Enantiomerically enriched compounds

It is well known that certain microorganisms are able to effect the deracemization of racemic secondary alcohols with a high yield of enantiomerically enriched compounds. These deracemization processes often involve two different alcohol dehydrogenases with complementary enantiospedficity. In this context Porto ef al. [24] have shown that various fungi, induding Aspergillus terreus CCT 3320 and A. terreus CCT 4083, are able to deracemize ortho- and meta-fluorophenyl-l-ethanol in good... 

A new BF3-induced stereospecific rearrangement of the epoxy ethers 68 gave the enantiopure tetrahydro 2-benzoxepin-4-ols 69a, b in generally good yields <06JOC1537>. The enantiomerically enriched compounds 69c,d were also produced. 

Molecular chirality, however, proved an extremely powerful tool in the quest for polar LCs. In 1974 Robert Meyer presented to participants of the 5th International Liquid Crystal Conference his now famous observation that a SmC phase composed of an enantiomerically enriched compound (a chiral SmC, denoted SmC ) could possess no reflection symmetry.1 This would leave only the C2 symmetry axis for a SmC a subgroup of C. The SmC phase is therefore necessarily polar, with the polar axis along the twofold rotation axis. 

The synthesis of enantiomerically enriched compounds can be accomplished by application of chiral Lewis acids or chiral auxiliaries attached to either one of the reactants. The latter application41,42 will be discussed in this section. 

This method has proven to be an extremely useful means of synthesizing enantiomerically enriched compounds. Various improvements in the methods for carrying out the Sharpless oxidation have been developed.48 The reaction can be done with catalytic amounts of titanium isopropoxide and the tartrate ester.49 This procedure uses molecular sieves to sequester water, which has a deleterious effect on both the rate and enantioselectivity of the reaction. Scheme 12.9 gives some examples of enantioselective epoxidation of allylic alcohols. 

The use of epoxides has expanded dramatically with the advent of practical asymmetric catalytic methods for their synthesis. Besides the enantioselective epoxida-tion of prochiral olefins, approaches for the use of epoxides in the synthesis of enantiomerically enriched compounds include the resolution of racemic epoxides. 

Frank proposed a mechanism for the autocatalytic self-replicating process in which a chemical substance catalyzes its own production and acts as an anticatalyst for the production of the enantiomer without mentioning any actual compound or actual reaction [17]. hi this kinetic model, it is possible to obtain an enantiomerically enriched compound from an ex-... 

An asymmetric 1,4-addition of arylboronic acids to coumarins such as 220 catalyzed by rhodium has been achieved in greater than 99% ee (Equation 21) <2005OL2285>. This method should prove useful for the synthesis of enantiomerically enriched compounds that contain a stereogenic center between two aryl groups. This methodology was used in the total synthesis of (R)-tolterodine. 

These diastereomerically and enantiomerically enriched compounds are useful as intermediates for a variety of interesting building blocks such as 1-aminobutanes, nonprotected homoallylamines, [3-amino acids, and y-amino alcohols (Figure 25.5). The conversion to 1-aminobutanes and homoallylamines will be described. 

Non-stabilised organolithiums - that is, organolithiums in which the lithium-bearing centre is tetrahedral - generally react with high stereospecificity. This fact is essential for the use of chiral bases such as s-BuLi-(-)-sparteine in the synthesis of enantiomerically enriched compounds by asymmetric deprotonation, as well as for the use of enantiomerically pure... 

Intermolecular cycloaddition reactions constitute an important and convergent route to piperidines and related compounds. The research group of Franklin Davis at Temple University published a novel route to optically active piperidines that proceeded through an imino Diels-Alder reaction with enantiomerically enriched compound 84 (Scheme 16) <02OL655>. On reaction with ftww-l,3-pentadiene, intermediate 85 was produced as a single diastereomer in 89% yield. Hydrogenation of this strained intermediate yielded the 2,6-disubstituted piperidine 86 in 75% yield. 

How could the same enantiomerically enriched compound be formed by chemical means What are the advantages and disadvantages of this method ... 

Brucine has been used to produce enantiomerically enriched compounds by selective reaction with or destruction of one of the enantiomers. The optical purity of the resulting compound is usually modest, although some exceptions have been described. For example, dibromo compound (9) was obtained [enriched in the (—)-enantiomer] by selective destruction of the (+)-enantiomer with brucine in chloroform. The resolution of ( )-2,3-dibromobutane may have also been a case of enantioselective destruction, although more recent reports suggest that it is more likely a case of enantioselective entrapment in the brucine crystals (eq 14). ... 

The importance of optically active vicinal thio- and selenoalcohols has been recognized as potential intermediates for enantiomerically pure epoxides, which have been used in the synthesis of more complex enantiomerically enriched compounds [54]. The synthesis of racemic vicinal thio- and selenoalcohols via stereoselective reduction of a-thio- [55] and a-selenoketones [56] has been reported, whereas very few asymmetric syntheses of highly optically active vicinal thioalcohols are known [57]. 

Since the publication of the first edition of this book in 1996, the industrial application of enantioselective homogeneous catalysts has made significant progress. The list of processes suitable for the manufacture of enantiomerically enriched compounds is compiled in [6]. Few have actually been implemented as production processes and run on a regular basis but there is every reason to assume that this technology is here to stay. The number of commercial applications will increase in the near future because development chemists who realize technical processes will be more aware of the potential of enantioselective catalysis. More and more specialized technology companies such as Solvias, ChiRex, or ChiroTech are devel-... 

Among the different possible methodologies available, the use of a chiral catalyst represents, in principle, the most attractive procedure to synthesize enantiomerically enriched compounds, since in a catalytic process a small amount of a smart molecule produces a large quantity of the desired chiral compound [ ] ... 

Conventional kinetic resolution procedures often provide an effective route for the preparation of enantiomerically enriched compounds. However, a resolution of two enantiomers will only provide a maximum of 50% yield of the enantiomerically pure material. This limitation can be overcome in a number of ways, including inversion of the stereochemistry of the unwanted enantiomer, racemization and recycling of the unwanted enantiomer or dynamic kinetic resolution. 

Due to the great importance of phosphines and phosphinites as chiral ligands for asymmetric catalysis, several hundred compounds of this type have been prepared. In this section, only those compounds which have been mentioned in this Houben-Weyl volume will be discussed. Because of their close relation to the specific topics, biaryl phosphines have already been mentioned in Section 6 and ferrocene derivatives in Section 7.1. All other phosphorus compounds are treated here. An excellent review on the synthesis of enantiomerically enriched compounds where phosphorus is a stereogenic center has recently been published73. 

More specifically, the stereoselective synthesis of an enantiomerically enriched compound requires that the two enantiomers of the product (that therefore must be a molecule contain-... 

Therefore, it seems unnecessary to present here another classification, and we will only report some examples of reactions illustrating stereoselective synthetic approaches relevant to the topic of this chapter, i.e., the preparation of enantiomerically enriched compounds. Stereoselective reactions leading to unequal amounts of racemic diastereoisomers will not be considered. 

Figure 5. Examples of stereoselective syntheses of enantiomerically enriched compounds by kinetic resolution.

A few examples of kinetic resolutions are reported in Fig. 5. These have been selected among those reactions leading to the preparation of enantiomerically enriched compounds that do not feature a handle for classical resolutions. 

The use of optically resolved PTC catalysts for the synthesis of enantiomerically pure compounds is no doubt an attractive field. Asymmetric PTC has become an important tool for both laboratory syntheses and industrial productions of enantiomerically enriched compounds. Recently, Lygo and coworkers [207-216] reported a new class of Cinchona alkaloid-derived quaternary ammonium PTC catalysts, which have been applied successfully in the enantioselective synthesis of a-amino acids, bis-a-amino acids, and bis-a-amino acid esters via alkylation [207-213] and in the asymmetric epoxidation of a/p-unsaturated ketones [214-216]. 

Racemic phenolic triazolones 411 form dimers, while the corresponding enantiomerically enriched compounds form extended chains. These differences in aggregation behavior were observed in crystalline states and in aprotic solvents. 

Substrates containing enantiotopic groups can be converted into enantiomerically enriched compounds using asymmetric catalysis with representative examples... 

Epoxides constitute a class of versatile intermediates, as they can be easily transformed into a wide variety of functional groups involving regioselective ring opening reactions [185], Thus, asymmetric epoxidation (AE) of olefins is a key reaction for the synthesis of enantiomerically enriched compounds. 

As the structure of an organic compound is altered in the course of a reaction, one or more chiral centers, usually at carbon, may be created, inverted, or destroyed. In Section 6.7A, we consider two alkene addition reactions in which a chiral molecule is created in an achiral environment. In doing so, we will illustrate the point that an optically active compound (i.e., an enantiomerically pure compound or even an enantiomerically enriched compound) can never be produced from achiral starting materials reacting in an achiral environment. Then in Section 6.7B, we consider the reaction of achiral starting materials reacting in a chiral environment—in this case in the presence of a chiral catalyst. We shall see that an enantiomerically pure product may be produced from achiral reagents if the reaction takes place in a chiral environment. 

Asymmetric synthesis has emerged as a major preparative method, widely used in organic chemistry and in the total synthesis of natural products, and which is also of interest for industrial chemistry. The importance of enantiomerically pure compounds is connected with the applications in pharmaceutical industries, since very often the biological activity is strongly linked to the absolute configuration. In this article the historical developments of asymmetric synthesis will be briefly presented, as well as the main methods to prepare enantiomerically enriched compounds. Then recent asymmetric synthesis of two classes of compounds will be discussed i) Sulfoxides, chiral at sulfur ii) Ferrocenes with planar chirality. The last part of the article will be devoted to asymmetric catalysis with transition-metal complexes. The cases of asymmetric oxidation of sulfides to sulfoxides and nonlinear effects in asymmetric catalysis will be mainly considered. 

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