Enantiotopic substituents

Scheme 2.11. Enantioselective lyansfomiatlons Based on Enzyme-Catalyzed Reactions Which Differentiate Enantiotopic Substituents...

The process of obtaining homochiral product from a prochiral starting material is known as asymmetrization. This encompasses reactions where a faster rate of attack of a reactive species occurs on one enantiotopic face of a prochiral trigonal biplanar system, or at one enantiotopic substituent of a C2 symmetrical system, resulting in the preferential formation of one product enantiomer. The latter is also frequently referred to as the meso-trick or desymmetrization . These transformations can be more easily defined in pictorial form (Figure 1.8). 

Enantioselective reactions are defined as transformations in which a prochiral substrate is converted into a chiral product such that one of the two enantiomers is formed in significant excess. The degree of enantioselectivity is measured by the enantiomeric excess (ee), as defined in Scheme 1. In this schematic example the prochiral substrate S represented by a triangle, is converted into the two enantiomeric, chiral tetrahedral products P1 and ent-P1 (enantioface-differentiat-ing reaction). Alternatively, but less commonly used, enantioselectivity can be induced by the differentiation of enantiotopic substituents, as depicted for S2 and Y 2lent-P2. 

Abstract The control elements that did not find mention in the earlier chapters are dealt with here. The prominent among these elements are spiroconjugation, peris-electivity in pericyclic reactions, torquoselectivity in conrotatory-ring openings, ambident nucleophiles and electrophiles, a-effect in nucleophilicity, carbene addition to 1,3-dienes, Hammett s substituent constants, Hammond postulate, Curtin-Hammett principle, and diastereotopic, homotopic, and enantiotopic substituents. 

Keywords Spiroconjugation Periselectivity Carbenes Ketenes Torquoselectivity Ambident nucleophiles and electrophiles a-effect Hammett s substituent constants Hammond postulate Curtin-Hammett principle Diastereotopic Homotopic Enantiotopic substituents... 

Enantioselective transformations based on enzyme-catalyzed reactions which differentiate between enantiomers or enantiotopic substituents... 

Starting from meso-complexes (achiral species), benchrotrenic planar chirality can be generated. The differentiation of the enantiotopic substituents on the aromatic ring has been achieved using enzymes or a chiral palladium catalyst. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

The enzyme-catalyzed interconversion of acetaldehyde and ethanol serves to illustrate a second important feature of prochiral relationships, that ofprochiral faces. Addition of a fourth ligand, different from the three already present, to the carbonyl carbon of acetaldehyde will produce a chiral molecule. The original molecule presents to the approaching reagent two faces which bear a mirror-image relationship to one another and are therefore enantiotopic. The two faces may be classified as re (from rectus) or si (from sinister), according to the sequence rule. If the substituents viewed from a particular face appear clockwise in order of decreasing priority, then that face is re if coimter-clockwise, then si. The re and si faces of acetaldehyde are shown below. 

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]. 

Since carbohthiations usually proceed as syn additions, 458 is expected to be formed first. Due to the configurationally labile benzylic centre it epimerizes to the trani-substitu-ted chelate complex epi-45S. The substitution of epi-458 is assumed to occur with inversion at the benzylic centre. Sterically more demanding reagents (t-BuLi) or the well-stabilized benzyllithium do not add. The reaction works with the same efficiency when other complexing cinnamyl derivatives, such as ethers and primary, secondary, or tertiary amines, are used as substrates . A substoichiometric amount (5 mol%) of (—)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ewf-459, since the opposite enantiotopic face of the double bond is attacked . 

Three types of reaction systems have been designed and applied for the enantioposition-selective asymmetric cross-coupling reactions so far. First example is asymmetric induction of planar chirality on chromium-arene complexes [7,8]. T vo chloro-suhstituents in a tricarhonyl("n6-o-dichlorobenzene)chromium are prochiral with respect to the planar chirality of the 7t-arene-metal moiety, thus an enantioposition-selective substitution at one of the two chloro substituents takes place to give a planar chiral monosubstitution product with a minor amount of the disubstitution product. A similar methodology of monosuhstitution can be applicable to the synthesis of axially chiral biaryl molecules from an achiral ditriflate in which the two tri-fluoromethanesulfonyloxy groups are enantiotopic [9-11]. The last example is intramolecular alkylation of alkenyl triflate with one of the enantiotopic alkylboranes, which leads to a chiral cyclic system [12], The structures of the three representative substrates are illustrated in Figure 8F.1. 

The reactions of l,3-thiazolium-4-olates with aliphatic aldehydes carried out in refluxing benzene or dichloromethane, have been reported to produce a series of highly functionalized (3-lactams and thiiranes at the same time [230]. The critical issue of the stereoselection was discussed in terms of the endo and exo approaches (respective to the aldehyde substituent) to any enantiotopic face of the heterocyclic dipole. Such orientations involved either the Re or the Si faces of the prochiral aldehydes (Scheme 105). 

A different mechanism operates in the direct a-heteroatom functionalization of carbonyl compounds when chiral bases such as cinchona alkaloids are used as the catalysts. The mechanism is outlined in Scheme 2.26 for quinine as the chiral catalyst quinine can deprotonate the substrate when the substituents have strong electron-withdrawing groups. This reaction generates a nucleophile in a chiral pocket (see Fig. 2.6), and the electrophile can thus approach only one of the enantiotopic faces. 

Some attempts have been made to modify diastereoselectivity by introducing chiral substituents into the azide precursor of the nitrene (see Sch. 28) [22,43,44]. The photocycloaddition of acyl nitrenes bearing chiral substituents to cycloalkenes having enantiotopic faces such as compound 85, or prochiral ketones, can lead to the formation of two diastereomers. However, this chiral induction has not been observed in the reaction of the nitrenes... 

Z)-l,2-disubstituted alkenes proved to be the most difficult class. In fact, they are not osmylated efficiently with the all purpose ligands 1F/2 F. Further studies, however, led to the discovery of the indolinyl ligands 11/21 that allowed cis dihydroxylation of these alkenes in up to 80% eel0. It should be kept in mind, however, that in the case of 1,1-disubstituted alkenes and of (Z)-l,2-disubstituted alkenes, a lowering of difference in steric requirement between the two vicinal substituents inevitably means a drop in the 7t-face discrimination since the two enantiotopic alkene 7t-faces lend to become quasi-homotopic . 

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