Prochirality centre

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). 

Some confusion can arise over use of the term prochiral to describe various sites within molecules and is perhaps best avoided for this reason. The term means literally, one step removed from being chiral (i.e., swap one of the protons for Z and you have a full chiral centre). The methylene in ethanol for example, would be a good example. What we have in the di-ethoxy molecule above is one prochiral centre acting in combination with another to render a pair of protons non-equivalent. 

Figure 12.7 Specific attachment of a prochiral centre to an enzyme-binding site enables the enzyme to distinguish between prochiral methylene protons in ethanol. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

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... 

NADH delivers hydride from a prochiral centre NAD has enantiotopic faces... 

During the reduction sequence, NADH transfers a hydride from a prochiral centre on the dihydropyridine ring, and is itself oxidized to NAD+ (nicotinamide adenine dinucleotide) that contains a planar pyridinium ring. In the oxidation sequence, NAD+ is reduced to NADH by acquiring hydride to an enantiotopic face of the planar ring. The reactions are completely stereospecific. 

Note also that transfer of hydride to the carbonyl compound is also stereospecific, as is removal of hydrogen from the prochiral centre of ethanol in the reverse reaction (see Section 3.4.7). 

Relatively few studies have been made of the isomer ratio obtained by reduction of open chain ketones possessing a prochiral centre adjacent to tlic carbonyl fimc-... 

The metabolism of ethylbenzene in humans occurs along one major pathway which is oxidation at the a-carbon, yielding 1-phenylethanol (also called a-methylbenzyl alcohol) as the primary product. A metabolic scheme is presented in Figure 1. The a-carbon of ethylbenzene is a prochiral centre and hydroxylation thus yields a chiral product. The issue of stereoselectivity has been addressed in animal studies (see Section 4.1.2). 

It must be pointed out than, in the case of phosphonium salts in which the phosphorus atom is a prochiral centre, attempted alkaline hydrolyses with asymmetric induction... 

The first example of absolute chiral recognition of a prochiral centre by a small molecule (cf. enzyme reactions) is the reaction of A( — )436-oc[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(m)]dichloride with a,a-aminomethylmalonate, which produces A( — )436-P2[(2S,9S)-2,9-diamino-4,7-diazadecanecobalt(in)-(R)-aminomethyl-malonate]+,401 and a crystal structure determination of the product has been performed.402... 

RDCs are commonly used for the structure elucidation of proteins and nucleic acids nowadays. Only recently the approach was transferred back to also obtain structural information of small- to medium-sized organic molecules. The central application in this case is the determination of relative configurations of distant chiral and prochiral centres, and also conformational studies of biologically active molecules, for example the enantiomeric differentiation of small molecules in chiral alignment media can be achieved. 

Label the hydrogen atoms at the prochirality centres in the following formulae with pro-R or pro-S. 

There are two prochirality centres in butanone at carbon atoms 2 and 3. 

A reaction forming enamine adducts between nitroalkenes and enamines takes place with excellent diastereoselectivity572,573 and enantioselectivity. Seebach and coworkers574-577 have proposed a topological rule for the carbon-carbon bond-forming process between prochiral centres in enamines and nitroalkenes. This reaction is very important in the synthesis of enantiomerically pure organic compounds. 

Reactions of nitroalkenes and enamines take place not only in good chemical yields but also in excellent diastereomeric yields (>90%)118. A topological rule has been formulated for carbon-carbon bond-forming processes between prochiral centres in enamines and nitroalkenes as well as other systems119. 

The asymmetric reduction of carbonyl groups to form enantiopure secondary alcohols is a reaction of fundamental importance in modern synthetic chemistry. The carbonyl group is prochiral centre (if different groups are attached to carbonyl carbon) and can be attacked by hydride from re or si face to generate a racemic product if there are no additional chiral centres in the molecule. 

R,S)- descriptors can be assigned to prochiral centres in more symmetrical molecules by a simple extension of the sequence rule. For example, in 1,3-cyclobutanediol the OH group at each centre has priority 1 and the H atom priority 4. 

Until recently, the preparation of the bicyclic ene-diones (47a,b), which are important intermediates in steroid total synthesis, has led only to racemic mixtures This deficiency has now been met as follows. Michael addition of the vinyl ketone (44) to the cyclic diketones (45a) and (45b) afforded the triketo-intermediates (46a) and (46b) in high yield, each containing a prochiral centre. Optically active amines and amino-acids were used as chiral reagents to... 

Therefore, an sp2 hybridized carbon bonded to three different groups will become chiral as the result of an addition reaction (which may also be a reduction) that results in formation of a bond between the sp2 hybridized carbon and a fourth group that differs from the other three. Such sp2 hybridized carbons are called prochiral. This raises an interesting point of nomenclature. A chiral molecule that has four different groups attached to a carbon atom is said to have a stereogenic centre, this term being preferred to chiral centre . However, a prochiral molecule is said to have a prochiral centre the term pro-stereogenic , preferred by Helmchen,2 is not yet widely adopted. 

The approach exploiting a chiral centre that is already in the synthon is effective in a number of cases. The chiral moiety in the synthon diverts a reaction at a nearby prochiral centre in favour of one enantiomer (asymmetric induction). An excellent example of the latter is the Schollkopf method (4 in Scheme 6.3, see also 5 in Scheme 6.7) hydrogenation of azlactones (3 in Scheme 6.3) using a homogeneous chiral catalyst is one route illustrating the former approach. Use of chiral five-membered heterocyclic compounds (e.g., 6 and 7) offers an alternative successful approach to asymmetric amino-acid synthesis. 

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