Biaryl Lactones Research Articles

Organocatalytic diastereo- and atropo-selective construction of eight-membered bridged (hetero)biaryls via asymmetric intramolecular [3 + 2] cycloaddition.

An unprecedented and straightforward route for the asymmetric construction of privileged atroposelective bridged (hetero)biaryl eight-membered scaffolds has been accomplished through chiral phosphoric acid catalyzed asymmetric intramolecular [3 + 2] cycloaddition of innovative (hetero)biaryl aldehydes with 3-aminooxindole hydrochlorides. A class of eight-membered bridged (hetero)biaryl lactones fused to spiro[pyrrolidine-oxindole] derivatives, possessing both chiral C-C/C-N axes and multiple contiguous stereocenters, were obtained in good yields with excellent enantioselectivities and diastereoselectivities in one step through this direct strategy. In addition, the good scalability and derivatization of the title compounds demonstrated their synthetic utility.

The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids.

The naphthylisoquinoline (NIQ) alkaloids are a thrilling class of natural biaryls─structurally, biosynthetically, and pharmacologically. A common feature of these metabolites is the biaryl bond between their naphthalene and isoquinoline moieties, which in most cases is rotationally hindered, leading to the phenomenon of axial chirality. Depending on their individual structures, including the respective axial configurations, NIQs show promising bioactivities. Their total synthesis is a challenging but rewarding goal, with the stereocontrolled construction of the biaryl linkage as the key step.The position of the biaryl axis and its configuration determine the overall molecular shape and thus the choice of the best possible method for efficient asymmetric aryl-aryl bond formation. The axis in NIQs can cover a broad range of steric hindrance, from freely rotating to configurationally stable. For dioncophylline B (1) and dioncophylline F (2a/b), with only two ortho-substituents next to the axis, the synthesis is easy to accomplish by direct coupling of the intact naphthalene moiety with the isoquinoline unit, and no atropo-selectivity is required.Naphthylisoquinolines with a configurationally stable biaryl axis are the focus of the present Account. They are more difficult to synthesize because, in addition to the problem of decreased chemical yields with increasing steric hindrance at the axis, the synthesis needs to proceed stereoselectively. Within this class of NIQs, 5,8'-coupled representatives, such as korupensamine A (3a), have received considerable synthetic attention because the rotational barrier is high enough for the existence of atropisomerism without being too excessive, and they show potent bioactivities. Their synthesis, as systematically presented herein, thus occupies a central role in this report. For their aryl-aryl bond formation, both intra- and intermolecular approaches can be successfully applied. Axial stereoinformation is introduced by internal asymmetric induction from stereogenic elements already present in the isoquinoline or its precursors, from chiral auxiliary elements artificially introduced, or by external asymmetric induction using chiral catalysts.To overcome even higher steric hindrance, as in ancistrocladine (4a), innovative approaches were developed. A most successful strategy is the "lactone concept" developed by the Bringmann group, which allows the directed synthesis of any desired atropisomer in high chemical and optical yields, thus permitting the atropo-divergent preparation of the two isomers from a single joint precursor. In this approach, the two formal tasks of stereoselective biaryl synthesis, which are usually done simultaneously─the C-C linkage and the asymmetric induction─are achieved consecutively. The coupling step is performed intramolecularly after prefixation of the coupling partners by an ester bridge. The resulting biaryl lactone already possesses the biaryl axis but is still configurationally unstable; it can then, with internal or external asymmetric induction, be cleaved atropo-divergently with high stereoselectivities. Besides its unique concept, the procedure excels by its broad applicability; among all presented methods, it has been used for the synthesis of the largest number of NIQs, more than 20 representatives, including those with the highest steric hindrance.This Account gives comprehensive insight into the plethora of conceptual approaches for the efficient formation of the hindered biaryl bond of NIQs.

Cobalt (II)‐catalyzed oxidation of 2‐aryl benzoic acids to access biaryl lactones

Cobalt/peroxymonosulfate (Co/PMS) system is an efficient advanced oxidation process (AOP) for degradation of organic pollutants in wastewater, however, has limitations in organic synthesis. Herein, we employ a Co/PMS system to the preparation of biaryl lactones by the valorization of 2‐aryl aromatic acids via intramolecular O‐H/C‐X oxidative coupling. This system exhibits intriguing advantages, such as non‐noble metal catalyst, common oxidant, mild condition, easy workup and product isolation. Mechanism studies, including the radical quenching experiments and multiple probe substrates, suggest that a high‐valent cobalt‐oxo intermediate should be one major active species. Meanwhile, both persulfate radical anion (SO4•−) and hydroxyl radical (•OH) are present in the process and contribute to the organic reaction. This work not only expands the synthetic application of Co/Oxone system beyond environmental fields, but also provides more active intermediates than generally‐accepted SO4•− in the known metal‐based AOPs.

Cerium Ammonium Nitrate-Mediated Access to Biaryl Lactones: Substrate Scopes and Mechanism Studies.

Herein we described an access to biaryl lactones from ortho-aryl benzoic acids via intramolecular O-H/C-H oxidative coupling with the commonly used cerium ammonium nitrate (CAN) as the one-electron oxidant under a thermal condition. The radical interrupting experiment suggested a radical process, while the kinetic isotope effect (KIE) showed that the C-H cleavage likely was not involved in the rate-determining step. Competitive reactions, especially the strikingly different ρ values of Hammett equations, indicated that the reaction rate was more sensitive to the electronic properties on the aryl moiety rather than the carboxylic moiety, which corresponded to the first single electron transfer (SET) step. In addition, the quite negative ρ values (-4.7) of the aryl moiety unveiled the remarkable electrophilic nature of the second intramolecular radical addition process, which was also consistent with product yields and regioselectivity. Moreover, control experiments disclosed that the single electron in the third step was also transferred to CeIV instead of molecular oxygen. Besides, the possible role of co-solvents trifluoroethanol (TFE) and its influences on the CeIV species were discussed. This work elucidated the possible mechanism by proposing the step that had more effects on the total reaction rate and the species that was responsible for the last single electron transfer.

Catalytic Atroposelective Dynamic Kinetic Resolution of Biaryl Lactones with Activated Isocyanides.

We report herein an unprecedented atroposelective dynamic kinetic resolution of Bringmann's lactones with C-nucleophiles. By the use of activated isocyanides as the reagent, a wide range of novel axially chiral oxazole-substituted biaryl phenols were accessed in high yields with high enantioselectivities. Key to the success of this process lies in the tandem atroposelective addition of isocyanides to the lactone substrate followed by a rapid cyclization, overcoming the challenge of stereochemical leakage induced by lactol formation.

Design and Synthesis of Chiral oxa-Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric Reduction of Bringmann's Lactones with Molecular H2.

We herein present a facile and column-free synthetic route toward a structurally unique oxa-spirocyclic diphenol, termed as O-SPINOL. Features of the synthesis include the construction of the all-carbon quaternary center at an early stage, a key double intramolecular SNAr step to introduce the spirocycles and the feasibility of operating on >100 g scale. Both enantiomers of O-SPINOL can be easily accessed through optical resolution with l-proline by control of the solvent. The chiral tridentate ligand O-SpiroPAP derived from O-SPINOL has been successfully synthesized and applied in the iridium-catalyzed asymmetric hydrogenation of bridged biaryl lactones under mild reaction conditions, providing valuable and enantioenriched axially chiral molecules in excellent yields and enantioselectivities (up to 99% yield and >99% ee). This method represents a rare example of constructing axially chiral molecules by direct reduction of esters with H2.

Microwave Specific Effect on Catalyticatropo-Enantioselective Ring-Opening Reaction of Biaryl Lactones

AbstractThe microwave specific effect on the catalytic atropo-enantioselective ring-opening reaction of biaryl lactones was investigated. Under strictly controlled temperature conditions, the reaction was accelerated by microwave irradiation without any loss of the enantioselectivity. Also, the racemization rate of the atropo-optically active biaryl lactone was enhanced by the microwave irradiation.

Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification.

A solution to the unmet synthetic challenge of achieving highly atropo-enantioselective transesterification of Bringmann's lactones has been realized, employing a chiral bifunctional amine thiourea as promoter. The synergistic activation of the lactones and alcohols/phenols by the respective thiourea and amine groups is crucial for achieving the highly enantioselective, high-yielding dynamic kinetic resolution process. This protocol gives highly optically pure, axially chiral biaryl compounds with a broad substrate scope under mild reaction conditions.

On the lipase-catalyzed resolution of functionalized biaryls

The implementation of lipase catalysis as a tool for the preparation of optically active biaryls is discussed. While attempts toward dynamic kinetic resolution based on the catalytic ring opening of configurationally unstable biaryl lactones were fruitless, kinetic resolution via transesterification of hydroxymethyl-decorated substrates was successfully employed in the generation of optically enriched, axially chiral biaryls.

ChemInform Abstract: Extraordinary Microwave Effect on atropo‐Enantioselective Catalytic Reduction of Biaryl Lactones.

AbstractThe catalytic atropo‐enantioselective Corey—Bakshi—Shibata reduction of biaryl lactones such as (I) and (III) is drastically enhanced under microwave conditions, while high enantioselectivity is maintained.

Pd-Catalyzed C–H Lactonization for Expedient Synthesis of Biaryl Lactones and Total Synthesis of Cannabinol

A practical Pd(II)/Pd(IV)-catalyzed carboxyl-directed C-H activation/C-O cyclization to construct biaryl lactones has been developed. The synthetic utility of this new reaction was demonstrated in an atom-economical and operationally convenient total synthesis of the natural product cannabinol from commercially available starting materials, with the newly developed method used for two key steps.

Extraordinary Microwave Effect on atropo-Enantioselective Catalytic Reduction of Biaryl Lactones

Abstract It was found that microwave irradiation under strictly controlled temperature conditions drastically enhanced the catalytic atropo-enantioselective Corey–Bakshi–Shibata (CBS) reduction of biaryl lactones. Since the high enantioselectivity was maintained completely compared with conventional heating conditions, the present enhancement is not caused by simple microwave heating. It was also revealed that the microwave irradiation could accelerate the racemization of the atropo-enantiomers of optically active biaryl lactone. It could be concluded that the drastic enhancement with retention of the high enantioselectivity was caused not by simple heating, but by some direct microwave effect on the substrate molecule.

Donor–acceptor biaryl lactones: pH induced molecular switches with intramolecular charge transfer modulation

The physical properties of biaryl-containing compounds are known to be highly dependent on molecular geometry. We report the syntheses and fundamental spectroscopic study of two donor–acceptor biaryl lactone (6H-benzo[c]chromen-6-one) pH-driven switches. These compounds have been determined to rapidly and efficiently switch between two geometric states upon cycling of acidic or basic stimuli. The planar lactone state exhibits enhanced intramolecular charge transfer (ICT) between the donor and acceptor units which is instantly attenuated upon addition of basic stimuli. The resulting lactone cleavage enables aryl–aryl bond rotation thus decreasing the extent of conjugation between the rings. Each state is readily identifiable by the significant changes that occur in their respective UV–vis spectra and luminescent character, indicative of the facile modulation of extended conjugation by pH.

ChemInform Abstract: One‐Pot Synthesis of Biaryl Lactones by Sonogashira Cross‐Coupling Reactions of 4‐Chloro‐3‐formylcoumarin and Subsequent Domino [5 + 1] Cyclization/Deacetylation Reactions with 1,3‐Dicarbonyl Compounds.

Biaryl lactones were prepared by a new palladium(0) and base-catalyzed one-pot reaction of 4-chloro-3-formylcoumarin with alkynes and 1,3- dicarbonyl compounds.

One‐Pot Synthesis of Biaryl Lactones by Sonogashira Cross‐Coupling Reactions of 4‐Chloro‐3‐formylcoumarin and Subsequent Domino [5+1] Cyclization/Deacetylation Reactions with 1,3‐Dicarbonyl Compounds

AbstractBiaryl lactones were prepared by a new palladium(0) and base‐catalyzed one‐pot reaction of 4‐chloro‐3‐formylcoumarin with alkynes and 1,3‐dicarbonyl compounds.

Extraordinary Effect of Microwave Irradiation on Asymmetric Catalysis

Abstract We here report the effect of microwave irradiation on the atropo-enantioselective ring-opening reaction of biaryl lactones with dynamic–kinetic resolution catalyzed by AgBF4–phosphine complexes. The multimode microwave reactor with a cooling system was employed and the fiber-optic sensor was used for measurement of the accurate internal reaction temperature. It was found that the reaction was accelerated by microwave irradiation without any loss of enantioselectivity at almost the same internal temperature as the conventional conditions.

Catalytic atropo-Enantioselective Ring Opening of Biaryl Lactones

Catalytic <i>atropo-</i>Enantioselective Ring Opening of Biaryl Lactones

Catalytic atropo-Enantioselective Preparation of Axially Chiral Biaryl Compounds

Abstract The atropo-enantioselective ring-opening of biaryl lactones with methanol was catalyzed by an optically active AgBF4–phosphine complex to afford axially chiral biaryl compounds. The addition of triisobutylamine provided a dramatic rate acceleration in the reaction. Various types of axially chiral biaryl compounds were obtained with high enantioselectivity.

Enantioselective Reduction of Biaryl Lactones via DKR

Chiral biaryl compounds are typically accessed by biaryl couplings followed by a resolution; a challenging approach in cases of hindered ortho-substituted aryl partners. The above strategy is advantageous since the biaryl coupling is effected on intramolecular aryl partners tethered by an ester function. The racemic atropisomer mixture is submitted to a dynamic kinetic resolution (DKR) where asymmetric reduction occurs at a temperature where rapid isomerization of the atropisomers can take place. Reduction of the matched atropisomer fully converts the racemic mixture into the desired enantiomer of the biaryl compound in high enantiomeric ecxess.

Catalytic atropo-Enantioselective Reduction of Biaryl Lactones to Axially Chiral Biaryl Compounds

The atropo-enantioselective borohydride reduction with dynamic kinetic resolution of biaryl lactones was catalyzed by an optically active beta-ketoiminatocobalt(II) complex to afford optically active biaryl compounds. Chiral HPLC analysis of the starting biaryl lactones was performed at various temperatures to determine suitable reaction conditions for dynamic kinetic resolution. Various types of axially chiral biaryl compounds were obtained with high enantioselectivity.