RESUMO
The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed. The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-Diels-Alder reaction creating two new chiral centers in a highly diastereoselective manner. The other key features of this synthesis included Brown's asymmetric allylation to install the requisite C-11 and C-13 stereocenters. The synthesis of the oxazole side chain consisted of a hydrozirconation of an alkynyl stannane to establish the Z stereochemistry, followed by a palladium catalyzed cross coupling to introduce the desired Z olefin in the oxazole side chain.
Assuntos
Macrolídeos/síntese química , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide.
Assuntos
Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Linhagem Celular Tumoral , Depsipeptídeos/química , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , EstereoisomerismoRESUMO
The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described.
RESUMO
Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a number of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens.