Mendeleev Communications Electronic Version, Issue 6, 1998 (pp. 207–248) Chiral glycouril, 2,6-diethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione: spontaneous resolution, reactivity and absolute configuration Remir G. Kostyanovsky,*a Konstantin A. Lyssenko,b Gulnara K. Kadorkina,a Oleg V. Lebedev,c Angelina N. Kravchenko,c Ivan I. Chervina and Vasily R. Kostyanovskya 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 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation. Fax: +7 095 135 5085; e-mail: kostya@xray.ineos.ac.ru c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 118913 Moscow, Russian Federation.Fax: +7 095 135 5328 The title glycouril 1 was spontaneously resolved into enantiomers by crystallisation from H2O and sorting of conglomerate crystals, then N-chlorination and N-aminomethylation to give 2, 3 and 4, respectively, were studied. The absolute configuration 1R,5R-(+) was determined by an X-ray diffraction study of diastereomeric N,N-bis-aminomethyl derivative (–)-4.Racemic bicyclic bis-lactams (BBL) were observed to selfassemble into the hydrogen bonded heterochiral polymeric linear zig-zag (lz) chains in crystals (Scheme 1), with space groups Pccn (for R = H)1 and P21/n (for R = CO2Et).2 Therefore, these compounds cannot be spontaneously resolved by crystallisation. It can be assumed that chain termination of hydrogen bonded polymerisation takes place in the case of homochiral selfassembling. Indeed, in a crystal of (R,R)-(–)-BBL (R = H) (space group P21212) a cyclic tetramer rather than the expected hexamer (cy) is formed.1 However, a similar self-assembling could be arranged along the diagonal line, for example, in the case of bicyclic bis-ureas (BBU) (Scheme 1) where two possibilities of hydrogen bonded polymerization without chain termination exist.One of them is a heterochiral diagonal zig-zag (dz) like BBL, and the other is a homochiral helical structure (he). Exactly the latter possibility, though in a more complicated form, is realised for BBU. According to an X-ray diffraction study the chiral BBU, 2,6-diethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione 1 forms a conglomerate (space group P41212)3,4 whereas its complex 1·ZnCl2(H2O) has a centrosymmetric structure (space group P21/c).5 Thus, for the first time, spontaneous resolution of glycouril (±)-1 was brought about successfully by routine crystallisation from H2O followed by the sorting of levo- and dextro-rotatory crystals (Scheme 2).Crystallisation of (±)-1 in open vessels at slow self-evaporation gives large transparent sparkling crystals; the weight ranges from 10 to 50 mg and more and the size is up to 1 cm3.Aggregations are also formed, and their fracture results in enantiomeric, levo- and dextro-rotatory samples. Repeated crystallisations lead to optical enrichment, and substantial amounts of optically pure crystals of (+)- and (–)-1, which show maximum optical rotation values and constant melting points, were obtained.They are characterised by NMR and CD spectra† (Figure 1). Results of their study by X-ray diffraction are in agreement with the previous data.4 It is noteworthy that enantiomers 1 are less soluble in H2O and MeOH compared with racemic sample. After boiling of enantiomer 1 in concentrated HCl (1 h) complete decomposition of the sample (1H NMR) and loss of the optical activity are observed.In order to determine the absolute configuration of enantiomers 1 a search for suitable derivatives was carried out (Scheme 2). The heavy atom containing derivative, 2,6-dichloro-BBU (–)-2 was prepared by N-chlorination of (+)-1; however, it is rather unstable and decomposes during crystallisation attempts from a benzene–hexane mixture.N-Aminomethylation of (–)-1 gives the stable crystalline 2,6-bis-morpholinomethyl-BBU (+)-3 and oily diastereoisomer (+)-4 containing an S-(–)-proline residue. Crystalline diastereomer (–)-4 was obtained from (+)-1 and its N N R R O H O H N N R R O H O H ... ... ... ... ... ... N N R H... ... ... ... BBL R = H, CO2Et BBU N N O O H R ...... N N R H N N O O H R Linear zig-zag (lz) Diagonal zig-zag (dz) L D 120° Cycle (cy) Helix (he) 120° L D Scheme 1 L L L L L L L L L L L L L N N N N Et NR2 Et R2N O O N N N N Et H Et H O O R-(+)-3 iii S-(–)-1 iv N N N N Et NR2 Et R2N O O R-(+)-4 N N N N Et Cl Et Cl O O N N N N Et H Et H O O S-(–)-2 ii R-(+)-1 iv N N N N Et R2N Et NR2 O O S-(–)-4 (±)-1 i i O N R2N = R2N = N CO2Me H n n Scheme 2 Reagents and conditions: i, crystallisation from H2O and sorting of crystals; ii, ButOCl in CH2Cl2 , 24 h, 20 °C; iii, MeOCH2N(CH2CH2)2O and molecular sieves 4 Å in PriOH, 1 week, 20 °C; iv, S-(–)-MeOCH2- N(CH2)3CHCO2Me and molecular sieves 4 Å in PriOH, 1 week, 20 °C.Mendeleev Communications Electronic Version, Issue 6, 1998 (pp. 207–248) molecular structure (Figure 2) and the absolute configuration 1S,5S were determined by X-ray diffraction.‡ The results obtained are of importance for the chemistry of glycouril, which has been developing extensively during the last 120 years.6–8 First of all 2,4,6,8-tetraalkyl-BBUs exhibit high psychotropic activity,9 and glycouril 1 is a precursor of 2,6-diethyl-4,8-dimethyl-BBU known as the medicine Albicar.These results open up possibilities for synthesis of chiral drugs.10 Gompper’s group has studied the rearrangement reactions † The NMR spectra were measured on a Bruker WM-400 spectrometer (at 400.13 MHz for 1H and 100.62 MHz for 13C from TMS). Optical rotation was measured on a Polamat A polarimeter. The CD spectra were recorded on a JASCO J-500A instrument with a DP-500N data processor.(±)-1: obtained by the method described in ref. 4, mp 286–288 °C. 1H NMR (CD3OD) d: 1.14 (t, 6H, 2Me, 3J 7.0 Hz), 3.25 (m, 4H, 2CH2, ABX3 spectrum, Dn 84.0 Hz, 2J –14.0 Hz, 3J 7.0 Hz), 5.39 (s, 2H, 2CH). 13C NMR (CD3OD) d: 13.25 (qt, Me, 1J 126.4 Hz, 2J 2.9 Hz), 36.56 (tq, CH2, 1J 138.1 Hz, 2J 4.4 Hz), 67.49 (d, CH, 1J 167.1 Hz), 161.64 (tt, CO, 3J 2.9 Hz).lmax 216.2 nm (MeOH). R-(+)-1: mp 330–331 °C (decomp.), [a]D 20 = 101.4° (c 1.2 H2O), De = = +9.62 (lmax 198 nm). S-(–)-1: mp 330–331 °C (decomp.), [a]D 20 = –93.8° (c 0.19 MeOH), De = = –9.3 (lmax 198 nm). R-(+)-2: obtained from S-(–)-1 {[a]D 20 = –84.4° (c 0.58 MeOH)}, yield 96%, mp 122–129 °C, [a]D 20 = +46.1° (c 0.3 MeOH). 1H NMR (C6D6) d: 0.87 (t, 6H, 2Me, 3J 7.5 Hz), 3.08 (br.q, 4H, 2CH2, 3J 7.5 Hz), 3.94 (s, 2H, 2CH). S-(–)-2: obtained in a similar manner from R-(+)-1 {[a]D 20 = +87.5° (c 0.37 MeOH)}, [a]D 20 = –53.2° (c 1.67 MeOH). R-(+)-3: obtained from the partly enriched S-(–)-1 and N-methoxymethylmorpholine [1H NMR (CDCl3) d: 2.66 (m, 4H, 2CH2N), 3.31 (s, 3H, MeO), 3.69 (m, 4H, 2CH2O), 3.98 (s, 2H, OCH2N)], yield 47%, mp 144–146 °C (benzene–n-hexane), [a]D 20 = +25.6° (c 0.2 MeOH), ee ª ª 15% [as found from 1H NMR spectrum, in C6D6 with addition of Eu(tfc)3, by displacement of the CH2N signal (from 2.15 to 2.55 ppm) and its split (Dn = 42 Hz) into two signals in a ratio of 1.35]. 1H NMR (C6D6) d: 0.96 (t, 6H, 2Me, 3J 7.0 Hz), 2.15 (m, 8H, 4CH2N), 3.39 (m, 2CH2Me, ABX3 spectrum, Dn 256.0 Hz, 2J –14.0 Hz, 3J 7.0 Hz), 3.45 (m, 8H, 4CH2O), 3.72 (m, 4H, 2NCH2N, AB spectrum, Dn 168.0 Hz, 2J –12.2 Hz). 13C NMR (CDCl3) d: 12.42 (q, Me, 1J 126.4 Hz), 37.02 (tq, CH2Me, 1J 138.1 Hz, 2J 4.4 Hz), 50.57 (t, NCH2C, 1J 133.7 Hz), 65.16 (t, NCH2N, 1J 145.3 Hz), 66.14 (d, CH, 1J 165.7 Hz), 66.38 (t, CH2O, 1J 142.4 Hz), 157.55 (s, CO). S-(–)-4: obtained from R-(+)-1 {[a]D 20 = +95.8° (c 0.24 MeOH)} and S-(–)-methyl 1-methoxymethylprolinate {[a]D 20 = –58.3° (c 1.3 MeOH)}, yield 34%, mp 98.5 °C (benzene–n-hexane), [a]D 20 = –122.5° (c 0.6 MeOH). 1H NMR (C6D6) d: 1.17 (t, 6H, 2Me, 3J 7.0 Hz), 1.38, 1.56–1.72 and 1.80 [m, 8H, 2(CH2)2CH], 2.43 and 2.87 (m, 4H, 2CH2N), 3.01 (dd, 2H, 2HCN, 3J 6.3 and 8.9 Hz), 3.28 (s, 6H, 2MeO), 3.55 (m, 4H, 2CH2Me, ABX3 spectrum, Dn 168.0 Hz, 2J –12.0 Hz, 3J 7.0 Hz), 4.20 (m, 4H, 2NCH2N, AB spectrum, Dn 252.0 Hz, 2J –14.0 Hz), 5.36 (s, 2H, 2CH).R-(+)-4: obtained from S-(–)-1 {[a]D 20 = –89.5° (c 0.83 MeOH)} and S-(–)-methyl 1-methoxymethylprolinate, yield 82.6%, oil, [a]D 20 = +7.23° (c 1.9 MeOH). 1H NMR (C6D6) d: 1.14 (t, 6H, 2Me, 3J 7.0 Hz), 1.28, 1.56 and 1.73 [m, 8H, 2(CH2)2CH], 2.19 and 2.82 (m, 4H, 2CH2N), 3.30 (m, 2H, 2CHN), 3.36 (s, 6H, 2MeO), 3.50 (m, 4H, 2CH2Me, ABX3 spectrum, Dn 196.0 Hz, 2J –14.0 Hz, 3J 7.0 Hz), 4.15 (m, 4H, 2NCH2N, AB spectrum, Dn 224.0 Hz, 2J –12.0 Hz), 5.55 (s, 2H, 2CH).‡ Crystallographic data for (–)-4: C22H36N6O6, M = 480.57, monoclinic crystals, space group P21, a = 9.616(3) Å, b = 8.952(3)Å, c = 14.783(5) Å, b = 98.14(3)°, V = 1259.6(7) Å3, Z = 4, dcalc = 1.267 g cm–3, m(MoKa) = = 0.94 cm–1, F(000) = 516.Intensities of 2859 reflections were measured on a Siemens P3 diffractometer at 20 °C (lMoKa radiation, q/2q scan technique, 2q < 52°) and were used in further calculations and refinement. The absolute configuration 1S,5S for the molecule of (–)-4 was confirmed on the basis of the known configuration (S) of the proline moiety. The structure was solved by a direct method and refined by full-matrix least-squares against F2 in the anisotropic–isotropic approximation.The positions of the hydrogen atoms were calculated. The refinement converged to wR2 = 0.2123 and GOF = 1.043 for all 2698 independent reflections [R1 = 0.0595 is calculated against F for the 1663 observed reflections with I > 2s(I)]. The number of the refined parameters is 307.All calculations were performed using SHELXTL PLUS 5.0 on an IBM PC/AT. Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun., 1998, Issue 1. Any request to the CCDC for data should quote the full literature citation and the reference number 1135/34.of glycouril derivatives, and based on them new tricyclic cis-diaziridines and polyaza heterocycles were synthesised.11 In 10 8 6 4 2 0 –2 –4 –6 –8 –10 200 220 l/nm De Figure 1 CD spectra of R-(+)-1 (top) and S-(–)-1 (bottom). C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22) O(1) O(2) O(3) O(4) O(5) O(6) N(1) N(2) N(3) N(4) N(5) N(6) Figure 2 General view of the molecule (–)-4.Only hydrogens linked with asymmetric carbon atoms are shown. Selected bond lengths (Å): O(1)–C(3) 1.223(5), N(1)–C(1) 1.449(6), N(1)–C(3) 1.368(6), N(1)–C(5) 1.451(7), N(2)–C(2) 1.431(5), N(2)–C(3) 1.367(6), N(2)–C(21) 1.441(7), N(5)–C(5) 1.447(8), C(1)–C(2) 1.549(6); selected bond angles (°): C(3)–N(1)–C(1) 112.4(4), C(3)–N(1)–C(5) 122.3(4), C(1)–N(1)–C(5) 121.7(4), C(3)–N(2)– C(2) 112.5(4), C(3)–N(2)–C(21) 121.9(4), C(2)–N(2)–C(21) 125.2(4), N(3)– C(1)–N(1) 115.2(4), N(3)–C(1)–C(2) 103.4(4), N(1)–C(1)–C(2) 102.8(3), N(2)–C(2)–N(4) 115.9(4), N(2)–C(2)–C(1) 103.8(3), N(4)–C(2)–C(1) 103.4(3), O(1)–C(3)–N(2) 125.3(4), O(1)–C(3)–N(1) 126.7(4), N(2)– C(3)–N(1) 108.0(4), N(5)–C(5)–N(1) 112.1(4).Mendeleev Communications Electronic Version, Issue 6, 1998 (pp. 207–248) the extensive studies of Rebek’s group12–16 and Nolte’s group17 achiral glycourils have been examined as structural units for the design of self-assembling molecular clips and capsules. A glycouril-based system (cucurbituril) was used by Kim’s group in the elegant design of a coordination polymeric polyrotaxane18 and polycatenated polyrotaxane.19 Readily accessible enantiomeric glycourils can give new, strong impetus to the synthesis of chiral supramolecular systems and can be used as new chiral reagents in asymmetric halogenation and aminomethylation reactions.This work was supported by the Russian Foundation for Basic Research (grant nos. 97-03-33021, 97-03-33786 and 96-15-97367).References 1 M.-J. Brienne, J. Gabard, M. Leclercq, J.-M. Lehn, M. Cesario, C. Pascard, M. Cheve and G. Dutruc-Rosset, Tetrahedron Lett., 1994, 35, 8157. 2 R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, I. I. Chervin and K. A. Lyssenko, Mendeleev Commun., 1998, 228. 3 M. G. Tsintsadze, A. Yu. Tsivadze, A. A. Dvorkin and T. B. Markova, Soobshcheniya AN GSSR, 1986, 121, 553 (in Russian). 4 E. B. Shamuratov, A. S. Batsanov, Yu. T. Struchkov, A. Yu. Tsivadze, M. G. Tsintsadze, L. I. 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C. Stinson, Chem. Eng. News, 1997, 75, 38. 11 R. Gompper, H. Nöth and P. Spes, Tetrahedron Lett., 1988, 29, 3639. 12 M. M. Conn and J. Rebek, Jr., Chem. Rev., 1997, 97, 1647. 13 D. M. Rudkevich and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1997, 36, 846. 14 Y. Tokunaga, D. M. Rudkevich and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1997, 36, 2656. 15 Y. Tokunaga and J. Rebek, Jr., J. Am. Chem. Soc., 1998, 120, 66. 16 J. M. Rivera, T. Martin and J. Rebek, Jr., J. Am. Chem. Soc., 1998, 120, 819. 17 R. J. Jansen, A. E. Rowan, R. de Gelder, H. W. Scheeren and R. J. M. Nolte, J. Chem. Soc., Chem. Commun., 1998, 121. 18 D. Whang, Y.-M. Jeon, J. Neo and K. Kim, J. Am. Chem. Soc., 1996, 118, 11333. 19 D. Whang and K. Kim, J. Am. Chem. Soc., 1997, 119, 451. Received: Moscow, 11th August 1998 Cambridge, 11th September 1998; Com. 8/06557H