Benzotriazolides 1 of alkanoic acids with one hydrogen atom in a-position to the carboxamide group can be deprotonated with lithium diisopropylamide or lithium hexamethyldisilazanide to amide enolates 2 which condense at -90 to -95°C with ketones or aldehydes 3 to afford benzotriazolides of 0-lithiated P-hydroxylalkanoic acids 4. These reactive carboxamide derivatives cyclize with elimination of lithium benzotriazolide to the corresponding di-and trisubstituted p-lactones. With regard to the formation of P-monosubstituted 0-lactones from aldehydes the use of benzotriazolides as active carboxylic acid derivatives proved to be superior to the application of the corresponding phenyl esters. An a-unsubstituted P-lactone 6 was obtained from l-acetylbenzotriazole only with cyclohexanone. The other carbonyl compounds 3 did not provide the corresponding a-unsubstituted 0-lactones 6.The decarboxylation of p-lactones to olefin~ ['-~], the stereoselective reactions of p-lactones with a variety of electrophiles ['-6], and the regioselective fission of (3-lactones by many different n u c l e~p h i l e s [~~~~ make these highly reactive compounds versatile intermediates for organic syntheses ['O]. But at least after the detection of the (3-lactone moiety in a series of biologically active natural products like lipstatin["], lupeolactone[I2], or valilact~ne['~I the interest in efficient syntheses of this class of strained four-membered rings has gained new attention.One of the most versatile procedures for the synthesis of (3-lactones consists in the addition of ketones or aldehydes to doubly lithiated alkanoic acids and subsequent cyclization of the thus obtained (3-hydroxyalkanoic acids with benzenesulfonyl chloride in pyridine['l. Later on, it was found that p-lactones can be prepared directly in a one-pot reaction when lithium ester enolates of S-phenyl alkan e t h i o a t e~ [~, '~I or phenyl alkanoates[151 are used instead of the doubly lithiated alkanoic acids for the aldolization with ketones or aldehydes. In these one-prot reactions the intermediately formed 0-lithiated P-hydroxy esters cyclize spontaneously with elimination of lithium benzenethiolate and lithium phenolate, respectively. A common feature of these procedures is the fact that the benzenethiolate and the phenolate residue are suitable leaving groups. They facilitate the attack of the electrophilic carbon atom of the activated ester group on the lithiated (3-hydroxy group of the inter- mediate and enable in this way the observed intramolecular acylation. In this connection the question arose whether there exist other active carboxylic acid derivatives, which are superior to the phenyl or S-phenyl esters with regard to the yield of the obtained p-lactone and the diastereoselectivity of the carbon-carbon bond formation. Here we report on the results of the aldolization of ketones or aldehydes with 1 -acylbenzotriazoles.N-Acyl derivatives of imidazole are known as powerful acylating agents and have found widespread application in organic synthesis [16%17]. ...
Dopaminergic (DA) midbrain neurons within the substantia nigra (SN) display an autonomous pacemaker activity that is crucial for dopamine release and voluntary movement control. Their progressive degeneration is a hallmark of Parkinson's disease. Their metabolically demanding activity-mode affects Ca2+ homeostasis, elevates metabolic stress, and renders SN DA neurons particularly vulnerable to degenerative stressors. Accordingly, their activity is regulated by complex mechanisms, notably by dopamine itself, via inhibitory D2-autoreceptors and the neuroprotective neuronal Ca2+ sensor NCS-1. Analyzing regulation of SN DA neuron activity-pattern is complicated by their high vulnerability. We studied this activity and its control by dopamine, NCS-1, and glucose with extracellular multi-electrode array (MEA) recordings from midbrain slices of juvenile and adult mice. Our tailored MEA- and spike sorting-protocols allowed high throughput and long recording times. According to individual dopamine-responses, we identified two distinct SN cell-types, in similar frequency: dopamine-inhibited and dopamine-excited neurons. Dopamine-excited neurons were either silent in the absence of dopamine, or they displayed pacemaker-activities, similar to that of dopamine-inhibited neurons. Inhibition of pacemaker-activity by dopamine is typical for SN DA neurons, and it can undergo prominent desensitization. We show for adult mice, that the number of SN DA neurons with desensitized dopamine-inhibition was increased (~60–100%) by a knockout of NCS-1, or by prevention of NCS-1 binding to D2-autoreceptors, while time-course and degrees of desensitization were not altered. The number of neurons with desensitized D2-responses was also higher (~65%) at high glucose-levels (25 mM), compared to lower glucose (2.5 mM), while again desensitization-kinetics were unaltered. However, spontaneous firing-rates were significantly higher at high glucose-levels (~20%). Moreover, transient glucose-deprivation (1 mM) induced a fast and fully-reversible pacemaker frequency reduction. To directly address and quantify glucose-sensing properties of SN DA neurons, we continuously monitored their electrical activity, while altering extracellular glucose concentrations stepwise from 0.5 mM up to 25 mM. SN DA neurons were excited by glucose, with EC50 values ranging from 0.35 to 2.3 mM. In conclusion, we identified a novel, common subtype of dopamine-excited SN neurons, and a complex, joint regulation of dopamine-inhibited neurons by dopamine and glucose, within the range of physiological brain glucose-levels.
H3Cy ' 7 3 3 5 6cladine (5, 1 S, 3 S ) and dioncophylline A (6, 1 R, 3 R) were also subjected to the same degradation conditions, thus serving as additional standards. The exclusive formation of the amino acids (R)-3 and D-4 in a practically enantiomerically pure form ( > 95: 5) clearly shows that both tetrahydroisoquinoline parts are stereochemically identical. This excludes the above-mentioned stereoisomers with identical configurations at the axes, but enantiomorphous tetrahydroisoquinoline parts. Furthermore, the identification of both amino acids in their (R)-configurated forms clearly rules out stereoisomer 1 a, thus unambiguously demonstrating michellamine B to be represented by the stereostructure 1 b, that is, a (1 R, 3 R, 5 M , 1"'R, 3"'R, 5"'P) configuration. Of course, this result again and independently confirms the relative trans configurations in both heterocyclic systems. The work described in this paper represents the first complete elucidation of the full stereostructure of a "dimeric" naphthylisoquinoline alkaloid. Michellamine b (1 b) is a constitutionally symmetrical, but heterochiral coupling product of two atropodiastereomeric biaryl alkaloids. These two naphthylisoquinoline "halves" formally do not constitute typical Ancistrocladaceae-type alkaloids (that is, with (S)configuration at C 3 and an oxygen function at C 6, as realized, for example, in 2 and 5), nor typical Dioncophyllaceaetype alkaloids, that is, with (3 R)-configuration and no oxygen at C6, like in 6), but rather one of the "mixed" Ancistrocladaceae/Dioncophyllaceae-type hybrids,17. since they combine the two properties by having (3 R)-configuration and an oxygen function at C6.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.