Tetrahedron Letters, Vol. 37, No. 50, pp. 8971-8974, 1996 Pergamon Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0040-4039/96 $15.00 + 0.(30 PII: S0040-4039(96)02104- I The Synthesis of 4,5-Methano Congeners of ¢x-Kainic and ~x-a//o-Kainic Acids as Probes for Glutamate Receptors Stephen Hanessian,* Sacha Ninkovic and Ulrich Reinhold Department of Chemistry, Universit6 de Montrtal, P.O.Box 6128, Station Centre-ville, Monutal, Quebec H3C 3J7, CANADA Abstract: The synthesis of diastereomeric 4.5-methano-L-proline 3-acetic acids is described starting from D-serine. The key reactions include a free-radical carbocyclization and an acid-catalyzed destannylative cyclopropanatian of an iminium ion intermediate. Copyright © 1996 Elsevier Science Ltd The synthesis of biologically relevant or-amino acids in which the carbon skeleton has been rigidified has been an area of active research for some years. 1 2,3-Methano amino acids, also known as "methanologs" have attracted considerable attention in this regard. 2 Many of these compounds were prepared with the intention of probing spatial, conformational and functional features of the natural substrates at their biological receptor sites. Methano 2,3 and related 4 analogs of L-glutamic acid have been of particular interest because of the importance of this amino acid in the CNS. Indeed, the glutamate receptor is considered to be an important target in the quest for therapeutically effective drugs in the cardiovascular and related areas 5 Cyclopropane it-amino acids are also natural products 2 or components of more elaborate structures.6 Receptors to excitatory amino acids include among others, those that have an affinity to a-kainic acid 1, 7 which, viewed in a different perspective, can be considered as a constrained L-glutamic acid 3. Indeed, in addition to a plethora of total 8 and partial syntheses 8 of ¢t-kainic acid 1 and allo-kainic acid 2, there are several reports of kainoid analogs8, 9 aimed at finding new bioactive compounds in this series. We report in this Letter, the design and synthesis of structurally novel 4,5-methanoproline 3-acetic acid analogs 4 and 5 in enantiomerically pure form (Figure 1). Examples of methanoprolines are rare, 10,11 and to the best of our knowledge compounds like 4 and 5 which are structurally and stereochemically related to ¢t-kalnic and a//o-kainic acids, are unprecedented. Figure 1 1, ot - kainic acid 2, allo-kainic acid 3, L-Glutamic acid 4, R=H 5, R=H 41=, R=vinyl 5It R=vinyl In order to have access to both isomers 4 and 5, we chose a method of synthesis that produced stereoisomeric intermediates from a common precursor (Scheme 1). D-Serine 6 was elaborated upon by a series of standard manipulations to give the diene 8. Treatment with trimethyhin hydride 12,13 led to a mixture of pyrrolidinones, which could be separated into the three isomers 9a, 9b, and 9c after conversion to 8971
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`8972 the N-boo derivatives and column chromatography. 14 The stereochemical outcome favoring the major trans- isomer 10a has been rationalized based on the prevalence of a late transition state. 11.15 In a key transformation, the lactam was sequentially reduced to the hemiaminal, then treated with acid to give the 4,5-methano derivative 10 via interrnolecular alkylation of the corresponding N-Boc iminium ion. 11 Subsequent steps relied on functional group manipulations to afford the diester 11 which was in turn hydrolyzed to the crystalline 4S,5S-methano-3S-carboxylmethyl-L-proline, 5. An X-ray crystal analysis provided conclusive proof for its structure and stereochemistry. The isomeric 4R,5R-analog 4 was prepared in a similar manner, to give an amorphous product, whose stereochemistry was rigorously assigned by detailed n.O.e, studies. Scheme 1
`
`1. Boc20
`2. CH2N2
`3. TBDPSCI
`4. Dibal then,
`(CsH5 }BP=CHCO2Me
`R = TBDPS
`
`~ R
`
`D-Serine
`
`6
`
`1. TFA, CH2C12
`.,~.~;O2M e 2. acryloyl chloride
`" 64 %
`~HBoc
`7, 70*/.
`
`\'~
`
`O
`
`N~CH2OR
`H
`8 (c1.1, CHCI3)
`
`>~nMe3
`~/
`.---~.(~..M°
`~
`~
`v_~..v
`
`1. M~SnCI, t-BuOH, reflux;
`slow add'n NaCNBH 3
`AIBN, MeOH, 76%
`2. Boc20, DMAP
`Et3N, CH3CN, 90*/.
`
`?nUe 3
`~,.
`~/"~
`~ O'~"'~I~I./"~CH2OR + O~I~
`Boc
`I~
`
`?nMe3
`".~t~--CO2Me
`""
`'~'CI-12OR + O~'"~N,/~"CH2OR
`~oc
`
`1. LiEtsBH, THF ~
`2. TFA, CH2CI2
`'~CH2OR
`67 %
`~
`
`..--CO2Me 1. TBAF, THF
`2. CrO 3, H2SO4 ~
`3. CHL~I 2, Et20 ~ ~c.,,~_,O
`71%
`
`.~'~GO2Me 1. KOH, MeOH
`2. TFA, CH2CI2
`3. Ion exchange resin
`65%
`
`2Me
`
`911
`
`~.-.CO2H
`
`CO2H
`
`"-"
`
`,-.--.CO2H
`
`~
`
`H
`
`mp 201-205°C (dec.)
`
`[O.]D +67 ° (c 0.69, CHCI a)
`
`The radical carbocyclization reaction can also be done on an extended dicnic system 12a which can
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`eventually lead to the functionalized 4,5-methano analogs 4a and 5a (Figure 1). The readily available diene 12 was subjected to the free radical carbocyclization reaction to give mainly the all-trans-pyrmlidinone which was isolated as the N-Boc derivative 13 (Scheme 2). Quenching the potassium dienolate of the all-trans-isomer 13 with dibenzylmalonate 16 as a proton source led to the isomeric product 14 as the major product. Formation of the N-Boo iminium ion by the method described above led to the vinyl cyclopropane 15 which was in turn converted into the a-kainic acid congener 4a, isolated as an amorphous solid. Application of the same methodology to the isomeric 13 gave 5a, also isolated as an amorphous solid. The structures in this series were unambiguously established by detailed N.M.R. studies and by an X-ray crystal analysis of 16.
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`[~D+9.4 °
`.."--CO:L~Me
`-- ~
`ratio 9a,b,c - 6:1:1 9a 9b 9c
`9b
`S 4
`[a]D +26.4* (c 0.28, CHCI3)
`

`
`8973 Scheme 2 nMe3 I riMe3 I" "~"~'COLiH ~ 3021Vle 2.1" Me3SnC" NaBH 3CN ~....~ 02MeAIBN,BOc20,I'BuOH'DMAP reflux), ~O:,Me
`
`12 R = TBDPS
`
`13
`
`1. KHMDS
`1, 14
`malonate
`
`1. UEtaBH, THF
`2. TFA, CH2C~ ~
`86 %
`
`14
`
`..--CO2Me 1. KOH, MeOH
`...¢'--CO2Me 1. TBAF, THF
`,,,,._.~¢"
`2. TFA, CH2CI 2
`2. CrO~, H2SO 4 ~
`•
`3. Ion exchange resin
`"l':~ff,1.N. ~
`3. CH2N2, EtL~O 4 P" -''~I
`I
`34 % ~
`"~/-"CO-J~e
`>80%
`Boc [o¢]0-5.0 °
`16
`(c0.2, CHCI3)
`rap. 66-69°C (dec.)
`
`I-~OR
`Boc [~D-14.9 °
`15
`(c0'7, CHCI3)
`
`°~ °
`
`i,
`
`...---C02H
`
`CO.~H
`
`.----CO:L~-I
`
`O2H
`
`16
`
`o . ~
`
`H
`4a
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`Sa Compounds 4, 4a, 5 and related amino acids from another series 11 were tested for their binding as antagonists and agonists in five receptor assays. 5a Unfortunately, no significant binding affinity was found at 1 I.tM in the DCKA (3H-5,7-dichlorokynurenic acid) assay for the glycine recognition site of the NMDA receptor. When tested in the AMPA, kainate, and other receptor binding assays at concentrations of 1 I.tM and l0 pM, again, activity was surprisingly low compared to standards. 17 Clearly, the structural requirements for effective binding to these receptors have not been satisfied by our methano analogs in spite of their novel structures. The lack of activity in the kainate receptor and the glutamate recognition site of N-methyl-D-aspartate receptor (CGP 39653) are reflective of the lack of our understanding for specific spatial requirements and hydrophobic interactions of the appended cyclopropane in analogs 4, 4a, 5 vis-a-vis the 2-propenyl group in (x-kainic acid itself. We are presently developing alternative, highly stereocontrolled methods for the synthesis of conformationally constrained analogs of L-proline and L-pipecolic acid. These should find specific applications in the design of peptidomimetics aimed at probing enzymatic reactions that involve cis/trans amide-bond isomerization 18 such as in the immunophilins, 19 as well as in the study of secondary and tertiary local structures of certain peptides. 20 Acknowledgments We thank NSERCC for generous financial assistance through the Medicinal Chemistry Chair program, and the Deutsche Forschungsgemeinschaft for a DFG research fellowship to U. R. We thank Dr. Michel Simard of our crystallography laboratory for the X-ray analyses. We thank Dr. S. Bischoff for the binding assays, and Dr. H. Allgeier for fruitful discussions (CIBA-Geigy AG, Basel).
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`2. dibenzyl
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`8974 References and Notes 1. For selected reviews on constrained peptides, see Giannis, A.; Kolter, T. An&ew, Chem. Int. Ed. Engl. 1993, 32, 1244; Kahn, M. Synlett 1993, 821; Rizo, J.; Gierasch, L. M. Ann. Rev. Biochem. 1992,61,387; Faueh6re, J.-L. Adv. Drug Res. 1986,15, 29. 2. For selected reviews, see Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994, 525; Alami, A.; Calmes, M.; Daunis, J.; Jacquier, R. Bull. Soc. Chin. Ft. 1993,130, 5. 3. For some examples, see Peilicciari, R.; Marinozzi, M.; Natalini, B.; Costantino, G.; Luneia, R.; Giorgi, G.; Moroni, F.; Thomson, C, J. bled. Chem. 1996, 39, 2259; Sagnard, I.; Sasaki, N. A.; Chiaroni, A.; Riche, C.; Potier, P. Tetrahedron Lett. 1995, 36, 3149; l-lanafi, N.; Ortuno, R. Tetrahedron: Asymmetry 1994, 5, 1657; Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y, J. Org. Chem. 1991, 56, 4167. 4. Raghavan, S.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Tetrahedron Lett. 1993, 34, 5765. 5. a. Kn(cid:127)pfe(cid:127)(cid:127) T.; Kuhn(cid:127) R. A(cid:127)(cid:127)gei(cid:127)r(cid:127) H. J. Med. (cid:127)hem. (cid:127)995(cid:127) 38(cid:127) (cid:127) 4 (cid:127) 7; J(cid:127)hnson(cid:127) R. L.; Keerner(cid:127) J. F. J. Med. Chem. (cid:127)9u(cid:127) 3 (cid:127) (cid:127) 2058; b. Glutamate: Transmitter in the CentralNervous System, Robots, P. J.; Storm-Mathesen, J.; Johnson, G. A. R. Eds.; Wiley, New-York, N. Y., 1981. 6. See for example, Charette, A. B.; C6t~, B. J. Am. Chem. Soc. 1995,117, 12721; Jimenez, J. M.; Rif6, J.; Ortuno, R. M. Tetrahedron: Asymmetry 1995, 6, 1849; Williams, R. M.; Fegley, G. J. J. Am. Chem. Soc. 1991,113, 8796; ffourden, L.; Kato, K.; Takita, T.; Umezawa, H. Tetrahedron Lett. 1980, 21, 4925; Smith, A. Millington, D. S.; Sheppard, R. C. Phytochemistry, 1972,11, 1105. 7. McGeer, E. G.; Olney, J. W. in Kainic Acid as Tool in Neurobiology ; Raven Press, New York, N. Y., 1978. 8. For a recent review, see Parsons, A. F. Tetrahedron 1996, 52, 4149 and references cited therein; see also Williams, R. M. Synthesis of Optically Active a-Amino Acids, Baldwin, J. E.; Magnus, P. D. Eds.; Pergamon Press, New York, N. Y., 1989; pp 306-320; for the first synthesis of ot-kainic acid, see Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982,104, 4978. 9. For representative examples, see Gill, P.; Lubell, W. D. J. Org. Chem. 1995, 60, 2658; Baldwin, J. E., Rudolph, M. Tetrahedron Left. 1994, 35, 6163; Ezquerra, J4 Escribano, A.; Rubio, A.; Remuinan, M. J.; Vaquero, J. J. Tetrahedron Left. 1995, 36, 6149; Hashimoto, K.; Harikawa, M.; Shirahawa, H. Tetrahedron Lett. 1990, 31, 7047; Kozikowski, A. P.; Fang, A. H. Tetrahedron Lett. 1990, 31, 2967. 10. For the synthesis of racemic and enantiopure 2,3-methanoproline, see Hercouet, A.; Bessi~res, B.; Le Corre, M. Tetrahedron: Asymmetry 1996, 7, 1267; Switzer, F. L.; van Halbeek, H.; Holt, E. M.; Stammer, C. H. Tetrahedron 1989, 45, 6091; for the synthesis of cis- and trams- 3,4-methanoprolines, see Fujimoto, Y.; Irrevere, F.; Karle, J. M.; Kurle, I. L.; Wilkop, B. J. Am. Chem. Soc. 1971, 93, 3471; for a recent discussion of cyclopropylpyrrolidines, see Harvey, D. F.; Sigano, D. M.J. Org. Chem. 1996, 61, 2268. 11. For related structures, see Hanessian, S.; Reinhold, U.; Ninkovic, S. Tetrahedron Lett., preceding paper. 12. a. Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996,61, 5419; b. Hanessian, S.; Leger, R. J. Am. Chem. Soc., 1992,114, 3115; c. Hanessian, S.; Leger, R. Synleu, 1992, 402. 13. Stork, G.; Sher, P.M.J. Am. Chem. Soc.,1986,108, 303. 14. New compounds were adequately characterized by spectoscopic and analytical data. 15. F~r a r~cent review ~n fre~-radical ch~mis~ty' see Jasp~rs~ C. P.; Curran~ D. P.; Fevig~ T. L. Chem. Rev. ~99~" 9~ ~237. 16. Dibenzylmalonate afforded the best selectivity compared to other protic and aprotic proton sources (ratio 14 : 15 = 1:3.9), see for example Baker, W.; Pratt, J. K. Tetrahedron 1993, 49, 8739 and refetonces therein. 17. CGP 39653, [3H]-E-2-amino-4-phosphonomethy-hept-3-enoic acid, antagonist for the glutamate recognition site of NMDA receptors; [3H]-MK-801, Merck's blocker of NMDA receptor associated ion channels; [3H]-kainic acid, agonist for Kainate receptors. 18. For recent reports, see Curran, T. P.; McEnaney, P. M, Tetrahedron Leu. 1995, 36, 191; Andre.s, C. J.; Macdonald, T. L.; Ocain, T. D.; Longhi, D.; J. Org. Chem. 1993, 58, 6609; Ebenhardt, E. S.; Loh, S. N.; Raines, R. T. Tetrahedron Lett. 1993, 34, 3055 and references cited therein. 19. Schreibet, S. L, Science 1990, 251,283; Freedman, R. B. Nature 1989, 341,692; 337, 407. 20. Bell, J. E.; Bell, T. E.; Proteins and Enzymes, Prentice Hall, Englewood Cliff, N. J., 1988; Robson, B.; Garner, J. Introduction to Proteins and Protein Engineering, Elsevier, Amsterdam, 1986; see also Bryson, J. W.; Betz, S. F.; Lu, H. S.; Svich, D. J.; Zhau, H. X.; O'Neill, K. T.; De Grado, W. F. Science 1995, 270, 935; Tramontano, A.; Bianchi, E.; Veaturini, S.; Martin, F.; Pessi, A.; Sollazzo, M. J. Mol. Recogn. 1994, 7, 9; Johnson, W. C., Jr. Proteins 1990, 7, 205. (Received in USA 19 August 1996; revised 21 October 1996; accepted 22 October 1996)
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