Acyl radical insertion for the direct formation of new seven-substituted pterin analogs

Abstract

A variety of pterin molecules were synthesized via an under-utilized acyl radical insertion, using aldehydes and α-keto esters as the acyl source. These reactions gave complete regiospecificity for the 7-isomer, with reaction times ranging in minutes, often with instantaneous product precipitation. This approach led to the construction of new pterin analogs unaccessable via traditional FriedelCrafts acylation. The compounds were characterized by NMR spectroscopy and high-resolution mass spectroscopy.Pterins have been shown to be a noteworthy lead in the search for Ricin A chain inhibitors. 1 In this context, we have explored different routes to pterin libraries, particularly those which remove extraneous steps often needed to circumvent pterins' insolubility and poor reactivity. As with other diazoaromatic compounds, such as pyrazines, direct substitution by electrophiles is not a viable reaction for pterins, as a result of their being so π-electron deficient. 2,3 For this reason, formation of acylpterins is typically done through oxidation of alkyl side-chains to carboxylates or alcohols. 4,5 Taylor developed a method for forming isomerically-pure alkyl pterins, though it requires a multi-step construction of the ring. 6 Methods exist for the formation of isomerically-enriched alkyl pterins through a traditional one step condensation, but formation of the undesirable isomer is still observed. 5 Furthermore, due to the poor solubility of pterins, isolation of the desired isomer can be difficult, often requiring further modifications. 5,7 Direct acylation of heteroaromatic bases was first shown by Caronna, whereby an aldehyde is allowed to react with a peroxide in the presence of iron sulfate, generating an acyl radical which can insert onto the protonated heterocyclic species. 8 This reaction has been performed on a variety of simple heterocycles, and has also been shown to proceed with α-keto esters as the acyl source. 2,9,10 Substituent-directing effects have been studied, and it was found that groups which are electron withdrawing by resonance and inductive effects direct to the para position. 11 As related to pterins, these directing effects would regiospecifically provide the 7-isomer. This reaction has previously been utilized on molecules containing the general pteridine substructure, and it was indeed found that when both heteroaromatic positions are available, only the 7-isomer is formed, while placement of electron-donating substituents on the 7-position allowed access to the 6-isomer. 12-14 However, these pteridine analogs often had *Corresponding author. Tel.: 512-471-0068; fax: 512-471-7791; anslyn@austin.utexas.edu. Supplementary MaterialSupplementary data (general experimental procedure, NMR and MS data) can be found in the online version.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and rev...

Peptide-Conjugated Pterins as Inhibitors of Ricin Toxin A

“…Optimization was slow due to the notorious insolubility associated with the pterin heterocycle, as traditional coupling techniques proved fruitless due to solvent restrictions. 8a, 10 Structures of a previous key pterin-based RTA inhibitors are shown in Figure 1 below.…”

7-Substituted pterins provide a new direction for ricin A chain inhibitors

“…It was previously seen that the pterin ring of pteroic acid and neopterin participate in a larger number and stronger interactions within the active site, compared to adenine [8b, 14]. As all current pterin-based inhibitors found from commercial libraries had relied on the 6-position for functionalization, we diversified our library by testing the regioisomeric 7-substituted derivatives, a task greatly assisted by our new synthetic means [13]. …”

“…2-Aminopteridin-4-one (2) , 7-methoxycarbonyl-pterin (3) , 7-carbamoyl-pterin (4 ), 7-propionyl-pterin (5) , 7-acetyl-pterin (6) and 7-(p-methoxybenzyl)-pterin (7) were all prepared through their literature procedures [12a, 13]. …”

“…4) can also be prepared by suspending 3 in ammonia saturated methanol, in a sealed conical vial, and heating to 80 °C overnight with stirring. Addition of a small amount of 0.5M HCl, to neutralize, followed by filtration gave a yellow solid which, after washing with methanol and drying, was identical to the sample prepared through the previous method [13]. …”

“…Many of the pterin based compounds evaluated were synthesized directly via a previously reported acyl radical insertion reaction ( 3 – 7 , Scheme 1) [13]. The simple pterin core ( 2 ), which was prepared via condensation of glyoxal with 1 , was taken up in aqueous sulfuric acid and treated with iron sulfate, tert-butyl hydroperoxide, and an acyl source to provide compounds 3 – 7 in yields ranging from 22–48%.…”