Chiral Hydrogen Bond Donor Research Articles

Synergistic Dual Photoredox and Chiral Hydrogen Bonding Catalysis: Recent Advances

AbstractIn the last two decades, chiral hydrogen bonding catalysis has been enormously utilized to trigger several valuable synthetic transformations. Similarly, modern day radical chemistry has witnessed the potency of visible light photoredox catalysis to generate radicals via single electron transfer pathway. Recently, their cooperative effect has proved to be a key strategy to access many elegant transformations that are only feasible under the synergistic action of these two catalytic systems. This dual catalytic system demonstrates high efficiency for introducing molecular complexity in an enantioselective fashion. In this mini review, we have compiled the most recent development of this dual catalytic system that surfaced in the last three years with particular attention paid to the mechanistic details and its substrate scope. We hope that this mini review will provide readers with a brief overview of the advancement and application of photoredox catalysts and chiral hydrogen bond donors for synergistic dual catalytic reactions.

Chiral Solvent Discovery: Exploring Chiral Eutectic Mixtures and Deep Eutectic Solvents

Deep eutectic solvents (DES) are mixtures that have a melting point much lower than any of the components. Because the properties of DES, such as chiral discrimination, can be controlled through choice of components, DES have potential as solvents in many chemical and industrial applications. However, the large number of potential components makes high throughput methods of DES discovery critical for their development. In this study, mixtures of small quantities of hydrogen bond acceptors (HBAs) and chiral hydrogen bond donors (HBDs) were mixed at 55 °C and cooled to 20 °C to screen for potential liquid formation. Variable molar ratios of 10 HBAs were mixed with 93 chiral HBDs to measure a total of 1250 mixtures, and 356 mixtures were liquid at 20 °C. All of the results including mixtures that did not form liquids are provided in a publicly available database. Several of the mixtures were prepared in larger quantities to characterize their physical properties, including melting points, densities, and viscosities. The results of this study can be used to guide the discovery and development of new chiral solvents, such as DES and eutectic mixtures.

Chloride-Mediated Alkene Activation Drives Enantioselective Thiourea and Hydrogen Chloride Co-Catalyzed Prins Cyclizations.

The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a catalytically active HCl·HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density functional theory (DFT) calculations, distortion-interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through the precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition-state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid-catalyzed reactions involving π-nucleophiles.

Rhodium(III) Werner Complexes with 1,2‐Diphenylethylenediamine Ligands: Syntheses, Structures, and Applications as Chiral Hydrogen Bond Donor Catalysts and Agents for Enantiomer Purity Determinations

AbstractReactions of RhCl3 and (S,S)‐1,2‐diphenylethylenediamine (S,S‐dpen) in DMSO at 140 °C give Λ‐[Rh(S,S‐dpen)3]3+3Cl− (Λ‐(S,S)‐43+3Cl−) in 76 % yield. When CH2Cl2/water suspensions are treated with 1.0 equiv. of Na+ B(C6F5)4− or Na+ B(3,5‐C6H3(CF3)2)4−, the mixed salts Λ‐(S,S)‐43+2Cl−B(aryl)4− can be isolated from the organic layers (95–91 %). A wide variety of mixed and non‐mixed salts involving these and other anions (BF4−, ClO4−, I−) are also prepared. The lipophilic salts are highly enantioselective catalysts for the Michael addition of dimethylmalonate to trans‐ß‐nitrostyrene (acetone, 0 °C; 92–85 % ee). The crystal structures of seven solvated salts are determined, and hydrogen bonding between the trications and anions or solvate molecules analyzed. There is a notable affinity of chloride anions for the C3 face of Λ‐(S,S)‐43+, which features three synperiplanar NH groups. Λ‐(S,S)‐43+2I−B(C6F5)4− is an excellent chiral solvating agent for determining enantiomeric purities of chiral organic molecules with hydrogen bond accepting functional groups (11 mol% (average), CDCl3).

Enantioselective Total Syntheses of Grayanane Diterpenoids: (-)-Grayanotoxin III, (+)-Principinol E, and (-)-Rhodomollein XX.

Enantioselective total syntheses of (-)-grayanotoxin III, (+)-principinol E, and (-)-rhodomollein XX were accomplished based on a convergent strategy. The left- and right-wing fragments were assembled via the diastereoselective Mukaiyama aldol reaction catalyzed by a chiral hydrogen bond donor. The unique 7-endo-trig cyclization based on a bridgehead carbocation forged the 5/7/6/5 tetracyclic skeleton that underwent redox manipulations and 1,2-migration to access different grayanane diterpenoids.

Chiral Eutectic Mixtures and Deep Eutectic Solvents for Induced Circularly Polarized Luminescence

AbstractDeep eutectic solvents (DES) or eutectic mixtures prepared with a chiral component can lead to new chiral solvents with applications that include asymmetric synthesis and chiral light emitting materials. DES have low melting points, because of strong interactions, such as hydrogen bonding, between components of the mixture. Mixtures are prepared with ammonium salts, tetrabutylammonium chloride ([TBA]Cl) and choline chloride ([Ch]Cl), as hydrogen bond acceptor (HBA) and L‐lactic acid, L‐leucic acid, L‐ascorbic acid, R/S‐acetoxypropionic acid, and methyl‐(S)‐lactate as chiral hydrogen bond donors (HBD). Eight combinations of the HBAs and HBDs were prepared, and a racemic mixture of dissymmetric chiral europium complexes was dissolved in the mixtures. The circularly polarized luminescence (CPL) spectra were measured to determine the chiral discrimination by these chiral solvents. The CPL spectra show that the handedness of the chiral HBD is important to the chiral discrimination exhibited. However, the inversion of the sign of the CPL spectra in 1 : 3 [TBA]Cl:L‐lactic acid vs. 1 : 3 [Ch]Cl:L‐lactic acid, and 1 : 1.5 [Ch]Cl:L‐leucic acid vs. 1 : 1 [TBA]Cl:L‐leucic acid shows that the achiral HBA also plays a critical role in the handedness of the chiral discrimination by the chiral solvent.

Monosaccharide-Based Deep Eutectic Solvents for Developing Circularly Polarized Luminescent Materials

Deep eutectic solvents (DES) with chiral components can function as solvents in circularly polarized light-emitting materials. Deep eutectic solvents were developed with chiral hydrogen bond donors...

Anion-binding catalyst designs for enantioselective synthesis

Abstract Select hydrogen bond donors can catalyze reactions of ion pairs through the recognition of anions. This mode of action can be exploited in enantioselective catalysis if a suitable chiral hydrogen bond donor is applied. Beyond just anionic recognition, an enantioselective anion-binding catalyst often must host numerous non-covalent interactions, including hydrogen bonding, general base, π-π, and π-cation, to achieve high levels of enantiocontrol. Anion-binding catalysts can be strategically designed to support those non-covalent interactions required to render a process highly stereoselective. Tactics applied in anion-binding catalyst development include enhancing arene substituents for improved π-stacking, linking two anion-binding units together on a single scaffold, expanding types of functional groups for anion recognition, and building frameworks with bifunctional modes of action. The intent of this digest is to highlight observations that suggest as anion-binding catalyst designs advance, their associated synthetic methodologies for complex molecule construction become increasingly impressive.

ChemInform Abstract: Tris(1,2‐diphenylethylenediamine)cobalt(III) Complexes: Chiral Hydrogen Bond Donor Catalysts for Enantioselective α‐Aminations of 1,3‐Dicarbonyl Compounds.

AbstractThis study expands the applicability of chiral Werner complexes, based upon ethylenediamine chelates as hydrogen bond donor catalysts for the enantioselective addition of dicarbonyl compounds to di‐tert‐butyl azodicarboxylate.

Eric N. Jacobsen

Eric N. Jacobsen

Tris(1,2-diphenylethylenediamine)cobalt(III) Complexes: Chiral Hydrogen Bond Donor Catalysts for Enantioselective α-Aminations of 1,3-Dicarbonyl Compounds

The enantiopure salt Δ-[Co((S,S)-dpen)3](3+)2Cl(-)B(C6F5)4(-) is an effective hydrogen bond donor catalyst for additions of 1,3-dicarbonyl compounds to di-tert-butyl azodicarboxylate in the presence of N-methylmorpholine (1.0:1.0:0.10) in CH3CN at 0 °C, as illustrated with educts derived from five- or six-membered ring ketones (99-88% yields, >99-91% ee) and cycloheptanone (94%, 72% ee) as well as 2-cyanocyclopentanone (92%, 45% ee) and an acyclic system (98%, >99% ee).

Cobalt(III) Werner Complexes with 1,2-Diphenylethylenediamine Ligands: Readily Available, Inexpensive, and Modular Chiral Hydrogen Bond Donor Catalysts for Enantioselective Organic Synthesis.

In the quest for new catalysts that can deliver single enantiomer pharmaceuticals and agricultural chemicals, chemists have extensively mined the “chiral pool”, with little in the way of inexpensive, readily available building blocks now remaining. It is found that Werner complexes based upon the D3 symmetric chiral trication [Co(en)3]3+ (en = 1,2-ethylenediamine), which features an earth abundant metal and cheap ligand type, and was among the first inorganic compounds resolved into enantiomers 103 years ago, catalyze a valuable carbon–carbon bond forming reaction, the Michael addition of malonate esters to nitroalkenes, in high enantioselectivities and without requiring inert atmosphere conditions. The title catalysts, [Co((S,S)-dpen)3]3+ ((S,S)-33+) 3X–, employ a commercially available chiral ligand, (S,S)-1,2-diphenylethylenediamine. The rates and ee values are functions of the configuration of the cobalt center (Λ/Δ) and the counteranions, which must be lipophilic to solubilize the trication in nonaqueous media. The highest enantioselectivities are obtained with Λ and 2Cl–BArf–, 2BF4–BArf–, or 3BF4– salts (BArf– = B(3,5-C6H3(CF3)2)4–). The substrates are not activated by metal coordination, but rather by second coordination sphere hydrogen bonding involving the ligating NH2 groups. Crystal structures and NMR data indicate enthalpically stronger interactions with the NH moieties related by the C3 symmetry axis, as opposed to those related by the C2 symmetry axes; rate trends and other observations suggest this to be the catalytically active site. Both Λ- and Δ-(S,S)-33+ 2Cl–BArf– are effective catalysts for additions of β-ketoesters to RO2CN=NCO2R species (99–86% yields, 81–76% ee), which provide carbon–nitrogen bonds and valuable precursors to α-amino acids.

ChemInform Abstract: Terpene‐Derived Bifunctional Thioureas in Asymmetric Organocatalysis

AbstractReview: 110 refs.

Enantioselective Organocatalytic Friedel-Crafts Alkylations

Over the last few decades, the catalytic asymmetric Friedel-Crafts alkylation has become a powerful strategy that provides enantioenriched structural motifs of established value in medicinal chemistry or complex target synthesis. While the traditionally chiral Lewis-acid catalyzed Friedel-Crafts alkylation has been extensively reviewed in the literature, we focused this review on the recent advances on organocatalytic Friedel-Crafts alkylations. According to activation modes, this review is divided into three main sections, including 1) alkylations via iminium catalysis, 2) alkylations via SOMO catalysis, and 3) alkylations by chiral hydrogen-bond donors.

ChemInform Abstract: Novel Chiral Hydrogen Bond Donor Catalysts Based on a 4,5‐Diaminoxanthene Scaffold: Application to Enantioselective Conjugate Addition of 1,3‐Dicarbonyl Compounds to Nitroalkenes.

AbstractCatalysts of type (I) are developed and successfully applied to the title reactions.

Enantioselective iridium-catalyzed vinylogous Reformatsky-aldol reaction from the alcohol oxidation level: linear regioselectivity by way of carbon-bound enolates.

Enantioselective iridium-catalyzed vinylogous Reformatsky-aldol reaction from the alcohol oxidation level: linear regioselectivity by way of carbon-bound enolates.

Novel chiral hydrogen bond donor catalysts based on a 4,5-diaminoxanthene scaffold: application to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived catalyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleophiles, asymmetric conjugate addition to β-aryl nitroalkenes proceeded with good diastereoselectivity to provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with up to 95% ee.

Enantioselective, Thiourea‐Catalyzed Intermolecular Addition of Indoles to Cyclic N‐Acyl Iminium Ions

Enantioselective, Thiourea‐Catalyzed Intermolecular Addition of Indoles to Cyclic <i>N</i>‐Acyl Iminium Ions

Chiral squaramide derivatives are excellent hydrogen bond donor catalysts.

Thioureas represent the dominant platform for hydrogen bond promoted asymmetric catalysts. A large number of reactions, reported in scores of publications, have been successfully promoted by chiral thioureas. The present paper reports the use of squaramides as a highly effective new scaffold for the development of chiral hydrogen bond donor catalysts. Squaramide catalysts are very simple to prepare. The (-)-cinchonine modified squaramide (5), easily prepared through a two-step process from methyl squarate, was shown to be an effective catalyst, even at catalyst loadings as low as 0.1 mol%, for the conjugate addition reactions of 1,3-dicarbonyl compounds to beta-nitrostyrenes. The addition products were obtained in high yields and excellent enantioselectivities.

Phase Transfer of Enantiopure Werner Cations into Organic Solvents: An Overlooked Family of Chiral Hydrogen Bond Donors for Enantioselective Catalysis

Werner complexes go organic! When orange aqueous solutions of [Co(1,2-diamine)3]X3 (X=I, Cl) are treated with solutions of NaBArf in CH2Cl2 (1:3 mol ratio), the aqueous phases decolorize (see scheme) and [Co(1,2-diamine)3](BArf)3⋅nH2O can be isolated from the CH2Cl2 phases (78–89 %). The ethylenediamine complex can catalyze enantioselective Michael additions, presumably by an outer-coordination-sphere mechanism involving hydrogen bonding.