Enantioselective synthesis of dual serotonergic azanoradamantane SC-52491

Abstract

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...

Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions

“…Chiral diester ent-25 also effectively opens a catalytic enantioselective route to the dual 5-HT 4 /5-HT 3 serotonergic agonist/antagonist SC-52491 (Scheme 11). 24 Diels−Alder Adducts of Furans as Key Synthetic Intermediates. The (4+2)-cycloaddition reactions of furans and various dienophiles have hardly been exploited in the synthetic literature, despite the fact that such processes generate a new six-membered ring which is functionalized at all six carbons and offers useful handles for derivatization.…”

Purification and biochemical characterisation of a novel glutamate decarboxylase from rice bran

“…Die Synthese von SC‐52491 ( 254 ), einem wirksamen Serotonin‐5‐HT 4 /5‐HT 3 ‐Antagonisten bei Magen‐Darm‐Erkrankungen, ist ein weiteres Anwendungsbeispiel für eine diastereoselektive DA‐Reaktion in größerem Maßstab. Die Synthese des Wirkstoffs erfolgte ursprünglich bei Pfizer (ehemals Searle)158 unter Verwendung von Cyclopentadien und tert ‐Butylmethylfumarat ( 251 ) in CH 2 Cl 2 in Gegenwart eines MAD‐Katalysators von Yamamoto et al 159. und führte zur Bildung der racemischen Monosäure 252 .…”

“…unter Verwendung von Fumarsäurediethyl‐( S )‐lactat ( 255 ) als chirales Dienophil in Betracht gezogen (Schema ). In der Größenordnung von 300 g wurde unter Verwendung von Et 3 N als Ersatz für toxisches Tetrachlormethan das DA‐Addukt 256 durch 18 h Rühren bei 20 °C mit hoher Diastereoselektivität und einem endo / exo ‐Verhältnis von 92.8 zu 7.2 gebildet 158. Nach Verseifung und Iodlactonisierung wurde die entsprechende kristalline Säure 257 in 63 % Ausbeute (über drei Stufen) mit ausgezeichneter Enantiomerenreinheit (>99 % ee , HPLC) nach Rekristallisation erhalten.…”

Determination of Sudan IV in hot chilli powder with luminol/dissolved oxygen chemiluminescence system

“…The synthesis of SC‐52491 ( 254 ) as a potent serotonin 5‐HT 4 /5‐HT 3 antagonist for gastrointestinal diseases is another illustration of a diastereoselective DA reaction applied on a large scale. It was originally synthesized at Pfizer (formerly Searle)158 by using cyclopentadiene and tert ‐butyl methyl fumarate ( 251 ) in CH 2 Cl 2 and in the presence of Yamamoto’s MAD catalyst159 to produce the racemic mono acid 252 . Even though the yield (95 %) and the endo / exo selectivity (98:2) were high, this process required the racemate to be separated later in the synthesis (Scheme ).…”

“…using fumaric acid diethyl ( S )‐lactate ( 255 ) as the chiral dienophile was considered (Scheme ). On a 300 g reaction, with Et 3 N used as a substitute for the toxic carbon tetrachloride, the DA adduct ( 256 ) was produced with high diastereoselectivity and an endo / exo ratio of 92.8:7.2 after 18 h stirring at 20 °C 158. After saponification and iodolactonization, the corresponding crystalline acid 257 was obtained in 63 % yield (over three steps) and excellent optical purity (>99 % ee , HPLC) after recrystallization.…”