Development of a Practical Synthesis of the 8-FDC Fragment of OPC-167832.

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (8-FDC) fragment of OPC-167832 in 41% yield and in >99% purity over four steps from 3-amino-4-fluorophenol. The key feature of this process is the development of a telescoped one-pot synthesis of the quinolone via a chemoselective amidation/acid-induced cyclization that allows for simple product isolation without the need for column chromatography.

DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.

A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.

Zinc Acetate-Promoted Buchwald-Hartwig Couplings of Heteroaromatic Amines.

Zinc salts have been shown to promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.

DBU catalysis of N,N'-carbonyldiimidazole-mediated amidations.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.

Mild and efficient DBU-catalyzed amidation of cyanoacetates.

A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.

Amidations using N,N '-carbonyldiimidazole: remarkable rate enhancement by carbon dioxide.

Carbon dioxide catalyzes the reaction of imidazolides with amines to form amides. A substantial rate enhancement is observed in the presence of CO(2) compared to the CO(2)-free case. The scope and limitations of this reaction are discussed.

Early amidation approach to 3-[(4-amido)pyrrol-2-yl]-2-indolinones.

A new synthesis of 3-[(4-amido)pyrrol-2-yl]-2-indolinones has been developed, where the amide side chain was installed prior to pyrrole formation. This strategy precludes the need to use any coupling reagents to install the amide side chain. This process includes a zinc-free alternative to the Knorr pyrrole synthesis.

Catalytic regioselective sulfonylation of alpha-chelatable alcohols: scope and mechanistic insight.

This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.

AM1-SM2 Calculations Model the Redox Potential of Nitroxyl Radicals Such as TEMPO.

Nitroxyl radicals can be oxidized to N-oxo ammonium salts that are themselves useful oxidants for primary and secondary alcohols. Several computational methods were investigated in order to predict the redox potential of nitroxyl radicals and to better understand the behavior of different nitroxides as catalysts for alcohol oxidation. The difference in calculated heats of formation for N-oxo ammonium ions and nitroxyl radicals using AM1 did not lead to a useful correlation with experimental redox potential as measured by cyclic voltammetry. However, when both the N-oxo ammonium ion and the nitroxyl radical were evaluated using the Cramer-Truhlar solvation model (SM2), a linear correlation was observed between the difference in heats of formation and the experimental redox values. This correlation may be used to correctly predict the redox potential of new nitroxyl radicals.

Synthesis of Chiral Nitroxides and an Unusual Racemization Reaction.

Lai's protocol for the synthesis of nitroxides has been extended to the synthesis of several new chiral piperazine and morpholine nitroxides. This strategy utilizes the Bargellini reaction as the key bond-forming step. Several optically pure nitroxides incorporating alpha-aromatic and alpha-spiro centers were prepared by this route. These chiral nitroxides will be of interest as enantioselective oxidants, as traps for prochiral radicals, and in the preparation of new materials. One of these nitroxides, compound 43, was found to racemize under mild oxidizing conditions. The mechanism for this unusual racemization reaction was investigated.