Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) Optically active 2,2-dimethyl-1,3,4-triazabicyclo[4.1.0]heptan-5-one: synthesis, spontaneous resolution and absolute configuration Remir G. Kostyanovsky,*a Pavel E. Dormov,a Peteris Trapencieris,b Boriss Strumfs,b Gulnara K. Kadorkina,a Ivan I. Chervina and Ivars Ya. Kalvin’sb a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation.Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru b Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia. E-mail: peteris@osi.lanet.lv Bicycle (±)-1 crystallises as a conglomerate (space group P21) and undergoes spontaneous resolution on crystallisation from chloroform or acetone (16–44% ee). The absolute configuration (S)-(–)-1 was determined by synthesis from (S)-Ser-OMe; mutarotation due to the partial conversion of 1 into the corresponding isopropylidene 4 was observed in MeOH solution.Derivatives of aziridine-2-carboxylic acid (Azy)1–4 have been studied intensively.5–7 Some of them (azimexon and leakadine) show high biological activity.8–10 The asymmetric synthesis of Azy derivatives was reported3,4,11 and a higher activity of the L-leakadine (amide of aziridine-2-carboxylic acid, Azy-NH2) with respect to the racemate was observed.10 The synthesis of these compounds in enantiopure form is of interest from the point of contemporary interest for chiral drugs.12 The simplest method for obtaining enantiopure materials is their spontaneous resolution by crystallisation, which may occur when the racemate is a conglomerate.13,14 For the strained aziridine-2-carboxylic acid derivative 2,2-dimethyl-1,3,4-triazabicyclo[ 4.1.0]heptan-5-one 15 the non-centrosymmetric space group P21 was determined by X-ray structural analysis.6 This means that compound 1 forms a conglomerate.Indeed, on crystallisation (from CHCl3 or acetone) of (±)-1 prepared by a known procedure,5 crystalline samples showing (+) or (–) rotation were obtained.† In order to determine its absolute configuration compound 1 was synthesised from commercial (S)-Ser-OMe hydrochloride {[a]D 23 = 3.5° (c 5.0 MeOH)} (Scheme 1), eventually giving (S)-(–)-1.Azy-OMe (S)-(–)-2 was prepared under Mitsunobu conditions15 and was converted into (S)-(–)-1 by a known procedure,5 the mp of (–)-2 is higher than that of its racemate: 135–136 °C and 126–127 °C, respectively. The rotation of (S)-(–)-1 in MeOH was found to decrease gradually from –87° to –68.1° (after 1.6 h), –65.7° (after 2.3 h), reaching a constant value of –59.8° after 24 h.According to 1H NMR, the isomerisation of (S)-(–)-1 into isopropylidenehydrazide (S)-(–)-4 to reach equilibrium 1:4 ª 2 (Scheme 2) is responsible for the observed mutarotation.All compounds were characterised by spectroscopic data (Figure 1). The 1H NMR spectra of aziridines (S)-(–)-2–4 were in line with those obtained from earlier detailed investigations of Azy and their 15N analogues.16 The 1H NMR signals of 1 (Figure 1) were assigned by selective heteronuclear double resonance.Thus, under the conditions {He, d 3.94 ppm}, the 13C NMR signal for carbon MeA (qqd, d 24.14 ppm) transforms † Characteristics and spectroscopic data. NMR spectra were recorded on a Bruker WM-400 spectrometer (with TMS as an internal standard) at 400.13 MHz (1H) and 100.62 MHz (13C). Optical rotation was measured on ‘Perkin Elmer-141’ and ‘Polamat A’ polarimeters. The CD spectra were taken on a JASCO-J-500A instrument with a DP-500N data processor.(±)-1: obtained by method described in ref. 5, mp 126–127 °C (acetone). 1H NMR (CDCl3) d: 1.29 (s, 3H, MeA), 1.40 (s, 3H, MeB), 2.13 (dd, 1H, Hb, 3Jab 5.9 Hz, 2Jbc 1.0 Hz), 2.25 (dd, 1H, Hc, 3Jac 3.0 Hz, 2Jbc 1.0 Hz), 2.65 (ddd, 1H, Ha, 3Jab 5.9 Hz, 3Jac 3.0 Hz, 4Jad 2.7 Hz), 3.94 (s, 1H, He), 6.82 (s, 1H, Hd). 13C NMR (CDCl3) d: 24.14 (qqd, MeA, 1J 127.9 Hz, 3JCH 4.4 Hz, 3JCHe 5.0 Hz), 24.98 (qq, MeB, 1J 127.9 Hz, 3JCHc 4.4 Hz), 25.08 (ddd, 7-C, 1JCHb 181.7 Hz, 1JCHc 162.8 Hz, 2JCHa 2.2 Hz), 32.73 (d, 6-C, 1J 183.8 Hz), 67.80 (s, 2-C), 169.48 (s, 5-C). Spontaneous resolution of (±)-1: by crystallisation of (±)-1 (68 mg) from CHCl3 at slow evaporation at 20 °C samples (+)-1 {2.0 mg, druse, [a]D 20 = 14.2° (c 0.2, MeOH), ee 16.3%} or (–)-1 {4.6 mg, small crystals, [a]D 20 = –14.8° (c 0.5, MeOH), ee 17.0%} were obtained.The crystallisation of (±)-1 (34 mg) from acetone at 4–6 °C gave one crystal (+)-1 {1 mg, [a]D 20 = 40.9° (c 0.1, EtOH), ee 44.3%}. (S)-(–)-1: yield 86%, mp 135–136 °C (acetone), [a]D 20 = –87° (c 2.1, MeOH), [a]D 20 = –92.2° (c 1.2, EtOH), [a]D 20 = –40.8° (c 0.9, CHCl3), De = –3.5 (237.5 nm), De = 0 (223 nm), De = +7.7 (212.5 nm) (c 0.13 mol l–1, MeOH).(S)-(–)-2: yield 36%, bp 72 °C (40 torr), [a]D 20 = –23.1° (c 1.0, MeOH) (cf. ref. 19). (S)-(–)-3: yield 50%, oil, [a]D 20 = –27.8° (c 1.0, MeOH). (S)-(–)-4: mp 117–118 °C (C6H6) (cf. ref. 5); [a]D 20 = –6.7° (c 0.2, MeOH), calculated from [a]D 20 for pure (S)-(–)-1 and [a]D 20 = –34.3° (c 0.2, MeOH) for mixture 4:1 = 2. 1H NMR (CDCl3) d: 1.68 (br. s, 1H, He), 1.87 (s, 3H, MeA), 1.90 (br. m, 1H, Hb), 2.06 (s, 3H, MeB), 2.09 (br. m, 1H, Hc), 2.83 (br. m, 1H, Ha), 8.51 (br. s, 1H, Hd). Ha N Hc Hb O N N Hd He MeA MeB (±)-1 6.82 3.94 2.65 2.25 2.13 1.40 1.29 3JHaHb 3JHaHc MeA MeB Ha Hb Hc Hd He Ha {Hd} Figure 1 1H NMR spectrum of (±)-1 in CDCl3. d/ppm NH (S)-(–)-2 HO CO2Me H3N H Cl CO2Me (S)-(+) i NH (S)-(–)-3 CONHNH2 ii iii (S)-(–)-1 Scheme 1 Reagents and conditions: i, NH3, CH2Cl2, then Ph3P–DIAD, CH2Cl2, 1 h, 3–5 °C and 12 h, 20 °C; ii, dry H2NNH2, 1.5 h, –10 °C, then 5 h, 20 °C; iii, Me2CO, 20 h, 55 °C.Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) into qq, and its coupling constant 3JMeA–He 5.0 Hz. At the same time under the conditions {MeB, d 1.40 ppm}, the spectrum for carbon MeB (qq, d 24.98 ppm) transforms into a pure q.This is in agreement with the molecular structure of 1:6 dihedral angles MeA–C–N–He ª 0°, MeB–C–N–He ª 90°. In addition, we observed two features in the 1H NMR spectrum of 1: large coupling constant 4JHaCNHd 2.7 Hz and a strikingly high difference in the coupling constants D1JCH = 18.9 Hz between protons Hb and Hc (usually for aziridine5 this difference does not exceed 11.6 Hz).17,18 This work was supported by the Russian Foundation for Basic Research (grant no. 97-03-33021) and the Latvian Scientific Council (grant no. 722). References 1 K. Okawa and K. Nakajima, Biopolymers, 1981, 20, 1811. 2 K. Okawa, K. Nakajima and T. Tanaka, J. Synth. Org. Chem. Jpn., 1984, 42, 390. 3 D. Tanner, Angew. Chem., Int. Ed. Engl., 1994, 33, 599. 4 W. H. Pearson, B. W. Lian and S. C. Bergmeier, Aziridines and Azirines: Monocyclic, in Comprehensive Heterocyclic Chemistry II, ed. A. Padwa, Pergamon, New York, 1996, vol. 1A, p. 1. 5 P. T. Trapentsier, I. Ya. Kalvin’sh, E. E. Liepin’sh, E. Ya. Lukevits, G. A. Bremanis and A. V. Eremeev, Khim. Geterotsikl. Soedin., 1985, 774 [Chem.Heterocycl. Compd. (Engl. Transl.), 1985, 21, 646]. 6 A. F. Mishniev, M. F. Bundule, Ya. Ya. Bleidelis, P. T. Trapentsier, I. Ya. Kalvin’sh and E. Ya. Lukevits, Khim. Geterotsikl. Soedin., 1986, 477 [Chem. Heterocycl. Compd. (Engl. Transl.), 1986, 22, 390]. 7 K. F. Koehler, H. Zaddach, G. K. Kadorkina, I. I. Chervin and R. G. Kostyanovsky, Izv. Akad.Nauk, Ser. Khim., 1993, 2136 (Russ. Chem. Bull., 1993, 42, 2049). 8 U. Bicker, Fortsch. Med., 1978, 96, 661. 9 I. Ya. Kalvin’sh and E. B. Astapenok, Belg. Patent, 860239, 1978 (Chem. Abstr., 1979, 90, 34103j). 10 I. Ya. Kalvin’s, N. M. Gipsh, A. G. Merson, E. B. Astapenok and P. T. Trapentsier, USSR Inventor’s Certificate no. 787994, (Byull. Izobret., 1980, no. 46, 214). 11 K. Jahnisch, F.Grundemann and A. Kunath, XIII International Symposium: Synthesis in Organic Chemistry, Oxford, 1993. 12 S. T. Stinson, Chem. Eng. News, 1997, 75 (42), 38. 13 J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publ. Comp., Malabar, Florida, 1994. 14 G. A. Potter, C. Garcia, R. McCague, B. Adger and A. Collet, Angew. Chem., Int. Ed. Engl., 1996, 35, 1666. 15 O. Mitsunobu, Synthesis, 1981, 1. 16 I. I. Chervin, A. A. Fomichov, A. S. Moskalenko, N. L. Zaichenko, A. E. Aliev, A. V. Prosyanik, V. N. Voznesenskii and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 1110 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 37, 972). 17 I. I. Chervin, A. E. Aliev, V. N. Voznesenskii, S. V. Varlamov and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1987, 1917 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 36, 1781). 18 I. I. Chervin, A. E. Aliev, V. N. Voznesenskii and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1992, 1688 (Bull. Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 1312). 19 G. V. Schustov, S. N. Denisenko, I. I. Chervin and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 1606 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 37, 1422). Ha N Hc Hb O N N Hd MeB MeA (S)-(–)-4 He (S)-(–)-1 MeOH Scheme 2 Received: Moscow, 17th September 1998 Cambridge, 5th November 1998; Com. 8/07878E