Stereocenters determining configuration

When we learned how to name compounds, we said that we would skip over the naming of stereocenters until we learned how to determine configuration. Now that we know how to determine whether a stereocenter is R or S, we can now see how to include this in the name of a compound. It is actually quite simple. If there is only one stereocenter, then you simply place either (R) or (S) at the beginning of the name. For example, 2-butanol has one stereocenter, and can either be (I )-2-bu-tanol or (S)-2-butanol, depending on the configuration of the stereocenter. If more than one stereocenter is present, then you must also use numbers to identify the location of each stereocenter. Consider the following example ... 

The cyclic structures are especially challenging. It is often most reasonable to start by drawing any arbitrary stereoisomer, determining configurations about its stereocenters, and then just switching the two external groups to correct any tliat are the opposite of what you need. 

Similarly the stereobonds" can be defined and added to the bond list in the fourth column of the CT. A single bond acquires the value of 0 if it is not a "stereobond, 1 for np (a wedged bond). 4 for either up or down, and 6 for down (a basbed bond), The cisjtrans or E[Z configuration of a double bond is determined by the x,y.2 coordinates of the atom block if the value is 0, Tf it is 3, the double bond is either cis or tmns. In the bond block of our example (Figure 2-76), the stereocenter is set to 1 (up) at atom 6 (row 6, column 4 in the bond block), whereas the configurations of the double bonds are determined by the x,y coordinates of the atom block. 

Chemical conversion of compounds to intermediates of known absolute configuration is a method routinely used to determine absolute configuration (86). This is necessary because x-ray analysis is not always possible suitable crystals are required and deterrnination of the absolute configuration of many crystalline molecules caimot be done because of poor resolution. Such poor resolution is usually a function of either molecular instability or the complex nature of the molecule. For example, the relative configuration of the macroHde immunosuppressant FK-506 (105) (Fig. 8), which contains 14 stereocenters, was determined by x-ray crystallographic studies. However, the absolute configuration could only be elucidated by chemical degradation and isolation of L-pipecoUc acid (110) (80). 

Configurations and d.r. s or ee s of remaining stereocenters presumed to be identical with that of starting complex 16. h Determined by H-NMR spectroscopy. c Enantiomerically pure compound. J Diastereomerically pure compound. Stereochemistry of minor isomer not reported. 

The 1,4-addition of the anion of a racemic /1-oxo sulfoxide to racemic 2-cyclopentenone was reported to give a single diastereomeric adduct resulting from addition opposite to the y-ace-toxy group20, t he relative configuration of the exocyclic stereocenter was not determined. 

Reactions of nitro compounds with chiral imines have only recently been described. Either chiral 1-phenylethylamine (auxiliary) or the glyceraldehyde acetonide aldehyde was used as the chiral precursors of the imines 66 and 68, which reacted with 3-mesyloxynitropropane to give the 3-nitropyrrolidines dl)-67 and 69, respectively, with good diastereoselectivity. In fact, both products were obtained (almost) exclusively as trans diastereomers with high level of asymmetric induction, but the configurations of the newly formed stereocenters were not determined [44] (Scheme 13). N-Boc imines can be formed... 

More recently, the addition of cyanide ion, generated from TMS cyanide and cesium fluoride, to a-aziridino N-siflfinyl imines, being chiral either at the a position or at sulfur, has been examined [87] (Scheme 28). The configuration of the newly formed stereocenter was determined only by the chiral (S)-sulfinyl group. In fact, the R configuration (diastereomeric excess, de, 98%) was obtained from either the Q -(ii)-imine 186 or the a-(S)-imine 188, giving 187 and 189, respectively. Acyclic 2,3-diaminonitriles can be obtained... 

Now that we can find stereocenters, we must now learn how to determine whether a stereocenter is R or S. There are two steps involved in making the determination. First, we give each of the four groups a number (from 1 to 4). Then we use the orientation of these numbers to determine the configuration. So, how do we assign numbers to each of the groups ... 

Now we need to leam how to use this numbering system to determine the configuration of a stereocenter. The idea is simple, but it is difficult to do if you have a hard time closing your eyes and rotating 3D objects in your mind. For those who cannot do this, don t worry. There is a trick. Let s first see how to do it without the trick. 

PROBLEMS For each compound below, find all stereocenters, and determine their configuration. 

If you are given two stereoisomers, you should be able to determine whether they are enantiomers or diastereomers. All you need to look at are the stereocenters. They must all be of different configuration for the compounds to be enantiomers. 

Notice that Ri is now pointing straight down, and the OH is now on a dash. The configuration has not changed. If you need to convince yourself of this, determine the configuration of that stereocenter in each of two drawings. You will see that it has not changed. 

Once you have a drawing with two straight lines, one dash and one wedge, then you should be able to determine whether the stereocenter is R or S. If you cannot, then you should go back and review the section on assigning configuration. 

EXERCISE 7.75 Determine the configuration of the stereocenter below. Then draw the enantiomer. 

PROBLEMS For each compound below, determine the configuration of every stereocenter. Then draw the enantiomer of each compound below (the COOH group is a carboxylic acid group). 

SnI and Sn2 reactions produce almost the same products. In both reactions, a leaving group is replaced by a nucleophile. The difference in products between SnI and Sn2 reactions arises when the leaving group is attached to a stereocenter. In this situation, the Sn2 mechanism will invert the stereocenter, while the SnI mechanism will produce a racemic mixture. That s the main difference—the configuration of one stereocenter. It seems like a lot of work to go through to determine the configuration of one stereocenter (which matters only some of the time). 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Entry 6 involves a titanium enolate of an ethyl ketone. The aldehyde has no nearby stereocenters. Systems with this substitution pattern have been shown to lead to a 2,2 syn relationship between the methyl groups flanking the ketone, and in this case, the (3-siloxy substituent has little effect on the stereoselectivity. The configuration (Z) and conformation of the enolate determines the 2,3-vyn stereochemistry.113... 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

Owing to the concerted mechanism, chirality at C(3) [or C(4)] leads to enantiospecific formation of new stereogenic centers formed at C(l) [or C(6)].203 These relationships are illustrated in the example below. Both the configuration of the new stereocenter and the new double bond are those expected on the basis of a chairlike TS. Since there are two stereogenic centers, the double bond and the asymmetric carbon, there are four possible stereoisomers of the product. Only two are formed. The Zs-double bond isomer has the 5-con figuration at C(4) and the Z-isomer has the -configuration. These are the products expected for a chair TS. The stereochemistry of the new double bond is determined by the relative stability of the two chair TSs. TS B is less favorable than A because of the axial placement of the larger phenyl substituent. 

Another problem, which is as a mle solved by physicochemical studies, is the determination of the configuration of the C=N double bond in nonsymmetrical nitronates and the determination of the configurations of the stereocenters. 

The related configurations of stereocenters in substituted cyclic nitronates can be determined by analyzing the spin—spin coupling constants between the vicinal protons in the stereoisomer discussed (Chart 3.7) (276). If needed, the results of this analysis are supplemented by special NOE experiments. 

Determination of the Configurations and Study of Stereodynamics of Cyclic Nitroso Acetals This determination is of obvious fundamental importance by itself and, in addition, it is of importance in considering the mechanism of [3+ 2]-cycloaddition and in predicting the conhgurations of the resulting stereocenters. 

Several SENAs derived from primary AN were involved in the reaction with ceptem (282) (Scheme 3.177, Eq. 1) (434) to prepare the diastereomeric pure cycloadducts, which were then transformed into isoxazolines (283). However, the configurations of the new stereocenters in products (283) were not determined. 

---