Chiral auxiliary recycling

Dihydrooxadiazoles 106 have been syntheised in moderate to high diastereomeric excess by the addition of aromatic nitrile oxides across the C=N bond of the hydrazones 105. The N-N bond can subsequently be cleaved with formic acid, and the chiral auxiliary recycled <99H(50)995>. The oxadiazolone 108 was produced (56%) from the oxime 107 by heating it with phenyl isocyanate <99SC3889>. ... 

The resolution process developed by Syntex is almost ideal (Pope Peachy resolution), with an efficient racemization and recycling of the unwanted (R) -enantiomer (yield >95% of (S)-naproxen from the racemate) and the chiral auxiliary (recovery >98%). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

The main disadvantage of this reaction is that it is necessary to use stoichiometric amounts, or more, of the organocopper reagent, together with stoichiometric amounts of the chiral auxiliary. The leaving group chiral auxiliary, however, can be recovered and recycled after the reaction. 

One major advantage of chiral auxiliary reagents over chiral a-substituted reagents is the fact that the chiral diol or diamine unit is not modified in the bond-making process and is thus potentially recyclable. The preparation of enan-tiomerically pure a-substituted reagents requires a stereoinductive transformation... 

A diol that has proved to be an ideal bridge is the rigid chiral [l,l -binaphthalene]-2,2 -diol which is commercially available in high optical purity in both enantiomers. Furthermore, this diol can be synthesized easily in enantiomerically pure form by phenolic oxidation25, followed by a resolution of the racemic mixture25 21. In addition, a part of this valuable chiral auxiliary can be recycled after the coupling reaction. 

To recover the chiral auxiliary, the aqueous phases are made basic with 2 M sodium hydroxide. After extraction with dielhyl ether, the amino alcohol is recycled in >80% yield. 

The chiral auxiliary can be recycled, since methanolysis of the 1-alkylated 3-trimethylsilyl-2-propynamines regenerated prolinol ether, a precursor of (S)-l-[(dimethoxy)methyl]-2-(meth-Oxymethyl)pyrrolidine. 

Acid hydrolysis of l-(2-alkyl-l-oxoalkyl)-a,a-dimethyl-2-pyrrolidinemethanols 2 furnishes 2-alkyl-alkanoic acids 4 in 76-99 % ee, along with the protonated chiral auxiliary 9. The latter can be recycled by acylation to yield l-acyl-a,a-dimethyl-2-pyrrolidinemethanols19-22. Although slightly more drastic conditions are required for hydrolysis of these derivatives compared with the conditions used for l-acyl-2-pyrrolidinemethanols (see Section 1.1.1.3.3.4.1.2.1.), racemiza-tion of the resulting acids does not seem to be a problem. 

The chiral auxiliary of alkylated A-acylbornane-10,2-sultams can be liberated by the use of hydroperoxide-assisted hydrolysis using lithium hydroxide/hydrogen peroxide9 in tetrahydro-furan/water (see Section 1.1.1.3.3.4.2.1.). This furnishes the chiral acids 2 in very high optical purities, along with the auxiliary which can be recycled. Other mild methods are available20. 

Reduction of the nitrosamine with lithium aluminum hydride in tetrahydrofuran allows recycling of the chiral auxiliary in 80% yield, however, a loss of up to 10% of the optical activity has been observed in some cases6,38. 

After use of this cleavage method, the chiral auxiliary may be partially recycled by neutralization and extraction of the aqueous layer. In this way a mixture of methylated hydrazine, the SAMP-hydrazone of formaldehyde and SAMP (1 7 2) is obtained, which is subjected to air oxidation and hydrolysis8. 

A useful method for the diastereoselective and enantioselective synthesis of trans-and m-l,2-disubstituted cycloalkanecarboxaldehydes was devised by Koga et al.1990 starting from cycloalkanecarboxaldehydes. (S)-/er/.-Leucine ter/.-butyl ester, a highly effective chiral auxiliary reagent, could be recovered for recycling without any loss of optical purity in a reaction sequence similar to that in the acyclic synthesis of (202). 

From an industrial chemist s point of view the use of proline, phenylalanine, valine, and other commercially available amino acids, is fine. To date, however, tert.-(S)-leucine is still an exotic compound. It should also be noted that the recycling of the chiral amino acid moiety is of importance for possible technical processes. On the other hand, the recovery of the chiral auxiliary sometimes does not make sense, especially in syntheses which the require the use of stochiometric amounts of expensive reagents, e.g. LDA. 

Bycroft and Lee (75CC988) developed this into a general method for the asymmetric synthesis of a-amino acids, wherein the chiral auxiliary (L-proline) could be recovered and recycled. Condensation of L-proline methyl ester with a-keto acids using DCC, followed by a treatment with anhydrous ammonia at room temperature, gave the 3-hydroxypiperazine-2,5-diones with high stereoselectivity (cf. Scheme 79). These could be... 

Oxazolidones, chiral, (1) and (2). Evans et al. have prepared these two chiral 2-oxazolidones by reaction of phosgene with (S)-valinol and (IS, 2R)-norephedrine, respectively, and used them as recyclable chiral auxiliaries for carboxylic acids in cnantioselective reactions of the derived imides. 

Dialkylalkoxyborane 29 is treated with ethanolamine to liberate homoallylic alcohol 7 - this work-up allows the recycling of the chiral auxiliary.13 After precipitation of the (IPC)2B-ethanolamine adduct 30 it can be transformed into the allylating agent 27 via compound 31. 

Using a chiral auxiliary. The achiral substrate is combined with a pure enantiomer known as a chiral auxiliary to form a chiral intermediate. Treatment of this intermediate with a suitable reagent produces the new asymmetric centre. The chiral auxiliary causes, by steric or other means (see section 10.2.2), the reaction to favour the production of one of the possible stereoisomers in preference to the others. Completion of the reaction is followed by removal of the chiral auxiliary, which may be recovered and recycled, thereby cutting down development costs (Figure 10.10). An advantage of this approach is that where the reaction used to produce the new asymmetric centre has a poor stereoselectivity the two products of the reaction will be diastereoisomers, as they contain two different asymmetric centres. These diastereoisomers may be separated by crystallization or chromatography (see section 10.2.1) and the unwanted isomer discarded. 

Chiral templates can be considered a subclass of chiral auxiliaries. Unlike auxiliaries that have the potential for recycle, the stereogenic center of a template is destroyed during its removal. Although this usually results in the formation of simple by-products that are simple to remove, the cost of the template s stereogenic center is transferred to the product molecule. Under certain circumstances, chiral templates can provide a cost-effective route to a chiral compound (Chapter 25). Usually, the development of a template is the first step in understanding a specific transformation and the knowledge gained is used to develop an auxiliary or catalyst system. 

Chiral auxiliaries play a key role in the scale up of initial samples of materials and for small quantities. In addition, this method of approach can be modified to allow for the preparation of closely related materials that are invariably required for toxicologic testing during a pharmaceutical s development. There are a number of advantages associated with the use of an established auxiliary The scope and limitations of the system are well defined it is simple to switch to the other enantiomeric series (as long as mismatched pairs do not occur) concurrent protection of sensitive functionality can be achieved. This information can result in a short development time. The auxiliary s cost has the potential to be limited through recycles. However, the need to put on and take off the auxiliary unit adds two extra steps to a synthetic sequence that will reduce the overall yield. Most auxiliaries are not cheap, and this must be considered carefully when large amounts of material are needed. Finally, because the auxiliary has to be used on a stoichiometric scale, a by-product—recovered auxiliary—will be formed somewhere in the sequence. This byproduct has to be separated from the desired product sometimes, this is not a trivial task. 

By definition, a chiral auxiliary differs from a chiral template in that the auxiliary is capable of being recycled after the desired asymmetric reaction. Hence, chiral templates will not be included in this chapter. The uses of a chiral moiety as a ligand for a reagent have also been excluded. 

The discovery that chiral Lewis acids can catalyze the asymmetric Diels-Alder reaction is a major milestone for the scale up and practice of this reaction on an industrial scale. The use of such a catalyst obviates the need for a chiral auxiliary on the diene or dienophile. The vast majority of chiral auxiliaries that have been used in the Diels-Alder reaction are either not commercially available or are expensive. In addition, the chemical steps needed to attach and remove the chiral auxiliary increase the cost and complexity of the synthesis. Chiral catalysts may also be recovered or recycled, further decreasing cost.47 Research in this area is very active, and catalysts based on a number of metals (Table 26.1) have shown encouraging asymmetric induction.21 Our understanding of the role these catalysts play in the asymmetric induction of Diels-Alder reactions is increasing, and more general reagents should appear. 27-48 54... 

The ethyl aluminum dichloride-catalyzed synthesis of (7 )-(+)-cyclohex-3-enecarboxylic acid, using galvinoxyl to inhibit polymerization, has been successfully scaled up to the kilogram level.106 An improved synthesis of the chiral auxiliary, /V-acryloylbornane-10,2-sultam, was also described together with a recycle protocol. 

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