Spectroscopic stereochemical determination

FIGURE 8 Understanding mistakes made in the spectroscopic stereochemical determination of EBC-23. 

Strategies to determine the nature of reacting RIs in solids are often based on product analyses, stereochemical correlations, kinetics measurements, and so forth, just as they are generally applied in solution media3 While there are challenges associated with the implementation of spectroscopic methods in the solid state, the direct observation of short-lived RIs can be used to support or reject mechanistic models. 

The theonezolides are 37-membered macrocycles, consisting of fatty acid chains with attached functionalities such as a sulfate ester and a thiazole [22]. Theonezolide A (610) is a cytotoxic metabolite of Theonella sp. from Okinawa. The structure was reported without stereochemical details [489]. The structures of theonezolides B (611) and C (612) from a Japanese Theonella sp. were determined by spectroscopic methods but without stereochemistry, except at one centre [490]. 

In addition to the spectroscopic investigations, there have been attempts to obtain structural and stereochemical information about radicals by chemical means.25 The approach generally taken is to generate radicals by one of the methods discussed in the next section at a carbon where stereochemistry can be determined. As an example, we may cite the experiment shown in Equation 9.6, in which an optically active aldehyde is heated in the presence of a source of radicals.26 The reaction follows the chain pathway indicated in Scheme 1 the loss of chirality indicates that the radical is either planar or, if pyramidal, undergoes inversion rapidly with respect to the rate (on the order of 10s sec-1) at which it abstracts a hydrogen atom from another molecule of aldehyde. 

As a result of mass spectral studies of alkaloid extracts of Crinum ornatum, the new alkaloids omazamine, and omazidine were identified, and the tentative structure assignments of 403-405, respectively, were made (42). The stereochemistry depicted is based on the obvious relationship between these alkaloids and pretazettine (395), but no stereochemical details were given in the original report (42). The structures of ungvedine (399) (83) and varadine (402) (54), the latter of which represented a new structural type in the Amaryllidaceae alkaloids, were determined by spectroscopic studies. Further chemical support for the proposed structure of ungvedine (399) was obtained by hydrogenation of O-methyltazettine to give 399 (83). 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

No one argued with this structure because it was determined by reliable spectroscopic methods— NMR plus an X-ray crystal structure of a derivative. This was not always the case. Go back another 25 years to 1946 and chemists argued about structures all the time. An undergraduate and an NMR spectrometer can solve in a few minutes structural problems that challenged teams of chemists for years half a century ago. In this chapter we will combine the knowledge presented systematically in Chapters 3,11, and 15, add your more recently acquired knowledge of stereochemistry (Chapters 16, 18, and 31), and show you how structures are actually determined in all their stereochemical detail using all the evidence available. 

The [MH(PF3)J complexes (M = Co, Rh, Ir) and the isoelectronic species [M H(PF3)4] (M = Fe, Ru, Os) are all stereochemically non-rigid, and detailed multinuclear NMR spectroscopic studies have been carried out and activation parameters determined. It has been proposed that the phosphorus environments are interchanged by a tetrahedral tunnelling rearrangement mechanism. Some typical temperature-dependent and 19F NMR spectra are shown in Fig. 7. 

In the series of the binary halides of selenium and tellurium, the crystal structure determinations of tellurium tetrafluoride (100) and of tellurium tetrachloride on twinned crystals (65, 66) were the key to understanding the various and partly contradictory spectroscopic and other macroscopic properties (e.g., 66,161,168,169,219,220, 412), as well as the synthetic potential of the compounds. In contrast to the monomeric molecular i//-tbp gas phase structures with C2v symmetry (417), the solid state structures of both are polynuclear. As the prototype of the chlorides and bromides of selenium and tellurium, crystalline tellurium(IV) chloride has a cubane-like tetrameric structure with approximate Td symmetry (Fig. 1). Within the distorted TeCla+a octa-hedra the bonds to the triply bridging chlorine ligands are much longer than to the terminal chlorines. The bonding system can be described either covalently as Te4Cli6 molecules, or, in an ionic approximation, as [(TeCl Cn4] with a certain degree of stereochemical activity of the lone pairs toward the center of the voluminous cubane center (65, 66). 

In the late 1800s, the stereochemical theories of van t Hoff and Le Bel on the tetrahedral geometry of carbon were barely a decade old, modern methods of product purification were unknown, and modern spectroscopic techniques of structure determination were undreamed of. Despite these obstacles, Emil Fuscher published in 1891 what remains today perhaps the finest use of chemical logic ever recorded—a structure proof of the stereochemistry of naturally occurring (+ )-glucose. Let s follow Fischer s logic and see how he arrived at his conclusions. 

The stereochemical outcome of a reaction can suggest much about its mechanistic pathway. If a molecular fragment, whose stereochemistry is clearly defined, can be attached to the reactant and remain attached during the course of the reaction without affecting the chemistry, then determination of product stereochemistry can be straightforward using spectroscopic means. 

Lauraceae), was assigned the structure 26 based on spectroscopic evidence (38). The oxygenation pattern of the aromatic rings and the presence of a C-2 phenolic function were determined by its UV spectrum, coupled with base-induced bathochromic shifts. The location of the hydroxy function at C-4, its stereochemical disposition, and the stereochemistry of 6a-H were determined with the help of and 13C NMR data and comparison with those of known compounds. The 3H and 13C NMR assignments for srilankine (26) are depicted in Fig. 1. 

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