Diastereoisomers complex types

The following three chapters describe different classes of X-ray contrast agents. The fourth chapter gives an overview on the chemistry of extracellular iodinated X-ray contrast agents starting with possible routes of synthesis. However, the main focus rests on analytical considerations with particular emphasis on the complex pattern of isomers. In particular dimeric compounds such as iodixanol and iotrolan exhibit a plethora of different types of isomers such as enantiomers, diastereoisomers, cis-trans isomers, and rotamers. In this chapter, the correlation of HPLC peaks with individual isomers is described in detail. 

Many types of chiral stationary phase are available. Pirkle columns contain a silica support with bonded aminopropyl groups used to bind a derivative of D-phenyl-glycine. These phases are relatively unstable and the selectivity coefficient is close to one. More recently, chiral separations have been performed on optically active resins or cyclodextrins (oligosaccharides) bonded to silica gel through a small hydrocarbon chain linker (Fig. 3.11). These cyclodextrins possess an internal cavity that is hydro-phobic while the external part is hydrophilic. These molecules allow the selective inclusion of a great variety of compounds that can form diastereoisomers at the surface of the chiral phase leading to reversible complexes. 

Two diastereoisomers are possible for an octahedral complex of the type MA3B3. Isomer (a) shown below has the three Cl- ligands in adjacent positions on one triangular face of the octahedron isomer (b) has all three Cl- ligands in a plane that contains the Co(III) ion. In isomer (a), all three Cl-Co-Cl bond angles are 90°, whereas in isomer (b) two Cl-Co-Cl angles are 90° and the third is 180°. 

Conversion of the separated diastereoisomers 10a and 10b into the enantiomers +9 and —9 was achieved by treatment with HC1 in benzene solution. In the examples given earlier, to accomplish conversion of diastereoisomers into enantiomers, only those bonds were broken that did not involve the chiral metal atom this was to avoid loss of optical purity through possible change in configuration of the metal atom. In this work, Ti—O bond cleavage had to be used to convert the diastereoisomers (10) to the enantiomers (9). However, HCI cleavage of the Ti—OR bond in compounds of type 10 was shown to be stereospecific with respect to the chiral Ti atom, and to occur with retention of configuration (44-48). Optically active complexes with a chiral Ti atom could also be obtained by asymmetric decomposition (49, 50). 

The deMayo-type photochemistry of 1,3-dioxin-4-ones has been beautifully applied by Winkler et al. to the synthesis of complex natural products. Substrate 133 gave under sensitized irradiation (with acetone as cosolvent) product 134 as single diastereoisomer (Scheme 6.47). The diastereoselectivity results from cyclic stereocontrol exerted by the two stereogenic centers in the spiro-bis-lactone part of the starting material. After installation of the furan, saponification and bond scission in a retro-aldol fashion generated a keto carboxylic add, which produced the natural product ( )-saudin (135) by simultaneous formation of two acetal groups [128]. 

In some cases, crystallisation of the intermediate organolithium-(-)-sparteine complexes is necessary to force their equilibration to the major diastereoisomer.54 This type of dynamic thermodynamic resolution was involved in one of the very first effective uses of (-)-sparteine in organolithium chemistry. Hoppe showed in 1988 that the carbamate 82 could be deprotonated in the presence of (-)-sparteine, and that when the product 83 was transmetallated with titanium and then added to an aldehyde, a homoaldol product 85 was formed in 83% ee. It became apparent that acceptable enantiomeric excesses were obtained only when the intermediate organolithium-(-)-sparteine complex was allowed to crystallise the complexes 83a and 83b interconvert in solution, but one diastereoisomer crystallises preferentially, leading to a dynamic resolution of the organolithium. 

Mathieu, in 1936, assembled (21) the available information on complexes of the type cis-[Co(en) 2XY]n+, from chemical transformations, less soluble diastereoisomers, and from circular dichroism, and as a result... 

A number of inexact applications have been made, some of which have been discussed in detail. As an example, in some work (147) on diastereoisomeric salts of (+)bromocamphorsulphonicacid, (+)tartaricacid, and of other resolving agents, with complexes of the type [Co(en)2(a)]2+, comparisons were made where a is glycinate, L-alaninate, L-leucinate, and L-phenylalaninate, which may not be justified, as owing to the differences in steric requirements of the amino acid, there is no reason to believe that these less soluble diastereoisomers will be isomorphous. 

Another example is the assembly of the complex [6-7-5]-fused tricyclic core 35 of guanacastepenes, obtained as a single diastereoisomer, as shown in Scheme 22 <2005OL3425>. The efficiency of this reaction is consistent with the gi OT-dialkyl effect that is required for the seven-membered ring formation in this type of electron-transfer reaction. 

Both GC and LC behavior of metal complexes of various ligand types including salicy-laldimines and Schiff bases and fluorinated /3-diketones was reported. Metal ions included the lanthanides, transition metals, Pt, Pd and Zn. Dissociation and thermal instabilities were found to be the main limitations in the chromatography of such derivatives. The data indicate that pre-column derivatization and GC is unlikely to provide a viable method for the ultratrace determination of metal ions except in rare circumstances. On the other hand, LC of complexed metal ions was found as a valuable technique that combines the advantages of versatility, specificity and sensitivity with the capacity for simultaneous determination and speciation. Diastereoisomers of oxovanadium(IV) complexes of tetradentate Schiff bases could be resolved by both GC and LC . ... 

The placement of ligands around the central atom must be described in order to identify a particular diastereoisomer. There are a number of common terms (e.g. cis, trans, mer and fac) used to describe the relative locations of ligands in simple systems. However, they can be used only when a particular geometry is present (e.g. octahedral or square planar), and when there are only two kinds of donor atom present (e.g. Ma2b2 in a square planar complex, where M is a central atom and a and b are types of donor atom). 

The major contribution to the rotational strength of optically active complexes of transition metals is usually the chiral arrangement of chelate rings. The additivity of the contributions to the rotational strength was demonstrated (1 ) for complexes of the type [Co(en)2(aa)] + (aa = amino acid anion). The A- and A- isomers of [Co(en)2(S-pala)] + are diastereoisomers, not enantiomers. The CD curves (Figure 1) are not mirror images. 

Both are stereoselective syntheses resulting from diastereoisomerically related attacks of the organometallic species on diastereotopic carbonyl faces. Reaction A generates enantiomers and results in the enantioselective production of one enantiomer over the other. Reaction B generates diastereoisomers and results in the diastereoselective production of one diaster-eoisomer over the other. The argument that the enantiotopic faces of benzaldehyde in A become diastereotopic only upon reagent complexation, whereas the 2-phenylpropanal faces in B are diastereotopic per se clearly cannot be used to classify these processes in a different way. Indeed, both reactions can be considered of type 2a according to the Mislow s classification of stereoselective processes [4]. 

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