Cyclohexane Core Research Articles

Asymmetric Formal Total Syntheses of (+)- and (-)-Limaspermidine from Chirally Resolved 2-Pyrone Diels-Alder Cycloadducts via Aromatic C-H Amidation and Imino-Diels-Alder Reaction.

A new asymmetric synthetic route to (+)- and (-)-limaspermidine was devised, starting with chirally resolved enantiomerically pure 2-pyrone Diels-Alder cycloadducts. This route utilizes intramolecular Pd-catalyzed aromatic C-H amidation and imino-Diels-Alder reactions to construct the key indoline and indolizidine subunits onto the central cyclohexane core, allowing the straightforward formal total syntheses of both (+)- and (-)-limaspermidine.

A Broadly Applicable Diels-Alder-Based Synthesis of Ketamine-Related Arylcyclohexylamines.

Herein, we report the synthesis of aryl derivatives of ketamine and of ketamine's major metabolites hydroxynorketamine (HNK), norketamine (NK), and dehydronorketamine (DHNK) via a microwave-assisted Diels-Alder reaction to form the substituted cyclohexane core structure. Starting with aryl acrylic esters as dienophiles and siloxybutadienes as diene counterparts, a wide range of substituted arylcyclohexylamines was obtained after several modification steps of the initial Diels-Alder products [El Sheikh, S.; Weber, H.; Kortenbrede, L.; Drouvé, N. A broadly applicable Diels-Alder based Synthesis of Ketamine related Arylcyclohexylamines. ChemRxiv 2022, 10.26434/chemrxiv- 2022-xf1l9].

Epicoccanes A-D, Four Oxidative Dimers of Pyrogallol Analogues from Epicoccum nigrum.

Epicoccanes A-D (1-4) are four novel metabolites of an endophytic fungus Epicoccum nigrum. Their distinct unprecedented structures are hypothesized as oxidative dimers of pyrogallol analogues. Compounds 1 and 2 possess a novel spirobicyclo[3.2.1]octane-6,1'-cyclopentane or -cyclohexane core skeleton. Compound 3 is of a unique cage-like pentacyclic system, which unusually contained three continuous spiro-carbons. Compound 4 is a highly rearranged dimer with five contiguous chiral centers. The absolute structures of 1 and 2 were deduced by electronic circular dichroism (ECD) calculations, and those of 3 and 4 were determined by X-ray crystallography. Compounds 1 and 4 showed potential antiliver fibrosis activity.

Scalable Asymmetric Synthesis of the All Cis Triamino Cyclohexane Core of BMS-813160.

BMS-813160 is a pharmaceutical entity currently in development at Bristol Myers Squibb. Its defining structural feature is a unique chiral all cis triamino cyclohexane core. Medicinal and process chemistry groups at BMS have previously published synthesis strategies for chemotypes similar to the target molecule, but a streamlined approach amenable for longer-term supply was necessary. A new synthetic route was conceptualized, experimentally investigated, and determined to meet the criteria for efficiency that addressed key limitations of previous approaches. Adopting/optimizing the Trost asymmetric allylic amination desymmetrization methodology was a key tool used to produce a synthesis intermediate with high optical purity. In addition, developing a tandem Mannich-aza-Michael reaction to obviate the need for a Curtis/acylation sequence and a novel reductive amination/thermal lactamization to circumvent Freidinger-type pyrrolidone preparation are some of the synthesis improvements that enabled access to the target molecule to fulfill long-term supply requirements.

Isolation and total synthesis of penicimutans- and aranorosin-type natural products - A summary

Penicimutans and aranorosins are a rich family of secondary metabolites produced by fungi of terrestrial and marine origin. These natural products contain polyketides, indole alkloids or both. The aranorosin-type polyketides feature an unusually hexa-functionalized cyclohexane core that contains an acid/base-sensitive cis -bisoxirane moiety, and is part of the 1-oxaspiro[4.5]decane ring skeleton. The penicimutan-type alkaloids contain a diketopiperazine-fused hexapyrroloindoline motif, which possesses a 1,1-dimethylpropenyl (reverse prenyl) group on the C3 carbon, generating the vicinal quaternary stereocenters. Both penicimutans and aranorosins display very promising biological activities against tumors and/or Gram-responsive microbial. Their drug lead potential attracted many synthetic efforts since 1990s. This review summarized all the synthetic studies until the February of 2021.

Tetrodotoxin Framework Construction from Linear Substrates Utilizing a Hg(OTf)2-Catalyzed Cycloisomerization Reaction: Synthesis of the Unnatural Analogue 11-nor-6,7,8-Trideoxytetrodotoxin.

In this contribution, we propose a new synthetic approach to tetrodotoxin (TTX), one of the most famous marine toxins that, after first preparing a functionalized linear substrate, forms a cyclohexane core from the substrate utilizing our mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization reaction. The concept was applied to the synthesis of 11-nor-6,7,8-trideoxyTTX and 11-nor-4,9-anhydro-6,7,8-trideoxyTTX, which are unnatural TTX analogues, demonstrating the validity of our new approach.

A study towards the synthesis of (-)-atrop-abyssomicin C core

An attempt to synthesize the cyclohexane core of antibiotic abyssomicin C is described. The initial, protecting group-free approach (relying on internal protection) failed and had to be modified, in order to allow for efficient deprotection of the acid-sensitive cyclization precursor in the penultimate synthetic step. Thus, a pyranoside structural unit was used as a latent lactone/ester functionality, which was deprotected via thioacetalization/hydrolysis/oxidation sequence, to give the ?-valerolactone-type cyclization precursor. Unfortunately, the key cyclization reaction was not feasible, even after structural modification of the cyclization precursor. Reluctance towards cyclization turned out to be a general property of (at least some) ?7-unsaturated esters, which required the development of a new strategy for this type of transformation.

Synthesis of partially bio‐based triepoxides from naturally occurring myo‐inositol and their polyadditions

AbstractPartially bio‐based triepoxides, 1,3,5‐tri‐O‐methyl‐2,4,6‐tri‐O‐(oxiran‐2‐yl‐methyl)‐myo‐inositol (4) and 2,4,6‐tri‐O‐(oxiran‐2‐yl‐methyl)‐myo‐inositol 1,3,5‐orthoacetate (5), were synthesized from naturally occurring myo‐inositol. These two triepoxides differ from each other in terms of rigidity of the core structure; while the former triepoxide has a more flexible cyclohexane core, the latter has a highly rigid adamantane‐like orthoester core. Triepoxide 5 readily reacted with nucleophilic monomers such as diamines, dithiol, and trithiol to yield networked polymers. The glass transition temperatures (Tgs) of these polymers were higher than those of comparable networked polymers obtained by the polyaddition of triepoxide 4 with the same nucleophilic monomers, implying that the rigidity of the orthoester moiety contributed to the efficient restriction of the polymer chain in the synthesized networked polymers.

Cyclohexane-cored dendritic host materials with high triplet energy for efficient solution-processed blue thermally activated delayed fluorescence OLEDs

Two dendritic host materials (CH-2D1 and CH-2D2) are developed by using non-conjugated cyclohexane core and two first/second generation carbazole dendrons, which show excellent solubility in organic solvents, high thermal stability and high triplet energy (ET) of 2.78–2.84 eV, making them suitable for fabrication of solution-processed blue thermally activated delayed fluorescence (TADF) organic light-emitting diodes (OLEDs). Compared to CH-2D1 with the first-generation carbazole dendron which shows low-lying highest occupied molecular orbital (HOMO) energy level of −5.48 eV, CH-2D2 with the second-generation carbazole dendrons exhibits higher HOMO level of −5.37 eV, which is more favourable for hole injection from the anode to the emissive layers. Consequently, solution-processed blue TADF OLEDs utilizing CH-2D2 as host show promising device performance with a low turn-on voltage of 3.4 V, maximum external quantum efficiency of 17.8%, maximum luminous efficiency of 41.3 cd A−1 and power efficiency of 33.9 lm W−1, which can compare with the most efficient solution-processed blue TADF OLEDs based on small-molecule and polymer hosts. These results indicate that dendritic host materials with well-defined chemical structure and good solubility are an attractive approach―beyond the soluble small-molecule hosts and polymer hosts―for the development of efficient solution-processed TADF OLEDs.

Neighboring Hydroxyl Group-Assisted Allylboration and Lewis Acid-Mediated Carbonyl-Ene Reaction for Access to a Hapalindole Cyclohexane Core with Multiple Contiguous Stereogenic Centers.

A neighboring hydroxyl group-assisted allylboration of 3-indolyl ketones with γ,γ-disubstituted allylboronic acids is reported, affording various 3-indolyl-substituted homoallylic alcohols in good yields with excellent diastereoselectivies (up to >20:1 dr). The hydroxyl group not only played a vital role in the challenging allylboration but was elaborated for the subsequent construction of a hapalindole cyclohexane core by a highly diastereoselective Lewis acid-catalyzed carbonyl-ene reaction. In the overall process, four contiguous stereogenic centers including two quaternary stereogenic centers were installed.

Stereoselective Synthesis of Cyclohexanes via an Iridium Catalyzed (5 + 1) Annulation Strategy.

An iridium catalyzed method for the synthesis of functionalized cyclohexanes from methyl ketones and 1,5-diols is described. This process operates by two sequential hydrogen borrowing reactions, providing direct access to multisubstituted cyclic products with high levels of stereocontrol. This methodology represents a novel (5 + 1) strategy for the stereoselective construction of the cyclohexane core.

Broadband-Emitting 2 D Hybrid Organic-Inorganic Perovskite Based on Cyclohexane-bis(methylamonium) Cation.

A new broadband-emitting 2 D hybrid organic-inorganic perovskite (CyBMA)PbBr4 based on highly flexible cis-1,3-bis(methylaminohydrobromide)cyclohexane (CyBMABr) core has been designed, synthesized, and investigated, highlighting the effects of stereoisomerism of the templating cation on the formation and properties of the resulting perovskite. The new 2 D material has high exciton binding energy of 340 meV and a broad emission spanning from 380 to 750 nm, incorporating a prominent excitonic band and a less intense broad peak at room temperature. Significant changes in the photoluminescence (PL) spectrum were observed at lower temperatures, showing remarkable enhancement in the intensity of the broadband at the cost of excitonic emission. Temperature-dependent PL mapping indicates the effective role of only a narrow band of excitonic absorption in the generation of the active channel for emission. Based on the evidences obtained from the photophysical investigations, we attributed the evolution of the broad B-band of (CyBMA)PbBr4 to excitonic self-trapped states.

Cooperativity Scale: A Structure-Mechanism Correlation in the Self-Assembly of Benzene-1,3,5-tricarboxamides.

ConspectusThe self-assembly of small and well-defined molecules using noncovalent interactions to generate various nano- and microarchitectures has been extensively studied. Among various architectures, one-dimensional (1-D) nano-objects have garnered significant attention. It has become increasingly evident that a cooperative or nucleation–elongation mechanism of polymerization leads to highly ordered 1-D supramolecular polymers, analogous to shape-persistent biopolymers such as actin. With this in mind, achieving cooperativity in self-assembled structures has been actively pursued with significant success. Only recently, researchers are focusing on the origin of the mechanism at the molecular level in different synthetic systems. Taking a step further, a thorough quantitative structure–mechanism correlation is crucial to control the size, shape, and functions of supramolecular polymers, and this is currently lacking in the literature.Among a plethora of molecules, benzene-1,3,5-tricarboxamides (BTAs) provide a unique combination of important noncovalent interactions such as hydrogen bonding, π-stacking, and hydrophobic interactions, for self-assembly and synthetic ease. Due to the latter, a diverse range of BTA derivatives with all possible structural mutations have been synthesized and studied during the past decade, mainly from our group. With such a large body of experimental results on BTA self-assembly, it is time to embark on a structure–mechanism correlation in this family of molecules, and a first step toward this will form the main focus of this Account. The origin of the cooperative mechanism of self-assembly in BTAs has been ascribed to 3-fold intermolecular hydrogen bonding (HB) between monomers based on density-functional theory (DFT) calculations. The intermolecular hydrogen-bonding interaction forms the central premise of this work, in which we evaluate the effect of different moieties such as alkyl chains, and amino acids, attached to the core amides on the strength of intermolecular HB, which consequently governs the extent of cooperativity (quantified by the cooperativity factor, σ). In addition to this, we evaluate the effect of amide connectivity (C- vs N-centered), the role of solvents, amides vs thioamides, and finally the influence of the benzene vs cyclohexane core on the σ. Remarkably, every subtle structural change in the BTA monomer seems to affect the cooperativity factor in a systematic and rationalizable way.The take home message will be that the cooperativity factor (σ) in the BTA family forms a continuous spectrum from 1 (isodesmic) to <10–6 (highly cooperative) and it can be tuned based on the appropriate modification of the BTA monomer. We anticipate that these correlations drawn from the BTA series will be applicable to other systems in which HB is the main driving force for cooperativity. Thus, the understanding gained from such correlations on a prototypical self-assembling motif such as BTA will aid in designing more complex systems with distinct functions.

Stereoselective Synthesis of (+)-Annuionone A and (-)-Annuionone B.

A stereoselective synthetic approach was utilized to synthesize enantiopure annuionones A (1b) and B (2b), two ionone-type norsesquiterpenoids that both bear a 6-oxabicyclo[3.2.1]octane framework and possess allelopathic activity. A stereoselective Diels-Alder reaction based on chiral trisubstituted dienophile 20 was employed to obtain the optically active polysubstituted cyclohexane core of both natural products. Using this approach, (+)-annuionone A (1b) and (-)-annuionone B (2b) were synthesized from lactol (+)-15 in 10% overall yield.

Cyclohexane-Coupled Bipolar Host Materials with High Triplet Energies for Organic Light-Emitting Diodes Based on Thermally Activated Delayed Fluorescence.

Thermally activated delayed fluorescence-based organic light-emitting diodes (TADF-OLEDs) have recently attracted tremendous research interest as next-generation optoelectronic devices. However, there are a limited number of host materials with an appropriately high lowest-excited triplet energy (ET) and bipolar charge transport properties for high-efficiency TADF-OLEDs. Moreover, these host materials should have high thermal and morphological stabilities. In this study, we develop novel bipolar host materials consisting of an electron-donating 9-phenylcarbazole unit and an electron-accepting triphenylphosphine oxide, triphenylphosphine sulfide, or 2,4,6-triphenyl-1,3,5-triazine unit linked by a nonconjugated cyclohexane core. These bipolar host materials possess high glass-transition temperatures of over 100 °C and high ET values of approximately 3.0 eV. TADF-OLEDs employing these bipolar host materials could achieve high external electroluminescence quantum efficiencies of up to 21.7% together with reduced efficiency roll-off characteristics, because of expansion of the charge-recombination zone within the emission layer arising from the bipolar charge transport ability of these host materials.

Perylene diimide isomers containing a simple sp3-core for non-fullerene-based polymer solar cells

In order to investigate the effect of the geometries of perylene diimide (PDI)-based small molecules, five different isomers were synthesized by using a cyclohexane core as a simple sp3-σ core.

Stereoselective Bulk Synthesis of CCR2 Antagonist BMS-741672: Assembly of an All-cis (S,R,R)-1,2,4-Triaminocyclohexane (TACH) Core via Sequential Heterogeneous Asymmetric Hydrogenations

A concise bulk synthesis of stereochemically complex CCR2 antagonist BMS-741672 is reported. A distinct structural feature is the chiral all-cis 1,2,4-triaminocyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction of a β-enaminoester, directed by (S)-α-methylbenzylamine as a low-cost chiral template, and reductive amination of a 3,4-cis-disubstituted cyclohexanone over sulfided Pt/C introduced a tert-amine, setting the third stereocenter in the all-cis cyclohexane core. The heterogeneous catalysts were recycled. Ester hydrolysis produced a γ-amino acid, isolated as its Na salt. A challenging Curtius reaction to introduce the remaining C–N bond at C-2 was strongly influenced by the presence of the basic tert-amine, providing a stereoelectronically highly activated isocyanate. Detailed mechanistic and process knowledge was required to enable clean trapping with an alcohol (t-BuOH) while avoiding formation of side produ...

Voglibose-inspired synthesis of new potent α-glucosidase inhibitors N-1,3-dihydroxypropylaminocyclitols

Voglibose, an N-1,3-dihydroxypropylaminocyclitol, has widely been used as an effective α-glucosidase inhibitor for diabetes therapy. Several attempts have been made to synthesize closely related analogues through the coupling of various aminocyclitols and propane-1,3-diol; however, most of them showed weaker or no inhibition. In this communication, we synthesized a pair of new N-1,3-dihydroxypropylaminocyclitols (10 and 11) using (+)-proto-quercitol (1) as a cyclitol core structure. The newly synthesized compounds revealed potent rat intestinal α-glucosidases, particularly against maltase, with IC50 values at submicromolar. Subsequent study on mechanisms underlying the inhibition of 11 indicated the competitive manner towards maltase and sucrase. The potent inhibition of these compounds was elaborated by docking study, in which their binding profiles towards key amino acid residues in the active site were similar to that of voglibose. Therefore, introduction of propane-1,3-diol moiety to suitable cyclohexane core structure such as aminoquercitol would be a potential approach to discover a new series of effective α-glucosidase inhibitors.

Asymmetric total synthesis of (−)-stenine

An efficient total synthesis of (−)-stenine in 14 steps with an overall yield of 5.9% is described. The key feature is the construction of the densely substituted cyclohexane core of stenine with two consecutive asymmetric Michael additions.

Total synthesis and biological evaluation of (−)-atrop–abyssomicin C

Enantioselective synthesis of a marine antibiotic (-)-atrop-abyssomicin C was accomplished in 21 steps, in 1.8% overall yield (4%, based on the recovered starting material). The key steps of the synthesis are the formation of the functionalized cyclohexane core by an organocatalyzed Tsuji-Trost reaction, the formation of a tricyclic spirotetronate unit by a gold-catalyzed reaction sequence and the highly efficient eleven-membered ring closure by a Nozaki-Hiyama-Kishi reaction. Biological tests showed all abyssomicin derivatives to possess strong antibacterial activity against methicillin resistant S. aureus strains; however, they also proved to be cytotoxic, both to malignant and to normal somatic cells.