Reactions That Create a Chirality Center

We will explore the use of the ruthenium BINAP catalysts in the synthesis of chiral drugs in Section 14.12. 

Many of the reactions we ve already encountered can yield a chiral product from an achiral starting material. Epoxidation of propene, for example, creates a chirality center by adding oxygen to the double bond. 

In this, as in other reactions in which achiral reactants yield chiral products, the product is formed as a racemic mixture and is optically inactive. Remember, for a substance to be optically active, not only must it be chiral but one enantiomer must be present in excess of the other. 

It is a general principle that optically active products cannot be formed from an optically inactive starting material unless at least one optically active reactant or catalyst is present. This principle holds irrespective of whether the addition is syn or anti, concerted or stepwise. No matter how many steps are involved in a reaction, if the reactants are achiral, formation of one enantiomer is just as likely as the other, and a racemic mixture results. 

Epoxidation of propene produces equai amounts of (/ )- and (S)-l,2-epoxypropane. 

In a second example, addition of hydrogen bromide converts 2-butene, which is achiral, to 2-bromobutane, which is chiral. But, as before, the product is racemic because both enantiomers are formed at equal rates. This is true regardless of whether the starting alkene is cis- or trans-2-hvXtnt or whether the mechanism is electrophilic addition or free-radical addition of HBr. 

Whatever happens at one enantiotopic face of the double bond of cis- or trans-2-butene happens at the same rate at the other, resulting in a 1 1 mixture of (R)- and (5)-2-bromobutane. 

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The Fe(CO)3 frmctionahty acts as a stericaUy bulky substituent attached to the planar diene. Reactions that create a new chiral center adjacent to the diene may occur in a diastereoselective fashion owing to approach of reagents to the complex on the side opposite to the iron center. For example, nucleophilic attack on a carbonyl at C-1 (such as 238) to afford complexed dienols (244) proceeds with high diastereoselectivity for ketones, and with lesser... 

The L amino acids in proteins, the D carbohydrates, the nucleic acids, aU are found to be homochiral, as observed as a single enantiomer. When the opposite enantiomers are found in biology, they are used for different functions, such as the D amino acids in some bacterial cell walls. Ordinary chemical reactions that create a new chiral center from optically inactive precursors normally produce a racemic mixture unless some chiral catalyst is present to direct the process. How did it get started before chiral catalysts such as enzymes were present ... 

The addition of OH at the olefinic center creates a chiral center at carbon in conjunction with the chiral center at cobalt. Two diastereoisomers are thereby produced. Addition of the bound OH is very rapid for the maleato system and essentially pH independent between pH 8-10. In this range the diastereoisomer ratio is 2 1 as shown below. However, at higher pH values the rate becomes first order in OH- and in 0.1 M NaOH at 25 the half-life for the production of malate is 3 sec (at least 106-fold faster than the uncoordinated hydration). Under these conditions the reaction becomes much more stereospecific with a 9 1 ratio of diastereoisomers. While it is clear that in the pH independent region, H+ addition at the 8 carbon atom is the rate-determining step, it looks as if in the high base region deprotonation of the CoOH entity and addition of Co-0 could be rate-determining. 

Any reaction that creates a new bond to an achiral carbon has the potential to create a new chiral center if that carbon has a tetrahedral geometry in the product. Examples in which the starting carbon was also tetrahedral include free-radical halogenation (replace H- with X-) and a-alkylation of an enolate... 

Asymmetric synthesis has achieved a position as one of the most important areas of modem organic chemistry. Dnring the past 20 years the number of publications in this area has been vast. On the pallet of organic reactions that are used in asymmetric synthesis, cycloadditions possess a prominent position, since they are some of the most efficient methods for creating new chiral centers with control of stereochemistry (1-4). The ability to introduce more than one new chiral center in a single step with control of both relative and absolute stereochemistry makes cycloaddition reactions highly attractive key reactions for stereoselective synthesis. 

Any structural feature of a molecule that gives rise to optical activity may be called a chiral center. In many reactions a new chiral center is created, e.g.,... 

This obviously is unlikely for the given example because there is no reason for cyanide ion to have anything other than an exactly equal chance of attacking above or below the plane of the ethanal molecule, producing equal numbers of molecules of the enantiomers, 21 and 22. However, when a chiral center is created through reaction with a dissymmetric (chiral) reagent, we should not expect an exactly 1 1 mixture of the two possible isomers. For example, in an aldol-type addition (Section 18-8E) of a chiral ester to a pro-chiral ketone the two configurations at the new chiral center in the products 23 and 24 are not equally favored. That is to say, asymmetric synthesis is achieved by the influence of one chiral center (R ) on the development of the second ... 

As described in this chapter, there are many reactions that can be performed by chemists to create new chiral centers. When these reactions are performed in such a way as to create one enantiomer in greater amounts than the other the process is called asymmetric or stereoselective synthesis. The term en-antioselectivity refers to the efficiency with which the reaction produces one enantiomer. This efficiency is quantitatively described as the enantiomeric excess (ee) of the product, which is the percentage by which one enantiomer is produced in excess of the other. Thus a 45 8 mixture of two enantiomers will have an enantiomeric excess of [(45 - 8)/(45 + 8)] X 100, which equals 70%. It should be noted that if neither the startingmaterial or reaction system is chiral and non-racemic, then the product will be formed as an equal mixture of the enantiomers (i.e., a racemate). 

EXAMPLE As an example of a molecular inversion, in a T order nucleophilic substitution (SnI reaction) the chirahty of a carbon can be flipped from S to R configuration (or vice versa) 50% of the time. This is due to the chiral carbon having only sp hybridization of its electrons in the intermediate state, which creates a carbon center that is flat and thus subject to nucleophilic attack from either the top or the bottom. If inversion occurs then it is considered to be proof that the reaction indeed is SnI and therefore has an intermediate molecule in its transition state. 

As the structure of an organic compound is altered in the course of a reaction, one or more chiral centers, usually at carbon, may be created, inverted, or destroyed. In Section 6.7A, we consider two alkene addition reactions in which a chiral molecule is created in an achiral environment. In doing so, we will illustrate the point that an optically active compound (i.e., an enantiomerically pure compound or even an enantiomerically enriched compound) can never be produced from achiral starting materials reacting in an achiral environment. Then in Section 6.7B, we consider the reaction of achiral starting materials reacting in a chiral environment—in this case in the presence of a chiral catalyst. We shall see that an enantiomerically pure product may be produced from achiral reagents if the reaction takes place in a chiral environment. 

A remarkable feature of this reaction is that it creates three chiral centers. Two of the chiral centers, namely those at the two ring junctions, are established by the Diels-Alder reaction. The third, namely the endo position of the ester group, is also established by the Diels-Alder reaction. Without the chiral auxiliary 8-phenylmenthyl group, two of the eight possible stereoisomers would be produced, namely the pair of enantiomers shown. Although both enantiomers of the bicyclic products were formed in Corey s scheme, they were formed in the ratio of 97 3 and the desired enantiomer could be separated in pure form. In subsequent steps, the 8-phenylmenthyl ester was hydrolyzed and the pure enantiomer was converted to the so-called Corey lactone and then to enantiometically pure prostaglandin... 

Substrate induction Here the substrate already contains a chiral center so that this creates uneven diastereotopic halves. The reaction proceeds via diasteromeric intermediates with different energies. The product resulting from the diastereo-meric intermediate with the lowest energy is IdneticaHy favored. 

Similar observations show that one enantiomer reacts with an achiral reagent to give unequal amounts of diastereomeric products. The relative yields of the diastereomers often depend on the structure of the existing stereogenic center and its proximity to the newly formed stereogenic center. Many stereogenic centers are present in an enzyme catalyst. They create a chiral environment, which leads to high stereoselectivity. Usually, only one diastereomer forms in enzyme-catalyzed reactions. 

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