The variety of alpha-diazo beta-keto esters (3a-f, 8a-f) with varying substituents (ED/EW) on the phenyl ring of the O-benzyl group were prepared. The rhodium(II) acetate catalyzed decomposition of diazo compounds in benzene reflux conditions. The ratio of 1,4 versus 1,2 migration product was determined. It was found that an increase in electron density on the benzylic carbon of the migrating group prefers 1,4 migration products (4, 9) while a decrease in electron density leads to a preponderance of 1,2 migration products (5, 10). The results obtained were correlated to the mechanistic aspect of the product selectivity. The intermediacy of the intramolecular oxonium ylide formation was demonstrated by crossover experiments. The preference for the formation of 2,3 sigmatropic rearrangement product over 1,2 and 1,4 was demonstrated by performing the reaction with alpha-diazo beta-keto esters (13a, 13b) with O-allyl and O-propargyl at C3. The effect of solvent, temperature, and mole percentage of rhodium(II) acetate was also studied.
The discovery of a series of thiophenephenylsulfonamides
as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine
receptor (α7 nAChR) is described. Optimization of this series
led to identification of compound 28, a novel PAM of
α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile
across species with excellent brain penetration and residence time.
Compound 28 robustly reversed the cognitive deficits
in episodic/working memory in both time-delay and scopolamine-induced
amnesia paradigms in the novel object and social recognition tasks,
at very low dose levels. Additionally, compound 28 has
shown excellent safety profile in phase 1 clinical trials and is being
evaluated for efficacy and safety as monotherapy in patients with
mild to moderate Alzheimer’s disease.
The sequential C-and N-allylation of D-glucose-derived nitrone 2 provides the required diene functionality with nitrogen linker that was used in ring-closing metathesis pathway in the synthesis of quinolizidine alkaloids 1a and 1b.The ring-closing metathesis (RCM) of diene-substrate containing nitrogen functionality has found wide applicability in the synthesis of nitrogen heterocycles, alkaloids, peptides and peptidomimetics. 1 The utility of this approach with sugar substrates wherein the presence of a hydroxylated carbon framework and feasibility to manipulate the functional groups into the required dienefunctionality, containing a nitrogen atom, give an easy access towards the synthesis of a variety of aza-sugars. 2 This class of compounds, especially the polyhydroxylated indolizidine and quinolizidine alkaloids are promising glycosidase inhibitors with potential antibacterial, antiviral, antimetastatic, and antidiabetes activity. 3 Most naturally occurring quinolizidine alkaloids 4 are devoid of polyhydroxylated functionalities and in the search for structureactivity relationship, the hydroxylated unnatural analogues are interesting targets for obtaining the better understanding of mechanisms of action and in design of even more potent inhibitors. As a part of our continuing efforts in the synthesis of aza-sugars, 5 we have developed a new methodology for the synthesis of trihydroxy quinolizidine alkaloids 1a and 1b using ring closing metathesis of D-glucose derived dienes with nitrogen linkage as a key step. A few reports are available for the synthesis of polyhydroxylated quinolizidine alkaloids. 2e,h,o,6 However, only a single report describes the synthesis of 1b while the synthesis of 1a has been reported so far. 2e Recently, we have described the preparation and reaction of D-glucose nitrone 2 in the synthesis of 6-deoxynojirimycin. 5a Similarly, the reaction of nitrone 2 with allylmagnesium bromide in the presence of TMSOTf (1 equiv) at -78°C in dry THF afforded a mixture of D-gluco-and L-ido-diastereomers 3a and 3b in the ratio of 86:14 (Scheme 1). The absolute configuration at the newly generated C5 in 3a and 3b was established by comparing the 1 H NMR data. 7 The appreciable difference in R f values allowed us to separate 3a and 3b by flash chromatography. Subsequently, the N-benzylhydroxylamine (3a) was treated with zinc in acetic acid-water and N-O bond reductive cleavage afforded the N-benzylamino sugar 4a in good yield. The reaction of 4a with allyl bromide, in the presence of potassium carbonate in dry DMF, afforded N-allylated product 5a.
This paper describes an efficient route for the synthesis of known and novel griseolic acid analogues 1d and 1e, respectively. The key intermediate dioxabicyclo derivative 6, with the required stereochemical orientation at C6, was obtained by rhodium acetate catalyzed reaction of d-glucose derived alpha-diazo-beta-keto ester 5 in a novel high-yielding methodology.
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