Synthesis and Investigation of Novel Spiro-isoxazolines as Anti-Cancer Agents.

A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 value ranging from 43µM to 56µM.

Oxonium Ion Mediated Synthesis of 4-Substituted Spiro-Isoxazolines.

The stereoselective synthesis of 4-bromo-spiro-isoxazolines was achieved in one step through the bromination of various isoxazoles that contain a pendant alcohol or carboxylic acid functional group. Isoxazole bromination leads to a bromonium ion intermediate which opens either by neighboring oxygen lone pair electrons or by intramolecular nucleophilic attack. Single X-ray crystal data provides evidence that the two contiguous stereocenters of the spiro-isoxazoline are formed by the anti intramolecular attack of the nucleophile relative to bromine since there is an anti stereochemical relationship between the spirocyclic ring oxygen and the bromine atom.

A Concise Synthesis of R-(-)-Cicutoxin, a Natural 17-Carbon Polyenyne.

A concise synthesis of the natural polyenyne R-(-)-cicutoxin (1) is described. After several trials, the successful synthesis commenced with three key fragments, R-(-)-1-hexyn-3-ol (8), 1,4-diiodo-1,3-butadiene (9), and the THP protected 4,6-heptadiyn-1-ol (6). Sonogashira coupling of compound 9 with acetylenes 6 and 8 gave the 17-carbon frame, which upon regio-selective reduction of a triple bond with red Al and removal of the THP protecting group afforded the natural product in four linear steps. The triply convergent synthesis gave R-(-)-cicutoxin in 18% overall yield.

Total synthesis of (+)- and (-)-duryne: a potent anticancer agent from the marine sponge Cribrochalina dura. Establishment of the central double bond geometry and the absolute configuration of the chiral centers.

Duryne is a C30 polyacetylenic alcohol with C2 symmetry. Despite its potent cytotoxicity, its central double bond geometry and the absolute configuration of the chiral centers were not determined. We report the total syntheses of both enantiomers of the anticancer natural product (+)-duryne and the establishment of its stereochemistry by synthesizing both geometric isomers. The natural (+)-duryne is identified as (15Z) and (3S,28S) as shown in structure 1. The autoxidation/Wittig coupling reaction was employed to synthesize the central (Z)-olefin. The stereochemistry of the (E)-alkene isomer was constructed stereoselectively by using LiAlH4 reduction of the corresponding alkyne. The absolute configurations of the chiral centers are established by using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase.

First Total Synthesis of the Potent Anticancer Natural Product Dideoxypetrosynol A: Preparation of the "Skipped" (Z)-Enediyne Moiety by Oxidative Coupling of Homopropargyl Phosphonium Ylide.

Dideoxypetrosynol A is a C30 polyacetylenic alcohol with C2 symmetry. The first total synthesis of both enantiomers of the potent anti-cancer natural product (+)- and (-)-dideoxypetrosynol A is reported. The key step is an oxidative coupling of a homopropargyl phosphonium ylide to prepare the "skipped" (Z)-enediyne moiety. The natural dideoxypetrosynol A was isolated as a racemic mixture as shown in structure 1. The absolute configurations of the chiral centers are established for the (+)- and (-)-enantiomers using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase.