Stereochemical Principles

For most combinations of atoms, a number of molecular structures that differ from each other in the sequence of bonding of the atoms are possible. Each individual molecular assembly is called an isomer, and the constitution of a compound is the particular combination of bonds and sequence of atoms (molecular connectivity) which is characteristic of that structure. Propanal, allyl alcohol, acetone, 2-methyl-oxirane, and cyclopropanol each correspond to the molecular formula C3H6O but differ in constitution. 

The lUPAC rules and definitions for fundamental stereochemistry are given with examples in J. Org. Chem. 35, 2849 (1970) see also G. Krow, Top. Stereochem. 5, 31 (1969). 

One characteristic of chiral molecules is that the separated enantiomers cause the plane of polarized light to rotate by opposite but equal amounts. Samples that have an excess of one enantiomer over the other show a net rotation and are said to be optically active. Samples that contain only one of the enantiomers are said to be optically j)ure. Samples that have equal amounts of two enantiomers show zero net rotation and are called racemic mixtures. 

In addition to constitution and configuration, there is a third significant level of structure, that of conformation. Conformations are discrete molecular arrangements that differ in spatial arrangement as a result of facile rotations about single bonds. The subject of conformational interconversion will be discussed in detail in Chapter 3. A special case arises when rotation about single bonds is restricted by steric or other factors so that the different conformations can be separated. The term atropisomer is applied to this type of stereoisomerism which depends upon restricted bond rotation.  

In this chapter, configurational relationships will be emphasized. Both structural and dynamic aspects of stereochemical relationships will be considered. We will be concerned both with the fundamental principles of stereochemistry and the conventions that have been adopted to describe the spatial arrangements of molecules. We will consider the stereochemical consequences of chemical reactions so as to provide a basis for understanding the relationship between stereochemistry and reaction mechanism that will be encountered later in the book. 

The material in this chapter is stereochemical, emphasizing and formalizing configurational relationships. These relationships will be considered from two points of view static and dynamic. We will be concerned with the fundamental principles of 

---

Our major objectives m this chapter are to develop a feeling for molecules as three dimensional objects and to become familiar with stereochemical principles terms and notation A full understanding of organic and biological chemistry requires an awareness of the spatial requirements for interactions between molecules this chapter provides the basis for that understanding... 

We 11 continue with the three dimensional details of chemical reactions later m this chapter First though we need to develop some additional stereochemical principles con cernmg structures with more than one chirality center... 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

In order to understand this concept, we need to learn some basic stereochemical principles and notations (optical activity, chirality, retention, inversion, racemisation, etc.). 

The same stereochemical principles are going to apply to both acyclic and cyclic compounds. With simple cyclic compounds that have little or no conformational mobility, it is easier to follow what is going on. Consider a disubstituted cyclopropane system. As in the acyclic examples, there are four different configurational stereoisomers possible, comprising two pairs of enantiomers. No conformational mobility is possible here. 

J. K. N. Jones and his colleagues have extensively studied the reaction of sulfuryl chloride with carbohydrates.21-29 This work has elucidated the stereochemical principles involved in the various transformations, and has made available a convenient and effective procedure for the preparation of chlorodeoxy sugars. Several examples of the utility of such derivatives, obtained by way of a reaction with sulfuryl chloride, in the synthesis of other rare sugars are discussed in Section III (see p. 281). In the present Section, the studies on the reaction itself are surveyed. 

Since molecular rotation does occur in certain crystals, it is necessary, when attempting to determine the structure of any crystal, to com sider this possibility. If there appears to be a conflict between the symmetry of a molecule in the crystal and the expectation based on stereochemical principles, or if it is found impossible to obtain correct calculated intensities on the assumption that the molecules are fixed, it should be considered whether the hypothesis of molecular rotation provides an explanation. 

Epoxides are generally very susceptible to attack by sulfur nucleophiles, in accordance with the recognized nucleophilicity of these reagents.1 The direction of ring fission is governed by the same electronic and stereochemical principles as those operating in other related reactions, e.p. the additions of hydroxylic nucleophiles discussed in section IV.4.A. 

To understand the stereochemistry of electrophilic addition, recall two stereochemical principles learned in Chapters 7 and 9. 

The antagonism or prevention of toxic effects may also benefit from stereochemical principles. Thus, optically active flavanones have been shown to inhibit the metabolic activation of the carcinogen benzo[a]pyrene to metabolites that bind covalently to DNA (Chae et al., 1992). Moreover, the (+) enantiomers of 3-0-methyicatechin and catechin have been demonstrated to protect stereoselectively against lipid peroxidation due to paracetamol (Devalia et al., 1982),... 

Problems of this sort require careful reasoning, a knowledge of the mechanism by which the reaction occurs, and a good grasp of stereochemical principles. Write the steps of the reaction mechanism, identify the step or steps in which product stereochemistry is determined, and decide what products will be formed. 

Cram and co-workers (93) once called [2.2] paracyclophane (77) one of the rigid cyclophanes that illustrate stereochemical principles, and they demonstrated various ways to desymmetrize its intrinsic DJjl symmetry by substitution. 

This section is limited to the stereochemical principles that govern [3,3] sigmatropic rearrangements and methods which allow the stereochemical outcome of these reactions to be controlled. 

It should be emphasized that, in order to make an assessment of the stereochemical principles involved in the formation of cyclic acetals of aldoses and aldosides, the reaction products from a given condensation must be analyzed quantitatively, and the structures of the products determined. In addition, the reaction should, ideally, have reached equilibrium under truly reversible conditions. It now seems that the interpretation of some of the previous results must be carefully reconsidered. The valuable investigations of Buchanan and Saunders have revealed the possibility that condensations catalyzed by zinc chloride may not proceed in a truly reversible manner. Dorcheus and Williams also remarked that the catalytic action of zinc chloride will be lost through formation of the hydrated complex, ZnCU (H80)2. This change will result in kinetic control of the reaction. It has been found, for example, that reaction of methyl a-D-altropyranoside (13) with acetone and sulfuric acid affords a 42% yield of the 3,4-0-isopropylidene acetal. Using zinc chloride as the catalyst, both the 3,4- and the 4,6-0-isopropylidene acetal are obtained. Similar results were re-... 

---