Fluorosulfonamide-Directed Heteroarylation of Aliphatic C(sp3)-H Bonds.

Herein, we describe a formal dehydrogenative cross coupling of heterocycles with unactivated aliphatic amines. The resulting transformation enables the direct alkylation of common heterocycles by merging N-F-directed 1,5-HAT with Minisci chemistry, leading to predictable site selectivity. The reaction provides a direct route for the transformation of simple alkyl amines to value-added products under mild reaction conditions, making this an attractive option for C(sp3)-H heteroarylation.

Regulation of vocal precision by noradrenergic modulation of a motor nucleus.

Recent theories of norepinephrine (NE) function suggest that NE modulates the transition between stereotyped, goal-directed behavior and more variable, exploratory behaviors that facilitate learning and adaptation. We provide evidence for context-dependent switching by NE that is analogous to this explore/exploit strategy in the vocal system of the zebra finch (Taeniopygia guttata). Stimulation of the locus coeruleus, the major source of NE in the brain, decreases song trial-to-trial variability, transforming the variable, exploratory "undirected" song into song that resembles the more stereotyped, exploitative "directed" song that males sing to females. This behavioral switch is mediated by NE acting directly on a cortical motor nucleus that integrates inputs from a premotor cortical nucleus and a basal ganglia circuit necessary for vocal motor learning. These findings suggest that NE can act directly on the motor system to influence the transition between exploratory and exploitative behavioral strategies.NEW & NOTEWORTHY Norepinephrine (NE) function is often implicated in regulating arousal levels. Recent theory suggests that the noradrenergic system also regulates the optimization of behavior with respect to reward maximization by controlling a switch between exploration and exploitation of the specific actions that yield greatest utility. We show in the songbird that NE can act directly on a cortical motor area and cause a switch between exploratory and exploitative behavior.

The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.

Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 µM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 µg/mL, representing a significant improvement in antitubercular potency in this class of compounds.