Chiral Phosphoric Acid Research Articles

Organocatalytic Dearomatization of β‐Naphthols through a 1,6‐Conjugated Addition of Alkynyl 7‐Methylene‐7H‐indoles Formed In Situ

AbstractOrganocatalytic dearomatization of β‐naphthols has been achieved via a 1,6‐conjugated addition of 2‐naphthols to alkynyl 7‐methylene‐7H‐indoles in situ generated from α‐(7‐indolyl)methanols. In the presence of racemic phosphoric acid, a series of tetrasubstituted allenes was obtained in high yields. Particularly, with the aid of chiral phosphoric acid, asymmetric dearomatization of β‐naphthols was investigated, affording axially chiral tetrasubstituted allenes with moderate enantioselectivity.

Organocatalytic Asymmetric Cascade Bicyclization of 2‐Indolylmethanols with α‐(2‐Indolyl) Propargylic Alcohols to Access Chiral Fluorescent Hexacyclic Bisindoles

AbstractA cascade regioselective 1,8‐addition/biscyclization of 2‐indolylmethanols with α‐(2‐indolyl) propargylic alcohols has been developed via chiral phosphoric acid (CPA) catalysis. A series of chiral cyclopenta[4,5]pyrrolo biindoles bearing a quaternary stereogenic center were obtained in modest to good yields (72–95%) with high enantioselectivities (82–94%). Additionally, the photophysical properties of these hexacyclic bisindoles are examined, revealing bright fluorescence with high quantum yields.

Synthesis of Chiral Axially Diaryl Aldehydes by Chiral Phosphoric Acid Catalyzed Desymmetrization Reaction

Axially chiral biaryl aldehydes are precursors for the synthesis of axially chiral compounds and novel chiral catalysts of great interest, which play vital roles in extensive research fields. However, limited strategies exist for the efficient synthesis of axially chiral aldehydes, and the construction of structurally diverse axially chiral aldehydes remains challenging. Herein, a strategy is reported for the synthesis of biaryl axially chiral aldehydes with varying structures from biaryl dialdehydes and aromatic amines in the presence of a chiral phosphoric acid catalyst. This protocol features excellent enantioselectivity, mild conditions, and good functional‐group tolerance.

Organocatalytic Asymmetric [3 + 2] Cyclization: Enantioselective Synthesis of α-Indolyl Pyrrolo[1,2-a]indole Scaffolds.

A novel asymmetric [3 + 2] cyclization of α-indolyl propargylic alcohols with 3-alkyl-1H-indoles via chiral phosphoric acid catalysis has been established. This strategy allowed the synthesis of chiral α-indolyl pyrrolo[1,2-a]indole derivatives with high yields (up to 91%) and excellent enantioselectivities (up to 99% ee), facilitating both the reaction activity and enantioselectivity by using the solvent of CH3CFCl2. Significantly, this protocol will provide an effective synthetic approach for constructing enantioenriched α-indolyl pyrrolo[1,2-a]indole cores of antimalarial natural product isoborreverine analogues.

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

The first asymmetric condensation of prochiral silacyclohexanones with hydroxylamines is developed by chiral phosphoric acid catalysis, which provided a facile and straightforward protocol for the enantioselective construction of valuable axially chiral silacyclohexylidene oxime ethers that are otherwise inaccessible. Notably, this constitutes a rare example for accessing silacycles featuring an axial chirality.

Theoretical Investigation on Intramolecular Friedel-Crafts Alkylation Of 2,2′-Disubstituted 1,3-Indandione Delivering Axially Chiral Biaryls Catalyzed by Chiral Phosphoric Acid

Our Density Functional Theory (DFT) calculations provide the first theoretical investigation on CPA-catalyzed intramolecular Friedel-Crafts alkylation of 1,3-indandione. The reaction is initiated by bis-coordination of CPA with carbonyl and phenol of indandione. The promotion of CPA lies in H-bridge and steric effect from big silyl substituents confirming less-hindered Re-face more favorable than more-shielded Si-face within central chiral alcohol. Next AlCl3-promoted process contains four steps. The dehydration gives positive carbocation, the rearrangement of which activates another carbonyl. The water reversely splits into hydrogen and hydroxyl to recover phenol. The naphthol is obtained from opening of five-membered ring. The central-to-axial chirality conversion is secured between methyl/phenol substituents and carboxylic moiety of axially chiral biaryls. The positive solvation effect is suggested by decreased absolute and activation energies in solution compared with in gas. These results are supported by Multiwfn analysis on FMO composition of specific TSs, and MBO value of vital bonding, breaking.

Asymmetric Aza Friedel-Crafts Reaction of 3,4-Dihydroisoquinolines with 1-Naphthols Catalyzed by Chiral Phosphoric Acids.

An efficient chiral phosphoric acid-catalyzed asymmetric aza Friedel-Crafts reaction of 3,4-dihydroisoquinolines and 1-naphthols is described. The reaction provides a general method for the synthesis of diverse chiral tetrahydroisoquinoline with 1-naphthol substituents at the C1-position in excellent yields and enantioselectivities. Based on the conducted mechanistic experiments, a plausible catalytic mechanism was proposed. Moreover, the practicability of the reaction is successfully demonstrated by its application on a gram scale.

Fortuitous Enantiomeric Self-Rectification of an Unreported Partial Racemisation in the Synthesis of a Chiral Phosphoric Acid: A Warning to Practitioners.

Racemisation without Consequence: MOM deprotection of an ether intermediate during a routine synthesis of phosphoric acid 1 promoted partial racemisation of the product BINOL 5. Surprisingly, however, after phosphorylation of the partially racemised BINOL, enantiopure acid 1 was isolated. Further inspection revealed that during phosphorylation, unhydrolysed racemic phosphorochloridate 6 precipitated, thus restoring homochirality in the product phosphoric acid 1. Moreover, MOM deprotection partial racemisation was avoided by conducting reactions at lower temperatures for no longer than the required deprotection time, and/or by application of other deprotection conditions from the literature.

Random Forest‐Based Prediction of Enantioselectivity in Thiol Addition to Imines Catalyzed by Chiral Phosphoric Acids

AbstractThis paper, for the first time, reports calculating molecular descripts from the combinations of catalysts and substrates, for enantioselectivity predictions in chiral phosphoric acid–catalyzed thiol addition to N‐acylimines. Ten molecular descriptors, together with random forest (RF) algorithm, were used to establish the quantitative structure–selectivity relationship (QSSR) model (RF Model I), yielding correlation coefficient of R=0.982, root mean square (rms) error of 0.604 kJ/mol (for 800 enantioselectivity ΔΔG from 32 catalysts in the training set), R=0.922, rms=1.075 kJ/mol (for 275 enantioselectivity ΔΔG from 11 new catalysts in the test set). The RF Model I was proved to be more accurate in enantioselectivity predictions, compared with the QSSR models reported in the literature and with the RF Model II and RF Model III in this work. Moreover, the RF Model I was based on simple Dragon descriptors and capable of extrapolative prediction for new catalysts. Therefore, it is reasonable deriving molecular descriptors from the combinations of catalysts and substrates (thiols and imines). This work provides a new method for the predictions of enantioselectivity ΔΔG.

Divergent asymmetric reactions of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acids

Divergent asymmetric synthesis provides access to a wide range of isomers from the same starting material by modifying the reaction conditions, which plays an important role in the efficient construction of a structurally diverse molecular library for structure-activity relationship studies. In this work, we present the divergent asymmetric addition of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acid catalysis. Despite the challenging presence of multiple reactive sites in both components, we successfully achieved the regioselective synthesis of both α-1,2-addition α-tertiary amines and γ-1,4-addition allenes with good to high regio-, diastereo- and enantioselectivities by modifying the reaction conditions. Moreover, the stereodivergent asymmetric synthesis of the four allene stereoisomers bearing contiguous central and axial chirality was achieved by adjusting the E/Z configuration of the α-alkenyl ketone substrates.

Asymmetric [3+3] Cycloaddition of N‐Vinyl Oxindole Nitrones with 2‐Indolylmethanols to Prepare Spirooxindole[1,2]oxazines

AbstractWe describe a chiral phosphoric acid (CPA) catalyzed asymmetric [3+3] cycloaddition of N‐viny oxindole nitrones with 2‐indolylmethanols to prepare various spirooxindole[1,2]oxazines in 43–93% yields and 88:12–97:3 enantiomeric ratios. Experimental results revealed that the addition of hexafluoroisopropanol (HFIP) played important roles to help CPA control the reaction reactivity and enantioselectivity. The present method features the construction of a tetrasubstituted chiral carbon stereocenter and the example of N‐vinyl nitrones in asymmetric [3+3] cycloaddition.

Asymmetric Synthesis of Axially Chiral N, N-1,2-Pentatomic Heterobiaryl Diamines by an Organocatalytic Arylation Reaction.

The utilization of axially chiral biaryl diamines has been widely acknowledged as highly advantageous structures for the advancement of chiral catalysts and ligands. This highlights their extensive range of applications in asymmetric catalysis and synthesis. Herein, we devised a direct arylation reactions of 5-aminopyrazoles with azonaphthalenes, utilizing chiral phosphoric acid as the catalyst. This method delivers structurally novel atroposelective N, N-1,2-azole heteroaryl diamines with high yields (up to >98 %) and good to excellent enantiomeric ratios while exhibiting a wide range of substrate compatibility.

Organocatalytic Asymmetric (4 + 3) Cycloaddition toward Optically Active Cyclohepta Fused Diindoles.

A novel asymmetric (4 + 3) cycloaddition of indole-2,3-quinodimethanes in situ generated from 3-methyl-2-indolylmethanols with 3-indolylmethanols via chiral phosphoric acid catalysis has been established. The cycloaddition reaction exhibits a broad substrate scope affording the diverse enantioenriched cyclohepta fused diindoles in high yields with good enantioselectivities. Significantly, this work represents the first application of 3-methyl-2-indolylmethanols as 4C synthons instead of the commonly reported three-atom synthons in cycloaddition reactions.

Enamine Acylation Enabled Desymmetrization of Malonic Esters.

Asymmetric enamine alkylation represents a powerful tool for stereoselective C-C bond formation; in contrast, the development of enantioselective enamine acylation remains elusive. Here, we report that a chiral phosphoric acid can render an in-situ-formed enamine to undergo a stereoselective intramolecular α-carbon acylation, providing an alternative approach for the synthesis of useful pyrrolinones and indolinones bearing tetrasubstituted stereocenters. Utilizing an effective integration of the desymmetrization strategy and bifunctional organocatalysis, the first example of enantioselective enamine acylation is achieved by employing readily available aminomalonic esters and cyclic ketones. Instead of reactive and moisture-sensitive acyl chlorides, common esters with low electrophilicity were successfully used as efficient acylating reagents via hydrogen bonding interactions. The utility is demonstrated in the concise and enantioselective synthesis of (+)-LipidGreen I and II. Experimental studies and DFT calculations establish the reaction pathway and the origin of stereocontrol.

Synthesis of Chiral 3H‐Pyrrolo[1,2‐a]indoles Via Organocatalytic Enantioselective Addition of Alkynyl Biphenyl Quinone Methides

AbstractAn organocatalytic enantioselective reaction utilizing α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols and 3‐substituted indoles has been successfully established for the synthesis of chiral 3H‐pyrrolo[1,2‐a]indoles. Through the assistance of an appropriate chiral phosphoric acid, a cascade sequence is facilitated, beginning with the dehydration of α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols to form alkynyl 4,4’‐biphenyl quinone methides (4,4’‐BQMs). Subsequently, 1,12‐addition of 3H‐pyrrolo[1,2‐a]indoles to these alkynyl 4,4’‐BQMs results in the formation of allenes, which are then protonated and regenerate 4,4’‐BQMs. Finally, an enantioselective intramolecular annulation of 4,4’‐BQMs occurs smoothly, leading to the production of a range of 3H‐pyrrolo[1,2‐a]indoles with high efficiency and asymmetric induction.

Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization.

The enantioenriched lactams disclosed in this work are synthesized concisely in four steps. In the penultimate reaction, a benzylamine species complexes with a chiral phosphoric acid to produce benzo-fused δ-lactams equipped with an all-carbon quaternary stereocenter. Partial and full reductions were carried out on the ester and amide moieties, and a Suzuki-Miyaura cross-coupling expanded the molecule from the aromatic ring. Finally, our method was successful at a >1 g scale, indicating that the method has important practical use.

Asymmetric 1,4-Reduction of Pyrano[2,3-b]indoles with Hantzsch Ester by Chiral Phosphoric Acid.

A highly regioselective and enantioselective transfer hydrogenation of pyrano[2,3-b]indoles with Hantzsch ester has been successfully realized using spiro-chiral phosphoric acid, affording a series of optically active 1,4-reductive adducts, 4,9-dihydropyrano[2,3-b]indoles, in 34-99% yields with 61-99% ee.

Catalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes via Sequential Povarov Reaction and Aromatizations

AbstractInherently chiral calix[4]arenes represent a unique type of chiral molecules with significant applications, yet their catalytic enantioselective synthesis remains largely underexplored. We report herein the catalytic enantioselective synthesis of inherently chiral calix[4]arenes through the sequential organocatalyzed enantioselective Povarov reaction and aromatizations. The chiral phosphoric acid catalyzed three‐component Povarov reaction involving amino group‐substituted calix[4]arenes, aldehydes and (di)enamides desymmetrized the prochiral calix[4]arene substrates, which was followed by various aromatization methods, resulting in a diverse array of novel quinoline‐containing calix[4]arenes with good yields and high enantioselectivities (up to 75 % yield, 99 % ee). The large‐scale enantioselective synthesis and diverse derivatizations of the chiral calix[4]arene products highlight the value of this method. Furthermore, preliminary exploration into their photophysical and chiroptical properties demonstrate the potential applications of these novel calix[4]arene molecules.

Catalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes via Sequential Povarov Reaction and Aromatizations.

Inherently chiral calix[4]arenes represent a unique type of chiral molecules with significant applications, yet their catalytic enantioselective synthesis remains largely underexplored. We report herein the catalytic enantioselective synthesis of inherently chiral calix[4]arenes through the sequential organocatalyzed enantioselective Povarov reaction and aromatizations. The chiral phosphoric acid catalyzed three-component Povarov reaction involving amino group-substituted calix[4]arenes, aldehydes and (di)enamides desymmetrized the prochiral calix[4]arene substrates, which was followed by various aromatization methods, resulting in a diverse array of novel quinoline-containing calix[4]arenes with good yields and high enantioselectivities (up to 75 % yield, 99 % ee). The large-scale enantioselective synthesis and diverse derivatizations of the chiral calix[4]arene products highlight the value of this method. Furthermore, preliminary exploration into their photophysical and chiroptical properties demonstrate the potential applications of these novel calix[4]arene molecules.

One-Pot Multienzyme Cascades for Stereodivergent Synthesis of Tetrahydroquinolines.

The tetrahydroquinoline (THQ) framework is commonly found in natural products and pharmaceutically relevant molecules. Apart from the use of transition metal catalysts and chiral phosphoric acids, the chiral 2-substituted 1,2,3,4-THQs are synthesized using amine oxidase biocatalysts. However, the use of imine reductases (IREDs) in their asymmetric synthesis remained unexplored. In the current work, IREDs are employed in telescopic multienzyme cascades to catalyze the intramolecular reductive amination leading to chiral 2-alkyl and 2-aryl substituted-1,2,3,4-tetrahydroquinolines starting from inexpensive nitroalkenones. The cascades containing NtDBR (an ene reductase), NfsB (a nitro reductase) with either Na2S2O4 or V2O5, various IREDs, and glucose dehydrogenase (for NADPH regeneration) are used to synthesize a broad range of (R)/(S)-2-alkyl-substituted (THQs) (26 examples) with high yield (up to 93%) and excellent ee (up to 99%) in one-pot. The method further facilitates the one-pot biocatalytic synthesis of chiral 2-aryl substituted THQs (26 examples) from amino chalcones. Lastly, the asymmetric synthesis of several (R)- and (S)-THQ based intermediates of Hancock alkaloids showed the practical application of the newly developed biocatalytic cascades.