Louis J. Todaro

High-Yielding Aqueous 18F-Labeling of Peptides via Al18F Chelation

The coordination chemistry of a new pentadentate bifunctional chelator (BFC), NODA-MPAA 1, containing the 1,4,7-triazacyclononane-1,4-diacetate (NODA) motif with a methylphenylacetic acid (MPAA) backbone, and its ability to form stable Al(18)F chelates were investigated. The organofluoroaluminates were easily accessible from the reaction of 1 and AlF(3). X-ray diffraction studies revealed aluminum at the center of a slightly distorted octahedron, with fluorine occupying one of the axial positions. The tert-butyl protected prochelator 7, which can be synthesized in one step, is useful for coupling to biomolecules on solid phase or in solution. High yield (55-89%) aqueous (18)F-labeling was achieved in 10-15 min with a tumor-targeting peptide 4 covalently linked to 1. Defluorination was not observed for at least 4 h in human serum at 37 °C. These results demonstrate the facile application of Al(18)F chelation using BFC 1 as a versatile labeling method for radiofluorinating other heat-stable peptides for positron emission imaging.

Synthesis of iso-ddA, member of a novel class of anti-HIV agents

Abstract Iso-ddA ( 3 ) represents a new class of potential anti-AIDS drugs. Synthetic approaches to this compound involving nucleophilic additions to a novel carbohydrate framework are discussed.

On The Two Component Microwave Mediated Reaction of Isonitriles with Carboxylic Acids: Regarding Alleged Formimidate Carboxylate Mixed Anhydrides

Microwave induced two-component coupling (2CC) reaction of carboxylic acids with isonitriles gives rise to various N-formylamides. The formimidate carboxylate mixed anhydride (FCMA) is proposed as the reactive intermediate, which undergoes 1,3-O-->N acyl transfer to give the observed product. The formation and survival of the labile FCMA system has been evaluated.

A comparison of the antibacterial and β-lactamase inhibiting properties of penam and (2,3)-β-methylenepenam derivatives : The discovery of a new β-lactamase inhibitor. Conformational requirements for penicillin antibacterial activity

Abstract The antibacterial potencies of 2a and 4 are shown to be diminished considerably from their penam analogues, penicillin G (1a) and mecillinam (3). Despite this, 2a is a substrate for bacterial β-lactamases, and compounds 6a, 8 and 10 were found to be β-lactamase inhibitors. Penicillin-binding protein (PBP) studies indicate that penicillin G and mecillinam have much greater affinity for these enzymes than the (2,3)-β-methylenepenam analogues. Based on a comparison of hydrolytic stabilities, it is proposed that the change in biological properties is due to conformational differences between the two types of penam nuclei. The cyclopropyl methylene of 2a and 4 blocks the side chain from forming an oxazolone with the β-lactam carbonyl. Hence, activation of the β-lactam is prevented and the molecules are rendered less active. We thus conclude that 19 is the biologically active conformation of penicillin antibacterials, and further suggest that the interaction of such antibiotics with their bacterial enzyme targets involves intermediates such as 25–27.

Self-organization of a new fluorous porphyrin and C60 films on indium-tin-oxide electrode

The highly fluorinated alkyl moieties of a new porphyrin drive the self-organization of thin films with C(60) on ITO electrodes.

Structure of 3-Acetyl-5-fluorouracil (5-FU): Implication for Its Rearrangements During Hydrolysis and upon Heating

Single-crystal X-ray diffraction data show that the 3-acetyl group in l,3-diacetyl-5-FU (FU = fluorouracil) is perpendicular to the plane of the 5-FU ring, while the 1-acetyl group is coplanar with the ring. Analyses of 1H NMR and IR spectra provide evidence that the 1-and 3-acyl groups are in different electronic environments, which is consistent with the X-ray diffraction structure. 3-Acetyl-5-FU is thermally unstable, giving mainly l-acetyl-5-FU (80%) and 5-FU (20%) upon heating. The hydrolysis of 3-acyl derivatives of 5-FU showed a biexponential relationship between In concentration and time which had not been previously observed. The behavior of 3-acetyl-5-FU during hydrolysis can be explained by postulating its initial rapid equilibrium with an intermediate, 2-acetyl-5-FU, which subsequently hydrolyzes to 5-FU or rearranges to l-acetyl-5-FU, which hydrolyzes to 5-FU. The 2-acetyl intermediate was trapped by its reaction with formaldehyde. The formaldehyde adducts of the symmetrical 2-acetyl intermediate rearranged to yield equal amounts of 1- and 3-acetyloxymethyl-5-FU.

Synthesis of 3′-C-Substituted-2′,3′-Dideoxynucleosldes as Potential Antcaids Agents

Abstract In this paper we report an efficient synthetic route to some novel 3′-C-substituted-2,3′-dideoxy-nucleosides. The critical 3′- C-C bond was constructed by an application of free radical methodology. This type of reaction was found to be stereoselective forming exclusively the 3′-“down” isomer. The stereo-chemical assignment at C-3′ was confirmed by both nmr nOe experiments and single crystal X-ray analysis.

Synthesis of the AB Subunit of Angelmicin B through a Tandem Alkoxy Radical Fragmentation-Etherification Sequence

The synthesis of the tricyclic enone 2, corresponding to the AB subunit of the novel tyrosine kinase inhibitor angelmicin B, is described. The strategy centers on an intramolecular Diels-Alder (IMDA) reaction on triene 4 to provide the complex decalin 3, which is elaborated to 2. Other key steps are the formation of the THF ring in 2 through a tandem alkoxy radical fragmentation-etherification on the lactol derived from 3, and the synthesis of 4 via a ring-closing ene-yne metathesis (RCEYM).

A facile entry into the ring system of sativene

Abstract The mechanism of the dehydrobromination of two isomeric dibromo-cis-4a-methyldecalin-2,5-diones and tribromo-cis-4a-methyldecalin-2,5-dione is described. Treatment of dione ( 2 ), with 2 equiv of bromine gave a mixture of dibromides ( 3 ) and ( 4 ) in a 1:1 ratio. Treatment of ( 2 ) with 3.2 equiv of bromine gave tribromide ( 5 ) as the major product. Dehydrobromination of ( 3 ) and ( 4 ), independently with DBU in THF, resulted in the loss of HBr and the exclusive formation of two isomeric tricyclic compounds ( 6 ) and ( 7 ) respectively. Dehydrobromination of tribromide ( 5 ) with DBU gave a mixture of two tricyclic compounds ( 6 ) and ( 8 ) in an approximate ratio of 1:1. The mechanisms of the formation of the isomeric tricyclic bromoketones ( 6 ) and ( 7 ) from compounds ( 3 ) and ( 4 ), and that of ( 6 ) and ( 8 ) from the tribromide ( 5 ) are discussed. Both tricyclic compounds ( 6 ) and ( 8 ), readily available in good yields from Wieland Miescher ketone ( 1 ), have the same carbon skeleton as the sesquiterpene hydrocarbon sativene.

A convenient route to substituted tetrahydrofuran-3-ones: Condensations of α-bromo ketones with aromatic aldehydes

Abstract In the presence of K 2 CO 3 , α-bromo ketones react with aromatic aldehydes in methanol to produce substituted tetrahydrofuran-3-ones 3a–g in good yields (55% to 83%). The reaction proceeds with initial formation of an α-ketoepoxide, followed by a tandem aldol reaction, cyclization and dehydration.