Sourcing chiral compounds

Synthesis of optically pure compounds via transition metal mediated chiral catalysis is very useful from an industrial point of view. We can produce large amounts of chiral compounds with the use of very small quantities of a chiral source. The advantage of transition metal catalysed asymmetric transformation is that there is a possibility of improving the catalyst by modification of the ligands. Recently, olefinic compounds have been transformed into the corresponding optically active alcohols (ee 94-97%) by a catalytic hydroxylation-oxidation procedure. 

The above results are valuable in that an optically active compound is produced in bulk from achiral material. Only a few successful examples of photochemical conversion of achiral into chiral material in the absence of a chiral source have been reported hitherto 49, and in these cases the conversion was carried out on a fragment of a chiral crystal. In our case, chiral crystals are available in bulk, and mass production of the chiral compound is possible. 

The use of enantiomers as additional markers for taxonomic characterization of aromatic plants may be very helpful. The differences in the enantiomeric distribution of trans- and cis- sabinene hydrates in two Origanum species enable the species to be distinguished in spite of their similar essential oil compositions. A further study on the natural variation of the enantiomeric composition within a wild population may be carried out in order to examine the stability in a taxon (including the possible presence of chemotypes). The enantiomeric ratio of essential oil components is a reliable parameter for assessing quality because it may be indicative of adulteration, contamination, aging, shelf life, technological process and the botanical source of a specific chiral compound. ... 

Repeated deprotonation of 278 removed due to a high H/D kinetic isotope effect the 1-proton, forming the dideuterio compound 279 with low diastereoselectivity . It is quite likely that a dynamic thermodynamic resolution is the origin. Intermediate 277 is configurationally labile, enabling an equilibration of the diastereomeric ion pairs 277 and epi-211. Similar studies were undertaken with 1-phenyl-l-pyrid-2-ylethane (280) and l-(4-chlorophenyl)-l-(pyrid-2-yl)-3-(dimethylamino)propane (281) (50% eef. An improvement of the achieved enantiomeric excesses resulted when external chiral proton sources, such as 282 or 283, were applied (84% ee for 280 with 283 and 75% ee for 281). 

The naturally occurring compounds in the flavan, flavan-3-ol, flavan-4-ol, flavan-3,4-diol, and proanthocyanidin classes, together with their plant sources, are listed in Table 11.2-Table 11.17. The lists are confined to new compounds reported in the post-1992 period or those that have been overlooked in the 1994 review, and therefore must be considered in conjunction with the corresponding tables of the Porter reviews to be comprehensive. Since many of the monomeric analogs have been published under trivial names these will be retained to facilitate electronic literature searches. Unfortunately, a considerable number of these potentially chiral compounds have been reported without assignment of absolute configuration, and are hence presented as such. 

Figure 5. Types of diastereomeric derivatives of chiral compounds selected for indirect enantiosepara-tion. (Source reprinted with permission from ref 250.)...

The first supplement to the three volume reference work Comprehensive Asymmetric Catalysis critically reviews new developments to the hottest topics in the field written by recognised experts. Eleven chapters which are already treated in the major reference work have been supplemented, and additionally five new chapters have been included. Thus the state-of-the art in this area is now re-established. Together with the basic three volume book set this supplement is not only the principal reference source for synthetic organic chemists, but also for all scientific researchers who require chiral compounds in their work (for example in biochemical investigations and molecular medicine) as well as for pharmaceutical chemists and other industrial researchers who prepare chiral compounds. 

Compounds isolated from natural sources are frequently optically pure. Thus camphor (11), cholesterol (14), morphine (16), for example, are isolated in the optically pure state. The parent molecule of (13) is D-glucose, and like camphor and cholesterol is readily available in very large quantities. These, and comparable compounds, form what is now described as a chiral pool, i.e. low-cost, readily available, chiral compounds which provide starting materials for conversion into other compounds, of simplified skeletal and functional structure, in which some or all of the chiral features have been retained. 

With few exceptions, enantiomers cannot be separated through physical means. When in racemic mixtures, they have the same physical properties. Enantiomers have similar cliemi cal properties as well. The only chemical difference between a pair of enantiomers occurs in reactions with other chiral compounds. Thus resolution of a racemic mixture typically takes place through a reaction with another optically active reagent. Since living organisms usually produce only one of two possible enantiomers, many optically active reagents can be obtained from natural sources. For instance muscle tissue and (S)-<-)-2-methyl-l-butanol, from yeast fermentation. 

Triacylglycerol lipases (EC 3.1.1.3) are attracting renewed attention since they were demonstrated to be active in organic solvents and to be suitable catalysts in industrial important reactions, such as the synthesis of flavors, emulsifiers, and chiral compounds, and the transesterifi cation of tow-value fats to triacylglycerols of high commercial value. Fbngi are a particularly valuable source of lipases because the enzymes produced by the majority of them are extracellular and readily separable from the mycelia after fermentation. The recent availability of... 

Use of existing chiral compounds as starting materials or templates in a stoichiometric fashion. The use of existing chiral compounds as a source of chiral center is popular among organic chemists. Natural amino acids have been extensively used for this purpose (4). While this method is most convenient, it is limited by the availability and die cost of the existing chiral pool. 

Sales of single enantiomer drugs exceeded 159 billion in 2002. Some of these come from biological sources, but the majority are synthetic. For this reason, the development of synthetic methods that produce only a single enantiomer of chiral compounds is a very active research area in both academic and pharmaceutical research labs. Chiral or asymmetric syntheses, which produce only the desired enantiomer, are much preferred over resolution processes, in which at least half of the initial compound is discarded. 

The chemistry of asymmetric protonation of enols or enolates has further developed since the original review in Comprehensive Asymmetric Catalysis [1], Numbers of literature reports of new chiral proton sources have emerged and several reviews [2-6] cover the topics up to early 2001. This chapter concentrates on new examples of catalytic enantioselective protonation of prochiral metal enolates (Scheme 1). Compounds 1-41 [7-45] shown in Fig. 1 are the chiral proton sources or chiral catalysts reported since 1998 which have been employed for the asymmetric protonation of metal enolates. Some of these have been successfully utilized in the catalytic version. 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

Alanine made in this way must be racemic, because the starting materials are achiral. However, if we isolate alanine from a natural source—by hydrolysing vegetable protein, for example—we find that this is not the case. Natural alanine is solely one enantiomer, the one drawn below. Samples of chiral compounds that contain only one enantiomer are called enan-tiomerically pure. We know that natural alanine contains only this enantiomer from X-ray crystal structures. 

Early in this chapter, we said that most of the molecules in nature are chiral, arid that Nature usually produces these molecules as single enantiomers. We ve talked about the amino acids, the sugars, ephedrine, pseudoephedrine, and tartaric acid—all compounds that can be isolated from natural sources as single enantiomers. On the other hand, in the lab, if we make chiral compounds from achiral starting materials, we are doomed to get racemic mixtures. So how do chemists ever isolate compounds as single enantiomers, other than by extracting them from natural sources We ll consider this question in much more detail in Chapter 45, but here we will look at the simplest way using nature s enantiomerically pure compounds to help us separate the components of a racemic mixture into its two enantiomers. This process is called resolution. 

Circularly polarized light (CPL), often used as a source for the absolute asymmetric synthesis of chiral compounds [76-79], can be used as a trigger... 

Reactions like these, in which stereoselectivity is the consequence of steric hindrance to bond rotation, are most well known among the biaryls, and derivatives of binaphthyl have provided chemists with a valuable range of chiral ligands [4-6]. But the biaryls are only a small subset of axially chiral compounds containing two trigonal centres linked by a rotationally restricted single bond. Many others are known, some with much greater barriers to rotation than Fuji s enol ether [7]. Yet until quite recently there were no reports of reactions in which nonbiaryl atropisomers were the source, conveyor, or product of asymmetric induction. 

Bidleman, T.F. Falconer, R.L., Enantiomer ratios for apportioning two sources of chiral compounds Environ. Sci. Technol. 1999, 33, 2299-2301. 

Many chiral compounds are known by the chemist to be racemic because of the lack of stereoselective influences on the synthesis or to be enantiopure because of natural origin. Such knowledge, while based on a sound technical foundation, may not be suitable for regulatory purposes. For example, the commercial availability of a racemate or the "opposite" enantiomer may make its substitution for the approved component conceivable. Therefore, it may be necessary to bring other factors (e.g synthetic feasibility or commercial sources) into consideration to establish whether a stereochemically specific identity test is necessary. 

Reactions in which bonds to chiral centers are not broken can be used to get one more highly important kind of information the specific rotations of optically pure compounds. For example, the 2-methyl-1-butanol obtained from fusel oil (which happens to have specific rotation -5.756°) is optically pure—like most chiral compounds from biological sources—that is, it consists entirely of the one enantiomer, and contains none of its mirror image. When this material is treated with hydrogen chloride, the l-chloro-2-methylbutanc obtained is found to have specific rotation of 4-1.64°. Since no bond to the chiral center is broken, eveyy... 

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