Synthetic strategies for the construction of enantiomeric azanoradamantanes

Becker, Daniel P.; Nosal, Roger; Zabrowski, Daniel L.; Flynn, Daniel L.

doi:10.1016/s0040-4020(96)00973-8

Cited by 14 publications

(16 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously reported a similar trend with compound 6 and its enantiomer, where the 5-HT 4 receptor showed a greater discernment of the antipodes than the 5-HT 3 receptor, although in that case the eutomer was the same compound for both receptors. 41 Functional antagonism of the 5-HT 3 receptor is demonstrated by inhibition of the von Bezold-Jarisch reflex in mice for both 12a and ent-12a (87% at 10 mpk for both compounds).…”

Section: Resultsmentioning

confidence: 98%

“…To indazole-3-carboxylic acid (172 mg, 1.06 mmol) dissolved in DMF (3 mL) was added 1,1'-carbodiimidazole (172 mg, 1.06 mmol) at rt and stirred for 1.5 h after which time alcohol 9 (150 mg, 1.06 mmol) in DMF (0.5 mL) was added and the reaction was stirred Compound 6 was prepared initially by synthesis involving resolution as previously described 41 then via an enantioselective synthesis commencing with an asymmetric DielsAlder reaction. …”

Section: (1s7ar)-hexahydro-1h-pyrrolizin-1-ylmethyl 1h-indazole-3-camentioning

confidence: 99%

See 1 more Smart Citation

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists

et al. 2006

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 98%

Section: (1s7ar)-hexahydro-1h-pyrrolizin-1-ylmethyl 1h-indazole-3-camentioning

confidence: 99%

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists

et al. 2006

Self Cite

View full text Add to dashboard Cite

“…Deprotection of the tosylamide proceeded cleanly with calcium metal in liquid ammonia. Calcium was chosen over lithium, which we employed earlier, 7 because of its safer handling characteristics. Coupling of the derived chiral aminoazanoradamantane 3 with 4-amino-5-chloro-2-methoxybenzoic acid utilizing carbonyldiimidazole (CDI) as the coupling reagent gave the desired benzamide in 70% yield, without the use of the acetamide protecting group that was employed in the earlier synthesis.…”

Section: Methodsmentioning

confidence: 99%

“…Coupling of the derived chiral aminoazanoradamantane 3 with 4-amino-5-chloro-2-methoxybenzoic acid utilizing carbonyldiimidazole (CDI) as the coupling reagent gave the desired benzamide in 70% yield, without the use of the acetamide protecting group that was employed in the earlier synthesis. 7 The product of the coupling was sufficiently pure to use after trituration with a minimum amount of ethyl acetate.The free base was then converted to the crystalline monohydrochloride salt, SC-52491. …”

mentioning

confidence: 99%

Enantioselective synthesis of dual serotonergic azanoradamantane SC-52491

Becker¹,

Husa²,

Moormann³

et al. 1999

Tetrahedron

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…The nitrogen atmosphere was essential as in air they obtained mixtures of the cyclopentanones and the cyclopentenones. This group has used this methodology for the synthesis of azaadamantanes like 209 as part of the structure of certain antagonists (Scheme 59) [182][183][184].…”

Section: Reductive Pkrmentioning

confidence: 99%

Cascade Reactions Involving Pauson—Khand and Related Processes

Pérez‐Castells

2006

ChemInform

View full text Add to dashboard Cite

show abstract

Synthetic strategies for the construction of enantiomeric azanoradamantanes

Abstract: Abstract:The amino azanoradamantane hexahydro-2,5b-methano-1H-3aS,3aa,6aa-cyclopenta-[c]

Cited by 14 publications

References 34 publications

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists

Enantioselective synthesis of dual serotonergic azanoradamantane SC-52491

Cascade Reactions Involving Pauson—Khand and Related Processes

Contact Info

Product

Resources

About

Synthetic strategies for the construction of enantiomeric azanoradamantanes

Abstract: Abstract:The amino azanoradamantane hexahydro-2,5b-methano-1H-3aS,3aa,6aa-cyclopenta-[c]

Cited by 14 publications

References 34 publications

Pyrrolizidine Esters and Amides as 5-HT4 Receptor Agonists and Antagonists

Pyrrolizidine Esters and Amides as 5-HT4 Receptor Agonists and Antagonists

Enantioselective synthesis of dual serotonergic azanoradamantane SC-52491

Cascade Reactions Involving Pauson—Khand and Related Processes

Contact Info

Product

Resources

About

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists

Pyrrolizidine Esters and Amides as 5-HT₄ Receptor Agonists and Antagonists