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Author

Nis Halland

Bio: Nis Halland is an academic researcher from National Research Foundation of South Africa. The author has contributed to research in topics: Enantioselective synthesis & Michael reaction. The author has an hindex of 21, co-authored 61 publications receiving 2238 citations.


Papers
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TL;DR: In this paper, a direct organocatalytic enantioselective α-chlorination of aldehydes has been developed, where the reaction proceeds with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine.
Abstract: The direct organocatalytic enantioselective α-chlorination of aldehydes has been developed. The reaction proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine. The α-chloro aldehydes are obtained in up to 99% yield and up to 95% ee. The synthetic utility of the enantioselective α-chlorination of aldehydes is demonstrated by transformation of the α-chloro aldehydes to the corresponding α-chloro alcohols (>90% yield) by standard reduction and further transformation to both a terminal epoxide and amino alcohol, both obtained without loss of optical purity. Oxidation of the α-chloro aldehydes followed by esterification gave optically active α-chloro esters without loss of optical purity. It is demonstrated that these optically active α-chloro esters can be converted into nonproteinogenic amino acids in overall high yields, maintaining the enantiomeric excess obtained in the catalytic enantioselectiv...

263 citations

Journal ArticleDOI
TL;DR: In this paper, a new catalytic enantioselective conjugate addition of nitroalkanes to acyclic α,β-unsaturated enones catalyzed by novel organic catalysts has been developed.
Abstract: A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic α,β-unsaturated enones catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4-addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization. The potential of the reaction is documented by the reaction of a series of substituted α,β-unsaturated enones with different nitroalkanes. Furthermore, the synthetic applicability of the reaction is demonstrated by the formation of optically active functionalized pyrrolines and pyrrolidines by reductive amination of the products. On the basis of the absolute configuration of the conjugate addition products, the mechan...

222 citations

Journal ArticleDOI
TL;DR: A simple, effective and highly atom-economical synthesis of optically active warfarin from 4-hydroxycoumarin and benzylideneacetone in the presence of imidazolidine catalysts is presented and the scope and potential of this new one-step, organocatalytic enantioselective Michael addition is demonstrated by the formation of a number of important compounds.
Abstract: As optically active drugs become increasingly important for the treatment of diseases in patients, still more enantiopure drugs are introduced to the market either as new drugs or as the result of a racemic switch. An important goal for asymmetric catalysis is to develop new reactions that afford optically active compounds from simple and easily available starting materials and catalysts. However, the ultimate goal would be if the new reaction could be used directly for a onestep synthesis of optically active molecules that have important biological and pharmaceutical activities. Herein we present such an advance and its direct application in an atom-economic synthesis of optically active drugs based on the development of a new organocatalytic enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to a,bunsaturated ketones. The present development leads to a catalytic enantioselective one-step procedure for the formation of one of the most widely used anticoagulants, warfarin (coumadin), and related important compounds. Warfarin has been prescribed as a racemate for more than 40 years and it is well-known that the anticoagulant activity of the S enantiomer is about 5–8 times higher than of the R enantiomer. Furthermore, the enantiomers are metabolized by different pathways, which is reflected by the different half-lives in the human body, 21–43 and 37–89 h, for (S)and (R)-warfarin, respectively. Due to these very different half-lives, one of the major problems with racemic warfarin is the delivery and maintenance of a stable dose as too high doses might lead to internal hemorrhages in the patient. The dosage problem is further complicated by the fact that the peak pharmacological effect of a single dose is not achieved until after approximately 48 h, and the pharmacological effect lasts 4–5 days. As patients respond differently, it is expected that treatment of patients with optically pure warfarin will reduce the dosage problem. Another advantage of optically pure warfarin would be that weakened patients unable to tolerate the stronger racemic or (S)-warfarin could be treated with the milder (R)-warfarin. However, probably the most important advantage of administering optically pure warfarin is the possibility of eliminating drug–drug interactions, which represents another serious problem with racemic warfarin, as enzymes that are responsible for metabolizing warfarin also metabolize many other drugs. Three different approaches towards the synthesis of optically active warfarin have been reported: Demir et al. used a diastereoselective Michael addition in which chiral enamines of 4-hydroxycoumarin were treated with benzylideneacetone in the presence of LDA and superstoichiometric amounts of Lewis acid to obtain warfarin in moderate yield and enantiomeric excess. Li and co-workers at DuPont Merck Pharmaceutical Company obtained enantioenriched warfarin from racemic warfarin through an oxidation procedure and subsequent asymmetric hydrogenation. The diastereoselective synthesis by Cravotto et al. involved a tandem Knoevenagel/hetero-Diels–Alder approach; however, yields were low owing to the somewhat lengthy synthesis. Herein we present, besides the development of a new organocatalytic enantioselective reaction, a simple, effective and highly atom-economical synthesis of optically active warfarin (1a) from 4-hydroxycoumarin (2a) and benzylideneacetone (3a) in the presence of imidazolidine catalysts (Table 1). Furthermore, the scope and potential of this new one-step, organocatalytic enantioselective Michael addition is demonstrated by the formation of a number of important

208 citations


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TL;DR: In this Review, the fundamental characteristics of azide chemistry and current developments are presented and the focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles.
Abstract: Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

1,766 citations

Journal ArticleDOI
TL;DR: An overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present is provided.
Abstract: Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

1,709 citations

Journal ArticleDOI
TL;DR: An up-to-date analysis of all GPCR drugs and agents in clinical trials is reported, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs act at 108 unique GPCRs.
Abstract: G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

1,588 citations

Journal ArticleDOI
TL;DR: This Minireview discusses the current development of domino reactions mediated by organocatalysts, as this principle is used very efficiently in the biosynthesis of complex natural products starting from simple precursors.
Abstract: The current status of organic synthesis is hampered by costly protecting-group strategies and lengthy purification procedures after each synthetic step. To circumvent these problems, the synthetic potential of multicomponent domino reactions has been utilized for the efficient and stereoselective construction of complex molecules from simple precursors in a single process. In particular, domino reactions mediated by organocatalysts are in a way biomimetic, as this principle is used very efficiently in the biosynthesis of complex natural products starting from simple precursors. In this Minireview, we discuss the current development of this fast-growing field.

1,432 citations