Synthesis of carbohydrate analogues of the THF-acetogenin 4-deoxyannomontacin and their cytotoxicity against human prostate cancer cell lines.

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis. The different analogues showed cytotoxicity in the low micromolar to nanomolar range against the human prostate cancer cell lines LNCaP and PC3. A relatively simple mannose-linked thiophene analog was found to be similar in activity to 4-DAN.

Diastereoselective Substitution Reactions of Acyclic ß-Alkoxy Acetals via Electrostatically Stabilized Oxocarbenium Ion Intermediates.

Substitution reactions of acyclic ß-alkoxy acetals proceeded with generally high diastereoselectivities (>90:10) to form the anti product. Mechanistic experiments supplemented with computational studies suggest that, upon activation of the acetal, the resulting oxocarbenium ion is electrostatically stabilized by the ß-alkoxy group. This stabilization defines the conformation of the reactive intermediate, which can be attacked preferentially from the more exposed face, leading to the observed products.

Using Neighboring-Group Participation for Acyclic Stereocontrol in Diastereoselective Substitution Reactions of Acetals.

Neighboring-group participation of an ester enabled stereocontrol in substitution reactions of acyclic acetals. The ester group formed a trans-fused dioxolenium ion intermediate, which underwent a substitution reaction at the acetal carbon atom to afford the product with high diastereoselectivity. Neighboring-group participation was confirmed by isolating dioxolane products resulting from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.