8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide (1, SC-19220) has been previously reported by us and others to be a PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activities. Analogs of SC-19220, in which the acetyl moiety has been replaced with pyridylpropionyl groups and their homologs, have been synthesized as illustrated by compounds 13 and 29. These and other members of this series have been shown to be efficacious analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure activity relationships within this series.

A racemic synthesis of azanoradamantane (± ± ± ±)-3 was accomplished via Yamamoto's MAD-catalyzed Diels-Alder protocol. Subsequently, a scalable asymmetric synthesis of azanoradamantane benzamide SC-52491 was carried out employing Helmchen's asymmetric Diels-Alder methodology to construct all four contiguous asymmetric centers with the correct relative stereochemistry and in 99.3% e.e.Keywords: asymmetric synthesis; Diels-Alder ; serotonin; 5-hydroxytryptamine; 5-HT; azanoradamantane Pharmaceutical companies are advancing an increasing number of enantiomerically pure drugs 1 in order to maximize potency and selectivity, and to eliminate the complications which may arise from the presence of a less active or inactive stereoisomer. The asymmetric Diels-Alder 2 reaction is a powerful synthetic method for the construction of non-racemic pharmacologically active agents.In earlier communications 3 we disclosed a series of azaadamantane and azanoradamantane benzamides, including the potent serotonin 5-HT 4 agonist/5-HT 4 antagonist SC-52491, which has an EC 50 of 51 nM in the 5-HT 4 tunica muscularis mucosae assay 4 and a K i of 1.2 nM at the 5-HT 3 receptor. 5 SC-52491 was chosen for further study of its gastrointestinal prokinetic activity and its antiemetic activity based on its potent 5-HT 4 agonism and its tandem property of potent 5-HT 3 antagonism, respectively, combined with its exceptional selectivity versus other monoamine receptors. 6 It is orally active and exhibits potent prokinetic activity and antiemetic activity in vivo, and compares very favorably with the marketed prokinetic cisapride. SC-52491 is the more active enantiomer with respect to both 5-HT 4 and 5-HT 3 activity, as it is 70X as potent as SC-52490 in the functional 5-HT 4 assay, and it is 3X as potent in its binding to the 5-HT 3 receptor. Scheme 1We envisioned a new approach based on the retrosynthetic analysis shown in Scheme 2, wherein the azanoradamantane 3 would be formed in one step from a tetrasubstituted cyclopentane 4 via a tandem cyclization involving SN 2 displacement of suitable leaving groups (X) by the primary amine. One of the two cyclizations is the same as the efficient cyclization employed in our previous synthetic approach. The tetrasubstituted cyclopentane 4 would then be derived from oxidative cleavage of a rigid norbornene 5, in which the four contiguous asymmetric centers could be easily defined and prepared via an asymmetric Diels-Alder reaction. Scheme 2We first employed Yamamoto's MAD-catalyzed Diels-Alder reaction 9 to prepare norbornene (± ± ± ±)-7(Scheme 3). This approach assembles the four requisite stereocenters in their proper relative orientation, albeit in racemic fashion. We originally hoped to employ an early-stage resolution or to employ a chiral Lewis acid catalyst in the Diels-Alder reaction to obtain the correct absolute configuration of the four stereocenters.Ultimately the Yamamoto approach allowed us to explore various means of installing functionality to provide the bridgehead nitrogen a...

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Reversal of a Michael AdditionReaction.-The Michael addition of nucleophiles of type (II) and (IV) to the furanoside (I) proceeds in a highly stereoselective manner but with different stereochemical outcome compared to the Michael addition of aerofoil-shaped nucleophiles such as (VI) and (VIII). This unexpected reversal of relative asymmetric induction is ascribed to the effect exerted by the wing tip carbonyls of (VI) and (VIII). This effect is termed as stealth stereocontrol. -(BARRETT, A. G. M.; WEIPERT, P. D.; DHANAK, D.; HUSA, R. K.; LEBOLD, S. A.; J. Am. Chem. Soc. 113 (1991) 26, 9820-9824; Dep. Chem., Colo. State Univ., Fort Collins, CO 80523, USA; EN)