Salts with chiral bases

In the only example of reagent-based induced diastereoselection reported to date for the [2,3] ylide rearrangement, treatment of the bisallylic sulfonium salt 29 with chiral bases results in an observable, but relatively inefficient, stereochemical induction121. 

The assignment of configurations supports the mechanisms proposed for some well-known reactions of furo- and pyranoquinoline alkaloids. Thus, balfourolone (103) is believed to be an artifact formed from 0-methyI-balfourodinium salt with aqueous base, and the (I ) configurations of both compounds are consistent with a mechanism involving nucleophilic reaction at the 2-position of the quinoline ring. Conversion of (—)-(K)-balfourolone (103) into (+)-( )-isobalfourodine (104) with aqueous acid occurs at the tertiary center without affecting the chiral center, as expected. 

Another different approach for carrying out the enantioselective 1,3-DCR involves the addition of a chiral base in substoichiometric amoimt. Many cinchonine and cinchonidine derivatives as well as silver salts were essayed. The best conversions and more reproducible results were obtained when employing silver fluoride and the highest ee resulted in the reactions performed with chiral base 61 (Scheme 18) [57]. The reaction between N-all lidene glycine esters 3 and terf-butyl acrylate catalyzed by silver fluoride and the commercially available chiral base dihydrocinchonine 61 (Scheme 17) proceeded with high endo-diastereoselectivity and moderate enantioselectivity (up to... 

An example that refers to the third method additives can be employed is described below. Markedly enhanced enantioselectivity was reported for P. cepacia lipase and subtilisin Carlsberg with chiral substrates converted to salts by treatment with numerous Bronsted-Lowry adds or bases [63]. This effect was observed in various organic solvents but not in water, where the salts apparently dissociate to regenerate... 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

The chiral centre first appears in cyanide (11) but the acid (10) is the ideal compound for resolution as it can form a salt with a naturally-occurring optically active base. 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Catalytic enantioselective crossed aldehyde-ketone benzoin cyclizations of ketoaldehydes, such as 13, readily obtained from an aryl nitrile oxide and a 1,3-diketone, were studied in order to perform the synthesis of complex molecules. Significant asymmetric induction was observed with chiral triazolium salts such as 14, in the presence of DBU as base, leading to compound 15 in high yield and with 99% ee in favor of the R enantiomer <06AG(E)3492>. 

In 1965, Denney et al. (98) reported the reaction of a number of alkenes with ferf-butyl hydroperoxide (TBHP) and cupric salts of chiral acids. The use of ethyl camphorate copper complex 144 in the allylic oxidation of cyclopentene provides, upon reduction of the camphorate ester, the allylic alcohol in low yield and low selectivity, Eq. 82. The initial publication only provided the observed rotation of cyclopentenol, but comparison to subsequent literature values (99) reveals that this reaction proceeds in 12% ee and 43% yield (based on the metal complex). 

Brunner et al. [26] synthesized and applied so-called dendrizymes in enan-tioselective catalysis. These catalysts are based on dendrimers which have a functionalized periphery that carries chiral subunits, (e.g. dendrons functionalized with chiral menthol or borneol ligands). The core phosphine donor atoms can be complexed to (transition) metal salts. The resultant dendron-enlarged 1,2-diphosphino-ethane (e.g. 16, see Scheme 17) Rh1 complexes were used as catalysts in the hydrogenation of acetamidocinnamic acid to yield iV-acetyl-phenylalanine (Scheme 17) [26]. A small retardation of the hydrogenation of the substrate was encountered, pointing to an effect of the meta-positioned dendron substituents. No significantly enantiomerically enriched products were isolated. However, a somewhat improved enantioselectivity (up to 10-11% e.e.) was... 

Introduction of nitrogen into the anulene ring (e.g. of 95) leads to a methano-azaanulene 107 121) with Q-symmetry which is therefore chiral (like its mono- or disubstituted derivatives)118). The low basicity of 107 (pKa 3.20) prevented its optical resolution by conventional methods (e.g. through salts with optically active acids). Excellent results were obtained, however, (as also in the case of the two isomeric carbocyclic methylesters 97 and 101 and of several derivatives of azaanulene) by chromatography on microcrystalline triacetyl cellulose in ethanol at 7 bar 1221 (see also Section 2.7.1). In many cases base line separations were accomplished to give both (optically pure) enantiomers. Enantiomeric relations were confirmed in all cases by recording the CD-spectra of both fractions. Some results of these separations are shown in Fig. 4 together with the optical rotations ([a]D in ethanol) of the enantiomers. 

The reaction of a racemic form with a chiral reagent, for example, a racemic ( ) acid with a (-) base, yields two diastereomeric salts ( + )(-) and (-)(-) with different solubilities. These salts can be separated by fractional crystallization, and then each salt is treated with a strong acid (HCI) which liberates the enantiomeric organic acid. This is shown schematically ... 

The principle is the same as for the resolution of a racemic acid with a chiral base, and the choice of acid will depend both on the ease of separation of the diastereomeric salts and, of course, on the availability of the acid for the scale ... 

Several years later, the group of Corma reported on a successful study on stereoselective olefin epoxidation with MTO using various chiral nitrogen bases. Although the conversion is low (10%), an enantiomeric excess (ee) of up to 36% can be obtained with cA-p-methylstyrene as the substrate and R-(+)-1 -phenylethylamine as base (Fig. 3b) [34], Also, the groups of Saladino and Crucianelli used /f-(+)- -phenylethylamine as chiral base in a 1 1 ratio with MTO, forming the corresponding perrhenate salt, but also here, very low conversion is obtained. In the same report, the use of Lrans-( R,2R)-, 2-diaminocyclohexane (Fig. 3c) in combination with MTO as... 

An overwhelming majority of classic resolutions still involve the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 6.1). These chiral-resolving agents are relatively inexpensive and readily available in large quantities (Table 6.2). They also tend to form salts with good crystalline properties.8... 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

Removal of the chiral-inducing agent was accomplished in a straightforward fashion by means of hydrogenolysis using H2 and 5% Pd-C in ethanol to give the amine 27 as its HC1 salt in 93% yield (ee >98%). The total reaction sequence from (R)-PGA (1) and 3,3-dimethyl-2-butanone (27) has been carried out to give a multi 10-g sample of (,S )-3,3-dimethylbutylamine (26) as its HC1 salt with an overall yield of 53% based on 1. 

One possibility to separate the enantiomers of rac- 1-phenylethanamine is to form diastereomeric salts with an enantiomerically pure chiral acid, e.g. (R,R) tartaric acid or (S)-2-hydroxysuccinic acid. These can be separated from each other by recrystallisation as a consequence of their different solubilities. Note, however, that the separation process is not complete at this stage since the amines are now present as salts. The separated salts must be treated with a strong base, e.g. aqueous sodium hydroxide, to convert them back to the free amines which can then be extracted into an organic solvent. After drying the extract distillation of the solvent leaves the pure amine. 

In many cases, amino acids can be resolved by the methods we have already discussed (Section 5-16). If a racemic amino acid is converted to a salt with an optically pure chiral acid or base, two diastereomeric salts are formed. These salts can be separated by physical means such as selective crystallization or chromatography. Pure enantiomers are then regenerated from the separated diastereomeric salts. Strychnine and brucine are naturally occurring optically active bases, and tartaric acid is used as an optically active acid for resolving racemic mixtures. 

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