Synthetic studies toward lapidilectine-type Kopsia alkaloids.

A rapid synthesis of the tetracyclic core of Kopsia indole alkaloids related to lapidilectine B, grandilodine C, and tenuisine A is reported. Key to the success of this route was an efficient and scalable Ugi four-component coupling to install all the necessary carbons found in the natural products.

Synthesis of the tetracyclic core of the neomangicols using a late-stage indene alkylation.

A general approach to the tetracyclic core of the neomangicol natural products via a late-stage indene alkylation reaction is presented. This strategy sets the stage for access to the neomangicol family and, in addition, provides a potential biogenetically inspired entry to the mangicol natural products.

Surveying ubiquitin structure by noncovalent attachment of distance constrained bis(crown) ethers.

Selective noncovalent adduct protein probing (SNAPP) mass spectrometry was recently developed to study solution-phase conformations of proteins by exploiting the specific affinity between 18-crown-6 ether (18C6) and lysine side chains. To obtain more detailed information about protein tertiary structure, a novel noncovalent cross-linking reagent with two 18C6 molecules bridged by a covalent phenyl linker (called PBC for phenyl bis-crown) was synthesized. PBC introduces a distance constraint into SNAPP experiments where pairs of lysine side chains that are held in proximity by tertiary structure should be the most favored binding sites. Application of this method to ubiquitin reveals that PBC can bind to one lysine in a monodentate fashion or bind to two lysines via a bidentate interaction. Comparison with 18C6 can be used to reveal the mode of binding. For the native state of ubiquitin, bidentate binding of PBC is not observed. The partially denatured A-state, however, contains a single pair of lysines that are both chemically available and spaced by less than approximately 19 A (the maximum distance spanning the crown ether binding sites in PBC). Collision-induced dissociation and site-directed mutagenesis reveal that the bidentate PBC attaches to K29 and K33, which is in agreement with previous structural data on the A-state of ubiquitin. PBC is shown to be an effective probe of protein structure in SNAPP experiments, although assigning the specific residues to which PBC is attached can be experimentally challenging.

Pt-catalyzed tandem epoxide fragmentation/pentannulation of propargylic esters.

A Pt-catalyzed pentannulation of propargylic esters containing an epoxide moiety has been developed. The present transformation achieves the formation of cyclopentenone products as single diastereomers in good yields. The observed products likely form from pyran intermediates that undergo an oxa-6pi electrocyclic ring opening to a functionalized dienone, followed by ring closure with an accompanying acyl shift.