: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

From 2000 to mid-2010: a fruitful decade for the synthesis of pyrazoles.

In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Drug Discovery Today

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Organocatalysis has captured the imagination of a significant group of synthetic chemists. Much of the mechanistic understanding of these reactions has come from computational investigations or studies involving both experimental and complementary computational explorations. As much as any other area of chemistry, organocatalysis has advanced because of both empirical discoveries and computational insights. Quantum mechanical calculations, particularly with density functional theory (DFT), can now be applied to real chemical systems that are studied by experimentalists; this review describes the quantum mechanical studies of organocatalysis.

The dramatic growth of computational investigations on organocatalysis in the last decade reflects the great attention focused on this area of chemistry since the discoveries of List, Lerner, and Barbas of the proline-catalyzed intermolecular aldol reaction, and by MacMillan in the area of catalysis by chiral amino-acid derived amines. The number of reports on the successful applications of organocatalysts and related mechanistic investigations for understanding the origins of catalysis and selectivities keep growing at a breathtaking pace. Literature coverage in this review is until October 2009, except for very recent discoveries that alter significantly the conclusions based on older literature.

1.1 Computational methods for organocatalysis
Over the last two decades, DFT has become a method of choice for the cost-effective treatment of large chemical systems with high accuracy.1 Most of the studies reported in this review were carried out using the B3LYP functional with the 6-31G(d) basis set, which is a standard in quantum mechanical calculations. Nevertheless, DFT is experiencing continuing developments of new functionals and further improvements. The availability of many new functionals and, in particular, the rapidly evolving performance issues of B3LYP have stimulated extra efforts on benchmarking DFT methods for the prediction of key classes of organic reactions.2 The well-documented deficiencies of B3LYP include the failure to adequately describe medium-range correlation and photobranching effects,3,4 delocalization errors causing significant deviations in π→σ transformations,2b,5 and incorrect description of non-bonding and long-range interactions,6 which are likely to be key factors in determining stereoselectivities. Benchmark results also show that newer functionals considerably improve some of the underlying issues.2–7 Recent advances, especially in the treatment of dispersion effects, now offer more reliable models of the reaction profiles and stereoselectivities.

Most benchmarks focus on energetics rather than stereoselectivities. Systematic benchmarking for stereoselectivities requires more sophisticated techniques and averaging over conformations. To date, such benchmarking based upon stereoselectivity is available for only three reactions,8 and even there only various basis sets with B3LYP, as well as comparisons of results predicted using enthalpies and free energies. It is not possible to assign error bars for stereoselectivities for the majority of reports discussed in this review. Because stereoisomeric transition structures are very similar species, their relative energies are likely to be calculated accurately, as shown by the good agreement between calculated and experimental values.

More recently Harvey (Harvey, 2010, faraday discussions) has studied two typical organic reactions of polar species (Wittig and Morita-Baylis-Hillman reactions) at different levels of theory.2i He showed that many standard computational methods, involving B3LYP, are qualitatively useful, but the energetics may be misleading for larger reactive partners; the quantitative prediction of rate constants remains difficult. These studies suggest that although B3LYP provides valuable qualitative insight into the reaction mechanisms and selectivities, the energetics may require testing with higher accuracy methods for complex organic systems. On the other hand, Simon and Goodman found B3LYP to be “only slightly less accurate” than newer methods, and recommended its use for organic reaction mechanisms.9

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Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

β-Amino acids with a single side chain in the α-position (β 2 -aminoacids or H-β 2 -aminoacids or H-β 2 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 -homo-aminoacids, the β 2 -homo-aminoacids, the β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -AminoAcid Building Blocks for Peptide Synthesis

Enantioselective Preparationof β²-Amino Acid Derivatives for β-Peptide Synthesis

The X-ray crystal structures of three (E)-1-cinnamoylidene iminium PF6 salts of 5-benzyl-3-methylimidazolidin-4-ones (2,2-dimethyl-, cis-2-(tert-butyl)-, and cis-2-styryl-substituted; 2-4, resp.) are reported (Figs. 3-5). In the 2,2-dimethyl and in the cis-2-styryl derivative, 2 and 4, respectively, a CH bond of the cis-substituent in 2-position points to the center of the benzene ring of the benzyl group above the five-membered ring (Fig. 6, a and b). NMR Measurements (Fig. 8) provide evidence that the same structure is present in solution, and that a fourth derivative of this type, 5 (Scheme), has (Z)- instead of (E)-configuration around the CN bond. In the cis-2-(tert-butyl) derivative 3, the benzyl group is located over the iminium -system (Figs. 4 and 6, c). Overlays with DFT-calculated crotonylidene analogs, A and B, show that the theoretical and experimental structures are almost superimposable (Fig. 9 and Table). The structures are discussed in view of their role as reactive intermediates in organocatalysis and in view of the help synthetic organic chemists may experience from theory.

5-Benzyl-3-methylimidazolidin-4-one-Derived Reactive Intermediates of Organocatalysis – A Comforting Resemblance of X-Ray, NMR, and DFT Solid-Phase, Liquid-Phase, and Gas-Phase Structures

Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease.

In CDCl 3 solution, enantiopure ( S )-1-benzyl-6-methylpiperazine-2,5-dione ( S )- 1a formed diastereomeric C O ⋯ H –N hydrogen-bonded associates with racemic ( RS , Z )-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b , ( RS )- tert -butyl pyroglutamate ( RS )- 2c and ( RS )- N -benzoylalanine methyl ester ( RS )- 2d . This resulted in splitting (doubling) of the characteristic signals in the 1 H NMR and 13 C spectra of racemic compounds 2a – d in the presence of 1 equiv of ( S )- 1a . The formation of hydrogen-bonded dimers in CDCl 3 solution was studied by 1 H NMR, 13 C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, ( S )- 1a and 2a – c . On the other hand, a slightly different binding mode was proposed for association of ( S )- 1a with alaninamide ( RS )- 2d . Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert -butyl pyroglutamate 2c were re-determined by 1 H NMR in the presence of ( S )- 1a in CDCl 3 . The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of ( S )- 1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.

Chiral solvating properties of (S)-1 -benzyl -6 -methylpiperazine -2,5 -dione

[2+2] Cycloaddition of electron-poor acetylenes to (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones: synthesis of highly functionalized 1-heteroaroyl-1,3-butadienes

Uroš Grošelj

Papers

Enantioselective Preparationof β²-Amino Acid Derivatives for β-Peptide Synthesis

5-Benzyl-3-methylimidazolidin-4-one-Derived Reactive Intermediates of Organocatalysis – A Comforting Resemblance of X-Ray, NMR, and DFT Solid-Phase, Liquid-Phase, and Gas-Phase Structures

Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease.

Chiral solvating properties of (S)-1 -benzyl -6 -methylpiperazine -2,5 -dione

[2+2] Cycloaddition of electron-poor acetylenes to (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones: synthesis of highly functionalized 1-heteroaroyl-1,3-butadienes