Organocatalytic Asymmetric Conjugate Addition Research Articles

Organocatalytic Asymmetric Conjugate Addition of Fluorooxindoles to Quinone Methides.

Fluorooxindoles undergo asymmetric Michael addition to para-quinone methides under phase-transfer conditions with 10 mol% of a readily available cinchona alkaloid ammonium catalyst. This reaction affords sterically encumbered, multifunctional fluorinated organic compounds displaying two adjacent chirality centers with high yields, ee's and dr's.

Enantioselective Synthesis of Chiral Organosilicon Compounds by Organocatalytic Asymmetric Conjugate Addition of Boronic Acids to β-Silyl-α,β-Unsaturated Ketones.

Herein, we report (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to β-silyl-α,β-unsaturated ketones, furnishing moderate to excellent yields of the corresponding β-silyl carbonyl compounds with stereogenic centers in excellent enantioselectivities (up to 98% ee). Moreover, the catalytic system features mild reaction conditions, high efficiency, broad substrate scope, and easy scale-up.

A versatile approach to functionalized cyclic ketones bearing quaternary carbon stereocenters via organocatalytic asymmetric conjugate addition of nitroalkanes to cyclic β-substituted α,β-Enones

Abstract A versatile organocatalytic asymmetric conjugate addition of nitroalkanes to β-substituted cyclic α,β-enones to yield cyclic ketones bearing all-carbon quaternary stereogenic centers at β-C has been developed. This is an extension of the method that we developed during the total synthesis of (−)-haliclonin A, which features the employment of structurally relatively simple, cheap and easily available primary amine-thiourea derived from (R,R)-1,2-diaminocyclohexane as the chiral catalyst. The method shows wide substrate scope, good functional group tolerance, which allows a quick access to multi-functionalized chiral compounds. The synthetic potential of the method was demonstrated by one-step transformations of the nitro-ketone adducts to four other classes of compounds. The absolute configurations of adducts were determined by comparison of both the retention time of chiral HPLC analysis and sense of specific optical rotation with those of a known compound. The enantioselective control mechanism was rationalized based on the DFT computational studies.

Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)‐Haliclonin A†

Summary of main observation and conclusionWe describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all‐carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C1N1 building block to form the 3‐azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3‐alkenyl cyclohex‐2‐enone, and the first Pd‐promoted intramolecular coupling of a thiocarbamate moiety onto an electron‐deficient alkene (enone) to form the 3‐azabicyclo[3,3,1]nonane core. The synthesis also features a SmI2‐mediated intermolecular reductive coupling of an enone with an aldehyde, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocycles, and an unprecedented direct transformation of enol into enone.

Organocatalytic asymmetric conjugate addition of substituted 5-benzylfurfurals to nitroalkenes based on stereocontrol of trienamine

Asymmetric ε-alkylation reaction of substituted 5-benzylfurfural derivatives to nitroalkenes by controlling the stereochemistry of the trienamine intermediate resulted in corresponding ε-regioselective addition products in high yields, diastereoselectivities, and enantioselectivities.

Organocatalytic Asymmetric Conjugate Addition of Aldehydes to Maleimides and Nitroalkenes in Deep Eutectic Solvents.

A chiral primary amine-salicylamide is used as an organocatalyst for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides and nitroalkenes. The reactions are performed in deep eutectic solvents as reaction media at room temperature, leading to the corresponding adducts with enantioselectivities up to 88% (for maleimides) and 80% (for nitroalkenes). Catalyst and solvent can be recovered and reused.

Organocatalytic enantioselective conjugate addition of pyrazolin-5-ones to arylomethylidene malonates.

An efficient asymmetric organocatalytic conjugate addition reaction of pyrazolin-5-ones with arylomethylidene malonates has been successfully developed by employing bifunctional Cinchona derived thiourea organocatalysts. The protocol provides straightforward access to pyrazole substituted scaffolds in good yields with high stereocontrol.

High pressure-assisted low-loading asymmetric organocatalytic conjugate addition of nitroalkanes to chalcones.

The application of high pressure (up to 9 kbar) allows for relatively fast (1-5 h) and highly enantioselective 1,4-addition of nitromethane and 2-nitropropane to chalcones at room temperature with substantial reduction of catalyst loading (0.2-1 mol% of cinchona alkaloid-based thioureas and squaramides). Various γ-nitroketones were obtained at 9 kbar with high yield and enantioselectivity (up to 98%), whereas in control experiments at atmospheric pressure usually only a small amount (<10%) of products were formed after 20 h.

Asymmetric Organocatalytic Conjugate Addition of Thiocarboxylic Acids to In Situ‐Generated ortho‐Quinomethanes in Oil‐Water Phases

AbstractAn asymmetric conjugate addition of thiocarboxylic acids to in situ‐generated ortho‐quinomethanes (o‐QMs) catalyzed by bifunctional squaramide catalysts has been developed. The transformation proceeds with high yields (up to 96%) and enantioselectivities (up to 96% ee) in the oil‐water phases. The resulting thioester could be converted facilely into the chiral benzyl mercaptan in high yield without loss of enantioselectivity. The study also showed that the oil‐water biphase contributed significantly to the efficiency of the catalytic system.magnified image

Organocatalytic asymmetric conjugate addition of 2-fluoro-1,3-diketones to nitroalkenes

The organocatalytic enantioselective conjugate reaction of 2-fluoro-1,3-diketones to nitroalkenes promoted by chiral binaphthyl-modified squaramide has been achieved. Treatment of 2-fluoro-1,3-diketones with nitroalkenes under mild reaction conditions afforded the corresponding Michael products containing fluorinated quaternary carbon stereocenter with excellent enantioselectivity (up to 98% ee).

Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes.

The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made during the last years in achieving efficiently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes developed between 2013 and early 2017.

Organocatalytic Asymmetric Tandem Conjugate Addition–Protonation of Azlactones to N-Itaconimides

An unprecedented catalytic asymmetric reaction between azlactones and N-itaconimides has been developed. In the presence of an l-tert-leucine-based urea–tertiary amine Brønsted base catalyst, the tandem conjugate addition–protonation products could be attained in moderate yields with excellent enantio- and diastereoselectivities (up to 99% ee and &gt;20:1 dr). The method provides an efficient approach to access valuable chiral γ-tertiary amine substituted succinimides containing nonadjacent stereocenters.

Organocatalytic asymmetric conjugate addition of t-butyl nitroacetate to o-quinone methides: synthesis of optically active α-nitro-β,β-diaryl-propionates

α-Nitro-β,β-diaryl-propionates were prepared with good yields and excellent enantioselectivities via asymmetric conjugate addition of t-butyl nitroacetate to in situ generated o-quinone methides.

ChemInform Abstract: Organocatalytic Asymmetric Conjugate Addition of Diaryloxazolidin‐2,4‐diones to Nitroolefins: An Efficient Approach to Chiral α‐Aryl‐α‐hydroxy Carboxylic Acids.

AbstractA series of chiral oxazolidin‐2,4‐diones is prepared by an asymmetric conjugate addition of diones (I) to nitroalkenes (II) in the presence of the urea catalyst PUFP.

ChemInform Abstract: Organocatalytic, Asymmetric Total Synthesis of (‐)‐Haliclonin A.

The first total synthesis of the alkaloid (−)-haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3-alkenyl cyclohex-2-enone to set the stereochemistry of the all-carbon quaternary stereogenic center. The synthesis also features a Pd-promoted cyclization to form the 3-azabicyclo[3,3,1]nonane core, a SmI2-mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.

Organocatalytic, Asymmetric Total Synthesis of (-)-Haliclonin A.

The first total synthesis of the alkaloid (-)-haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3-alkenyl cyclohex-2-enone to set the stereochemistry of the all-carbon quaternary stereogenic center. The synthesis also features a Pd-promoted cyclization to form the 3-azabicyclo[3,3,1]nonane core, a SmI2 -mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.

Organocatalytic, Asymmetric Total Synthesis of (−)‐Haliclonin A

AbstractThe first total synthesis of the alkaloid (−)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI2‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.

Organocatalytic asymmetric conjugate addition of diaryloxazolidin-2,4-diones to nitroolefins: an efficient approach to chiral α-aryl-α-hydroxy carboxylic acids

The first asymmetric conjugate addition of diaryloxazolidin-2,4-diones to nitroolefins using an l-threonine-based tertiary amine-urea catalyst has been developed.

Asymmetric Organocatalytic Conjugate Addition of Trifluoroborates

Asymmetric Organocatalytic Conjugate Addition of Trifluoroborates

Efficient and highly enantioselective construction of trifluoromethylated quaternary stereogenic centers via high-pressure mediated organocatalytic conjugate addition of nitromethane to β,β-disubstituted enones.

A very effective high-pressure-induced acceleration of asymmetric organocatalytic conjugate addition of nitromethane to sterically congested β,β-disubstituted β-CF3 enones has been developed. A combination of pressure (8-10 kbar) and noncovalent catalysis with low-loading of chiral tertiary amine-thioureas (0.5-3 mol %) is shown to provide very efficient access to a wide range of γ-nitroketones containing trifluoromethylated all-carbon quaternary stereogenic centers in the β-position (80-97%, 92-98% ee).