Ephedrine chiral centers

In this thiamine pyrophosphate-mediated process, ben2aldehyde (29), added to fermenting yeast, reacts with acetaldehyde (qv) (30), generated from glucose by the biocatalyst, to yield (R)-l-phen5l-l-hydroxy-2-propanone (31). The en2ymatically induced chiral center of (31) helps in the asymmetric reductive (chemical) condensation with methylamine to yield (lR,23)-ephedrine [299-42-3] (32). Substituted ben2aldehyde derivatives react in the same manner (80). 

Amino alcohols, which have a broad spectrum of biological activities, can be categorized as adrenahne-like with one chiral center at C-1 or as ephedrine-like with two chiral centers at C-1 and C-2 (Scheme 7). Although a variety of methods have been developed for the stereoselective preparation of 1,2-amino alcohols, " in most cases it is easier and more efficient to prepare these important compounds stereoselectively starting from chiral cyanohydrins (Scheme... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Chiral formylcyclopropanes.2 The oxazolidine (1), obtained by reaction of cinnamaldehyde with l>-( -)-ephedrine, reacts with diazomethane [Pd(OAc)2 catalysis] to give 2 in at least 90% ee. Hydrolysis of 2 to 3 is effected by moist SiO,. It is also possible to prepare cyclopropanes with three chiral centers, such as 5. 

In the above-discussed examples, a chiral inductor is used to induce chirality on the product of a reaction. In the absence of any specific interaction between a chiral inductor and a reactant, it is unable to force every reactant molecule close to the chiral agent. This is one of the main reasons for poor enantioselectivity. The 69% ee obtained in the case of tropolone phenylethyl ether/ephedrine/NaY (dry) despite this limitation is remarkable. In an effort to reduce this limitation and to maintain closeness between the chiral center and the reaction site, Ramamurthy et... 

There are two chirality centers, so the formula predicts a total of four stereoisomers. However, each of the chirality centers has identical groups attached to the carbon, so fewer than four stereoisomers actually exist. The analysis can be conducted in the same manner as was done previously for ephedrine. We start by drawing one of the stereoisomers, the (2/ ,37 )-isomer for example. Then the mirror image of this, the (25,35 )-stereoisomer is drawn. These two compounds are nonsuperimposable mirror images—enantiomers. 

The ability of pyruvate decarboxylase from many microbial sources to produce phenylacetylcarbinol has been exploited for many years in the synthesis of ephedrine, a natural adrenergic compound (92). The acyloin is reductively aminated to produce the ethanolamine product, (1R,2S)-ephediine, with two chiral centers. 

In addition to the R and S designations, compounds with two chiral centers may also be identified by stereochemical nomenclature that describes the entire system. For example, the erythro and threo nomenclature derived from carbohydrate chemistry may be employed to describe the relative positions of similar groups on each chiral carbon. Thus, the ephedrines are designated as erythro forms since the similar groups (OH and NHCH3) are on the same side of the vertical axis of the Fischer projection, and the pseudo-ephedrines are designated as threo forms since like groups are on opposite sites of the vertical axis of the projection (Fig. 10). 

Pseudoephedrine is a stereoisomer of ephedrine, in which two of three chiral centers are different. 

Shen Nung also observed the stimulant properties of another Chinese plant. Ma Huang, now known as Ephedra sinica [9]. The chief active ingredient, ephedrine, is a sympathomimetic amine, and therefore it is clear in this case also that the use of Ma Huang as a stimulant had a rational basis. The ephedrine molecule is simple and contains two chiral centers the compound from ephedra is unichiral and has the 1R,2S configuration 2. Ephedrine was first isolated from Ma Huang in 1887... 

Ephedrine and pseudoephedrine are structurally mirror images of each other. This is possible because they have a chiral center, the isopropyl carbon to which the nitrogen atom is attached. If the reduction is done in such a manner that the chiral nature of the substance is not jumbled (i.e. racemization), then ephedrine and pseudoephedrine give rise to "1" and "d" methamphetamine, respectively. The "1" form is several times more potent than the "d" form. Meth produced from phenylacetone is a racemic mixture, meaning that it is a 50-50 mix of the "1" and "d" forms of meth. Obviously, a batch of pure "1" form is most desirable, a racemic mixture is OK, and pure... 

The chemistry of ephedrines is summarized in Figure 9-9. It will be noted that the four isomers generated by the two chiral centers (22) exist as two nonsuperimposable image pairs. The two ephedrines are enantiomers. Epimerization of the a-carbon produces the other pair—the -ephedrines. Each -ephedrine is an enantiomer of the other however,... 

Compounds containing more than one chiral center probably are the most common type of diastereoisomer used as drugs. The classic example of compounds of this type is the diastereoisomers ephedrine and pseudoephedrine (Fig. 2.21). When a molecule contains two chiral centers, there can be as many as four possible stereoisomers consisting of two sets of enantiomeric pairs. For each enantiomeric pair, there is inversion of both chiral centers, whereas the difference between diastereomers is inversion of only one chiral center (Problem 9 at the end of this chapter helps to illustrate this point). 

Using the Cahn-Ingold-Prelog rules, assign the absolute configuration to each chiral center of ephedrine and pseudoephedrine (Fig. 2.21). 

The p-position has not been particularly well investigated. Perhaps the best-studied derivatives are ephedrine and norephedrine—and even these agents have not been especially well investigated. Ephedrine and norephedrine are phenylpropanolamines that may be viewed as the p-hydroxy analogues of methamphetamine and amphetamine, respectively. Actually, p-hydroxylation of amphetamine or methamphetamine results in the creation of a new chiral center hence, a total of four optical isomers result from hydroxylation in each case. These eight structures are shown in Figure 23.3. Relatively little comparative information is available regarding the central stimulant actions of these phenylpropanolamine isomers. 

Considering the chemical characteristics, ephedrine has two chiral centers, and therefore four isomers can be identified ( )-ephedrine and ( )-pseudoephedrine [39]. (lR,2S)-(—)-ephedrine is the major isomer found in Ephedra sp., and pharmacological studies have shown it as responsible for the pharmacological activities of ephedra. Not only (—)-ephedrine has the widespread use but also (+)-pseudoephedrine is added in over-the-counter decongestant preparations [40]. The four isomers of ephedrine may be naturally present in Ephedra species, and they are usually used as a hydrochloride form, being the classical purification method for ephedrine hydrochloride a combination of conventional infusion and organic solvent extraction or adsorption [41]. Other alkaloids are also present in smaller amounts, and the minor ephedrine alkaloids include (+)-pseudoephedrine and the demethyl analogues (—)-norephedrine and (+)-norpseudoephedrine [40]. 

Figure 8.37 The optical isomers of methamphetamine and its precursors. Ephedrine has two chiral carbons—a and /3—to the phenyl ring, but the a carbon is reduced to —CH2, leaving only one chiral center. 

Assign R ov S configuration to each chirality center in pseudo-ephedrine, an over-the-counter decongestant found in cold remedies. 

Natural products of the general formula PhCH(OH)CH(NHMe)CH3 are isolated from Ephedra species and are called ephedrine and pseudoephedrine. They have various physiological effects, including uses as decongestants and appetite suppressants. Draw all four of the possible stereoisomers as Fischer projections, and assign the stereochemistry at each chiral center. Why do ephedrine and pseudoephedrine have different physiological effects Do the natural and unnatural isomers have different effects What is the relationship of these molecules to methamphetamine ... 

Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the opposite enantioselectivity of the overall process results. However, this effect is also seen with catalysts that are of analogous configuration, but not derived from trans-1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived catalyst shown in Scheme 5, having (5)-configuration at the centers of chirality, shows some preference for the (5)-azlactone kinetically favors the (5)-azlactone in alcoholytic ring opening [37]. 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

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