Jacek Gawronski

Recent Progress in Lewis Base Activation and Control of Stereoselectivity in the Additions of Trimethylsilyl Nucleophiles

Trimethylsilyl nucleophiles (Me3SiNu), with silicon atoms attached to carbon, nitrogen, oxygen, or sulfur atoms, have long been recognized as effective alternatives for proton nucleophiles (HNu) in addition reactions to such electrophiles as aldehydes, ketones, imines, oxiranes, aziridines, nitrones, and polar conjugated systems. The number of examples of such additions has been growing steadily over the past 40 years, while the availability of trimethylsilyl nucleophiles was on the rise and new methods of transformation of silylated pronucleophiles into active nucleophiles were emerging. The interest in Me3SiNu additions was stimulated by the properties of the silicon atom, allowing the generation of active nucleophilic species (Nu), under different conditions in comparison to HNu sources. Activation of Me3SiNu by a Lewis base is primarily due to the affinity of silicon to fluorine or oxygen, facilitating the formation of a reactive pentacoordinate or hexacoordinate silicon intermediate, whereas HNu activation requires Brønsted or Lewis basemediated proton abstraction. Although activation of Me3SiNu and HNu may frequently be carried out with the same catalyst, deprotonation of weakly acidic carbon nucleophiles by strong bases in certain cases may be incompatible with the reaction conditions or with certain functional groups. Desilylative nucleophile activation occurs smoothly under catalytic conditions. Either 1,2-, 1,3-, or 1,4-additions can be carried out with trimethylsilyl nucleophiles, as shown in Scheme 1. The catalytic effect of the fluoride ion as well as polar N-oxide, P-oxide, and S-oxide bonds can be correlated with the dissociation energies of the Si-F and Si-O bonds (Figure 1), which are among the strongest single bonds and much stronger than the corresponding C-F and C-O bonds. Either anionic or neutral Lewis bases are suitable for activation of silylated nucleophiles. Both inorganic (especially CsF) and organic fluorides (most frequently tetra-nScheme 1. Catalytic Nucleophilic 1,2-Additions of Me3SiNu to Aldehydes, Ketones, and Imines (a) or to Epoxides and Aziridines (b), 1,3-Addition to Nitrones (c), and 1,4Additions to r, -Unsaturated Carbonyl Compounds (d) and Nitroalkenes (e) Chem. Rev. 2008, 108, 5227–5252 5227

Chiral iminospherand of a tetrahedral symmetry spontaneously assembled in a [6 + 4] cyclocondensation.

Thermodynamically driven cyclocondensation of (R,R)-1,2-diaminocyclohexane and 1,3,5-triformylbenzene yields solely a [4 + 6] spherand type product. This is a unique example of spontaneous formation of an organic compound of permanent chiral tetrahedral (T) symmetry.

Circular dichroism and stereochemistry of chiral conjugated cyclohexenones

Abstract An empirical analysis of CD spectra of variety of cyclohexenones, including variable temperature and solvent studies, reveals the presence of up to three Cotton effects in the 260-185 nm region, in addition to the well- recognized n-π* Cotton effect of 300–350 nm. The long-wavelength band I and band II Cotton effects are ascribed respectively to the first (allowed) and second (formally forbidden) π-π* transitions. The third (band III) Cotton effect at below 200 nm is of different nature and is attributed to the n-σ* transition in the CO group. It is shown that CD spectra of cyclohexenones not only are influenced by the conformation of the chromophore but also reflect the presence of allylic axial substituents (n-π* and band I), the absolute configuration of the cyclohexenone ring (band II), and the presence of axial alkyl groups in α′ or β′ positions (band III).

Chirality of aromatic bis-imides from their circular dichroism spectra

It is demonstrated that chirality of molecules composed of 1,2,4, 5-benzenetetracarboxydiimide (pyromellitic diimide) or 1,4,5, 8-naphthalenetetracarboxydiimide units is reflected by their exciton Cotton effects. The analysis is based on the calculated (ZINDO/S) excited states of the model diimide chromophores 1a and 2a. Rotation of the diimide chromophores around the C-N bond in diimides 3-5 is evaluated from the dynamic (1)H NMR data. A comparison of chiroptical properties of bis-diimides 3-5 with the CD spectra of bis-imides 6-8 is also presented. Copyright 2000 Wiley-Liss, Inc.

Factors Affecting Conformation of (R,R)-Tartaric Acid Ester, Amide and Nitrile Derivatives. X-Ray Diffraction, Circular Dichroism, Nuclear Magnetic Resonance and Ab Initio Studies

Abstract Derivatives 2a–15a of (R,R)-tartaric acid (1a) with all combinations of methyl ester, amide, N-methylamide and N,N-dimethylamide groups, as well as the corresponding O,O′-dibenzoyl derivatives 1b–15b and nitriles 16–18 have been synthesized. Their conformations have been studied by the NMR and CD methods in solution as well as by X-ray diffraction in the crystalline state. The preference for planar. T conformation of the four carbon chain is observed under conditions restricting the α-hydroxyacid, ester or amide group to be nearly planar, this conformation being stabilized by intramolecular hydrogen bonds of the S(5) motif and the electrostatic CO/C(β)H and CN/C(β)H coplanar bond interactions. The C=O/C(α)-O bond system tends to be either synplanar (ester, acid), or antiplanar (ester, primary and secondary amide). Ab initio calculations allowed to demonstrate that for the isolated molecules of diamides 10a and 15a there is strong preference for gauche G+(a,a) conformers, the driving force being the formation of the hydrogen bonded six-membered cycles of the S(6) motif joining the OH and C=O groups from two different halves of the molecule. The results compare favourably with the experimental values derived from NMR spectra of 15a in nonpolar solvent. In the absence of intramolecular hydrogen bonding the N,N-dimethylamide group is better accomodated in a gauche G− conformer. This releases the nonbonded interaction due to the amide methyl group anti to the carbonyl group.

Determination of absolute configuration—An overview related to this Special Issue

Rapid progress in asymmetric synthesis stimulated a further development of methods and techniques for the determination of absolute configuration of chiral molecules. In recent years the direct methods, i.e. X-ray diffraction analysis, circular dichroism (vibrational and electronic), Raman optical activity, optical rotation measurements, as well as indirect methods for relative configuration assignment with the use of NMR spectroscopy or enzymatic transformations, are receiving increasing attention not only by specialists in the field but also by synthetic and structural chemists alike. This paper provides a short overview of the methods currently used, as well as references to contributions collected in this Thematic Issue of Chirality.

Density Functional Theory Calculations of the Optical Rotation and Electronic Circular Dichroism: The Absolute Configuration of the Highly Flexible trans-Isocytoxazone Revised

Ab initio calculations of the optical rotation (OR) and electronic circular dichroism (ECD) for a series of trans-diastereomers of the natural cytokine modulator cytoxazone 1-4 have been performed by density functional theory (DFT). The calculation of OR and ECD curves provides, after critical assessment, a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The effects of the level of theory used for calculations, changes of conformer equilibrium, and the solvent influence on the geometry and values of calculated OR data are discussed, leading to the conclusion that the most frequently used B3LYP/6-31G(d) method is not adequate for prediction of the absolute configuration of this type of highly flexible molecules. The absolute configurations of levorotatory trans-isocytoxazone 2 and analogues 1, 3, and 4 have been established as (-)-(4S,5S)-trans-1-4; i.e., it is in opposition to the previously published configuration (-)-(4R,5R)-trans-2.

Tandem reformatsky reactions of 2-bromopropionates in the presence of chlorotrimethylsilane

Abstract Tandem aldol-like reactions are accessible through the addition of the Reformatsky reagent derived from 2-bromopropionate to either formate /eq 2/ or orthoformate /eq 3/ acceptor in the presence of chlorotrimethylsilane.

Conformational disparity of (R,R)-tartaric acid esters and amides

Abstract Exciton chirality method is used to determine anti and gauche conformations, respectively, of ester and dialkylamide derivatives of (R,R) - tartaric acid. Gauche conformation of (R,R)-N,N,N′-tetramethyltartamide and its O,O-dibenzoyl derivative is found in the solid state by X-ray analysis.

Circular Dichroism of 9,10‐Dihydrophenanthrene Derivatives Reveals both the Absolute Configuration and Conformation: A Novel Approach to Mislow's Helicity Rule

The absolute configuration and the conformation of 9,10-trans-disubstituted 9,10-dihydrophenanthrenes, known chiral metabolites of phenanthrene-9,10-oxide, have been determined by circular dichroism. The absolute configuration assignment is based on the sign of the long-wavelength Cotton effect (A-band), which is conformation invariant and originates from benzylic chirality. This provides a new interpretation of the Mislow biphenyl-helicity rule for the case of the 9,10-dihydrophenanthrene chromophore. The sign of the B-band Cotton effect reflects the conformation of the biphenyl chromophore in 9,10-dihydrophenanthrenes. It is shown that the origin of chiroptical properties of 9,10-dihydrophenanthrenes is closely related to those of 5,6-trans-disubstituted 1,3-cyclohexadienes.