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Doi:10.1016/j.tetlet.2005.06.093

Tetrahedron Letters 46 (2005) 5559–5562 Muneo Shoji,a Kaoru Shiohara,a Masato Oikawa,a Ryuichi Sakaib and Makoto Sasakia,* aGraduate School of Life Sciences, Tohoku University, Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan bSchool of Fisheries Science, Kitasato University, Sanriku-cho, Iwate 022-0100, Japan Received 4 April 2005; revised 6 June 2005; accepted 8 June 2005 Abstract—Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesisfeatures a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C6 stereocenter and 5-exoring-closure to form the tetrahydrofuran ring. The results of preliminary biological studies of 4 are also provided.
Ó 2005 Elsevier Ltd. All rights reserved.
Dysiherbaine (1), isolated from the Micronesian sponge, Dysidea herbacea, is a novel excitatory amino acid with potent convulsant activity.Dysiherbaine activates namely, AMPA and kainic acid (KA) receptors, with considerable preference over KA receptors (K 1: dysiherbaine
2: neodysiherbaine A
of 26 and 153 nM for KA and AMPA receptors, respec-tively).Moreover, it has been shown that dysiherbaine could differentially activate one of the activation sites within the subunit of a heteromeric GluR5/KA2 recep-tor complexThis discrete affinity of dysiherbaine has enabled characterization of the unexpectedly complex behavior of the heteromeric KA receptors. Neodysiher- baine A (2isolated as a minor congener from the same Figure 1. Structures of dysiherbaine and its analogues.
sponge, differs from dysiherbaine in the functionalgroup at the C8 position and is also a selective agonistfor non-NMDA type glutamate receptors ( tors.These studies revealed that neodysiherbaine A issimilar to dysiherbaine in its pharmacological activity Due to these unusual pharmacological properties of on KA receptors, albeit with slightly different binding dysiherbaine to KA receptors and its potent epilepto- affinities for individual receptor subunits, whereas genic activity, dysiherbaine and its designed analogues analogue 3, lacking the hydroxyl and N-methyl groups are anticipated to serve as useful tools for understanding on the tetrahydropyran ring, is a selective antagonist the structure and functions of glutamate receptors in the for GluR5KA receptors. These results strongly suggest central nervous system. Thus, the total synthesis of dysi- that the C8 and C9 functional groups are critical struc- tural elements for specificity and selectivity for KA receptors. In order to reveal further the detailed struc-ture–activity relationship profiles of dysiherbaine, we Recently, Swanson and co-workers have characterized undertook a diverted synthesis of structural analogues the pharmacological action of neodysiherbaine A and of dysiherbaine. In this letter, we describe a synthesis simplified synthetic analogue 3on glutamate recep- of dysiherbaine analogue 4, corresponding to 8,9-epi-neodysiherbaine A, for the biological evaluation.
* Corresponding author. Tel.: +81 22 717 8828; fax: +81 22 717 The synthesis started with C-glycosylation of allylsilane 6with diacetyl-L-arabinal (5).Thus, reaction of 5 0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.093 M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562 Scheme 2. Reagents and conditions: (a) SO CH2Cl2, 0 °C; (b) Ph3P@CHCO2Me, CH2Cl2, rt, 88% (two steps); (c) DIBALH, CH2Cl2, À78 °C, 98%; (d) t-BuOOH, Ti(Oi-Pr)4, (+)-DIPT, ˚ MS, CH2Cl2, À20 °C, 95%; (e) BnNCO, i-Pr2NEt, benzene, 50 °C, 80%; (f) KOt-Bu, THF, À20 ! 0 °C, 61%; (g) NaH, CS2, MeI, THF,0 °C ! rt, 80%; (h) Bu Scheme 1. Reagents and conditions: (a) compound 6, Yb(OTf) (10 mol %), CH2Cl2, rt, 85%; (b) AD mix-b, MeSO2NH2, t-BuOH/H2O, 0 °C ! rt, quant.; (c) TBSOTf, Et3N, DMAP, CH2Cl2, 0 °C, ylcarbamate with KOt-Bu afforded cyclic carbamate 14 87%; (d) K2CO3, MeOH, rt, 92%; (e) m-CPBA, CH2Cl2/pH 7 (61%). Subsequent deoxygenation was carried out phosphate buffer, 0 °C ! rt, then SiO2, 89%; (f) Me2C(OMe)2, CSA, according to the method of Barton and MaCombie CH2Cl2, 0 °C, 85%; (g) H2, Pd/C, hexane, rt, 11a, 60%; 11b, 38%.
to provide 15 in 66% yield for the two steps.
depicted in Oxidation to the acid and subse- quent esterification provided methyl ester overall yield. Desilylation followed by oxidation with effected regioselective dihydroxylation of the exocyclic SO3Æpyr/DMSO afforded an aldehyde, which was approximately 1.6:1 mixture of diastereomers, which the three steps. Selective reduction of the enoate moiety was carried forward without separation through the of diester 17 was achieved by exposure to DIBALH in subsequent transformations. The primary hydroxy THF to yield an allylic alcohol (90%), which upon asym- group of 8 was selectively protected as the tert-butyldi-methylsilyl (TBS) ether to give 9 in 87% yield. Afterremoval of the acetyl group (92%), treatment of the resultant allylic alcohol with m-CPBA led exclusively was subjected to purification by column chromato- graphy on silica gel, epoxide ring-opening by an intra- molecular attack of the tertiary alcohol occurred to 11b: R = CH2OH
generate diol 10 in 89% yield. Protection of the diol as 16: R = CO2Me
the acetonide (85%) followed by removal of the benzyl group under hydrogenolysis afforded alcohols 11a (60%) and 11b (38%), which were readily separable by flash column chromatoThus, the synthesis of the bicyclic ether skeleton was realized in only seven 19: R = CO2Me
Oxidation of the major alcohol 11a with SO3Æpyr/DMSO 15: R = CH2OTBS
followed by Wittig reaction, gave enoate 12 in 88% over-all yield ). DIBALH reduction and Sharpless Scheme 3. Reagents and conditions: (a) TEMPO, NaClO2, cat.
asymmetric epoxidation using (+)-diisopropyl tartrate NaClO, MeCN/pH 7.0 phosphate buffer, 75%; (b) K2CO3, MeI,DMF, rt, 80%; (c) TBAF, THF, rt, 85%; (d) SO (DIPT) delivered epoxy alcohol 13 in 93% yield for the two steps. Stereoselective introduction of the amino 2Cl2, 0 °C; (e) Ph3P@CHCO2Me, CH2Cl2, rt, 60% (two steps); (f) DIBALH, THF, À78 °C, 90%; (g) t-BuOOH, Ti(i-PrO)4, (+)-DIPT, group at the C2 position was carried out following the ˚ MS, À20 °C, 83%; (h) BnNCO, i-Pr2NEt, benzene, 50 °C, procedure of Kishi and co-workersThus, treatment 95%; (i) KOt-Bu, THF, À20 °C, 78%; (j) NaH, CS2, MeI, THF, of 13 with benzyl isocyanate (i-Pr2NEt, benzene, 0 °C ! rt, 80%; (k) Bu3SnH, AIBN, toluene, 110 °C, 75%; (l) LiBH4, 50 °C, 80%) followed by reaction of the resultant benz- THF, 0 ! 60 °C, 74%; (m) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 87%.
M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562 metric epoxidation delivered epoxy alcohol 18 in 83% the C8 and C9 hydroxy groups of 24 should lead to var- yield. Elaboration of 18 to cyclic carbamate 19 was readily accomplished as described above. The resultantester 19 was then converted to 15 by ester reduction The toxicity of dysiherbaine analogue 4 was preliminar- ily tested on mice. Intracerebral injection of 4 againstmice did not induce any behavioral effects such as vio- Cyclic carbamate 15 was subsequently transformed to lent scratching and head bobbing even at higher dose diol 20 by a four-step sequence of protective group manipulations, including reductive debenzylation withlithium tert-butylbiphenylide (LDBB),reprotection In conclusion, we have developed a synthetic route to as the Boc group, ethanolysis of the cyclic carbamate dysiherbaine analogue 4, which features a concise synthe- and desilylation with TBAF (). Oxidation of sis of the bicyclic ether skeleton through stereoselective 20 with KMnO4 (1 M NaOH, H2O) gave a mixture of C-glycosylation to set the C6 stereocenter and 5-exo cycli- diacid 21 and aminal 22, which without separation was zation for constructing the tetrahydrofuran ring. Further further oxidized with catalytic amounts of tetra-n-prop- neurophysiological studies of compound 4 and synthesis ylammonium perruthenate (TPAP) and N-methyl- of other analogues from a key intermediate 23 to probe morpholine N-oxide (NMOand subsequently treated the structure–activity relationship of dysiherbaine are with excess trimethylsilyldiazomethane to deliver di- in progress and will be reported in due course.
methyl ester 23 in 61% yield over the three steps. Finally,global deprotection by acid hydrolysis (6 M HCl, 65 °C)furnished the target compound 4 in 90% yThus, the synthesis of analogue 4 was completed in 23 stepsand 3.4% overall yield from diacetyl- This work was financially supported by Yamada Science 11a. In addition, selective deprotection of the acetonide Foundation and a Grant-in-Aid for Scientific Research on Priority Area ÔCreation of Biologically Functional to give diol 24 in 85% yield.Further modification of MoleculesÕ from the Ministry of Education, Science,Sports, Culture and Technology, Japan.
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Scheme 4. Reagents and conditions: (a) LDBB, THF, À78 °C, 76%; 9. Konosu, T.; Furukawa, Y.; Hata, T.; Oida, S. Chem.
(b) Boc2O, Et3N, DMAP, CH2Cl2, 85%; (c) Cs2CO3, EtOH, rt, 95%; ˚ MS, rt, 94%; (e) KMnO4, aq NaOH, rt; (f) 10. Diacetyl-L-arabinal (5) is readily available in two steps ˚ MS, CH2Cl2, rt; (g) TMSCHN2, MeOH, rt, 61% from L-arabinose Hullomer, F. L. In Methods in Carbo- (three steps); (h) 6 M HCl, 65 °C, 90%; (i) DDQ, CH3CN/H2O, 50 °C, hydrate Chemistry; Academic Press: New York, 1962; Vol.
M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562 11. Takhi, M.; Rahman, A. A.-H. A.; Schmidt, R. R.
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12. The stereochemistry at C4 position of each compound was determined by NOE experiments of the corresponding 17. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
18. Selected data for compound 4: ½aŠ25 À40.0 (c 0.05, H 1H NMR (600 MHz, D2O) d 2.00 (dd, J = 15.6, 10.6 Hz, 1H, 3-H), 2.09 (dd, J = 14.1, 3.8 Hz, 1H, 5-H), 2.53 (dd, J = 15.6, 2.3 Hz, 1H, 3-H); 2.54 (d, J = 14.1 Hz, 1H, 5-H),3.39 (dd, J = 10.6, 10.6 Hz, 1H, 10-H), 3.47 (dd, J = 10.6, 5.0 Hz, 1H, 10-H), 3.61 (dd, J = 10.6, 2.3 Hz, 1H, 2-H), 3.93 (ddd, J = 10.6, 5.0, 3.2 Hz, 1H, 9-H), 4.05 (m, 1H, 7- H), 4.09 (m, 1H, 8-H), 4.13 (m, 1H, 6-H); 13C NMR(125MHz, D 13. Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc.
2O) d 178.57, 174.12, 86.89, 83.97, 74.24, 67.42, 65.11, 64.43, 53.79, 44.31, 39.70; HRMS (FAB) 14. Barton, D. H. R.; MaCombie, S. W. J. Chem. Soc., Perkin 19. Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem.
15. Attempts to remove the benzyl group of compound 19

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Psychopharmacology (2010) 211:245–257DOI 10.1007/s00213-010-1900-1Genetics of caffeine consumption and responses to caffeineAmy Yang & Abraham A. Palmer & Harriet de WitReceived: 25 March 2010 / Accepted: 25 May 2010 / Published online: 9 June 2010associated with risk of myocardial infarction in caffeineRationale Caffeine is widely consumed in foods and bev-erages and is also used

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