Chiral Alkyl Research Articles

The staying power of electron-poor ligands

Organic Chemistry The venerable Suzuki coupling reaction originally used palladium to pair up unsaturated carbon centers. The protocol has been widely extended to chiral saturated alkyl carbons, but control over product stereochemistry is a pressing challenge. Zhao et al. systematically studied how the properties of the phosphine ligands that are coordinated to the catalyst influence the stereochemical outcome. Certain electron-withdrawing phosphines favored retention of the initial configuration in chiral alkyltrifluoroborate reactants. Conversely, bulky electron-rich phosphines lead to inverted configurations in the products. Science , this issue p. [670][1] [1]: /lookup/doi/10.1126/science.aat2299

Impact of 2-Ethylhexyl Stereoisomers on the Electrical Performance of Single-Crystal Field-Effect Transistors.

Many organic semiconductors (OSCs) inherit chiral alkyl chains, which ensure the desirable high solubility for solution-processing but may also lead to disorder, inhomogeneous film-formation, as well as interfacial defects due to the presence of mixtures of stereoisomers or diastereomers, which impair their peak performance. Here, single-crystal field-effect transistors (SCFETs) of a diketopyrrolopyrrole-based organic semiconductor with chiral 2-ethylhexyl substituents by sublimation in air and organic ribbon mask method are fabricated. Devices of the mesomer (R/S), both enantiomers (R/R, S/S), as well as mixtures of these three stereoisomers measured under ambient conditions exhibit all appreciable p-channel charge carrier mobilities of > 0.1 cm2 V-1 s-1 despite different packing arrangement in the R/S, R/R (or S/S), and racemate crystal structures. These results suggest a surprising tolerance for isomeric impurities. The highest literature-reported p-channel mobility so far for a diketopyrrolopyrrole-based OSC of 3.4 cm2 V-1 s-1 (Ion /Ioff of 1 × 106 ) is, however, only obtained for the pure R/S mesomer, illustrating the inherent potential of stereochemical purity. These results on SCFETs are further substantiated by studies on organic thin-film transistors (OTFTs) of pure and mixed thin films of the different stereoisomers.

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem-Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents.

An unprecedent gem-carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B2 pin2 to a carbonyl compound generates α-oxyl-substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2-metalate rearrangement process. The organolithium reagents can also be generated by C-H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst-controlled.

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

AbstractAn unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B2pin2 to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C−H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.

Ultrafast Iron-Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines, Oxaheterocycles, and Aminoalcohols.

A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h-1 at -30 °C highlight the activity of this earth-abundant metal catalyst which tolerates a large number of functional groups.

Molybdenum-Catalyzed Enantioselective Sulfoxidation Controlled by a Nonclassical Hydrogen Bond between Coordinated Chiral Imidazolium-Based Dicarboxylate and Peroxido Ligands.

Chiral alkyl aryl sulfoxides were obtained by molybdenum-catalyzed oxidation of alkyl aryl sulfides with hydrogen peroxide as oxidant in mild conditions with high yields and moderate enantioselectivities. The asymmetry is generated by the use of imidazolium-based dicarboxylic compounds, HLR. The in-situ-generated catalyst, a mixture of aqueous [Mo(O)(O2)2(H2O)n] with HLR as chirality inductors, in the presence of [PPh4]Br, was identified as the anionic binuclear complex [PPh4]{[Mo(O)(O2)2(H2O)]2(μ-LR)}, according to spectroscopic data and Density Functional Theory (DFT) calculations. A nonclassical hydrogen bond between one C–H bond of the alkyl R group of coordinated (LR)− and one oxygen atom of the peroxido ligand was identified as the interaction responsible for the asymmetry in the process. Additionally, the step that governs the enantioselectivity was theoretically analyzed by locating the transition states of the oxido-transfer to PhMeS of model complexes [Mo(O)(O2)2(H2O)(κ1-O-LR)]− (R = H, iPr). The ∆∆G≠ is ca. 0 kcal∙mol−1 for R = H, racemic sulfoxide, meanwhile for chiral species the ∆∆G≠ of ca. 2 kcal∙mol−1 favors the formation of (R)-sulfoxide.

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent

PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with S,S configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (R,R)-7, thus reducing the final yield significantly. Therefore, we have investigated potential alternatives to improve the efficiency of this synthesis. The first phase of the study has demonstrated proof of principle for a chiral alkylation of ketone 3 using phase-transfer catalysis, providing a key intermediate ketone (S)-4. The parent alkaloids required for the synthesis of PH46A, quinine or cinchonidine, have also been identified. Promising enantiomeric excesses of up to 50% have been achieved to date, and the use of an alternative substrate, unsaturated ketone 9, has also opened up further avenues for optimisation in future studies. The second part of the study involved preliminary screening the effects of a panel of hydrolase enzymes on (rac)-4 in order to identify a potential chemo-enzymatic route to optimise the introduction of chirality into PH46A at early stage of the synthesis. The hydrolase module has also yielded positive results; enzyme AH-46 with MtBE providing a selectivity factor of 8.4 with enantiomeric excess of 77%. Overall, positive results were obtained in this proof of concept study described herein. It is believed that conditions of both chiral PTC alkylation and biocatalytic hydrolysis could be optimised to further enhance the selectivity and improve the overall yield. This work is currently ongoing.

Estimation of the helical twisting power of chiral inducers by time-dependent density functional theory (TD-DFT) for electrochemical polymerization in cholesteric liquid crystals

Five chiral compounds were designed and synthesized using the Mitsunobu reaction to act as chiral inducers (i.e., chiral dopants) for the transformation of a nematic liquid crystal (LC) (4-n-octoxy-4′-cyanobiphenyl) into a cholesteric LC. These chiral inducers contain two types of chiral alkyl chains with different kinds of achiral mesogenic cores (biphenylcarboxylate, biphenoxy, and cyanobiphenoxy). We observed that the achiral mesogenic cores affected the helical twisting power in terms of both induction strength and helicity (left-/right-hand introduction). All the ester type inducers exhibited a positive Cotton effect and right-hand helical twisting power (HTP). However, ethers exhibited a negative Cotton effect and left-hand HTP. The microscopic HTPs (βM) of these inducers demonstrate a linear relation with their optical activities (ellipticity near the absorption maximum). Further, the time-dependent density functional theory (TD–DFT) calculation using the B3LYP/6-311++G (d, p) method has been used to predict the circular dichroism spectra of these inducers. The predicted optical activity was observed to be in accordance with that observed in the experimental result. This study proposes a method for predicting the HTP of chiral inducers that can be applied to achieve polymerization in the reaction fields of cholesteric LCs.

A Complementary Toolbox of Iterative Methods for the Stereo­selective Synthesis of Heteroatom-Rich Motives from C1-Building Blocks

The ability to assemble organic molecules one carbon atom at a time has been a long-held dream for chemists. Modern boronate homologations with chiral carbenoids allow for the assembly-line synthesis of long chiral alkyl chains with excellent control over individual stereocenters. Nevertheless, heteroatom rich motives present a serious synthetic challenge to this approach. Interestingly, older methods based on substrate-controlled homologations of chiral boronic esters or umpolung of a carbonyl nucleophile can offer complementary solutions. A combination of these approaches might thus extend the range of possible targets currently within grasp of a C1-based synthesis. Link to video abstract: https://www.youtube.com/watch?v=PH_HBrqQwtg .1 Introduction2 Substrate Control: Stereoselective Addition of d1-Reagents to Aldehydes­3 Stereocontrol by Chiral Auxiliary/Director: The Matteson Boronate Homologation4 Reagent Control: Moving Chiral Information to the Carbenoid5 Conclusions and Outlook

Exploiting Chromophore-Protein Interactions through Linker Engineering To Tune Photoinduced Dynamics in a Biomimetic Light-Harvesting Platform.

Creating artificial systems that mimic and surpass those found in nature is one of the great challenges of modern science. In the context of photosynthetic light harvesting, the difficulty lies in attaining utmost control over the energetics, positions and relative orientations of chromophores in densely packed arrays to transfer electronic excitation energy to desired locations with high efficiency. Toward achieving this goal, we use a highly versatile biomimetic protein scaffold from the tobacco mosaic virus coat protein on which chromophores can be attached at precise locations via linkers of differing lengths and rigidities. We show that minor linker modifications, including switching chiral configurations and alkyl chain shortening, lead to significant lengthening of the ultrafast excited state dynamics of the system as the linkers are shortened and rigidified. Molecular dynamics simulations provide molecular-level detail over how the chromophore attachment orientations, positions, and distances from the protein surface lead to the observed trends in system dynamics. In particular, we find that short and rigid linkers are able to sandwich water molecules between chromophore and protein, leading to chromophore-water-protein supracomplexes with intricately coupled dynamics that are highly dependent on their local protein environment. In addition, cyclohexyl-based linkers are identified as ideal candidates to retain rotational correlations over several nanoseconds and thus lock relative chromophore orientations throughout the lifetime of an exciton. Combining linker engineering with judicious placement of chromophores on the hydrated protein scaffold to exploit different chromophore-bath couplings provides a clear and effective path to producing highly controllable artificial light-harvesting systems that can increasingly mimic their natural counterparts, thus aiding to elucidate natural photosynthetic mechanisms.

Solvent polarity effects on supramolecular chirality of a polyfluorene-thiophene copolymer.

This study demonstrates the supramolecular chirality control of a conjugated polymer via solvent polarity. We designed and synthesized a chiral polyfluorene-thiophene copolymer having two different chiral side chains at the 9-position of the fluorene unit. Chiral cyclic and alkyl ethers with different polarities were selected as the chiral side chains. The sign of the circular dichroism spectra in the visible wavelength region was affected by the solvent system, resulting from the change of supramolecular structure. The estimation of the solubility parameter revealed that the solubility difference of the side chains contributed to the change of the circular dichroism sign, which was also observed in spin-coated films prepared from good solvents having different polarities.

Noticeable Chiral Center Dependence of Signs and Magnitudes in Circular Dichroism (CD) and Circularly Polarized Luminescence (CPL) Spectra ofall-trans-Poly(9,9-dialkylfluorene-2,7-vinylene)s Bearing Chiral Alkyl Side Chains in Solution, Aggregates, and Thin Films

Effects of chiral alkyl side chains in poly(9,9-dialkyl-fluorene-2,7-vinylene)s [PFVs, (S)-3-methylpentyl (3mpe), (S)-4-methylhexyl (4mhex), (S)-5-methylheptyl (5mhep), (S)-6-methyloctyl (6moct), and (S)-3,7-dimethyloctyl (dmo)] toward aggregation-induced circular dichroism (AICD) and circularly polarized luminescence (AICPL) and CD/CPL spectra in solution and in thin film have been explored. The (all-trans) PFV samples with similar conjugation repeat units containing well-defined (vinyl) end groups were prepared by acyclic diene metathesis polymerization using Ru catalyst. The PFV aggregates, prepared in situ in a mixed solution of CHCl3/MeOH, showed clear CD signals ascribed to AICD, whereas these samples showed CD-silent in the CHCl3 solution. The absolute magnitude (gCD value) was affected by the chiral side chains (without obey the even–odd rule) and increased in the order 3mpe, 5mhep < 4mhex < dmo < 6mcot. Both the 6-moct and dmo aggregates showed clear CPL signals ascribed to AICPL, whereas signals...

A Pure Polyproline Type I-like Peptoid Helix by Metal Coordination.

Peptoids, N-substituted glycine oligomers, are an important class of foldamers that can adopt polyproline-type helices (PP-I and PP-II), given that the majority of their sequence consists of chiral, bulky side chains. Herein a new approach for the stabilization of a pure PP-I-like peptoid helix through metal coordination is introduced. A systematic spectroscopic study was performed on a series of peptoid heptamers bearing two 8-hydroxyquinoline ligands at fixed positions, and a mixture of chiral benzyl and alkyl substituents in varied positions along the peptoid backbone. When the benzyl groups are located at the 3rd and 4th positions, the peptoid (7P6) gives upon Cu2+ binding a circular dichroism (CD) signal similar to that of a PP-I helix. Exciton couplet CD spectroscopy and EPR spectroscopy, as well as modifications to the length of 7P6 and derivatization through acetylation provided insights into the unique folding of 7P6 upon Cu binding, showing that it is led by two competing driving forces, namely coordination geometry and sequence.

Enantioselective Phosphine-Catalyzed Allylic Alkylations of mix-Indene with MBH Carbonates.

The first enantioenriched synthesis of 1,1,3-trisubstituted (trifluoromethyl)indene derivatives, bearing a quaternary stereogenic carbon center, is reported using a simple chiral sulfinamide phosphine-catalyzed asymmetric allylic alkylation of a mixture of indenes with Morita-Baylis-Hillman carbonates. The resulting derivatives can serve as a valuable synthetic building block for some drugs and natural products. Broad substrate scope and high regio- and enantioselectivity of this reaction were particularly remarkable.

Magnesium Catalysis Mediated Tetrazoles in Desymmetrization Reaction of Aziridines.

A magnesium-catalyzed asymmetric ring-opening reaction of aziridines with substituted tetrazoles is reported. The current protocol proceeds smoothly and gives the corresponding desymmetrization products in high yields and good enantioselectivities. A new chiral ligand was synthesized from azetidine and (R)-BINOL and was employed in the current in situ generated magnesium catalyst. The Mg(II)-mediated desymmetrization reaction could be performed on gram scale under mild conditions and was transformed to chiral alkyl amines by a deprotection process.

A highly active chiral (S,S)-bis(oxazoline) Pd(ii) alkyl complex/activator catalytic system for vinyl polymerization of norbornene in air and water

The air/water-tolerant chiral Pd alkyl complexes/borate systems promote the norbornene polymerization both in air and water using unpretreated technical grade solvent and monomer with extremely high activity up to 1.7 × 109 g PNB per molPd per h.

A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters.

Alkylboron compounds are an important family of target molecules, serving as useful intermediates, as well as end points, in fields such as pharmaceutical science and organic chemistry. Facile transformation of carbon-boron bonds into a wide variety of carbon-X bonds (where X is, for example, carbon, nitrogen, oxygen, or a halogen), with stereochemical fidelity, renders the generation of enantioenriched alkylboronate esters a powerful tool in synthesis. Here we report the use of a chiral nickel catalyst to achieve stereoconvergent alkyl-alkyl couplings of readily available racemic α-haloboronates with organozinc reagents under mild conditions. We demonstrate that this method provides straightforward access to a diverse array of enantioenriched alkylboronate esters, in which boron is bound to a stereogenic carbon, and we highlight the utility of these compounds in synthesis.

Chiral Alkyl Halides: Underexplored Motifs in Medicine.

While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.

ChemInform Abstract: Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram.

AbstractA range of chiral diaryl alkyl carbinols is prepared with excellent yields and enantioselectivities as well as broad functional group tolerance utilizing a Rh/(R,R,R,R)‐WingPhos catalyst.

Simple Modular Synthetic Approaches to Asymmetric NN′N′′, NN′C, or NN′P-Type Amido Pincer Ligands: Synthesis, Characterisation, and Preliminary Ligation Studies

A simple modular approach is presented which has been directed towards the synthesis of potentially monoanionic NN′N′′, NN′C, and NN′P pincer-type ligands. These pincers incorporate an amide functionality derived from the skeletal structure of readily available 2-(2-aminophenyl)-4,5-dioxooxazoles. All of the pincers are synthesized in moderate yields (up to 74%) and are characterised by nuclear magnetic spectroscopy (NMR), elemental analyses, and infrared (IR) spectroscopy. X-ray crystallography is also performed on the chiral and achiral alkyl halide precursors and on an oxide derivative of a pincer with a NN′P-atom donor set. A palladium derivative of one of the NN′N′′-pincers is shown to be an active catalyst for the addition of an allyl group to various benzaldehydes using n-Bu3Sn(allyl) as allyl source.