Chiral centres, optically pure

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Optically pure mandelic acid (see Structure 7.6) can be a useful chiral resolving agent where the compound you are looking at has a basic centre, as it can form an acid-base pair with it, which is a stronger form of association. This compound is of sparing solubility in CDCI3 however and can precipitate out your compound if, as is often the case, its protonated form is of low solubility in CDCI3. 

Chromium(III) forms stable complexes with adenosine-S -triphosphate.840,841,842 These are kinetically inert analogues of magnesium ATP complexes and may be used to study enzyme systems. The complexes prepared are chiral and may be distinguished in terms of chirality at the metal centre (198,199).843 The related complex of chromium(lll) with adenosine-5 -(l-thiodiphosphate) has been prepared the diastereoisomers were separated.844 The stereospecific synthesis of chromium(III) complexes of thiophosphates has been reported845 by the method outlined in equation (47), enabling the configuration of the thiophosphoryl centre to be determined. The availability of optically pure substrates will enable the stereospecificity of various enzyme systems to be investigated.845... 

Before 1940 optically active compounds could only be obtained in stereo-isomerically pure form by isolation from natural sources, by resolution of racemic mixtures, or by a few laboratory controlled enzymic reactions. Many of the chemical reactions described in this book lead to products which contain chiral centres, axes, or planes, but in which the isolated material is the optically inactive (racemic) form. This is a direct consequence of the fact that the reactants, reagents, or solvents are achiral or are themselves racemic. The following selection of reactions drawn from the text illustrate this statement they may be cross-referenced to the relevant discussion sections, namely (a) Section 5.4.1, p. 519, (b) Section 5.4.3, p.542, (c) Section 5.11.7, p.687, (d) Section 8.1.3, p. 1133, e) Section 5.2.4, p. 504 and (/) Section 5.4.2, p. 531. 

Enantiomers have identical physical and chemical properties to one another except the direction in which they rotate plane polarised light (clockwise or anticlockwise). They may be separated by interaction with a second chiral species. This gives two diastereoisomers (if the two chiral centres are the same we can describe the diastereoisomers as optically pure meso AA and the racemic or rac form which itself occurs as two pairs of enantiomers, AA and AA) which do differ in their physical properties e.g. have different NMR spectra, can be separated by achiral chromatography etc). For example, Scheme 3.1 shows the experimental resolution of [Co(en)3]3+ using tartrate. 

The importance of this mode of separation lies in the shear scale of the market for optically pure molecules. The sales of single enantiomer chiral drugs is currently U 180 billion per annum and —65% of active pharmaceutical ingredients (APIs) currently in development have at least one chiral centre. Apart... 

If enantiomers are derivatized with a chiral, optically pure reagent a pair of diastereomers is formed. Diastereomers are molecules with more than one centre of asymmetry, which therefore differ in their physical properties. From the scheme in Figure 22.5 it is clear that they are not mirror images. Diasetereomers can be separated with a nonchiral chromatographic system, but in any case the derivatization reagent must be chosen very carefully. 

Some metallodendrimers with one or more stereogenic centers have been prepared without control of the chirality. Vogtle and Balzani [74] have tried several strategies to prepare dendrimers in which a ruthenium cation is the core of the final compound. In these compounds, the only centre of chirality is that of the metal, but as it was not controlled racemic mixtures were obtained. Controlling the stereochemistry of the starting complex would have allowed the authors to prepare a optically pure metallodendrimer. Denti, Campagna, Balzani, and their co-workers have studied polymetallic dendrimers based on bipyridine and 2,3- 7s -(2-pyridyl)pyrazine (2,3-... 

Optically pure compounds with one chiral centre... 

Optically pure compounds with two chiral centres... 

We now have four chiral centres. Three of them are new and put in place relative to the starting chiral centre. Since that was optically pure we have an optically pure product. Diol 181 is an intermediate on the way to a fragment of Spongistatin 1 - a chain extension, asymmetric dihydroxylation and stereoselective intramolecular Michael addition all feature on the way there.43... 

The resolving agent must now be removed by hydrolysis of the amide. This is a risky business as enolisation would destroy the newly formed stereogenic centre, and a cunning method was devised to rearrange the amide 30 into a more easily hydrolysed ester by acyl transfer from N to O. The rest of the synthesis is as before. By this means the alcohol 28 was obtained almost optically pure, <0.4% of the other enantiomer being present. No further reactions occur at the newly formed stereogenic centre, so the absolute chirality of 22 is as shown. 

In the previous chapter we discussed various reagent-based strategies for the enantioselective formation of chiral centres. The next two chapters are also concerned with reagent-directed strategy but with an important difference. The source of asymmetry is used in a much lower concentration it is a catalyst. We may put in a few milligrams of an optically active compound and get out grams or even kilograms of enantiomerically pure product. This chapter concerns the formation of C-O and C-N bonds, the next the formation of C-H and C-C bonds. 

We have already seen in earlier chapters how one chiral centre can lead to another. We have seen this in the context of racemic compounds and in the context of optically pure ones. So for instance, new chiral centres are made when unsaturated acid ( )-2 reacts to form the iodolactone 1. If the acid 2 is racemic, both enantiomers of one diastereoisomer of the lactone 1 are formed but if 2 is optically pure, only one is formed. The existing chiral centre in 2 controls the two new ones in 1. The relative stereochemistry in the racemic product ( )-l is exactly the same if we start with optically pure material. 

For the tris(amino acidato)metal(III) complexes four geometrical and chiral isomers are possible, as shown in Scheme 2, where NO is the chelated amino acid anion, mer and fac refer to the meridional and facial geometrical isomers and A and A refer to the configuration at the metal centre. For the glycine complexes A and A are an enantiomeric pair, while for the optically pure forms of the other amino acids they form a diastereomeric pair and hence are easier to separate. For most of the simple bidentate amino acids of the kinetically inert metal ions Cr" , Co " and Rh ", the four isomers have been obtained. The isomers are distinguishable by their UV/visible, CD and NMR spectra. Not all the isomers can be found in certain cases, for example, with L-proline the k-fac isomer could not be prepared, a fact which was predicted on steric grounds." ... 

The product sec-butyl acetate is optically active and we can measure its optical rotation. But this tells us nothing. Unless we know the true rotation for pure sec-butyl acetate, we don t yet know whether it is optically pure nor even whether it really is inverted. We expect it to have R) stereochemistry, but we can easily find out for sure. All we have to do is to hydrolyse the ester and get the original alcohol back again. We know the true rotation of the alcohol—it was our starting material—and we know that ester hydrolysis (Chapter 10) proceeds by attack at the carbonyl carbon—it can t affect the stereochemistry of the chiral centre. 

The use of sulfoxides as chiral synthons has, over recent years, become a highly dependable protocol in synthetic organic chemistry. To some extent, however, the use of sulfoxides in asymmetric synthesis has been limited by the lack of a reliable and general method for their preparation in optically pure form. In this review we present the development of chiral sulfoxide synthesis via nucleophilic displacement at sulfur from the pioneering work of Andersen in 1962 to more recent methods. Sulfoxides have become associated with many diverse areas of synthetic chemistry indeed, their ability to act as a handle for the stereoselective generation of chirality at proximate centres has attracted much research worldwide. 

Enantiomerically enriched Q, o -disubstituted phenylacetonitriles have been prepared from 2-alkyl-2-[2-(p-tolylsulflnyl)phenyl]acetonitriles by reaction with alkylating and acylating reagents under basic conditions. The use of enantiomerically pure )3-ketosulfoxides as nucleophiles in 1,4-additions to a,)3-unsaturated aldehydes catalysed by proline derivatives allows complete control of the two chiral centres to be simultaneously created in the reaction (Scheme 2). Because the catalyst and the sulfinyl group mainly control the configuration of the carbon atoms acting at the electrophile and nucleophile, respectively, the method allows the preparation of all four possible diastereoisomers in optically pure form. 

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