Special Issue Article Enantioselective Preparation, Conformational Analysis and Absolute Configuration of Highly Substituted Aziridines † GIORGIO BENCIVENNI, * PAOLO RIGHI, LODOVICO LUNAZZI, SILVIA RANIERI, MICHELE MANCINELLI, AND ANDREA MAZZANTI ** Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Italy ABSTRACT The first example of organocatalytic aziridination reaction of α-substituted-α,β- unsaturated ketones is presented. The reaction was found to be highly enantio- and diastereoselective, yielding N-tosylated aziridines. Low-temperature nuclear magnetic resonance (NMR) spectra allowed for the determination of the N-inversion barrier, that was found to be quite lower with respect to unsubstituted aziridines. A thorough conformational analysis sup- ported by low-temperature NMR data allowed for the determination of the absolute configuration of the main stereoisomer by means of time-dependent Density Functional Theory simulation of the electronic circular dichroism spectra. Chirality 27:875–887, 2015. © 2015 Wiley Periodicals, Inc. KEY WORDS: aziridines; organocatalysis; dynamic-NMR; DFT calculations; absolute configuration During the last years many important organic transforma- tions have been realized by means of the efficient mediation of small chiral organic molecules as catalysts. 1 In this context the enantioselective construction of highly strained three- membered rings has always represented an intriguing chal- lenge often pursued using different catalytic strategies. 2–4 Chiral organic bases, Brønsted acids, and amino catalysis have been successfully employed for the synthesis of cyclo- propanes, 5–11 in the preparation of epoxides 12–16 and aziridines. 17–20 Chiral aziridines are well recognized as valu- able nitrogen-containing compounds that found wide applica- tions both as biologically active compounds and precursors for the synthesis of highly functionalized chiral mole- cules. 21,22 For this reason it is not surprising that many re- search groups focused their efforts on the aminocatalytic synthesis of such important scaffolds. α,β-Unsaturated alde- hydes 23–25 (Scheme 1a) and linear or cyclic α,β-unsaturated ketones 26,27 (Scheme 1b,c) are privileged substrates that un- dergo aziridination reaction with different catalytic systems. Enals are generally activated using proline-derived secondary amines catalysts, 28 while enones require the use of primary amine catalysts. 29–31 As is well established, the use of a different kind of catalyst is required for the activation of substrates that present a diverse steric hindrance around the carbonyl group. Nevertheless, several examples of aziridination of α-substituted-α,β-unsaturated aldehydes have been reported also using a chiral secondary amine as catalyst (Scheme 2a,b), whereas the challenging aziridination of α-substituted- α,β-unsaturated ketones remains unexplored (Scheme 2c). 32–34 EXPERIMENTAL Synthesis of Compounds (E)-3-methylnon-3-en-2-one 35 (6a): 2-Butanone (50 mmol, 4.48 ml) and hexanal (5.0 mmol, 600 μl) were added to a mixture of 50 ml of glacial acetic acid and 5 ml of concentrated H 2 SO 4 . The resulting mixture was stirred at room temperature for 12 h. The crude mixture was diluted with diethyl ether and neutralized with a saturated solution of NaHCO 3 . Water layers were furthermore extracted twice with ether. The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using hexane/ethyl acetate (3-8%) as the eluent mixture to give pure 6a in 52% yield. 1 H nuclear magnetic resonance (NMR) (400 MHz) δ ppm 1.28–1.37 (m, 6H), 1.42–1.51 (m, 3H), 1.76 (s, 3H), 2.19–2.27 (m, 2H), 2.30 (s, 3H), 6.63 (tq, 1H, J 1 = 7.2 Hz, J 2 = 1.4 Hz). (E)-3,6-dimethylhept-3-en-2-one (6b): 2-Butanone (50 mmol, 4.48 ml) and 3-methylbutanal (5.0 mmol, 536 μl) were added to a mixture of 50 ml of glacial acetic acid and 5 ml of concentrated H 2 SO 4 . The resulting mixture was stirred at room temperature (RT) for 12 h. The crude mix- ture was diluted with diethyl ether and neutralized with a saturated solu- tion of NaHCO 3 . Water layers were furthermore extracted twice with ether. The combined organic phases were dried over MgSO 4 and concen- trated under reduced pressure. The crude mixture was purified by flash chromatography using hexane/ethyl acetate (3–8%) as the eluent mixture to give pure 6b in 52% yield. 1 H NMR (400 MHz) δ ppm 0.94 (d, 6H, J = 6.6 Hz), 1.70–1.84 (m, 4H), 2.09–2.16 (s, 3H), 6.64 (tq, 1H, J 1 = 7.4 Hz, J 2 = 1.4 Hz). Benzyl (tosyloxy)carbamate 36 (2a): To a solution of N-Cbz- hydroxylamine hydrochloride (8.87 mmol, 1.80 g) in diethyl ether (100 ml), TsCl (9.76 mmol, 1.85 g) and Et 3 N (9.32 mmol, 1.3 ml) were added at 0°C. The reaction mixture was allowed to warm to RT and reacted for 12 h. The reaction mixture was washed with water and extracted with diethyl ether. The combined organic layers were treated over MgSO 4 , filtered, and concen- trated under reduced pressure. Crude 2a was crystallized with a 1:1 solution of hexane/diethyl ether (160 ml overall volume). Pure 2a was obtained in 50% yield. 1 H NMR (400 MHz) δ ppm 2.43 (s, 3H), 5.03 (s, 2H), 7.18–7.21 (m, 2H), 7.25–7.28 (m, 2H), 7.32–7.36 (m, 3H), 7.81–7.84 (m, 2H). 4-methyl-N-(tosyloxy)benzenesulfonamide 37 (4a): A solution of hy- droxylamine hydrochloride (10 mmol, 969 mg) in pyridine (10 ml) was cooled to 0°C and DMAP (1.0 mmol, 122 mg) was added followed by a portion-wise addition of TsCl (21 mmol, 3.99 g) and stirring was main- tained at 0°C for 1 h. The reaction mixture was allowed to warm to RT. [This article is part of the Thematic Issue: “Chirality in Separation Science and Molecular Recognition Honoring Prof. F. Gasparrini.” See the first articles for this special issue previously published in Volumes 27:9, 27:10, and 27:11. More special articles will be found in this issue as well as in those to come.] *Correspondence to: G. Bencivenni or A. Mazzanti, Department of Industrial Chemistry “Toso Montanari,” Viale Risorgimento 4, 40136, Bologna, Italy. , E-mail: giorgio.bencivenni2@unibo.it, andrea.mazzanti@unibo.it † Dedicated to Professor Francesco Gasparrini on the occasion of his 70 th birthday. Received for publication 28 May 2015; Accepted 4 August 2015 DOI: 10.1002/chir.22522 Published online 13 October 2015 in Wiley Online Library (wileyonlinelibrary.com). © 2015 Wiley Periodicals, Inc. CHIRALITY 27:875–887 (2015)