Programmed Polyene Cyclization Enabled by Chromophore Disruption.

A new polyene cyclization strategy exploiting ß-ionyl derivatives was developed. Photoinduced deconjugation of the extended π-system within these chromophores unveils a contrathermodynamic polyene that engages in a Heck bicyclization to afford [4.4.1]-propellanes. This cascade improves upon the limited regioselectivity achieved using existing biomimetic tactics and tolerates both electron-rich and electron-deficient (hetero)aryl groups. The utility of this approach was demonstrated with the diverted total synthesis of taxodione and salviasperanol, two isomeric abietane diterpenes that were previously inaccessible along the same synthetic pathway.

Site-Specific Alkene Hydromethylation via Protonolysis of Titanacyclobutanes.

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2 Ti(µ-Cl)(µ-CH2 )AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo-, regio-, and site-selective manner. The broad utility of this method is demonstrated across a series of mono- and di-substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.

Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light-Triggered Selective Toxicity Toward Cancer Cells.

Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)2Ru(PL)]2+ were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1A: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2A: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4A: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5A: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pKa values for conversion from the acidic form (XA) to the basic form (XB) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2A, 2B, 3A, 4B, and 5A. All complexes except 5A showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1A-4A and their deprotonated analogues (1B-4B), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)2Ru(H2O)2]2+. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1A-5A showed that complex 3A is the most cytotoxic complex of this series with IC50 values as low as 4 µM (with blue light) versus two breast cancer cell lines. Complex 3A is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3A were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3A and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1A, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells.

A Stereoselective Photoinduced Cycloisomerization Inspired by Ophiobolin A.

A stereoselective synthetic entry point to the 5-8-5 carbocyclic core of the ophiobolins was developed. This strategy exploits the chiral tertiary alcohol of ophiobolin A to guide assmebly of the 5-8-5 scaffold in a single step via a photoinitiated cycloisomerization. Mechanistic insights into the origin of stereocontrol in this reaction are described, as are efforts to elaborate the resultant fused 5-8-5 ring system to the pharmacophore of ophiobolin A.

Modular access to functionalized 5-8-5 fused ring systems via a photoinduced cycloisomerization reaction.

A 5-8-5 carbocyclic ring system forms the core of over 30 distinct natural products. Several members of this family have gained attention for their diverse activity in cell culture. In these cases, biological function is mediated by the arrangement of substituents around a conserved 5-8-5 nucleus. Despite the potential applications of this privileged substructure in medicinal chemistry, modular strategies for its assembly are underdeveloped. Herein, we describe a cycloisomerization reaction that forms the 5-8-5 framework directly. This strategy uniquely allows access to gram quantities of this valuable scaffold in four steps.