Total Syntheses of the Tropolone-Containing Sesquiterpene Olaximbriside A and Its Decarbonylated Counterpart Olaximbriside B.

The racemic modification of the α-tropolone-containing sesquiterpene olaximbriside A [viz. (±)-4)] has been prepared over 12 steps from the readily accessible decalin derivative 12. The last two of these steps involve a fully regiocontrolled substitution reaction of bromotropone 24. The aromatization of a stereoisomeric and co-produced form of compound 12 has provided (±)-olaximbriside B [(±)-5)].

Radical versus Non-Radical Reactivity in ortho- and para-Quinonedimethides and Implications for Cycloaddition Mechanisms.

The latent singlet diradical character of the parent ortho-quinonedimethide (o-QDM), as revealed by valence bond calculations, is demonstrated experimentally by trapping with the kinetically stable free radical TEMPO at room temperature. In the absence of TEMPO, the main pathway for decomposition at ambient temperature is not (as previously proposed in the literature) a radical reaction but instead a concerted Diels-Alder dimerization, which through ωB97X-D/aug-cc-pVTZ/SMD//M06-2X-D3/6-31+G(d,p)/SMD calculations is shown to proceed through an ambimodal bispericyclic transition state. The predominantly non-radical reactivity of o-QDM at room temperature differs from that of its isomeric para-quinonedimethide (p-QDM) congener, which self-reacts exclusively through radical pathways. These findings suggest the potential for tunable concerted/stepwise cycloadditions.

Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19).

The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate B0AT1 inhibitors with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.

Aluminyl derived ethene functionalization with heteroallenes, leading to an intramolecular ligand rearrangement.

The aluminacyclopropane K[Al(NON)(η-C2H4)] ([NON]2- = [O(SiMe2NDipp)2]2-, Dipp = 2,6-iPr2C6H3) reacts with CO2 and iPrNCNiPr to afford ring-expanded products of C-C bond formation. The latter system undergoes a 1,3-silyl retro-Brook rearrangement of the NON-group, to afford the [NNO]2- ligand ([NNO]2- = [N(Dipp)SiMe2N(Dipp)SiMe2O]2-). The mechanism of transformation was examined by density functional theory (DFT).

Polymers from Cellulosic Waste: Direct Polymerization of Levoglucosenone using DBU as a Catalyst.

The bio-based platform molecule levoglucosenone (LGO) is now produced at multi-ton scale by the pyrolysis of cellulosic waste. As such it has become an industrially viable, non-petroleum-derived chemical feedstock. Herein we report the direct (one-step) and operationally simple polymerization of LGO that provides a highly sustainable method for polymer synthesis. Specifically, the ability of LGO to act as an electrophile has been harnessed so as to deliver high molecular weight polymers (Mn=236,000 g/mol, D=2.4) possessing excellent thermal stabilities (TD5 %=249 °C). Furthermore, there is a significant capacity for the effective chemical manipulation of these polymers as exemplified by treatment of them under Baeyer-Villiger conditions and so creating a simple and green route to hydrophilic materials. These one- and two-step transformations provide the most direct route to new, LGO-derived polymer scaffolds yet reported. E-factors of ca. 0.012 and atom economies of up to 99 % have been realized.

A Rapid Aza-Bicycle Synthesis from Dendralenes and Imines.

The diene-transmissive 2-fold Diels-Alder sequence between carbon-based dienophiles and [3]dendralenes is becoming an established method for polycarbocycle synthesis. Here, we demonstrate for the first time that imines are competent participants in intermolecular formal [4 + 2] cycloadditions with dendralenes. After a second Diels-Alder process with a carbadienophile, hexahydro- and octahydro-isoquinoline structures are formed. The formal aza-Diels-Alder reaction, which requires Lewis acid promotion, proceeds in high regio- and stereoselectivity under optimized conditions. ωB97XD/Def2-TZVP//M06-2X/6-31+G(d,p) calculations reveal a stepwise ionic mechanism for the formal aza-dienophile cycloadditions and also explain an unexpected Z → E olefin isomerization of a non-reacting C═C bond in the first formal cycloaddition.

Computational and Experimental Confirmation of the Diradical Character of para-Quinonedimethide.

The ground-state structure of the parent para-quinonedimethide (p-QDM) molecule is generally represented in its closed shell form, i.e., as a cyclic, nonaromatic, through-conjugated/cross-conjugated hybrid comprising four C═C bonds. Nonetheless, p-QDM has been theorized to contain a contribution from its open-shell aromatic singlet diradical form. VBSCF calculations identify an open-shell contribution of 29% to the structure, while CASPT2(16,16)/def2-TZVP and ωB97XD/aug-cc-pVTZ calculations predict that dimerization proceeds along an open-shell singlet diradical pathway with a low (77 kJ/mol) barrier toward dimerization, which occurs by way of C-C bond formation between the exocyclic methylene carbons. A similar low (98 kJ/mol) barrier exists toward the reaction between a p-QDM molecule and the radical trap TEMPO. These predictions are verified experimentally through the isolation of bis-TEMPO-trapped p-QDM, its C-C coupled dimer, and by demonstrating that a mixture of p-QDM and TEMPO can initiate the radical polymerization of n-butyl acrylate at ambient temperature. In contrast to p-QDM, tetracyanoquinone (TCNQ) neither dimerizes nor reacts with TEMPO, despite having a similar diradical character to p-QDM. This lack of reactivity is consistent with both a higher kinetic barrier and a thermodynamically unfavorable process, which is ascribed to destabilizing steric clashes and polar effects.

Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles.

Atropisomeric, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. Using the isoindoles 5d-f as models, the stereochemistry and conformational folding of the systems were examined. Chiral UHPLC was used to analyze the rate of racemization and calculate the Gibbs free energy of enantiomerization (ΔG‡Enant). X-ray crystallography, 1H NMR spectroscopy, and DFT calculations were used to elucidate the three axes of chirality and clarify the structural factors contributing to ΔG‡Enant. Tandem rotation around the axes of chirality precludes the formation of diastereomers, with rotational restriction of the Caryl-Nsulfonamide bond determined as the moderator of atropisomeric stability in the system, affected primarily by steric hindrance as well as by π-stacking interactions facilitated by the folded conformation of the sulfonamide over the isoindole moiety.

Palladium-catalysed enantio- and regioselective (3 + 2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes towards spirocyclic cyclopentanes.

An enantio- and diastereoselective Pd-catalysed (3 + 2) cycloaddition of bis(trifluoroethyl) 2-vinyl-cyclopropane-1,1-dicarboxylate (VCP) with cyclic sulfamidate imine-derived 1-azadienes (SDAs) has been developed. These reactions provide highly functionalized spiroheterocycles having three contiguous stereocentres, including a tetrasubstituted carbon bearing an oxygen functionality. The two geminal trifluoroethyl ester moieties can be manipulated in a facially selective manner to afford more diversely decorated spirocycles with four contiguous stereocentres. In addition, diastereoselective reduction of the imine moiety can also afford a fourth stereocentre and exposes the important 1,2-amino alcohol functionality.

Amino Acid Sulfinate Salts as Alkyl Radical Precursors.

A general approach to the synthesis of amino acid sulfinate salts from commercially available α-chiral hydroxylated amino acids is reported. These reagents are shown to be valuable precursors to alkyl radicals under mild photochemical oxidation conditions. The photochemically generated amino acid radicals engage readily with alkyl and aryl disulfide radical traps to afford a diverse suite of modified amino acids.

Divergent reactivity of usnic acid and evaluation of its derivatives for antiproliferative activity against cancer cells.

Natural products continue to be an inspiration for new drugs to treat debilitating diseases such as cancer. Usnic acid is a secondary metabolite isolated predominately from lichen species and has been shown to exhibit antiproliferative properties, however its application is limited by poor drug-like properties and low specificity. We report our work on investigating the reactivity of usnic acid for incorporating heterocyclic rings and the divergent reactivity that can be obtained by simply altering the reaction solvent and temperature. The synthesised derivatives were then tested against HeLa cancer cells for their antiproliferative properties. A number of promising compounds were obtained including 4, 5 and 9 that showed an IC50 of 878, 311 and 116 nM, respectively, against HeLa cancer cells after 48 h of treatment.

The in vivo metabolism of Jungle Warfare in greyhounds.

Δ6-Methyltestosterone was reported as the main active ingredient of the purported "dietary supplement" Jungle Warfare. This compound is structurally similar to 17α-methyltestosterone, containing an additional Δ6 double bond, and is reported to possess notable androgenic activity, raising concerns over the potential for abuse of Jungle Warfare in sport. The in vivo metabolism of Δ6-methyltestosterone in greyhounds was investigated. Urinary phase I (unconjugated) and phase II (glucuronide) metabolites were detected following oral administration using liquid chromatography-mass spectrometry. No phase II sulfate metabolites were detected. The major phase I metabolite was confirmed as 16α,17ß-dihydroxy-17α-methylandrosta-4,6-dien-3-one by comparison with a synthetically-derived reference material. Minor amounts of the parent drug were also confirmed. Glucuronide conjugated metabolites were also observed, but were found to be resistant to hydrolysis using the Escherichia coli ß-glucuronidase enzyme. Qualitative excretion profiles, limits of detection, and extraction recoveries were determined for the parent drug and the major phase I metabolite. These results provide a method for the detection of Jungle Warfare abuse in greyhounds suitable for incorporation into routine screening methods conducted by anti-doping laboratories.

Total Synthesis of Matrine Alkaloids.

The total synthesis of three diastereomeric matrine natural products is reported. The 8-step synthesis commences with simple acyclic precursors, forms all 4 rings of the tetracyclic natural product framework, and forges 10 of the 20 covalent bonds of the target structure. A cross-conjugated triene is positioned at the core of an acyclic branched structure. This precursor collapses to the tetracyclic natural product framework through an orchestrated sequence of two separate intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. An unprecedented carba-analogue is prepared in the same way. Semisynthetic manipulations of matrine provide access to 10 additional natural products.

A General Stereoselective Synthesis of [4]Dendralenes.

The first general synthesis of branched tetraenes ([4]dendralenes) involves two or three steps from inexpensive, commodity chemicals. It involves an unprecedented variation on Suzuki-Miyaura cross-coupling, generating two new C-C bonds in a one-flask operation with control of diastereoselectivity. The broad scope of the method is established through the synthesis of more than 60 diversely substituted [4]dendralene molecules, along with substituted buta-1,3-dienes and other [n]dendralenes. [4]Dendralenes are demonstrated to be significantly more kinetically stable than their well-known [3]dendralene counterparts. The first stereoselective synthesis of these compounds is also reported, through the catalyst-controlled generation of both E- and Z-diastereomeric products from the same precursor. Novel, through-conjugated/cross-conjugated hybrid molecules are introduced. The first selective dienophile cycloadditions to substituted [4]dendralenes are reported, thus paving the way for applications in target-oriented synthesis.

Total Syntheses of the Structures Assigned to the Marine Natural Products Orthoscuticellines A-E.

The readily prepared and vinylated ß-carboline 11 has been converted over one or two steps into compounds 1-5, the structures assigned to the recently reported marine natural products orthoscuticellines A-E. The spectral data recorded on the synthetically derived compounds are fully consistent with the assigned structures and, on making allowances for variations in the pH of the medium in which the spectra of the natural products were recorded, it is concluded that the structures assigned to orthoscuticellines A-E are most likely correct. Certainly, the calculated 13C NMR spectra of the α-, γ-, and δ-carboline isomers of compounds 1-5 suggest that orthoscuticellines A-E do incorporate the assigned ß-carboline core.

Enantioselective oxa-Diels-Alder Sequences of Dendralenes.

Diene-transmissive hetero-Diels-Alder sequences involving carbonyl dienophiles are reported for the first time. High enantioselectivities are achieved in the reaction of phenylglyoxal with a broad range of dendralene structures, through the optimization of a Pd2+ catalyst system. The initial catalyst-controlled enantioselective oxa-Diels-Alder (ODA) cycloaddition to a [3]dendralene generates a dihydropyran carrying a semicyclic diene. This participates in a subsequent catalyst or substrate-controlled Diels-Alder reaction to generate sp3 -rich fused polycyclic systems containing both heterocycles and carbocycles. Computational investigations reveal a concerted asynchronous mechanism. π-Complexation of a diene C=C bond to Pd2+ occurs in both the pre-transition state (TS) complex and in cycloaddition TSs, controlling stereoselectivity. A formal enantioselective [4+2]cycloaddition of a CO2 dienophile is demonstrated.

Water Sorption Controls Extreme Single-Crystal-to-Single-Crystal Molecular Reorganization in Hydrogen Bonded Organic Frameworks.

As hydrogen bonded frameworks are held together by relatively weak interactions, they often form several different frameworks under slightly different synthesis conditions and respond dynamically to stimuli such as heat and vacuum. However, these dynamic restructuring processes are often poorly understood. In this work, three isoreticular hydrogen bonded organic frameworks assembled through charge-assisted amidinium⋅⋅⋅carboxylate hydrogen bonds (1C/C , 1Si/C and 1Si/Si ) are studied. Three distinct phases for 1C/C and four for 1Si/C and 1Si/Si are fully structurally characterized. The transitions between these phases involve extreme yet recoverable molecular-level framework reorganization. It is demonstrated that these transformations are related to water content and can be controlled by humidity, and that the non-porous anhydrous phase of 1C/C shows reversible water sorption through single crystal to crystal restructuring. This mechanistic insight opens the way for the future use of the inherent dynamism present in hydrogen bonded frameworks.

Extending chain growth beyond C1 → C4 in CO homologation: aluminyl promoted formation of the [C5O5]5- ligand.

(NONDipp)Al-K(TMEDA)2 (NONDipp = [O(SiMe2NDipp)2]2-, Dipp = 2,6-iPr2C6H3), containing an Al-K bond, activates and reductively couples cabon monoxide gas to form the [C4O4]4- ligand. This oxocarbon anion is thermally isomerised in the presence of CO and TMEDA. In contrast, the dimeric potassium aluminyl [K{Al(NONDipp)}]2 yields an aluminium complex containing the hitherto unknown [C5O5]5- ligand.

α-Iodo-α,ß-Unsaturated Ketones as Vicinal Dielectrophiles: Their Reactions with Dinucleophiles Provide New Annulation Protocols for the Formation of Carbo- and Heterocyclic Ring Systems.

α-Iodo-α,ß-unsaturated ketones such as compound 1 serve as vicinal dielectrophiles and react with a range of dinucleophiles including pentane-2,4-dione and 1,3-indandione to produce [3 + 2]- and [2 + 1]-adducts such as 5 and 38, respectively. [4 + 2]- and [5 + 2]-cycloadducts have been obtained from compound 1 by related means. Preliminary studies reveal that α-iodinated α,ß-unsaturated esters can also participate in at least some of these same processes.