Practical and Scalable Two-Step Process for 6-(2-Fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane: A Key Intermediate of the Potent Antibiotic Drug Candidate TBI-223.

A low-cost, protecting group-free route to 6-(2-fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (1), the starting material for the in-development tuberculosis treatment TBI-223, is described. The key bond forming step in this route is the creation of the azetidine ring through a hydroxide-facilitated alkylation of 2-fluoro-4-nitroaniline (2) with 3,3-bis(bromomethyl)oxetane (BBMO, 3). After optimization, this ring formation reaction was demonstrated at 100 g scale with isolated yield of 87% and final product purity of >99%. The alkylating agent 3 was synthesized using an optimized procedure that starts from tribromoneopentyl alcohol (TBNPA, 4), a commercially available flame retardant. Treatment of 4 with sodium hydroxide under Schotten-Baumann conditions closed the oxetane ring, and after distillation, 3 was recovered in 72% yield and >95% purity. This new approach to compound 1 avoids the previous drawbacks associated with the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. The optimization and multigram scale-up results for this new route are reported herein.

Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and Alkynylcyclopropanols to Cyclopentenones.

A comparison study of the Ru(II)-catalyzed rearrangements of allenyl- and alkynylcyclopropanols to the corresponding cyclopentenones has been undertaken with the aid of an alkyl substituent on the three-membered ring. These ring expansion reactions proceed with exceptional regioselectivity irrespective of the cis/trans stereochemistry of the substituents on the three-membered ring. ß-Carbon elimination is the common feature in the absence of a chelating group at the 4'-position in the alkyne chain.

Formation of oxo-centered trinuclear chromium carboxylate complexes and hydrolysis of Cr3 as established by paramagnetic (2)H NMR spectroscopy.

Paramagnetic (2)H NMR techniques have been utilized to study the mechanism of formation of the oxo-bridged trinuclear Cr(III) carboxylate assembly [Cr3O(O2CCD3)6(H2O)3](+) from [Cr(H2O)6](3+) and d4-acetic acid. These studies reveal a complex mechanism dominated by the involvement of dinuclear intermediates. The oxo-bridged trinuclear Cr(III) carboxylate assembly [Cr3O(O2CCH2CH3)6(H2O)3](+) has been suggested for use as a chromium nutritional supplement and therapeutic agent as it is readily absorbed and has been proposed to enter cells intact. The paramagnetic (2)H NMR technique has been utilized to follow the stability of this Cr(III) carboxylate assembly in biologically relevant media; its stability is consistent with the assembly being able to enter cells intact.

Paramagnetic 19F NMR and Electrospray Ionization Mass Spectrometric Studies of Substituted Pyridine Complexes of Chromium(III): Models for Potential Use of 19F NMR to Probe Cr(III)-Nucleotide Interaction.

The synthesis and characterization of chromium basic carboxylate complexes, [Cr3(O2CR)6L3]+, containing trifluoroacetate, 3-fluoropyridine, 3-trifluoromethylpyridine, and 4-trifluoromethylpyridine are described. The substituted pyridine ligands are used as models of DNA bases to determine whether 19F NMR would be a potentially useful probe of the binding of Cr3+ to DNA. The 19F NMR resonances of the coordinated ligands, while broadened by delocalization of unpaired electron density from the S=3/2 chromic centers, are readily discernable, and the contact shifts are of sufficient magnitude that the signals from coordinated and free ligands can easily be differentiated. Thus, 19F NMR appears to be a potentially useful probe of the binding of Cr3+ to DNA containing F-labeled bases. Additionally, electrospray MS is shown to be a convenient method to establish the identity of chromium basic carboxylate assemblies.

Synthesis and characterization of 5,10,15,20-tetra[3-(3-trifluoromethyl)phenoxy] porphyrin.

The newly synthesized 5,10,15,20-tetra[3-(3-trifluoromethyl)phenoxy]porphyrin, TTFMPP, has been characterized using mass spectroscopy, 1H-, 13C- and 19F-NMR, MALDI-TOF mass spectrometry, UV-Vis and fluorescence spectrophotometry, and cyclic voltammetry. The NMR confirmed the structure of the compound and the mass spectrum was in agreement with the proposed molecular formula. The UV-Vis absorption spectrum of TTFMPP shows characteristic spectral patterns similar to those of tetraphenyl porphryin, with a Soret band at 419 nm and four Q bands at 515, 550, 590, and 648 nm. Protonation of the porphyrin with TFA resulted in the expected red shift of the Soret band. Excitation at 419 nm gave an emission at 650 nm. The quantum yield of the porphyrin was determined to be 0.08. Cyclic voltammetry was used to determine the oxidation and reduction potentials of the new porphyrin. Two quasi-reversible one-electron reductions at -1.00 and -1.32 V and a quasi-reversible oxidation at 1.20 V versus the silver/silver chloride reference electrode with tetrabutylammonium tetrafluoroborate as the supporting electrolyte in methylene chloride were observed.