The titanium-catalyzed asymmetric cyclopropanation of cyanoesters with Grignard reagents was investigated for the first time. Particularly, the study of the efficiency of Taddol-based titanium complexes has shown that the prior preparation of Taddol titanium complexes was not required and a large panel of ligands was evaluated by using this approach. The spirocyclopropanelactams were obtained with good diastereoselectivity and with moderate enantioselectivities from the main diastereoisomer (up to 32%).Key words cyclopropanes, enantioselectivity, Grignard reagents, nitriles, spiro compounds, titaniumThe aminocyclopropane moiety is present in a large number of biologically active compounds, 1 including important active manufactured drugs present in the World Health Organization's list of Essential Medicines, 2 such as ciprofloxacin (broad spectrum antibiotic), nevirapine and abacavir (anti-HIV). More specifically, chiral enantioenriched cyclopropylamines represent useful scaffolds for the preparation of drugs such as Ticagrelor 3 (platelet aggregation inhibitor), Ciluprevir 4 and Vaniprevir 5 (hepatitis C). In addition, this motif represents an important synthetic intermediate, as pointed out in recent publications. 6 In this context, the most used access to enantioenriched cyclopropylamines remains the stereoselective transition-metalcatalyzed diazoester addition to olefins, followed by a Curtius degradation. 7 Several other asymmetric routes have also been explored to directly introduce the nitrogen atom during the [2+1] cycloaddition step, by using nitrogen-substituted olefins 8 or α-nitrodiazoesters. 9 Zinc α-aminocarbenoids 10 or Sm-catalyzed amine addition to cyclopropenes 11 were also used with success. However, the above methods suffer from several drawbacks such as catalyst availability and/or a multistep synthesis to provide the cyclopropylamine targets. Since the discovery by Kulinkovich of the Ti-catalyzed conversion of esters into cyclopropanols using Grignard reagents, 12,13 two direct methods to access cyclopropylamines rapidly emerged, from N,N-disubstituted amides 14 and from nitriles. 15 In this context, the development of efficient asymmetric syntheses of cyclopropane derivatives by titanium-catalyzed cyclopropanation of acid derivatives would be an interesting alternative to syntheses described previously.The asymmetric cyclopropanation of carboxylic acid derivatives remains in its infancy, despite the pioneering asymmetric example of the Kulinkovich reaction, described as early as 1994. 16 In this reaction, cyclopropanol 1 was obtained in 65-72% yield with an enantiomeric excess of 70-78% by using the Taddol derived spirotitanate 2 (Scheme 1, Eq. 1). 17 A few unsuccessful attempts at asymmetric cyclopropanation have been described thereafter. 18 Recently, Kulinkovich reported significant results by using catalytic amounts of the Taddol complex 3 (ee up to 65%, Eq. 2). 19 Importantly, the use of hexafluoroisopropyl esters afforded the cyclopropanols in good yields and with higher e...
