Macrocyclics chiral compounds

Recently, macrocyclic chiral compounds of crown ether or cyclamen type have been attracting wide interest. These compounds contain numerous heteroatoms in their molecules (mainly oxygen, sulfur, and nitrogen) and can find practical applications, for example, as chiral selectors [69,70] and chiral NMR discriminating agents [71]. Asymmetric substitution of two carbon atoms in the ring of crown ether or cyclamen can lead to many different optically active compounds useful in various branches of supramolecular chemistry. Such substitution can be accomplished with appropriate starting compounds that are optically active, for example, amino acids and polyhydroxy alcohols. 

Many chiral compounds can be used as selectors, for example, chiral metal complexes, native and modified cyclodextrins, crown ethers, macrocyclic antibiotics, noncyclic oligosaccharides, and polysaccharides all have been shown to be useful for efficient separation of different types of compounds. 

Since the natural target of macrocyclic antibiotics is the A-acyl-D-alanyl-D-alanine terminus (see Section 2.1), the early choice of suitable substrates for this kind of CSPs was that of amino acids [45]. However, it turned out that the macrocyclic CSPs were very successful not only in amino acids enantioresolution, but also in the separation of a wide variety of different structures. The early stages of application of macrocyclic antibiotics have been surveyed in the different fields of chromatography [1,2]. A summary of the different categories of chiral compounds separated by HPLC on glycopeptides containing CSPs is reported in Table 2.3. 

Cyclic amines (including local anesthetic drugs) and amides were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], and ristocetin A [33] CSPs, under RPmode systems. Cyclic imides (including barbiturates, piperidine-2,6-diones, and mephenytoin) have been separated on a vancomycin CSP [157], under NP and RP mobile phase conditions. 

Like every (macrocyclic) molecule, a calixarene can be converted into a chiral compound by the attachment of various chiral residues.13 Although this approach does not make (in terms of chirality) any use of the nonplanar, spherical structure of the calixarene skeleton, it is often the most simple one, and can lead to very efficient enantioselective host molecules. 

ENANTIOSEPARATION OF PHARMACEUTICALLY RELEVANT CHIRAL COMPOUNDS USING CYCLODEXTRIN, MACROCYCLIC ANTIBIOTIC. AND CROWN-ETHER TYPE CSPs... 

As in the case of chromatography, a chiral selector is also required in CE for enantiomeric resolution. Generally, suitable chiral compounds are used in the background electrolyte (BGE) as additives and hence are called chiral selectors or chiral BGE additives. There are only a few publications available that deal with the chiral resolution on a capillary coated with the chiral selector in CE. The analysis of the chiral pollutants discussed in this chapter is restricted only to using chiral selectors in the BGE. The most commonly used chiral BGE additives are cyclo-dextrins, macrocyclic glycopeptide antibiotics, proteins, crown ethers, ligand exchangers, and alkaloids.A list of these chiral BGE additives is presented in Table 1. 

Topics which have formed the subjects of reviews this year include theoretical studies of the photochemistry of thiiranes, photoaddition of amines to aryl olefins and arenes, the synthesis of heterocyclic compounds, photoamination directed towards the synthesis of heterocycles, selective addition of organic dichalcogenides to carbon-carbon unsaturated bonds, photocyclisation mechanisms of c/5-stilbene analogues, synthetic utility of the photocyclisation of aryl-and heteroarylpropenoic acids, photochromic diarylethenes, spiropyrans, cy-clophanes, and polycondensed aromatics," photochromic organic media, photophysics and photochemistry of P-carbolines, and the photochemical synthesis of macrocycles.Chirality switching by light has also been described. ... 

Despite these evident drawbacks, a broad variety of SOs have been used in CMPA-based enantiomer separations, including cyclodextrins, proteins, macro-cyclic antibiotics, chiral ion-pairing agents, amino acids in combination with transition metal salts, and crown ethers. Recent application for the separation of pharmaceutically relevant chiral compounds utilized P-cyclodextrins [46-48] charged cyclodextrins [49, 50], macrocyclic antibiotics [51, 52] and chiral ion-pairing agents [53, 54]. A more detailed discussion of CMPA-based enantiomer separation is beyond the scope of this chapter. The interested reader is referred to dedicated reviews [55, 56]. 

Multi-carbo grlated (or multi-thiolated and multi-carbonyl) compounds, as well as synthetic macrocyclic compounds, are always introduced to stabilize metal nanoparticles. For example, quantum dots (QDs) have been hybridized with cyclodextrin and calixarene derivatives to construct hybrid materials used as sensors for ions, organic molecules and chiral compounds. Thus, CP[5]A with 10 carbo qrl anion groups on both rims of the cavity has... 

There are many classes of CSPs applicable in different mobile-phase modes. In particular, CSPs based on derivatized polysaccharides, native and derivatized cyclodextrins, macrocyclic glycopeptides, and Pirkle-type chiral selectors operate quite well in four separation modes, i.e RP, polar organic phase, NP, and super- or subcritical fluid chromatography (SFC) conditions. It is common that a chiral compound can be separated on the same CSP in more than one separation mode [58, 160, 166, 170-176]. For example, Nutlin-3, a small molecule antagonist of MDM2, has been baseline resolved from its enantiomer in all four mobile-phase conditions (Fig. 16) [170]. Multimodal enantioseparation on the same CSP would be greatly beneflcial for chiral method development in pharmaceutical industry. 

Cyclodextrins are macrocyclic compounds comprised of D-glucose bonded through 1,4-a-linkages and produced enzymatically from starch. The greek letter which proceeds the name indicates the number of glucose units incorporated in the CD (eg, a = 6, /5 = 7, 7 = 8, etc). Cyclodextrins are toroidal shaped molecules with a relatively hydrophobic internal cavity (Fig. 6). The exterior is relatively hydrophilic because of the presence of the primary and secondary hydroxyls. The primary C-6 hydroxyls are free to rotate and can partially block the CD cavity from one end. The mouth of the opposite end of the CD cavity is encircled by the C-2 and C-3 secondary hydroxyls. The restricted conformational freedom and orientation of these secondary hydroxyls is thought to be responsible for the chiral recognition inherent in these molecules (77). 

Enantiomeric recognition of amino compounds by chiral macrocyclic receptors including pyridine or triazole subunits 97CRV3313. 

Each glycopeptide CSP has unique selectivity as well as complementary characteristics, and a considerable number of racemates have been resolved on all three of them. Interestingly, most of the resolved enantiomers have the same retention order on these macrocyclic CSPs. When they are mixed or coupled with each other, the selectivity on one CSP will not be canceled by another. Even if some compounds may not have the same retention order, the complementary effects will result in an identifiable selectivity. Therefore, the coupled chiral columns can be used as a screening tool and save chromatographers substantial time in method development. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

Zhang, X.X., Bradshaw, J.S. and Izatt, R.M. (1997) Enantiomeric recognition of amine compounds by chiral macrocyclic receptors. Chemical Reviews, 97, 3313-3361. 

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