Planar racemic ester

Enantiomer-differentiating hydrolysis with pig liver esterase has, as with other hydrolases, become an important method for resolution (Table 11.1-5). Kinetic resolution of oxirane mono- and dicarboxylic acid esters with pig liver esterase proceeds effeciently with good selectivities, as demonstrated in the cases 14 and 15. Resolution is of course not restricted to enantiomers with central chirality. Axial and planar chiral racemic ester have been resolved with moderate to good results with pig liver esterase (33-36). 

The racemization process involves removal of the a-hydrogen to form the enolate anion, which is favoured by both the enolate anion resonance plus additional conjugation with the aromatic ring. Since the a-protons in esters are not especially acidic, the additional conjugation is an important contributor to enolate anion formation. The proton may then be restored from either side of the planar system, giving a racemic product. 

The main interest in (212) and related dibenzo and dinaphtho compounds is in the conformational barrier to racemization of optically active derivatives, which requires deformation of the tub to the planar form. The compounds have proven to be optically stable at very high temperatures (64JCS2326). A minimum AH value of 71 kJ mol-1 has been calculated for racemization of the resolved 3,10-dicarboxylic esters of (212). Thermal decomposition sets in at 240 °C and leads to the phenanthridine (214) and benzonitrile, presumably via a diradical (213) (63JOC3007). 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

In 1932 Kon and Naji reported that pyrolysis of trans-2,3-ethoxycarbonyl-methylenecyclopropane ( Feist s ester ) resulted in an isomerization to give compounds later identified as the stereoisomeric 2-carbethoxy-l-(carbethoxy-methylene)cyclopropanes (Figure 36). Subsequent studies by Ullman " using the optically resolved reactant showed that the products were not racemic and that the planar trimethylenemethane biradical could not, therefore, be the sole intermediate in the... 

Most alkyl carbanions undergo facile pyramidal inversion. Cyclopropyl anions are an exception, presumably because the transition state, with a planar trigonal carbon, is more strained than the ground state. The configurational stability of cyclopropyl anions is of value in the synthesis of deuterated cyclopropanes by the Haller-Bauer reaction (see Section II.B). An interesting dilemma arises when a cyclopropyl anion is stabilized by a n-electron acceptor substituent such as a nitrile or an ester. Will the anion then retain its pyramidal equilibrium geometry for the strain reasons alluded to above, or will it become planar in order to maximize overlap of the filled orbital on carbon with the n orbital of the substituent Walborsky and coworkers addressed this question in a series of experiments in which rates of H/D exchange and racemization were compared for an optically active cyclopropane exposed to a base in a deuterated hydroxylic solvent. The outcome can be illustrated with the particular example of 1,1-diphenylcyclopropane-2-... 

Isomerization may accompany nucleophilic substitution during the solvolysis of carboxylate and arenesulfonate esters of unsaturated alcohols. Most of the substrates for which such isomerization reactions have been observed are esters of allylic alcohols. If such an ester is optically active by virtue of having an asymmetric a-carbon atom, three experimentally observable processes occur simultaneously racemization, solvolysis, and allylic isomerization. All three of these processes involve formation of planar, achiral allylic carbonium ions as intermediates, viz-... 

It is worth noting that the two optical isomers of ferroquine exist due to the planar chirality of the unsymmetrically 1,2-substituted ferrocene moiety. Both enantiomers were prepared by enzymatic resolution of an ester intermediate in >98% optical purity. Both isomers display similar activity in vitro " Although both enantiomers are less active than the racemate in vivo the (+)-enantiomer displays better curative effects than the optical antipode. This different behavior indicates different pharmacokinetics of the two enantiomers. Ferrocene derivatives of other antimalarial drugs like artemisinine, quinine, and mefloquine have also been tested, as well as various other chloroquine-derived organometallics. Moss and coworkers synthesized and tested chloroquine and ferroquine derivatives with other organometallic groups. 

For overlap between the 2p orbitals on carbon and oxygen to be maximized, the eno-late must be planar, and the planar structure has a nonstereogenic carbon at the a position. A racemic mixture is formed when the enolate reprotonates (Rg. 19.32). Addition of a proton must take place with equal probability at the two equivalent faces ( top = green bottom = red) of the planar molecule. Racemization will also occur with esters and other acid derivatives that have a hydrogen on a stereogenic a carbon. 

Hydroxyferrocene was converted into a phosphite ester with chiral (racemic) butane-1,3-diol which then yielded a cyclopalladated complex when reacted with PdCl2 planar chirality has been observed but no diastereoselectivity. Chiral ferrocenylimines were reacted with Na2PdCl4 and NaOAc to give a mixture of diastereomeric cyclopalladated products.Enantiopure compounds were isolated via column-layer chromatography. 

A unique example of a planar chiral catalyst displaying an imine as reactive function was reported by Kunz et al. [29] in 2007 (Scheme 8.10). Readily accessible pseudo-gem aldehyde-methyl ester Pc [30] in racemic form was condensed with fully protected galacto-pyranosylamine to give diastereoisomeric imines with respect to the Pc chirality. HPLC separation delivered the (Rp) stereoisomer in pure form, which showed a remarkable ability to perform highly enantioselective Strecker reactions (up to 99% ee). It is assumed that the imine catalyst acts as a Br0nsted base toward hydrocyanuric acid produced in situ and generates an iminium-cyanide pair that can interact with the imine substrate and direct cyanide addition on a unique face of the latter. 

The difference in physical properties of diastereoisomers suggests a route that we might use to separate enantiomers (a process described as resolution)—vte will convert them, by some reversible process, into separable diastereoisomers. If we consider the reduction of 7.55 using sodium borohydride (weTl meet this reaction in Chapter 14), the ketone is planar and can be approached from either face by Na[BHj. These approaches are equally likely, so the product obtained will be racemic. If this alcohol is then reacted with a chiral carboxylic acid (Equation 7.3), then two distinct esters will be formed, with R,R- and R,S-stereochemistries. The two esters are diastereoisomers, which may be separated by physical techniques. Once the esters have been separated, then they can be hydrolyzed to obtain the separated alcohols and recover the chiral acid ... 

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