Determination of Absolute Stereochemistry

Nowadays we are in the fortunate position of being able to carry out X-ray crystallography on crystalline derivatives of optically active terpenoids. This enables us to see the actual handedness of molecules. In the early days of stereochemistry, this was not possible and absolute stereochemistry could only be determined relative to a standard. Since the initial work on stereochemistry was carried out on sugars and their 

Similarly, oxidative degradation of (+ )-a-phellandrene gives ( + )-isopropylsuccinic acid. This is identical to that obtained from (—)-glyceraldehyde except for the direction of rotation of polarised light. So the absolute stereochemistry of C-4 in ( + )-a-phellandrene is opposite to that of (-)-glyceraldehyde. 

Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley, New York, 1994. 

Investigations into the chemistry of pine components made invaluble contributions to our understanding of carbocation chemistry 

Occasionally, the bond between a carbon atom and another atom can be broken to leave a positive charge on the carbon atom. The carbocation thus produced can then undergo a reaction, for example with a nucleophile, to give a new molecule. There are also times when old bonds are broken and new ones formed without it being clear at which point, if any, a carbocation exists. In such cases, there is often a synchronous push and pull of electrons across the reaction centre. In examples where the carbocation exists only transiently, if at all, the reaction environment is restricted and the presence of neighbouring groups and other species in the vicinity can have a profound effect on the course of the reaction. 

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Other examples of determination of absolute stereochemistry by theoretical calculation of the CD spectra include ( + )-l,8a-dihydro-3,8-dimethylazulene (2)93 and ( + )-halenaquinol (3) and its derivatives94. 

The Red Sea sponge Lamellodysidea herbacea contains the new dysidamides D-H (960-965) and ring-opened analogs 966 and 967 998). As has been pointed out several times 999), the determination of absolute stereochemistry of the Dysidea polychlorinated peptides has been difficult and revisions are not uncommon. The X-ray crystal structure of a zinc chelate of dechlorinated dysidenin has confirmed its absolute configuration as (55,135) as shown in UU 999). 

Fig. 39. Determination of absolute stereochemistry through NMR in chiral solvent...

X-ray analysis of a derivative of (130) has led to the determination of absolute stereochemistry/ Suzuki et aC have also established the absolute stereochemistries of the metabolites (132)—(136) from Laurencia glandulifera Kiitzing by an X-ray analysis of (132) and subsequent chemical interconversions with the other four compounds. 

Fig. (6). NOE interactions observed for 70 and determination of absolute stereochemistry of 70 by evaluating its degradation products (+)-70b and (-)-70c.

Scheme 5.2 Determination of absolute stereochemistry of C-H bond activation.

Harada N, Watanahe M, Kuwahara S. Novel chiral derivatiz-ing agents powerful for enantioresolution and determination of absolute stereochemistry by X-ray crystallographic and H NMR anisotropy methods. In Busch KW, Busch MA, editors. Chiral analysis. Amsterdam Elsevier Science Publishers 2006. p 661-691. 

Figure 1.1 Schematic diagram explaining the Cahn-Ingold-Prelog convention for determining the absolute stereochemistry of a chiral molecule.

X-Ray diffraction analysis was utilized for the determination of the stereochemistry of bis-boraadamantane derivatives (see Section 12.13.3.2.1) as well as for the estimation of absolute configuration of adducts of chiral... 

This chapter has provided a general introduction to stereochemistry, the nomenclature for chiral systems, the determination of enantiomer composition and the determination of absolute configuration. As the focus of this volume is asymmetric synthesis, the coming chapters provide details of the asymmetric syntheses of different chiral molecules. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

Circular dichroism (CD) has also been used as a tool in determining the absolute stereochemistry of a side chain of a benzothiazine. The CD spectrum was compared against a computer-generated model <1999J(P1)149>. 

L. patella from Fiji contained patellins 1-5 (50-54) [82] and earlier, solution- and solid-state conformational studies were carried out on patellin 2 (51), and the structure was determined by X-ray analysis [83]. A Lissoclinum sp. from the Great Barrier Reef yielded patellins 3 (52), 5 (54) and 6 (55) and the heptapeptide trunkamide A (56) [82]. Compounds 50-56 were all identified by interpretation of spectral data and through use of Marfey s method to determine the absolute stereochemistry of the constituent amino acids [82]. A total synthesis of the proposed structure of trunkamide A (56) revealed that the structure... 

Cornelius and Cleland have recently determined the absolute stereochemistry of the Mg2+ complex of ATP that is active with yeast hexokinase (43). MgATP can exist in solution as a pair of bidentate diastereomers (monodentate and tridentate complexes can also exist). The two possible bidentate isomers are shown schematically in Fig. 11. The two configurations have been labeled A and A (44). There are also four possible tridentate isomers. 

Use of diastereotopic probes for determination of absolute (as distinct from relative, e.g. meso vs. dl) stereochemistry is rare an example relating to chiral amine oxides is shown in Fig. 39 26b>. The solute-solvent complex shown, composed of the (S)-amine oxide and (S)-phenyltrifluoromethylcarbinol, has the ethyl group of the... 

The importance of resolution and determination of absolute configuration cannot be overemphasized. There was, in this writer s opinion, little significant progress in developing useful receptor models prior to the determination of the absolute configurations for the active enantiomers of apomorphine, I, certain N-substituted 5-hydroxy-2-amino-l,2,3,4-tetrahydronaphthalenes, and of 6,7-ADTN (X). It is very common to see structures drawn in the literature with their chiral center shown as a particular absolute configuration, for example similar to that of apomorphine. Yet, in many of these cases there is no evidence as to which isomer is active. The reversed stereochemistry for the active enantiomers of apomorphine and... 

Equally successful has been the group of Quallich at Pfizer46 who reported the preparation of a substituted dihydronaphthalenone, a pivotal intermediate in the preparation of the antidepressant sertraline (Lustral ) (10) (Scheme 16.6). In this synthesis, the new chiral center created subsequently determines the absolute stereochemistry of the final product (see Chapter 31). 

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