Copper-Catalyzed Racemization-Recycle of a Quaternary Center and Optimization Using a Combined Kinetics-DoE/MLR Modeling Approach.

The copper-catalyzed racemization of a complex, quaternary center of a key intermediate on route to lanabecestat has been identified. Optimization and mechanistic understanding were achieved through the use of an efficient, combined kinetic-multiple linear regression approach to experimental design and modeling. The use of a definitive screening design with mechanistically relevant factors and a mixture of fitted kinetic descriptors and empirical measurements facilitated the generation of a model that accurately predicted complex reaction time course behavior. The synergistic model was used to minimize the formation of dimer byproducts, determine optimal conditions for batch operation, and highlight superheated conditions that could be accessed in flow, leading to a further increase in yield which was predicted by the original model.

Tuning for rate and duration of frequency-modulated sweeps in the mammalian inferior colliculus.

Responses of auditory duration-tuned neurons (DTNs) are selective for stimulus duration. We used single-unit extracellular recording to investigate how the inferior colliculus (IC) encodes frequency-modulated (FM) sweeps in the big brown bat. It was unclear whether the responses of so-called "FM DTNs" encode signal duration, like classic pure-tone DTNs, or the FM sweep rate. Most FM cells had spiking responses selective for downward FM sweeps. We presented cells with linear FM sweeps whose center frequency (CEF) was set to the best excitatory frequency and whose bandwidth (BW) maximized the spike count. With these baseline parameters, we stimulated cells with linear FM sweeps randomly varied in duration to measure the range of excitatory FM durations and/or sweep rates. To separate FM rate and FM duration tuning, we doubled (and halved) the BW of the baseline FM stimulus while keeping the CEF constant and then recollected each cell's FM duration tuning curve. If the cell was tuned to FM duration, then the best duration (or range of excitatory durations) should remain constant despite changes in signal BW; however, if the cell was tuned to the FM rate, then the best duration should covary with the same FM rate at each BW. A Bayesian model comparison revealed that the majority of neurons were tuned to the FM sweep rate, although a few cells showed tuning for FM duration. We conclude that the dominant parameter for temporal tuning of FM neurons in the IC is FM sweep rate and not FM duration. NEW & NOTEWORTHY Reports of inferior colliculus neurons with response selectivity to the duration of frequency-modulated (FM) stimuli exist, yet it remains unclear whether such cells are tuned to the FM duration or the FM sweep rate. To disambiguate these hypotheses, we presented neurons with variable-duration FM signals that were systematically manipulated in bandwidth. A Bayesian model comparison revealed that most temporally selective midbrain cells were tuned to the FM sweep rate and not the FM duration.

Organization and trade-off of spectro-temporal tuning properties of duration-tuned neurons in the mammalian inferior colliculus.

Neurons throughout the mammalian central auditory pathway respond selectively to stimulus frequency and amplitude, and some are also selective for stimulus duration. First found in the auditory midbrain or inferior colliculus (IC), these duration-tuned neurons (DTNs) provide a potential neural mechanism for encoding temporal features of sound. In this study, we investigated how having an additional neural response filter, one selective to the duration of an auditory stimulus, influences frequency tuning and neural organization by recording single-unit responses and measuring the dorsal-ventral position and spectral-temporal tuning properties of auditory DTNs from the IC of the awake big brown bat (Eptesicus fuscus). Like other IC neurons, DTNs were tonotopically organized and had either V-shaped, U-shaped, or O-shaped frequency tuning curves (excitatory frequency response areas). We hypothesized there would be an interaction between frequency and duration tuning in DTNs, as electrical engineering theory for resonant filters dictates a trade-off in spectral-temporal resolution: sharp tuning in the frequency domain results in poorer resolution in the time domain and vice versa. While the IC is a more complex signal analyzer than an electrical filter, a similar operational trade-off could exist in the responses of DTNs. Our data revealed two patterns of spectro-temporal sensitivity and spatial organization within the IC: DTNs with sharp frequency tuning and broad duration tuning were located in the dorsal IC, whereas cells with wide spectral tuning and narrow temporal tuning were found in the ventral IC.

Tautomerism troubles: proton transfer modifies the stereochemical assignments in diastereoisomeric structures of spiro-cyclic 5-methyl-2H-imidazol-4-amine dimers.

During the racemization of a novel pharmaceutical spiro-cyclic imidazole-amine compound, namely, 6'-bromo-N-(6'-bromo-4-meth-oxy-4''-methyl-3'H-di-spiro[cyclo-hexane-1,2'-indene-1',2''-imidazol]-5''-yl)-4-meth-oxy-4''-methyl-3'H-di-spiro-[cyclo-hexane-1,2'-indene-1',2''-imidazol]-5''-imine, C36H41Br2N5O2, two impurities were isolated. These impurities were clearly dimers from mass spectroscopic analysis, however single-crystal diffraction characterization was required for the assignment of stereochemistry. The single-crystal diffraction results revealed subtly different structures to those proposed, due to an unexpected proton transfer. The dimers contain four stereocentres, but two of primary inter-est, and are centrosymmetric, so after careful structure refinement and close inspection it was possible to unambiguously assign the stereochemistry of both the homochiral [(S),(S)- and (R),(R)-] and the heterochiral [(S),(R)- and (R),(S)-] compounds.