Chiral Auxiliary-Directed Site-Selective Deprotonation of the Cubane Skeleton.

The first diastereoselective synthesis of trisubstituted cubanes was achieved using a chiral auxiliary. To establish chirality within the cubane skeleton, at least three substituents must be introduced at the appropriate positions. Ready conversion of cubane carboxylic acid to a chiral amide followed by sequential ortho-selective deprotonations and electrophilic trapping afforded the corresponding 1,2,3-trisubstituted cubanes with high diastereoselectivity. This route opens new possibilities for the preparation of enantio-enriched cubanes.

Cubane, Bicyclo[1.1.1]pentane and Bicyclo[2.2.2]octane: Impact and Thermal Sensitiveness of Carboxyl-, Hydroxymethyl- and Iodo-substituents.

With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.1]pentane (BCP), and bicyclo[2.2.2]octane (BCO) were evaluated via hammer test and sealed cell differential scanning calorimetry, respectively. Iodo-substituted systems were found to be more impact sensitive, whereas hydroxymethyl substitution led to more rapid thermodecomposition. Cubane was more likely to be impact sensitive with these substituents, followed by BCP, whereas all BCOs were unresponsive. The majority of derivatives were placed substantially above Yoshida thresholds-a computational indicator of sensitivity.

Cubane Chirality via Substitution of a "Hidden" Regular Tetrahedron.

In the hexahedral hydrocarbon cubane, replacing hydrogen with other atoms at three positions within any one of the internal tetrahedrons can conceptually lead to the formation of a unique class of chiral molecules. In pursuit of this endeavor, we prepared 1,3-dibromo-4-deuteriocubane-N,N-diisopropylcarboxamide, which upon treatment with zincates affords 1,3,5-trisubstituted cubanes via simultaneous two-position substitution reactions. The proposed chiral attributes of this stereogeometric class were confirmed by enantiomeric resolution of a p-bromobenzyl derivative using chiral HPLC.

The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Thermal and Sensitiveness Determination of Cubanes: Towards Cubane-Based Fuels for Infrared Countermeasures.

As infrared seeking technology evolves, threats are better able to distinguish defensive infrared (IR) flares from true targets. Spectrally matched flares, which generally employ carbon-based fuels, are better able to decoy some advanced missiles by more closely mimicking the IR emission of the target. Cubane is a high-energy carbon-based scaffold which may be suitable for use as a fuel in spectrally matched flares. The enthalpy of formation and strain energy of a series of cubanes was predicted in silico, and their thermal and impact stability examined. All were found to undergo highly exothermic decomposition in sealed cell differential scanning calorimetry, and two cubanes subsequently underwent quantitative sensitiveness testing. Despite their F of I values being in the secondary explosive range, cubane-1,4-dicarboxylic acid (F of I=70) and 4-carbamoylcubane-1-carboxylic acid (F of I=90) were identified as potentially useful fuels for pyrotechnic infrared countermeasure flare formulations.

Enantioselective synthesis of (R)-2-cubylglycine including unprecedented rhodium mediated C-H insertion of cubane.

The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C-H insertion.

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

Cyclooctatetraenes through Valence Isomerization of Cubanes: Scope and Limitations.

The scope and limitations of Eaton's rhodium(I)-catalyzed valence isomerization of cubane to cyclooctatetraene (COT) were investigated in the context of functional group tolerability, multiple substitution modes and the ability of cubane-alcohols to undergo one-pot tandem Ley-Griffith Wittig reactions in the absence of a transition metal catalyst.

A Protocol for an Iodine-Metal Exchange Reaction on Cubane Using Lithium Organozincates.

The iodine-metal exchange reaction on cubane was examined using various lithium organozincates. Among these, the dianionic zincate, n-Bu4ZnLi2, gave optimum results. The resulting cubyl metal species could be converted into various cubane derivatives via addition reactions with electrophiles, such as an organohalide or aldehyde. The potential functional group tolerance of organozincates lends this protocol to the synthesis of polyfunctionalized cubane derivatives.

Cubanes in Medicinal Chemistry.

Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

Inhibition of tyrosinase by 4H-chromene analogs: Synthesis, kinetic studies, and computational analysis.

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a Ki value of 4 µm, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site.

Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere.

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Enantioselective total synthesis of the mexicanolides: khayasin, proceranolide, and mexicanolide.

The enantioselective total synthesis of the limonoids khayasin, proceranolide and mexicanolide was achieved via a convergent strategy utilizing a tactic aimed at incorporating natural products as advanced intermediates. This extended biomimetically inspired approach additionally achieved the enantioselective total synthesis of the intermediates azedaralide and cipadonoid B.