Isolation and structure elucidation of unexpected in-process impurities during tetrazole ring formation of an investigational drug substance.

During the formation of a tetrazole ring on an investigational drug, two in-process impurities were detected and analyzed by LC-MS, which suggested that both impurities were drug-related with the same mass-to-charge ratio. To understand and control their formation, both impurities were isolated from the mother liquor of the reaction using a multi-step isolation procedure to obtain a sufficient amount for high-resolution mass spectrometry (HRMS) and NMR structural analysis. HRMS suggested a protonated mass of 577.32 Da for both impurities; however, MS fragmentation patterns provided limited information on their structures. NMR analysis indicated the presence on an additional NH functional group in both isolates with similar spatial and bond correlations to one of the dimethylcarbamoyl moieties and the corresponding aromatic ring. A phenyldimethylcarbamoylamino moiety was supported by the NMR and HRMS data and could be explained based on the 'Schmidt-like' reaction mechanism, which was an unexpected reaction pathway. Because the reaction conditions were fixed because of safety concerns, the crystallization protocol was redesigned to reduce the levels of these impurities significantly. Copyright © 2016 John Wiley & Sons, Ltd.

Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization.

The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)-H vs the C(4)-H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For N-oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C-H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C-H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consistent with the observed poor site selectivity in the reaction of a pyridine substrate, the overall energy barriers for functionalization of the two positions are nearly identical. High C(2)-selectivity in the C-H activation step of the reaction of the N-oxide is due to a cooperative effect of the C-H Brønsted acidity, the strength of the forming C-Rh bond, and intramolecular electrostatic interactions between the [Rh]Cp* and the heteroaryl moieties. On the other hand, some of these forces are in opposition in the case of the pyridine substrate, and C(4)-H activation is moderately favored overall. The alkyne insertion step is favored at C(2) over C(4) for both substrates, and this preference is largely influenced by electrostatic interactions between the alkyne and the heteroarene. Experimental results that support these calculations, including kinetic isotope effect studies, H/D exchange studies, and results using a substituted pyridine, are also described.

Rh(III)-catalyzed C-H activation and double directing group strategy for the regioselective synthesis of naphthyridinones.

A general Rh(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide N-oxides as substrates. In general, high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures.

Synthesis of the C1-C52 fragment of amphidinol 3, featuring a beta-alkoxy alkyllithium addition reaction.

An advanced intermediate for the synthesis of amphidinol 3 has been prepared. A cross-metathesis reaction was used to couple the C1-C12 and C13-C26 segments. An unusual beta-alkoxy alkyllithium reagent was generated from this segment and added to a Weinreb amide to assemble the C1-C52 section of amphidinol 3. These compounds represent some of the most advanced intermediates reported to date for the synthesis of amphidinol 3.

Synthesis of optically pure arylsilylcarbinols and their use as chiral auxiliaries in oxacarbenium ion reactions.

A family of arylsilylcarbinols was synthesized and investigated as chiral auxiliaries for oxacarbenium ion reactions. The optically pure arylsilylcarbinols were prepared using Noyori's transfer hydrogenation catalyst 11. The transfer hydrogenation shows very good enantioselectivities and turnover efficiency for the aryl silyl ketones and is the method of choice for preparing these optically pure alcohols. The diastereoselective addition of allyltrimethylsilane to an in situ generated oxacarbenium ion was explored using Marko's conditions. The selectivity for a representative aliphatic aldehyde was very good, but the selectivity was significantly reduced with unsaturated and aromatic aldehydes. The range of selectivities with different auxiliaries was narrow, and the most practical auxiliary is the phenylsilylcarbinol 2.