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...
