Iron-Catalyzed [3 + 2] Annulation of Aminocyclopropanes with Aldehydes: Stereoselective Synthesis of Aminotetrahydrofurans

Abstract

The first method for the [3+2] annulation of donor-acceptor aminocyclopropanes with aldehydes is reported. The reaction is catalyzed by iron trichloride on alumina in yields up to 99% and with excellent cis selectivities (up to >20:1), and represents a stereoselective and atom economic access to valuable 2-aminotetrahydrofurans, which constitute the core of DNA and RNA. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/ol203144v SnX4). 7 In the last decade, this transformation has been the focus of a renewed research effort. In particular, Johnson and co-workers developed catalytic methods for the highly stereoselective synthesis of tetrahydrofurans (THFs) using Lewis acids (i.e. Sn(OTf)2, Hf(OTf)4) under mild conditions. 8 In the [3+2] annulation with aldehydes and ketones, D-A cyclopropanes bearing oxygen donor group(s) were most frequently exploited, 4b-g,8e but the use of aryl, 4a,8a,c alkenyl, 8b,d alkyl, 4a,8d and silylmethyl 2c donors has also been documented. To the best of our knowledge, this transformation has never been reported using D-A cyclopropanes substituted with a nitrogen-containing donor group instead. 9 In fact, aminocyclopropanes are generally underrepresented in annulation and cyclization reactions, 10 despite the abundance of synthetic methods for their preparation. 11 The development of [3+2] annulations of aminocyclopropanes with aldehydes would constitute an important progress in the field, as this reaction allows the one-pot, atom-economic assembly of 2-aminotetrahydrofurans, a common motif in "evolutionarily selected" molecules such as nucleosides, as well as in synthetic drugs such as AZT (1) It is well-known that nucleosides and their mimetics 13 are widespread as therapeutic agents for the treatment of cancer, infections and viral diseases. Therefore the 2-aminotetrahydrofuran core may be rightly considered as a privileged scaffold for drug discovery. Donor-acceptor (D-AHerein, we describe the first catalytic method for the [3+2] annulation of donor-acceptor aminocyclopropanes with aldehydes affording 2-aminotetrahydrofurans with excellent diastereoselectivity (Scheme 1).Our group has been interested in the use of D-A cyclopropanes (D = NPg or aryl, Pg = protecting group) as precursors of reactive intermediates in cyclization reactions onto electron-rich olefins or heterocycles. 14 In particular, we made use of aminocyclopropanes as acyl iminium precursors in the synthesis of natural alkaloids. 14b In 2011, we decided to investigate the use of more convergent annulation reactions of aminocyclopropanes for the efficient synthesis of carbo-and hetero-cycles. As a result of these efforts, we reported the first catalytic, enantiospecific [3+2] annulation between silyl enol ethers and D-A aminocyclopropane 2a to give cyclope...

Ein neues goldenes Zeitalter in der Chemie Donor‐Akzeptor‐substituierter Cyclopropane

“…Dabei waren 2,5-cis-konfigurierte Tetrahydrofurane 43 a die Hauptprodukte, was die Autoren auf einen ungewçhnlichen S N 2-Reaktionsmechanismus zurückführten (Tabelle 4, Nr. [38] Wurde SnCl 4 als Katalysator genutzt, konnten auch Ketone insertiert und so Aminotetrahydrofuran-Derivate 43 f mit quartären Stereozentren diastereoselektiv aufgebaut werden (Tabelle 4, Nr. [35] Enantiomerenreine Produkte konnten sowohl durch die Verwendung enantiomerenreiner Substrate als auch durch eine dynamisch-kinetische asymmetrische Transformation (DyKAT) erreicht werden.…”

“…4). [38] Wurde SnCl 4 als Katalysator genutzt, konnten auch Ketone insertiert und so Aminotetrahydrofuran-Derivate 43 f mit quartären Stereozentren diastereoselektiv aufgebaut werden (Tabelle 4, Nr. 9).…”

Stereospecific Reactions of Donor–Acceptor Cyclopropanes with Thioketones: Access to Highly Substituted Tetrahydrothiophenes

“…[13] One-, two-, three-, and four-atom components have successfully been inserted, leading to four-, five-, six-, and seven-membered carbo-and heterocyclic compounds through [3 + n]a nnulation reactions. [11][12][13] To afford substituted tetrahydrofurans,J ohnson and Waser have made use of the dipolar C À Odouble bond in aldehydes and ketones, [14,15] whereas cyclopentane or cyclopentene derivatives have been obtained by inserting highly polarized CÀCdouble or triple bond systems. [16,17] Whereas these types of annulations are well established, and even catalytic enantioselective methods have been developed, higher homologues of ketones such as thio-and selenoketones have never been subjected to [3+ +2] cycloaddition with D-A cyclopropanes.…”

Synthesis of l‐threitol‐based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions

“…The MIRC reaction strategy may also be utilized through a one-pot multicomponent reaction, which has been gaining interest by synthetic organic chemists in recent times. [62][63][64][65][66][67][68][69][70][71] Surprisingly, the use of chiral phase transfer catalysts to established asymmetric cyclopropanation reactions has so far been limited to only a few examples. [72][73][74] Previously Waser and Herchl investigated the asymmetric reaction of bromomalonates with trans-chalcones in the presence of cinchona alkaloid ammonium salt catalysts to furnish cyclopropane derivatives.…”