Igor V. Trushkov

Donor–Acceptor Cyclopropanes as Three‐Carbon Components in a [4+3] Cycloaddition Reaction with 1,3‐Diphenylisobenzofuran

Substituted cyclopropanes have found broad application in modern organic synthesis owing to the unique reactivity of the cyclopropane moiety. Cyclopropanes can often be considered as three-carbon analogues of C=C bonds. For example, alkenes and cyclopropanes react with strong electrophiles and various radicals. Both undergo the addition of hydrogen and can be oxidized at the a position. The reactivity of cyclopropanes with electron-withdrawing substituents is similar to that of electron-deficient alkenes. However, the cycloaddition reactions of alkenes and cyclopropanes are quite different. In particular, the thermal reactions of alkenes are represented mainly by [1+2], [3+2], and [4+2] cycloaddition processes; thermal [2+2] cycloaddition occurs in very specific cases only. In contrast, the most well known type of cyclopropane cycloaddition is the [2p + 2s] reaction with alkenes. As this reaction yields cyclopentanes, it can also be considered as a [2+3] cycloaddition. The scope of such [2+3] cycloaddition reactions has been expanded significantly through the use of donor–acceptor cyclopropanes. The presence of both electron-donating and electron-withdrawing substituents on the cyclopropane ring enables cycloaddition to various multiple bonds, including C=C, C=O, C=N, and C N bonds. The [4+3] cycloaddition of cyclopropanes with dienes (Scheme 1) has not been reported previously, although this

Cycloaddition to buckminsterfullerene C60: advancements and future prospects

Investigations on mono-[2+1]-, -[2+2]-, -[2+3]-, -[2+4]-, and polycycloaddition to [60]fullerene are reviewed. The main reagents used in cycloaddition and the reaction mechanisms are surveyed. The possible applications of cycloadducts are considered. The review covers the investigations of the last five years as well as the most important earlier studies.

Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N-Heterocycles

A general method for ring opening of various donor-acceptor cyclopropanes with the azide ion through an SN 2-like reaction has been developed. This highly regioselective and stereospecific process proceeds through nucleophilic attack on the more-substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the SN 2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91 % yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity-oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five-, six-, and seven-membered N-heterocycles, as well as complex annulated compounds, including natural products and medicines such as (-)-nicotine and atorvastatin.

(3 + 3)-Cyclodimerization of donor-acceptor cyclopropanes. Three routes to six-membered rings.

The ability of donor-acceptor cyclopropanes to (3 + 3)-cyclodimerize is disclosed. It has been found that Lewis acid-induced transformations of 2-(hetero)arylcyclopropane-1,1-dicarboxylates containing electron-abundant aromatic substituents led to the construction of six-membered cyclic systems. Depending on the substrate properties and the Lewis acid applied, three types of products can be obtained: (1) 1,4-diarylcyclohexanes, (2) 1-aryl-1,2,3,4-tetrahydronaphthalenes, and (3) 9,10-dihydroanthracenes.

Duality of Donor–Acceptor Cyclopropane Reactivity as a Three‐Carbon Component in Five‐Membered Ring Construction: [3+2] Annulation Versus [3+2] Cycloaddition

Quo vadis? The Lewis acid catalyzed reaction of (hetero)aryl-derived donor-acceptor cyclopropanes with alkenes can be selectively directed along a [3+2] annulation pathway (see scheme). This new process provides convenient and efficient access to indanes and other cyclopentannulated (hetero)arenes, among which polyoxygenated 1-arylindanes exhibit significant cytotoxicity against several cancer cell lines with an IC50 of 10(-6)-10(-5)  M.

Domino Cyclodimerization of Indole-Derived Donor–Acceptor Cyclopropanes: One-Step Construction of the Pentaleno[1,6-a,b]indole Skeleton

Bisindoles represent an extensive group of both naturally occurring and synthetically available compounds with a broad range of biological activities, such as antitumor, antiviral, and antibacterial activities. To date, over 200 bisACHTUNGTRENNUNGindole alkaloids have been isolated from various natural sources (Figure 1). Furthermore, considerable attention is currently being paid to the development of synthetic routes to bisindoles. Structurally, bisindoles vary significantly, resulting in a lack of general methods for the synthesis of these compounds, although, most synthetic approaches are based on the coupling of two indole-containing molecules. Herein, we report a new synthetic strategy towards bisACHTUNGTRENNUNGindoles through an interaction of two indole-derived donor– acceptor (DA) cyclopropane molecules. DA cyclopropanes are of particular interest because they are promising synthetic reagents with versatile reactivity. In particular, DA cyclopropanes with aryl and heteroaryl substituents are widely used for the synthesis and modification of various indole-containing molecules. In this study, we investigate in detail the dimerization of indole-containing DA cyclopropanes and present evidence for a new type of reactivity of DA cyclopropanes, which opens up routes to a novel bisindole scaffold. Coupling of DA cyclopropanes has received very little attention in the literature, with only one report thus far, which deals with the transformation of aryl 2-(3-indolyl)cyclopropyl ketones into cyclopentacarbazoles. As part of our investigation into DA cyclopropane dimerization, we studied the Lewis acid induced transformation of 2-(3-indolyl)cyclopropane-1,1-dicarboxylates (1). We found that this reaction yields angularly fused tetracyclic compounds 2, containing the previously unknown pentalenoACHTUNGTRENNUNG[1,6a–b]indole scaffold. Reagent cyclopropanes 1 are readily available from the corresponding indole-3-carbaldehydes through a standard synthetic sequence of Knoevenagel/Corey–Chaykovsky reactions. These cyclopropanes have low stability at elevated temperatures and on silica gel, but can be isolated as pure materials by chromatography on neutral alumina. N-BenACHTUNGTRENNUNGzylindoles 1 were found to be more stable during storage than their N-methyl analogues. To find the optimal conditions for the Lewis acid induced DA cyclopropane dimerization, we selected cyclopropane 1 a as a model substrate. Building on a previous study of the related indole-substituted DA cyclopropanes, we started by using the SnCl4/CH3NO2 system as the reaction initiator (Table 1). It is noteworthy that the reaction without Lewis acid leads to complete destruction of 1 a into a mixture of polymeric and ring-opened byproducts (Table 1, entry 1). If [a] Dr. O. A. Ivanova, Dr. E. M. Budynina, Dr. A. O. Chagarovskiy, E. R. Rakhmankulov, Dr. I. V. Trushkov, Prof. M. Y. Melnikov Department of Chemistry M. V. Lomonosov Moscow State University Leninskie Gory 1–3, Moscow 119991 (Russia) Fax: (+7) 495-9391814 E-mail : melnikov@excite.chem.msu.ru [b] Dr. E. M. Budynina, Dr. A. O. Chagarovskiy, Dr. I. V. Trushkov Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology, and Immunology Leninskii av. 117/2, Moscow 117997 (Russia) [c] Dr. A. V. Semeykin, Prof. N. L. Shimanovskii Medico-Biological Faculty, The Russian State Medical University Bolshaya Pirogovskaya st. 9A, Moscow 119435 (Russia) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201101687. Figure 1. Examples of biologically active bisindole alkaloids.

A Simple Route to Polysubstituted Indoles Exploiting Azide Induced Furan Ring Opening

A straightforward, efficient indole synthesis based on thermolysis of 2-(2-azidobenzyl)furans with attack of the formed nitrene moiety onto the ipso position of furan ring has been developed. The cyclization is accompanied by furan ring opening and affords indoles with a 2-acylvinyl substituent suitable for further modifications.

Fullerene-based Low Toxic Nanocationite Particles (Porphyrin Adducts of Cyclohexyl Fullerene-C60) to Treat Hypoxia-induced Mitochondrial Dysfunction in Mammalian Heart Muscle

BACKGROUND This is the first report on the targeted delivery of fullerene-based low toxic nanocationite particles (porphyrin adducts of cyclohexyl fullerene-C(60)) to treat hypoxia-induced mitochondrial dysfunction in mammalian heart muscle. METHODS The magnetic isotope effect generated by the release of paramagnetic (25)Mg(2+) from these nanoparticles selectively stimulates the ATP overproduction in the oxygen-depleted cell. RESULTS Because nanoparticles are membranotropic cationites, they will only release the overactivating paramagnetic cations in response to hypoxia-induced acidic shift. The resulting changes in the heart cell energy metabolism result in approximately 80% recovery of the affected myocardium in <24 h after a single injection (0.03-0.1 LD(50)). CONCLUSIONS Pharmacokinetics and pharmacodynamics of the nanoparticles suggest their suitability for safe and efficient administration in either single or multi-injection (acute or chronic) therapeutic schemes for the prevention and treatment of clinical conditions involving myocardial hypoxia.

From Umpolung to Alternation: Modified Reactivity of Donor–Acceptor Cyclopropanes Towards Nucleophiles in Reaction with Nitroalkanes

A conceptually new type of donor-acceptor cyclopropane reactivity towards nucleophiles has been disclosed. An essential characteristic of the process is an unusual nucleophilic attack on the C(3)-position of a cyclopropane, combined with typical small ring-opening by cleavage of the C(1)-C(2) bond between the acceptor and the donor. Based on this new reaction between cyclopropane-1,1-diesters and nitroalkanes, we developed a convenient approach to γ-nitroesters that can be efficiently transformed to the substituted pyrrolidones, structural analogues of racetame family drugs (rolipram, phenylpiracetam, etc.).

Lewis and Brønsted acid induced (3 + 2)-annulation of donor-acceptor cyclopropanes to alkynes: indene assembly.

(3 + 2)-Annulation of donor-acceptor cyclopropanes to alkynes induced by both Lewis and Brønsted acids has been developed. The reaction provides a rapid approach to functionalized indenes displaying intense visible emission (λmax = 430 nm, Φ = 0.28-0.34).