One Chiral Center

The familiar carbon chiral center has four different substituents as shown in 3-hydroxybutanoic acid (com- 

Chemical shift nonequivalence of the methyl groups of an isopropyl moiety near a chiral center is frequently observed the effect has been measured through as many as seven bonds between the chiral center and the methyl protons. The methyl groups in the terpene alcohol 2-methyl-6-methylen-7-octen-4-ol (ipsenol) are not chemical shift equivalent (Fig. 4.49) even though the 

Since the nonequivalent methyl groups are each split by the vicinal CH proton, we expect to see two separate doublets. At 300 MHz, unfortunately, the pattern appears to be a classical triplet, usually an indication of a CH3—CH2 moiety—impossible to reconcile with the structural formula and the integration. Higher resolution would pull apart the middle peak to show two doublets. Actually, in an earlier study at lower resolution (100 MHz), the two doublets overlapped to show four peaks. To remove the coincidence of the inner peaks that caused the apparent triplet, we used the very useful technique of titration with deuterated benzene, which gave convincing evidence of two doublets at 20% C6D6/80% CDC13 and optimal results at about a 50 50 mixture (Fig. 4.49). 

Note also that the chiral center accounts for the 

FIGURE 4.49. 2-Mcthyl-6-methylen-7-octen-4-ol (ipsenol) in CDC13 at 300 MHz. Titration with QD. The sample was a gift from Phero Tech, Inc., Vancouver, BC, Canada. 

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A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

Noting the presence of one (but not more than one) chirality center is a simple rapid way to determine if a molecule is chiral For example C 2 is a chirality center m... 

One final very important point Everything we have said in this section concerns molecules that have one and only one chirality center molecules with more than one chirality center may or may not be chiral Molecules that have more than one chirality center will be discussed m Sections 7 10 through 7 13... 

We 11 continue with the three dimensional details of chemical reactions later m this chapter First though we need to develop some additional stereochemical principles con cernmg structures with more than one chirality center... 

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... 

Eleven chirality centers may seem like a lot but it is nowhere close to a world record It is a modest number when compared with the more than 100 chirality centers typ ical for most small proteins and the thousands of chirality centers present m nucleic acids A molecule that contains both chirality centers and double bonds has additional opportunities for stereoisomerism For example the configuration of the chirality center m 3 penten 2 ol may be either R or S and the double bond may be either E or Z There fore 3 penten 2 ol has four stereoisomers even though it has only one chirality center... 

The double bond m 2 methyl(methylene)cyclohexane is prochiral The two faces however are not enantiotopic as they were for the alkenes we discussed m Section 7 9 In those earlier examples when addition to the double bond created a new chirality cen ter attack at one face gave one enantiomer attack at the other gave the other enantiomer In the case of 2 methyl(methylene)cyclohexane which already has one chirality center attack at opposite faces of the double bond gives two products that are diastereomers of each other Prochiral faces of this type are called diastereotopic... 

Glyceraldehyde can be considered to be the simplest chiral carbohydrate It is an aldotriose and because it contains one chirality center exists in two stereoisomeric forms the D and l enantiomers Moving up the scale m complexity next come the aldotetroses Examining their structures illustrates the application of the Fischer system to compounds that contain more than one chirality center... 

Molecules like lactic acid, alanine, and glyceraldehyde are relatively simple because each has only one chirality center and only two stereoisomers. The situation becomes more complex, however, with molecules that have more than one chirality center. As a general rule, a molecule with n chirality centers can have up to 2n stereoisomers (although it may have fewer, as we ll see shortly). Take the amino acid threonine (2-amino-3-hydroxybutanoic acid), for example. Since threonine has two chirality centers (C2 and C3), there are four possible stereoisomers, as shown in Figure 9.10. Check for yourself that the R,S configurations are correct. 

In the special case where two diastereomers differ at only one chirality center but are the same at all others, we say that the compounds are epimers. Cholestanol and coprostanol, for instance, are both found in human feces and... 

Let s look at one more example of a compound with more than one chirality center, the tartaric acid used by Pasteur. The four stereoisomers can be drawn as follows ... 

Some molecules have more than one chirality center. Enantiomers have opposite configuration at all chirality centers, whereas diastereomers have the same configuration in at least one center but opposite configurations at the others. Epimers are diastereomers that differ in configuration at only one chirality center. A compound with n chirality centers can have a maximum of 2n stereoisomers. 

Carbohydrates with more than one chirality center are shown in. Fischer projections by stacking the centers on top of one another. By convention, the carbony] carbon is always placed either at or near the top. Glucose, for... 

A molecule such as CHQBrl, which exists in two different forms that are not superim-posable mirror images, is said to be chiral. The two different forms are referred to as enantiomers, or optical isomers. Any molecule in which four different groups are bonded to carbon will be chiral the carbon atom serves as a chiral center. Molecules may contain more than one chiral center, in which case there can be more than two enantiomers. 

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... 

Secoquettamine (234) and dihydrosecoquettamine (235) together with their probable biogenetic precursor quettamine (236) form a small group of alkaloids. They were isolated by Shamma et at. (179) from Berberis baluchista-nica in yields of 0.00036,0.00017, and 0.0012%, respectively. These alkaloids incorporate either a benzofuran or a dihydrobenzofuran ring within the molecular framework, and the seco ones possess the /V,W-dimethylaminoethyl substituent. The structures of these bases were determined on the grounds of spectral data as well as by total synthesis. There is one chiral center at C in dihydrosecoquettamine (235) however, the base was isolated in the form of a racemic mixture (179). 

Compound (+ )-(53) has been made from one of the diastereomers of the (—)-menthyl ester of 3-(p-anisylmethyl-l-naphthylstannyl)propionic acid, (54) ([a]p°° — 24) which could be obtained from the mixture of diastereomers because it is much less soluble in -pentane at low temperature than the other one. Their separation could be followed by NMR, both diastereomers differing by the position of their methoxy signal. The pure less soluble diastereomer (54) reacts with methylmagnesium iodide to give a tetraorganotin compound containing only one chiral center, the asymmetric tin atom 36> 87>. 

These differences reflect the conformations of (+)- and meso-isomers as they sit at the air-water interface. What is much harder to elucidate is the effect of stereochemistry on intermolecular interactions. How does changing the stereochemistry at one chiral center affect interactions between diastereomers Ab initio molecular orbital calculations have been used to address the problem of separating stereochemically dependent inter- and intra-molecular interactions in diastereomeric compounds (Craig et al., 1971). For example, diastereomeric compounds such as 2,3-dicyanobutane exhibit significant energetic dependence on intramolecular configuration about their chiral centers. So far, however, little experimental attention has been focused on this problem. 

Two compounds are diastereomers when they contain more than one chiral center. If the number of dissymmetric centers is given by N, then the number of possible diastereomers is given by 2N. Of these 2 v diastereomers, each will be characterized by its mirror image, so that the number of enantiomers is given by 2NI2. Whereas the physical properties of enantiomers in an achiral environment are necessarily identical, the physical properties (including solubility) of diastereomers are normally different. The differences arise since there is no structural requirement that the crystal lattices of different diastereomers be the same. For instance, the solubility of an (SS )-diastereomer could differ substantially from that of the (/ S)-diastereomer. However, it should be remembered that the solubility of the (SS)-diastereomer must be exactly identical to that of the (I 7 )-diastereomer, since these compounds are enantiomers of each other. At the same time, the solubilities of the (SI )-diastereomer and the (I S)-diastereomer must also be identical. 

If a molecule contains more than one chiral center, there are other forms of stereoisomerism. As mentioned in Section 1.1, nonsuperimposable mirror images are called enantiomers. However, substances with the same chemical constitution may not be mirror images and may instead differ from one another... 

For an adamantane-type compound, it is possible to substitute the four tertiary hydrogen atoms and make four quaternary carbon atoms. These carbon atoms can be asymmetric if the four substituents are chosen properly. It is possible to specify these chiral centers separately, but their chiralities can also be so interlinked that they collectively produce one pair of enantiomers with only one chiral center. Usually it is more convenient to collectively specify the chirality with reference to a center of chirality taken as the unoccupied centroid of the adamantane frame. 

To obtain VRCI for molecules containing more than one chiral center, the root mean square of VRCI for all the chiral centers is taken. 

Since the commercial introduction of the P-CAC in 1999, several industrial applications have been shown to be transferable to the system. Moreover, users in the biopharmaceutical and foodstuff industry have seen their productivity increasing dramatically as a result of using the P-CAC technology. Furthermore, a P-CAC has been shown capable of continuously separating stereoisomers when using chiral stationary phases even when there is more than one chiral center in the desired molecule. Below some of the applications are described in more details. Others are proprietary and hence cannot be disclosed. 

The reaction appears to be general and the additions are regiospecific and stereoselective. The product from the reaction with 2-propanol has been used for the synthesis of cis-chrysanthemic acid,8 and the product with methanol has been used for the construction of novel 2, 3 -dideoxy-3 -hydroxymethylnucleosides.9 In addition, ethane-1,2-diol provides the expected photoadduct as a 1 1 mixture of the two possible diastereoisomers, and these can be easily separated as their acetonides, to provide compounds with three contiguous chiral centers emanating from furan-ones with only one chiral center.9 More recently, we have shown that photoinduced-... 

From the examples cited above, it is evident that a great deal of research remains to be done on the chiral-amine-catalyzed Michael reaction. All mechanistic proposals have been based solely on knowledge of the absolute configuration of the products, while kinetic data as well as steric factors have not been carefully delineated. Since the research thus far has been restricted entirely to products in which just one chiral center is formed, it is clear that there is no lack of problems to be studied. 

It is worth mentioning that the extent of asymmetric induction in the sulfinate synthesis is comparable with that observed in the reaction of sulfinyl chlorides with optically active alcohols. However, in this case, the sulfinate products contain only one chiral center on sulfur the chiral-inducing amine is very easily recovered as the hydrochloride. 

The two molecules are enantiomers. If two of four groups attached to the C are identical as in CH3CH2CO2H, the 2 H s are enantiotopic and are attached to a prochiral center. Replacement of one of the H s by OH obviously leads to enantiomers. If there is already one chiral center in the molecule, as in (R)-malic acid... 

Recently, CE has been developed for the analysis of drug substances. It is not employed with great frequency for quality control (owing to inherent sensitivity issues), but on occasion, CE procedures can be employed when HPLC procedures have failed to adequately measure the impurities. CE is particularly useful for the separation of closely related compounds such as the diastereomers and enantiomers of compounds with more than one chiral center. Figure 1.8 illustrates the separation of the diastereomers quinine (QN) and quinidine (QD) and some impurities using CE [17]. 

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