Enantiomeric acids

R)-Hydroxy-4-pentenoic44,322 (R-94) and 3(R)-hydroxy-3(R)-methyl-4-hexenoic (R-99, R = H)4S acids were obtained from the racemic acids by recrystallization of their quinine salts. Compound R-94 served322 as the substrate for the synthesis of 2-deoxy-L-eri/t/iro-pen-tose as in 94 —> 98. The enantiomeric acid R-99 was employed46 for the preparation of D-everniicose (see 99 — 105). 

Asymmetric Michael addition to enoatesThe known conjugate addition of RCu BF, (8, 324-325) to a,/(-unsaturated carbonyl compounds4 proceeds with high chiral induction to trans- )-8-phenylmenthyl crotonate (2). Addition to the isomeric ei.v-crotonate (5) is less selective, but results mainly in the enantiomeric acid (6). 

Amines react with strong acids to form amine salts. The pKas of amine salts are related to the base strength of the corresponding amines. Alkylammonium salts have pKas of 9-10 while arylammonium salts have pKas of 4-5. The fact that these salts are usually water-soluble can be exploited in separating amines from neutral or acidic contaminants. Chiral amines can be used to resolve enantiomeric acids, through the formation of diastereomeric salts. 

Explain how chiral amines can be used to resolve a mixture of enantiomeric acids. 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

Substituted 3,4-dihydropyrimidines are inherently asymmetric. They are usually obtained as racemic mixtures. Enantiomerically pure and optically stable dihydropyrimidine-5-carboxylic acids (381) have been obtained by optical resolution effected by fractional crystallization of their diastereo-meric a-methylbenzylammonium salts. The absolute stereochemistry was established by x-ray analysis of diastereomeric a-methylbenzylammonium carboxylate. The enantiomeric acids (/ )-(381) and... 

A related methodology (ref. 112) was employed in which rather than a C.,5 farnesyl component a compound was reacted with a chroman-2-acetaldehyde derivative. In this scheme the C.,4 aldehyde simultaneously formed at the ozonolysis stage in the previosly described synthesis was used. Thus, 2-carboxymethyl-6-hydroxy-2,5,7,8-tetramethylchroman, [(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid] served as a source by resolution with (S)-a-methylbenzylamine of the two enantiomeric acids. The 2(S)-enantiomer was converted by way of the acid chloride to the aldehyde, a homologue of that employed by the Swiss workers in the foregoing method. The aldehyde was reacted with the triphenylphosphonium salt from the C bromide by the Wittig reaction to afford 2R,4 R,8 R-a-tocopherol. A novel aspect of this approach was that it enabled a synthesis of 2R,3 E,7 E-a-tocotrienol to be achieved from the same carboxymethyl intermediate. 

The recovery of the individual enantiomeric acids from the diastereomeric amides has not been carried out to any large extent, because of the inherent stability of the amide bond and the risk of racemization during hydrolysis. Jiang and Soderlund [62] reported the recovery of the individual enantiomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, a synthetic pyrethoid precursor, from its S( — )-(phenyl)ethylamide diastereomers by refluxing in 6 M hydrochloric acid at... 

FIGURE 20.2 Resolution of the racemic form of an organic acid by the use of an optically active amine. Acidification of the separated diastereomeric saits causes the enantiomeric acids to precipitate (assuming they are insoluble in water) and leaves the resolving agent in solution as its conjugate acid. 

In this procedure the single enantiomer of an amine, (i )-l-phenylethylamine, is added to a solution of the racemic form of an acid. The salts that form are diastereomers. The chirality centers of the acid portion of the salts are enantiomericaUy related to each other, but the chirality centers of the amine portion are not. The diastereomers have different solubilities and can be separated by careful crystallization. The separated salts are then acidified with hydrochloric acid and the enantiomeric acids are obtained from the separate solutions. The amine remains in solution as its hydrochloride salt. 

Amines also form salts with organic acids. This reaction is used to resolve enantiomeric acids (Sec. 5.12). For example, (f )- and (S)-lactic acids can be resolved by reaction with a chiral amine such as (S)-l-phenylethylamine ... 

FIGURE 4.44 Two alkaloids, bmcine and strychnine, are commonly used to separate the enantiomers of chiral organic adds. Diastereomeric salts are first formed, separated hy crystallization, and the individual enantiomeric acids are regenerated. 

It was considered that the optically active polyamines interact more strongly with the acid chloride or anhydride than acid salt. Accordingly higher optical yield was anticipated in the products. However, only slight enantiomer selection was observed in reactions (3) or (4). The diastereomeric energy difference is apparently too small to differenciate the enantiomeric acid chloride or anhydride. 

Here, represents the dissociation constant of the enantiomeric acid, L- or D-form IQb represents the dissociation constant of the optically active base B, and K represents the acid-base reaction equilibrium constant, Kd for the D-form and /Cl for the L-form. Further, Kiu, represents the equilibrium solubility parameter of the salt i. However, the process is useful because varies with the enantiomeric salt species i, i.e. whether it is D-AHB or L-AHB. We identify this via and Klu,. 

Diastereomeric salts are formed between enantiomeric acids or bases and a chiral resolving bases or acids, respectively. Unlike enantiomers, diastereomers do not exhibit mirror symmetry therefore, they have different physicochemical properties including solubility. This difference in solubility makes the separation of the two diastereomers by crystallization possible. Furthermore, the extent of the difference in solubility determines the efficiency of the separation. 

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