Synthesis of C14-Desmethylene Corialactone D and Discovery of Inhibitors of Nerve Growth Factor Mediated Neurite Outgrowth.

An asymmetric synthesis of C14-desmethylene corialactone D is described on the basis of strategic application of a metallacycle-mediated annulative cross-coupling reaction, a Still [2,3]-Wittig rearrangement, and Morken's hydroxyl-directed diboration reaction. While representing a convenient approach to access novel compositions of matter inspired by the sesquiterpenoid natural product class (including classic natural product synthesis targets including the picrotaxanes and dendrobine), these studies have led to the discovery of natural product-inspired agents that inhibit nerve growth factor (NGF)-mediated neurite outgrowth in PC-12 cells.

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.

Carbohydrate/DBU Cocatalyzed Alkene Diboration: Mechanistic Insight Provides Enhanced Catalytic Efficiency and Substrate Scope.

A mechanistic investigation of the carbohydrate/DBU cocatalyzed enantioselective diboration of alkenes is presented. These studies provide an understanding of the origin of stereoselectivity and also reveal a strategy for enhancing reactivity and broadening the substrate scope.

Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems.

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with ß- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.