Current Organic Chemistry - Volume 16, Issue 19, 2012

The use of active methylene reagents in asymmetric catalysis allows interesting and wide synthetic applications for the preparation of highly elaborated enantioenriched compounds. In this review, the chemistry in which sulfur groups, such as a sulfone or more recently even a sulfoxide, in the reagent is utilized to activate the α-methylene position towards either an electrophilic or a nucleophilic attack is compiled. The review is divided into three sections that expose these two activation approaches and the combination of both, and, in each part, the examples are classified according to the reaction type involved. Moreover, the possibility of further functionalization of the products in has also been exemplified.

Enantioselective protonation of prostereogenic enol derivatives has been shown to be an attractive route for the preparation of enantiomerically pure carbonyl compounds. Indeed, this strategy can be regarded as a two steps deracemization process starting from racemic carbonyl compounds. It has therefore attracted a lot of research efforts in the last twenty years to design general and efficient catalytic approaches. Herein, we report an up-to-date review of what have been done in the field from the pionner work to the latest developments. This manuscript is divided into three parts corresponding to the three main classes of enolates encountered in the enantioselective protonation namely lithium or silyl enolates and enol acetates. For each type of substrates, several approaches will be disclosed covering all the modern chemical tools (including organometallic, organocatalytic or enzymatic processes) recently developed.

The Horner-Wadsworth-Emmons reaction has evolved in the last years as one of the most powerful and reliable method for stereocontrolled olefin synthesis. The reaction has become a widespread standard tool in natural products total syntheses, providing access to relatively simple as well as highly complex synthetic targets. In this work we present the most representative applications within the field of natural product synthesis from 2000 to the present year. The examples comprise the synthesis of macrocycles, 5 to 7 membered rings, lipids and related compounds, alkaloids and cyclic ethers. They were chosen from a large amount of literature reports and illustrate the use of the HWE reaction in the synthesis and elaboration of key intermediates and in the crucial assembly of highly functionalized synthetic precursors.

Last decades have witnessed the golden rush of organocatalysis, which opened an effective and efficient way to high yielding, metal free, stereoselective strategies toward the synthesis of a plethora of natural products. The present review provides an overview of the current achievements of those organocatalytic methodologies in which active methylene compounds have been used as key intermediates. Ranging from covalent to non-covalent activation mode, from monofunctional to bifunctional catalysts, recent results suggest a variety of new powerful tools to accomplish the formal and total synthesis of both the simplest and the most complex natural compounds with facile procedures in high yields and excellent stereoselectivities. At the same time, it is clear how the organocatalytic approach might offer an outstanding and impressive answer to unsolved longstanding synthetic challenges. Finally the possible application to industrial protocols and to the preparation of novel potential drugs has been highlighted.

The aldol addition of active methylene compounds has been shown to be an important challenge for current organic chemistry, even if the aldol adducts can be particularly useful in the synthesis of complex valuable molecules. Starting from the early unsuccessful attempts employing “standard” methodologies, this review describes the most recent successful one-pot multicomponent procedures and the first examples of synthesis of valuable compounds, both cyclic and acyclic.

Molecules containing 3-substituted isobenzofuranones and isoindolinones skeletons are found in important bioactive compounds and in a number of natural products. As a consequence several synthetic strategies, both asymmetric and non-asymmetric, have been developed. Thus, this review focuses on the main synthetic approaches to obtain these classes of compounds, analysing the common features, the scope and the limitations and at the same time giving particular emphasis to the role of active methylene compounds.

In the present study, prior MD investigation or Monte-Carlo search, our step-by-step search for the real lowest energy conformers and the properties of taxol (Also called paclitaxel) is presented theoretically. The paper completes the old paper of Ballone and Marchi (JPC A 1999) which carried out LDA calculations on taxol. A total of 216 initial trial structures were generated by all combinations of internal single-bond rotamers and optimized at the B3LYP/3-21G* level and further optimized at the B3LYP/6-311G* level. A total of 12 unique conformers are found, and their relative energies, dipole moments, rotational constants, zero point vibrational energy, and harmonic frequencies are determined. Their relative electronic energies were determined at the M06L/6-311G(2df,p) level. Combined with statistical mechanics principles, conformational distributions at various temperatures are computed. Characteristic Hbonding types are classified and demonstrated in the taxol structure. It is found that various hydrogen bonds (red shift H-bonding, blueshifted H-bonding and dihydrogen bond) coexist in the title compound. The NBO analysis was performed showing the change of the charge and stereoelectronic effect of different radicals. The UV spectra of the lowest-lying conformer of taxol in methanol are investigated with the TD CAM-B3LYP/6-311+G(2df,p) calculations. The S0-S1, S0-S2, and S0-S3 excitations of taxol are mixed ππ*/πσ*/nπ* transitions at 4.32, 5.02, and 5.13 eV, respectively. The theoretical IR spectrum and UV absorption spectrum of the taxol agree with the available experimental data of taxol very well. Calculations in the solution using SCRF/CPCM method at the M06L/6- 311G(2df,p) level showing the hydrophobic nature of taxol.

A new method of the synthesis of 2-(hydroxymethyl-2H-oxazolo[3,2-a]pyrimidin-7(3H)-ones, commonly known as pyrimidine acyclo-2,2'-anhydronucleosides, was developed. Under the Mitsunobu reaction conditions, 5-substituted 1-(3'-alkoxy-2'- hydroxypropyl)uracil derivatives underwent an intramolecular cyclization to the corresponding 2-alkoxymethyl-2,3-dihydro-7Hoxazolo[ 3,2-a]pyrimidin-7-ones. The various synthetic methods have been demonstrated in the reactions with several N-nucleophiles. Importantly from the mechanistic point of view, in the case of 6-bromo-2-(hydroxymethyl)-2H-oxazolo[3,2-a]pyrimidin-7(3H)-one treated with chiral isocyanate the inversion of configuration at the C-4' carbon atom accompanied by the oxazolidine ring opening was observed.

The bonding evolution in hetero-Diels-Alder (HDA) reactions has been studied by an ELF analysis of the electron reorganization along the HDA reaction between nitroethylene 6 and dimethylvinylamine (DMVA) 9 at the B3LYP/6-31G* level. This cycloaddition takes place along a two-stages one-step mechanism. In the first stage of the reaction, the C1-C6 bond is formed by coupling of two pseudoradical centers positioned at the most electrophilic carbon of nitroethylene 6 and the most nucleophilic center of DMVA 9. In the second stage, the formation of the second O4-C7 bond takes place between a pseudoradical center positioned at the C7 carbon of DMVA and some electron-density provided by the lone pairs of the O4 oxygen. This behavior is in complete agreement with the analyses of the local electrophilicity and nucleophilicity indices, and the spin density of the radical anion of nitroethylene 6 and of the radical cation of DMVA 9. Finally, a relationship between the polar character of the reaction and the regioselectivity is established.