Dearomatizing anionic cyclization of N-alkyl-N-benzyl(dinaphthyl)phosphinamides. A facile route to gamma-(amino)dihydronaphthalenylphosphinic acids.
The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(n-naphthyl)phosphinamides (n = 1, 2) and subsequent trapping with a series of electrophiles (MeOH, MeI, CF3SO3Me, Me3O+BF4-, AllylBr, and PhCH2Br) have been accomplished. Optimized reaction conditions (base, temperature, reaction time) allow for synthesizing tetrahydro-1H-naphtho[1,2-c][1,2]-azaphosphole 1-oxides 13 and 18 and tetrahydro-1H-naphtho[2,1-c][1,2]azaphosphole 3-oxides 16 and 27-29 in high yield and diastereoselectivity. Appropriate selection of the base proved to be critical for promoting anionic cyclization of 2-naphthyl derivatives. The dearomatized heterocycles are transformed quantitatively into gamma-(N-alkylamino)phosphinic acids by acid hydrolysis of the P-N linkage. Bioactivity assays on five human tumor cell lines for one of these amino acids revealed growth inhibition factors (GI50) at a micromolar scale. Additionally, evidence for the feasibility of intermolecular nucleophilic dearomatization and sequential nucleophilic attack to both aromatic rings of dinaphthylphosphinamides have been obtained.
Ruiz-Gómez
Gloria
G
Area de Química Orgánica, Universidad de Almería, Carretera de Sacramento, 04120 Almería, Spain.
Iglesias
María José
MJ
Serrano-Ruiz
Manuel
M
López-Ortiz
Fernando
F
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000577:Amides; D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids