Stereocontrolled Synthesis and Structural Revision of Plebeianiol A.

We report the structural revision via synthesis of the abietane diterpenoid plebeianiol A. The synthesis was accomplished by a short and convergent sequence that featured our previously established cobalt-catalyzed hydrogen-atom-transfer-induced radical bicyclization. We further connected plebeianiol A as the likely biogenetic precursor to another previously reported ether-bridged abietane. Finally, we demonstrated that the key cyclization event is efficient with the A-ring diol protected as two different cyclic acetals or in unprotected form.

Stereocontrolled Radical Bicyclizations of Oxygenated Precursors Enable Short Syntheses of Oxidized Abietane Diterpenoids.

The power of cation-initiated cyclizations of polyenes for the synthesis of polycyclic terpenoids cannot be overstated. However, a major limitation is the intolerance of many relevant reaction conditions toward the inclusion in the substrate of polar functionality, particularly in unprotected form. Radical polycyclizations are important alternatives to bioinspired cationic variants, in part owing to the range of possible initiation strategies, and in part for the functional group tolerance of radical reactions. In this article, we demonstrate that Co-catalyzed MHAT-initiated radical bicyclizations are not only tolerant of oxidation at virtually every position in the substrate, oftentimes in unprotected form, but these functional groups can also contribute to high levels of stereochemical control in these complexity-generating transformations. Specifically, we show the effects of protected or unprotected hydroxy groups at six different positions and their impact on stereoselectivity. Further, we show how multiply oxidized substrates perform in these reactions, and finally, we document the utility of these reactions in the synthesis of three aromatic abietane diterpenoids.

Cobalt-Catalyzed Hydrogen-Atom Transfer Induces Bicyclizations that Tolerate Electron-Rich and Electron-Deficient Intermediate Alkenes.

A novel CoII -catalyzed polyene cyclization was developed that is uniquely effective when performed in hexafluoroisopropanol as the solvent. The process is presumably initiated by metal-catalyzed hydrogen-atom transfer (MHAT) to 1,1-disubstituted or monosubstituted alkenes, and the reaction is remarkable for its tolerance of internal alkenes bearing either electron-rich methyl or electron-deficient nitrile substituents. Electron-rich aromatic terminators are required in both cases. Terpenoid scaffolds with different substitution patterns are obtained with excellent diastereoselectivities, and the bioactive C20-oxidized abietane diterpenoid carnosaldehyde was made to showcase the utility of the nitrile-bearing products. Also provided are the results of several mechanistic experiments that suggest the process features an MHAT-induced radical bicyclization with late-stage oxidation to regenerate the aromatic terminator.

Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1.

Three new isocyanoditerpenes (5-7) have been characterized from Australian specimens of the nudibranch Phyllidiella pustulosa. The planar structure and (3R,6S,7R) absolute configuration of pustulosaisonitrile-1 were deduced by spectroscopic analyses at 900 MHz informed by molecular modeling, DFT calculations, and computational NMR chemical shift predictions and by comparison of experimental electronic circular dichroism (ECD) data with TDDFT-ECD calculations for the truncated model compound 8. A catalyst-controlled enantio- and diastereoselective total synthesis of the two most likely diastereomeric candidates for the structure of 5 solidified its (3R,6S,7R,10S,11R,14R) absolute configuration. Three individual enantioselective methods provided stereochemical control at key positions, permitting an unambiguous final structural assignment. Isocyanide 5 and synthetic diastereomers 5a and 5c showed activity against Plasmodium falciparum malaria parasites (IC50 ∼1 µM).