Enantiotopic groups, differentiation

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Enantiotopic group differentiating reactions54 include the following 5 examples. 

Enantiotopic functional group differentiation is the domain of enzymes, whose use for such purposes is now well established as a method of broad applicability. This topic has been reviewed extensively 84 90-90a. The utility of nonenzymatic methods to achieve enantiotopic group differentiation is less well established. This topic has also been reviewed3. Diastereotopic group differentiation thus far involves substrates with chiral amide groups. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

The first enantioselective total synthesis of (-)-denticulatin A was accomplished by W. Oppolzer. The key step in their approach was based on enantiotopic group differentiation in a meso dialdehyde by an aldol reaction. In the aldol reaction they utilized a bornanesultam chiral auxiliary. The enolization of A/-propionylbornane-10,2-sultam provided the (Z)-borylenolate derivative, which underwent an aldol reaction with the meso dialdehyde to afford the product with high yield and enantiopurity. In the final stages of the synthesis they utilized a second, double-dlastereoditferentiating aldol reaction. Aldol reaction of the (Z)-titanium enolate gave the anf/-Felkin syn product. The stereochemical outcome of the reaction was determined by the a-chiral center in the aldehyde component. 

Enzyme-catalyzed reactions can provide a rich source of chiral starting materials for organic synthesis.2 Enzymes are capable of differentiating the enantiotopic groups of prochiral and mew-compounds. The theoretical conversion for enzymatic desymmetrization of mew-compounds is 100% therefore enzymatic desymmetrization of mew-compounds has gained much attention and constitutes an effective entry to the synthesis of enantiomerically pure compounds. 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Asymmetric bond disconnection is less frequently employed than asymmetric bond formation for the synthesis of chiral, nonracemic compounds. The substrates for these transformations contain either enantiotopic (diastereotopic) hydrogen atoms or enantiotopic (diastereotopic) functional groups. In some cases the classification of a given transformation of such a substrate as asymmetric bond disconnection or bond formation is somewhat arbitrary. Thus, enantiotopic and diastereotopic group differentiation is also described at appropriate places in various sections but more specifically in part B of this volume. 

The compound /3-phenylglutaric anhydride, 49, contains enantiotopic ligands. On reaction with ( —)-a-phenylethylamine the two diastereoisomers of the monoamide, 50 and 51, were formed in unequal amounts [67]. In contrast to the earlier statement (the products are usually enantiomers in an enantiodifferentiating process), the products here are diastereoisomers. Of course, if the amine component of the amide were to be removed, the products from the substrate anhydride would be enantiomers. This differentiation between enantiotopic groups was important in the early days of the citrate story. It proved the possibility of differentiation in homogeneous solution, presumably without a three-point attachment. 

Thiazolidinethiones constitute a class of versatile chiral auxiliaries for asymmetric synthesis. Their easy preparation from readily available /3-amino alcohols and the high levels of asymmetric induction they provide make them excellent chiral auxiliaries for the preparation of chiral intermediates in the synthesis of natural products. These chiral auxiliaries have been utilized in a wide variety of synthetic transformations such as asymmetric aldol-type acyloin condensation, stereoselective alkylation of different electrophiles (Stetter reaction), and stereoselective differentiation of enantiotopic groups in molecules bearing prochiral centers <2002COR303>. 

Unsaturation in the alkyl chain frequently leads to the monoacetate of a higher ee value as exemplified with 16 and 17. Comparison of the enantioselectivities of the hydrolysis of diacetates to the corresponding monoacetates is often complicated by the lack of information on the amount of diol formed. The later arises from the hydrolysis of the monoacetate that may proceed under enantiomer differentiation, and thus the ee value of the monoacetate will be a composite of two enantioselective processes. Interestingly, upon changing the configuration of the double bond of the substituent R from ( ) to (Z) the enantiotopic group recognition by pig pancreas lipase inverts, as demonstrated by the monoacetates 8 and 9 as well as 11 and 12 (Table 11.1-10). 

The kinetic resolution developed by Katsuki-Sharpless30 for allylic alcohols is superior in enantiotopic face differentiation and in versatility. Another interesting chiral induction method has been developed by Dondoni31 using 2-(trimethylsilyl)thiazole as a masking formyl group. These methods are... 

It has been long appreciated that a chiral environment may differentiate any physical property of enantiomeric molecules. NMR spectroscopy is a sensitive probe for the occurrence of interactions between chiral molecules [4]. NMR spectra of enantiomers in an achiral medium are identical because enantiotopic groups display the same values of NMR parameters. Enantiodifferentiation of the spectral parameters (chemical shifts, spin-spin coupling constants, relaxation rates) requires the use of a chiral medium, such as CyDs, that converts the mixture of enantiomers into a mixture of diastereomeric complexes. Other types of chiral systems used in NMR spectroscopy include chiral lanthanide chemical shift reagents [61, 62] and chiral liquid crystals [63, 64). These approaches can be combined. For example, CyD as a chiral solvating medium was used for chiral recognition in the analysis of residual quadrupolar splittings in an achiral lyotropic liquid crystal [65]. 

If a prochiral substrate (C), bearing two chemically identical but stereochemi-cally different enantiotopic groups (A), is involved, the same model can be applied to rationalize the favored transformation of one of the two groups A leading to an enantiotopos differentiation (Scheme 1.4, Fig. 1.5). 

One of the most outstanding features in enzyme-catalyzed reactions is stereochemical completeness. A high percentage of stereospecific reactions, such that only one chiral product is formed in an excellent enantiomer excess (e.e.) and that only one of two enantiomers is available as a substrate, readily take place. In addition, the spectacular feature that an enzyme can also differentiate enantiotopic groups or faces that are nonenzymatically (chemically) equivalent has also been found. For example, enzymes distinguish two hydrogens attached to a prochiral carbon, >CH2. Even the three... 

While enantioconvergent as well as divergent sequences at any rate need chiral starting materials, the very useful and highly efficient differentiation of enantiotopic groups asks only for prochiral compounds, as for instance 325. To arrive at pure enantiomers, one of the two structurally identical side chains of the starting material 325 has to be attacked enantioselectively, as is demonstrated with the Sharpless oxidation, which in this case leads to epoxide 326 as the main reaction product [115]. 

As with enantiotopic groups, enantiotopic faces are differentiated in reactions by chiral reagents or catalysts. The chiral hydride reducing agent in Equation 3.7 selectively adds a hydride to the si face of the carbonyl carbon. 

A number of examples have been mentioned which illustrate that the receptor site can differentiate between enantiomeric forms of a pheromone. It is common knowledge that many enzymes are specific for only one of a pair of enantiomers. Also, many differentiate between enantiotopic groups of a single substrate molecule 347). If binding of a pheromone to a receptor takes place, it is probably analogous to the formation of an enzyme-substrate complex. The combination of each member of an enantiomeric pair with receptors of a given chirality results in the formation of two complexes that are physically and chemically distinct diastereomeric combinations. Therefore the differentiation between enantiomers may be dependent upon the creation of diastereomeric relationships. Should two enantiomers have equal activity, then the pheromone-receptor interaction may not involve the chiral centers of the enantiomers. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

In the orthorhombic point group mm2 there is an ambiguity in the sense of the polar axis c. Conventional X-ray diffraction does not allow one to differentiate, with respect to a chosen coordinate system, between the mm2 structures of Schemes 15a and b (these two structures are, in fact, related by a rotation of 180° about the a or c axis) and therefore to fix the orientation and chirality of the enantiomers with respect to the crystal faces. Nevertheless, by determining which polar end of a given crystal (e.g., face hkl or hkl) is affected by an appropriate additive, it is possible to fix the absolute sense of the polar c axis and so the absolute structure with respect to this axis. Subsequently, the absolute configuration of a chiral resolved additive may be assigned depending on which faces of the enantiotopic pair [e.g., (hkl) and (hkl) or (hkl) and (hkl)] are affected. 

As mentioned above, the advantage of the prochiral 3-methyl-pentane-1,5-diol (26) is that we should be able to derive the two enantiomers (R)-29 and (S)-29 necessary for the synthesis of methanophenazine (10) in enantiomerically pure form by differentiating its enantiotopic (CH2)20H groups [40]. 

The principle has been successfully applied to the differentiation between enantiotopic methylene groups in 1-phenylphospholane- and 1-phenylphosphorinane-borane complexes (199, 200) by Kobayashi and coworkers (equation 46) . The conditions for optimized yields, diastereomeric and enantiomeric ratios of appropriate 2-carboxylic acids 201 or 202 were carefully worked out. For the deprotonation of 199, the application of... 

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