Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane.

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20-Diisocyanoadociane.

The flagship member of the antiplasmodial isocyanoterpenes, 7,20-diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps, and in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging only productive transformations to deliver DICA in fewer than half the number of steps of our original effort. Important contributions, in addition to the particularly concise strategy, include a solution to the problem of axial nucleophilic methylation of a late-stage cyclohexanone, and the first selective synthesis and antiplasmodial evaluation of the DICA stereoisomer with both isonitriles equatorial.

An Oxetane-Based Polyketide Surrogate To Probe Substrate Binding in a Polyketide Synthase.

Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multidomain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly-ß-ketone substrates. This has hampered structural and mechanistic characterization of PKS-polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereospecificity. As a first step toward a general plan to use oxetanes as carbonyl isosteres to broadly interrogate PKS chemistry, we describe the development and application of an oxetane-based PKS substrate mimic. This enabled the first structural determination of the acyl-enzyme intermediate of a ketosynthase (KS) in complex with an inert extender unit mimic. The crystal structure, in combination with molecular dynamics simulations, led to a proposed mechanism for the unique activity of DpsC, the priming ketosynthase for daunorubicin biosynthesis. The successful application of an oxetane-based polyketide mimic suggests that this novel class of probes could have wide-ranging applications to the greater biosynthetic community interested in the mechanistic enzymology of iterative PKSs.

Hughes and Gleason's Virosaine†A-Appreciating the Art in Synthesis.

The synthesis of the Securinega alkaloid virosaine A by Hughes and Gleason is a perfect example of the intersection of art and chemical synthesis. An ingenious cascade reaction builds most of the polycyclic architecture, but necessitates a challenging C-H functionalization, which is ultimately accomplished by an unusual directed lithiation reaction.

From Substituent Effects to Applications: Enhancing the Optical Response of a Four-Component Assembly for Reporting EE Values.

High-throughput screening for asymmetric catalysts has stimulated an interest in optically-based enantiomeric-excess (ee) sensors, primarily for their improved time and cost efficiency when compared to the standard HPLC analysis. We present herein substituent-effect studies on a recently reported Zn(II) multicomponent assembly that is used for chiral, secondary alcohol ee detemination. The systematic altering of assemblies formed from select substituted pyridyl ligands pointed to the conclusion that steric effects dominate the mode of interaction at the pyridyl 3- and 6- positions. From these results we identified a new Zn(II)-centered multicomponent assembly with a higher dynamic range than previously reported. Calibration curves of the CD signals resulting from the new assembly led to an ee assay with a 1.7% error. To further the utility of the new assembly, a correlation was developed between alcohol substituent size to the respective enantiopure CD value.