Synthesis of α-Arylated Cycloalkanones from Congested Trisubstituted Spiro-epoxides: Application of the House-Meinwald Rearrangement for Ring Expansion.

A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging cycloheptanones is reported. First, an efficient one-pot synthesis of ß,ß'-disubstituted benzylidene cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available feedstock chemicals is described. Furthermore, an epoxidation followed by the House-Meinwald rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated cycloalkanones upon ring expansion. Reactions catalyzed by bismuth triflate underwent quasi-exclusively ring expansion for all substrates (electronically poor and rich), with yields ranging from 15% to 95%, thus demonstrating the difficulty of achieving ring enlargement for electron-deficient spiro-epoxides. On the other hand, by means of catalysis with aluminum trichloride, the rearrangement of spiro-epoxides proceeded typically in high yields and with remarkable regioselectivity on a broader substrate scope. In this case, a switch of regioselectivity was achieved for spiro-epoxides with electron-withdrawing substituents which enable the method to be successfully extended to some chemospecific arene shifts and the synthesis of aldehydes bearing a α-quaternary carbon. While the HMR has been extensively studied for smaller ring enlargement, we are pleased to report herein that larger cyclohexanones and cycloheptanones can be obtained efficiently from more sterically demanding trisubstituted spiro-epoxides bearing electron-releasing and electron-neutral arene substituents.

Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy.

A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pKa 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 µmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100.