Sevan David Houston

Cubane, bicyclo[1.1.1]pentane (BCP) and bicyclo[2.2.2]octane derivatives of benzene‐containing fragrances (e. g., benzyl esters) were prepared to evaluate whether odor characteristics would be retained to give same or similar scents. It was observed that each molecule maintained a distinctive aroma, sometimes quite similar to the benzene ring containing fragrance, and in other cases very different, with several perceived to produce high intensity odors. These results suggest that saturated cage bicyclic hydrocarbon bioisosteres have potential as new tools for the discovery of novel fragrances.

Charged functional groups can control gas-phase radical reactions in a predictable and tuneable manner by creating an internal oriented electric field that modulates the rate-limiting transition state.

The weakly coordinating dianion [B₁₂Cl₁₂]²⁻ originates from a family of carboranes typically reserved for application in coordination chemistry. Herein, we show that its readily accessible Ag(I) salt, [Ag]₂[B₁₂Cl₁₂], can be used as a catalyst in the PhICl₂ mediated chlorination of arenes, alkenes, and alkynes. The promising activity displayed by [Ag]₂[B₁₂Cl₁₂] over a variety of commercially available Ag(I) sources merits its incorporation to the toolkit of commonly screened silver catalysts in synthesis.

The weakly coordinating [B12Cl12]2- originates from a family of carboranes typically reserved for application in coordination chemistry. Here, we show its readily accessible Ag(I) salt, [Ag]2[B12Cl12], can be used as a catalyst in the PhICl2 mediated chlorination of arenes, alkenes, and alkynes. The promising activity displayed by [Ag]2[B12Cl12] over a variety of commercially available Ag(I) sources merits its incorporation to the toolkit of commonly screened silver catalysts in synthesis.

PhI(OTf)₂ has been used for the past 30 years as a strong I(III) oxidant for organic and inorganic transformations. It has been reported to be generated in situ from the reactions of either PhI(OAc)₂ or PhI=O with two equivalents of trimethylsilyl trifluoromethanesulfonate (TMS‐OTf). In this report it is shown that neither of these reactions generate a solution with spectroscopic data consistent with PhI(OTf)₂, with supporting theoretical calculations, and thus this compound should not be invoked as the species acting as the oxidant for transformations that have been associated with its use.

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.

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e. bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein we show the successful incorporation of a range of phenyl bioisosteres during the open source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum when compared to the parent phenyl compound, however these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, thirty-two compounds.

The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s–1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C–H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cube ring opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C–H abstraction and C–O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.

The highly oxygenated pimarane diterpenoids basimarols A, B, and C (3–5) were isolated from the plant species Basilicum polystachyon, which was collected within the Australian arid zone. Structure elucidation was performed using a suite of spectroscopic techniques, including X-ray crystallography. Anticancer and anti-DENV activity of 3–5 was explored, but only limited activity was observed. More extensive antiviral evaluation of stachyonic acid A (1), which was also isolated from B. polystachyon, revealed broad spectrum antiviral activity against West Nile virus (Kunjin strain, WNV_Kun) and human influenza viruses H1N1 and H3N2.