Gem-dimethyl Group Research Articles

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease.

Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.

Sp3 -Rich Glycyrrhetinic Acid Analogues Using Late-Stage Functionalization as Potential Breast Tumor Regressing Agents.

Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.

Geminal Dimethyl Substitution Enables Controlled Polymerization of Penicillamine-Derived β-Thiolactones and Reversed Depolymerization

Summary To access infinitely recyclable plastics, one appealing approach is to design thermodynamically neutral systems based on dynamic covalent bond, the (de)polymerization of which can be easily manipulated with low energy cost. Here, we demonstrate the feasibility of this concept via the efficient synthesis of polythioesters PNR-PenTE from penicillamine-derived β-thiolactones and their convenient depolymerization under mild conditions. The gem-dimethyl group adjusts the thermodynamics of (de)polymerization to near equilibrium, confers better (de)polymerization control by reducing the activity and conformational possibilities of the chain-end thiolate groups, and stabilizes the thioester linkages in the polymer backbone. PNR-PenTE with tailored properties is conveniently accessible by altering the side chains. PNR-PenTE can be recycled to pristine enantiopure β-thiolactones at >95% conversion from minutes to a few hours at room temperature. This work highlights the power of judicious molecular design and could greatly facilitate the development of a wide range of recyclable polymers with immense application potentials.

Asymmetric Synthesis of a Bacteriochlorophyll Model Compound Containing trans-Dialkyl Substituents in Ring D

Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include creating the macrocycle along with the trans-dialkyl substituents in both pyrroline rings (B and D). A known route to a model bacteriochlorophyll with a gem-dimethyl group in each pyrroline ring has been probed for utility in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1), which contains a trans-dialkyl group in ring D and a gem-dimethyl group in ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl, β-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z, 3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions) gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the desired trans-dialkyl stereochemistry in ring D and was obtained as a 7:1 mixture of (expected) epimers owing to the configuration of the 132-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.

Arylpyran Pseudoacid Racemization: Rate Estimation and Structural Influences

Arylpyran pseudoacids showed slow ring-opening to the oxocarboxylic acids, and fast ring-closure to the lactols (pseudoacids) in a process that amounts to racemization. Compounds studied were patterned on “Cooper’s Pseudoacid” [3-hydroxy-4,4-dimethylisobenzopyran-1-one, 1], to which modifications were introduced to influence racemization rates by steric compression. Pseudoacid 1 in d6-DMSO had a barrier to racemization (ΔH‡) of +77.8(3) kJ/mol determined by dynamic nuclear magnetic resonance line-broadening measured from 25 °C to 100 °C, and coalescence of its diastereotopic gem-dimethyl signals at 78.5 °C. The solution half-life of 1 at room temperature is a few seconds. Introduction of various aryl 5-substituents lead to similar racemization barriers for the 5-fluoro-8-methyl derivative, and increasingly higher barriers for 5-methyl-8-methyl, 5-chloro-8-methyl, and 5-bromo-7-methyl derivatives. In 3-hydroxy-4,4,5,8-tetramethylisobenzopyran-1-one, the barrier was + 104(6) kJ/mol, and the solution enantiomer t1/2 at room temperature was of the order of hours. Chemical shift differences (ΔνMe) between diastereotopic methyls of 8-methyl-5-substituted enantiomeric pseudoacids were observed in the order F < CH3 < Cl, and generally decrease with increasing temperatures. The pseudoaxial and pseudoequatorial dispositions of the gem-dimethyl groups show smaller torsional differences in the presence of adjacent aryl 5-substituents. The crystal structures of 5-fluoro, 5-chloro and 5-methyl derivatives of 3-hydroxy-4,4,8-trimethylisobenzopyran-1-ones and of 5-bromo-3-hydroxy-4,4,7-trimethylisobenzopyran-1-one are reported, along with several relevant secondary endocyclic pseudoamide derivatives. Electronic energy computations (B3LYP/6-31 + (G(d,p) level of theory) generally support the steric compression model. Equilibration between diastereomeric pseudoacids 3-hydroxy-4-ethyl-4-methylisobenzopyran-1-one and 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one were rapid with trans isomers decreasingly favored as temperature increases, and cis isomers less stable by + 4.8(2) kJ/mol and + 7.0(4) kJ/mol, respectively. The first-order rate of cis → trans conversion was measureable for 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one at 25 °C was found to be 0.00403/min, t1/2 = 2.87 h. Attempts to produce 5-isopropyl, 5-t-butyl and 4-phenyl-5-methyl pseudoacid derivatives were frustrated by aryl substituent rearrangement upon ring closure to the intermediate indanones. Structures of rearranged 3-hydroxy-4-methyl-4-(2′-chloro-5′-methylphenyl)isobenzopyran-1-one (pseudoacid) and N-benzyl-6-isopropyl-4,4,8-trimethylisobenzopyrimidin-1-one (pseudoamide) are reported. Arylpyran pseudoacids undergo slow ring opening and fast ring closing in solution amounting to racemization, rates of which can be slowed considerably by steric compression between the 5-substituent and the adjacent gem-dimethyl groups.

Ring-expansion cationic cyclopolymerization for the construction of cyclic cyclopolymers

A “cyclic cyclopolymer” was successfully synthesized via ring-expansion cationic cyclopolymerization with a cyclic initiator by using a divinyl ether carrying a gem-dimethyl group on the spacer as the monomer.

Chain Substituted Cannabilactones with Selectivity for the CB2 Cannabinoid Receptor.

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1′-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain’s length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (Ki = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 3.7 ± 1.5 nM, E(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol.

Synthesis of Quaternary Carbon-Centered Benzoindolizidinones via Novel Photoredox-Catalyzed Alkene Aminoarylation: Facile Access to Tylophorine and Analogues

Photoredox-catalyzed aminoarylation and thioamination of unactivated alkenes have been developed, providing novel synthetic routes to access synthetically challenging quaternary carbon-centered ben...

Pd(II)-Catalyzed Asymmetric Oxidative Annulation of N-Alkoxyheteroaryl Amides and 1,3-Dienes.

The first Pd(II)-catalyzed asymmetric oxidative annulation of N-alkoxyaryl amides and 1,3-dienes is reported, which features particular applicability for quick assembly of different types of chiral heterocycles with high yields and enantioselectivities. A novel chiral pyridine-oxazoline bearing a methoxyl group at the C-5 position and a gem-dimethyl group on the oxazoline moiety was found to be crucial for conversion.

Steric influence of salicylaldehyde-based Schiff base ligands on the formation of trans-[Re(PR3)2(Schiff base)]+ complexes.

Complexes of the type trans-[Re(PR3)2(Schiff base)]+ (R = ethyl and/or phenyl) 2-7 were prepared by the reaction of (nBu4N)[ReOCl4] with H2sal2en or H2sal2ibn followed by addition of a tertiary phosphine. The trans-[Re(PR3)2(sal2en)]+ complexes 2-4 were stable in solution, whereas the trans-[Re(PR3)2(sal2ibn)]+ complexes 6-7 were observed to convert to their corresponding cis-[ReO(PR3)(sal2ibn)]+ products through a process involving ligand dissociation, metal oxidation, and Schiff base ligand rearrangement. The conversion of the trans-[Re(PR3)2(sal2ibn)]+ complexes is likely driven by steric interactions between the bulky backbone gem-dimethyl groups of the sal2ibn ligand and the phosphine ligands. These complexes were isolated and characterized by 1H and 13C NMR, FT-IR spectroscopy, cyclic voltammetry, and single crystal X-ray diffraction. The results reported herein provide insight into the factors that drive trans-[Re(PR3)2(Schiff base)]+ complex formation. This will aid in the development of novel 186/188Re therapeutic agents and the design of novel bifunctional N2O2 Schiff base ligands.

Metal-Controlled Switching of Enantioselectivity in the Mukaiyama-Michael Reaction of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Metal-Pybox Complexes.

Metal-directed switching of enantioselectivity in the Mukaiyama-Michael reaction of silyl enol ethers to α,β-unsaturated 2-acyl imidazoles using the same chiral indapybox ligand has been reported. The utility of this approach has been portrayed in the synthesis of both enantiomers of optically active δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of the tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors

1. Due to its unique C–C and C–H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability.2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH.3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question.

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.

The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

Absolute configuration of the ocimene monoterpenoids from Artemisia absinthium.

The absolute configuration (AC) of the naturally occurring ocimenes (-)-(3S,5Z)-2,6-dimethyl-2,3-epoxyocta-5,7-diene (1) and (-)-(3S,5Z)-2,6-dimethylocta-5,7-dien-2,3-diol (2), isolated from the essential oils of domesticated specimens of Artemisia absinthium, followed by vibrational circular dichroism (VCD) studies of 1, as well as from the acetonide 3 and the monoacetate 4, both derived from 2, since secondary alcohols are not the best functional groups to be present during VCD studies in solution due to intermolecular associations. The AC follows from comparison of experimental and calculated VCD spectra that were obtained by Density Functional Theory computation at the B3LYP/DGDZVP level of theory. Careful nuclear magnetic resonance (NMR) measurements were compared with literature values, providing for the first time systematic 1 H and 13 C chemical shift data. Regarding homonuclear 1 H coupling constants, after performing a few irradiation experiments that showed the presence of several small long-range interactions, the complete set of coupling constants for 3, which is representative of the four studied molecules, was determined by iterations using the PERCH software. This procedure even allowed assigning the pro-R and pro-S methyl group signals of the two gem-dimethyl groups present in 3.

An efficient synthesis of structurally diverse 2-methyl-N-[(3-phenylamino)oxetan-3-yl]-2-propanesulfinamide derivatives under catalyst free conditions

A convenient and straightforward synthesis of structurally diverse 2-methyl-N-[(3-phenylamino)oxetan-3-yl]-2-propanesulfinamide derivatives from 3-oxetan-3-tert-butylsulfinimine and substituted aromatic amines in methanol at 60 °C temperature is described. The corresponding diaminooxetane derivatives are obtained in good to excellent yield under optimized reaction conditions. The method presented herein was found to be advantageous for diaminooxetane derivatives as emerging building block for future drug discovery. The title diaminooxetanes should be considered as bioisosteric to isopropylidenediamines and urea derivatives rather than to gem-dimethyl and carbonyl groups, respectively.

Synthesis and Structure of 3,3-Dimethylindoline Squaraine Rotaxanes.

Squaraine rotaxanes are mechanically interlocked molecules comprised of a dumbbell shaped squaraine dye inside a tetralactam macrocycle. Previous squaraine rotaxanes have employed planar squaraine dyes with 4-aminophenyl, 2-aminothiophene, or N-amino units appended to the central C4O2 core. Here we describe two rotaxanes that encapsulate a 3,3-dimethylindoline squaraine inside a tetralactam with anthracene sidewalls. The rotaxanes were prepared by a templated clipping reaction and an X-ray crystal structure shows that the squaraine gem-dimethyl groups force a relatively wide separation between the macrocycle anthracene sidewalls. The decreased interaction between the encapsulated squaraine and the anthracene sidewalls leads to a smaller red shift of the squaraine absorption and emission bands. Solution-state studies show that the gem-dimethyl groups in 3,3-dimethylindoline squaraine dyes are large enough to prevent macrocycle threading or rotaxane unthreading. One of the new rotaxanes emits an orange light (560-650 nm), and there is a 10-fold enhancement in the squaraine fluorescence quantum yield upon encapsulation as a rotaxane. This orange-emitting dye completes the palette of known squaraine rotaxane fluorophores whose emission profiles span the color range from green to near-infrared.

Synthesis and Spectral Properties of meso-Arylbacteriochlorins, Including Insights into Essential Motifs of their Hydrodipyrrin Precursors.

Synthetic bacteriochlorins—analogues of bacteriochlorophylls, Nature’s near-infrared absorbers—are attractive for diverse photochemical studies. meso-Arylbacteriochlorins have been prepared by the self-condensation of a dihydrodipyrrin–carbinol or dihydrodipyrrin–acetal following an Eastern-Western (E-W) or Northern-Southern (N-S) joining process. The bacteriochlorins bear a gem-dimethyl group in each pyrroline ring to ensure stability toward oxidation. The two routes differ in the location of the gem-dimethyl group at the respective 3- or 2-position in the dihydrodipyrrin, and the method of synthesis of the dihydrodipyrrin. Treatment of a known 3,3-dimethyldihydrodipyrrin-1-carboxaldehyde with an aryl Grignard reagent afforded the dihydrodipyrrin-1-(aryl)carbinol, and upon subsequent acetylation, the corresponding dihydrodipyrrin-1-methyl acetate (dihydrodipyrrin–acetate). Self-condensation of the dihydrodipyrrin–acetate gave a meso-diarylbacteriochlorin (E-W route). A 2,2-dimethyl-5-aryldihydrodipyrrin-1-(aryl)carbinol underwent self-condensation to give a trans-A2B2-type meso-tetraarylbacteriochlorin (N-S route). In each case, the aromatization process entails a 2e−/2H+ (aerobic) dehydrogenative oxidation following the dihydrodipyrrin self-condensation. Comparison of a tetrahydrodipyrrin–acetal (0%) versus a dihydrodipyrrin–acetal (41%) in bacteriochlorin formation and results with various 1-substituted dihydrodipyrrins revealed the importance of resonance stabilization of the reactive hydrodipyrrin intermediate. Altogether 10 new dihydrodipyrrins and five new bacteriochlorins have been prepared. The bacteriochlorins exhibit characteristic bacteriochlorophyll-like absorption spectra, including a Qy band in the region 726–743 nm.

Preparation and structures of nickel(II) compounds of 2,9-meso-7,14-rac-2,5,5,7,9,12,12,14-octamethyl-1,4,8,11-tetraazacyclotetradecane

Preparations and structures are reported for compounds of 2RS,7RS,9SR,14RS-[(2,5,5,7,9,12,14,14-octamethyl-1,4,8,11-tetrazacyclotetradecane)nickel(II)]2+: trans-octahedral [Ni(mr-III-L)(NCS)2], cis-octahedral [Ni(mr-V-L)(OAc)]ClO4 (and –H2O) with asymmetrical chelate acetato, [Ni(mr-V-L)(acac)]ClO4 and [Ni(mm1-III L)]·2[Ni(mr-V-L)(acac)](ClO4)4 with chelate pentane-2,4-dionato, trigonal pyramidal [Ni(mr-V-L)Cl]ClO4 and [Ni(mr-V-L)(NCS)]ClO4 and square-planar [Ni(mr-V-L)](ClO4)2, where III and V indicate the nitrogen configurations 1R,4S,8S,11R and 1R,4S,8R,11S respectively and mm1-L is the 2R,7S,9S,14R isomer of the amine. The preparations of [Ni(mr-V-L)(A)](ClO4), where A−=chelate nitrato, nitrito and μ-oxalato are reported.

Composición química del extracto de spilanthes americana

la flor del Spilanthes Americano ha sido comúnmente utilizada para el tratamiento del herpes labial recurrente mediante el uso del extracto de la flor en aceite amarillo, diluido en vaselina o alcohol. Objetivo: identificar y comparar los componentes químicos de la cabezuela de la flor con su diluido en alcohol y vaselina. Método: estudio descriptivo que identificó los componentes químicos de la cabezuela de la flor de Spilanthes americano, y del extracto diluido en vaselina y alcohol, mediante la aplicación de proceso de Espectroscopia Infrarroja Transformada de Fourier. Resultados: se identificaron grupos funcionales comunes a la cabezuela de la flor y a los diluidos en ambos vehículos como los grupos característicos del spilantol (N-isobutil-2,6,8-decatrienamida),compuestos químicos de hidrocarburos alifáticos lineales, gem dimetil, grupos carbonilos, y alquenos insaturados disustituidos. En el Spilanthes americano puro se encontró una amina secundaria, un grupo nitro, un ester, un nitrito y nitrato y azufre en forma de sulfonamida aromática. En los espectros de la muestra del sólido puro y el extracto diluido en vaselina se observaron alquenos insaturados disustituídos con isomería tipo trans, mientras que en el extracto diluido en alcohol se encontró una configuración tipo cis. Conclusiones: el análisis espectroscópico evidenció la presencia de grupos funcionales característicos del compuesto Spilantol, el cual cambió el tipo de isomería trans de la muestra pura y diluida en vaselina a cis en el extracto preparado en alcohol. Se encontraron como compuestos comunes a las 3 muestras azufre, y un grupo funcional orgánico tipo éster.

Computational study of C(sp3)-O bond formation at a PdIV centre.

This report describes a computational study of C(sp3)-OR bond formation from PdIV complexes of general structure PdIV(CH2CMe2-o-C6H4-C,C')(F)(OR)(bpy-N,N') (bpy = 2,2'-bipyridine). Dissociation of -OR from the different octahedral PdIV starting materials results in a common square-pyramidal PdIV cation. An SN2-type attack by -OR (-OR = phenoxide, acetate, difluoroacetate, and nitrate) then leads to C(sp3)-OR bond formation. In contrast, when -OR = triflate, concerted C(sp3)-C(sp2) bond-forming reductive elimination takes place, and the calculations indicate this outcome is the result of thermodynamic rather than kinetic control. The energy requirements for the dissociation and SN2 steps with different -OR follow opposing trends. The SN2 transition states exhibit "PdCO" angles in a tight range of 151.5 to 153.0°, resulting from steric interactions between the oxygen atom and the gem-dimethyl group of the ligand. Conformational effects for various OR ligands and isomerisation of the complexes were also examined as components of the solution dynamics in these systems. In all cases, the trends observed computationally agree with those observed experimentally.