Organocatalysis in Enantioselective α‐Functionalization of 2‐Cyanoacetates

Dı́az-de-Villegas, Marı́a D.; Gálvez, José A.; Badorrey, Ramón; López‐Ram‐de‐Víu, Pilar

doi:10.1002/adsc.201400404

Cited by 27 publications

(11 citation statements)

References 128 publications

(90 reference statements)

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“…A broad range of these compounds have been found to exhibit potency as nicotinic acetylcholine receptor ligands (Toma et al, 2002;Artali et al, 2005;Bunnelle et al, 2007;Anderson et al, 2008;Li et al, 2010;Beinat et al, 2015;Bertrand et al, 2015). As a result of the occurrence of two chiral centers, 2,5-diazabicyclo[2.2.1]heptanes are utilized as chiral scaffolds in asymmetric catalysis (Jordis et al, 1999;Gonzá lez-Olvera et al, 2008;Castillo et al, 2013;Díaz-de-Villegas et al, 2014;Avila-Ortiz et al, 2015). The diamine system of 2,5-diazabicyclo[2.2.1]heptane is traditionally included in screening libraries as a rigid counterpart of the flexible piperazine ring (Siebeneicher et al, 2016;Dam et al, 2016;Cernak et al, 2017;Llona-Minguez et al, 2017;Wei et al, 2017).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Britvin

Rumyantsev

2017

Acta Cryst E

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The cage of 2,5-diazabicyclo[2.2.1]heptane is frequently employed in synthetic chemistry as a rigid bicyclic counterpart of the piperazine ring. The 2,5-diazabicyclo[2.2.1]heptane scaffold is incorporated into a variety of compounds having pharmacological and catalytic applications. The unsubstituted parent ring of the system, 2,5-diazabicyclo[2.2.1]heptane itself, has not been structurally characterized. We herein report on the molecular structure of the parent ring in (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide, C 5 H 12 N 2 2+ Á2Br À . The asymmetric unit contains two crystallographically independent cages of 2,5-diazabicyclo[2.2.1]heptane. Each cage is protonated at the two nitrogen sites. The overall charge balance is maintained by four crystallographically independent bromide ions. In the crystal, the components of the structure are linked via a complex three-dimensional network of N-HÁ Á ÁBr hydrogen bonds.

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Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Britvin

Rumyantsev

2017

Acta Cryst E

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“…To date, various asymmetric Michael addition reactions have been developed . Chiral α‐cyanoacetates bearing a quaternary stereogenic center are an important class of substrates that serve as precursors of the highly functionalized chiral compounds such as amino acids and amino alcohols with simple functional group transformation . Recently, organocatalytic enantioselective conjugate addition reactions of α‐substituted cyanoacetates with various Michael acceptors have been reported .…”

Section: Optimization Of the Reaction Conditionsmentioning

confidence: 99%

Diastereo‐ and Enantioselective Conjugate Addition of α‐Substituted Cyanoacetates to Maleimides Catalyzed by Binaphthyl‐based Thiourea

Kang

Kim

2015

Bulletin Korean Chem Soc

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The Michael addition reaction is widely recognized as one of the most efficient and powerful methods for the C-C bonds formation in organic synthesis.1 To date, various asymmetric Michael addition reactions have been developed.2 Chiral α-cyanoacetates bearing a quaternary stereogenic center are an important class of substrates that serve as precursors of the highly functionalized chiral compounds such as amino acids and amino alcohols with simple functional group transformation.3 Recently, organocatalytic enantioselective conjugate addition reactions of α-substituted cyanoacetates with various Michael acceptors have been reported. 4 Until now, there are a few reports for the catalytic conjugate addition of α-substituted cyanoacetates to maleimides using organocatalysts.5 Although these methods are satisfyingly efficient in some extent, new organocatalytic conjugate addition of α-substituted cyanoacetates to maleimides is highly desired.As part of our research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported the asymmetric Michael addition reactions of active methines using chiral catalysts.7 Herein, we wish to describe the conjugate addition of α-substituted cyanoacetates with maleimide promoted by binaphthyl-based organocatalysts.To determine suitable reaction conditions for the catalytic enantioselective Michael addition of α-substituted cyanoacetates, we initially investigated the reactions with N-phenylmaleimide (2a) in the presence of 10 mol % binaphthyl-based organocatalysts I-IV bearing both central and axial chiral elements ( Figure. 1). As shown in Table 1, binaphthyl-based (thio)urea catalysts I-III effectively promoted the reaction in toluene with high enantioselectivities (entries 1-3, Table 1). Replacement of urea function with squaramide (catalyst IV) slightly decreased the enantioselectivity (entry 4, - Table 1), and the highest enantioselectivities obtained with the binaphthyl-based thiourea catalyst II. For further improvement of selectivity, different solvents were then tested in the presence of 10 mol % of catalyst II. Aprotic solvents such as toluene, benzene, diethyl ether, THF, and dichloromethane were well tolerated in this Michael addition without a significant decrease of enantioselectivities (76-96% enantiomeric excesses [ee], entries 2 and 5-9, Table 1). Among the solvents probed, toluene provided the best results (79% yield, 9:1 dr, 96% ee, entry 2, Table 1). The present catalytic system tolerates catalyst loading down to 5 mol %, and both the yields and enantioselectivities were retained (entries 4 and 10-11, Table 1).With the optimized conditions in hand, we proceeded to investigate the scope of the enantioselective conjugate addition of various α-substituted cyanoacetates 1 and N-phenylmaleimide (2a) in the presence of 5 mol % of binaphthylbased thiourea-tertiary amine catalyst II in toluene at room temperature. The results of conjugate addition reaction are summarized in Table 2. A ra...

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“…Our groups have been engaged in the design and use of chiral ammonium salt catalysts for (novel) asymmetric α‐(hetero)functionalizations of prochiral C‐nucleophiles for a while [10,11] . Based on the general high interest in acyclic compounds bearing a quaternary stereogenic center we now became interested in introducing the novel orthogonally functionalized α‐cyanoacetates 3 as a versatile substrate for (chiral ammonium salt‐catalyzed) asymmetric α‐alkylations [12] . As outlined in Scheme 1, these starting materials should be accessible by alkylation of cyanoacetates 1 with the dioxolane‐based electrophile 2 and asymmetric α‐alkylations with Csp 3 ‐based electrophiles 4 will give access to the highly functionalized chiral acyclic targets 5 then.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis

et al. 2021

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We herein report an asymmetric protocol to access a series of orthogonally functionalized acyclic chiral target molecules containing a quaternary stereogenic center by carrying out the enantioselective α‐alkylation of novel orthogonally functionalized dioxolane‐containing cyanoacetates under chiral ammonium salt catalysis. By using just 1 mol % of Maruoka's spirocyclic ammonium salt catalysts enantioselectivities up to e.r.=97.5 : 2.5 could be achieved and further functional group manipulations of the products were carried out as well.

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Organocatalysis in Enantioselective α‐Functionalization of 2‐Cyanoacetates

Cited by 27 publications

References 128 publications

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Diastereo‐ and Enantioselective Conjugate Addition of α‐Substituted Cyanoacetates to Maleimides Catalyzed by Binaphthyl‐based Thiourea

Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis

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