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Special Issue "Stereogenic Centers"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (30 July 2018)

Special Issue Editor

Guest Editor
Dr. Alejandro Baeza Carratalá

Organic Chemistry Department and Instituto de Síntesis Orgánica, Universitat d'Alacant, Alicante, Spain
Website | E-Mail
Interests: asymmetric catalysis; organocatalysis; green chemistry

Special Issue Information

Dear Colleagues,

The importance of having access to chiral molecules is a well-known fact for the scientific community. This is due to the fact that most of the biological activity that some molecules possess is associated to one of the all-possible enantiomers, which can interact differentially with chiral recognition entities, triggering distinct biochemical responses.

It is not surprising then that different methodologies have been developed in the last century, within the frame of so-called asymmetric synthesis, in order to tackle the challenging task of constructing such chiral compounds, as most of these strategies are based on the construction of stereogenic centers starting from racemic and/or pro-chiral compounds.

Thus, the aim of this Special Issue is to gather recent developments in the establishment of stereogenic centers in organic molecules. Therefore, asymmetric synthesis, kinetic resolutions, asymmetric catalysis (metal-, organo- and biocatalysis), among other strategies, as well as studies that help in the understanding of the mechanism behind these processes will be covered in this Special Issue.

Dr. Alejandro Baeza Carratalá
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Chirality
  • Stereogenic Centers
  • Asymmetric Synthesis
  • Asymmetric Catalysis
  • Enantiomers

Published Papers (10 papers)

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Research

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Open AccessArticle Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions
Molecules 2018, 23(9), 2351; https://doi.org/10.3390/molecules23092351
Received: 1 September 2018 / Revised: 8 September 2018 / Accepted: 10 September 2018 / Published: 14 September 2018
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Abstract
The versatile synthesis of (−)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen
[...] Read more.
The versatile synthesis of (−)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen rearrangements of lactam precursors. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Graphical abstract

Open AccessFeature PaperCommunication One-pot Fluorination and Organocatalytic Robinson Annulation for Asymmetric Synthesis of Mono- and Difluorinated Cyclohexenones
Molecules 2018, 23(9), 2251; https://doi.org/10.3390/molecules23092251
Received: 4 August 2018 / Revised: 29 August 2018 / Accepted: 31 August 2018 / Published: 4 September 2018
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Abstract
A one-pot fluorination and organocatalytic Robinson annulation sequence has been developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-1-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three stereocenters in good to excellent yields with up to 99% ee and
[...] Read more.
A one-pot fluorination and organocatalytic Robinson annulation sequence has been developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-1-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three stereocenters in good to excellent yields with up to 99% ee and 20:1 dr. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Graphical abstract

Open AccessCommunication Oxidative Asymmetric Formal Aza-Diels–Alder Reactions of Tetrahydro-β-carboline with Enones in the Synthesis of Indoloquinolizidine-2-ones
Molecules 2018, 23(9), 2228; https://doi.org/10.3390/molecules23092228
Received: 26 July 2018 / Revised: 26 August 2018 / Accepted: 29 August 2018 / Published: 1 September 2018
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Abstract
Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Diels–Alder reaction for enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-β-carbolines and α,β-unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-catalyzed formal aza-[4 +
[...] Read more.
Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Diels–Alder reaction for enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-β-carbolines and α,β-unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-catalyzed formal aza-[4 + 2] cycloaddition, providing a step-economical strategy for the synthesis of these valuable heterocyclic products. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessArticle Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine
Molecules 2018, 23(9), 2207; https://doi.org/10.3390/molecules23092207
Received: 20 July 2018 / Revised: 25 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
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Abstract
In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination,
[...] Read more.
In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessArticle Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst
Molecules 2018, 23(8), 2003; https://doi.org/10.3390/molecules23082003
Received: 23 July 2018 / Revised: 6 August 2018 / Accepted: 7 August 2018 / Published: 10 August 2018
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Abstract
Various optically active 2-hydroxyamide derivatives are produced based on the kinetic resolution of racemic 2-hydroxyamides with a diphenylacetyl component and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst, via asymmetric esterification and acylation. It was revealed that a tertiary amide can
[...] Read more.
Various optically active 2-hydroxyamide derivatives are produced based on the kinetic resolution of racemic 2-hydroxyamides with a diphenylacetyl component and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst, via asymmetric esterification and acylation. It was revealed that a tertiary amide can be used with this novel protocol to achieve high selectivity (22 examples; s-value reaching over 250). The resulting chiral compounds could be transformed into other useful structures while maintaining their chirality. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessArticle One-Dimensional 13C NMR Is a Simple and Highly Quantitative Method for Enantiodiscrimination
Molecules 2018, 23(7), 1785; https://doi.org/10.3390/molecules23071785
Received: 21 June 2018 / Revised: 13 July 2018 / Accepted: 17 July 2018 / Published: 20 July 2018
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Abstract
The discrimination of enantiomers of mandelonitrile by means of 1D 13C NMR and with the aid of the chiral solvating agent (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol (TFAE) is presented. 1H NMR fails for this specific compound because proton signals either overlap with the signals of
[...] Read more.
The discrimination of enantiomers of mandelonitrile by means of 1D 13C NMR and with the aid of the chiral solvating agent (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol (TFAE) is presented. 1H NMR fails for this specific compound because proton signals either overlap with the signals of the chiral solvating agent or do not show separation between the (S)-enantiomer and the (R)-enantiomer. The 13C NMR method is validated by preparing artificial mixtures of the (R)-enantiomer and the racemate, and it is shown that with only 4 mg of mandelonitrile a detection limit of the minor enantiomer of 0.5% is obtained, corresponding to an enantiomeric excess value of 99%. Furthermore, the method shows high linearity, and has a small relative standard deviation of only 0.3% for the minor enantiomer when the relative abundance of this enantiomer is 20%. Therefore, the 13C NMR method is highly suitable for quantitative enantiodiscrimination. It is discussed that 13C NMR is preferred over 1H NMR in many situations, not only in molecules with more than one chiral center, resulting in complex mixtures of many stereoisomers, but also in the case of molecules with overlapping multiplets in the 1H NMR spectrum, and in the case of molecules with many quaternary carbon atoms, and therefore less abundant protons. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessArticle Chiral 2-Aminobenzimidazole as Bifunctional Catalyst in the Asymmetric Electrophilic Amination of Unprotected 3-Substituted Oxindoles
Molecules 2018, 23(6), 1374; https://doi.org/10.3390/molecules23061374
Received: 9 May 2018 / Revised: 4 June 2018 / Accepted: 5 June 2018 / Published: 6 June 2018
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Abstract
The use of readily available chiral trans-cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained a dimethylamino moiety (5). With this catalyst under optimized
[...] Read more.
The use of readily available chiral trans-cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained a dimethylamino moiety (5). With this catalyst under optimized conditions, different oxindoles containing a wide variety of substituents at the 3-position were aminated in good yields and with good to excellent enantioselectivities using di-tert-butylazodicarboxylate as the aminating agent. The procedure proved to be also efficient for the amination of 3-substituted benzofuranones, although with moderate results. A bifunctional role of the catalyst, acting as Brønsted base and hydrogen bond donor, is proposed according to the experimental results observed. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessFeature PaperCommunication Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes
Molecules 2018, 23(4), 961; https://doi.org/10.3390/molecules23040961
Received: 6 April 2018 / Revised: 17 April 2018 / Accepted: 17 April 2018 / Published: 20 April 2018
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Abstract
A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents are required since
[...] Read more.
A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Open AccessArticle Asymmetric Conjugate Addition of α,α-Disubstituted Aldehydes to Nitroalkenes Organocatalyzed by Chiral Monosalicylamides from trans-Cyclohexane-1,2-Diamines
Molecules 2018, 23(1), 141; https://doi.org/10.3390/molecules23010141
Received: 25 December 2017 / Revised: 8 January 2018 / Accepted: 9 January 2018 / Published: 11 January 2018
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Abstract
Primary amine-salicylamides derived from chiral trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to arylated and heteroarylated nitroalkenes. The reaction is performed in the presence of 4-dimethylaminopyridine as an additive in dichloromethane as a solvent at room
[...] Read more.
Primary amine-salicylamides derived from chiral trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to arylated and heteroarylated nitroalkenes. The reaction is performed in the presence of 4-dimethylaminopyridine as an additive in dichloromethane as a solvent at room temperature. The corresponding enantioenriched γ-nitroaldehydes are obtained with enantioselectivities up to 95%. Theoretical calculations are used to justify the reasons of the stereoinduction. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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Review

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Open AccessReview Practical Enantioselective Reduction of Ketones Using Oxazaborolidine Catalysts Generated In Situ from Chiral Lactam Alcohols
Molecules 2018, 23(10), 2408; https://doi.org/10.3390/molecules23102408 (registering DOI)
Received: 21 August 2018 / Revised: 18 September 2018 / Accepted: 18 September 2018 / Published: 20 September 2018
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Abstract
Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during
[...] Read more.
Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during storage. Therefore, we investigated a more reliable and practical method for the reduction of a variety of ketones including challenging substrates, primary aliphatic ketones, α,β-enones, and trifluoromethyl ketones. This review surveys the developments in borane reduction using oxazaborolidine catalysts generated in situ from chiral lactam alcohols and borane. Full article
(This article belongs to the Special Issue Stereogenic Centers)
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