acids to Generate Equireactive Building Block Mixtures: A Spectrometric Assay

Unexpected fragmentation of β-substituted meso-tetraphenylporphyrins induced by high-energy collisional activation

A Reactivity Test for HBTU-Activated Carboxylic Acids with Low Reactivity and Competitive Coupling ofN-Methylpyrrole Derivatives

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