Chirality prochirality

M. Bhupathy, J. L. Leazer J. M. McNamara, D. R. Sidler P. J. Reider, and E. J. J. Grabowski, lipase-catalyzed asymmetric hydrolysis of esters having remote chiral/prochiral centers,/. Org. Chem. 1990, 55, 6252-6259. 

At first glance inositol appears to be a relatively simple molecule - on closer examination, a host of sophisticated stereochemical issues, chiral, prochiral, and conformational reveal themselves (Parthasarathy and Eisenberg, 1986, 1990 Postemak, 1965). In fact, the complexity of stereochemical issues in cyclitols, namely cyclohexanes with one hydroxyl group on three or more ring atoms, is well recognized (IUPAC, 1976 Postemak, 1965) inositol can serve as a good model for a sophisticated discussion of various forms of isomerism. 

Reactions of Chiral Prochiral Dialkoxysilanes with Ethyllithium (86)... 

TABLE 7. Reactions of chiral prochiral dialkoxysilanes with ethyllithium (after Reference 55)... 

The desymmetrization of some prochiral dithioacetal esters possessing up to five bonds between the prochiral center and the ester carbonyl - the site of reaction -proceeded with high selectivity using PSL [454], This example of a highly selective chiral recognition of a remote chiral/prochiral center is not unusual amongst hydrolytic enzymes [455 57]. 

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

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). 

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 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... 

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...

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. 

Chiral Alcohols and Lactones. HLAT) has been widely used for stereoselective oxidations of a variety of prochiral diols to lactones on a preparative scale. In most cases pro-(3) hydroxyl is oxidized irrespective of the substituents. The method is apphcable among others to tit-1,2-bis(hydroxymethyl) derivatives of cyclopropane, cyclobutane, cyclohexane, and cyclohexene. Resulting y-lactones are isolated in 68—90% yields and of 100% (164,165). 

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

The two protons at C-1 are topologically nonequivalent, since substitution of one produces a product tiiat is stereochemically distinct fiom that produced by substitution of the other. Ligands of this type are termed heterotopic, and, because the products of substitution are enantiomers, the more precise term enantiotopic also applies. If a chiral assembly is generated when a particular ligand is replaced by a new ligand, the original assembly is prochiral. Both C-1 and C-3 of 1,3-propanediol are prochiral centers. 

The enzyme-catalyzed interconversion of acetaldehyde and ethanol serves to illustrate a second important feature of prochiral relationships, that ofprochiral faces. Addition of a fourth ligand, different from the three already present, to the carbonyl carbon of acetaldehyde will produce a chiral molecule. The original molecule presents to the approaching reagent two faces which bear a mirror-image relationship to one another and are therefore enantiotopic. The two faces may be classified as re (from rectus) or si (from sinister), according to the sequence rule. If the substituents viewed from a particular face appear clockwise in order of decreasing priority, then that face is re if coimter-clockwise, then si. The re and si faces of acetaldehyde are shown below. 

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

Chiral chemical reagents can react with prochiral centers in achiral substances to give partially or completely enantiomerically pure product. An example of such processes is the preparation of enantiomerically enriched sulfoxides from achiral sulfides with the use of chiral oxidant. The reagent must preferential react with one of the two prochiral faces of the sulfide, that is, the enantiotopic electron pairs. 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

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