Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands.
(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.
Atobe
Masakazu
M
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Yamazaki
Naoki
N
Kibayashi
Chihiro
C
D000588:Amines / Q000138:chemical synthesis*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002118:Calcium / Q000819:agonists; D004987:Ethers / Q000737:chemistry; D008024:Ligands; D008094:Lithium / Q000737:chemistry*; D018716:Molecular Mimicry; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D009942:Organometallic Compounds / Q000737:chemistry*; D010627:Phenethylamines; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011437:Propylamines; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013237:Stereoisomerism
D000588:Amines; D000814:Aniline Compounds; D004987:Ethers; D008024:Ligands; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D064729:Neurokinin-1 Receptor Antagonists; D009942:Organometallic Compounds; D010627:Phenethylamines; D010880:Piperidines; D011437:Propylamines; D043562:Receptors, G-Protein-Coupled; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D008094:Lithium; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine; D002118:Calcium