Stereochemistry that produce chiral molecules

Most of the biochemical reactions that take place in the body and many organic reactions in the laboratory yield products with chirality centers. For example, addition of HBr to 1-butene yields 2-bromobutane, a chiral molecule. What predictions can we make about the stereochemistry of this chiral product If a single enantiomer is formed, is it R or S If a mixture of enantiomers is formed, how much of each In fact, the 2-bromobutane produced is a racemic mixture of R and S enantiomers. Let s see why. 

We now wish to consider how these elements of stereochemistry come into play in synthesis. It is important to know how reaction stereochemistry is controlled by structural features of the reactant molecules. This topic can be broadly covered by the term asymmetric synthesis, which has been defined as 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 stereoisomeric products are produced in unequal amounts. Thus, we will be dealing with methods for controlling the configuration of newly formed chiral centers. As will be seen, these methods often depend on the fact that reagents attack molecules along the less hindered path. 

The Diels-Alder reaction has high stereoselectivity. One way to create enantiomeri-cally pure target molecules is to use a chiral auxiliary, which is a chiral molecule available as a single enantiomer that is bonded to the starting material. The use of a chiral auxiliaiy can influence the resulting stereochemistry of a Diels-Alder reaction, producing a desired enantiomer in excess. The chiral auxiliary is then removed. 

Hydrolysis of aspartame hydrolyzes both the amide group and the ester group in the molecule. Hydrolysis of the ester group produces methanol and the carboxylic acid group in phenylalanine, shown below. Hydrolysis of the amide group converts this group to an amine (shown below on phenylalanine) and a carboxylic acid (on the left side of aspartic acid below). Note that the stereochemistry at both chirality centers is retained because none of the bonds to the chirality centers are broken in this transformation. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Another chemical property relevant to druglike behavior is stereochemistry. These are molecules that contain a chiral center (a carbon with four different attachments) causing molecules with different chiral centers to be non-superimposable. These molecules present different three-dimensional arrays to proteins, and it is presumed that this controls biological potency and efficacy. For instance, the Easson-Stedman hypothesis proposes that a biologically active enantiomer interacts with at least three points on receptor to produce biological activity. Since three points... 

As the number of stereocenters in a molecule increases, the number of possible diastereomers increases. A molecule with four dissimilar stereocenters, for example, can exist as one of sixteen stereoisomers. Of these sixteen stereoisomers there are four pairs of enantiomers, and the remaining four pairs are diastereomers. Molecules with configurational diastereomers also arise from many systems other than those with stereocenters. One of the most common examples is a double bond that is substituted in such a way that diastereomers exist. Any combination of two or more molecular features that give rise to stereoisomers will always produce diastereomers, whereas sources of chirality are needed to produce enantiomers. Because stereochemistry can have a high impact on molecular properties, diastereomers generally have easily discernable differences in their physical and chemical behaviors. Some molecules possess greater than or equal to two tetrahedral stereocenters and are nonetheless achiral. These are called meso stereoisomers. These occur when the internal symmetry of the molecule makes it superimposable on its mirror image. 

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