Asymmetric Desymmetrization Research Articles

A Squaramide‐Tagged Proline‐Mediated Direct Asymmetric Aldol Addition in the Presence of Water

A squaramide moiety introduced at the C‐4 position of proline produced an organocatalyst that promoted the direct asymmetric aldol addition in the presence of water. A variety of aldol adducts, majorly from the reaction cyclohexanone with aldehydes, were obtained in yields generally in the range of 53‐99%, accompanied by 71‐97% ee and 82:18 to >99:1 diastereomeric ratios. An asymmetric desymmetrization of 4‐alkyl cyclohexanones was also achieved using the transformation.

Palladium-Catalyzed Asymmetric Desymmetrization for the Simultaneous Construction of Chiral Phosphorus and Quaternary Carbon Stereocenters.

A palladium-catalyzed asymmetric tandem Heck and carbonylation of bisallyl-phosphine oxides has been developed. This desymmetrization process provided an efficient route to the simultaneous synthesis of a chiral P-stereogenic center and a chiral quaternary carbon stereocenter in good yields with good diastereo- and enantioselectivities.

Catalytic Enantioselective Synthesis of Axially Chiral Diaryl Ethers Via Asymmetric Povarov Reaction Enabled Desymmetrization.

Axially chiral diaryl ethers represent a distinct class of atropisomers, characterized by a unique dual C─O axes system, which have been found in a variety of natural products, pharmaceuticals, and ligands. However, the catalytic enantioselective synthesis of these atropoisomers poses significant challenges, due to the difficulty in controlling both chiral C─O axes, and their more flexible conformations. Herein, an efficient protocol for catalytic enantioselective synthesis of axially chiral diaryl ethers is presented using organocatalyzed asymmetric Povarov reaction-enabled desymmetrization, followed by aromatizations. This method yields a wide range of novel quinoline-based diaryl ether atropoisomers in good yields and high enantioselectivities. Notably, various aromatization protocols are developed, resulting in a diverse set of polysubstituted quinoline-containing diaryl ether atropisomers. Thermal racemization studies suggested excellent configurational stabilities for these novel diaryl ether atropisomers (with racemization barriers up to 38.1kcalmol-1). Moreover, this research demonstrates for the first time that diaryl ether atropisomers lacking the bulky t-Bu group can still maintain a stable configuration, challenging the prior knowledge in the field. The fruitful derivatizations of the functional group-rich chiral products further underscore the value of this method.

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.

Catalytic asymmetric desymmetrization of 1,4-cyclohexadienes for the synthesis of chiral quinolinone derivatives

Quinolinone is a prevalent nitrogen-containing heterocycle in organic and pharmaceutical chemistry. In this report, we developed an intramolecular catalytic asymmetric Heck reaction of symmetrical 1,4-cyclohexadiene to construct quinolinone derivatives. The Pd(OAc)2/(R)-BINAP catalytic system enabled a series of quinolinone analogs containing two consecutive chiral centers to be obtained with up to 76% yield and 95% ee. Meanwhile, the synthesis of quinolinones bearing an all-carbon quaternary center and three consecutive chiral centers was also achieved in 85% ee via PdCl2/(R)-BoPhoz catalyzed intramolecular asymmetric Heck/alkylation reaction.

Phosphine-Catalyzed Stereospecific and Enantioselective Desymmetrizative [3+2] Cycloaddition of MBH Carbonates and N-(2-tert-Butylphenyl)maleimides.

Herein, we report an l-valine-derived amide phosphine-catalyzed [3+2] cyclization of MBH carbonates and N-(2-tert-butylphenyl)maleimides via asymmetric desymmetrization. Bicyclic N-aryl succinimide derivatives bearing three continuous chiral centers with a remote C-N atropisomeric chirality were constructed stereospecifically and enantioselectively. A wide variety of MBH carbonates could be employed in this process to deliver highly optically pure succinimide derivatives in moderate to excellent yields.

Catalytic Asymmetric Desymmetrization of Cyclic 1,3-Diketones Using Chiral Boro-phosphates.

Herein, we report a chiral boro-phosphate-catalyzed reductive amination for the desymmetrization of 2,2-disubstituted 1,3-cyclopentadiones with pinacolborane as the reducing agent, delivering chiral β-amino ketones with an all-carbon quaternary stereocenter in good yields (≤94%), high enantioselectivities (≤97% ee), and excellent diastereoselectivities (>20:1 dr). This reaction has a broad substrate scope and high functional group tolerance. The importance of the chiral products was also demonstrated through the preparation of multifunctional building blocks and heterocycles.

Synthesis of Tricyclic Fused 6-5-4 Carbocycles via Acid-Promoted Cascade Intramolecular Cyclization of Allenylsilane-Tethered Cyclohexadienones.

The reaction of 2,5-cyclohexadienones with methylene-tethered allenylsilane in the presence of Lewis or Brønsted acids leads to a cascade of intramolecular cyclization, yielding stereoselective tricyclic fused 6-5-4 carbocycles featuring a silyl-methylenecyclobutane ring. This transformation is notable for the diastereoselective asymmetric desymmetrization of prochiral dienones, attributed to the axial chirality of allene.

Silver-Catalyzed Asymmetric Double Desymmetrization via Vinylogous Michael Addition of Prochiral α,α-Dicyanoalkenes to Cyclopentendiones.

An asymmetric double desymmetrization methodology has been developed for synthesizing densely functionalized chiral cyclopentylcyclohexane scaffolds. We have constructed four chiral centers, including an all-carbon quaternary stereocenter in a single C-C bond formation event. The methodology has high functional-group tolerance and delivers a broad range of enantioenriched products. This vinylogous Michael addition reaction of prochiral α,α-dicyanocyclohexane to 2,2-disubstituted cyclopentene-1,3-dione is catalyzed by a chiral Ag-(R)-DTBM-SEGPHOS catalyst.

Enantioselective Total Synthesis of (-)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy.

The first enantioselective total synthesis of (-)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.

Novel porous organic polymer supported chloramphenicol base derivatives: A highly enantioselective, recyclable heterogeneous organocatalyst for asymmetric desymmetrization reaction

A series of porous organic polymer (POP) supported chloramphenicol base (ANP) derived catalysts are designed and prepared. A deep study of the polymerization condition, including reaction temperature, the ratio of monomers and the option of polymetric position on ANP scaffold was conducted. The best catalyst, poly-Ia, performs high stereoselectivity and catalytic activity (up to 98% yield and 99% ee) in asymmetric alcoholysis of meso-cyclic anhydride with the possibility of high recyclability (at least 10 times). More importantly, poly-Ia even obtains higher enantioselectivity compared to its homogeneous monomer, which overcomes the common drawback of heterogeneous organocatalysts, for instance, lower selectivity and diminished reactivity.

Chromium(III)-Catalyzed Desymmetrization of meso-Epoxides via Remote Stereocontrol: Synthesis of Chiral Fluorenes Bearing All-Carbon Quaternary Stereocenters.

An asymmetric desymmetrization of fluorene-derived meso-epoxides is disclosed for the construction of chiral fluorenes bearing an all-carbon quaternary stereocenter at C9. This desymmetrization is catalyzed by a chiral (salen)CrIII complex via remote stereocontrol, producing diverse chiral fluorenes with excellent yields and stereoselectivity. The practicality of this protocol was demonstrated through the transformation of the obtained products to some intriguing enantioenriched polymerizable monomers.

Strategic enzymatic enantioselective desymmetrization of prochiral cyclohexa-2,5-dienones.

Asymmetric desymmetrization through the selective reduction of one double bond of prochiral 2,5-cyclohexadienones is highly challenging. A novel method has been developed for synthesizing chiral cyclohexenones by employing an ene-reductase (Bacillus subtilis YqjM) enzyme that belongs to the OYE family. Our strategy demonstrates high substrate scope and enantioselectivity towards substrates containing all-carbon as well as heteroatom (O, N)-containing quaternary centers. The mechanistic studies (kH/D = ∼1.8) indicate that hydride transfer is probably the rate-limiting step. Mutation of several active site residues did not affect the stereochemical outcomes. This work provides a convenient way of synthesizing various enantioselective γ,γ-disubstituted cyclohexanones using enzymes.

Organocatalytic enantioselective desymmetrization of enal-tethered cyclohexane-1,3-diones.

Organocatalytic asymmetric desymmetrization of prochiral cyclohexane-1,3-diones has been demonstrated through the merging of iminium and enamine activation. The tandem annulation reaction proceeds through a sequential oxa-Michael addition/intramolecular aldol reaction/[1,3]-amino oxetane rearrangement pathway. Mechanistic study using an 18O-water experiment suggests oxetane rearrangement instead of direct dehydration. The formation of other competing Rauhut-Currier products via alkoxy-elimination was not observed.

Thiourea-Assisted Chiral Bicyclic Imidazole Organocatalysts: Design, Synthesis, and Application in Asymmetric Acylative Desymmetrization of Bisphenols for the Construction of P-Stereocenters

Thiourea-Assisted Chiral Bicyclic Imidazole Organocatalysts: Design, Synthesis, and Application in Asymmetric Acylative Desymmetrization of Bisphenols for the Construction of P-Stereocenters

Chiral N,N'-Dioxide Ligands Tune Diastereoselectivity in Mg(II)-Catalyzed Asymmetric Ring-Opening Desymmetrization of Azetidiniums.

A diastereodivergent asymmetric desymmetrization of azetidinium salts with benzothiazoleamides as carbon nucleophiles through a chiral N,N'-dioxide/Mg(II) complex-promoted ring-opening reaction is realized by tuning ligands. Both syn- and anti-chiral δ-amino acid derivatives bearing benzothiazole structure were obtained in moderate to good yields and dr and ee values. DFT calculations indicated that the diastereodivergency stems from the different size of the chiral pocket formed by variable substructures of the ligands, leading to the opposite attack direction of the nucleophiles.

Chiral Phosphoric Acid-Palladium(II) Complex Catalyzed Asymmetric Desymmetrization of Biaryl Compounds by C(sp3)-H Activation.

Desymmetrization is an essential method for the synthesis of chiral compounds, particularly chiral biaryls. We have developed an enantioselective synthesis of axially chiral biaryls by desymmetrization using C(sp3)-H activation catalyzed by chiral palladium phosphate. Mechanistic studies show that C-H activation is the rate- and enantiomer-determining step. To the best of our knowledge, this is the first report of asymmetric desymmetrization of axially chiral compounds by C(sp3)-H activation.

Asymmetric Dihydroxylation-Based Desymmetrization Enabled by Lone-Pair−π Interaction

Asymmetric Dihydroxylation-Based Desymmetrization Enabled by Lone-Pair−π Interaction

Organocatalytic DYKAT of Si-Stereogenic Silanes.

Chiral organosilanes do not exist in nature and are therefore absent from the "chiral pool". As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, are rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, the utilization of racemic silanes in a dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR) would significantly expand the breadth of accessible Si-stereogenic compounds. We now report a DYKAT of racemic allyl silanes enabled by strong and confined imidodiphosphorimidate (IDPi) catalysts, providing access to Si-stereogenic silyl ethers. The products of this reaction are easily converted into useful enantiopure monohydrosilanes. We propose a spectroscopically and experimentally supported mechanism involving the epimerization of a catalyst-bound intermediate.