Chiral Carbonyl Compounds Research Articles

Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity.

The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-(exo)-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for β,β'-disubstituted α,β-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (-)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all the isomers tested in cell culture, only (-)-parthenolide showed potent inhibition of microtubule detyrosination in living cells, confirming its exquisite selectivity on tubulin carboxypeptidase activity. On the other hand, the anti-inflammatory activity of the parthenolides was weaker and less selective with regard to compound stereochemistry.

New Developments in Chiral Cooperative Ion Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From Protonation to Deprotonation Reactions.

This personal account summarizes our contribution to the ion pairing organocatalysis mainly by use of chiral quaternary or tertiary ammonium fluorides, aryloxides and carboxylates. Starting from an experimental observation, we were able to develop several approaches for the enantioselective protonation of silyl enolates and enol esters giving rise to chiral carbonyl compounds bearing a stereogenic center at the α-position. Moving from protonation to deprotonation reactions, chiral ammonium ion pair catalysts were successfully applied to several asymmetric transformations such as an Henry reaction or a direct vinylogous aldol reaction to cite a few. An outlook of further possible developments in this field of research will also be discussed.

ChemInform Abstract: Chiral Cinchona Alkaloid‐Thiourea Catalyzed Mannich Reaction for Enantioselective Synthesis of β‐Amino Ketones Bearing Benzothiazol Moiety.

AbstractThe preparation of catalyst QTU is presented as well.

Chemoenzymatic Reduction of Conjugated CC Double Bonds

Asymmetric reduction of conjugated C=C double bonds with use of enoate reductases (ERs) has generated a renewed interest for the preparation of chiral carbonyl compounds. With more and more ERs identified and their usefulness for preparative chemistry manifesting, the quest for the ideal regeneration system has begun. ERs utilize the reduced, enzyme-bound flavin mononucleotide (FMNH2) as a primary reductant. [1]

Chiral Cinchona Alkaloid‐Thiourea Catalyzed Mannich Reaction for Enantioselective Synthesis of β‐Amino Ketones Bearing Benzothiazol Moiety

AbstractMannich reactions of imine with acetylacetone were effectively catalyzed by the modified chiral cinchona alkaloid‐derived thiourea. The reactions led to chiral β‐amino carbonyl compounds in high yields and good enantioselectivities. The study demonstrated for the first time that Mannich reactions of unmodified acetylacetone with heterocyclic imine derived from benzothiazole can be promoted by chiral bifunctional organocatalyst.

ChemInform Abstract: Menthone and p‐Menthyl‐3‐carboxaldehyde as Chiral Auxiliaries

AbstractReview: 70 refs.

Menthone and p-menthyl-3-carboxaldehyde as chiral auxiliaries

Two chiral auxiliaries and the role they play in the preparation of chiral carbonyl compounds and heterocyclic compounds are presented. Key reactions include S(N)2' displacements, Mitsunobu with hydrazoic acid, and 3,3-sigmatropic rearrangements. One of the auxiliaries serves many functions and is removed either by oxidative cleavage or RCM reaction.

ADDITION AGAINST THE GRAIN

WITH THE HELP of zinc reagents, chemists have found a way to circumvent rules that govern additions to chiral carbonyl compounds, a fundamental reaction in organic synthesis. The work, presented on March 24 at the ACS national meeting in San Francisco, could lead to more efficient syntheses of pharmaceuticals. In compounds in which a carbonyl group is next to a hydroxyl stereocenter that has a protecting group, time-honored models predict the chirality of the new stereocenter that arises after adding a carbon nucleophile to the carbonyl, converting it to a second hydroxyl. If the protecting group is small, the Cram chelation model predicts that the product will be a syn-diol (both hydroxyls on the same side). Bulky protecting groups, in contrast, obstruct chelation, leading to an anti-diol (hydroxyls on opposite sides) per the Felkin-Anh model. Using these predictive models has a drawback—chemists sometimes choose protecting groups that suit the carbonyl addition reaction but aren’t ...

Recent Developments in Asymmetric Alkynylation of Imines

This review deals with the asymmetric alkynylation of imines (and iminium ions) to give chiral nonracemic propargylamines. Diastereoselective procedures involved the addition of metal alkynylides to chiral nonracemic imines derived from chiral amines or chiral carbonyl compounds. Enantioselective non-catalytic procedures have been achieved with the use of stoichiometric additives or alkynylboron reagents. Finally, catalytic addition of terminal alkynes or zinc acetylides has been carried out in the presence of chiral metal complexes, especially copper complexes as catalysts.

Synthesis of chiral hydrazine reagents and their application for liquid chromatographic separation of carbonyl compounds via diastereomer formation

Five new chiral derivatizing reagents 5-hydrazino-2,4-dinitrophenyl- l-alaninamide (HDNP- l-Ala-NH 2), 5-hydrazino-2,4-dinitrophenyl- l-phenylalaninamide (HDNP- l-Phe-NH 2), 5-hydrazino-2,4-dinitrophenyl- l-valinamide (HDNP- l-Val-NH 2), 5-hydrazino-2,4-dinitrophenyl- l-leucinamide (HDNP- l-Leu-NH 2) and 5-hydrazino-2,4-dinitrophenyl- l-phenylglycinamide (HDNP- d-Phg-NH 2) were synthesized by straightforward two-step synthesis starting from 1,5-difluoro-2,4-dinitrobenzene. Nucleophilic substitution of one fluorine atom in DFDNB with different amino acid amides yielded Marfey's reagent (5-fluoro-2,4-dinitrophenyl- l-alaninamide) and its structural variants (5-fluoro-2,4-dinitrophenyl- l-phenylalaninamide, 5-fluoro-2,4-dinitrophenyl- l-valinamide, 5-fluoro-2,4-dinitrophenyl- l-leucinamide and 5-fluoro-2,4-dinitrophenyl- d-phenylglycinamide). Chiral hydrazine reagents were prepared by nucleophilic substitution of remaining fluorine atom in Marfey's reagent and its variants with hydrazine under basic conditions. These reagents react quantitatively with chiral carbonyl compounds under mild conditions (30 °C, 30 min) to form hydrazone diastereomers. The labeling reaction occurs only in the presence of acid which has a catalytic action and diastereomers have strong absorbance around 348 nm. The separation of diastereomers was tried on a reversed-phase C 18 HPLC column using different binary solvent combinations. Excellent separation was achieved in case of cyclic ketones having substitution at α-position. Optimization for derivatization yield, limit of detection, limit of quantification, linearity, accuracy and precision was carried out with respect to HDNP- l-Val-NH 2. Studies related to effects of structural modification in reagents and analytes on chromatographic behavior of diastereomers were also analyzed.

Enantiodifferentiation by 1H and 13C NMR Spectroscopy (Dirhodium Method) – Selectivity of Oxygen Functionalities

Chiral carbonyl compounds can easily be enantiodifferentiated by the dirhodium method. The rhodium atoms reveal a remarkable selectivity in binding to oxygen atoms, which is of great advantage for discriminating chiral polyoxygenated natural products. Amides are the strongest ligands followed by ketones and esters; ethers and alcohols/phenols are even less effective. This sequence is rationalized by electronic charges at the oxygen atoms, as obtained from density functional calculations.

Novel Multichiral Diols and Diamines by Highly Stereoselective Pinacol Coupling of Planar Chiral [2.2]Paracyclophane Derivatives

The TiCl4/Zn-mediated intermolecular pinacol coupling of the planar chiral carbonyl compounds [2.2]paracyclophane-4-carbaldehyde, 4-acetyl[2.2]paracyclophane (ketone) and the four regioisomeric 5-, 7-, 12- and 13-methoxy[2.2]paracyclophane-4-carbaldehydes as well as the pTosOH-Zn/Cu-promoted coupling of their N-substituted imines is described. Coupling of the enantiomerically pure substrates (most of carbonyl compounds and all imines) occurs stereoselectively giving rise to diastereomerically pure 1,2-diols and 1,2-diamines. Racemic aldehydes and ketone react with different degrees of stereoselectivity (depending on the substituents in certain positions) and produce one to three diastereomers. 7-methoxy[2.2]paracyclophane-4-carbaldehyde undergoes a tandem pinacol coupling-pinacol rearrangement to yield bis-(7-methoxy[2.2]paracyclophane-4-yl)acetaldehyde. Coupling of the racemic imines produces a mixture of single racemic D,L-diamine and single meso-diamine in each case. The stereoselective formation of the asymmetric centres is governed by the planar chiral [2.2]paracyclophanyl moiety. The techniques elaborated are extended to the intramolecular coupling of [2.2]paracyclophane-4,13-dicarbaldehyde and its bis-N-phenylimine, resulting in stereoselective formation of the chiral triply-bridged diol and exclusive formation of the meso-diamine. X-Ray investigations of several diols and diamines have been carried out and the structural features of these derivatives are discussed.

Diastereoselective formation of highly functionalised α-substituted amino acid derivatives via aldol addition

Highly diastereoselective aldol additions of (2 R,4 S)-3- tert-butyl 4-methyl 2- tert-butyloxazolidine-3,4-dicarboxylate ( 1) are reported. The utility of the highly substituted oxazolidines of type 1 for diastereoselective α-addition of the fully protected amino acid l-serine with achiral and chiral carbonyl compounds is demonstrated and the relative and absolute configuration of the aldol products are discussed on the basis of NOESY data and solid state structures of selected examples. The aldol products represent highly useful intermediates in the syntheses of sphingosine-related metabolites.

6-Chloro-2,4-dinitrophenylhydrazine as a useful crystalline agent for the determination of absolute configuration

For the determination of absolute configuration, we designed and synthesized some hydrazines as crystalline auxiliaries having a heavy atom, and found that 6-chloro-2,4-dinitrophenylhydrazine is a useful crystalline agent for chiral carbonyl compounds. The absolute configurations of chiral hydrazones prepared from the hydrazine and chiral ketones were determined by X-ray crystallographic analysis.

Preparation of Chiral Hydroxy Carbonyl Compounds and Diols by Ozonolysis of Olefinic Isoborneol and Fenchol Derivatives: Characterization of Stable Ozonides by1H-,13C-, and17O-NMR and Electrospray Ionization Mass Spectrometry

The allylic and homoallylic alcohols 1 – 8, prepared from (+)-camphor and (−)-fenchone, were ozonized in Et2O at −78° and treated with Et3N or LiAlH4 to give the chiral hydroxy carbonyl compounds 9 – 16 and the diols 17 – 24, respectively (Scheme 1). In the case of the diols 19 and 24, the formation of new chiral centers proceeded with high diastereoselectivity. These diols were prepared highly diastereoselectively also by LiAlH4 reduction of the hydroxy carbonyl compounds 11 and 16a, respectively (Scheme 2). The absolute configuration of the new chiral centers in 19 and 24 was determined by X-ray and NMR methods. The ozonization of compounds 2, 3, 7, and 8 provided the relatively stable hydroxy-substituted 1,2,4-trioxolane derivatives (ozonides) 37 – 40 (Scheme 5) which were characterized by 1H- and 13C-NMR spectra, ESI-MS, and natural-abundance 17O-NMR spectra.

ChemInform Abstract: The Origin of π‐Facial Diastereoselectivity in Nucleophilic Additions to Chiral Carbonyl Compounds. Part 3. Rotational Profiles of 2‐Methoxypropanal and 2‐N,N‐Dimethylaminopropanal.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: The Origin of π‐Facial Diastereoselectivity in Nucleophilic Additions to Chiral Carbonyl Compounds. Part 4. Calculated Transition State Structures for the Addition of Nucleophiles to 2‐Methoxypropanal and 2‐N,N‐Dimethylaminopropanal.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

On the origin of π-facial diastereoselectivity in nucleophilic additions to chiral carbonyl compounds 4. Calculated transition state structures for the addition of nucleophiles to 2-methoxypropanal and 2-N,N-dimethyl-aminopropanal.

The transition state structures of the nucleophilic addition of LiH to 2-methoxypropanal and 2-N,N-dimethylaminopropanal have been calculated using ab initio methods at the MP2/6-31G*//3-21G level of theory. The analysis of the theoretical data shows that Coulombic, electronic and steric interactions as well as conformational energies may be dominant for determining the energetically lowest lying transition states.

On the origin of π-facial diastereoselectivity in nucleophilic additions to chiral carbonyl compounds 3. Rotational profiles of 2-methoxypropanal and 2-N,N-dimethylaminopropanal.

The rotational profiles of 2-methoxypropanal and 2-N,N-dimethyl-aminopropanal are theoretically predicted using ab initio methods at the MP2/6-31G*//3-21G level of theory. The conformational energies show a strong dependence on the torsion angle not only around the CC bond but also around the CR (ROMe, NMe 2) bond.

フランを合成素子として活用する天然物合成

Furans have been recognized as useful intermediates in organic synthesis. Among the synthetic utilities of furans, 1, 4-dicarbonyl equivalence is one of the characteristic features. This article describes the methodology for the synthesis of natural products, such as physiologically active steroids and lactonic antibiotics, employing the 1, 4-dicarbonyl equivalents derived from furan derivatives. The synthetic strategy is based on oxidative conversion of chiral furfuryl alcohols into the pyranones followed by their functionalization with appropriate nucleophiles and electrophiles to provide the modified pyrans possessing desired stereochemistries. These intermediates have been transformed into withanolide and brassinolide side chains, styryl lactones such as goniothalamin and goniodiol, malyngolide, and canadensolide. Chiral furfuryl alcohols have been prepared as follows. 1) Diastereoselective addition of 2-lithiofurans to chiral carbonyl compounds. 2) Kinetic resolution of secondary furfuryl alcohols using Sharpless reagent.