Resolving agents basic

In this method the alcohol is converted to an acid ester, usually the sulfate, phthalate, or succinate. The acid ester is then resolved by crystallization of its salts with active bases, and the active esters are recovered from the salts and saponified to yield the corresponding active alcohols. The method has been by far the most generally applicable. It was developed because of the relative ease and certainty with which racemic acids may be resolved by means of their salts with active bases. Basic resolving agents are sufficiently numerous and accessible so that it usually is possible to find some combination of active base and solvent that will yield separable crystalline salts with nearly any type of acid. A list of basic resolving agents is given later (p. 394). 

The enantiomers of racemic mandelic acid have since been obtained through the use of practically every known basic resolving agent, and the enantiomers are commercially available in any desired quantity. 

At the time of the initial DR work, various families of acidic and basic resolving agents were available (Figure 7.6).21... 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

Design of Basic Resolving Agents for 2-Arylalkanoic Acids... 

The general procedure for separation of enantiomers through formation of dissociable dlastereomers can be illustrated for the instance where a racemic acid is to be resolved through the use of a basic resolving agent. The first step of the resolution procedure involves formation of the p- and n-diastereomeric salts ... 

In the next stage, the enantioseparation of racemic 2-hydroxy-4-phenylbutyric acid with (T)-l-(4-methylphenyl)ethylamine was tried several solvents (dioxane, 4-methyl-2-pentanone, and water) were tried and a relatively higher resolution efficiency was observed with water which is economically and environmentally favorable. The addition of NaOH was also effective, and the highest resolution efficiency (0.76, 78% yield, 98% enantiomeric excess) was achieved when the molar ratio of the basic resolving agent/NaOH was 1/1 for racemate/water = 1/2.8. 

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. 

Tartaric acid (9) is the most conventional acidic resolving agent for basic race-mates. A great number of basic racemates have been resolved by 9 so far. In Nature, the L-form (+)-d-form is abundant and occurs in many fruits. However, not only the L-isomer but also the D-isomer are commercially available in fairly low costs. This makes the availability of this acid notable. 

The preceding example demonstrates the general view that the procedure most likely to alter the crystallization thermod)mamics of true race-mate systems will entail the formation of dissociable diastereomer species [50-54]. In most instances, these diastereomers are simple salts formed between proton donors and proton acceptors, or electron-pair donors and electron-pair acceptors. For example, the first resolving agents introduced for acidic enantiomers were alkaloid compounds, and hydroxyl acids were used for the resolution of basic enantiomers. This t) e of resolution procedure has been known since the time of Pasteur, and extensive tables of resolving agents and procedures are available [48,55,66]. 

Chemical Resolution of Compounds Containing Basic Groups. 3-Bromocamphor-8-sulfonic acid has been widely used as a resolving agent for compounds containing basic groups. A number of primary (1), secondary (2), and tertiary (3) amines as well as oxazolines (4) have been resolved by the formation of diastereomeric salts derived from 3-bromo-8-camphorsulfonic acid. 

Problem 20.9 Alcohols are the class of compounds most commonly resolved (Sec. 7.9), despite the fact that they are not acidic enough or basic enough to form (stable) salts. Outline all steps in a procedure for the resolution of sec-butyl alcohol, using as resolving agent the base (-)-B. 

Other companies (Cilag AG and R. W. Johnson) required the pyridine-containing P-amino acid 11 or, to be more accurate, the ester dihydrochloride4 12. This combination of acidic and basic functional groups offers a wide choice of resolving agents. 

Some commonly used resolving agents are summarized in Table 1 [15-48]. The formation of non-covalent diastereomeric salts is driven by ionic interactions. Therefore, suitable functional groups (acidic or basic) are required to be present in both counterparts. This makes impossible a direct application of the diastereomeric crystallization technique to several classes of chiral compounds such as alcohols, aldehydes, ketones, diols, thiols, dithiols, and phenols. This is a critical disadvantage of this technique. The compounds of the above-mentioned groups may be transformed to their more polar derivatives and resolved as such. However, this requires an additional reaction step, and reagents, and the recovery of the starting material after the resolution may not always be easy. 

Table 2. Resolving agents suitable for resolution of enantiomers of chiral compound without polar "acidic or basic functionality [49-64] ...

Crystallization of diastereomeric salts obtained from an optically pure acid or an optically pure base is a classical method for the resolution of atropisomeric heterocycles presenting the complementary basic or acid functions. The method requires several trials to find the optimal resolving agent. Atropisomers bearing mono or diphosphine groups are separated using optically pure Pd(ll) complexes. Table 2 reports some selected examples. 

Resolution of compounds containing functional groups that are not acidic or basic requires a reversible functional group interconversion involving a chiral resolving agent. For example, the reaction of a racemic alcohol with a chiral carboxylic acid results in a mixture of diastereomeric esters that can be separated. After separation, hydrolysis of the ester regenerates the desired alcohol. To resolve a racemic ketone or aldehyde, a reaction with a chiral diol or a chiral amine could be employed to form diastereomeric acetals or imines, respectively. 

Since l-amino-2-cyclohexene is basic, a chiral acid is needed. When (+)-mandelic acid is the resolving agent used, a mixture of diastereomeric salts is formed as shown. These diastereomers have different physical properties and can therefore be separated (often by recrystaUization). Treatment with base neutralizes the amine and allows it to be separated from the charged mandelate salt (typically by extraction), to give the neutral amines as pure enantiomers. 

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