Squaramide Organocatalyst Research Articles

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.

Squaramide-Catalyzed Asymmetric Mannich Reactions of Azlactones with Isatin-Derived Ketimines: Access to α,β-Diamino Acid Derivatives Bearing Vicinal Quaternary Stereocenters.

A highly stereoselective Mannich reaction of α-amino acid derived azlactones with isatin-derived ketimines enabled by a chiral bifunctional squaramide organocatalyst is reported, affording α,β-diamino acid derivatives bearing vicinal quaternary stereocenters in moderate to good yields (40-95%), moderate to excellent diastereoselectivities (3:1 → 20:1), and good to excellent enantioselectivities (66-97%). This reaction can be readily performed on gram scale, and the Mannich adduct could be easily converted to the corresponding α,β-diamino ester via simple operations.

Asymmetric Organocatalytic Synthesis of 2,3-Allenamides from Hydrogen-Bond-Stabilized Enynamides.

Asymmetric catalytic synthesis of 2,3-allenamides from hydrogen-bond-stabilized enynamides in the presence of quinine-based bifunctional squaramide organocatalysts is described. This protocol forms a variety of 2,3-allenamides in high yields and excellent stereoselectivities, in which the elaborated introduction of intramolecular H-bonds within the N, N-bidentate amide group constitutes one of the keys to this highly enantioselective transformation. The synthetic practicality of this reaction has been demonstrated by the axis-to-center chirality transfer of allenamides to furnish enantiomerically enriched building blocks.

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[γ-butyrolactone-pyrrolidin-4,4'-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons α-imino γ-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Stereoselective Synthesis of Tetrahydroquinolines via Asymmetric Domino Reaction Catalyzed by a Recyclable Ionic‐Liquid‐Supported Bifunctional Tertiary Amine

The most recyclable ionic liquid‐supported bifunctional tertiary amine–squaramide organocatalyst for the asymmetric domino reaction has been found. Over this catalyst, ortho‐aminochalcones protected with Tosyl or Nosyl groups underwent the aza‐Michael/Michael domino reaction with nitroolefins to afford corresponding 2,3,4‐trisubstituted tetrahydroquinolines as single diastereomers in nearly quantitative yield with up to 99 % ee. The catalyst was readily separated from the reaction mixture via a simple centrifugation/decantation workup and 19 times reused in the catalytic reaction without noticeable conversion or enantioselectivity reduction. The N‐nosylated products proved their synthetic value for pharmacology given their facile conversion to fused pirrolidino‐tetrahydroquinolines of high diastreomeric and enantiomeric purity via successive deprotection and reductive amination.

Organocatalytic Asymmetric Synthesis of 3,3'-Pyrrolidinyl-bispirooxindoles via Michael/ N-Hemiketalization Cascade Reaction between 3-Aminooxindoles and Isatin-Derived β,γ-Unsaturated α-Keto Esters.

A novel strategy for the construction of 3,3'-pyrrolidinyl-bispirooxindoles through a Michael/ N-hemiketalization cascade reaction of 3-aminooxindoles and isatin-derived β,γ-unsaturated α-keto esters was developed. Under mild conditions, a series of 3,3'-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereo- and enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. This work represents the first example using the 3-aminooxindoles for the construction of 3,3'-pyrrolidinyl-bispirooxindoles.

Catalytic Asymmetric Conjugate Addition of Tritylthiol to Azadienes with a Bifunctional Organocatalyst

AbstractA highly enantioselective sulfa‐Michael addition of tritylthiol to azadienes catalyzed by a bifunctional squaramide organocatalyst is described, giving the chiral aminothioethers bearing benzofuran motif with high yields and up to 94 % of enantioselectivity. Notably, the aromatization to form the benzofuran is the driving force.

Enantioselective Michael addition of 3-ethyl carboxylate substituted pyrazolones to 5-alkenyl thiazolones catalyzed by squaramide organocatalyst

Asymmetric Michael addition between 3-ethyl carboxylate substituted pyrazolones and 5-alkenylthiazolones catalyzed by a series of chiral bifunctional hydrogen bonding organocatalysts was investigated. Good yields (up to 96%) and excellent enantioselectivities (up to 99% ee) were achieved by using a squaramide containing piperidine group derived from (1S, 2S)-cyclohexanediamine. This strategy provides facile access to a diverse library of thiazole-pyrazolone derivatives with potential bioactivity.

Cinchona Squaramide-Based Chiral Polymers as Highly Efficient Catalysts in Asymmetric Michael Addition Reaction.

We have synthesized novel chiral polymers containing a cinchona-based squaramide in the main chain. We designed a novel cinchona squaramide dimer that contains two cinchona squaramide units connected by diamines. The olefinic double bonds in the cinchona squaramide dimer were used for Mizoroki–Heck (MH) polymerization with aromatic diiodides. The MH polymerization of the cinchona squaramide dimer and aromatic diiodide proceeded well to give the corresponding chiral polymers in good yields. The catalytic activity of the chiral polymers was investigated for asymmetric Michael addition reactions. The effect of the squaramide structure of the polymeric catalyst on the catalytic performance is discussed in detail. We have surveyed the influence of the chiral polymer structure on the catalytic activity and enantioselectivity of the asymmetric reaction. The asymmetric Michael addition of β-ketoesters to nitroolefins was successfully catalyzed by polymeric cinchona squaramide organocatalysts to obtain the corresponding Michael adducts in good yields with excellent enantio- and diastereoselectivities. The polymeric catalysts were insoluble in commonly used organic solvents and easily recovered from the reaction mixture and reused several times without the loss of catalytic activity.

Bifunctional Squaramide Organocatalysts for the Asymmetric Addition of Formaldehyde tert-Butylhydrazone to Simple Aldehydes.

The nucleophilic addition of formaldehyde tert-butylhydrazone to simple aldehydes (a formal hetero-carbonyl-ene reaction) can be performed with good reactivity and excellent enantioselectivity by virtue of the dual hydrogen-bonding activation exerted by amide-squaramide organocatalysts. The resulting hydroxydiazenes (azo alcohols) were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent derivatization provides an entry to relevant amino alcohols, oxazolidinones, and derivatives thereof.

Organocatalytic Three‐Component, One‐Pot Reaction of Highly Substituted Tetrahydropyrano[2, 3‐c]pyrazoles

AbstractWe have developed an efficient synthetic method for the production of substituted tetrahydropyrano[2, 3‐c]pyrazoles using (E)‐2‐nitro‐1,3‐enynes, 1‐aryl‐3‐substituted pyrazolones and methyl vinyl ketone. The sequential, one‐pot reaction proceeded smoothly to give the desired products in high to excellent yields and stereoselectivities in the presence of a quinine‐derived squaramide organocatalyst.

Enantioselective sulfa-Michael addition reaction of methyl thioglycolate to chalcones derivatives with sterically encumbered quinine squaramide organocatalyst

Asymmetric organocatalytic sulfa-Michael reactions give access to enantiomerically enriched sulfur containing adducts that can be used as valuable chiral building blocks. A variety of chalcone derivatives were allowed to react with methyl thioglycolate under optimized conditions, in the presence of a bifunctional quinine derived sterically encumbered squaramide organocatalyst, giving rise to excellent stereoselectivities, up to 99% ee. The designed catalyst system proved to be efficient even at gram scale and under milder reaction conditions.

Asymmetric Michael addition between kojic acid derivatives and unsaturated ketoesters promoted by C2-symmetric organocatalysts.

An efficient sterically hindered C2-symmetric bifunctional tertiary amine-squaramide organocatalyst for the asymmetric Michael addition/hemiketalization domino reaction of kojic acid derivatives with β,γ-unsaturated α-ketoesters has been designed. Pharmacology-relevant functionalized 2,3,4,8-tetrahydropyrano[3,2-b]pyran derivatives were produced over the catalyst in as low as 1 mol% with up to 99% yield and 99% ee. The procedure is at least 30-fold scalable and the catalyst is readily reusable in the catalytic reaction via acid-base extraction. Acylation of the products with (S)- or rac-ibuprofen and with undec-10-enoic acid afforded the corresponding chiral esters containing two privileged pharmacophoric motifs.

Green asymmetric synthesis of tetrahydroquinolines in carbon dioxide medium promoted by lipophilic bifunctional tertiary amine – squaramide organocatalysts

Novel pseudo-enantiomeric bifunctional tertiary amine-squaramides modified with long-chained alkoxy or polyfluoroalkoxy groups, have been synthesized. They catalyzed the asymmetric double-Michael cascade reactions of o-N-tosylaminophenyl α,β-unsaturated ketones with α-nitroolefins in carbon dioxide medium at significantly lower pressure (75 bar) and temperature (35 °C), than known less lipophilic catalysts. Both enantiomers of the pharmacologically valuable methoxy-substituted tetrahydroquinoline derivatives can be prepared in moderate to high yield with promising enantioselectivity (up to 98% ee) under the optimized conditions.

Organocatalytic Enantioselective Vinylogous Henry Reaction of 3,5-Dimethyl-4-nitroisoxazole with Trifluoromethyl Ketones

The enantioselective vinylogous Henry reaction of 3,5-dimethyl-4-nitroisoxazole with trifluoromethyl ketones employing a bifunctional squaramide organocatalyst has been developed. A series of isoxazole bearing trifluoromethyl-substituted tertiary alcohols, 2-substituted (R)-1,1,1-trifluoro-3-(3-methyl-4-nitroisoxazol-5-yl)propan-2-ols, were obtained under these mild reaction conditions in good yields and moderate to good enantioselectivities

Enantioselective Conjugate Addition of Pyrazolones to Nitroalkenes Catalyzed by Binaphthyl‐modified Squaramide Organocatalyst

Enantioselective Conjugate Addition of Pyrazolones to Nitroalkenes Catalyzed by Binaphthyl‐modified Squaramide Organocatalyst

Asymmetric Synthesis of Amino-Bis-Pyrazolone Derivatives via an Organocatalytic Mannich Reaction.

A new series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in asymmetric Mannich reactions with pyrazolones. The amino-bis-pyrazolone products are obtained in excellent yields and stereoselectivities by employing a very low loading of 1 mol % of a bifunctional squaramide organocatalyst. Depending on the substitution at position 4 of the pyrazolones, the new protocol allows for the generation of one or two tetrasubstituted stereocenters, including a one-pot version combing the Mannich reaction with a base-mediated halogenation.

Enantioselective Synthesis of Chiral Pyrazolo[3,4‐d]azepin‐7(2H,4H,8H)‐one Derivatives through a Sequential Michael Addition and Reductive Ring‐Closing Strategy

The asymmetric Michael addition of ethyl (5‐oxo‐1‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)acetate to nitroalkenes catalyzed by a squaramide organocatalyst to give chiral pyrazoles was studied. Subsequent one‐pot reductive ring closing in the same pot gave a series of biologically important chiral pyrazolones with seven‐membered lactam frameworks in good yields with excellent enantioselectivities (up to 99 % ee).

Enantioselective aza-Henry reaction of t-Boc protected imines and nitroalkanes with bifunctional squaramide organocatalysts

A quinine-derived sterically encumbered squaramide organocatalyst afforded high enantioselectivity and excellent conversion in an aza-Henry reaction performed with imines and nitroalkanes.

ChemInform Abstract: Enantioselective Michael Addition of Pyrazolin‐5‐ones to β‐CF3‐β‐Disubstituted Nitroalkenes Catalyzed by Squaramide Organocatalyst.

ChemInformVolume 47, Issue 52 Heterocyclic Compounds ChemInform Abstract: Enantioselective Michael Addition of Pyrazolin-5-ones to β-CF3-β-Disubstituted Nitroalkenes Catalyzed by Squaramide Organocatalyst. Xiaoyan Lai, Xiaoyan Lai Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorGaofeng Zha, Gaofeng Zha Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorWei Liu, Wei Liu Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorYan Xu, Yan Xu Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorPanpan Sun, Panpan Sun Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorTao Xia, Tao Xia Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorYongcun Shen, Yongcun Shen Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this author Xiaoyan Lai, Xiaoyan Lai Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorGaofeng Zha, Gaofeng Zha Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorWei Liu, Wei Liu Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorYan Xu, Yan Xu Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorPanpan Sun, Panpan Sun Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorTao Xia, Tao Xia Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this authorYongcun Shen, Yongcun Shen Dep. Pharm., Sch. Chem. Chem. Eng. Life Sci., Wuhan Univ. Technol., Wuhan, Hubei 430070, Peop. Rep. ChinaSearch for more papers by this author First published: 06 December 2016 https://doi.org/10.1002/chin.201652240Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume47, Issue52December, 2016 RelatedInformation