Achieving conformational control over C-C, C-N and C-O bonds in biaryls, N,N'-diarylureas and diaryl ethers: advantages of a relay axis

The orientation of Ar-C, Ar-N and Ar-O bonds in biaryls, N,N'-diarylureas and diaryl ethers (whose conformers are distinguishable by NMR) may be controlled with a selectivity up to >95 : 5 by an adjacent stereogenic centre; the selectivity may be greater when a second stereogenic axis is inserted between the controlling centre and the slowly rotating bond.     

Diastereoselective synthesis of atropisomers containing two non-biaryl stereogenic axes: stereochemical relay through stereogenic centres in dihydrostilbene-2,2'-dicarboxamides

Addition of laterally lithiated tertiary aromatic amides to benzaldimines controls the formation of a new stereogenic centre adjacent to the benzaldimine aromatic ring. Drawing on the fact that such amino-substituted stereogenic centres may themselves control the conformation of amides, with amido-substituted benzaldimines we found it becomes possible to relay stereochemistry from one amide to another via this intervening stereogenic centre. A group of dihydrostilbene-2,2'-dicarboxamide derivatives bearing one or two stereogenic axes are made by this method, which demonstrates the use of combined kinetic and thermodynamic control for the relay of stereochemical information.     

Highly efficient synthesis of chiral aminoalcohols and aminodiols with camphane skeleton

Methylidene substituted camphor was easily epoxidized to give bridgehead oxirane-substituted camphor in the form of two diastereoisomers, isolated in pure form. These were used in aminolysis reactions with different secondary amines leading to series of chiral aminoalcohols bearing a ketone functionality. The latter could be reduced by using LAH or DIBAL to a series of aminodiols. For the determination of the configuration of the newly formed stereogenic centre, advanced NMR experiments and X-ray crystallography were used. The new aminoalcohols and aminodiols were tested as pre-catalysts for the enantioselective addition of Et₂Zn to benzaldehyde showing moderate enantioselectivity.     

Asymmetrically induced alkylation of 2-benzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione

The substitution of the 4-methyl group by a 4-isopropyl group in the 2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione system allows a notable improvement in the stereoselective alkylation at C-1. The configuration of the newly introduced stereogenic centre has been assigned on the basis of ¹H NMR data and NOE measurements.     

Comparison of high-performance liquid chromatography of cyclotriphosphazene derivatives with one or two equivalent stereogenic centres

High-performance liquid chromatographic (HPLC) methods have been developed for investigating the stereogenic properties of two analogous series of dibenzylamino derivatives of cyclotriphosphazene containing either one or two equivalent stereogenic centres. Separation of the enantiomers of all the racemic compounds has been investigated by chiral HPLC using Whelk-01 and Chiralcel OD columns. In all cases, conditions for separation of enantiomers have been found using a Whelk-01 column with different ratios of tetrahydrofuran in n-hexane as the mobile phase. It is found that both the separation factor (alpha) and resolution factor (R(S)) of molecules with two equivalent stereogenic centres are greater than those for analogues with only one centre.     

Chirality transfer in the aza-[2,3]-Wittig sigmatropic rearrangement

The aza-[2,3]-Wittig sigmatropic rearrangements of substrates derived from enantiomerically pure alanine, valine and serine with phenyl and ester anion stabilising groups were investigated for their efficiency in chirality transfer. It was found that a methyl substituent at the stereogenic centre of the rearrangement precursors was inadequate to control the alkene stereoselectivity and enantioselectivity of the rearrangement. Ester stabilised anions of valine and serine derivatives were the most successful with up to 66% yield, 14 : 1 alkene (E)-stereoselection and 88% chirality transfer. A limitation to the steric bulk of the stereogenic centre was noted in that the substituent has to be bulky enough to dictate alkene stereoselection, but not too large to compromise the directing effect of the activating phenyldimethyl silyl substituent on the anion stabilising group. Experimental evidence suggested a possible complimentary coordinating effect of an O-MOM serine substituent, which may assist alkene stereoselectivity and enantioselectivity.     

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.     

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large‐ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]‐macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic “ribbon” shape is adopted by the [13]‐macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle‐biomolecule interactions and for the preparation of macrocycles with designed properties and activities.     

Synthesis and characterisation of medium-sized ring systems by oxidative cleavage. Part 2: Insights from the study of ring expanded analogues

Variable temperature NMR analysis and computational methods have been used to develop a detailed understanding of the ¹H NMR spectra of a family of medium-sized ring containing compounds. The family consists of analogues containing 10-, 11- and 12-membered rings and in all cases the NMR spectra at room temperature showed a series of diastereotopic methylene signals despite the lack of a stereogenic centre in these systems. On repeating the NMR analysis at higher temperatures, all the signals coalesced for the 12-membered ring system consistent with full interconversion of ring conformers. This was not observed in the analogous 10- and 11-membered ring systems with the interchange of conformers remaining slow on the NMR timescale. However, 1D gs-NOESY/EXSY NMR experiments showed that in the smaller ring systems interconversion of diastereotopic protons did occur. Computational studies suggest that the dynamic process observed by NMR for the 10- and 11-membered rings systems is different from that observed in the 12-membered ring containing compound.     

Stereochemistry of phenyl alpha-nitronyl nitroxide radicals

An extensive investigation of the conformations adopted by the family of phenyl alpha-nitronyl nitroxides has been carried out. A database containing 110 crystal structures was used in a statistical study of the solid-state geometries and conformations of these radicals. This study revealed that the favoured conformations involve a twisted distortion in the imidazolyl rings and a twist between the aromatic and heterocyclic rings in the molecules. As a consequence, these radicals show two types of preferred conformations in the solid state: the pseudo-anti enantiomeric pair and the pseudo-eclipsed pair, the latter type being the most statistically probable. A new chiral member of this group of radicals that bears a lactate moiety, (R)-1, and its corresponding racemic compound, (R,S)-1, have been prepared in order to study the influence of chiral induction from the stereogenic centre on the torsion angle between the aromatic and heterocyclic rings of the alpha-nitronyl nitroxides. The X-ray crystal structures of the enantiopure and racemic compounds, which both reveal chains of molecules sustained by strong O-H...O hydrogen bonds between the carboxylic acid group and the ON group of the radical in the solid, as well as their magnetic properties have been determined. Remarkably, the molecules with a given stereogenic centre have a single helical sense between their component rings, even in the racemic crystal. Chiral induction from the stereogenic centre to the radical unit has also been proved by CD spectroscopy in the solid state. The results of these experiments have been rationalised by ab initio calculations of the spectra.     

Asymmetric synthesis of 2-substituted piperidines using a multi-component coupling reaction: rapid assembly of (S)-coniine from (S)-1-(1-phenylethyl)-2-methyleneaziridine

(S)-Coniine is made using a reaction which assembles the piperidine ring by the sequential formation of four new chemical bonds and installs the C-2 stereogenic centre with high levels of diastereocontrol (90% de).     

A convergent preparation of the C1-C13 fragment of amphotericin B from a single chiral precursor

A short, highly efficient, stereoconvergent synthesis of the polyolic chain, C1-C13, of the macrolide antibiotic amphotericin B is described. The key features of the synthesis are the use of a single chiral precursor for the establishment of the stereogenic centres in a short synthetic sequence, and the final alkyl lithium addition to the appropriate aldehyde, which showed high diastereoselectivity for the correct stereochemistry at the fifth stereogenic centre.     

Intrazeolite photooxygenation of chiral alkenes. Control of facial selectivity by confinement and cation-π interactions

Depending on the nature of the substituents on the stereogenic carbon atom, the ene reaction of singlet oxygen with several chiral alkenes by confinement within thionin-supported zeolite NaY, may exhibit significant changes on facial selectivity by comparison to their photooxygenation reaction in solution. It is proposed that, apart from the conformational consequences as a result of the alkene confinement within the zeolite cavities, a synergism between Na⁺-π interactions and singlet oxygen-Na⁺ interactions plays a significant role in the transition states of ene hydroperoxidation. Within NaY, the diastereoselectivity may significantly depend on the site selectivity, as probed through specific deuterium labelling of trisubstituted alkenes bearing a gem-dimethyl group. In certain cases, a remote stereogenic centre relative to the reacting double bond may induce enhanced diastereoselection and regioselectivity.     

Asymmetric oxidation of sulfenates to sulfinates as a new route to optically active ortho-phosphorylated phenyl sulfoxides

An asymmetric synthesis of benzenesulfinates bearing a phosphonate group at the ortho-position, based on the diastereoselective oxidation of the corresponding sulfenates, has been developed. For this purpose, a number of sulfenates were prepared in high yields by TFFA-promoted condensation of different chiral alcohols with a suitable sulfenyl chloride precursor. Diastereomeric excesses were determined by ³¹P NMR spectroscopic data with the configuration of the newly created stereogenic centre being assigned through correlation and chemical studies. A practical synthesis of both enantiomers of diisopropyl (2-methylsulfinyl)phenylphosphonate 6 in enantiomeric excess close to 85% is also presented.     

A concise approach towards the bicyclo[3.3.1]nonan-9-one core present in the phloroglucin natural product hyperforin

An approach towards the bicyclo[3.3.1]nonan-9-one core present in the bioactive phloroglucin natural product hyperforin is delineated in which the key C8 stereogenic quaternary centre is appropriately installed.     

Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and hydroxy-substituted allylstannanes with aldehydes

Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively with tin(iv) halides to generate allyltin trihalides which react with aldehydes to give (Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall (Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the hydroxy and methyl substituents.     

Achiral deuterated derivatizing agent for enantiomeric analysis of carboxylic acids by NMR in a chiral liquid crystalline solvent

The use of a deuterated ‘probe’ for the enantiomeric analysis of chiral carboxylic acids is proposed. The probe is the perdeuterobenzyl fragment which can be easily attached to the acid and removed from the corresponding ester. The analysis is performed through the measurement of the proton-decoupled deuterium NMR spectrum of the chiral benzyl ester dissolved in poly-γ-benzyl-l-glutamate/dimethylformamide liquid crystal. Enantiomeric discrimination was observed for all the studied compounds on the para and/or α deuterons. There is no need for the deuterons to be located close to the stereogenic centre. Thus enantiomers were correctly distinguished from the signal of a deuterium located 12 bonds away from the asymmetric carbon. The major interest of this general technique is that no kinetic resolution should occur during the derivatization process.     

Fast racemisation and slow epimerisation of laterally lithiated amides: stereochemical evidence for the mechanism of inversion of amide-substituted benzyllithiums

Tertiary 1-naphthamides racemise much more slowly than their laterally lithiated derivatives, and the relative rates of racemisation and epimerisation of these derivatives indicate that the lithium-bearing stereogenic centre inverts via a "conducted tour" mechanism, in which the lithium cation is delivered from one face to the other by coordination to the rotating amide group.     

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 2. Structural studies of host-guest complexes with chiral alcohol and monoamine conjugates.

A structural study of complexes formed between a dimeric zinc porphyrin tweezer (host) and chiral monoalcohols and monoamines derivatized by a bidentate carrier molecule (guest) confirmed that their CD couplets arise from the preferred porphyrin helicity of 1:1 host-guest complexes. NMR experiments and molecular modeling of selected tweezer complexes revealed that the preferred conformation is the one in which the L (larger) group protrudes from the porphyrin sandwich; this preferred helicity of the complex determines the CD of the complexes. It was found that the porphyrin ring-current induced (1)H chemical shifts and molecular modeling studies of the complex lead to the assignments of relative steric size of the L (large)/M (medium) substituents attached to the stereogenic center. The assignments, in turn, are correlated with the sign of the CD exciton couplet that establishes the absolute configuration at the stereogenic center. Variable-temperature NMR experiments proved that the observed increase in CD amplitude at lower temperatures derives from conformational changes in the preferred offset geometry between two porphyrin rings.     

Diastereo- and enantioselective synthesis of a conagenin skeletal amide moiety

A synthetic study was carried out to obtain epimers of a protected 2,4-dihydroxy-3-methylpentanoic ester 9, which is a central building block of the immunomodulator (+)-conagenin 1. The configuration of the three contiguous stereogenic centers was determined by NMR measurements and comparison with the stereogenic centers of lactone 10.