Prochirality

Closely related to the concept of chirality, and particularly important in biological chemistry, is the notion of prochirality. A molecule is said to be prochiral if it can be converted from achiral to chiral in a single chemical step. For instance, an unsymmetrical ketone like 2-butanone is prochiral because it can be converted to the chiral alcohol 2-butanol by addition of hydrogen, as we ll see in Section 17.4. 

In addition to compounds with planar, sp -hybridized atoms, compoimds with tetrahedral, sp -hybridized atoms can also be prochiral. An sp -hybridized atom is said to be a prochirality center if, by changing one of its attached groups, it becomes a chirality center. The -CH2OH carbon atom of ethanol, for instance, is a prochirality center because changing one of its attached H atoms converts it into a chirality center. 

A large number of biological reactions involve prochiral compounds. One of the steps in the citric acid cycle by which food is metabolized, for instance, is the addition of H2O to fumarate to give malate. Addition of OH occurs on the Si face of a fumarate carbon and gives (S)-malate as product. 

As another example, studies with deuterium-labeled substrates have shown that the reaction of ethanol with the coenzyme nicotinamide adenine dinucleotide (NAD+) catalyzed by yeast alcohol dehydrogenase occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the RefaceofNAD+. 

Determining the stereochemistry of reactions at prochirality centers is a powerful method for studying detailed mechanisms in biochemical reactions. 

Molecules that are superimposable on their mirror images are achiral 

We can thus deduce that alcohol dehydrogenase stereospecifically removes the pro-R hydrogen from the prochiral methylene. 

This example is from biochemistry. It is a feature of biochemical reactions that enzymes almost always catalyse reactions in a completely stereospecific manner. They are able to distinguish between enantiotopic hydrogens because of the three-dimensional nature of the binding site (see Section 13.3.2). There are also occasions where chemical reactions are stereospecific refer to the stereochemistry of E2 eliminations for typical examples (see Section 6.4.1). 

Citric acid has three prochiral centres The Krebs cycle is a process involved in the metabolic degradation of carbohydrate (see Section 15.3). It is also called the ciU ic acid cycle, because citric acid was one of the first intermediates identified. Once formed, citric acid is modified by the enzyme aconitase through the intermediate 

This is followed by an anti addition reaction in which water is added to the new double bond, but in the reverse sense. The hydrogen retained throughout the process is shown with an asterisk. Note that we 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

A large number of biological reactions involve prochiral compounds. One of the steps in the citric acid cycle by which food is metabolized, for instance, is 

In the transformations shown in Equations 19-5 and 19-6, the organic reactants are symmetrical molecules (with no chiral centers), but the products are asymmetric molecules (each has a chiral carbon)  

There is a special term for molecules that are achiral but which can be converted to molecules with chiral centers by a single chemical substitution or addition reaction. They are said to be prochiral. 

By this definition, ethanol is a prochiral molecule. The two methylene hydrogens are enantiotopic (Section 9-10C) and substituting each separately (with, say, one deuterium) leads to a pair of enantiomers  

Prochiral molecules can be distinguished readily from more symmetrical molecules because they lack a two-fold symmetry axis passing through the prochiral center, as the following rotations show  

Organic chemists have not had much use for prochirality, but it is an important concept for biochemists following the stereochemistry of bio-organic reactions. Almost all biochemical reactions are under the control of enzymes, which function asymmetrically even on symmetrical (but prochiral) molecules. Thus it has been found that only one of the two methylene groups of 

At the very start of Chapter 17, we introduced stereochemistry by thinking about the reactions of two sorts of carbonyl compounds. They are shown again here the first has a prochiral carbonyl group. The second, on the other hand, is not prochiral because no stereo genic centre is created when the compound reacts. 

Tetrahedral carbon atoms can be prochiral too—if they carry two identical groups (and so are not a chiral centre) but replacement of one of them leads to a new chiral centre, then the carbon is prochiral. 

Glycine is the only a amino acid without a chiral centre, but replacing one of the two protons on the central carbon with, say, deuterium creates one the CH2 carbon is prochiral. Similarly, converting malonate derivate into its monoesler makes a chiral centre where there was none the central C is prochiral.  

does this ring any bells It should remind you very much of the definitions in Chapter 32 of H enantiotopic and diastereotopic in connection with NMR spectra. Replacing one of two enantiotopic Enantiotopic and diastereotopic groups with another group leads to one of two enantiomers replacing one of two diastereotopic chapter 32 pr 837 dl9CU9sed in 

Exactly the same things are true for the faces of a prochiral carbonyl group or double bond. 

Divalent sullur compounds are achiral, but trivalent sulfur com ounds called sulfonhim salts can be chiral. Like phosphines, sulfonium salts 

Enantiotopic and diastereotopic protons and groups are discussed in Chapter 32, p. 837. 

Knowing this throws some new light on the last chapter. Almost without exception, every stereoselective reaction there involved a double bond (usually C=C sometimes C=0) with diastereotopic 

Consider two chemical changes one occurring at a tetrahedral sp carbon C(jc,jc,y,z), the other at a trigonal sp carbon C(x,y,z), where x, and z are different atoms or groups attached to C. Each reactant is achiral both are converted to the chiral product C(w,x,j,z). In the first case w replaces one of the x atoms or groups, in the other w adds to the trigonal carbon. 

Both transformations convert C in each achiral reactant to a chirality center in the product. The two achiral reactants are classified as prochiral. C is a prochirality center in C(x,x,y,z) and has two prochiral faces in C(x,y,z). 

In achiral molecules with tetrahedral prochirality centers, substitution of one of the two x groups by w gives the enantiomer of the product that results from substitution of the other. The two X groups occupy mirror-images sites and are enantiotopic. 

Citric acid played a major role in the development of the concept of prochirality. Its two CH2CO2H chains groups behave differently in a key step of the Krebs cycle, so differently that some wondered whether citric acid itself were really involved. Alexander Ogston (Oxford) provided the answer in 1948 when he pointed out that the two CH2CO2H groups are differentiated when citric acid interacts with the chiral environment of an enzyme. 

The two prochiral faces of a trigonal atom C(x,y,z) are enantiotopic and designated Re and Si according to whether x, y, and z trace a clockwise Re) or counterclockwise Si) path in order of decreasing Cahn-Ingold-Prelog precedence. An acetaldehyde molecule that lies in the plane of the paper, for example, presents either the Re or Si face according to how it is oriented. 

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Chiral aluminium hydride for the asymmetric reduction of prochiral ketones... 

Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective,... 

A highly diastereoselective alkcnylation of c/s-4-cyclopentene-l,3>diols has been achieved with 0-protected (Z)-l-iodo-l-octen-3-ols and palladium catalyst (S. Torii, 1989). The ( )-isomers yielded 1 1 mixtures of diastcrcomcric products. The (Z)-alkenylpalladium intermediate is thought to undergo sy/i-addition to the less crowded face of the prochiral cyclopentene followed by syn-elimination of a hydropalladium intermediate. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Achiral molecules which can be converted to chiral molecules by the chemical change of one atom — substitution on an sp -atom or addition on an sp -atom — are called prochiral molecules (Y. Izumi, 1977). The atom involved is a prochiral centre. Pairs of atorns or groups... 

Analogous definitions and designations apply to molecules containing a chiral centre and a prochiral tetrahedral or trigonal centre. The plane containing the chiral and prochiral centres is called a diastereo-zeroplane (Y. Izumi, 1977). 

The prochiral meso form of 2-cyclopenlen-1,4-diol (101) reacts with the (Z)-alkenyl iodide 102 to give the 3-substituted cyclopentanone 103 with nearly complete diastereoselectivity (98 2)[92], The reaction is used for the synthesis of prostaglandin. The alkenyl iodide 102 must be in the Z form in order to obtain the high diastereoselectivity. The selectivity is low when the corresponding (Z)-alkenyl iodide is used[93]. 

In this example addition to the double bond of an alkene converted an achiral mol ecule to a chiral one The general term for a structural feature the alteration of which introduces a chirality center m a molecule is prochiral A chirality center is introduced when the double bond of propene reacts with a peroxy acid The double bond is a prochi ral structural unit and we speak of the top and bottom faces of the double bond as prochiral faces Because attack at one prochiral face gives the enantiomer of the com pound formed by attack at the other face we classify the relationship between the two faces as enantiotopic... 

The pro in prochiral means before or in advance of in roughly the same way as in proactive... 

We can view this reaction as the replacement of one or the other of the two methylene protons at C 2 of butane These protons are prochiral atoms and as the red and blue protons m the Newman projection indicate occupy mirror image environments... 

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... 

FIGURE 17 14 (a) Binding sites of enzyme discriminate between prochiral faces of substrate One prochiral face can bind to the enzyme better than the other (b) Reaction attaches fourth group to substrate producing only one enantiomer of chiral product... 

Prochiral (Section 7 9) The capacity of an achiral molecule to become chiral by replacement of an existing atom or group by a different one... 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

Asymmetric Hydroboration. Hydroboration—oxidation of (Z)-2-butene with diisopinocampheylborane was the first highly enantioselective asymmetric synthesis (496) the product was R(—)2-butanol in 87% ee. Since then several asymmetric hydroborating agents have been developed. Enantioselectivity in the hydroboration of significant classes of prochiral alkenes with representative asymmetric hydroborating agents is shown in Table 3. 

Table 3. Enantioselectivity in the Hydroboration of Prochiral Alkenes with Various Hydroborating Agents ...

An efficient general synthesis of a-chiral (Z)- and (H)-a1kenes ia high enantiomeric purity is based on the hydroboration of alkynes and 1-bromoaIkynes, respectively, with enantiomericaHy pure IpcR BH readily available by the hydroboration of prochiral alkenes with monoisopiaocampheylborane, followed by crystallization (519). 

In the earlier, longer approach to (Z)-and (E)-alkenes, ThxR BH was used iastead of IpcR BH. It is also possible to prepare a-chiral acetylenes and alkanes by this method (76,520). In a shorter synthesis of a-chiral alkynes, a prochiral disubstituted (Z)-a1kene is hydroborated with... 

Efficient enantioselective asymmetric hydrogenation of prochiral ketones and olefins has been accompHshed under mild reaction conditions at low (0.01— 0.001 mol %) catalyst concentrations using rhodium catalysts containing chiral ligands (140,141). Practical synthesis of several optically active natural... 

The strategy of the catalyst development was to use a rhodium complex similar to those of the Wilkinson hydrogenation but containing bulky chiral ligands in an attempt to direct the stereochemistry of the catalytic reaction to favor the desired L isomer of the product (17). Active and stereoselective catalysts have been found and used in commercial practice, although there is now a more economical route to L-dopa than through hydrogenation of the prochiral precursor. 

Fig. 4. Schematic representation of energy profiles for the pathways for the hydrogenation of a prochiral precursor to make L-dopa (19). The chiral...

The situation is different if the substrate is a prochiral or meso compound. Since these molecules have a center or plane of symmetry the binding of pro-S or pro-R forms is equivalent. The chirahty appears only as a result of the transformation. Hence, at least theoretically, the compound can be converted to one enantiomer quantitatively. 

It is generally beheved that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens Hpase (PEL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

Mono cylDiols. Enzymatic synthesis of chiral monoacyl diols can be carried out either by direct enzymatic acylation of prochiral diols or by hydrolysis of chemically synthesized dicarboxylates. 

A number of examples of monoacylated diols produced by enzymatic hydrolysis of prochiral carboxylates are presented in Table 3. PLE-catalyzed conversions of acycHc diesters strongly depend on the stmcture of the substituent and are usually poor for alkyl derivatives. Lipases are much less sensitive to the stmcture of the side chain the yields and selectivity of the hydrolysis of both alkyl (26) and aryl (24) derivatives are similar. The enzyme selectivity depends not only on the stmcture of the alcohol, but also on the nature of the acyl moiety (48). 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

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