Reactions at Chiral Carbon

As described above, nucleophilic substitution at a chiral a-carbon atom normally occurs with retention of the configuration. Exceptions are possible only when the 

As to the nucleophiles that can be applied in the nucleophilic reactions, ammonia and amines, water and alcohols, and mercaptans have been mentioned already. Sulfide and thiourea have been used only with the achiral ferrocenylmethylium ion [97]. To obtain chiral derivatives of 1-ferrocenyl-ethylmercaptan, substitution of the acetate with potassium thioacetate in acetic acid, followed by reduction with LiAlH4, was found appropriate [98, 99]. Reaction of (R)-l-ferrocenylethanol with NaH and 

with subsequent alkylation with methyl iodide, led to (i )-l-ferrocenylethyl-5-methyltrithiocarbonate, which involves a rearrangement with retention (Fig. 4-17, top) [100]. Sulfides [101], tertiary phosphines [101], and tertiary amines [102] are also reasonably good nucleophiles and form reactive ionic products, e.g., pyridinium salts [103], but this has only been verified for achiral or racemic substrates. Pyridinium salts may be considered as a storage form of a-ferrocenylalkyl carbocations, and show almost the same behaviour towards nucleophiles [103, 104]. Primary and 

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Scheme 12.2. Stereochemistry of Radical Reactions at Chiral Carbon...

Stereochemistry of radical reactions at chiral carbon atoms... 

Compound 6 is an example of an enantiometrically pure tetracoordinate boron compound. In contrast to the exhaustive investigations of substitution reactions at chiral carbon atoms much less attention has been paid to isoelec-tronic and isostructural boron atoms. In the current work, in the first such investigation of its kind, 6 has been used to investigate the stereochemistry of a number of substitution reactions occurring at a boron atom. The presence of a bromine atom attached to the boron atom gives a ready site for substitution reactions while the presence of a phosphine ligand helps to confer air- and moisture-stability on the product. 

Fig. 4-17. Reactions of ferrocenylalkyl amines and related compounds at chiral carbon.

Sulfonates react with various orga nometal lie reagents and with chiral substrates. The reaction occurs with stereochemical inversion of configuration (see Chapter 3, p. 30 and Chapter 5, p. 63) (Scheme 46a). On the other hand, if the reaction at the carbon atom is sterically hindered or elimination is difficult, then attack at sulfur occurs (Scheme 46b). 

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

The reaction of diethyl tartrate with sulfur tetrafluonde at 25 °C results in replacement of one hydroxyl group, whereas at 100 °C, both hydroxyl groups are replaced by fluonne to form a,a -difluorosuccinate [762] The stereochemical outcome of the fluonnation of tartrate esters is retention of configuration at one of the chiral carbon atoms and inversion of configuration at the second chiral center [163,164, 165] Thus, treatment ofdimethyl(+)-L-tartrate with sulfur tetrafluonde gives dimethyl meso-a,a difluorosuccinate as the final product [163, 164], whereas dimethyl meso tartrate is converted into a racemic mixture of D- and L-a,a -difluorosuccmates [765] (equation 80)... 

The steroid ring structure is complex and contains many chiral carbons (for example at positions 5, 8, 9,10,13,14 and 17) thus many optical isomers are possible. (The actual number of optical isomers is given by 2" where n = the number of chiral carbons). From your knowledge of biochemistry you should have realised that only one of these optical isomers is likely to be biologically active. Synthesis of such a complex chemical structure to produce a single isomeric form is extremely difficult, especially when it is realised that many chemical reactions lead to the formation of racemic mixtures. Thus, for complete chemical synthesis, we must anticipate that... 

Aldol reactions of a-substituted iron-acetyl enolates such as 1 generate a stcrcogenic center at the a-carbon, which engenders the possibility of two diastereomeric aldol adducts 2 and 3 on reaction with symmetrical ketones, and the possibility of four diastereomeric aldol adducts 4, 5, 6, and 7 on reaction with aldehydes or unsymmetrical ketones. The following sections describe the asymmetric aldol reactions of chiral enolate species such as 1. 

Clear evidence in favor of 6.75 being an intermediate came, however, from stereochemistry. If the indazole cyclization takes place at a chiral carbon atom in the exposition of the alkyl group in 6.78, the stereochemistry of the 3-i/-indazole 6.79 can indicate whether the 5-diazo-6-methylene-l,3-cyclohexadiene 6.75 is an intermediate or whether, on the other hand, deprotonation and cyclization are synchronous. In the first case a racemic indazole 6.79 is expected. In the case of a synchronous reaction, however, a stereospecific product, probably with retention of the chirality at Ca, should be observed. 

Subsequently, a number of reactions at poly-L-valine coated carbon electrodes 237-243) gj.g reported to yield optically active products. Reductions, e.g. of citraconic acid or l,l-dibromo-2,2-diphenylcyclopropane as well as the oxidation of aryl-alkyl sulfides proceeded with chiral induction at such electrodes... 

When the reaction step R—X R- takes place at a chiral carbon, racemization is almost always observed because free radieals do not retain configuration. Exceptions to this rule are found at cyclopropyl substrates, where both inversion and retention of eonfiguration have been reported, and in the reactions mentioned on page 899. 

Chiral //A(oxazolinc) ligands disubstituted at the carbon atom linking the two oxazolines by Frechet-type polyether dendrimers coordinated with copper(II) triflate were found to provide good yields and moderate enantioselectivities for Mukaiyama aldol reactions in water that are comparable with those resulting from the corresponding smaller catalysts.291 AgPF6-BINAP is very active in this reaction and the addition of a small amount of water enhanced the reactivity.292... 

To create a chiral center at an sp3-hybridized carbon requires a chiral environment to stereodirect the reaction. This chiral environment may exist as a chirally substituted sp3-hybridized carbon, on which appropriate substitution creates a new molecule with the same or inverted chirality at the former chiral center or as a chiral arrangement near a prochiral (prechiral) sp2 carbon. 

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