Prochiral molecules

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... 

Figure 9.18 (a) When a prochiral molecule is held in a chiral environment, the two seemingly identical substituents (red) are distinguishable, (b) Similarly, when an achiral coffee mug is held in the chiral environment of your hand, it s much easier to drink from one side than the other because the two sides of the mug are now distinguishable. 

Of further particular interest was that the crystallographic results on 2,5-DSP and poly-2,5-DSP had pointed out a very important future possibility that an absolute asymmetric synthesis could be achieved if any prochiral molecule, e.g. an unsymmetrical diolefin derivative, could be crystallized into a chiral crystal and if the reaction of the chiral crystal proceeded in the same manner as the 2,5-DSP crystal with retention of the crystal lattice (Wegner, 1972, 1973). Such types of absolute asymmetric synthesis with a high enantiomeric yield have now been performed by topochemical [2+2] photoreaction of unsymmetric diolefin crystals (Addadi etal., 1982 Hasegawa et al., 1990 Chung et al., 1991a,b). 

Prochiral Molecules Interacting with Chiral Surfaces... 

A. G. Ogston in 1948 explained the dilemma of how an enzyme can enan-tiospecifically produce a chiral product from a prochiral molecule such as citric acid or 2-aminomalonic acid. He pointed out two requirements three-point contact at three active sites (a, b, and c ) and catalytic dissimilarity between the two active sites (a and b ) associated with the pro-R and pro-5 groups (a and b) of the prochiral molecule as shown in Fig. 3.2. 

The quest for more economic and greener routes has triggered a lot of developments in reductive asymmetric synthesis tools based on prochiral molecules during the past two decades. Very powerful hydrogenation tools have been developed, for which William S. Knowles and Ryoji Nyori received the 2001 Noble Prize in Chemistry [30]. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

The so-modified catalysts were tested in the enantioselective hydrogenation of prochiral molecules containing C=C bonds. 

We should note that prochiral molecules have the potential to become chiral if we make certain changes, and we have used the term enantiotopic to identify the groups at -hybridized carbon or the faces of sp -hybridized carbon where alternative changes lead to the... 

Terms containing prochiral, such as prochiral unit or element, prochiral molecule or prochi-rality, must be abandoned. Perhaps in order to ridicule the pro-terminology", it was recently extended with terms such as pro-pro (CH3COOH), pro-pro-pro-stereogenic (CH4), and even pro-chirotopic6. There is but one comment - protest ... 

Asymmetric synthesis is a term first used in 1894 by E. Fischer and defined4 in 1904 by W. Markwald as a reaction which produces optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . A modem definition was proposed 5) by Morrison and Mosher An asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereosiomeric products (enantiomeric or diastereomeric) are formed in unequal amounts. This is to say, an asymmetric synthesis is a process which converts a prochiral6) unit into a chiral unit so that unequal amounts of stereoisomeric products result . When a prochiral molecule... 

If equivalent or catalytic amounts of a chiral molecule (5) react with a prochiral molecule (6) — the complex (5) (6) is formed as an intermediate — to give the new chiral compounds (9a) and/or (9b), one speaks of an enantioselective reaction [Eq. (d)]. The enantioselectivity of such a reaction is given by the enantiomeric excess (ee) or by the optical yield ... 

Stereochemical numbering. In some prochiral molecules, such as glycerol, the two ends of the main carbon chain form identical groups. Since the two ends are distinguishable to an enzyme, it is important to decide which should be labeled C-l and which C-3. Hirschmann proposed a stereochemical numbering system100 in which the carbons are numbered beginning with the end of the chain that occupies the pro-S position. 

Stereochemical numbering for a symmetric prochiral molecule. Carbons are numbered beginning with the end of the chain that occupies the pro-S position. 

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... 

Prochiral molecule. A nonchiral molecule that may react with an enzyme so that two groups that have a mirror image relationship to each other are treated differently. 

The molecule in Figure I is an example of a prochiral molecule. The asymmetrical enzyme binds only to hydrogen a and not to hydrogen b due to the spatial arrangement of its active site with respect to the other substituents on the prochiral carbon. All known dehydrogenases are stereospecific in this manner. 

An alternative concept is asymmetric desymmetrization of a prochiral molecule of type 83. The starting materials 83 have three keto groups and one carbon atom bearing at least three substituents. A prerequisite is the presence of a prochiral carbon atom with two identical substituents bearing a keto functionality (Scheme 6.39, Eq. (2)). This type of asymmetric intramolecular aldol reaction proceeds with formation of cyclic ketols of type 84 with two stereogenic centers. Dehydration can subsequently be performed, leading to optically active enones of type 85. The two types of intramolecular aldol reaction are shown conceptually in Scheme 6.39. 

Enzymes often prove to be the catalyst of choice for numerous transformations, and their prowess is particularly noteworthy for the synthesis of chiral molecules. The ability of biocatalysts to impart chirality through conversion of prochiral molecules or by transformation of only one stereoisomer of a racemic mixture stems from the inherent chirality of enzymes. As noted in the introduction to this book (Chapter 1), the chiral drug market is increasing, partly as a result of the need to produce single enantiomers as advocated by the U.S. Food and Drag Administration.1 The ability to extend the patent life of a drug through a racemic switch also plays a role in this increase. An example of a racemic switch is Astra Zeneca s Esomeprazole, a proton pump inhibitor (see Chapter 31).2... 

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