Design, Synthesis, and Physicochemical Studies of Configurationally Stable ß-Carboline Atropisomers.

Axially chiral atropisomers have energetic barriers to rotation, ΔGrot, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-ß-carbolines with varying ΔGrot, from which a strong structure-activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, 1d and 1f, by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental ΔGrot values of 39.5 and 33.0 kcal/mol for 1d and 1f, respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV-vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.

Metal-Catalyzed Cyclotrimerization Reactions of Cyanamides: Synthesis of 2-Aryl-α-carbolines.

The synthesis of annulated 2-aryl-α-carboline heterocycles is described using transition metal catalysis. A linear strategy is described that uses Rh(I) catalysis to form the α-carboline scaffold by [2+2+2] cyclotrimerization. Alternatively, a tandem catalytic approach using a Pd(II) precatalyst afforded the same target molecules by mediating a Sonogashira reaction and a [2+2+2] cyclotrimerization in the same reaction flask. In each case, nine different 2-aryl-α-carbolines have been prepared in high to modest isolated yields.

Parallel Strategies for the Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)- and Pd(0)-Catalyzed Cyclotrimerization.

Two different pathways for the synthesis of annulated pyrido[3,4-b]indoles are reported using metal-catalyzed cyclotrimerization reactions. A stepwise process using Rh(I)-catalysis in the final step of the synthesis and a multicomponent, tandem catalytic approach using Pd(0)-catalysis both lead to complex nitrogen-containing heterocycles in good yields. Substituent effects are investigated for both pathways, demonstrating that the Pd(0)-catalyzed approach is more sensitive to electron- withdrawing groups.

DNA-binding studies of the natural ß-carboline eudistomin U.

Eudistomin U is a member of the ß-carboline class of heterocyclic amine-containing molecules that are capable of binding to DNA. The structure of eudistomin U is unique since it contains an indole ring at the 1-position of the pyridine ring. While simple ß-carbolines are reported to intercalate DNA, an examination of the mode of binding of eudistomin U has been lacking. We report preliminary spectroscopic (UV-Vis, thermal denaturation, CD) and calorimetric (DSC) data on the binding of eudistomin U to DNA, which suggest that eudistomin U binds weakly according to a mechanism that is more complicated than other members of its class.

Concise Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)-Catalyzed Cyclization.

The synthesis of pyridines bearing multiple ring fusions poses a considerable challenge for organic chemists. To address this problem, we describe the synthesis of a small library of pyrido[3,4-b]indoles via an efficient, five-step sequence. The key transformation is a Rh(I)-catalyzed [2 + 2 + 2] cyclization that forms three rings in one reaction flask. Our method is high yielding, accommodates a variety of functional groups, and suffers no entropic costs as ring size increases.

Efficient synthesis of eudistomin U and evaluation of its cytotoxicity.

Eudistomin U is a member of a subclass of naturally occurring indole alkaloids known as ß-carbolines. These molecules are reported to have diverse biological activity and high binding affinity to DNA, which make them attractive targets for total synthesis. We describe an efficient, five-step synthesis of eudistomin U by employing two key reactions: a Bischler-Napieralski cyclization and a Suzuki cross coupling. We also describe the cytotoxicity of eudistomin U against various cancer cell lines and human pathogens, in which we observed potent antibacterial activity against Gram-positive bacteria.

Three-step synthesis of an annulated ß-carboline via palladium catalysis.

The synthesis of ß-carbolines is a mature field, yet new methods are desirable to introduce new functionality onto the core scaffold. We describe the incorporation of an additional fused ring onto the ß-carboline via a novel palladium-catalyzed, one-pot Sonogashira coupling/intramolecular [2+2+2] cyclization. This method generates three rings in one flask and produces an annulated ß-carboline in 80% yield. A preliminary mechanistic study into the sequence of events is described, which confirms an unprecedented catalytic role for palladium.

Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry.

A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu(2)bpy)(2)(phox)]PF(6) (complex 1), with tBu(2)bpy = 4,4'-di-tert-buty-2,2'-bipyridine and Hphox = 2-(2'-hydroxyphenyl)oxazoline, displaying an LC(50) value in HeLa cells of 1.3 microM and 0.3 microM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.

Chiral salicyloxazolines as auxiliaries for the asymmetric synthesis of ruthenium polypyridyl complexes.

Chiral auxiliaries are promising emerging tools for the asymmetric synthesis of octahedral metal complexes. We recently introduced chiral salicyloxazolines as coordinating bidentate chiral ligands which provide excellent control over the metal-centered configuration in the course of ligand substitution reactions and can be removed afterward in an acid-induced fashion under complete retention of configuration (J. Am. Chem. Soc. 2009, 131, 9602-9603). Here reported is our detailed investigation of this sequence of reactions, affording virtually enantiopure ruthenium polypyridyl complexes. The control of the metal-centered chirality by the coordinated chiral salicyloxazolinate ligand was evaluated as a function of reaction conditions, the employed bidentate 2,2'-bipyridine and 1,10-phenanthroline ligands, and the substituent at the asymmetric 5-position of the oxazoline heterocycle. Most striking was the strong influence of the reaction solvent, with aprotic solvents of lower polarity providing the most favorable diastereoselectivities. Through a combination of computational and experimental results, it was revealed that the observed stereoselectivities are under thermodynamic control. The removal of the chiral salicyloxazoline auxiliary under retention of the configuration requires acidic conditions and a coordinating solvent such as MeCN or THF in order to prevent partial racemization. This method represents the first general strategy for the asymmetric synthesis of enantiopure heteroleptic ruthenium polypyridyl complexes.

Chiral-auxiliary-mediated asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes.

A strategy for the asymmetric synthesis of chiral-at-metal [Ru(pp)(pp')(pp'')](2+) complexes, where pp, pp', and pp'' are achiral 2,2'-bipyridines, is introduced. The method employs isopropyl-2-(2'-hydroxyphenyl)oxazolines as chiral auxiliaries, which serve in their deprotonated forms as strong bidentate ligands that provide excellent asymmetric induction in the course of the coordination chemistry and, importantly, can afterward become substituted with complete retention of configuration in the presence of acid.

Strategy for the stereochemical assignment of tris-heteroleptic Ru(II) complexes by NMR spectroscopy.

The relative stereochemistry of tris-heteroleptic ruthenium complexes [Ru(pp)(pp')(pp'')](PF(6))(2), where pp = 1,10-phenanthroline-4-carboxamide, pp' = 5,6-dimethyl-1,10-phenanthroline, and pp'' = 7,8-dimethyl dipyrido[3,2-a:2',3'-c]phenazine, was studied using NMR spectroscopy. The (1)H and (13)C spectra were assigned by using double-quantum-filtered correlation spectroscopy (DQF-COSY), heteronuclear single-quantum correlation (HSQC), and heteronuclear multiple-bond correlation (HMBC) experiments for the two diastereomers, each a pair of enantiomers. Nuclear Overhauser effect contacts between the neighboring ligands differentiated the two halves of each symmetrical ligand, thus enabling a full assignment of the NMR signals and an accurate determination of the relative stereochemistry of the complexes. The introduction of an additional chiral center to ligand pp by coupling it with L-lysine caused removal of the enantiomerism. Thus, four diastereomers were observed and their relative stereochemistry determined.

Solid-phase synthesis of tris-heteroleptic ruthenium(II) complexes and application to acetylcholinesterase inhibition.

A synthetic route with two consecutive coordination chemistry steps on a solid support affords tris-heteroleptic ruthenium(II) polypyridyl complexes with high purity and in good yields. As an application we report the identification of a nanomolar acetylcholinesterase inhibitor from a small ruthenium complex library synthesized on Lanterns.

Synthesis and cyclometalation of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c]fluorene-1,3-dione scaffold.

The synthesis of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c]fluorene-1,3-dione scaffold is disclosed, which was synthesized using a Suzuki cross-coupling reaction and an intramolecular Heck cyclization as the key steps. This heterocyclic system can serve as a bidentate ligand as demonstrated by the formation and structural analysis of a derived ruthenium complex. The new scaffold constitutes an interesting candidate for the development of organometallic protein kinase inhibitors.