Toward the Asymmetric de Novo Synthesis of Lanostanes: Construction of 7,11-Dideoxy-Δ5-lucidadone H.

Efforts to establish an asymmetric entry to hexanorlanostanes has resulted in a concise synthesis of 7,11-dideoxy-Δ5-lucidadone H from epichlorohydrin. By exploiting metallacycle-mediated annulative cross-coupling (to establish a functionalized hydrindane) and stereoselective formation of the steroidal C9-C10 bond to establish a stereodefined 9-alkyl estrane, 14 subsequent steps have been established to generate a hexanorlanostane system. Key transformations include formal inversion of the C13 quaternary center, oxidative dearomatization/group-selective Wagner-Meerwein rearrangement, and Lewis acid mediated semi-Pinacol rearrangement.

Progress toward the De Novo Asymmetric Synthesis of Euphanes.

Progress toward an asymmetric synthesis of euphanes is described. A C14-desmethyl euphane system possessing five differentially substituted and electronically distinct alkenes has been prepared. The route employed is based on sequential metallacycle-mediated annulative cross-coupling, double asymmetric Brønsted acid mediated intramolecular Friedel-Crafts alkylation, and an oxidative rearrangement to establish the requisite C10 quaternary center. These studies have also led to the discovery of a novel euphane-based modulator of the Liver X Receptor.

Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol.

A metallacycle-centered approach to the assembly of partially aromatic synthetic steroids was investigated as a means to prepare a boutique collection of unique steroidal agents. The synthesis and discovery of estra-1,3,5(10),6,8-pentaene-2,16α-diol (VII) is described, along with structure-activity relationships related to its cytotoxic properties. Overall, VII was found to have a GI50 = 0.2 µg/mL (∼800 nM) in MDA-MB-231 human breast cancer cells, be an efficacious estrogen receptor agonist with potency for ERß > ERα (ERß EC50 = 21 nM), possess selective affinity to the cdc-2-like kinase CLK4 (Kd = 350 nM), and be phenotypically related to paclitaxel by an unbiased panel assessment.