Beschleunigung von Substitutionsreaktionen eines Phosphorsäurediesters durch Bis(guanidinium)‐Verbindungen

Abstract

Acceleration of Substitution Reactions of a Phosphoric Acid Diester by Bis(guanidinium) CompoundsIon-pair coordination of phosphoric acid diesters with positively charged guanidines may cause large rate accelerations in substitution reactions. Here we present a comparative study on the catalytical influence of several mono-bis-and tris(guanidines) and of other cationic compounds. Large rate effects occur if 1,3-bis(aminomethyl)benzene or 1,2-ethy-RNA cleaving agents. lenediamine are used as spacers. Further acceleration can be achieved by exchanging guanidinium groups by 2-aminoimidazolines. The 4800-fold rate enhancement seen in the best case demonstrates the importance of the bis(guanidinium) moiety of staphylococcal nuclease and gives good perspectives towards future uses of guanidinium compounds as Als verknupfende Strukturelemente der Nucleinsauren sind Phosphorsaurediester von zentraler Bedeutung fur die Chemie lebender Systeme. Uns erscheint deshalb die Suche nach Katalyse-Prinzipien fur Phosphoryl-ubertragungsreaktionen als lohnende Zielsetzung, die wir gegenwartig mit Nachdruck verfolgen.So konnten wir kurzlich uber die Phosphorylierung des Amidiniumalkohols 1 berichten[la1, der in dipolar-aprotischen Solventien mit dem Phosphorsaurediester 2 reversi-be1 Ionenpaarkomplexe 3 bildet und in einer quasi-intramolekularen Substitution zum zwitterionischen Produkt 4 abreagiert. Dabei ubertrifft die Phosphorylierungs-Geschwindigkeit von 1 diejenige des analogen ungeladenen Alkohols 5 bei weitem, ein Effekt, der fur die Entwicklung synthetischer Phosphorsaurediesterasen ausgenutzt werden soll.Bei diesen Experimenten fie1 auf, daD Zusatze des Amidinium-Salzes 1 die Kontrollreaktion von 2 mit 5 zu 6 um etwa das 25fache beschleunigen: Durch die Koordination an das Amidinium-Ion (als Komplex 3) wird der Phosphodiester 2 fur Substitutionsreaktionen aktiviert. In der vorliegenden Arbeit beschreiben wir nun eine systematische Untersuchung des Einflusses verschiedener Mono-, Bis-und Tris(guanidinium)-Verbindungen auf die Geschwindigkeit der Ringoffnung von 2 durch 2-Phenylethanol (5)[lb1. Die von einigen Verbindungen hervorgerufenen Effekte sind so ausgepragt, daD ein zukunftiger Einsatz als RNA-schneidendes Agens moglich erscheint.Nucleophile Substitutionen an Phosphorsaurediester-Anionen verlaufen auDergewohnlich langsam, weil die Elektrophilie am Phosphor-Atom durch die negative Ladung stark verringert ist. In der Regel wird uber einen Additions-Eliminierungs-Mechanismus eine dianionische, trigonal-bipyramidale Zwischenstufe durchschritten[21, auch wenn experi-Schema 1 2a: Tetramethylguanidiniumsalz von 2 clod-TMG'mentell die Abgrenzung zum konzertierten Reaktionsverlauf nicht immer einfach istL3]. In jedem Fall steigt die Ladungsdichte auf dem Weg vom Grund-zum Ubergangszustand, so da13 die Barriere durch die Koordination elektrophiler Teilchenr4I erniedrigt werden kann.

Hydrolytical Cleavage of TAR‐RNA, the trans‐Activation Responsive Region of HIV‐1, by a Bis(guanidinium) Catalyst Attached to Arginine

“…3; Fig. 2): in dipolar aprotic solvents nucleophilic substitutions of a model phosphodiester are accelerated by factors up to 4800 [62] [63]. Similar results have been obtained by other scientists [59] [64] [65].…”

Design of a Neutral Macrocyclic Ionophore: Synthesis and Binding Properties for Nitrate and Bromide Anions

“…Our strategy for the formation of 8 (X ϭ O) and 8 (X ϭ S) is similar to that reported by Lehn et al, [38] which focused on the addition of amines and isothiocyanates, and that reported by Göbel et al, [29] in which a thiourea unit bearing two terminal amines reacts with a diisothiocyanate in the final macrocyclization step. Treatment of a twofold excess of diamine 2 with Boc anhydride, with use of a continuous extraction method for product isolation, gave a mixture of 97% monoprotected 3 and 3% diprotected diamine 4.…”

“…Density functional theory (DFT) calculations (at the B3LYP/6-31G* level of theory) on the macrocycles with X ϭ S and O and with C 3 symmetry (the highest point group in which all macrocycles are minima) predict a cavity size of 2.727 Å for X ϭ O and 2.922 Å for X ϭ S. Interestingly, the macrocycles with X ϭ NH and X ϭ CH 2 or CH, such as Göbels macrocycle 19 [29] (the size of which is between that of the O-and that of S-macrocycle) can be ruled out as potential receptors, because the hydrogen atoms in the spacer group X would sterically interfere with a bound nitrate and with the thiourea NϪH groups. This leaves the macrocycles with X ϭ O and S as possible candidates for synthesis.…”

“…To answer this question, the nitrate-binding abilities of macrocycles 8 (X ϭ S) and 19 [29] (Scheme 3)Ϫ with related, but slightly different structures Ϫ were determined in DMSO by NMR titration. For comparison, compound 9, which has only two thiourea binding sites, was also tested.…”

On Facts and Artefacts: The Difficulty to Evaluate an Artificial Nuclease

“…They generally consist of oligo amines [4], guanidines, or structurally analogous heterocycles [2] [3]. In recent years, we have studied the catalysis of phosphoryl-transfer reactions by guanidinium salts {3-[(guanidino)methyl]phenyl}methylguanidine (1b) and 2-[(3-{[(4,5-dihydro-1H-imidazol-2-yl)amino]methyl}phenyl)methyl]amino-4,5-dihydro-1H-imidazole (2b) [5] [6]. With highly reactive model substrates in dipolar aprotic solvents, large rate increases could be observed.…”