Atropisomeric amides as chiral ligands: using (-)-sparteine-directed enantioselective silylation to control the conformation of a stereogenic axis

An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermodynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation and functionalization of the amide in the 6-position allows the single amide conformer to be trapped as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute configuration, whose barriers to racemization have been determined by polarimetry. Enantiomerically pure amides bearing phosphine substituents are effective ligands in a Pd-catalyzed allylic substitution reaction-the first use of a nonbiaryl atropisomer as a chiral ligand-and give products with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced by the presence of palladium.     

Computational validation of the importance of absolute stereochemistry in virtual screening

Consideration of stereochemistry early in the identification and optimization of lead compounds can improve the efficiency and efficacy of the drug discovery process and reduce the time spent on subsequent drug development. These improvements can result by focusing on specific enantiomers that have the desired potential therapeutic effect (eutomers), while removing from consideration enantiomers that may have no, or even undesirable, effects (distomers). A virtual screening campaign that correctly takes stereochemical information into account can, in theory, be utilized to provide information about the relative binding affinities of enantiomers. Thus, the proper enumeration of the relevant stereoisomers in general, and enantiomeric pairs in particular, of chiral compounds is crucial if one is to use virtual screening as an effective drug discovery tool. As is obvious, in cases where no stereochemical information is provided for chiral compounds in a 2D chemical database, then each possible stereoisomer should be generated for construction of the subsequent 3D database to be used for virtual screening. However, acute problems can arise in 3D database construction when relative stereochemistry is encoded in a 2D database for a chiral compound containing multiple stereogenic atoms but absolute stereochemistry is not implied. In this case, we report that generation of enantiomeric pairs is imperative in database development if one is to obtain accurate docking results. A study is described on the impact of the neglect of enantiomeric pairs on virtual screening using the human homolog of murine double minute 2 (MDM2) protein, the product of a proto-oncogene, as the target. Docking in MDM2 with GLIDE 4.0 was performed using the NCI Diversity Set 3D database and, for comparison, a set of enantiomers we created corresponding to mirror image structures of the single enantiomers of chiral compounds present in the NCI Diversity Set. Our results demonstrate that potential lead candidates may be overlooked when databases contain 3D structures representing only a single enantiomer of racemic chiral compounds.     

Conformational communication between the Ar-CO and Ar-N axes in 2,2'-disubstituted benzanilides and their derivatives

Benzanilides containing two or more potentially stereogenic amide axes exist in solution as mixtures of conformers which are detectable by NMR. For simple tertiary benzanilides carrying an ortho substituent on each ring, conformational control can be high (up to about 10:1) providing the substituents are large, indicating that the two axes are in conformational communication with one another. For more complex diamides, conformational communication breaks down, and mixtures of conformers are evident by NMR.     

Stereoselective reactions. XXXII. Enantioselective deprotonation of 4-tert-butylcyclohexanone by fluorine-containing chiral lithium amides derived from 1-phenylethylamine and 1-(1-naphthyl)ethylamine

Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1-phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily accessible in both enantiomeric forms, and were found to induce good enantioselectivity in the present reaction.     

On the equivalence of conformational and enantiomeric changes of atomic configuration for vibrational circular dichroism signs

We study systematically the vibrational circular dichroism (VCD) spectra of the conformers of a simple chiral molecule, with one chiral carbon and an "achiral" alkyl substituent of varying length. The vibrational modes can be divided into a group involving the chiral center and its direct neighbors and the modes of the achiral substituent. Conformational changes that consist of rotations around the bond from the next-nearest neighbor to the following carbon, and bond rotations further in the chain, do not affect the modes around the chiral center. However, conformational changes within the chiral fragment have dramatic effects, often reversing the sign of the rotational strength. The equivalence of the effect of enantiomeric change of the atomic configuration and conformational change on the VCD sign (rotational strength) is studied. It is explained as an effect of atomic characteristics, such as the nuclear amplitudes in some vibrational modes as well as the atomic polar and axial tensors, being to a high degree determined by the local topology of the atomic configuration. They reflect the local physics of the electron motions that generate the chemical bonds rather than the overall shape of the molecule.     

Combining magnetic resonance spectroscopies, mass spectrometry, and molecular dynamics: investigation of chiral recognition by 2,6-di-O-methyl-beta-cyclodextrin

EPR spectroscopy has been employed to investigate the formation of complexes between heptakis-(2,6-O-dimethyl)-beta-cyclodextrin (DM-beta-CD) and different enantiomeric pairs of chiral nitroxides of general structure PhCH2NO.CH(R)R'. Accurate equilibrium measurements of the concentrations of free and included radicals afforded the binding constant values for these nitroxides. The relationship between the stereochemistry of the DM-beta-CD complexes and the thermodynamics of complexation was elucidated by correlating EPR data with 1H-1H NOE measurements carried out on the complexes between DM-beta-CD and the structurally related amine precursors of nitroxides. NOE data suggested that inclusion of the stereogenic center in the DM-beta-CD cavity occurs only when the R substituent linked to the chiral carbon contains an aromatic ring. For these types of complexes, molecular dynamics simulation indicated that the depth of penetration of the stereogenic center into the cyclodextrin cavity is determined by the nature of the second substituent (R') at the asymmetric carbon and is responsible for the observed chiral selectivity. Analysis of mass spectra showed that, for the presently investigated amines, electrostatic external adducts of CDs with protonated amines are detected by ESI-MS.     

Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche- and anti-3-fluoro- and 3-hydroxypyrrolidines

N-acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C(β)-gauche and C(β)-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K(T/C) values of N-acetylamide conformers in both CDCl(3) (43-54% trans) and D(2)O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl(3) (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D(2)O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K(T/C) results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.     

Diastereoisomeric derivatization and liquid chromatographic analysis of N-(phenylsulfonyl)-2-phenylglycine aldose reductase inhibitors

A series of (S)- and (R)-N-(phenylsulfonyl)-2-phenylglycines are synthesized as potential inhibitors of the enzyme aldose reductase. In vitro analysis of these compounds reveals that the S-enantiomers are more potent than the corresponding R-enantiomers and that the difference in potencies between enantiomeric pairs is dependent on the nature of the ring substituent. To ensure that the enantioselectivity observed does not reflect varying degrees of racemization during the synthesis of the N-(phenylsulfonyl)-2-phenylglycines, the enantiomeric purity of these products is determined by HPLC after chiral derivatization. Each 2-phenylglycine inhibitor is derivatized with R-alpha-methylbenzylamine, and the resulting diastereomers are analyzed using reversed and normal achiral stationary phases. Reversed-phase methods with C18 or phenyl stationary phases and solvent mixtures of acetonitrile or methanol in water do not provide satisfactory resolution of the diastereomers. However, normal-phase analyses with a silica stationary phase and mixtures of methanol, ethanol, or acetonitrile in chloroform provide good separations with relatively short analysis times. The normal-phase analyses demonstrate that a single diastereomeric amide forms from each N-(phenylsulfonyl)-2-phenylglycine product, establishing that these compounds do not racemize during synthesis.     

Intramolecularly competitive Ireland-Claisen rearrangements: scope and potential applications to natural product synthesis

A variety of bis-allylic esters were prepared by vinylmetal addition to cycloalkenones followed by esterification either in situ or in a separate operation. For chiral cyclohexenones, the vinyl additions generally occurred with >10:1 diastereoselectivity. Although in some cases the bis-allylic esters proved to be sensitive to silica gel or other adsorbents, all of the esters examined could be isolated in acceptable purity. The Ireland-Claisen rearrangement of the bis-allylic esters occurred with complete regioselectivity via the exocyclic alkene. The alkene stereochemistry and the stereochemistry at C-2 and C-3 of the pentenoic acid products were consistent with a chairlike transition state in the rearrangement. Substituents at the carbons adjacent to the allylic carbinol carbon (i.e., C-2 or C-6 in cyclohexenone-derived substrates) directed the stereochemical course of the rearrangement. The rearrangements generally proceeded so as to place the larger of the C-2 or C-6 substituents in the pseudoequatorial position with respect to the chairlike transition state. For a bis-allylic ester bearing both a C-2-CH(3) and a C-6-OMEM substituent, the rearrangement product resulted from the nominally smaller OMEM substituent occupying a pseudoequatorial position with respect to the chairlike transition state.     

Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines

From the pK(a) values of the conjugate acids of a large series of hydroxylated piperidines and hexahydropyridazines, a consistent difference in basicity was found between stereoisomers having an axial or equatorial hydroxyl (OH) group either beta or gamma to the amine. Compounds with an equatorial OH group in the 3-position were 0.8 pH units more acidic than otherwise identical compounds with an axial OH group, whilst compounds with an equatorial OH group in the 4-position relative to the amine were 0.4 pH units more acidic than the corresponding compound with an axial OH. A similar effect was observed for the COOMe substituent. The difference in electron-withdrawing power of axial and equatorial substituents was explained by a difference in charge-dipole interactions in the two systems. Since this stereoelectronic substituent effect causes differences in basicity in different conformers, certain piperidines and hexahydropyridazines were found to change conformation upon protonation. A method for predicting the pK(a) of piperidines which takes stereochemistry into account is described.     

Chiral ionic liquids: synthesis, properties, and enantiomeric recognition

We have synthesized a series of structurally novel chiral ionic liquids which have a either chiral cation, chiral anion, or both. Cations are an imidazolium group, while anions are based on a borate ion with spiral structure and chiral substituents. Both (or all) stereoisomeric forms of each compound in the series can be readily synthesized in optically pure form by a simple one-step process from commercially available reagents. In addition to the ease of preparation, most of the chiral ILs in this series are liquid at room temperature with a solid to liquid transformation temperature as low as -70 degrees C and have relatively high thermal stability (up to at least 300 degrees C). Circular dichroism and X-ray crystallographic results confirm that the reaction to form the chiral spiral borate anion is stereospecific, namely, only one of two possible spiral stereoisomers was formed. Results of NMR studies including 1H{15N} heteronuclear single quantum coherence (HSQC) show that these chiral ILs exhibit intramolecular as well as intermolecular enantiomeric recognition. Intramolecularly, the chiral anion of an IL was found to exhibit chiral recognition toward the cation. Specifically, for a chiral IL composing with a chiral anion and a racemic cation, enantiomeric recognition of the chiral anion toward both enantiomers of the cation lead to pronounced differences in the NMR bands of the cation enantiomers. The chiral recognition was found to be dependent on solvent dielectric constant, concentration, and structure of the ILs. Stronger enantiomeric recognition was found in solvent with relatively lower dielectric constants (CDCl3 compared to CD3CN) and at higher concentration of ILs. Also, stronger chiral recognition was found for anions with a relatively larger substituent group (e.g., chiral anion with a phenylmethyl group exhibits stronger chiral recognition compared to that with a phenyl group, and an anion with an isobutyl group has the weakest chiral recognition). Chiral anions were also found to exhibit intermolecular chiral recognition. Enantiomeric discrimination was found for a chiral IL composed of a chiral anion and achiral cation toward another chiral molecule such as a quinine derivative.     

Enantiomeric and enantiotopic analysis of cone-shaped compounds with C(3) and C(3)(v) symmetry using NMR spectroscopy in chiral anisotropic solvents

We describe the enantiomeric and enantiotopic analysis of the NMR spectra of compounds derived from the functionalized cone-shaped core, cyclotriveratrylenes (CTV), dissolved in weakly oriented lyotropic chiral liquid crystals (CLCs) based on organic solutions of poly-gamma-benzyl-L-glutamate. The CTV core lacks prostereogenic as well as stereogenic tetrahedral centers. However, depending on the pattern of substitution, chiral and achiral compounds with different symmetries can be obtained. Thus, symmetrically nonasubstituted CTVs (C(3) symmetry) are optically active and exhibit enantiomeric isomers, while symmetrically hexasubstituted (C(3v) symmetry) derivatives are prochiral and possess enantiotopic elements. In the first part we use (2)H and (13)C NMR to study two nonasubstituted (-OH or -OCH(3)) CTVs, where the ring methylenes are fully deuterated, and show for the first time that the observation of enantiomeric discrimination of chiral molecules with a 3-fold symmetry axis is possible in a CLC. It is argued that this discrimination reflects different orientational ordering of the M and P isomers, rather than specific chiral short-range solvent-solute interactions that may affect differently the magnetic parameters of the enantiomers or even their geometry. In the second part we present similar measurements on hexasubstituted CTV with flexible side groups (-OC(O)CH(3) and the, partially deuterated bidentate, -OCH(2)CH(2)O-), having on the average C(3v) symmetry. No spectral discrimination of enantiotopic sites was detected for the -OC(O)CH(3) derivative. This is consistent with a recent theoretical work (J. Chem. Phys. 1999, 111, 6890) that indicates that in C(3v) molecules no chiral discrimination between enantiotopic elements, based on ordering, is possible. In contrast, a clear splitting was observed in the (2)H spectra of the enantiotopic deuterons of the side groups in the tri(dioxyethylene)-CTV. It is argued that this discrimination reflects different ordering characteristics of the various, rapidly (on the NMR time scale) interconverting conformers of this compound. Assuming two twisted structures for each of the dioxyethylene side groups, four different conformers are expected, comprising two sets of enantiomeric pairs with, respectively, C(3) and C(1) symmetries. Differential ordering and/or fractional population imbalance of these enantiomeric pairs leads to the observed spectral discrimination of sites in the side chains that on average form enantiotopic pairs.     

Medium‐Sized‐Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

Analogues of dibenzodiazepines, in which the seven‐membered nitrogen heterocycle is replaced by a 9–12‐membered ring, were made by an unactivated Smiles rearrangement of five‐ to eight‐membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron‐withdrawing activating groups, and provides a method for n →n +4 ring expansion. The medium‐ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.     

Diastereomeric Xe chemical shifts in tethered cryptophane cages

Cryptophane cages serve as host molecules to a Xe atom. Functionalization of cryptophane-A has permitted the development of Xe as a biosensor. Synthetic routes used to prepare cryptophanes result in racemic mixtures of the chiral cages. In the preparation of a tethered cryptophane-A cage for biosensor applications, some achiral and chiral substituents such as left-handed amino acids have been used. When the substituent is achiral, the NMR signal of the Xe atom in the functionalized cage in solution is a single isotropic peak, since the Xe shielding tensor components in the R and L cages differ by no more than the signs of the off-diagonal elements. Chiral substituents can split the cage-encapsulated Xe NMR signal into one or more sets of doublets, depending on the number of asymmetric centers in the substituent. We carry out quantum mechanical calculations of Xe nuclear magnetic shielding for the Xe atom at the same strategic position within an L cryptophane-A cage, under the influence of chiral potentials that represent r or l substituents outside the cage. Calculations of the Xe shielding response in the Lr and Ll diastereomeric pairs permit the prediction of the relative order of the Xe chemical shifts in solutions containing the Rl and Ll diastereomers. Where the substituent itself possesses two chiral centers, comparison of the calculated isotropic shielding responses in the Llr, Lrl, Rll, and Lrr systems, respectively, permits the prediction of the Xe spectrum of diastereomeric systems in solutions containing Llr, Rlr, Lll, and Rll systems. Assignment of the peaks observed in the experimental Xe NMR spectra is therefore possible, without having to undertake the difficult synthetic route that produces a single optically pure enantiomer.     

Design of chiral bis-phosphoric acid catalyst derived from (R)-3,3'-di(2-hydroxy-3-arylphenyl)binaphthol: catalytic enantioselective Diels-Alder reaction of α,β-unsaturated aldehydes with amidodienes

Chiral bis-phosphoric acid 1 was designed to identify a new class of structural features in chiral Br?nsted acid catalysts. X-ray diffraction analysis revealed the single atropisomer 1, bearing S axial chirality at 3,3'-biaryl substituents on (R)-binaphthyl and intramolecular hydrogen bonding between the two phosphoric acid moieties. The newly designed bis-phosphoric acid 1 was evaluated in the Diels-Alder reaction of α,β-unsaturated aldehydes 4 with 1-N-acylamino-1,3-butadienes 3. After systematic variation of the catalyst substituents, as well as the N-acyl substituents of 1,3-butadiene, the use of an N-Cbz amidodiene 3a in the presence of bis-phosphoric acid 1e with a 2,4,6-tri-isopropylphenyl group was found to be optimal to yield the 1S,6R enantiomeric product 5aa in a Diels-Alder reaction of acrolein (4a). Application of this method to substituted substrates was found to be an efficient approach to the enantioselective synthesis of 3- and 3,6-substituted cyclic formylcarbamates 5. The specific character as well as the utility of 1e was further established by comparing its enantioselectivity, absolute stereochemistry, and catalytic efficiency with those of mono-phosphoric acid 2.     

Resolution of enantiomeric triols, triol-hydroxyethylthioethers, and methoxy-triols derived from three benzo[a]pyrene diol-epoxides by chiral stationary phase high-performance liquid chromatography

Benzo[a]pyrene 7,8-diol-anti-9,10-epoxide, 7,8-diol-syn-9,10-epoxide, and 9,10-diol-anti-7,8-epoxide were converted to triol, triol-hydroxyethylthioether, and methoxy-triol derivatives. Enantiomeric pairs of these derivatives were resolved by high-performance liquid chromatography with Pirkle's pi-electron acceptor chiral stationary phases. Resolution of enantiomers was confirmed by ultraviolet-visible absorption, circular dichroism, and mass spectral analyses. Relative to those of tetrols, these derivatives are less polar and have shorter retention times and improved enantiomeric resolution on chiral stationary phases. Absolute stereochemistries of most enantiomeric derivatives were deduced by comparing their circular dichroism spectra to those of similar compounds derived from enantiomeric diol-epoxides of known absolute stereochemistry.     

Advances in chiral separations of small peptides by capillary electrophoresis and chromatography

Many chemical and biological processes are controlled by the stereochemistry of small polypeptides (di‐, tri‐, tetra‐, penta‐, hexapeptides, etc). The biological importance of peptide stereoisomers is of great value. Therefore, the chiral resolution of peptides is an important issue in biological and medicinal sciences and drug industries. The chiral resolutions of peptide racemates have been discussed with the use of capillary electrophoresis and chromatographic techniques. The various chiral selectors used were polysaccharides, cyclodextrins, Pirkle types, macrocyclic antibiotics, crown ethers, imprinted polymers, etc. The stereochemistry of dipeptides is also discussed. Besides, efforts are made to explain the chiral recognition mechanisms, which will be helpful in understanding existing and developing new stereoselective analyses. Future perspectives of enantiomeric resolution are also predicted. Finally, the review concludes with the demand of enantiomeric resolution of all naturally occurring and synthetic peptides.     

Enantioselective α-alkylation of unsaturated carboxylic acids using a chiral lithium amide

The regio- and stereochemistry of the alkylation of dienediolates from unsaturated carboxylic acids with benzylic halides, which often results in mixtures of isomers, can be controlled by means of changes in the lithium amide, allowing the α-regioisomer to be obtained as the major diastereoisomer. In addition, when chiral amines are used, moderate enantiomeric excesses can be attained.     

1,5] Sigmatropic hydrogen shifts in cyclic 1,3-dienes

Density functional calculations have been carried out for [1,5] hydrogen shifts in 1,3-cycloalkadienes (cyclohexadiene, cycloheptadiene, and cyclooctadiene). The complexity of the potential surfaces of these reactions was found to increase with ring size. For 1,3-cyclohexadiene a single transition structure for the [1,5] hydrogen shift was located, which connects the two enantiomeric conformers. For 1,3-cycloheptadiene two enantiomeric transition structures for the [1,5] hydrogen shift were located, which interconnect three conformers of the diene, a pair of enantiomeric conformers and a third achiral conformer. Finally for 1,3-cyclooctadiene two diastereomeric transition structures were found in addition to six conformers (three pairs of enantiomeric conformers) of the diene. Calculated activation energies for the [1,5] hydrogen shifts were found to be in qualitative agreement with experiment. Variation in these energies are attributed to strain energies present in either the diene or the transition structure.     

Chiral lithium binaphtholate aqua complex as a highly effective asymmetric catalyst for cyanohydrin synthesis

A highly enantioselective cyanohydrin synthesis with aromatic aldehydes using chiral lithium binaphtholate aqua or alcohol complexes has been developed and is a simple and inexpensive catalyst suitable for process chemistry to give gram-scale cyanohydrins successfully. Dramatic improvements in enantiomeric excess have been realized along with an interesting changeover in absolute stereochemistry of cyanohydrin product against the thoroughly "dry" catalytic systems.