Diastereomeric amides

Mixtures of stereoisomeric 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acids (the acid moieties of permethrin insecticide), CDI, and chiral amines have been investigated by capillary gas chromatography. The diastereomeric amides could be identified by GC/MS-spectrometry [413... 

The two diastereomeric amides exhibit different retention times. Other l-aryl-2-aminopropanes substituted in the phenyl ring as well as a-methylbenzylamine have also been investigated by this method.[44]... 

As shown in Tables 1 and 2, iV-protectcd amino acids have been widely used as CDAs mainly because of their ready availability. However, it was noticed that chromatographic resolution of the diastereomeric amides increased when the space-filling protecting group (e.g., Boc) was cleaved, indicating that the bulky Boc group shields the diastereodifferentiation and the specific adsorption sites of the analyte with the stationary phase94. 

To 1 mmol of 2-chloro-4-methyl-5-phenyl-l,3,2-oxazapHospholidine 2-sulfide dissolved in 5 mL of THF and 1.5 mmol of F,t3N is added 1.00 mmol of the amine of interest. The mixture is stirred at r.t. for 24 h, then at 65 °C for 24 h and then is poured into Et.O and HzO. The organic layer is separated, dried over Na2SQ4, and concentrated. The diastereomeric amides are analyzed without further purification. 

It has been reported that Horeau s method can be applied to micromolar quantities of secondary alcohols, if the enantiomeric composition of the remaining 2-phenylbutanoic anhydride is determined by means of gas chromatography. To the acylation mixture an optically active amine [(+)-(R)-l-phenylethanamine] is added which reacts rapidly with the excess of 2-phenylbutanoic anhydride. The resulting diastereomeric amides are then characterized by GLC. The amine salts of 2-phenylbutanoic acid do not interfere. Success is dependent upon rapid amide formation (without significant resolution of the anhydride by the amine)236. The application of this method to (+)-(A/)-binaphthol (9) is shown237. 

Diastereomeric amides of l,12-dioxa[12]paracyclophanedicarboxylic acid (20, as the first example of diastereomers with a plane of pseudo-asymmetry) could be separated by chromatography on silicagel on the basis of their 1H-NMR spectra tentative configurations were assigned to the amides 38). 

Such racemic lactones as substituted -butyrolactones and -valerolactones are resolved by means of the diastereomeric salt formation or the diastereomeric amide formation method.24,25 For example, -decalactone is successfully resolved in the form of its diastereomeric amides derived from a-methylbenzylamine (Figure ll).24... 

Analytical Properties Separation of diastereomeric amides and carbamates the separation of olefinic geometrical isomers is dependent upon the position of the double bond Reference 29, 30... 

Sonnet (1984) developed another general method of synthesizing chiral methylalkanes, based on fractional crystallization of the mixture of diastereomeric amides generated from... 

R. Carney, of Zoecon Corporation, Palo Alto, Calif., who is collaborating in this research, developed a synthesis of 96% ee (R)-2-methylbutyric acid from D-isoleucine (Figure 14). Another approach that involved HPLC purification of diastereomeric amides with subsequent cleavage of the amide link gave the R-acid in 94% ee. 

Southern corn rootworm. The structure of the southern corn rootworm has been defined as 10-methyl 2-tridecanone, XI (Figure 16) (5J3). Alkylation of undecanoic acid with n-propyl bromide was followed by conversion to the diastereomeric amides with either (S)- or (R)-a-methylbenzylamine that had been purified previously by recrystallization of D and L tartaric acid salts, respectively. Recrystallizations of these amides from ethanol (4 was sufficient) gave 32% yields of pure (>99.5%) diastereo-mers (Figure 16). Hydroxyethylation labilized the amides toward hydrolysis. It was convenient to intercept the aminoesters and reduce them with LAH. The resulting carbinols were than carried forward in standard manner to provide the ketones. 

Figure 17. Solution conformers of diastereomeric amides and carbamates. Rj and Rt are saturated alkyl groups Rt is longer than R,.

GAS LIQUID CHROMATOGRAPHIC DATA FOR DIASTEREOMERIC AMIDES AND CARBAMATES. 

There are few differences between the separation in gas chromatography [14-16] and the separation in liquid chromatography (LC), because it is assumed that the differential solvation of the diastereomeric compounds during the LC separation does not play a very important role [17], Helmchen et al. [18] explained the separation of diastereomeric amides using LC with a silica gel stationary phase under normal-phase conditions. In order to explain their separation, the authors made some assumptions ... 

B. L. Karger, R. L. Stern, and W. Keanr, Gas-liquid chromatographic separation of diastereomeric amides of racemic cyclic amines. Anal. Chem. 39 (1967), 228. 

G. Helmchen, G. Nill, D. Flockerzi, W. Schuhle, and M. S. K. Yousef, Extreme liquid chromatographic separation effects in the case of diastereomeric amides containing polar substituents, Angew. Chem. Int. Ed. Engl. 18 (1979), 62. 

Resolving Reagent for Carboxylic Acids and Other Types of Compounds. A large number of carboxylic acids have been resolved via their diastereomeric salts with (S)- or (7 )-a-methylbenzylamine (1). The ready availability of both enantiomers of (1) guarantees access to both enantiomers of the desired acid. Compounds (2)-(6) are representative examples of acids obtained in high enantiomeric purity. " Alternatively, racemic carboxylic acids have been resolved by covalent derivatization with (1) and separation of the resulting diastereomeric amides by physical means such as chromatography (eq 1) or fractional crystallization (eq 2). ... 

Chromatographic Resolutions. 1-(1-Naphthyl)ethylamine serves as a chiral derivatization agent useful in preparing diastereomeric amides from racemic acids for chromatographic resolution. For example, various terpenoid acids, after conversion to the diastereomeric amides using (R)-(+)-NEA, were analyzed by HPLC to define the enantiomeric composition (eq 4). Application of the procedure has been used to analyze the enantiomeric purity of several carboxylic acid derivatives. ... 

In some cases the resolution of the diastereomeric amides on silica gel is sufficiently large to achieve preparative separation. The preparative separation of diastereomeric hydroxy amides has proved useful in supplying quantities of enantiomerically pure lactones (eq 5). ... 

This is not surprising, since amide-forming reactions between amines and (activated) carboxylic acids proceed readily, and many optically active carboxylic acids are readily available. Furthermore, the diastereomeric amides produced are often well-resolved by LC or GLC. A variety of leaving groups (X in Eq, 1) have been used in the acylation reactitm, for example, chloride, imidazole, carboxylate, etc. 

To form the amide derivatives, the acid and amine are condensed in the presence of such agents as N,N -carbonyldiimidazole (18) or a carbodiimide and 1-hydroxybenzotriazole (17). The amides can also be formed via the add chlorides (200,201). Bjorkman (199) described a novel approach to the formation of diastereomeric amides The NSAID indoprofen was coupled by means of ethyl chloroformate to L-leucinamide in a reaction that is complete in 3 min. The derivatives were separated by RP LC, and the procedure was used to study the disposition of the drug in surgical patients (199). Others have adopted this derivatization scheme (209). The chloroformate activation method has also been used with (R)-[42] for resolution of several acids (210). It was found that when hydroxyacids were derivatized, not only did the reaction produce the desired amide moiety at the carboxyl group, but the hydroxyl group was converted to the carbonate derivative of the chloroformate (210). 

In addition to the resolution of amide derivatives of NSAIDS, diastereomeric amides of terpenoid (202), pyrethroid (201), and other (200) acids have also been resolved chromatographically. 

The product Is very moisture sensitive and should be handled under dry nitrogen or argon. Despite this precaution, the product 1s always contaminated by small amounts of (+)-c1trone11a1, which has an optical rotation opposite to that of the enamlne. To determine the optical purity of the product enamlne, the specific rotation measured therefore must be corrected for the (+)-c1tronellal Impurity. It is more reliable to base optical purity on the specific rotation of the citronellal obtained by hydrolysis of the enamlne (Part C). The absolute method using HPLC of the diastereomeric amide derivative also may be useful as a check of the optical purity. 

Resolution of diastereomeric amides by preparative HPLC has been developed for a-branched alkanoic acids, and has been employed to prepare dimethyl branched alkanes implicated in tsetse fly sexual communication (6). In much of our own work we have made use of fractional crystallization whereby racemic acids are converted to amides of either (R)- or (S)-ot-methylbenzylamine. These amines are available from Hexcel Corp., Zeeland, MI, and the diastereomeric amides can be analyzed for purity chromato-graphically. 

Figure 3. Comparison of GLC separations of diastereomeric amides on several liquid phases...

The unsaturated acid, a compound that could not be prepared readily by asymmetric induction, seemed a good candidate for resolution. In fact, this acid was resolved by fractional crystallization of diastereomeric amides (Figure 10), and then the pure diastereomers were cleaved by means described above. 

We also felt that the relative solubilities of the diastereomeric amides (or their crystal lattice energies) might be related to the sense of steric bulk disymmetry about that central backbone. If one could perform a chemical reaction, such as addition to the double bond, that could alter the distribution of steric bulk, one could hope to invert diastereomer solubility. Addition of a symmetrical reagent, such as bromine, avoids positional isomerism and the stability of the bromonium ion ensures stereoselectivity. Thus each diastereomeric amide gave only one bromine adduct. The solubilities were indeed dramatically altered and, since bromine is easily removed (Zn, acetic acid) it became possible to use the amide mixture that had been recovered from purification to claim the more soluble diastereomer as its bromine adduct. A process was established to obtain both enantiomeric cyclohexene acids using only one chiral amine. 

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