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N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2′-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediac...
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... [14] In 2015, Lupton's group reported an N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of trienyl esters to construct tetrasubstituted benzaldehydes. [15] In the case of utilizing 1 as substrates, the axially chiral biaryl aldehydes 2 were formed with moderate yields and stereoselectivities in the presence of NHC Cat. 1* and KHMDS, as depicted in Scheme 1. ...
The burgeoning field of asymmetric catalysis has significantly advanced the construction of axially chiral compounds, recognized for their distinct three‐dimensional structures that are relevant in drug discovery, catalyst design and material science. Particularly, the atropisomeric aldehydes, characterized by a chiral axis and the presence of an aldehyde functionality, are of increasing value and interest in chemistry‐related domains, such as serving as privileged chiral catalysts for activation of amines. In recent years, elegant environmentally‐friendly metal‐free catalytic asymmetric methodologies based on de novo formation of (hetero)aromatic rings, dynamic kinetic resolution and desymmetrization have been established to build this fascinating class of atropisomers. In this review, we would like to highlight recent research progress on enantioselective synthesis of atropisomeric aldehydes by means of organocatalysis and biocatalysis, including their scopes, limitations, mechanisms, synthetic applications and provide some insights into future development.
... Beyond oxidation reactions, such as the one used in the seminal example by Meyers and which will be the focus of this review, other mechanistic pathways are available to achieve conversions of chirality and have been discussed in more general reviews [46][47][48][49][50][74][75][76][77][78][79][80][81][82]. We can notably cite eliminations [83][84][85][86][87][88], retro-cycloadditions [89,90], opening of strained rings [91], and tautomerizations and isomerizations [57,92,93]. To really appreciate the impact of central-to-axial conversion of chirality during aromatization for the synthesis of enantioenriched atropisomers, and the importance of understanding it, one must also realize that in addition to the explicit examples presented here, many reactions actually proceed via an implicit conversion of chirality [47]. ...
Atropisomers are fascinating objects of study by themselves for chemists but also find applications in various sub-fields of applied chemistry. Obtaining them in enantiopure form is far from being a solved challenge, and the past decades has seen a surge of methodological developments in that direction. Among these strategies, oxidative aromatization with central-to-axial conversion of chirality has gained increasing popularity. It consists of the oxidation of a cyclic non-aromatic precursors into the corresponding aromatic atropisomers. This review proposes a critical analysis of this research field by delineating it and discussing its historical background and its present state of the art to draw potential future development directions.
... Using the unique activation modes employing NHCs, atroposelective construction of differently substituted axially chiral C-C bonds leading to the synthesis of biaryls and related compounds are possible. In the last decade, a variety of structurally diverse C-C axially chiral biaryls and styrenes were demonstrated using carbene-catalyzed strategies involving kinetic resolutions, desymmetrizations, (benz)annulations, central to axial chirality transfers, etc. by the groups of Zhao, 13 Wang, 14 Lupton, 15 Zhu, 16 Du, 17 Ye, 18 and Chi (Scheme 1a). 19 ...
Although the atroposelective synthesis of biaryls and related compounds bearing axially chiral C-C bonds are well-known, the synthesis of axially chiral C-N bond-containing compounds are relatively less explored, and the construction of axially chiral N-N bonds has received only scant attention. Demonstrated herein is the N-heterocyclic carbene (NHC)-catalyzed selective amidation reaction leading to the atroposelective synthesis of N-N axially chiral 3-amino quinazolinones. The NHC-catalyzed reaction of quinazolinones containing a free N-H moiety with -unsaturated aldehydes under oxidative conditions furnished the atropisomeric quinazolinone derivatives under mild conditions and broad scope. Preliminary studies on experimental and DFT-based N-N rotational barrier determination is also presented.
... Here, we disclose an N-heterocyclic carbene (NHC)-catalytic approach for highly atroposelective and efficient synthesis of axially chiral styrenes bearing both sulfone and carboxylic ester units (Fig. 1c). In the confined arena of axially chiral molecule synthesis, NHC catalysis was previously used by us 52,53 and others 30,[54][55][56][57][58][59][60][61][62][63][64] to mediate cycloaddition 30,52,[54][55][56][57][58] , desymmetrization 53,59-61 or kinetic resolution [62][63][64] to construct molecules bearing the chiral axis between two rigid rings. In our present study, nucleophilic 1,4addition of sulfur atom of sulfinic acid to an NHC-activated ynal set up the chiral axis. ...
... Here, we disclose an N-heterocyclic carbene (NHC)-catalytic approach for highly atroposelective and efficient synthesis of axially chiral styrenes bearing both sulfone and carboxylic ester units (Fig. 1c). In the confined arena of axially chiral molecule synthesis, NHC catalysis was previously used by us 52,53 and others 30,[54][55][56][57][58][59][60][61][62][63][64] to mediate cycloaddition 30,52,[54][55][56][57][58] , desymmetrization 53,59-61 or kinetic resolution [62][63][64] to construct molecules bearing the chiral axis between two rigid rings. In our present study, nucleophilic 1,4addition of sulfur atom of sulfinic acid to an NHC-activated ynal set up the chiral axis. ...
Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N -heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E -selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to > 99:1 e.r ., > 20:1 E / Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.
... It has been well-established that NHC organocatalytic reactions are robust for the preparation of central chiral molecules.I ti s, therefore,a ne ffective strategy to establish stereogenic axes through central-to-axial chirality conversions.The initial report on this approach was from the Lupton group in 2015, when they disclosed an NHC-catalyzed intramolecular isomerization of esters 32 to afford functional benzaldehydes 33 (Scheme 7a). [21] Va rious central chiral intermediates are formed during the formation of the biaryl product 33.I nm ost cases,t he chiral information of these intermediates is lost during the dehydrogenative aromatization process.H owever,t he chiral information of these intermediates can be effectively trans- ...
Atropisomeric molecules have found proven applications and have shown promising potential in chemistry and medicine. The design of N‐heterocyclic carbene (NHC) catalyzed reactions to construct atropisomerically enriched molecules has emerged as an important research topic in recent years. These reactions include kinetic resolutions, asymmetric desymmetrizations, central‐to‐axial chirality conversions, and cycloadditions. This Minireview evaluates and summarizes the progress in NHC‐based organic catalysis for access to atropisomers, and briefly states our personal perspectives on the future advancement of this topic. NHC catalysis has provided rich and unique reaction modes that have led to success in the asymmetric synthesis of central‐chiral molecules. It is expected that similar success could also be achieved in developing NHC catalysis to prepare atropisomeric molecules, including those not easily accessible by other methods.
... In the con ned arena of axially chiral molecule synthesis, NHC catalysis were previously used by us 52,53 and others 30,[54][55][56][57][58][59][60][61][62][63][64] to mediate cycloaddition 30,52,[54][55][56][57][58] , desymmetrization 53,[59][60][61] or kinetic resolution [62][63][64] to construct molecules bearing the chiral axis between two rigid rings. In our present study, nucleophilic 1,4-addition of sulfur atom of sul nic acid to an NHC-activated ynal set up the chiral axis. ...
... In the con ned arena of axially chiral molecule synthesis, NHC catalysis were previously used by us 52,53 and others 30,[54][55][56][57][58][59][60][61][62][63][64] to mediate cycloaddition 30,52,[54][55][56][57][58] , desymmetrization 53,[59][60][61] or kinetic resolution [62][63][64] to construct molecules bearing the chiral axis between two rigid rings. In our present study, nucleophilic 1,4-addition of sulfur atom of sul nic acid to an NHC-activated ynal set up the chiral axis. ...
Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N -heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E -selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to >99:1 e.r., >20:1 E / Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.
... In 2015, Lupton's group impacted the field again by reporting an NHC-catalyzed redox isomerization approach to synthesize highly substituted 2-aryl-3-carboxy-4-alkyl benzaldehydes 41 from conjugated ester starting materials 31 (Scheme 5). [20] The stepwise mechanism proceeds via a similar lactone intermediate 37 as discussed previously, but instead of undergoing decarboxylation, the lactone further reacts with the NHC catalyst to form an acyl azolium enolate 38. A subsequent β-deprotonation event generates Breslow-type intermediate 39, followed by dehydration to form aromatic intermediate 40. ...
... In an effort to develop the asymmetric version of NHC-catalyzed benzannulation reactions, a previously discussed report by the Lupton group in 2015 unfortunately suffered from low enantioselectivity, presumably due to an inefficient enantiodetermining β-lactone formation step. [20] However, this report opened up the possibilities of developing other enantioselective benzannulation reactions by using a chiral NHC-catalyst. Although the atroposelectivity of NHC-catalyzed methods do not exhibit to the generality of more established transition metal-catalyzed methods, [33] the ability to generate atropisomers stereoselectively with organocatalysts represents an emerging conceptual advance in the field. ...
Aromatic compounds are ubiquitous in pharmaceutical agents and other functional materials. Therefore, synthetic methods to construct highly functionalized aromatic frameworks have attracted considerable attention, especially when utilizing acyclic precursors instead of pre‐existing benzenoid cores. A plethora of methods exist in the literature for the construction of substituted aromatic products by using transition metal catalysis and base‐promoted benzannulation reactions starting from acyclic precursors. In recent years, organocatalytic approaches such as N‐heterocyclic carbene catalysis have emerged as effective tools for the efficient and regioselective construction of highly functionalized aryl rings under metal‐free and mild reaction conditions. The fundamental objective of this minireview is to highlight the synthetic potential of NHC‐catalyzed benzannulations for the generation of aromatic rings with complex substitution patterns and to discuss these reactions from the perspective of their mechanistic design.
... In 2015, Lupton et al. reported the first NHCcatalyzed enantioselective cycloisomerization of triene, providing tri-ortho-substituted axially chiral biaryls in moderate yields and enantioselectivities via central-to-axial chirality conversion. [19] Very recently, Zhu et al. developed an efficient approach for the synthesis of tri-ortho-substituted axially chiral biaryls via NHC-catalyzed enantioselective benzannulation of dienals with benzyl ketones. [20] To the best of our knowledge, the synthesis of sterically hindered tetra-orthosubstituted biaryls is still a challenging but unsolved issue under NHC catalysis. ...
Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N‐heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra‐ortho‐substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC‐catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzyl‐benzothiophene/benzofuran‐3‐carbaldehydes through a [2+4] annulation, decarboxylation, and oxidative aromatization cascade with central‐to‐axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran‐fused biaryls in high enantioselectivities and works well for the synthesis of tetra‐ortho‐substituted biaryls.
... Lupton and co-workers developed an NHC-catalyzed benzannulation reaction of trienyl esters 133, affording the desired tetrasubstituted benzaldehydes 136 in good to excellent yields. [58] Experiment optimization showed that the reaction displayed significant sensitivity to solvent and water, the desiccant and benzene resulted in the improvement of yield. Further mechanism study suggested that β-lactone 135 was first obtained as reactive intermediate, which was next converted into the tetrasubstituted benzaldehydes 136 by the addition of the NHC to 135/subsequent proton transfer/elimination of water/removal of the NHC process (Scheme 31). ...
Aromatic compounds are omnipresent in organic chemistry, which are the broadest skeletons of bioactive molecules, medicines, and materials. Due to their importance, conventional methods to assemble aromatic rings have attracted considerable attention. The direct formation of benzene cores from readily available acyclic precursors offers a highly versatile and superior approach to prepare both small organic molecules and sophisticated natural products. Recently, organocatalyst‐mediated annulation reaction, including phosphine‐, tertiary amine‐, secondary amine‐, primary amine‐, and NHC‐mediated benzannulation reactions, is considered as an efficient method to access multi‐substituted arenes. In this review, we will emphasize the selected examples of organocatalyst‐mediated benzannulation reactions of available acyclic precursors for the construction of diverse aromatics.
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... [7] In 2015, Lupton et al. reported the NHC-catalyzed synthesis of benzaldehydes by an interesting redox isomerization of dienyl a,b-unsaturated esters (Scheme 1b). [8] In 2016, Wang and our group independently reported the NHC-catalyzed synthesis of benzenes from enals and a-cyano-b-methylenones (Scheme 1c). [9] Lately,t he reactionf rom bromoenals was also developed in our group. ...
Annulation: N‐heterocyclic carbene‐catalyzed synthesis of 2,2′‐dihydroxybenzophenones from β‐methylenals and aurones was developed. The cleavage of the C−O bond by retro‐Michael addition is the key step from the spirocyclic intermediate to final product (see scheme). image
