Reactions That Create a Stereogenic Center

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 stereogenic center by addition of 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. 

FIGURE 7.7 Epoxidation of propene produces equal amounts of (/ )- and (S)-1,2-epoxypropane. 

It is often helpful, especially in a multistep reaction, to focus on the step that creates the stereogenic center. In the ionic addition of hydrogen bromide to 2-butene, for example, the stereogenic center is generated when bromide ion attacks iec-butyl cation. 

It is a general principle that optically active products cannot be formed when optically inactive substrates react with optically inactive reagents. 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. 

---

The invention and use of chirai auxiiiaries has been growing exponentiaiiy over the past 40 years, such that nowadays there are few if any reactions in which a stereogenic center is created that cannot be controiied by a stoichiometric chirai auxiiiary. indeed chirai auxiiiaries have moved on from mereiy controiiing the construction of singie or muitipie stereogenic centers to show great versatiiity in enantiodiscrimination (kinetic resoiution) and deracemization phenomena. 

The acyl addition reaction created a stereogenic center, but the experiment shows that alkyne-cdcohol 21 is racemic. Why If 17 approaches 19 from the top (path a), the oxygen is pushed down and one enantiomer is formed (S-21). If 17 approaches from the bottom (path b), however, the oxygen is pushed to the top and the opposite enantiomer is formed (i -21). Because there is nothing to bias one side from the other as 17 approaches 19, both enantiomers are formed in equal amounts. Therefore, a racemic mixture is formed (see Chapter 9, Section 9.2.4). Nucleophilic acyl addition to aldehydes or ketones is assumed to generate racemic alcohol products in the absence of any additional information. 

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

Any structural feature of a molecule that gives rise to optical activity may be called a stereogenic center (the older term is chiral center) In many reactions, a new chiral center is created, for example. 

Active Substrate. If a new chiral center is created in a molecule that is already optically active, the two diastereomers are not (except fortuitously) formed in equal amounts. The reason is that the direction of attack by the reagent is determined by the groups already there. For certain additions to the carbon-oxygen double bond of ketones containing an asymmetric a carbon. Cram s rule predicts which of two diastereomers will predominate (diastereoselectivity). The reaction of 46, which has a stereogenic center at the ot-carbon, and HCN can generate two possible diastereomers. 

The ability to interconvert one functional group into another is of fundamental importance in organic synthesis. Often, these interconversions involve reduction or oxidation of a functional group, and such transformations also may either create or destroy a stereogenic center. The first part of Section 12-1 will explore transition metal-catalyzed hydrogenations of C=C and C=0 bonds, which can exhibit a high degree of stereoselectivity. The second part will consider oxidation reactions that are also catalyzed by transition metal complexes, which can lead to enantioenriched products. 

Holmes et al. used another interesting pericyclic domino reaction in the synthesis of (-)-histrionico-toxine 116 (scheme 23).1631 In a not fully understood sequence 113 at 190 °C generates the cydoadduct 115 in 80% yidd with loss of styrene. It can be assumed that the process consists of a retro-13-dipolar and a 13-dipolar cydoaddition with the intermediary formation of the nitrone 114. Overall, three new stereogenic centers, necessary for the natural product, have been efficiently created. An... 

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant ot-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004,6,3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontroJ. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastcrcocontrol. 

For any one of the DHAP aldolases, the absolute configuration at the newly created stereocenter at C-3 is invariably conserved upon reaction with any electrophile, apparently for mechanistic reasons [199] no exceptions are known so far. For the stereogenic center at C-4, the relative positioning of the aldehyde carbonyl in the transition state, and thus the relative configuration in the product, usually follows closely that of the natural substrates. Depending on the nature of the enzyme used and on the pattern of substitution present in the aldehydic component, a distinct fraction of the 4-epimeric diastereomers may also be observed which is presumably the result of incorrect binding of the respective aldehyde (cf. Sect. 3.1). 

---