Asymmetric total synthesis of bioactive cyclic peroxides from the marine sponge Plakortis angulospiculatus: Design and synthesis of orally available cisplatin analogs.

摘要

The total syntheses of two cyclic peroxy esters (methyl [3R,6 R(5E,2R*,4R*)] and [3S,6S(5E,2 R*,4R)]-6-(4-ethyl-2-methyl-5-octenyl)-4,6-diethyl-3,6-dihydro-1,2-dioxin-3-yl-3-acetate) are described. The reported strategy relies on a Diels Alder [4 + 2] singlet oxygen addition to an acyclic triene carboxylic acid precursor for the construction of the 3,6-dihydrodioxin ring. The total synthesis features a flexible synthetic strategy. It involves an asymmetric alkylation process using a chiral alkylating agent to afford the skipped dialkyl substituted fragment, Julia olefination for the construction of the E-double bond, and a carbocuperation. reaction followed by in situ coupling with propionyl chloride in the presence of a catalytic amount of palladium(0) to afford the E conjugated ketone stereoselectively. The beta,delta-diene carboxylic acid moiety was constructed via Honner-Emmons olefination of the conjugated ketone followed by hydroboration of a TMS-protected terminal alkyne. Alternatively, the same beta,delta-diene carboxylic acid moiety was also constructed using Stille coupling. By comparing the spectral data of these synthetic compounds with that of the natural product from the marine sponge Plakortis angulospiculatus, a tentative assignment for the absolute stereochemistry of the natural product as 3S, 6S, 8S, 10R was made.;The synthesis, physical properties, antitumor activity, structure-activity relationship, and neurotoxicity of a series of water-soluble platinum(II) complexes are described. Of all these platinum(II) complexes that have a diamino acid carrier ligand, one was found to exhibit both in vitro and in vivo activity. As carnitine esters, these diamino ligated platinum(II) complexes are freely soluble in water and show low neurotoxicity against normal glial cells. One of them showed excellent in vitro antitumor activity against both normal A2780 and cisplatin-resistant A2780 cell lines. Increasing the lipophilicity of the ligand around the region of the metal was found to be associated with increased cytotoxicity.