Desymmetrization Strategy Research Articles

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.

Asymmetric Total Synthesis of Alstrostine G Utilizing a Catalytic Asymmetric Desymmetrization Strategy.

A highly effective enantioselective monobenzoylation of 1,3-diols has been developed for the synthesis of 1,1-disubstituted tetrahydro-β-carbolines. The chemistry has been successfully applied to the asymmetric total synthesis of (+)-alstrostine G, which also features a cascade Heck/hemiamination reaction enabling facile construction of the pivotal pentacyclic core.

Asymmetric Total Synthesis of Alstrostine G Utilizing a Catalytic Asymmetric Desymmetrization Strategy

AbstractA highly effective enantioselective monobenzoylation of 1,3‐diols has been developed for the synthesis of 1,1‐disubstituted tetrahydro‐β‐carbolines. The chemistry has been successfully applied to the asymmetric total synthesis of (+)‐alstrostine G, which also features a cascade Heck/hemiamination reaction enabling facile construction of the pivotal pentacyclic core.

Enantioselective Construction of Anthracenylidene-Based Axial Chirality by Asymmetric Heck Reaction.

Anthracenylidene is an intriguing structural unit with potential in various fields. The study presents a novel approach to introducing axial chirality into this all-carbon core skeleton through a remotely controlled desymmetrization strategy. A palladium-catalyzed enantioselective Heck arylation of exocyclic double bond of anthracene with two distinct substituents at the C10 position is harnessed to realize such a transformation. The judicious identification of the P-centrally chiral ligand is pivotal to ensure the competitive competence in reactivity and stereocontrol when the heteroatom handle is absent from the anthracenylidene skeleton. Both C10 mono- and disubstituted substrates were compatible for the established catalytic system, and structurally diverse anthracenylidene-based frameworks were forged with good-to-high enantiocontrol. The subsequent derivatization of the obtained products yielded a valuable array of centrally and axially chiral molecules, thus emphasizing the practicality of this chemistry. DFT calculations shed light on the catalytic mechanism and provided insights into the origin of the experimentally observed enantioselectivity for this reaction.

Rapid Access to Chiral Spiro[2.3] Lactams: Stereoselective Hydroborylation and Hydrosilylation and Remote Control of Axial Chirality by Copper-Catalyzed Desymmetrization of Spirocyclopropenes.

Chiral spirocyclopropyl β-lactams are common motifs in bioactive compounds and pharmaceuticals. Here we disclose a diastereoselective and enantioselective hydroborylation and hydrosilylation of spirocyclopropenes, via a Cu-catalyzed desymmetrization strategy, for the rapid preparation of enantio-enriched spirocyclopropyl β-lactams. The efficient desymmetrization strategy allows the remote control of axial chirality, offering the borylated and silylated products bearing central, spiro, and axial chirality. The combination of multichiral elements would provide a novel motif for biological evaluation in potential drug discovery.

CoH-catalyzed asymmetric remote hydroalkylation of heterocyclic alkenes: a rapid approach to chiral five-membered S- and O-heterocycles.

Saturated heterocycles, which incorporate S and O heteroatoms, serve as fundamental frameworks in a diverse array of natural products, bioactive compounds, and pharmaceuticals. Herein, we describe a unique cobalt-catalyzed approach integrated with a desymmetrization strategy, facilitating precise and enantioselective remote hydroalkylation of unactivated heterocyclic alkenes. This method delivers hydroalkylation products with high yields and excellent stereoselectivity, representing good efficiency in constructing alkyl chiral centers at remote C3-positions within five-membered S/O-heterocycles. Notably, the broad scope and good functional group tolerance of this asymmetric C(sp3)-C(sp3) coupling enhance its applicability.

Synthesis of axially chiral thiourea by NHC-catalyzed desymmetrizative amidation

NHC-catalyzed desymmetrization amidation of biaryl dialdehydes has been developed for NH-free axially chiral thiourea. Sequential kinetic resolution enhances the chirality induction of the desymmetrization strategy, expanding the applicable scope.

Enantioselective Synthesis of C-O Axially Chiral Diaryl Ethers by NHC-Catalyzed Atroposelective Desymmetrization.

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C-O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C-O axis remains a significant challenge. Herein, we demonstrate the first N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. Mechanistically, the reaction proceeds via NHC-catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C-O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C-O bonds are also presented.

Enantioselective Synthesis of C−O Axially Chiral Diaryl Ethers by NHC‐Catalyzed Atroposelective Desymmetrization**

AbstractAxially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N‐heterocyclic carbene (NHC)‐catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde‐containing diaryl ethers. Mechanistically, the reaction proceeds via NHC‐catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented.

Catalytic Synthesis of Silanols by Hydroxylation of Hydrosilanes: From Chemoselectivity to Enantioselectivity.

As a crucial class of functional molecules in organosilicon chemistry, silanols are found valuable applications in the fields of modern science and will be a potentially powerful framework for biologically active compounds or functional materials. It has witnessed an increasing demand for non-natural organosilanols, as well as the progress in the synthesis of these structural features. From the classic preparative methods to the catalytic selective oxidation of hydrosilanes, electrochemical hydrolysis of hydrosilanes, and then the construction of the most challenging silicon-stereogenic silanols. This review summarized the progress in the catalyzed synthesis of silanols via hydroxylation of hydrosilanes in the last decade, with a particular emphasis on the latest elegant developments in the desymmetrization strategy for the enantioselective synthesis of silicon-stereogenic silanols from dihydrosilanes.

Endowing Porphyrinic Metal-Organic Frameworks with High Stability by a Linker Desymmetrization Strategy.

The fabricating of metal-organic frameworks (MOFs) that integrate high stability and functionality remains a long-term pursuit yet a great challenge. Herein, we develop a linker desymmetrization strategy to construct highly stable porphyrinic MOFs, namely, USTC-9 (USTC represents the University of Science and Technology of China), presenting the same topological structure as the well-known PCN-600 that readily loses crystallinity in air or upon conventional activation. For USTC-9, the involved porphyrinic linker (TmCPP-M) with carboxylate groups located in the meta-position presents a chair-shaped conformation with lower C2h symmetry than that (D4h) of the common porphyrinic carboxylate (TCPP) linker in PCN-600. As a result, the wrinkled and interlocked linker arrangements collectively contribute to the remarkable stability of USTC-9. Given the high stability and porosity as well as Lewis acidity, USTC-9(Fe) demonstrates its excellent performance toward catalytic CO2 cycloaddition with diverse epoxides at moderate temperature and atmospheric pressure.

Palladium-Catalyzed Directed Atroposelective C-H Iodination to Synthesize Axial Chiral Biaryl N-Oxides via Enantioselective Desymmetrization Strategy.

The discovery of enantioselective desymmetrization reactions to provide practical synthesis of enantio-enriched atropisomeric biaryls is a challenging topic in the field of asymmetric catalysis. Herein, we report a highly enantioselective desymmetrization reaction for the synthesis of axially chiral biaryl N-oxides by atroposelective C-H iodination by using Pd(II) coordinated by N-benzoyl-l-phenylalanine as a chiral catalyst at room temperature. A broad range of products were obtained in high yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee). The products could be synthesized in gram scale, one of which was proved to be a powerful organocatalyst in asymmetric allylation reaction. Mechanistic evidence as well as DFT calculations point towards the factors that lead to high reactivity and excellent enantiocontrol in this reaction.

Catalytic desymmetrization of the mechanical bond

In the October issue of Chem , Chong Tian, Ye Zhu, and co-workers describe a post-synthetic catalyst-controlled desymmetrization strategy for synthesizing mechanically planar chiral rotaxanes by relying on distal ionic interactions between a prochiral rotaxane and a novel anionic chiral phosphine ligand to trigger a desymmetrizing Pd-catalyzed Suzuki-Miyaura coupling. In the October issue of Chem , Chong Tian, Ye Zhu, and co-workers describe a post-synthetic catalyst-controlled desymmetrization strategy for synthesizing mechanically planar chiral rotaxanes by relying on distal ionic interactions between a prochiral rotaxane and a novel anionic chiral phosphine ligand to trigger a desymmetrizing Pd-catalyzed Suzuki-Miyaura coupling.

Synthesis of optical active tetramethyl-1,1′-spirobiindane-based iodoarenes and evaluation of their use as axially chiral organocatalysts

Three novel axially chiral iodoarenes based on the tetramethyl-1,1′-spirobiindane skeleton were successfully prepared starting from Bisphenol A. The reactivity and selectivity were evaluated in the asymmetric oxidative formation of CN bonds through an intramolecular desymmetrization strategy, resulting in ee’s up to 92% with high yield.

Mechanically planar chiral rotaxanes through catalytic desymmetrization

<h2>Summary</h2> Establishing mechanical chirality has remained a substantial synthetic hurdle despite the fast-growing applications of interlocked architectures in supramolecular chemistry. Here, we report the development of a catalyst-controlled desymmetrization strategy that decouples the creation of mechanically planar chirality and assembly of interlocked bonds. Employing a novel class of anionic chiral phosphine ligands, the Pd-catalyzed Suzuki-Miyaura reactions enable enantioselective access to various mechanically planar chiral rotaxanes. This study demonstrates that precise catalytic stereocontrol over mechanical chirality is achievable by engaging distal ionic substrate-catalyst interactions, despite the noncovalent nature of the interlocking stereogenic elements.

Catalytic Friedel-Crafts Alkylative Desymmetrization of Cyclohexa-2,5-dienones: Access to Linear and Bridged Polycyclic Pyrroles and 3-Arylpyrroles.

A catalytic [3 + 2]-cycloaddition/Friedel-Crafts alkylative desymmetrization strategy has been developed for the stereoselective construction of linear and bridged polycyclic pyrroles from alkynylcyclohexa-2,5-dienones. This strategy was further explored for the synthesis of 3-arylpyrroles under Brønsted acid catalysis. Reaction is highly chemo-, regio-, and stereoselective and is compatible with wide range of functionalized cyclohexa-2,5-dienones/pyrroles (>51 examples, ≤98% yields). Gram-scale synthesis and synthetic utility of the products have also been demonstrated to showcase the robustness of present method.

Fully Supramolecular Chiral Hydrogen-Bonded Molecular Tweezer.

Molecular tweezers are open-ended, cavity-possessing U-shaped molecular architectures with high potential for various applications in supramolecular chemistry. Their covalent synthesis, however, is often tedious and the structures obtained lack structural responsiveness beyond the limited conformational flexibility of the scaffold. Herein we present a proof-of-concept study on the design, synthesis, assembly, and transformations of a novel supramolecular construct─a fully noncovalent molecular tweezer. The supramolecular tweezer was assembled from a set of four building blocks, composed of two identical molecular angle bars and two flat aromatic extension wings, using hydrogen bonding only. The chirality-assisted aggregation process was utilized to ensure scaffold bending directionality using enantiomerically pure bicyclic angle bars. To address the challenges associated with shifting of the equilibrium from strong cooperative narcissistic self-sorting of self-complementary angle bars in cyclic aggregates toward integrative self-sorting in molecular tweezers, a rational desymmetrization strategy was applied. The dynamic supramolecular tweezer has been shown to display rich supramolecular chemistry, allowing for stimuli-responsive change in aggregate topology and solvent-responsive supramolecular polymerization.

Enantioselective Total Synthesis of [3]‐Ladderanol through Late‐Stage Organocatalytic Desymmetrization**

AbstractLadderane phospholipids, with their unusual ladder‐like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]‐ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2)−H alkylation. Our synthetic strategy rests on the late‐stage introduction of chirality, thus allowing facile access to both enantiomers of [3]‐ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]‐ladderanol. The scope of this desymmetrizing C(sp2)−H alkylation of meso‐cyclobutane‐fused cyclohexenediones is also presented.

Enantioselective Total Synthesis of [3]‐Ladderanol through Late‐Stage Organocatalytic Desymmetrization**

Ladderane phospholipids, with their unusual ladder-like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]-ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2 )-H alkylation. Our synthetic strategy rests on the late-stage introduction of chirality, thus allowing facile access to both enantiomers of [3]-ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]-ladderanol. The scope of this desymmetrizing C(sp2 )-H alkylation of meso-cyclobutane-fused cyclohexenediones is also presented.

Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy.

Pd-catalyzed asymmetric dearomative arylation of C3-substituted indoles is realized via a desymmetrization strategy. A BINOL-derived chiral phosphoramidite ligand is found to be highly efficient for the stereoselective control in this reaction. This method provides a convenient synthesis of spiroindolenines bearing two stereogenic centers in good yields (up to 98%) with excellent diastereo- and enantioselectivities (up to >20:1 dr and 97% ee), which could also be applied in asymmetric dearomative arylation of the simple C3-tethered indoles.