Chiral Bidentate Research Articles

Synthesis of Cyclic Anhydrides via Ligand‐Enabled C–H Carbonylation of Simple Aliphatic Acids

AbstractThe development of C(sp3)–H functionalizations of free carboxylic acids has provided a wide range of versatile C−C and C−Y (Y=heteroatom) bond‐forming reactions. Additionally, C–H functionalizations have lent themselves to the one‐step preparation of a number of valuable synthetic motifs that are often difficult to prepare through conventional methods. Herein, we report a β‐ or γ‐C(sp3)–H carbonylation of free carboxylic acids using Mo(CO)6as a convenient solid CO source and enabled by a bidentate ligand, leading to convenient syntheses of cyclic anhydrides. Among these, the succinic anhydride products are versatile stepping stones for the mono‐selective introduction of various functional groups at the β position of the parent acids by decarboxylative functionalizations, thus providing a divergent strategy to synthesize a myriad of carboxylic acids inaccessible by previous β‐C–H activation reactions. The enantioselective carbonylation of free cyclopropanecarboxylic acids has also been achieved using a chiral bidentate thioether ligand

Chiral Bidentate Phosphoramidite-Pd Catalyzed Asymmetric Decarboxylative Dipolar Cycloaddition for Multistereogenic Tetrahydrofurans with Cyclic N-Sulfonyl Ketimine Moieties.

An asymmetric [3 + 2] cycloaddition of vinyl ethylenecarbonates (VECs) and (E)-3-arylvinyl substituted benzo[d] isothiazole 1,1-dioxides has been developed using the Pd complex of a bidentate phosphoramidite (Me-BIPAM) as the catalyst, providing a wide variety of chiral multistereogenic vinyltetrahydrofurans in good yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, 99% ee).

Regio- and Stereoselective Functionalization Enabled by Bidentate Directing Groups.

Chelation-assisted C-H bond and alkene functionalization using bidentate directing groups offers an elegant and versatile approach to overcome regiocontrol issues by allowing the catalyst to come into close proximity with the targeted sites. In this personal account, we highlight our recent works in developing regio- and stereocontrolled functionalizations through transition-metal catalysis enabled by bidentate directing groups. We classify our results into two categories: (1) regioselective alkene functionalization using bidentate directing groups, and (2) asymmetric C-H functionalization using chiral bidentate directing groups. Furthermore, density functional theory studies to elucidate the origin of the regio- and stereoselectivity exerted by bidentate directing groups are discussed.

Catalytic Enantioselective Aminopalladation–Heck Cascade

AbstractDomino processes initiated by intramolecular nucleopalladation of alkynes have been developed into powerful synthetic tools for the synthesis of functionalized heterocycles. However, a catalytic enantioselective version of this class of reactions remains scarce. We report herein that reaction of 2‐alkynylanilines with prochiral cyclopentenes in the presence of a catalytic amount of Pd(OAc)2, a chiral bidentate pyrox ligand and O2 as terminal oxidant affords the structurally diverse indole‐cyclopentene conjugates bearing two stereocenters in a highly diastereo‐ and enantio‐selective manner. One of the products is converted to a heavily functionalized tetracyclic indolinone derivative.

Catalytic Enantioselective Aminopalladation-Heck Cascade.

Domino processes initiated by intramolecular nucleopalladation of alkynes have been developed into powerful synthetic tools for the synthesis of functionalized heterocycles. However, a catalytic enantioselective version of this class of reactions remains scarce. We report herein that reaction of 2-alkynylanilines with prochiral cyclopentenes in the presence of a catalytic amount of Pd(OAc)2 , a chiral bidentate pyrox ligand and O2 as terminal oxidant affords the structurally diverse indole-cyclopentene conjugates bearing two stereocenters in a highly diastereo- and enantio-selective manner. One of the products is converted to a heavily functionalized tetracyclic indolinone derivative.

Larger scale Stahl oxidation with instant Cu removal in convenient synthesis of chiral bidentate N–heterocyclic carbene precursor

Commercially available N-Boc protected l-proline can be efficiently converted into a chiral, bidentate, aminoalkyl N-heterocyclic carbene ligand precursor in high yield (50% total after 4 steps) without column chromatography purification at any moment. The developed synthetic path includes: (1) redox step leading to an aldehyde, (2) imine condensation and in situ reduction to 1,2-diamine; (3) heterocyclization; (3) removal of the protecting group. Instant separation of Cu traces after the key Stahl oxidation at gram-scale was facilitated by the use of bis(isocyanide) scavenger, SnatchCat, forming insoluble, easy to remove RNC:→[Cu] complexes that allowed usto obtain crude intermediate suitably pure for next steps without tedious purification.

Iridium-Catalyzed Regio- and Enantioselective Borylation of Unbiased Methylene C(sp3 )-H Bonds at the Position β to a Nitrogen Center.

Reported herein is the pyrazole-directed iridium-catalyzed enantioselective borylation of unbiased methylene C-H bonds at the position β to a nitrogen center. The combination of a chiral bidentate boryl ligand, iridium precursor, and pyrazole directing group was responsible for the high regio- and enantioselectivity observed. The method tolerated a vast array of functional groups to afford the corresponding C(sp3 )-H functionalization products with good to excellent enantioselectivity.

Iridium‐Catalyzed Regio‐ and Enantioselective Borylation of Unbiased Methylene C(sp3)−H Bonds at the Position β to a Nitrogen Center

AbstractReported herein is the pyrazole‐directed iridium‐catalyzed enantioselective borylation of unbiased methylene C−H bonds at the position β to a nitrogen center. The combination of a chiral bidentate boryl ligand, iridium precursor, and pyrazole directing group was responsible for the high regio‐ and enantioselectivity observed. The method tolerated a vast array of functional groups to afford the corresponding C(sp3)−H functionalization products with good to excellent enantioselectivity.

C 1-Symmetric diphosphorus ligands in metal-catalyzed asymmetric hydrogenation to prepare chiral compounds.

Asymmetric hydrogenation has remained an important and challenging research area in industry as well as academia due to its high atom economy and ability to induce chirality. Among several types of ligands, chiral bidentate phosphine ligands have played a pivotal role in developing asymmetric hydrogenation. Although C2-symmetric chiral bidentate phosphine ligands have dominated the field, it has been found that several C1-symmetric ligands are equally effective and, in many cases, have outperformed their C2-symmetric counterparts. This review evaluates the possibility of the use of C1-symmetric diphosphorus ligands in asymmetric hydrogenation to produce chiral compounds. The recent strategies and advances in the application of C1-symmetric diphosphorus ligands in the metal-catalyzed asymmetric hydrogenation of a variety of CC bonds have been summarized. The potential of diphosphorus ligands in asymmetric hydrogenation to produce pharmaceutical intermediates, bioactive molecules, drug molecules, agrochemicals, and fragrances is discussed. Although asymmetric hydrogenation appears to be a problem that has been resolved, a deep dive into the recent literature reveals that there are several challenges that are yet to be addressed. The current asymmetric hydrogenation methods mostly employ precious metals, which are depleting at a fast pace. Therefore, scientific interventions to perform asymmetric hydrogenation using base metals or earth-abundant metals that can compete with established precious metals hold significant potential.

Highly Enantioselective Iridium-Catalyzed Hydrogenation of Conjugated Trisubstituted Enones.

Asymmetric hydrogenation of conjugated enones is one of the most efficient and straightforward methods to prepare optically active ketones. In this study, chiral bidentate Ir–N,P complexes were utilized to access these scaffolds for ketones bearing the stereogenic center at both the α- and β-positions. Excellent enantiomeric excesses, of up to 99%, were obtained, accompanied with good to high isolated yields. Challenging dialkyl substituted substrates, which are difficult to hydrogenate with satisfactory chiral induction, were hydrogenated in a highly enantioselective fashion.

Iridium‐Catalyzed Enantioselective Unbiased Methylene C(sp3)–H Borylation of Acyclic Amides

AbstractWe herein report amide directed enantioselective β‐C(sp3)−H borylation of unbiased methylene C−H bonds of acyclic amides enabled by iridium catalysis for the first time. The key to the success of this transformation relies on the careful selection of the combination of iridium precursor and chiral bidentate boryl ligands. A variety of functional groups are well‐tolerated, affording chiral β‐functionalized amides in good to excellent enantioselectivities. We also demonstrate the application of the current method by stereospecific conversion of C−B bond into other functionalities.

Iridium-Catalyzed Enantioselective Unbiased Methylene C(sp3 )-H Borylation of Acyclic Amides.

We herein report amide directed enantioselective β-C(sp3 )-H borylation of unbiased methylene C-H bonds of acyclic amides enabled by iridium catalysis for the first time. The key to the success of this transformation relies on the careful selection of the combination of iridium precursor and chiral bidentate boryl ligands. A variety of functional groups are well-tolerated, affording chiral β-functionalized amides in good to excellent enantioselectivities. We also demonstrate the application of the current method by stereospecific conversion of C-B bond into other functionalities.

Front Cover: Asymmetric Synthesis of Multi‐substituted Prolines via a Catalytic 1,3‐Dipolar Cycloaddition Using a Monocationic ZnIIOAc Complex of a Chiral Bisamidine Ligand, Naph‐diPIM‐dioxo‐R (ChemCatChem 22/2020)

The Front Cover shows a highly efficient catalytic enantioselective 1,3-dipolar cycloaddition of tridentate-type α-imino esters and acrylates. In their Communication, I. N. Chaithanya Kiran et al. explain the catalyst's design concept and its performance for the reaction. The catalyst is a monocationic zinc acetate complex of a chiral bisamidine-type bidentate ligand. An anionic acetate ligand of the Lewis acidic Zn complex acts as a Brønsted base to facilitate a smooth intramolecular deprotonation to generate an imino N,O-cis-Zn enolate. The oxygen atoms of two dioxolanes of the ligand form a C2 chiral scaffold, in which the Zn enolate position is well controlled by a non-bonding n-π* interaction. The catalyst shows high activity, diastero-/enantio-/regio-selectivity, productivity, and broad generality. This reaction provides a path for the synthesis of pyrrolidine-containing chiral bioactive compounds, ligands and organocatalysts. More information can be found in the Communication by I. N. Chaithanya Kiran et al.

A New Mechanically-Interlocked [Pd2 L4 ] Cage Motif by Dimerization of two Peptide-based Lemniscates.

Most metallo‐supramolecular assemblies of low nuclearity adopt simple topologies, with bridging ligands spanning neighboring metal centers in a direct fashion. Here we contribute a new structural motif to the family of host compounds with low metal count (two) that consists of a pair of doubly‐interlocked, Figure‐eight‐shaped subunits, also termed “lemniscates”. Each metal is chelated by two chiral bidentate ligands, composed of a peptidic macrocycle that resembles a natural product with two pyridyl‐terminated arms. DFT calculation results suggest that dimerization of the mononuclear halves is driven by a combination of 1) Coulomb interaction with a central anion, 2) π‐stacking between intertwined ligand arms and 3) dispersive interactions between the structure's compact inner core bedded into an outer shell composed of the cavitand‐type macrocycles. The resulting cage‐like architecture was characterized by NMR, MS and X‐ray structure analyses. This new mechanically bonded system highlights the scope of structural variety accessible in metal‐mediated self‐assemblies composed of only a few constituents.

Iridium‐Catalyzed Enantioselective C(sp3)–H Borylation of Cyclobutanes

Summary of main observation and conclusionWe herein report the first example of iridium‐catalyzed enantioselective C(sp3)–H borylation of cyclobutanes using benzoxazoline as the directing group. The combination of a chiral bidentate boryl ligand and an iridium precursor has found to effectively catalyze C(sp3)–H borylation to afford a variety of cyclobutylboronates with good to excellent enantioselectivities. We also demonstrate the synthetic utility of the current method by converting the stereogenic C—B bond to other functionalities.

Iridium-Catalyzed Enantioselective α-C(sp3)-H Borylation of Azacycles.

We herein report an iridium-catalyzed enantioselective α-C(sp3)-H borylation of a wide range of azacycles. The combination of an iridium precursor and a chiral bidentate boryl ligand has been shown to effectively differentiate enantiotropic methylene C-H bonds from a single carbon center, affording a variety of synthetically useful azacycles from readily available starting materials with good to excellent enantioselectivities.

Impact of Enantiomeric Ligand Composition on the Photophysical Properties of Chiral Ag29 Nanoclusters

Abstract Chiral surface ligands have often been employed to impart optical activity to metal nanoclusters, metal nanoparticles and semiconductor nanocrystals. They are considered to form a chiral structure to a certain degree whereas the effect of such chiral structure on the global physicochemical properties apart from chiroptical ones has been unexplored. We herein demonstrate the impact of optical purity of chiral surface ligand on the emission property of silver nanocluster (NCs). Chiral bidentate α-dihydrolipoic acid (DHLA) with varied enantiomeric excess (ee) values was employed as a surface capping ligand to prepare a series of silver NCs, displaying identical absorption and emission profiles typical for Ag29 NCs. Interestingly, the emission quantum yields exhibited a clear dependence on the enantiopurity of DHLA. The more enantiopure DHLA afforded more emissive NCs. This |ee|-dependent emission efficiency was discussed in association with the orientation of ligands on the Ag29 NCs. The surface structures of Ag29(dithiolate)12 models composed of enantiopure and racemic ligand systems were compared with the aid of DFT calculations, suggesting that the enantiopure surface is more stable with one-handed ligand orientation. Two-dimensional NMR technique also supported the observation that well-defined ligand orientations depend on the enantiomeric composition of chiral ligand.

Cover Picture: Bidentate Chiral Bis(imidazolium)‐Based Halogen‐Bond Donors: Synthesis and Applications in Enantioselective Recognition and Catalysis (Angew. Chem. Int. Ed. 17/2020)

Halogen bonding is by now established in noncovalent organocatalysis, but enantioselective applications are still very rare. In their Communication on page 6806, S. M. Huber et al. show that chiral bidentate halogen bond donors are able to differentiate the enantiomers of a diamine via NMR spectroscopy and that they can also be used to induce moderate enantioselectivity in a Mukaiyama aldol reaction. This is the first case in which enantioinduction was achieved with a “pure” halogen bond donor.

Bidentate Chiral Bis(imidazolium)-Based Halogen-Bond Donors: Synthesis and Applications in Enantioselective Recognition and Catalysis.

Even though halogen bonding—the noncovalent interaction between electrophilic halogen substituents and Lewis bases—has now been established in molecular recognition and catalysis, its use in enantioselective processes is still very rarely explored. Herein, we present the synthesis of chiral bidentate halogen‐bond donors based on two iodoimidazolium units with rigidly attached chiral sidearms. With these Lewis acids, chiral recognition of a racemic diamine is achieved in NMR studies. DFT calculations support a 1:1 interaction of the halogen‐bond donor with both enantiomers and indicate that the chiral recognition is based on a different spatial orientation of the Lewis bases in the halogen‐bonded complexes. In addition, moderate enantioselectivity is achieved in a Mukaiyama aldol reaction with a preorganized variant of the chiral halogen‐bond donor. This represents the first case in which asymmetric induction was realized with a pure halogen‐bond donor lacking any additional active functional groups.

Strong chiroptical activity in Au25 clusters protected by mixed ligands of chiral phosphine and achiral thiolate.

We report the successful synthesis of a chiroptically active Au25 cluster protected by mixed ligands of chiral bidentate S-BINAP and achiral dodecanethiol (DDT), which can be formulated as [Au25(S-BINAP)4(DDT)5X4] (X = Cl or Br). The UV-vis absorption spectral pattern is similar to that of the well-known bi-icosahedral cluster [Au25(PPh3)10(SR)5X2]2+, so the obtained cluster should also have a similar bi-icosahedral structure assembled from two vertex-sharing icosahedral Au13 units. With a closer inspection of the optical absorption, interestingly, the lowest-energy peak is red-shifted as compared to that of [Au25(PPh3)10(SR)5X2]2+. Quantum chemical calculations for model bi-icosahedral Au25 structures suggest the reason of the red shift. On the other hand, the obtained Au25 cluster exhibits a weak CD signature in the lowest-energy transition region, whereas higher-energy transitions have very large chiroptical responses with a maximum g-factor of 1.7 × 10-3. The calculations also give implications for the origin of the CD response in the Au25 cluster. We then believe that bi-icosahedral Au25 clusters with chirality will be a good prototype for understanding the influence of constituent Au13 units on the chiroptical activity of their assembling structures.