Diastereomerism

A further advancement in organic synthesis was the accomplishment of multi-step syntheses comprising 20 and more steps and the synthesis of rather unstable organic compounds. It was now feasible to do an experiment on a milligram scale and to separate and identify products from by-products in order to analyze them separately. The application of selective reagents or reaction conditions allowed the synthesis of enantiomerically or diastereomerically pure compounds. 

In cyclic sulfoxides Che diastereomeric product ratio is even higher, and the chirality of the sulfur atom has been efficiently transferred to the carbon atom in synthesis. 

In the Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

The cyclic 2,4-dienoate 184, formed by the Pd-catalyzed cyclization of the 1,6-enyne 183, reacted with 154 to form the azulene derivative 185[118], The 3-methylenepyrrolidine 188 is formed by the reaction of the Zn reagent 186 with the chiral imine 187 with high diastereomeric excess. The structure of the allylic ethers is important for obtaining high diastereoselectivity[l 19],... 

The reduction of a number of thiazolium salts had been shown to yield diastereomeric mixtures of thiazolidines from which it has been possible, in some cases (including that of thiamine), to isolate one pure species (Schemes 94 and 94a). 

FIGURE 7 8 Stereo isomeric 2 3 dihydroxybu tanoic acids Stereoisomers I and II are enantiomers Stereoisomers III and IV are enantiomers All other rela tionships are diastereomeric (see text)... 

To convert a molecule with two chirality centers to its enantiomer the configura tion at both centers must be changed Reversing the configuration at only one chirality center converts it to a diastereomeric structure... 

The diastereomeric salts are separated and the individual enantiomers of the amine lib erated by treatment with a base... 

In the resolution of 1 phenylethylamine using (-) malic acid the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )... 

A variety of strategies have been devised to obtain chiral separations. Although the focus of this article is on chromatographicaHy based chiral separations, other methods include crystallisation and stereospecific ensymatic-catalysed synthesis or degradation. In crystallisation methods, racemic chiral ions are typically resolved by the addition of an optically pure counterion, thus forming diastereomeric complexes. 

Most chiral chromatographic separations are accompHshed using chromatographic stationary phases that incorporate a chiral selector. The chiral separation mechanisms are generally thought to involve the formation of transient diastereomeric complexes between the enantiomers and the stationary phase chiral ligand. Differences in the stabiHties of these complexes account for the differences in the retention observed for the two enantiomers. Often, the use of a... 

The dependence of chiral recognition on the formation of the diastereomeric complex imposes constraints on the proximity of the metal binding sites, usually either an hydroxy or an amine a to a carboxyHc acid, in the analyte. Principal advantages of this technique include the abiHty to assign configuration in the absence of standards, enantioresolve non aromatic analytes, use aqueous mobile phases, acquire a stationary phase with the opposite enantioselectivity, and predict the likelihood of successful chiral resolution for a given analyte based on a weU-understood chiral recognition mechanism. 

Fig. 22. Principle of chiral receptor—substrate recognition (a) formation of diastereomeric inclusion complexes (b) three-point interaction model.

Fig. 4. Chiroselective inclusion formation of racemic l-phenylethylammonium salt ((R/S)-14) using optically active crown compound ((i, 5)-13) [53955-48-9]. The diastereomeric inclusion complex (R)-(14) is more stable than (3, 3)-(13)-(3)-(14) (top views, dotted lines represent hydrogen...

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Diastereomeric derivathation of a chiral alcohol (111) with an enantiopure compound such as Mosher s reagent [20445-33-4] (a-ttifluoromethyl-a-methoxy-a-phenylacetjichloride) (112) (91) results in two distinct compounds (113) and (114) with nonequivalent chemical shifts in the H-nmr spectmm (92). 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Diastereoisomeric Salts. The formation of salts of optically active bases with racemic acids or of optically active acids with racemic bases leads to diastereomeric mixtures which may be resolved by the differential solubiUty of the components of such mixtures (49), ie,... 

The principle of this method depends on the formation of a reversible diastereomeric complex between amino acid enantiomers and chiral addends, by coordination to metal, hydrogen bonding, or ion—ion mutual action, in the presence of metal ion if necessary. L-Proline (60), T.-phenylalanine (61),... 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Formylation of folate (3) or hydrolysis of 5,10 — CH+ — folate (9) gives (6R,3)-5-formyltetrahydrofohc acid (6) (5-HCO-H folate) (55). On the other hand, (63)-5-HCO-H4 folate is obtained by selective crystaUi2ation in the form of its calcium salt from the diastereomeric mixture of (63, R)-5-HC0-H4 folate (56). 10-Formyltetrahydrofohc acid (7) is a coen2yme in purine synthesis which is synthesi2ed by hydrolysis of 5,10 — CH+ — folate (9) or by hydrogenation of lO-CHO-folate (57). 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

For the 1,2- and 3,4-addition, a chiral carbon (marked by an asterisk) is formed which has an R or 3 configuration, but there is no net optical activity, because equal amounts of the R and S configurations are formed. The R and S configurations along the polymer chains lead to diastereomeric isomers called isotactic, syndiotactic, and atactic. In isotactic polyisoprene all monomer units have the same configuration as illustrated for isotactic... 

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