General Enantioselective and Stereochemically Divergent Four-Stage Approach to Fused Tetracyclic Terpenoid Systems.

Tetracyclic terpenoid-derived natural products are a broad class of medically relevant agents that include well-known steroid hormones and related structures, as well as more synthetically challenging congeners such as limonoids, cardenolides, lanostanes, and cucurbitanes, among others. These structurally related compound classes present synthetically disparate challenges based, in part, on the position and stereochemistry of the numerous quaternary carbon centers that are common to their tetracyclic skeletons. While de novo syntheses of such targets have been a topic of great interest for over 50 years, semisynthesis is often how synthetic variants of these natural products are explored as biologically relevant materials and how such agents are further matured as therapeutics. Here, focus was directed at establishing an efficient, stereoselective, and molecularly flexible de novo synthetic approach that could offer what semisynthetic approaches do not. In short, a unified strategy to access common molecular features of these natural product families is described that proceeds in four stages: (1) conversion of epichlorohydrin to stereodefined enynes, (2) metallacycle-mediated annulative cross-coupling to generate highly substituted hydrindanes, (3) tetracycle formation by stereoselective forging of the C9-C10 bond, and (4) group-selective oxidative rearrangement that repositions a quaternary center from C9 to C10. These studies have defined the structural features required for highly stereoselective C9-C10 bond formation and document the generality of this four-stage synthetic strategy to access a range of unique stereodefined systems, many of which bear stereochemistry/substitution/functionality not readily accessible from semisynthesis.

Toward the Asymmetric Synthesis of Cardenolides and Related Steroidal Systems: syn-SN2' of Organometallics with C14-C17 Vinylepoxides.

In a program aimed at establishing a common sequence of C-C bond-forming reactions for asymmetric construction of tetracyclic triterpenoid natural products and related synthetic systems, effort has been directed toward introducing C17ß-substitution by late-stage functionalization of stereodefined "steroidal" D-ring vinylepoxides (spanning C14-C17). It has been found that cyanocuprates participate in syn-SN2' reactions that result in products bearing various C17ß-substituents and containing a ß-OH at C14.

From Metallacycle-Mediated Annulative Cross-Coupling to Steroidal Tetracycles through Intramolecular C9-C10 Bond Formation.

While semisynthesis is a common platform for medicinal investigation of steroidal systems, varying the nature of substitution and stereochemistry at C9 and C10 remains challenging. It is demonstrated here that de novo synthesis, enabled by a metallacycle-centered annulation reaction, provides a uniquely effective means of addressing this problem. In short, double asymmetric Friedel-Crafts cyclization proved most effective for establishing anti- relative stereochemistry (with respect to C13), while an intramolecular Heck reaction reliably delivered the syn- diastereomers with high selectivity. In addition, these studies reveal that this oxidative rearrangement is effective for establishing a C10 quaternary center boasting variable alkyl or aryl substitution.

A Complementary Process to Pauson-Khand-Type Annulation Reactions for the Construction of Fully Substituted Cyclopentenones.

A complementary process to the Pauson-Khand annulation is described that is well suited to forging densely substituted/oxygenated cyclopentenone products (including fully substituted variants). The reaction is thought to proceed through a sequence of metallacycle-mediated bond-forming events that engages an internal alkyne and a ß-keto ester in an annulation process that forges two C-C bonds. A variant of this annulation process has also been established that delivers deoxygenated cyclopentenones that lack the allylic tertiary alcohol.