Alexey V. Varlamov

The first synthesis and X-ray crystal structure of tetrahydropyrrolo[2,3-d]azocines

Tetrahydropyrrolo[3,2-c]pyridines (THPP) upon the reaction with DMAD in acetonitrile or DMSO at rt underwent ring expansion, affording tetrahydropyrrolo[2,3-d]azocines; these latter compounds have not previously been reported in the literature. The crystal structure and conformation of these derivatives was established by X-ray crystallography.

Inhibition of 6-hydroxydopamine-induced oxidative damage by 4,5-dihydro-3H-2-benzazepine N-oxides

A number of new analogs of 3,3-dimethyl-4,5-dihydro-3H-2-benzazepine 2-oxide, structurally related to the nitrone spin trap alpha-phenyl-N-tert-butylnitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinsons disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based nitrones were shown to decrease hydroxyl radicals (OH) generated during 6-OHDA autoxidation. The inhibition effects on the OH formation shown by the 5-gem-dimethyl derivatives, 2-4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5-gem-dimethyl group on the azepine ring, which should enhance nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the OH-scavenging activity of the nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11), bearing 5-gem-dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC50 values of 20 and 48 microM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved.

A general strategy for the synthesis of oxoisoindolo[2,1-a]quinoline derivatives: the first efficient synthesis of 5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acids

An efficient two-step synthesis of new isoindolo[2,1-a]quinoline-10-carboxylic acids via [4+2] cycloaddition of the 4-α-furyl-4-N-arylaminobut-1-enes and maleic anhydride is described.

Synthesis and reactivity of a novel class of long-lived ammonium ylides: derivatives of benzo[b]pyrrolo[2,1-f][1.6]naphthyridine.

Reaction of 10-cyanotetrahydrobenzo[b][1,6]naphthyridines (1-6) with activated alkynes affords stable benzo[b]pyrrolo[2,1-f][1,6]naphthyridine-4-ium ylides (7-14) in moderate yields. A proposed mechanism for their formation consists of a new tandem multistage process.

Aromatization of IMDAF adducts in aqueous alkaline media

In this paper, we propose a simple synthesis of isoindoline-4-carboxylic acids by means of the aromatization of 3a,6-epoxyisoindoles in alkaline media. The method is facile from an experimental point of view: a short-term (0.5–2h) reflux of epoxyisoindoles in 5% aqueous solutions of alkali leads to the target products in 40–90% yields. The absence of by-products, ease of isolation of the target products and applicability to acidophobic group bearing substrates favorably distinguishes the proposed procedure from previously utilized acid-catalyzed methods. The proposed strategy has been successfully utilized for isoindole containing compounds and nuevamine-type alkaloids.

Preparative Synthesis of 7-Carboxy-2-R-isoindol-1-ones

A preparative method for the synthesis of 7-carboxy-2-R-isoindol-1-ones was developed on the basis of the [4+2] cycloaddition of secondary furfurylamines to maleic anhydride.

Perhydrofuro[3,2-c]-, perhydropyrano[3,2-c]-, and 4-ethoxy-2-(5-R-furan-2-yl)tetrahydroquinolines. Synthesis and transformations

Partly hydrogenated 2-[5-methyl(bromo, nitro)furan-2-yl]-substituted furo[3,2-c]quinolines, pyrano-[3,2-c]quinolines, and 4-ethoxyquinolines were synthesized by the imino Diels-Alder (Povarov) reaction. Cycloadditions of these compounds with maleic, citraconic, and dibromomaleic anhydrides, as well as with acryloyl, methacryloyl, and cinnamoyl chlorides led to the formation of substituted epoxyisoindolo[2,1-a]-quinolines and -quinolinecarboxylic acids. Oxidation of the double C=C bond in the adducts, esterification of the carboxy group, and aromatization of the 7-oxabicycloheptene fragment were accomplished.

Chapter 2 Synthesis of Heteroannulated Azocine Derivatives

Publisher Summary This chapter reviews that azocinoindoles have been investigated extensively due to the host of alkaloids with an azocinoindole fragment in their structure. The existence of six isomeric azocinoindoles, in which an azocine ring is annulated with a pyrrole fragment, is possible. This chapter explores that the first method for the preparation of tetrahydroazocino indoles was reported in 1966. In the succeeding years, this reaction came to be known as the witkop photocyclization. The main reasons for investigating the reactivity of azocinoindoles is connected with the synthesis of pentacyclic indole alkaloids of the Strychnos group. A different approach to the derivation of Strychnos-type pentacyclic alkaloids has been used. Photocyclization of N-chloroacetyl derivative 99 takes place in position 4 of the indole core to form 100.

TANDEM MICHAEL ADDITION - HOFFMAN ELIMINATION SEQUENCE OF DMAD ON TETRAHYDROPYRROLO[3,2-C]PYRIDINES. NEW ROUTE TO VINYLPYRROLES .

The reaction of tetrahydropyrrolo[3,2-c]pyridines with DMAD in THF at room temperature results in piperidine ring cleavage producing aor ß-vinylpyrroles in moderate to good yields. The resulting compounds are haidly available by other synthetic means and are good candidates for further transformations . Introduction. There are two well-known procedures for piperidine ring cleavage: Hofmann (1) and von Braun (2) reactions . The scope of these reactions is limited and they are most frequently used to determine substituents position in piperidine moiety of natural and synthetic compounds. Recently we have reported piperidine ring cleavage in 1etrahydropyrrolo[3,2-c]pyridines under the action of acetic anhydride at 70° C resulting with the formation of 2-(amethyl-ß-acetamidoethyl)-3-vinylpyrroles in moderate yields, while the target 2-acetyl substituted pyrroles have not been isolated (3). In continuation of our studies of pyrrolo[3,2-c]piperidines reactivity and biologic activity investigation (4), we have carried out the reaction of 2-trifluoroacetylsubstituted derivative 1 with DMAD under reflux in THF in the presence of triphenyl phosphine . Results and Discussion. According to the literature data (5) we expected the formation of a corresponding trifluoromethyl substituted lactone that could exhibit very interesting biologic properties. Scheme 1 Et / Et— DMAD CF3 THF.r.t. CF3 1 2 62 % Ο

2-Benzazepine Nitrones Protect Dopaminergic Neurons against 6-Hydroxydopamine-Induced Oxidative Toxicity

A number of C‐3 spirocyclic 2‐benzazepine analogs of α‐phenyl‐N‐tert‐butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) neurons against 6‐hydroxydopamine (6‐OHDA), a toxin inducing destruction of the DA nigro‐striatal pathway in rodent models of Parkinsons disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6‐OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2‐benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure–activity relationships. In particular, 5 and 10, bearing C‐3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 µM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6‐OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC50 value of 16.8 µM, which would enhance its potential as neuroprotective agent in Alzheimers neurodegeneration. These findings extend the utility of benzazepine‐based PBN analogs in the treatment of age‐related free radical‐mediated disorders.