Da1198 1089.109

mate, the excitatory amino acid antagonist activities of a series of decahydroisoquinoline-3-carboxylic acids were explored. It was found that compound (III) possesses both NMDA and AMPA receptor antagonist activity (Simmons et al., 1998; A new route to the synthesis of (III) was proposed, based on an intermolecular Diels±Alder cycloaddition reaction of a 6-substituted dihydropyridone with an appropriate diene. This and AMPA receptor antagonist activity key reaction would need a group at position 6 (to the nitro- gen) in an axial position, so before the cycloaddition reaction was attempted, a crystal structure determination of (I) was J. Zukerman-Schpector,a,b* Mauricio Vega,b I. Caracelli,b undertaken. After con®rmation that the methyl group (at Luiz C. Diasc and Anna M. A. P. Fernandesc position 6, labelled C5 in the ®gure) occupied an axial posi- tion, a thermally induced Diels±Alder reaction was performed aInstituto de QuõÂmica, Universidade de SaÄo Paulo, SaÄo Paulo, SP, Brazil, using the highly reactive Danishefsky's diene, (IV). As the bLaboratoÂrio de Cristalografia, EstereodinaÃmica e Modelagem Molecular, Diels±Alder reaction could lead to several different products Departamento QuõÂmica, Universidade Federal de SaÄo Carlos, Caixa Postal 676,13565-905 SaÄo Carlos, SP, Brazil, and cInstituto de QuõÂmica, UNICAMP, Caixa and as the relative stereochemistry of this product is of great Postal 6154, 13083-970 Campinas, SP, Brazil importance for subsequent reaction steps, the crystal structure Correspondence e-mail: [email protected] The molecular structure of (I) is shown in Fig. 1. As stated, the methyl group at C5 is in an axial position, as required for the continuation of the reaction path. The piperidone ring is in 6-methyl-N-(4-nitrobenzoyl)-5,6-dihydropyridin-2(1H)- a half-chair conformation distorted towards a half-boat, as indicated by the Cremer & Pople (1975) puckering parameters 13H12N2O4, (I), the piperidone ring is in a distorted half-chair conformation. In 8-methoxy-3-methyl-N-(4-nitro- shown in Table 3. The lone pair of the piperidone N atom is benzoyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline-1,6-dione, C involved in conjugation with the carbonyl groups. This is indicated by the slight lengthening of the C O double bond 20N2O6, (II), the heterocyclic ring is in a slightly distorted half-boat conformation, while the other six-membered ring is [1.214 (3) AÊ] and the concomitant shortening of the two NÐ in a distorted chair conformation. Compound (II) presents a Csp2 single bonds [1.395 (3) and 1.399 (3) AÊ]. Accordingly, the strong intramolecular CÐHÁ Á ÁO hydrogen bond. In both (I) state of hybridization of the N atom is sp2, as shown by the and (II), the molecules interact through CÐHÁ Á ÁO interac- sum (358.2) of the angles around it and the small deviation [À0.050 (2) AÊ] of the atom from the N1/C2/C4/C13 plane.
CommentGlutamate is the major excitatory neurotransmitter in the brain and can act on three major types of ligand-gated ion channels that are de®ned by the activity of the subtype- The molecular structure of (I) showing the atomic labelling and 50% probability displacement ellipsoids.
selective agonists NMDA (N-methyl-d-aspartate), kainate and (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (Ornstein et al., 1994). In a search for new therapeutic The molecular structure of (II) showing the atomic labelling and 50% agents which are potent and selective antagonists of gluta- probability displacement ellipsoids.
# 2001 International Union of Crystallography  Printed in Great Britain ± all rights reserved The molecular diagram of (II) is shown in Fig. 2, and shows that the two rings have a cis fused stereochemistry with an Selected geometric parameters (AÊ, ) for (I).
H1ÐC1ÐC6ÐH6 torsion angle of 41. The heterocyclic ring is in a slightly distorted (towards a chair) half-boat confor- mation, whereas the other six-membered ring is in a distorted chair (towards a half-chair) conformation, as indicated by the Cremer & Pople (1975) puckering parameters given in Table 6.
The existence of a CÐHÁ Á Á% interaction between C12ÐH12B and the C14±C19 phenyl ring is noted. According to Ciunik et al. (1998), this kind of interaction should be characterized by three parameters. In the present structure, these are the H12BÁ Á ÁCgi (Cg is the centroid of the C14±C19 ring) distance Hydrogen-bonding geometry (AÊ, ) for (I).
of 2.69 AÊ, the C12ÐH12BÁ Á ÁCgi angle of 158 and the angle between the HÁ Á ÁCg vector and the plane of the aromatic ring, which in this case is 88 [symmetry code: (i) 1 These values are in the expected ranges of 2.7±3.4 AÊ, 140±160 and 80±100, respectively, as described by Ciunik et al. (1998).
This compound also exhibits three intramolecular hydrogen bonds (Table 5); in fact, C11ÐH11AÁ Á ÁO4 and C15Ð Symmetry codes: (i) 2 À xY 12 ‡ yY 32 À z; (ii) 32 À xY 1 À yY 12 ‡ z; (iii) 2 À xY y À 12Y 32 À z; (iv) H15Á Á ÁO3 are responsible for the particular arrangement of the phenyl ring. In order to study the in¯uence of these hydrogen bonds on molecular conformation, a series of Cremer & Pople (1975) puckering parameters (AÊ, ) for (I).
Potential Energy Surfaces (PES) calculations were performed [MOPAC7.01: Stewart (1990) and Csern (2000); GAMESS98: Schmidt et al. (1993)]. The geometry optimization calculations, using AM1 and 6±31G*, showed a change in the conformation involving the three CÐHÁ Á ÁO interactions; the H15Á Á ÁO3 distance changes from 2.49 to 2.58 AÊ, while the other two followed by addition of phenylselenyl bromide. This last distances, H5BÁ Á ÁO3 and H11CÁ Á ÁO4, shorten to 2.47 and intermediate was converted into (I) using standard oxidation 2.49 AÊ, respectively. The PES obtained after rotation of the and elimination conditions. Heating of (I) with an excess of C4ÐN1ÐC13ÐC14 torsion angle showed that there were two Danishefsky's diene (IV) at re¯ux in xylene in the presence of minima, one corresponding to the global minimum (162.77), BHT, followed by treatment of the intermediate adduct with which is close to the crystallographic conformation [144.0 (2)], and the other at À77.32. This last conformation is around 7 kcal higher (1 kcal = 4.184 kJ) than the other and results in the loss of the C15ÐH15Á Á ÁO3 hydrogen bond. We can postulate that, in this case, the molecular conformation is driven more by the intramolecular interactions.
In both compounds, the molecules interact through a series of CÐHÁ Á ÁO interactions, as shown in Tables 2 and 5.
Whether all these interactions are true hydrogen bonds is dif®cult to assert because, as pointed out by Cotton et al.
(1997), `the ®eld is getting muddier and muddier as the de®- nition of a hydrogen bond is relaxed'. In any case, the Tables include those contacts with an HÁ Á ÁO distance less than the sum of the van der Waals radii (Pauling, 1960) plus 10% and a CÐHÁ Á ÁO angle greater than 100.
Addition of methyl magnesium bromide to commercially available glutarimide, followed by treatment of the inter- sponding lactam. The lactam was then N-protected using n-BuLi in tetrahydrofuran (THF) followed by addition of p-nitrobenzoyl chloride to afford the corresponding imide which, in turn, was deprotonated with LiHMDS in THF, 1090 J. Zukerman-Schpector et al.  C13H12N2O4 and C18H20N2O6 Selected geometric parameters (AÊ, ) for (II).
Cremer & Pople (1975) puckering parameters (AÊ, ) for (II).
C1ÐC6ÐC7ÐC8ÐC9ÐC10 0.11 (2) 0.47 (2) À95 (11) 13 (3) 0.49 (2) N1ÐC2ÐC1ÐC6ÐC5ÐC4 0.297 (3) 0.380 (3) À122.4 (5) 38.2 (3) 0.482 (3) 1.2 (for the other H atoms) times the value of the equivalent isotropic displacement parameter of the attached atom.
For both compounds, data collection: CAD-4 Software (Enraf± Nonius, 1989); cell re®nement: CAD-4 Software; data reduction: Hydrogen-bonding geometry (AÊ, ) for (II).
XCAD4 (Harms & Wocadlo, 1995). Program(s) used to solve struc- ture: SHELXS86 (Sheldrick, 1985) for compound (I) and SIR92 (Altomare et al., 1993) for compound (II). For both compounds, program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ZORTEP (Zsolnai, 1995); software used to prepare material for publication: PARST95 (Nardelli, 1995), PLATON (Spek, 1998) and WinGX (Farrugia, 1999).
This work has received partial support from FAPESP, CNPq and CAPES. MVacknowledges FAPESP for a PhD fellowship (98/13927-3). The X-ray facility at the Instituto de QuõÂmica- USP was installed with a grant from FAPESP (94/2061-4).
Symmetry codes: (i) À12 À xY yY Àz; (ii) xY y À 1Y z; (iii) x À 12Y ÀyY z; (iv) À12 À xY 12 À yY 12 À z; (v) x À 12Y 1 À yY z; (vi) 12 À xY 12 À yY 12 À z; (vii) 12 ‡ xY 1 À yY z; (viii) Supplementary data for this paper are available from the IUCr electronic archives (Reference: DA1198). Services for accessing these data are described at the back of the journal.
Altomare, A., Cascarano, G., Giacovazzo, C. & Guagliardi, A. (1993). J. Appl.
Ciunik, Z., Berski, S., Latajka, Z. & Leszczynski, J. (1998). J. Mol. Struct. 442, Cotton, F. A., Daniels, L. M., Jordan, G. T. IV & Murillo, C. A. (1997). J. Chem.
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Csern, I. (2000). MOPAC7.01 for LINUX (public domain version). Institute of Nuclear Research, Hungarian Academy of Science, H-4001 Debrecen POB Enraf±Nonius (1989). CAD-4 Software. Version 5.0. Enraf±Nonius, Delft, The Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837±838.
Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.
Nardelli, M. (1995). J. Appl. Cryst. 28, 659.
O'Neill, M. J., Bond, A., Ornstein, P. L., Ward, M. A., Hicks, C. A., Hoo, K., Bleakman, D. & Lodge, D. (1998). Neuropharmacology, 37, 1211±1222.
Ornstein, P. L., Augenstein, N. K. & Arnold, M. B. (1994). J. Org. Chem. 59, Pauling, L. (1960). The Nature of the Chemical Bond, 3rd ed. Ithaca: Cornell Schmidt, M. W., Baldridge, K. K., Boatz, J. A., Elbert, S. T., Gordon, M. S., Jensen, J. H., Koseki, S., Matsunaga, N., Nguyen, K. A., Su, S. J., Windus, T. S., Dupuis, M. & Montgomery, J. A. (1993). J. Comput. Chem. 14, 1347± Sheldrick, G. M. (1985). SHELXS86. University of GoÈttingen, Germany.
Sheldrick, G. M. (1997). SHELXL97. University of GoÈttingen, Germany.
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J. Zukerman-Schpector et al.  C13H12N2O4 and C18H20N2O6

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