Alexey O. Chagarovskiy

(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.

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).

Formal [3 + 2]-Cycloaddition of Donor–Acceptor Cyclopropanes to 1,3-Dienes: Cyclopentane Assembly

We report a new simple method to access highly substituted cyclopentanes via Lewis acid-initiated formal [3 + 2]-cycloaddition of donor-acceptor cyclopropanes to 1,3-dienes. This process displays exceptional chemo- and regioselectivity as well as high diastereoselectivity, allowing for the synthesis of functionalized cyclopentanes and bicyclic cyclopentane-based structures in moderate to high yields. Moreover, one-pot synthesis of biologically relevant cyclopentafuranones, based on reaction of donor-acceptor cyclopropanes with dienes, has been developed.

Reaction of donor-acceptor cyclopropanes with 1,3-diphenylisobenzofuran. Lewis acid effect on the reaction pathway

Reaction of donor-acceptor cyclopropanes with 1,3-diphenylisobenzofuran in the presence of lanthanide triflates, as well as CuOTf, Sn(OTf)2, SnCl2, ZnCl2, GaCl3, and MgI2, proceeds as a formal [3+4]-cycloaddition leading to a newly formed seven-membered ring. This reaction was found to be typical of cyclopropane-1,1-diesters and dinitriles, as well as 1-nitrocyclo-propanecarboxylates containing aromatic, heteroaromatic, and vinylic substituents at the C(2) atom of the small ring. When Me3SiOTf, TiCl4, SnCl4, or BF3·OEt2 were used as initiators, unusual cyclic hemiacetals were formed via the conjugate 1,4-addition of a cyclopropane and a nucleophile to the diene moiety.

Reaction of dimethyl (S)-2-(p-tolyl)cyclopropane-1,1-dicarboxylate with acetonitrile

The Lewis acid-activated reactions of donor-acceptor cyclopropanes with nitriles are the basis of a convenient method for the synthesis of -pyrrolines and pyrroles [1-5]. The use of 1,2,3-substituted donoracceptor cyclopropanes leads to the formation of -pyrrolines with high diastereoselectivity. Depending on the type of substrate and the reaction conditions, either reversal [5] or retention [1] of the configuration of the cyclopropane carbon atom bearing donor substituent and taking part in the interaction with the nitrile nitrogen atom is observed. In order to determine the stereoselectivity of nitrile reactions with 2-arylcyclopropane-1,1-dicarboxylates without a substituent at the C-3 atom [4], we have prepared the optically pure donor-acceptor cyclopropane (S)-1 and studied its reaction with acetonitrile. The synthesis of enantiomerically pure cyclopropane (S)-1 includes the hydrolysis of the racemic diester (rac)-1 to the 2-(p-tolyl)cyclopropane-1,1-dicarboxylic acid, its conversion to (S)-1-phenylethylamine salt as two diastereomers and recrystallization. We have modified the previously reported method [6] for the synthesis of enantiomerically pure 2-phenylcyclopropane-1,1-dicarboxylates. In particular, shorter hydrolysis time for the compound (rac)-1 and two successive crystallizations of the salt allowed us to avoid lactonization and gave the diester (S)-1 with ee > 98%.

Domino Staudinger/aza-Wittig/Mannich Reaction: an Approach to Diversity of Di- and Tetrahydropyrrole Scaffolds

A highly efficient and selective domino reaction producing valuable di- and tetrahydropyrrole-based skeletons from azidoethyl-substituted CH-acids and (thio)carbonyl compounds has been developed. By involving the additional functional groups in starting compounds into the domino reaction or postmodification of the primary reaction products, the simple construction of the pharmaceutically relevant three- and polycyclic azaheterocyclic scaffolds was demonstrated.

Lewis Acid Triggered Vinylcyclopropane–Cyclopentene Rearrangement

We report a mild Lewis acid induced isomerization of donor-acceptor cyclopropanes, containing an alkenyl moiety and diverse electron-withdrawing group(s) at the adjacent positions, into substituted cyclopentenes. We have found that 1,1,2-trisubstituted cyclopent-3-enes were exclusively obtained in yield of 51-99% when cyclopropanes with a 2-substituted alkenyl group as a donor underwent isomerization. For cyclopropanes bearing a trisubstituted alkenyl group either the corresponding cyclopent-3-enes or isomeric cyclopent-2-enes having two acceptor groups at the C(1) atom were formed, with the reaction selectivity being determined by the applied Lewis acid. We have shown that the reactivity of the donor-acceptor cyclopropane increases with the increase of the electron-donating character of (hetero)aromatic group attached to the alkenyl moiety. The synthetic utility of the developed methodology was also demonstrated through the synthesis of polysubstituted cyclopentane and piperidine derivatives.