RESUMEN
In contrast to 2,3-dihydroxypyridine, the 3-benzyloxy protected derivative, 2, undergoes facile alkylation at ambient temperatures with a variety of functionalized alkyl halides in good yields. This alkylation has been used to prepare a number of linkers that permit the attachment of 3,2-HOPO moieties onto various scaffolds using a wide range of coupling methods. The Mitsunobu reaction of 2 with representative alcohols was found to be of limited value due to competing O-alkylation that led to product mixtures. The phthalimide 3j can be converted in two steps to HOPO isocyanate 6 in excellent yields. Isocyanate 6 can be coupled to amines at room temperature or to alcohols in refluxing dichloroethane to obtain the corresponding urea or carbamate linked ligand systems. The coupling of isocyanate 6 with TREN followed by deprotection gave the tris-HOPO 10, an interesting target as it has both cationic and anionic binding sites. The HOPO hydroxylamine linker 11 was shown to be especially valuable as its coupling with carboxylic acids proceeds with the concomitant generation of an additional hydroxamate ligand moiety in the framework. The utility of this linker was shown by the preparation of two mixed HOPO-hydroxamate chelators, 16 and 19, based on the structure of desferrioxamine, a well-known trihydroxamate siderophore.
RESUMEN
The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10, were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates.
RESUMEN
Synthetic approaches to mixed ligand chelators on readily available t-butylphenol-formaldehyde oligomer, PFO, scaffolds were examined. In a promising approach, tris and tetraphenol oligomers were selectively mono or di protected using t-butyldiphenyl silyl chloride. The utility of these protected intermediates to prepare representative mixed PFO chelators, carrying ligands such as hydroxamic acid, 3,2-hydroxypyridinones and others was then demonstrated. The introduction of the ligand tethers onto the phenolic scaffold can be done sequentially under relatively mild conditions that tolerate the presence of other sensitive ligand groups. The differential reactivity of the disilyl derivative 20b, allowed stepwise introduction of two different ligands on the internal phenolic positions. This enabled the introduction of three different ligand groups of choice onto the tetra phenol platform.
RESUMEN
Two novel bifunctional N-methylhydroxamate-isocyanate linkers 20 and 21 were prepared in good yield and high purity from the corresponding amine salts using a biphasic reaction with phosgene. The facile ring opening reaction of N-Boc lactams using the anion of O-benzylhydroxylamine gave the protected amino hydroxamates 6a and 6c in good yields. The selective methylation of the hydroxamate nitrogen in the presence of the N-Boc group in these intermediates could be readily accomplished. The utility of the linkers was clearly demonstrated by the synthesis of the carbamate-tethered trishydroxamic acid 27 and the urea-tethered 29.
RESUMEN
Unsaturated acyloxy sulfones 3 undergo intramolecular cyclization upon deprotonation with LHMDS in THF. Dehydration and double bond isomerization of the products upon exposure to acid, gave the fused ring furans, 4, in good yields. This strategy could be readily adapted to 12 from the cyclization reactions of acyloxy sulfones 11 prepared from phenols. Finally, this approach could be successfully modified to access dihydropyrans and benzopyrans.
RESUMEN
The HOPO sulfonamide reagent, 3, was prepared from commercial 2,3-dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunobu conditions. The utility of this nucleophilic HOPO reagent was demonstrated by the synthesis some tris and tetraHOPO chelators. This approach for tethering HOPO ligands is unique and flexible as shown by the preparation of HOPO/iminocarboxylic acid chelator 17.
RESUMEN
The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides and phosphonates proceed in high yields to obtain functionalized γ and δ lactams. The chiral oxazolidinone precursors can be readily synthesized from commercial amino acids. The lactams from this study are useful synthetic intermediates, as demonstrated by the synthesis of a precursor for levetiracetam, an antiepileptic drug.
RESUMEN
N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized 5- and 6-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,ß-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15.
RESUMEN
The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log ß(110) = 27.34 ± 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log ß(230) = 60.46 ± 0.04 and log ß(110) = 20.39 ± 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log ß(230); log ß(110) was found to be 20.45 ± 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.
Asunto(s)
Hierro/química , Piridinas/química , Sideróforos/química , Ligandos , Protones , EspectrofotometríaRESUMEN
The concurrent esterification and N-acetylation of amino acids has been studied with triethyl orthoacetate (TEOA) and triethyl orthoformate (TEOF). In a surprising finding, only one equivalent of TEOA in refluxing toluene was necessary to convert L-proline and L-phenylalanine to the corresponding N-acetyl ethyl esters in good yield. The same transformation using TEOF was not effective. Stereochemical outcome and stoichiometric studies as well as structural variation of the amino acids in this reaction provided unexpected mechanistic insight.
RESUMEN
Hydroxamic acids are an important class of chelators of hard metal ions such as Fe(III), which have found applications in therapeutic, diagnostic, and separation chemistry. Hence, methods for their preparation and incorporation into various matrices are important. A new strategy for the preparation of hydroxamic acids that uses readily available N-benzyloxy carbamic acid ethyl ester, 1, has been developed. N-Alkylation of 1 occurs readily to give N-alkyl-N-benzyloxy carbamates, 2, which react with a variety of stabilized carbon nucleophiles to give functionalized protected hydroxamic acids, 3, in good to excellent yields. The O-protected hydroxamate intermediates 3 can be further alkylated with halides to access a variety of potential metal binding hosts. The usefulness of this methodology has been demonstrated by the synthesis of a novel trihydroxamic acid 6, mixed ligand systems 9 and 12, and the macrocyclic dihydroxamic acid 16.
Asunto(s)
Carbamatos/química , Carbono/química , Ácidos Hidroxámicos/síntesis química , Polímeros/síntesis química , Quelantes/química , Ácidos Hidroxámicos/química , Ligandos , Polímeros/químicaRESUMEN
A convenient synthesis of a variety of substituted N-hydroxysulfamides from chlorosulfonyl isocyanate is reported. Alkyl groups can be introduced selectively on the N-Boc nitrogen of key intermediates 1a or 1b using the Mitsunobu reaction with alcohols. Subsequently the nitrogen carrying the silyloxy group can be alkylated under traditional conditions. Deprotection to the desired N-hydroxysulfamide can be achieved in high yields. Using this method, a number of structurally diverse N-hydroxysulfamides have been prepared. The usefulness of this methodology has further been demonstrated by the synthesis of more complex targets such as bis-hydroxysulfamide, 5, and cyclic hydroxysulfamides 7 and 8.
RESUMEN
The reactions of the electrophilic iminium ester mesylate salt 1 with alcohols, phenols and thiols has been investigated. In the presence of base, thiols, phenols and thiophenol react with 1 to give the corresponding ether linked HOPO derivatives in good yields. However, the ring opening of salt 1 with alcohols could only be accomplished efficiently using a large excess of the alcohol in the presence of methanesulfonic acid at 80°C. The synthetic utility of HOPO precursor, 1, has been demonstrated by the synthesis of two polyHOPO chelators 7 and 9.
RESUMEN
The reactions of N-hydroxybenzenesulfonamide (Piloty's acid, PA) with a variety of metal oxidants are reported. Either nitric oxide or nitrite is the final reaction product, along with benzenesulfinate and the reduced metal compound. The nitrogen product depends on the oxidation potential of the metal oxidant and its ability to further oxidize NO to nitrite. The observation and preliminary interpretation of unusual kinetic behavior of Piloty's acid as a reductant is also described. Analogues of PA were also prepared and found to show similar reactivity.
RESUMEN
The preparation of partial esters of methylenebisphosphonic acids has been of recent interest due to their potential therapeutic applications. This paper describes a convenient method to prepare symmetrical methylenebis(alkyl hydrogen phosphonates) by the selective cleavage of the corresponding methylenebis(dialkyl phosphonate) with refluxing morpholine. The effects of structural variations on the amine as well as the substrate have been investigated to understand the scope and limitations of this reaction. A superior approach to hindered bisphosphonic acid esters involves the cleavage of their dimethyl esters, 4, using morpholine. This method is also useful to access a number of C-alkyl dialkyl methylenebisphosphonic acids such as 6. This study clearly shows that cleavage with morpholine is convenient, inexpensive, and allows for the preparation of a variety of P,P'-disubstituted partial esters in good yields and high purity.
RESUMEN
The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21. This method allows the introduction of the HOPO ligand onto a variety of amine platforms without the concomitant formation of an amide bond and provides access to HOPO chelators of increased water solubility.