Abstract:A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S, 9S)-9-alkyl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described. These compounds were designed to gain additional information on the structure-sigma binding relationship of the 6,7-benzomorphan class of sigma ligands. In contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-isomers of 2a-c showed greater affinity for the sigma(1) receptor than the (1S, 5S,9S)-isomers. Despite reversal of enantioselectivi… Show more
“…46,47 (+)-Pentazocine (Chart 1), a classical σ 1 receptor ligand of such a class, and related (+)-(1S,5S,9S)-compounds display higher σ 1 receptor affinity and selectivity relative to σ 2 receptor subtype than their corresponding (-)-(1R,5R,9R)-isomers. 48,49 Therefore, in pursuing our search for selective σ-subtype ligands we prepared the compound 15 and its homologue 12 along with some chiral related isomers (compounds 13, 14, 16-18, Table 1), to evaluate the influence exerted by the presence of a stereogenic center near the pharmacophoric nitrogen atom on the selective binding at σ 1 site. The chiral center was originated by inserting a methyl group in any position of the intermediate chain.…”
Section: Introductionmentioning
confidence: 99%
“…The stereochemistry appears to regulate mainly σ ligands selectivity. For example, (+)- N -substituted N -normetazocines preferentially bind σ receptors whereas their (−)-enantiomers bind opioid receptors. , (+)-Pentazocine (Chart ), a classical σ 1 receptor ligand of such a class, and related (+)-(1 S ,5 S ,9 S )-compounds display higher σ 1 receptor affinity and selectivity relative to σ 2 receptor subtype than their corresponding (−)-(1 R ,5 R ,9 R )-isomers. , 1 …”
Sumitomo's patented sigma ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at sigma1, sigma2, and sterol Delta8-Delta7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective sigma(1) binding relative to other sigma family sites. Generally high sigma1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase sigma1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((-)-(S)-17) reached the highest sigma1 affinity (K(i) = 0.34 nM) and the best selectivity relative to the sigma2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
“…46,47 (+)-Pentazocine (Chart 1), a classical σ 1 receptor ligand of such a class, and related (+)-(1S,5S,9S)-compounds display higher σ 1 receptor affinity and selectivity relative to σ 2 receptor subtype than their corresponding (-)-(1R,5R,9R)-isomers. 48,49 Therefore, in pursuing our search for selective σ-subtype ligands we prepared the compound 15 and its homologue 12 along with some chiral related isomers (compounds 13, 14, 16-18, Table 1), to evaluate the influence exerted by the presence of a stereogenic center near the pharmacophoric nitrogen atom on the selective binding at σ 1 site. The chiral center was originated by inserting a methyl group in any position of the intermediate chain.…”
Section: Introductionmentioning
confidence: 99%
“…The stereochemistry appears to regulate mainly σ ligands selectivity. For example, (+)- N -substituted N -normetazocines preferentially bind σ receptors whereas their (−)-enantiomers bind opioid receptors. , (+)-Pentazocine (Chart ), a classical σ 1 receptor ligand of such a class, and related (+)-(1 S ,5 S ,9 S )-compounds display higher σ 1 receptor affinity and selectivity relative to σ 2 receptor subtype than their corresponding (−)-(1 R ,5 R ,9 R )-isomers. , 1 …”
Sumitomo's patented sigma ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at sigma1, sigma2, and sterol Delta8-Delta7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective sigma(1) binding relative to other sigma family sites. Generally high sigma1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase sigma1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((-)-(S)-17) reached the highest sigma1 affinity (K(i) = 0.34 nM) and the best selectivity relative to the sigma2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
“…We recently described a new asymmetric synthesis of opium alkaloids ( 1 and 2 ) involving a novel base-promoted intramolecular hydroamination which requires tungsten light irradiation. This reaction forges the key piperidine ring of this family of alkaloids, which previously were cyclized using stoichiometric mercury salts or via the chromium tricarbonyl complex from free amine. The benzomorphans served as an ideal target to gain better understanding of the key cyclization reaction and assess the possibility of establishing the rather challenging benzylic quaternary carbon center through palladium-catalyzed asymmetric allylic alkylation (AAA) of a prochiral ketone .…”
We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.
“…The required reduction step was carried out with lithium aluminum hydride providing cleaner methylene-producing reactions (Scheme 11). 32 The same hydroamination protocol based on an oxymercuriation followed by a reductive . H g ( T F A ) 2 v i .…”
Section: Scheme 10 Aminohydroxylation From a Tethered Azido Alkenementioning
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