Mendeleev Communications Electronic Version, Issue 3, 1999 (pp. 87–128) 2,5-Diazabicyclo[2.2.2]octane-3,6-dione-1,4-dicarboxylic acids: synthesis, resolution, absolute configuration and crystal structures of the racemic and (–)-enantiomeric forms Remir G. Kostyanovsky,*a Yuri I. El’natanov,a Oleg N. Krutius,a Konstantin A. Lyssenko,b Ivan I. Chervina and Denis A. Lenevc 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 Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation.Fax: +7 095 978 8527; e-mail: lenev@hotmail.com Title dilactam diacid 1 has been synthesised and resolved into enantiomers via diastereomeric salts 2 with a chiral amine; the absolute configuration of (1R,4R)-(–)-1 was established by decarboxylation and transformation into the parent dilactam (1R,4R)-(–)-C; the molecular and crystal structures of (±)-1 and (–)-1 (space groups P21/n and P21, respectively) were determined.Bicyclic bislactams (BL) of the symmetry C2 are perfect building blocks for supramolecular chemistry and the engineering of crystals on the basis of self-assembling due to H-bonding1–7 (Scheme 1, other H-bonded systems see in refs. 7–11). Chirally directed self-assembling of crystalline parent bislactam C into heterochiral infinite tapes of the linear zigzag type [for the (±)-form] and into intricate tetramers of a quite different type [for the (–)-form] were studied by the J.-M.Lehn’s group.2 In the latter case, the expected hexamers have not been realised despite a careful selection of well-matched guest molecules.3 Functionalised derivatives D and E have been synthesised, and compound D (R = Pr) was resolved into enantiomers;3 however, its deacylation with the aim of preparing optically active derivatives such as E was unsuccessful.We have developed simple methods for the synthesis of functionalised bislactam A from this series4 as well as parent bislactams F and G and their functionalised derivatives H and I.5,6 For crystalline bislactam A, heterochiral self-assembling of the linear zigzag type was observed4 like the case of (±)-C.2 For bislactams F5 and I,6 heterochiral self-assembling of a new type (diagonal zigzag) was found, whereas homochiral selfassembling into helical suprastructures (space group P212121) takes place in the case of G6 (Scheme 1).NH HN X X O O NH HN O O OCOR RCOO NH HN O O CO2R RO2C NH HN O O n X X A X = CO2Et C X = H F X = H, n = 0 G X = H, n = 1 H X = CO2Et, n = 0 I X = CO2Et, n = 1 D E Scheme 1 Scheme 2 Reagents and conditions: i, KOH in EtOH–H2O (3:2), 10 h at 20 °C, then CF3CO2H in H2O at 20 °C and 5 days at 3–5 °C; ii, 2B in H2O at 20 °C and evaporation; iii, triple crystallisation from EtOH–H2O (10:1), evaporation of combined mother solutions and triple crystallisation of the residue from the same solvent.The residue after evaporation of the initial mother liquid was used in iv; iv, double crystallisation from the same solvent as in iii; v, CF3CO2H in H2O at 20 °C and crystallisation. HN OC NH CO CO2Et CO2Et HN OC NH CO CO2H CO2H (±)-1 ·2H2O HN OC NH CO CO2 CO2 (±)-2·BH ·2BH+ i ii B = (1S,2S)-(+)-PhCH CHCH2OH HO NH2 a,b c d (±)-2·2BH (1S,4S)-(+)-1 (1S,4S)-(+)-2·2BH (1R,4R)-(–)-2·2BH (1R,4R)-(–)-1 iv iii v v (±)-A C(1) N(2) C(3) C(4) N(5) C(6) C(7) C(8) H(7A) H(7B) H(8A) H(8B) C(9) O(4) H(4) O(3) C(10) O(6) H(6) O(5) H(5) O(2) O(1) H(2) Figure 1 The general view of (±)-1 and (1R,4R)-(–)-1.Selected bond lengths (Å) for (±)-1 and (1R,4R)-(–)-1 (in brackets): O(1)–C(3) 1.229(1) [1.224(3)], O(2)–C(6) 1.228(1) [1.220(3)], O(3)–C(9) 1.211(1) [1.207(3)], O(5)–C(10) 1.205(1) [1.193(3)], N(2)–C(3) 1.333(1) [1.337(3)], N(2)–C(1) 1.460(1) [1.455(3)], N(5)–C(6) 1.343(1) [1.340(3)], N(5)–C(4) 1.466(1) [1.467(3)]; selected bond angles (°) for (±)-1 and (1R,4R)-(–)-1 (in brackets): C(3)–N(2)–C(1) 117.74(8) [117.9(2)], C(6)–N(5)–C(4) 117.20(8) [117.2(2)], N(2)–C(1)–C(6) 107.84(8) [107.8(2)], N(2)–C(1)–C(7) 108.22(8) [108.3(2)], C(6)–C(1)–C(7) 105.51(8) [105.9(2)], O(1)–C(3)–N(2) 126.3(1) [126.7(2)], O(1)–C(3)–C(4) 124.91(9) [124.7(2)], N(2)–C(3)–C(4) 108.79(8) [108.5(2)], N(5)–C(4)–C(3) 107.55(8) [107.8(2)], N(5)–C(4)–C(8) 108.44(8) [107.8(2)], C(3)–C(4)–C(8) 105.86(8) [106.0(2)], O(2)–C(6)–N(5) 125.8(1) [126.4(2)], O(2)–C(6)–C(1) 125.38(9) [124.9(2)], N(5)–C(6)–C(1) 108.75(8) [108.8(2)], C(8)–C(7)–C(1) 108.28(8) [107.8(2)].Mendeleev Communications Electronic Version, Issue 3, 1999 (pp. 87–128) In this work, bislactam diacid 1 has been synthesised from bislactam diester A4 for the first time, and its complete resolution into enantiomers was carried out using aminodiol B stable to carbonization as a resolving reagent12 (Scheme 2). The esterification, N-methylation and decarboxylation of enantiomers 1 were studied (Scheme 3).All products were characterised by elemental analysis and spectroscopic data (cf. A4).† The optical purity (> 95%) of derivative (–)-4 was determined by 1H NMR spectroscopy using a chiral shift reagent. The absolute configuration of diacid (1R,4R)-(–)-1 was found on the basis of its thermal decarboxylation into the bislactam of the known absolute configuration (1R,4R)-(–)-C [the synthesis of (1S,4S)-(+)-C based on (S)- homoserine was reported earlier13].Under severe conditions of decarboxylation,13 the optical purity of product C substantially decreases (ref. 2). The X-ray diffraction study‡ of dihydrates (±)-1 and (–)-1 (Figure 1) revealed an astonishing similarity between their crystal packing patterns (Figure 2).The molecules are assembled by H-bonding both of the lactamic CO with NH groups and the lactamic NH with CO of the group CO2H (Table 1, entries 1 and 2, respectively). As a result, the homochiral helices are formed, which can be regarded as tapes of the double zigzag type with the zigzag width d1 equal to 11.26 and 11.59 Å for (–)-1 and (±)-1, respectively (Figure 2). These tapes are aThe symmetrical transformation was used to generate equivalent atoms. Table 1 The parameters of H-bonds in the crystal stuctures of (±)-1 and (1R,4R)-(–)-1. Entry Parameter (±)-1 (1R,4R)-(–)-1 1 N(2)–H(2)···O(5') N(2)–H(2)–O(5') N(2)···O(5') 1.96 Å 156° 2.791(1) Å (1/2 – x, –1/2 + y, 3/2 – z)a 1.97 Å 161° 2.780(2) Å (–x, 1/2 + y, –2 + z) 2 N(5)–H(5)···O(1'') N(5)–H(5)–O(1'') N(5)···O(1'') 2.33 Å 166° 3.198(1) Å (1/2 – x, –1/2 + y, 3/2 – z) 2.22 Å 163° 3.086(3) Å (–x, –1/2 + y, 2 – z) 3 O(4)–H(4)···O(1w) O(4)–H(4)–O(1w) O(4)···O(1w) 1.545 Å 177° 2.542(1) Å 1.76 Å 176° 2.559(3) Å 4 O(6)–H(6)···O(2w) O(6)–H(6)–O(2w) O(6)···O(2w) 1.689 Å 176° 2.600(1) Å 1.675 Å 167° 2.581(3) Å 5 O(1w)–H(1wA)···O(1) O(1w)–H(1wA)–O(1) O(1w)···O(1) 2.074 Å 155° 2.868(1) Å 2.15 Å 146° 2.848(3) Å 6 O(1w)–H(1wB)···O(2') O(1w)–H(1wB)–O(2') O(1w)···O(2') 2.04 Å 176° 2.901(1) Å (1/2 – x, –1/2 + y, 3/2 – z) 1.93 Å 173° 2.848(3) Å (–x, 1/2 + y, –3 + z) 7 O(2w)–H(2wA)···O(2) O(2w)–H(2wA)–O(2) O(2w)···O(2) 2.39 Å 176.3° 3.086(1) Å 2.294 Å 149° 2.977 Å 8 O(2w)–H(2wA)···O(4) O(2w)–H(2wA)–O(4) O(2w)···O(4) 2.116 Å 141° 2.843(1) Å 2.38 Å 130° 2.933(3) Å 9 O(2w)–H(2wB)···O(3'') O(2w)–H(2wB)–O(3'') O(2w)···O(3'') 1.926 Å 177° 2.834(1) Å (1/2 – x, 1/2 + y, 3/2 + z) 2.022 Å 163° 2.832(3) Å (1 – x, –1/2 + y, 3 – z) Scheme 3 Reagents and conditions: i, 2 equivalents of CH2N2 in Et2O/ MeOH, 15 min at 20 °C; ii, excess of CH2N2 in Et2O/MeOH, 24 h at 20 °C; iii, heating of the mixture with sand, 15–20 min at 250–280 °C in vacuo (10–20 Torr) accompanied with sublimation of the product.HN OC NH CO CO2Me CO2Me MeN OC NMe CO CO2Me CO2Me NMe CO MeN OC CO2Me CO2Me ii (1S,4S)-(+)-1 (1R,4R)-(–)-1 i ii (1S,4S)-(+)-3 (1S,4S)-(–)-4 (1R,4R)-(+)-4 NH CO HN OC CO2H CO2H (1R,4R)-(–)-1 NH CO HN OC H H (1R,4R)-(–)-C 1 2 3 4 5 6 7 8 iii ·2 H2O O(4) H(4) O(3) O(2) N(5) H(5) N(2) H(2) O(6) H(6) O(5) O(1) H(1wA) O(1w) H(1wB) H(6') O(6') O(1') N(2') H(2') O(3') O(4') H(4') O(2') N(5') H(5') H(6'') O(6'') O(1'') H(5'') N(5'') O(2'') O(4'') H(4'') O(3'') N(2'') H(2'') H(2wA) O(2w) H(2wB) O(5'') H(4) O(4) O(3) O(2) H(2wB) O(2w) N(5) N(2) H(2) O(5') H(6') O(6') H(1wA) O(1w) H(1wB) H(6'') O(6'') O(5'') H(5'') N(5'') O(2'') O(3'') O(4'') H(4'') C(7'') N(2'') H(2'') O(1'') O(5) H(5) H(6) O(6) O(1) O(3') O(4') H(4') O(2') N(5') H(5') N(2') H(2') O(1') C(7') d1 Figure 2 The embedding of the ‘corrugated’ layers in the crystal structures of (±)-1 and (1R,4R)-(–)-1.Mendeleev Communications Electronic Version, Issue 3, 1999 (pp. 87–128) assembled by H2O molecules into the corrugated homochiral layers (Figure 3, Table 1), and the layers are embedded to one another in a manner as the (–) layer into (–) layer in a homochiral crystal and the (–) layer into the (+) layer in a racemic † Characteristics and spectroscopic data.The NMR spectra were measured on a Bruker WM-400 spectrometer (at 400.13 MHz for 1H and 100.62 MHz for 13C with reference to TMS). Optical rotation was measured on a Polamat A polarimeter. The CD spectra were taken on a JASCO J-500A instrument. Compound (±)-A was obtained by the method described previously.4 (±)-1: yield 80%, mp 284–286 °C (H2O). 1H NMR (CD3OD) d: 2.33 (m, 7,8-CH2, AA'BB' spectrum, Dn 38.0 Hz, 2JAB = 2JA'B' = –13.5 Hz, 3JAB' = 3JA'B = 10.9Hz, 3JBB' 4.8 Hz, 3JAA' 3.9 Hz). Found (%): C, 36.36; H, 4.56. Calc. for C8H12N2O8 (%): C 36.37; H 4.58. dipotassium salt of (±)-1: mp > 360 °C. 1H NMR (D2O) d: 2.28 (m, 7,8-CH2, AA'BB' spectrum, Dn ª 25 Hz). 13C NMR {1H}(D2O) d: 30.38 (7,8-CH2), 68.75 (1,4-C), 173.22 (3,6-CO), 174.60 (CO2 –). (1S,2S)-(+)-B: [a]D 20 +27.0° (c 1.0, MeOH). 1H NMR (CD3OD) d: 2.90 (ddd, 1H, Hc, 3Jcd 6.7 Hz, 3Jac 6.4 Hz, 3Jbc 4.4 Hz), 3.38 (m, 2H, CH2, ABX spectrum, Dn 52 Hz, 2Jab –10.7 Hz, 3Jac 6.4 Hz, 3Jbc 4.4 Hz), 4.55 (d, 1H, Hd, 3Jcd 6.7 Hz), 7.26–7.35 (m, 5H, Ph). (±)-2·2BH: yield ª 100%, mp 231–233 °C, [a]D 20 20.3° (c 1.2, H2O). 1H NMR (CD3OD) d: 2.22 (m, 4H, 7,8-CH2, AA'BB' spectrum, Dn 96 Hz), 3.27 (ddd, 2H, 2Hc, 3Jcd 8.8 Hz, 3Jac 6.0 Hz, 3Jbc 3.4 Hz), 3.46 (m, 4H, 2CH2, ABX spectrum, Dn 56 Hz, 2J –11.7 Hz, 3Jac 6.0 Hz, 3Jdc 3.4 Hz), 4.73 (d, 2H, 2Hd, 3Jcd 8.8 Hz), 7.30–7.45 (m, 10H, 2Ph). (1R,4R)-(–)-2·2BH: yield 46%, mp 238–239 °C, [a]D 20 +17.2° (c 0.7, H2O). (1S,4S)-(+)-2·2BH: yield 22.6%, mp 240–241 °C, [a]D 20 +23.5° (c 0.7, H2O).(1S,4S)-(+)-1: yield 50%, mp 273–275 °C, [a]D 20 +35.3° (c 0.7, MeOH); CD (MeOH): De +0.3 (246 nm), +0.25 (243 nm), +5.35 (225 nm), 0 (210 nm), –4.5 (201.5 nm). (1R,4R)-(–)-1: yield 70%, mp 275 °C (decomp.), [a]D 20 –35.8° (c 0.6, MeOH); CD (MeOH): De –0.37 (246 nm), –0.28 (243 nm), –6.53 (225 nm), 0 (210 nm), –5.5 (201.5 nm).(1S,4S)-(+)-3: yield 70.5%, mp 234 °C (MeOH), [a]D 20 +45.2° (c 0.6, MeOH). 1H NMR (CDCl3) d: 2.40 (m, 4H, 7,8-CH2, AA'BB' spectrum, Dn 84 Hz), 3.95 (s, 6H, 2MeO), 6.82 (br. s, 2H, 2,5-NH). (1S,4S)-(–)-4: yield 50%, mp 160–162 °C (MeOH), [a]D 20 –12.2° (c 0.3, MeOH). 1H NMR (CDCl3) d: 2.25 (br. s, 4H, 7,8-CH2), 2.98 (s, 6H, 2,6-MeN), 3.94 (s, 6H, 2MeO). (1R,4R)-(+)-4: yield 76.3%, mp 161–162 °C (MeOH), [a]D 20 +12.5o [c 1.7, in the presence of the chiral shift reagent Eu(tfc)3, the signal of MeN was shifted from 2.98 to 3.27 ppm; when (+)-4 was added, another signal (Dn 4.4 Hz) appeared in this field; thus, the optical purity of (–)-4 is higher than 95%].(1R,4R)-(–)-C: yield 30–52%, mp 272–273 °C, [a]D 20 –7.0° (c 0.6, MeOH), optical purity ª 9%. 1H NMR (CD3OD) d: 1.98 (m, 4H, 7,8- CH2, AA'BB' spectrum at {3.9 ppm}, Dn 64 Hz), 3.90 (m, 2H, 1,4-CH, 3J ª 3.0 Hz). ‡ Crystallographic data for (±)-1 and (1R,4R)-(–)-1 at 25 °C: crystals of C8H12N2O8 (±)-1 are monoclinic, space group P21/n, a = 8.900(4) Å, b = 11.590(3) Å, c = 10.401(2) Å, b = 92.93(3)°, V = 1071.5(6) Å3, Z = 4, M= 264.20, dcalc = 1.638 g cm–3, m(MoKa) = 1.40 cm–1, F(000) = 552; crystals of C8H12N2O8 (1R,4R)-(–)-1 are monoclinic, space group P21, a = 6.871(3) Å, b = 11.260(3) Å, c = 7.162(2) Å, b = 93.98(3)°, V = 552.8(3) Å3, Z = 2, M= 264.20, dcalc = 1.587 g cm–3, m(MoKa) = = 1.44 cm-1, F(000) = 276.Intensities of 4101 reflections for (±)-1 and 1373 reflections for (1R,4R)-(–)-1 were measured on a Siemens P3 diffractometer at 25 °C (l MoKa radiation, q/2q-scan technique, 2qmax 52° and 63°), 3894 for (±)-1 and 1272 for (1R,4R)-(–)-1 independent reflections were used in further calculations and refinement.The structures were solved by the direct method and refined by a full-matrix least squares against F2 in the anisotropic–isotropic approximation. Hydrogen atoms were located from the difference Fourier synthesis and refined in the isotropic approximation.The refinement converged to wR2 = 0.1310 and COF = 1.040 for all independent reflections [R1 = 0.0419 is calculated against F for the 3314 observed reflections with I > 2s(I)] for structure (±)-1 and to wR2 = 0.0955 and COF = 1.063 for all independent reflections [R1 = 0.0319 is calculated against F for the 1186 observed reflections with I > 2s(I)] for structure (1R,4R)-(–)-1.All calculations were performed using the SHELXTL PLUS 5.0 program 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., 1999, Issue 1. Any request to the CCDC should quote the full literature citation and the reference number 1135/45.one. The parameters of embedding d2 are equal to 1.13 and 1.21 Å for (–)-1 and (±)-1, respectively (Figure 3). Like (±)-A,4 in the case of (±)-1, the C–H···O contacts (ca. 3.28 Å) were found between the bridge C(7)–C(8) hydrogen and O(2), O(5) oxygen atoms of the adjacent layer. It is noteworthy that the similarity of packings was not observed for the pair of (–)- and (±)-C.2 In the latter, as well as in all other bislactams studied earlier such as (±)-A,5 F, H,5 and G, I,6 the molecular selfassembling in crystals occurs solely by H-bonding of lactam groups.This work was supported by the Russian Foundation for Basic Research (grant nos. 97-03-33021 and 97-03-33786). References 1 J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995. 2 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. 3 M.-J. Brienne, J. Gabard, M. Leclercq, J.-M. Lehn and M. Cheve, Helv. Chim. Acta, 1997, 80, 856. 4 R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, I. I. Chervin and K. A. Lyssenko, Mendeleev Commun., 1998, 228. 5 R. G. Kostyanovsky, Yu. I. El’natanov, O. Krutius, K. A. Lyssenko and Yu. A. Strelenko, Mendeleev Commun., 1999, 70. 6 R. G. Kostyanovsky, K. A. Lyssenko, Yu. I. El’natanov, O. N. Krutius, I. A. Bronzova, Yu. A. Strelenko and V. R. Kostyanovsky, Mendeleev Commun., 1999, 106. 7 J. C. MacDonald and G. M. Whitesides, Chem. Rev., 1994, 94, 2383. 8 J. P. Matias, E. E. Simanek and G. M. Whitesides, J. Am. Chem. Soc., 1994, 116, 4326. 9 S. Koe, J. Kane, T. L. Nguyen, L. M. Toledo, E.Wininger, F. W. Fowler and J. W. Lauher, J. Am. Chem. Soc., 1997, 119, 86. 10 S. Palacin, D. N. Chin, E. E. Simanek, J. C.MacDonald, G. M.Whitesides, M. T. McBride and G. T. R. Palmore, J. Am. Chem. Soc., 1997, 119, 11807. 11 M. M. Conn and J. Rebek, Jr., Chem. Rev., 1997, 97, 1647. 12 A. I. Meyers and B. A. Lefker, Tetrahedron, 1987, 43, 5663. 13 D. S. Kemp and E. T. Sun, Tetrahedron Lett., 1982, 23, 3759. C(7' )C(8' ) C(7) C(8) d2 Figure 3 ‘Corrugated’ layers in the crystal structures of (±)-1 and (1R,4R)-(–)-1. Received: 22th December 1998; Com. 98/1418