ABSTRACT
Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.
Subject(s)
Drug Carriers , Hypnotics and Sedatives/administration & dosage , Organophosphonates/administration & dosage , Propofol/administration & dosage , Administration, Oral , Animals , Dogs , Female , Hypnotics and Sedatives/pharmacokinetics , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred ICR , Propofol/pharmacokinetics , Spectrometry, Mass, Electrospray IonizationABSTRACT
The kinetic resolution of 2-substituted-2,3-dihydro-4-pyridones was realized via a Pd-catalyzed allylic substitution reaction using a commercially available (S)-P-Phos as a ligand, affording optically active dihydropyridones and C-allylated dihydropyridones in high yields and good enantioselectivities with the S-factor up to 43. With this protocol, a catalytic asymmetric total synthesis of indolizidine (-)-209I was realized for the first time.
Subject(s)
Alkaloids/chemical synthesis , Indolizidines/chemical synthesis , Palladium/chemistry , Pyridones/chemistry , Alkaloids/chemistry , Alkylation , Animals , Catalysis , Combinatorial Chemistry Techniques , Indolizidines/chemistry , Kinetics , Molecular Structure , Ranidae , Skin/chemistry , StereoisomerismABSTRACT
α-Carbanions of cyclic and acyclic imines have been successfully applied as nucleophiles in the Pd-catalyzed allylic alkylation reaction. Tuning of chemo- and regioselectivity has been realized by using t-BuOK/THF and LDA/toluene to give branched and linear products, respectively, with high regio- and diastereoselectivities. A plausible mechanism is proposed on the basis of the experimental results and DFT calculations.
Subject(s)
Imines/chemistry , Palladium/chemistry , Alkylation , Catalysis , StereoisomerismABSTRACT
The kinetic resolution of a carbon nucleophile is realized for the first time via Pd-catalyzed asymmetric allylic alkylation with "unstabilized" ketone enolates as the nucleophile, providing both allylated 2,3-disubstituted 2,3-dihydro-4-quinolones and recovered substrates in high yields and high ee (S-factor is 40-145). The application of the methodology in organic synthesis is demonstrated by the ready transformation of an allylated adduct into pyrrolo[3,2-c]quinoline, which features a core structure of biologically active Martinella alkaloids.
