Chemical Research (RIKEN) for donation of rutheniumcatalysts. We are also indebted to Professor S. Suzuki of our department for the suggestion for the malonaldehyde assay. We also thank Professor K. Hirao of our University for his helpful guidance in conducting MO calculations.A mechanistic investigation is described for the cycloaddition induced between RNH2+CH2C=CH and RNHz+CH2CHzN3 (R = H, t-Bu) consequent to encapsulation by the polycyclic molecular receptor cucurbituril (C3BH9sNU012). The reaction is shown to be substantially accelerated (ca. lo5-fold), and the kinetic characteristics of catalytic saturation behavior, substrate inhibition, and slow product release are documented. For substrates with R = t-Bu a rotaxane product results, and inhibition kinetics with NH3+CH2CH2C(CH3), are also examined. A rate enhancement attributed to bound-substrate destabilization is detected. The significance of this effect and its connection with the phenomenon of nonproductive binding in catalytic systems are discussed.Understanding enzymic catalysis represents perhaps the most severe challenge of mechanistic organic chemistry. Because of the complexity of proteins, analogues which mimic aspects of biochemical catalysis are desirable. Excellent progress has been made in devising synthetic molecular receptors, and much is being learned about spe-(1). Taken in part from the Ph.D. Thesis of M. Adhya, University of Illinois, Chicago, 1986; Diss. Abstr. Int. B 1986, 47, 1056. 0022-3263/89/1954-5302$01.50/0 0 cificity in molecular recognition from imaginatively engineered models of this naturee2 Even more arduous is (2) Recent reviews: Brealow, R. Adv. Enzymol. Relat. Areas Mol. Biol. 1986, 58, 1. Franke, J.; Vogtle, T. Top. Curr. Chem. 1986, 132, 135. Sutherland, I. 0. Chem. SOC. Rev. 1986, 15, 63. Cram, D. J. Angew,
As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.
Substoichiometric quantities of copper or zinc species dramatically improve both conversion rate and efficiency of Pd(0)-catalyzed cyanation reactions. The optimum reaction conditions involve the use of a nitrile solvent, NaCN, and a catalyst system employing the combination of cuprous iodide with tetrakis(triphenylphosphine)palladium(0), [Pd(PPh3)4]. Beneficial effects were observed for the conversion of aryl halides, aryl triflates, and a vinyl bromide to the corresponding nitriles. The process was demonstrated on preparative scale with a broad range of aromatic and heteroaromatic substrates containing diverse functionality. A dual catalytic cycle is proposed to explain the profound influences of the cocatalyst system.
Syntheses of the potent 5-HT 1A agonists 2 and 3 were accomplished in several steps from the 6-iodo partial ergoline alkaloid 8. Disparate tactics available for construction of differentially substituted oxazoles led to the development of new and general methodology critical to the efficient preparations of 2 and 3. A novel palladium(0)-and copper(I)-cocatalyzed cyanation reaction provided efficient access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(0)-catalyzed crosscoupling reaction of 16 with oxazol-2-ylzinc chloride formed the potent 5-HT 1A agonist 3.When appropriately substituted at the 6-position, the partial ergolines 1 are potent serotonin agonists at the 5-HT 1A receptor. Among the earliest examples of these agents are the 6-methoxy compound 1a and the 6-carboxamido compound 1b. 1 Later, 6-acyl derivatives such as 1c were also found to have powerful serotonergic activity. Extensive pharmacological studies on both 1b and 1c have been conducted. 2 More recently, derivatives containing various heterocyclic functionalities at the 6-position were identified which exhibit strong serotonergic activity. 3 Connection of an oxazole either through its 5 or 2 position to the partial ergot alkaloid framework led to compounds 2 and 3, both of which exhibit particularly interesting 5-HT 1A agonist activity.The clinical potential of the oxazolyl ergoline derivatives prompted our investigation into the development of efficient preparation of the two drug candidates, 2 and 3. Substituted tricyclic partial ergolines 1 have been prepared from the Kornfeld-Woodward ketone 4 (eq 1). 2a,4 Lilly workers have recently reported an enantiospecific synthesis of 5, a key indoline precursor to optically pure 1b. 4a,b With access to 5 thus provided, our efforts focused on the selective functionalization of this advanced intermediate. The development of new methodology proved critical to the efficient preparations of 2 and 3. Most notably, we were challenged with adapting key palladium(0)-catalyzed coupling processes to ensure safe and reproducible production of the desired targets.The strategies required to produce the structurally similar candidates 2 and 3 were governed by the disparate methodologies available for construction of the two oxazoles. 5 5-Aryl oxazoles may be prepared by the condensation of an aryl aldehyde with tosylmethyl isocyanide (TosMIC) (eq 2). 6 This reaction was expected to serve as a key step in the synthesis of 2; however, this methodology does not accommodate the preparation of 2-substituted oxazoles such as 3. Preliminary experiments indicated that related cyclodehydration strategies would also be ineffective for the synthesis of 3 (eq 3). 7 The convergent cross-coupling approach detailed herein was therefore pursued (eq 4). Despite these strategic differences, a parallel development of 2 and 3 demanded
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